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Common Office Medical Problems Christian Wagner, MD Clinical Assistant Professor Department of Family Medicine University of Illinois College of Medicine.

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Presentation on theme: "Common Office Medical Problems Christian Wagner, MD Clinical Assistant Professor Department of Family Medicine University of Illinois College of Medicine."— Presentation transcript:

1 Common Office Medical Problems Christian Wagner, MD Clinical Assistant Professor Department of Family Medicine University of Illinois College of Medicine at Urbana-Champaign June 2010

2 Hyperlipidemia Hypertension Diabetes Congestive Heart Failure

3 Hyperlipidemia

4 Types: heterozygous form - associated with total cholesterol level > 300 mg/dL (7.7 mmol/L), high risk of coronary artery disease by 30-40, 50% reduction in LDL receptor activity homozygous form - associated with total cholesterol of mg/dL ( mmol/L), rare, myocardial infarction by age 10 and death by age 20 is common, total deficiency of LDL receptor activity familial hypercholesterolemia Fredrickson Type IIa hyperlipoproteinemia hyperbetalipoproteinemia group A hyperlipidemia LDL hyperlipoproteinemia

5 Incidence/Prevalence: hypercholesterolemia is eleventh most common diagnosis made during family physician visits; analysis of patient visits to family physicians in United States in National Ambulatory Medical Care Survey; hypercholesterolemia diagnosis coded in 2.8% of visits (Ann Fam Med 2004 Sep-Oct;2(5):411 full-text)Ann Fam Med 2004 Sep-Oct;2(5):411full-text estimated risk for developing dyslipidemia by age 50 years –> 80% for "borderline-high" LDL cholesterol ( 130 mg/dL [3.4 mmol/L]) –50% for "high" LDL cholesterol ( 160 mg/dL [4.1 mmol/L]) –25% women and 65% men for "low" HDL cholesterol (< 40 mg/dL [1 mmol/L]) –Reference - based on 4,701 Framingham Offspring study participants (Am J Med 2007 Jul;120(7):623)Am J Med 2007 Jul;120(7):623 prevalence of elevated cholesterol in children and adolescents –based on cohort of 9,868 children aged 6-17 years from National Health and Nutrition Examination Survey –prevalence of elevated total cholesterol (cut point 200 mg/dL or 5.2 mmol/L) 10.7% –mean total cholesterol 163 mg/dL (4.2 mmol/L) –prevalence of elevated LDL cholesterol in 2,724 adolescents aged years (cut point 130 mg/dL or 3.4 mmol/L) 6.6% –mean LDL cholesterol in adolescents 90.2 mg/dL (2.3 mmol/L) –estimated only 0.8% of adolescents exceed LDL threshold for considering for pharmacological treatment by current AAP guidelinecurrent AAP guideline –Reference - Circulation 2009 Mar 3;119(8):1108Circulation 2009 Mar 3;119(8):1108

6 Causes: autosomal dominant LDL receptor defect (heterozygous), inherited as autosomal codominant trait, else polygenic hyperlipidemia Likely risk factors: diet hypothyroidism nephrotic syndrome obstructive liver disease hepatoma Cushing's syndrome anorexia nervosa Werner's syndrome acute intermittent porphyria

7 Complications: very high risk of CAD, premature atherosclerosis elevated cholesterol clearly shown to be a risk factor for cardiovascular mortality in men elevated cholesterol in younger men (35-39) shown to be associated with increased long-term risk for cardiovascular and total mortality; study of 64,205 men followed 16 years plus 2 other studies of 12,283 men followed years; increasing total cholesterol level associated with strong graded independent risk for total mortality and cardiovascular disease; total cholesterol > 240 mg/dL (6.2 mmol/L) compared with cholesterol < 200 mg/dL (5.2 mmol/L) associated with significantly increased risk for total mortality, corresponding to reduce life expectancy of years (JAMA 2000 Jul 19;284(3):311), editorial can be found in JAMA 2000 Jul 19;284(3):365JAMA 2000 Jul 19;284(3):311 JAMA 2000 Jul 19;284(3):365 Associated conditions: association with subclinical hypothyroidism controversial –hypercholesterolemia associated with subclinical hypothyroidism, based on study of 1,191 patients 40-60, 10.3% prevalence of subclinical hypothyroidism among patients with total cholesterol > 309 mg/dL (8 mmol/L) (Clin Endocrinol (Oxf) 1999 Feb;50(2):217 in QuickScan Reviews in Fam Pract 1999 Sep;24(6):21)Clin Endocrinol (Oxf) 1999 Feb;50(2):217 –subclinical hypothyroidism not associated with abnormal lipid levels after adjusting for confounding factors in US population-based study of 8,218 adults > 40 years old (Ann Fam Med 2004 Jul-Aug;2(4):351 full-text)Ann Fam Med 2004 Jul-Aug;2(4):351full-text smoking associated with elevated LDL cholesterol in study of 492 persons aged with hypercholesterolemia (Clin Exp Med 2002 Jul;2(2):83)Clin Exp Med 2002 Jul;2(2):83

8 Diagnosis Rule out: hypothyroidism nephrotic syndrome diabetes obstructive liver disease hypercholesterolemia secondary to diet anorexia nervosa Testing to consider: TSH, blood glucose, creatinine fasting lipid profile –LDL = total cholesterol - HDL - TG/5 –not valid if TG > 400 cardiovascular risk by lipid panel appears similar in patients fasting and non-fasting –based on data from 302,430 people without initial vascular disease –Reference - JAMA 2009 Nov 11;302(18):1993JAMA 2009 Nov 11;302(18):1993

9 chemistry - cholesterol/triglyceride > 1.5 (high TG if IIb) high cholesterol mg/dL ( homozygous) electrophoresis - increased beta (increased pre-beta if IIb) ultracentrifugation - high LDL, normal TG (high VLDL if IIb) apolipoprotein B may help guide statin therapy in subgroup analysis of Collaborative Atorvastatin Diabetes Study (CARDS) (Clin Chem 2009 Mar;55(3):473), editorial can be found in Clin Chem 2009 Mar;55(3):391)Clin Chem 2009 Mar;55(3):473Clin Chem 2009 Mar;55(3):391

10 Prognosis: homozygous - myocardial infarction in teens, heterozygous - MI in 40's about 40% persons with familial hypercholesterolemia have normal lifespan, based on study of large family pedigree (BMJ 2001 Apr 28;322(7293):1019 full-text)BMJ 2001 Apr 28;322(7293):1019full-text

11 Treatment overview: diet low in cholesterol and total fat, increased polyunsaturated-to- saturated fat ratiodiet statins are drug of choice target LDL cholesterol levels –"high risk" if coronary heart disease, diabetes, peripheral arterial disease, stroke, or 10-year cardiovascular risk > 20% LDL goal < 100 mg/dL (2.6 mmol/L) optional goal < 70 mg/dL (1.8 mmol/L) encouraged if very high risk –"moderately high risk" if 2 or more major risk factors LDL goal < 130 mg/dL (3.4 mmol/L) optional goal < 100 mg/dL (2.6 mmol/L) if 10-year risk of cardiovascular disease 10-20% –"lower risk" if 0 or 1 major risk factor LDL goal < 160 mg/dL (4.1 mmol/L) –Reference update to NCEP/ATP III guidelines (Circulation 2004 Jul 13;110(2):227 full-text)Circulation 2004 Jul 13;110(2):227full-text –see Cholesterol screening and management for cardiovascular disease prevention for details

12 Diet: diet low in cholesterol and total fat, increased polyunsaturated-to- saturated fat ratio adherence to diet may result in 10-15% reduction in cholesterol level insufficient evidence to evaluate cholesterol-lowering diet or other dietary interventions for familial hypercholesterolemia –based on Cochrane review –systematic review of 11 short-term randomized and quasi-randomized trials evaluating cholesterol-lowering diet in 331 children and adults with familial hypercholesterolemia –all trials of short duration and no primary outcomes evaluated ischemic heart disease, number of deaths and age at death) –no significant differences in most secondary outcomes –Reference - Cochrane Database Syst Rev 2010 Jan 20;(1):CD001918Cochrane Database Syst Rev 2010 Jan 20;(1):CD001918

13 Activity: moderate intensity walking may reduce total cholesterol/HDL ratio in men with hypercholesterolemia (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence –based on randomized trial without clinical outcomes –67 men (mean age 55.1 years) with hypercholesterolemia randomized to brisk walking (burning 300 kcal/walk) vs. control for 12 weeks –walking group had significant reduction in total cholesterol/HDL and weight and borderline reduction in triglycerides –Reference - Prev Med 2008 Jun;46(6):545Prev Med 2008 Jun;46(6):545

14 use of medications depend on patient's risk factors for atherosclerotic disease secondary prevention (treatment for patients with atherosclerotic disease) typically targeted at LDL cholesterol level < 100 mg/dL (2.6 mmol/L) for help in determining need for medications in primary prevention of atherosclerotic disease, see Revised Sheffield table for determining risk of coronary artery disease evidence-based assessment finds that lipid-lowering therapy generally indicated for patients with diabetes or diagnosis of coronary artery disease (JAMA 1999 Dec 1;282(21):2051), summary can be found in Am Fam Physician 2000 May 15;61(10):3133JAMA 1999 Dec 1;282(21):2051Am Fam Physician 2000 May 15;61(10):3133 statins would be agents of first choice

15 bile acid sequestrants - cholestyramine (Questran), colestipol (Colestid), colesevelam (Cholestagel) decreases LDL (and cholesterol) up to 25% second line drugs, large doses three times daily, start at low dose side effects - constipation, fullness, discomfort, increases TGs if type IIb, interferes with drug absorption

16 nicotinic acid side effects often occur > 1 year after initiating drug therapy; follow-up of 110 individuals taking nicotinic acid (133 drug exposures), 63 took regular nicotinic acid (target dose 3,000 mg/day), 65 took SR nicotinic acid (1500 mg/day); 42-43% of each group discontinued the drug due to side effects, most commonly abnormal liver function tests (11 reg, 9 SR), flushing (7 reg, 5 SR), abdominal pain (6 reg, 7 SR), nausea/emesis (6 reg, 4 SR), rash (4 reg, 4 SR), hyperuricemia (6 reg, 1 SR), and hyperglycemia (4 reg, 2 SR); other side effects included fatigue, ankle swelling, headache, itching, and arrhythmias; patients took nicotinic acid an average of 16.7 (reg) and 14.9 (SR) months prior to developing the symptoms resulting in drug cessation (Am J Med 1995 Oct;99(4):378 in QuickScan Reviews in Fam Pract 1996 Mar;14)Am J Med 1995 Oct;99(4):378

17 in children review of dietary therapy in children can be found in Am Fam Physician 2000 Feb 1;61(3):675, editorial can be found in Am Fam Physician 2000 Feb 1;61(3):633Am Fam Physician 2000 Feb 1;61(3):675Am Fam Physician 2000 Feb 1;61(3):633 if cholesterol remains < 300 mg/dL (7.8 mmol/L), bile acid-binding resins (cholestyramine, colestipol) are safe and efficacious little experience with other lipid-lowering drugs in children homozygous form very resistant to treatment - consider repeated exchange transfusion, portocaval shunting, liver transplantation cholesterol-lowering treatments not associated with increased risk for non-illness mortality; no significant associations between cholesterol-lowering treatments (diet, drugs, partial ileal bypass) and non-illness mortality (suicide, accident, trauma) in meta-analysis of 19 randomized controlled trials lasting at least 1 year; non-significant trend observed in trials of dietary interventions and non-statin drugs, no increase with statins (BMJ 2001 Jan 6;322(7277):11 full-text)BMJ 2001 Jan 6;322(7277):11full-text

18 Screening: see updated NCEP guidelines cardiac risk factors - male > 45, female > 55, FH premature CHD, smoking, hypertension, HDL 60

19 United States Preventive Services Task Force (USPSTF) screening recommendations USPSTF guidelines for screening for lipid disorders in adults –strongly recommend routine screening in men 35 years old and women 45 years old (USPSTF Grade A recommendation)USPSTF Grade A recommendation –recommend screening men aged years and women aged years if at increased risk for coronary heart disease (USPSTF Grade B recommendation)USPSTF Grade B recommendation –no recommendation for or against routine screening in men aged or women 20 years old who are not at increased risk for coronary heart disease (USPSTF Grade C recommendation)USPSTF Grade C recommendation –Reference - USPSTF 2008 Jun or at National Guideline Clearinghouse 2008 Jul 28:12634, previous version can be found in Am J Prev Med 2001 Apr;20(3 Suppl):73USPSTF 2008 JunNational Guideline Clearinghouse 2008 Jul 28:12634Am J Prev Med 2001 Apr;20(3 Suppl):73 USPSTF concludes there is insufficient evidence to recommend for or against routine screening for lipid disorders in children (USPSTF Grade I recommendation) (Pediatrics 2007 Jul;120(1):e215 or at National Guideline Clearinghouse 2007 Oct 15:10865), supporting systematic review can be found in Pediatrics 2007 Jul;120(1):e189USPSTF Grade I recommendationPediatrics 2007 Jul;120(1):e215National Guideline Clearinghouse 2007 Oct 15:10865Pediatrics 2007 Jul;120(1):e189 United States Preventive Services Task Force (USPSTF) grades of recommendation –grade A - USPSTF recommends the service with high certainty of substantial net benefit –grade B - USPSTF recommends the service with high certainty of moderate net benefit or moderate certainty of moderate to substantial net benefit –grade C - USPSTF recommends against routinely providing the service with at least moderate certainty that net benefit is small, but in individual patients considerations may support providing the service –grade D - USPSTF recommends against providing the service with moderate to high certainty of no net benefit or harms outweighing benefits –grade I - insufficient evidence to assess balance of benefits and harms –see USPSTF Grade Definitions for more detailUSPSTF Grade Definitions

20 Reviews: review can be found in BMJ 2008 Aug 21;337:a993, commentary can be found in BMJ 2008 Sep 3;337:a1493, BMJ 2008 Sep 16;337:a1681BMJ 2008 Aug 21;337:a993BMJ 2008 Sep 3;337:a1493BMJ 2008 Sep 16;337:a1681 review of treatment of cholesterol abnormalities can be found in Am Fam Physician 2005 Mar 15;71(6):1137, commentary can be found in Am Fam Physician 2006 Mar 15;73(6):973Am Fam Physician 2005 Mar 15;71(6):1137Am Fam Physician 2006 Mar 15;73(6):973 Applied Evidence review of treatment of hyperlipidemia can be found in J Fam Pract 2002 Apr;51(4):370J Fam Pract 2002 Apr;51(4):370 review of dyslipidemia can be found in Am Fam Physician 1998 May 1;57(9):2192Am Fam Physician 1998 May 1;57(9):2192 review of drug treatment of lipid disorders can be found in N Engl J Med 1999 Aug 12;341(7):498 (author may have conflict of interest [N Engl J Med 2000 Feb 24;342(8):586]), commentary can be found in N Engl J Med 1999 Dec 23;341(26):2020N Engl J Med 1999 Aug 12;341(7):498N Engl J Med 2000 Feb 24;342(8):586N Engl J Med 1999 Dec 23;341(26):2020 review of lifestyle, diet, dietary supplements and botanicals in management of hyperlipidemia can be found in Altern Ther Health Med 2003 May-Jun;9(3):28Altern Ther Health Med 2003 May-Jun;9(3):28

21 Guidelines: synthesis of 3 guidelines (UMHS 2009, USPSTF 2008, VA/DoD 2006) on screening for lipid disorders in adults can be found at National Guideline Clearinghouse 2010 Mar 8:LIPSCREEN7National Guideline Clearinghouse 2010 Mar 8:LIPSCREEN7 United States Preventive Services Task Force (USPSTF) guidelines for screening for lipid disorders in adults can be found in USPSTF 2008 Jun or at National Guideline Clearinghouse 2008 Jul 28:12634, previous version can be found in Am J Prev Med 2001 Apr;20(3 Suppl):73USPSTF 2008 JunNational Guideline Clearinghouse 2008 Jul 28:12634Am J Prev Med 2001 Apr;20(3 Suppl):73 USPSTF guidelines for screening for lipid disorders in children can be found in Pediatrics 2007 Jul;120(1):e215 or at National Guideline Clearinghouse 2007 Oct 15:10865, supporting systematic review can be found in Pediatrics 2007 Jul;120(1):e189Pediatrics 2007 Jul;120(1):e215National Guideline Clearinghouse 2007 Oct 15:10865Pediatrics 2007 Jul;120(1):e189 American Academy of Pediatrics (AAP) clinical report on lipid screening and cardiovascular health in childhood (grade C recommendation [lacking direct evidence])grade C recommendation [lacking direct evidence] –recommendations include increased physical activity and dietary changes for children at risk of overweight or obesity screening between age 2-10 years in children with family history of dyslipidemia or premature cardiovascular disease or dyslipidemia (or if unknown family history or those with other cardiovascular disease risk factors) consider pharmacologic intervention in patients 8 years old with LDL level 190 mg/dL (4.9 mmol/L) ( 160 mg/dL [4.1 mmol/L] with family history of early heart disease or 2 other risk factors present or 130 mg/dL [3.4 mmol/L] if diabetes mellitus) –limitations of recommendations no data to predict risk of cardiovascular disease as an adult based on cholesterol levels in children insufficient data to support specific evidence-based recommendation for cholesterol screening in children insufficient data to support specific evidence-based recommendation for specific age to implement pharmacologic treatment –Reference - Pediatrics 2008 Jul;122(1):198 or at National Guideline Clearinghouse 2009 May 18:13438, commentary can be found in BMJ 2008 Jul 23;337:a886Pediatrics 2008 Jul;122(1):198National Guideline Clearinghouse 2009 May 18:13438BMJ 2008 Jul 23;337:a886 –previous American Academy of Pediatrics statement on cholesterol levels in children can be found in Pediatrics 1998 Jan (Am Fam Physician 1998 May 1;57(9):2266 full-text)Am Fam Physician 1998 May 1;57(9):2266full-text commentary stating that childhood cholesterol screening is not justified can be found in Pediatrics 2000 Mar;105(3):637 and in Pediatrics 2001 May;107(5):1229Pediatrics 2000 Mar;105(3):637Pediatrics 2001 May;107(5):1229 parent history screening criteria not much better than random population screening in cohort of 2,475 Quebec youths ages 9-16 years; parent history had 41% sensitivity, 75% specificity, 8% positive predictive value and 96% negative predictive value for identifying high LDL cholesterol (Pediatrics 2004 Jun;113(6):1723), commentary can be found in Pediatrics 2005 Jan;115(1):195, summary can be found in Am Fam Physician 2005 Mar 15;71(6):1203Pediatrics 2004 Jun;113(6):1723Pediatrics 2005 Jan;115(1):195Am Fam Physician 2005 Mar 15;71(6):1203

22 Hypertension

23 stage 1 hypertension if SBP mm Hg or DBP mm Hg stage 2 hypertension if SBP > 160 mm Hg or DBP > 100 mm Hg stages of hypertension in children and adolescents stage 1 hypertension if blood pressure 95th percentile to 99th percentile plus 5 mm Hg, based on charts for gender, age and height stage 2 hypertension if blood pressure > 99th percentile plus 5 mm Hg, based on charts for gender, age and height Reference - Pediatrics 2004 Aug;114(2 Suppl 4th Report):555 full- text, commentary can be found in Pediatrics 2005 Mar;115(3):826Pediatrics 2004 Aug;114(2 Suppl 4th Report):555full- textPediatrics 2005 Mar;115(3):826

24 Types of Hypertension types of hypertension based on renin-angiotensin system type 1 hypertension is vasoconstrictor, high renin –renin secretion inappropriately high for blood pressure, exaggerated renal elimination of sodium –common in young white people –responds better to ACE inhibitors, angiotensin receptor blockers and beta blockers type 2 hypertensin is sodium dependent, low renin –renin secretion suppressed by kidney's detection of excessive sodium reabsorption –common in young black people –responds better to diuretics and calcium channel blockers Reference - BMJ 2006 Apr 8;332(7545):833, commentary can be found in BMJ 2006 Apr 22;332(7547):974BMJ 2006 Apr 8;332(7545):833BMJ 2006 Apr 22;332(7547):974

25 Causes unknown 90%-95% hypertension is essential hypertension

26 Pathogenesis volume expansion, vasoconstriction - increased total peripheral resistance resistant hypertension associated with elevated aldosterone and natriuretic peptide levels based on case-control study 279 consecutive patients with resistant hypertension (nonresponsive to 3 antihypertensive drugs) were compared to 53 controls with normal pressure or controlled hypertension resistant hypertension associated with higher levels of aldosterone, brain-type natriurietic peptide and atrial natriuretic peptide Reference - Arch Intern Med 2008 Jun 9;168(11):1159Arch Intern Med 2008 Jun 9;168(11):1159 bosentan, endothelin receptor antagonist, shown to reduce blood pressure in 4-week randomized trial with effect similar to enalapril; adverse effects included headache, flushing, leg edema and elevated transaminases (N Engl J Med 1998 Mar 19;338(12):784), commentary can be found in N Engl J Med 1998 Jul 30;339(5):346N Engl J Med 1998 Mar 19;338(12):784N Engl J Med 1998 Jul 30;339(5):346 review of pathogenesis of hypertension can be found in BMJ 2001 Apr 14;322(7291):912BMJ 2001 Apr 14;322(7291):912 review of pathogenesis of hypertension can be found in Ann Intern Med 2003 Nov 4;139(9):761Ann Intern Med 2003 Nov 4;139(9):761

27 review of role of aldosterone in pathogenesis of metabolic syndrome and resistant hypertension can be found in Ann Intern Med 2009 Jun 2;150(11):776Ann Intern Med 2009 Jun 2;150(11):776 review of role of endothelin in pathogenesis of hypertension can be found in Mayo Clin Proc 2005 Jan;80(1):84Mayo Clin Proc 2005 Jan;80(1):84 review of sodium and potassium in pathogenesis of hypertension can be found in N Engl J Med 2007 May 10;356(19):1966, commentary can be found in N Engl J Med 2007 Aug 23;357(8):827N Engl J Med 2007 May 10;356(19):1966N Engl J Med 2007 Aug 23;357(8):827

28 patients with normal and high-normal blood pressure at significant risk for developing hypertension over 4 years based on 9,845 men and women with blood pressure < 140/90 mm Hg in Framingham Heart Study 4-year risk for hypertension in persons < 65 years old –5.3% for those with optimum blood pressure (< 120/80 mm Hg) –17.6% with normal blood pressure ( /80-84 mm Hg) –37.3% with high-normal blood pressure ( /85-89 mm Hg) 4-year risk for hypertension in persons > 65 years old –16% for those with optimum blood pressure –25.5% with normal blood pressure –49.5% with high-normal blood pressure Reference - Lancet 2001 Nov 17;358(9294):1682, editorial can be found in Lancet 2001 Nov 17;358(9294):1659Lancet 2001 Nov 17;358(9294):1682Lancet 2001 Nov 17;358(9294):1659

29 light-to-moderate alcohol use associated with increased risk of hypertension in men but not women based on 2 prospective cohort studies 28,848 women from Women's Health Study followed for 10.9 years and 13,455 from Physicians' Health Study followed for 21.8 years all were without hypertension at baseline 8,680 women and 6,012 men developed hypertension adjusted relative risks for developing hypertension in women (compared to rare/never drinkers) –0.98 (95% CI ) for 1-3 drinks monthly –0.96 (95% CI ) for 1 drink daily –1.1 (95% CI ) for 2-3 drinks daily –1.84 (95% CI ) for 4 drinks daily adjusted relative risks for developing hypertension in men (compared to rare/never drinkers) (p < ) –1.11 (95% CI ) for 1-3 drinks monthly –1.26 (95% CI ) for 1 drink daily –1.29 (95% CI ) for 4 drinks daily in women, relative risks similar with specific alcohol types compare to total alcohol intake relative risks remained similar after adjusting for baseline blood pressure in women and men Reference - Hypertension 2008 Apr;51(4):1080Hypertension 2008 Apr;51(4):1080 alcohol intake > 2 drinks/day associated with increased blood pressure in men but not women in cross-sectional study of 5,448 adults > 20 years old (J Hypertens 2007 May;25(5):965)J Hypertens 2007 May;25(5):965

30 dyslipidemia modestly associated with subsequent hypertension in prospective study of 16,130 women > 45 years old followed for 10.8 years (Arch Intern Med 2005 Nov 14;165(20):2420)Arch Intern Med 2005 Nov 14;165(20):2420 time urgency/impatience and hostility significantly associated with developing hypertension in 15-year prospective follow-up of 3,308 black and white United States adults aged years at baseline; no consistent associations with depression, anxiety, or achievement striving/competitiveness (JAMA 2003 Oct 22-29;290(16):2138), editorial can be found in JAMA 2003 Oct 22-29;290(16):2190, commentary can be found in JAMA 2004 Feb 11;291(6):692JAMA 2003 Oct 22-29;290(16):2138 smaller retinal arteriolar diameters associated with development of hypertension in cohort of 2,451 normotensive persons aged years followed for 10 years (BMJ 2004 Jul 10;329(7457):79), correction can be found in BMJ 2004 Aug 14;329(7462):384, commentary can be found in BMJ 2004 Aug 28;329(7464):514 and replyBMJ 2004 Jul 10;329(7457):79BMJ 2004 Aug 14;329(7462):384BMJ 2004 Aug 28;329(7464):514reply

31 Factors increasing risk of Hypertension higher salt intake may be associated with increased risk for hypertension urinary sodium levels strongly associated with systolic blood pressure in 10,074 men and women ages years in 32 countries (BMJ 1996 May 18;312(7041):1249 full-text), editorial can be found in BMJ 1996 May 18;312(7041):1241, commentary can be found in BMJ 1996 Jun 29;312(7047):1659 and BMJ 1997 Aug 23;315(7106):484BMJ 1996 May 18;312(7041):1249full-textBMJ 1996 May 18;312(7041):1241BMJ 1996 Jun 29;312(7047):1659BMJ 1997 Aug 23;315(7106):484 some evidence supports international consensus of lower risk of hypertension when salt intake is lower; 24-hour urinary sodium excretion associated with systolic blood pressure, diastolic blood pressure and hypertension over range of sodium excretion rates from mmol/day (Arch Intern Med 1997 Jan 27;157(2):234)Arch Intern Med 1997 Jan 27;157(2):234

32 red meat intake may be associated with risk of hypertension in women 45 years old based on prospective cohort study 28,766 women 45 years old followed for 10 years frequency of red meat intake assessed by food surveys and diagnosis of hypertension identified in annual follow- up questionnaires incidence of hypertension in women who consumed (p = for trend) –no red meat 21.7% –< 0.5 servings daily 29.2% (relative risk [RR] 1.24) –0.5-1 servings daily 29.8% (RR 1.25) –1-1.5 servings daily 33.1% (RR 1.32) – 1.5 servings daily 35.6% (RR 1.35) Reference - J Hypertens 2008 Feb;26(2):215J Hypertens 2008 Feb;26(2):215

33 association of caffeine intake with hypertension may depend on beverage type coffee intake over years associated with small increase in blood pressure –1,017 white male former medical students (mean age 26) followed for median 33 years –consumption of 1 cup of coffee a day raised adjusted systolic blood pressure by 0.19 mm Hg (95% CI ) and diastolic pressure by 0.27 mm Hg (95% CI ) –coffee drinkers had increased risk for hypertension compared with nondrinkers at baseline (28.3% vs. 18.8%, p = 0.03), drinking 5 or more cups/day associated with x relative risk for hypertension; none of these associations were statistically significant after adjusting for other variables –Reference - Arch Intern Med 2002 Mar 25;162(6):657, commentary can be found in Arch Intern Med 2003 Feb 10;163(3):370Arch Intern Med 2002 Mar 25;162(6):657Arch Intern Med 2003 Feb 10;163(3):370

34 oral contraceptives may increase risk of hypertension based on prospective cohort study of 68,297 healthy female nurses aged years followed for 4 years 1,567 developed hypertension 1.5 times relative risk of hypertension with current use of oral contraceptives, increased to 1.8 times when adjusted for other factors no increased risk from past use of oral contraceptives absolute risk of hypertension due to oral contraceptives was only 41.5 cases/10,000 person-years Reference - Circulation 1996 Aug 1;94(3):483Circulation 1996 Aug 1;94(3):483

35 some prospective cohorts find increased risk of hypertension with frequent analgesic use higher daily doses of acetaminophen and NSAIDs associated with hypertension in 2 prospective cohort studies of women ages years and women ages years (Hypertension 2005 Sep;46(3):500)Hypertension 2005 Sep;46(3):500 frequent analgesic use, based on Nurses Health Study with 80,020 women ages years followed for 2 years (Arch Intern Med 2002 Oct 28;162(19):2204), commentary can be found in Arch Intern Med 2003 May 12;163(9):1113Arch Intern Med 2002 Oct 28;162(19):2204Arch Intern Med 2003 May 12;163(9):1113 aspirin, acetaminophen and ibuprofen use each associated with increased risk of incident hypertension in Nurses' Health Study (Hypertension 2002 Nov;40(5):604 in CMAJ 2003 May 27;168(11):1445)Hypertension 2002 Nov;40(5):604CMAJ 2003 May 27;168(11):1445

36 Short sleep duration: sleep duration < 5 hours/night associated with 2.1 times risk of hypertension in cohort of 4,810 United States persons aged years followed for 8-10 years of whom 647 were diagnosed with hypertension (Hypertension 2006 May;47(5):833)Hypertension 2006 May;47(5):833 sleep duration 5 hours/night associated with about 2 times risk of hypertension for women (but not in men) in cross- sectional analysis of 5,766 British persons aged years, but results not statistically significant in longitudinal analysis (3,691 participants normotensive at baseline and followed mean 5 years) after adjusting for cardiovascular risk factors and psychiatric comorbidities (Hypertension 2007 Oct;50(4):693)Hypertension 2007 Oct;50(4):693 shorter sleep duration associated with increasing risk of hypertension –based on prospective cohort of 535 participants aged years who had objective sleep duration and maintenance measurements and followed for 5 years –incident hypertension in 14% over 5-year follow-up –37% increase in odds of incident hypertension associated with each hour of reduction in sleep duration –Reference - Arch Intern Med 2009 Jun 8;169(11):1055Arch Intern Med 2009 Jun 8;169(11):1055

37 elevated C-reactive protein levels associated with increased risk of developing hypertension based on 2 cohort studies elevated C-reactive protein levels associated with increased risk of developing hypertension in dose- dependent fashion in prospective cohort study of 20,525 United States nurses > 45 years old followed median 7.8 years (JAMA 2003 Dec 10;290(22):2945), editorial can be found in JAMA 2003 Dec 10;290(22):3000, commentary can be found in Am Fam Physician 2004 Jun 15;69(12):2924JAMA 2003 Dec 10;290(22):2945Am Fam Physician 2004 Jun 15;69(12):2924 elevated C-reactive protein levels associated with incident hypertension in 7-year follow-up of 3,919 young adults ages years, but no significant association after adjusting for body mass index (Arch Intern Med 2006 Feb 13;166(3):345), commentary can be found in Arch Intern Med 2006 Jul 24;166(14):1526Arch Intern Med 2006 Feb 13;166(3):345 Arch Intern Med 2006 Jul 24;166(14):1526

38 various single nucleotide polymorphisms in CYP19A1 gene associated with essential hypertension based on case-control study with 218 patients with essential hypertension and 225 matched controls Reference - Int J Med Sci 2008 Feb 7;5(1):29 full-textInt J Med Sci 2008 Feb 7;5(1):29full-text low ghrelin levels associated with type 2 diabetes and hypertension based on case-control study with 1,045 subjects Reference - Diabetes 2003 Oct;52(10):2546Diabetes 2003 Oct;52(10):2546 high levels of trait anger associated with increased risk for hypertension in men but not in women based on cohort of 2,334 men and women aged years with prehypertension but without heart disease or stroke at baseline and followed for 4-8 years risk of progression to hypertension –59.9% with low trait anger –55.6% with medium trait anger –66.7% with high trait anger –association significant in men but not in women

39 Factors not associated with increased risk: modifiable low-risk factors associated with decreased risk in healthy women based on prospective cohort study 83,882 women aged years in second Nurses Health Study without hypertension, cardiovascular disease, diabetes, or cancer, and with normal reported blood pressure were followed for 14 years incident hypertension in 14.7% modifiable low-risk factors independently associated with risk of hypertension –body mass index (BMI) < 25 kg/m2 –daily vigorous exercise (mean 30 minutes) –high score on Dietary Approaches to Stop Hypertension (DASH) diet based on responses to food frequency questionnaire –modest alcohol intake ( 10 g/day) –use of nonnarcotic analgesics < 1/week –intake of supplemental folic acid 400 mcg/day

40 high job stress not associated with developing hypertension in 5-year follow-up of 292 healthy adults (mean age 38 years) (Hypertension 2003 Dec;42(6):1112)Hypertension 2003 Dec;42(6):1112 job strain associated with modest increases in systolic blood pressure in prospective study of 8,395 white-collar workers followed 7.5 years (Am J Public Health 2006 Aug;96(8):1436)Am J Public Health 2006 Aug;96(8):1436 vitamin D intake not associated with risk of hypertension in 3 cohorts with 209,313 nurses and physicians followed for at least 8 years (Hypertension 2005 Oct;46(4):676)Hypertension 2005 Oct;46(4):676 high levels of anxiety and depression appear associated with lower systolic blood pressure 11 years later based on cohort study in Norway 36,530 persons aged years followed for 11 years Reference - Br J Psychiatry 2008 Aug;193(2):108Br J Psychiatry 2008 Aug;193(2):108

41 birth weight does not appear to significantly affect adult blood pressure –systematic review found that birth weight has little effect on blood pressure later in life 55 studies that reported regression coefficients found weaker associations with larger studies studies with > 3,000 participants found inverse association of birth weight and blood pressure of only 0.6 mm Hg/kg only 25 of 48 studies that did not report regression coefficients found inverse association Reference - Lancet 2002 Aug 31;360(9334):659, commentary can be found in Lancet 2002 Dec 21-28;360(9350):2072Lancet 2002 Aug 31;360(9334):659Lancet 2002 Dec 21-28;360(9350):2072 –low birth weight has been suggested as risk factor for hypertension, but likely a confounding factor as maternal hypertension associated with low birth weight and parental hypertension increases risk of hypertension (BMJ 1998 Mar 14;316(7134):834), commentary can be found in BMJ 1998 Sep 5;317(7159):680 and in BMJ 1999 Apr 3;318(7188):943BMJ 1998 Mar 14;316(7134):834BMJ 1998 Sep 5;317(7159):680BMJ 1999 Apr 3;318(7188):943

42 Complications of Hypertension Hypertension is a risk factor for: Coronary artery disease (CAD) Heart failure Chronic kidney disease Stroke Intracerebral hemorrhage Transient ischemic attack (TIA) Peripheral arterial disease (PAD) Aortic regurgitation Atrial flutter

43 Mortality associated with Hypertension usual blood pressure directly related to vascular mortality at all pressures above 115/75 mm Hg and at all ages above 40 years based on meta-analysis of individual patient data from 1 million adults in 61 prospective studies Reference - Lancet 2002 Dec 14;360(9349):1903, correction can be found in Lancet 2003 Mar 22;361(9362), commentary can be found in Lancet 2003 Apr 19;361(9366):1389, Evidence-Based Medicine 2003 Jul- Aug;8(4):122Lancet 2002 Dec 14;360(9349):1903Lancet 2003 Apr 19;361(9366):1389 increased blood pressure associated with increased all-cause and cardiovascular mortality based on prospective cohort study in China 169,871 Chinese adults 40 years old examined in 1991 and followed up hypertension and prehypertension associated with increased all-cause and cardiovascular mortality (p < ) estimated deaths attributable to increased blood pressure in China in 2005 –2.33 million cardiovascular deaths –1.27 million premature (< 72 years old in men and < 75 years in women) cardiovascular deaths –1.86 million blood pressure-related deaths attributed to cerebrovascular diseases Reference - Lancet 2009 Nov 21;374(9703):1765, editorial can be found in Lancet 2009 Nov 21;374(9703):1728Lancet 2009 Nov 21;374(9703):1765 Lancet 2009 Nov 21;374(9703):1728

44 elevated blood pressure associated with increased long-term mortality in young men –study of 10,874 men aged years followed for 25 years –blood pressure above normal associated with increased long-term mortality due to coronary heart disease, cerebrovascular disease, and all causes –Reference - Arch Intern Med 2001 Jun 25;161(12):1501, commentary can be found in Arch Intern Med 2002 Mar 11;162(5):610Arch Intern Med 2001 Jun 25;161(12):1501Arch Intern Med 2002 Mar 11;162(5):610 systolic (but not diastolic) blood pressure is a strong, positive, continuous and independent indicator of mortality risk in the elderly; 10-year follow-up of 3,858 outpatients > 65, 74 patients (1.9%) were lost to follow-up and 1,561 (41.3%) died, 709 (45.4% all deaths) died from cardiovascular causes; positive continuous, graded, strong and independent association observed with both total (P < 0.001) and cardiovascular (P < 0.001) mortality for systolic blood pressure (SBP) but not for diastolic blood pressure (DBP), no J-shaped mortality curve in subjects with lowest SBP and DBP (Arch Intern Med 1999 Jun 14;159(11):1205)Arch Intern Med 1999 Jun 14;159(11):1205 Stroke:

45 Stroke hypertension and type 2 diabetes increase risk of stroke independently based on 19-year prospective follow-up of 49,582 Finnish persons ages years (Stroke 2005 Dec;36(12):2538)Stroke 2005 Dec;36(12):2538 stroke risk correlates with diastolic blood pressure (Lancet 1995 Dec 23-30;346( ):1647 in J Watch 1996 Jan 15;16(2);14)Lancet 1995 Dec 23-30;346( ):1647 midlife blood pressure associated with late-life stroke risk (Arch Intern Med 2001 Oct 22;161(19):2343), summary can be found in Am Fam Physician 2002 Mar 1;65(5):963Arch Intern Med 2001 Oct 22;161(19):2343 Am Fam Physician 2002 Mar 1;65(5):963 blood pressure important determinant of stroke risk in eastern Asian populations, whereas cholesterol concentration less important; association between blood pressure and stroke seems stronger than in western populations; population-wide reduction of 3 mm Hg in diastolic blood pressure should eventually decrease number of strokes by about 1/3 (Lancet 1998 Dec 5;352(9143):1801)Lancet 1998 Dec 5;352(9143):1801

46 Cognitive decline: midlife hypertension associated with late-life cognitive dysfunction (JAMA 1995 Dec 20;274:1846 in J Watch 1996 Jan 15;16(2):14) hypertension associated with cognitive decline in 20-year follow-up of 529 persons aged years (Hypertension 2004 Nov;44(5):631 in BMJ 2004 Nov 20;329(7476):1246)Hypertension 2004 Nov;44(5):631BMJ 2004 Nov 20;329(7476):1246 End-stage regnal disease: elevated blood pressure is a strong risk factor for the development of end-stage renal disease (N Engl J Med 1996 Jan 4;334(1):13 in QuickScan Reviews in Fam Pract 1996 Aug;21(5):9, Arch Intern Med 2005 Apr 25;165(8):923)N Engl J Med 1996 Jan 4;334(1):13Arch Intern Med 2005 Apr 25;165(8):923

47 Perinatal mortality: maternal chronic hypertension associated with increased perinatal mortality in male infants –based on prospective cohort study of 866,188 women with singleton pregnancies –4,749 (0.55%) were diagnosed with chronic hypertension –chronic hypertension in mothers associated with intrauterine death odds ratio 3.07 for males neonatal death odds ratio 2.99 for males intrauterine death odds ratio 0.98 for females (not significant) neonatal death odds ratio 1.88 for females (not significant) –Reference - BJOG 2008 Oct;115(11):1436BJOG 2008 Oct;115(11):1436

48 Associated Conditions obstructive sleep apnea sleep disordered breathing and sleep apnea syndrome associated with hypertension –based on cross-sectional study of 6,132 middle aged or older individuals –association weak after adjustment for obesity –Reference - JAMA 2000 Apr 12;283(14):1829, correction can be found in JAMA 2002 Oct 23/30;288(16):1985JAMA 2000 Apr 12;283(14):1829 –editorial states that hypertension alone does not warrant testing for sleep apnea (JAMA 2000 Apr 12;283(14):1880JAMA 2000 Apr 12;283(14):1880 strong association between hypertension and obstructive sleep apnea –based on cohort of 2,677 adults ages years referred to sleep clinic for suspected sleep apnea –Reference - BMJ 2000 Feb 19;320(7233):479 full-text, commentary can be found in BMJ 2000 Jul 22;321(7255):237 full-textBMJ 2000 Feb 19;320(7233):479full-textBMJ 2000 Jul 22;321(7255):237full-text sleep-disordered breathing associated with hypertension –based on study of 1,741 persons ages years selected as those with higher risk for sleep-disordered breathing from interviews of 16,583 persons –Reference - Arch Intern Med 2000 Aug 14/28;160(15):2289, commentary can be found in Arch Intern Med 2001 Nov 26;161(21):2634Arch Intern Med 2000 Aug 14/28;160(15):2289Arch Intern Med 2001 Nov 26;161(21):2634 sleep-disordered breathing associated with increased risk for hypertension –based on prospective study of 709 persons who had polysomnography and were followed 4 years –dose-response relationship found even after adjustment for known confounding factors –Reference - N Engl J Med 2000 May 11;342(19):1378, commentary can be found in N Engl J Med 2000 Sep 28;343(13):966N Engl J Med 2000 May 11;342(19):1378N Engl J Med 2000 Sep 28;343(13):966 drug-resistant hypertension may be associated with high rate of sleep apnea –based on case series of 41 patients on 3 or more antihypertensive medications –83% found to have AHI > 10/hour on overnight polysomnography –Reference - J Hypertens 2001 Dec;19(12):2271J Hypertens 2001 Dec;19(12):2271 see Cardiovascular disease and obstructive sleep apnea for details

49 higher blood pressure associated with higher rate of bone loss in 3,676 elderly white women followed mean 3.5 years, even among women not taking antihypertensive agents (Lancet 1999 Sep 18;354(9183):971)Lancet 1999 Sep 18;354(9183):971 increased prevalence of panic attacks and panic disorder among hypertensive patients; 351 hypertensive patients compared with normotensive controls, 17-19% vs. 11% had panic attacks within 6 months, 33-39% vs. 22% had history of panic attacks, 13% vs. 8% had panic disorder (Am J Med 1999 Oct;107(4):310 in JAMA 2000 Jan 5;283(1):29)Am J Med 1999 Oct;107(4):310

50 hypertension is a risk factor for type 2 diabetes prospective study of 12,550 persons in Atherosclerosis Risk in Communities (ARIC) study who did not have diabetes at baseline and were evaluated at 3 years and 6 years diabetes defined at all time points as fasting glucose > 125 mg/dL (7 mmol/L), nonfasting glucose > 200 mg/dL (11 mmol/L), use of insulin or oral hypoglycemic agent, or physician's diagnosis of diabetes overall incidence of diabetes was 16.6 cases per 1,000 person-years hypertension increased risk by relative risk of 2.43 (95% CI ) –incidence of diabetes was 12 per 1,000 person-years in 8,746 subjects with normal blood pressure –incidence of diabetes was 29.1 per 1,000 person-years in 3,804 subjects with hypertension among 3,804 subjects with hypertension –subgroup analysis performed to examine risk differences between different classes of antihypertensives and no treatment –classification of use of medications based on asking patient whether the medication had been prescribed to treat high blood pressure –thiazide diuretics, ACE inhibitors and calcium channel blockers were not shown to increase risk of diabetes {significance of this finding is that "risk" of diabetes is not a valid reason to withhold thiazide diuretics} –no significant differences upon comparing drug classes –beta blockers associated with statistically significant increased risk for diabetes compared to no treatment for hypertension with relative risk of 1.28 (95% CI , number needed to harm [NNH] with use of beta blockers if this association is true is 122 patients per year) Reference - N Engl J Med 2000 Mar 30;342(13):905, editorial can be found in N Engl J Med 2000 Mar 30;342(13):969,N Engl J Med 2000 Mar 30;342(13):905N Engl J Med 2000 Mar 30;342(13):969

51 hypothyroidism; thyroid replacement in 30 patients with hypothyroidism and hypertension led to reduction in aortic stenosis in all and normalization of blood pressure in 15 (Am Heart J 2002 Apr;143(4):718 in Am Fam Physician 2002 Sep 1;66(5):851)Am Heart J 2002 Apr;143(4):718Am Fam Physician 2002 Sep 1;66(5):851 heart failure found in 2-3% patients with hypertension; study of 388 patients with hypertension, 1.8% had left ventricular systolic ejection fraction < 40%, 2.8% had heart failure defined as dyspnea plus objective evidence of cardiac dysfunction (systolic dysfunction, atrial fibrillation or clinically significant valve disease) (BMJ 2002 Nov 16;325(7373):1156full-text)BMJ 2002 Nov 16;325(7373):1156full-text erectile dysfunction common in men with hypertension; questionnaires sent to 467 men aged years with hypertension, 104 (22%) returned questionnaires (mean age 62); 85% were sexually active, of whom 68% reported some degree of erectile dysfunction, 45% reported severe erectile dysfunction (J Urol 2000 Oct;164(4):1188)J Urol 2000 Oct;164(4):1188 systemic hypertension more common in glaucoma patients (odds ratio 1.29) based on case-control study with 27,080 glaucoma patients (Br J Ophthalmol 2005 Aug;89(8):960)Br J Ophthalmol 2005 Aug;89(8):960 hypermetropia (farsightedness) associated with hypertension in study of 321 patients with essential hypertension and 188 matched controls (Am J Ophthalmol 2005 Sep;140(3):446)Am J Ophthalmol 2005 Sep;140(3):446 review of retinal vascular disease associated with hypertension can be found in Postgrad Med 2005 Jun;117(6):33, commentary can be found in Postgrad Med 2005 Sep;118(3):1Postgrad Med 2005 Jun;117(6):33 Postgrad Med 2005 Sep;118(3):1

52 Family History (FH): 75% FH hypertension and cardiovascular disease parental hypertension associated with blood pressure change and hypertension –based on cohort study –1,160 male persons followed for 54 years (29,867 blood pressure measurements) –264 (23%) reported a parent with hypertension and 583 new cases of parental hypertension occurred during follow-up –mean systolic and diastolic blood pressure significantly higher at baseline with parental hypertension –rate of annual blood pressure increase slightly higher (0.03 mm Hg) with parental hypertension for systolic blood pressure (p = 0.04), but not diastolic blood pressure –risk of hypertension development in men (after adjustment for body mass index, alcohol consumption, coffee drinking, physical activity, and cigarette smoking) compared to men with parents without hypertension hazard ratio 1.5 (95% CI 1.2-2) with maternal hypertension only hazard ratio 1.8 (95% CI ) with paternal hypertension only hazard ratio 2.4 (95% CI ) with hypertension in both parents –early-onset hypertension (age 55 years) in both parents associated with 6.2-fold higher adjusted risk (95% CI ) for hypertension at any point in adult life 20-fold higher adjusted risk (95% CI ) at age 35 years –Reference - Johns Hopkins Precursors Study (Arch Intern Med 2008 Mar 24;168(6):643)Arch Intern Med 2008 Mar 24;168(6):643

53 Physical Findings General Physical: see Blood pressure measurement check pulse - decreased if increased ICP, increased if hyperthyroidism (also a fib) BP 2 times at visit, both arms, lying and standing (orthostatic hypotension with diabetic autonomic neuropathy, pheo, drugs) suggestion to use standing BP for management decisions in elderly, to avoid risk of orthostatic hypotension (letter in Am Fam Physician 1996 May 15;53(7):2282) If BP difference between arms, use arm with consistently higher BP readings for monitoring (letter in JAMA 1995 Nov 1;274(17):1345) height and weight important for determining hypertension in children

54 HEENT: retinopathy –Stage I and II arterial narrowing, AV compression, silver/copper wiring (dilated vein over narrowed artery) –Stage III soft exudates (cotton-wool spots, micro-infarctions), flame hemorrhage –Stage IV papilledema –picture of hypertensive retinopathy can be found in Lancet 2004 Feb 7;363(9407):456Lancet 2004 Feb 7;363(9407):456 –review of hypertensive retinopathy can be found in N Engl J Med 2004 Nov 25;351(22):2310N Engl J Med 2004 Nov 25;351(22):2310 –review of hypertensive retinopathy can be found in Lancet 2007 Feb 3;369(9559):425, correction can be found in Lancet 2007 Jun 23;369(9579):2078Lancet 2007 Feb 3;369(9559):425 –routine funduscopy not supported by current evidence; systematic review of studies assessing hypertensive retinopathy in adults; large variation between observers in assessment of microvascular retinal changes; hypertensive retinopathy did not predict hypertension well with 3% to 21% sensitivity, 88% to 98% specificity, positive predictive values from 47% to 72% and negative predictive values from 32% to 67%; inconsistent associations between retinal microvascular changes and cardiovascular risk except for retinopathy and stroke (increased risk of stroke also present in normotensive people with retinopathy) (BMJ 2005 Jul 9;331(7508):73 full-text)BMJ 2005 Jul 9;331(7508):73full-text check visual fields (tumor)

55 Neck: JVD, carotid bruits Cardiac: PMI, S3 (from high LA pressure, suggests CHF, volume overload, need for treatment), S4 (usually stiff ventricle, diastolic heart failure), RV heave and murmur in back with coarctation of aorta, murmurs (TR and MR from dilation, rub in hyperthyroidism, murmurs with increased pulse and anemia) Abdomen: AAA (palpate), abdominal bruits (press until scope pulsates), hepatomegaly (pulsatile if tricuspid regurgitation), renal mass, striae Extremities: edema, decreased extremity pulses, listen for femoral bruits decreased, absent and/or delayed femoral pulses in coarctation of the aorta Neuro: look neurologic deficit as sign of stroke

56 Diagnosis of Hypertension in pediatric patients hypertension defined as average systolic and/or diastolic blood pressure 95th percentile for gender, age, and height on 3 or more occasions –see blood pressure charts for boys and girlsboysgirls –Reference - Pediatrics 2004 Aug;114(2 Suppl 4th Report):555 full-text, commentary can be found in Pediatrics 2005 Mar;115(3):826Pediatrics 2004 Aug;114(2 Suppl 4th Report):555full-textPediatrics 2005 Mar;115(3):826 new normative BP data in children and adolescents can be found in NHLBI Update on 1987 Task Force Report (Pediatrics 1996;98:649 in Am Fam Physician 1997 May 1;55(6):2340) study suggests that recommendations on BP cuff selection in children need to be reviewed, further study may be necessary to establish accuracy of published nomogram on normal BP in children (Pediatrics 1999 Sep;104(3):e30 full-text)Pediatrics 1999 Sep;104(3):e30full-text

57 JNC 7 report recommends blood pressure cutoff when using ambulatory monitoring should be 135/85 while awake and 120/75 while asleep until relationship between self-recorded pressure and incidence of cardiovascular morbidity and mortality is further clarified by prospective studies, mean self-recorded blood pressure > 135 mm Hg systolic or 85 mm Hg diastolic may be considered hypertensive; based on meta-analysis of summary data from 17 studies comparing self-recorded and standard blood pressures, 9 of which only included normotensive subjects (Arch Intern Med 1998 Mar 9;158(5):481), commentary can be found in Arch Intern Med 1999 May 10;159(9):1007 and in Arch Intern Med 1999 Oct 25;159(19):2365Arch Intern Med 1998 Mar 9;158(5):481Arch Intern Med 1999 May 10;159(9):1007Arch Intern Med 1999 Oct 25;159(19):2365 evidence-based review of diagnosis of essential and secondary hypertension can be found in Applied Evidence in J Fam Pract 2001 Aug;50(8):707J Fam Pract 2001 Aug;50(8):707 review of diagnosing secondary hypertension can be found in Am Fam Physician 2003 Jan 1;67(1):67, commentary noting excess licorice as possible cause can be found in Am Fam Physician 2003 Jul 1;68(1):42Am Fam Physician 2003 Jan 1;67(1):67Am Fam Physician 2003 Jul 1;68(1):42

58 Recommended Testing diagnostic workup of hypertension recommended by JNC 7 electrocardiogram (ECG) urinalysis blood glucose serum potassium, creatinine, and calcium hematocrit lipid profile - HDL cholesterol, LDL cholesterol, triglycerides optional - urinary albumin/creatinine ratio or urinary albumin excretion

59 assess for other major cardiovascular disease risk factors - obesity (BMI > 30 kg/m2), dyslipidemia, diabetes mellitus, cigarette smoking, physical inactivity, microalbuminuria (estimated glomerular filtration 55 years, women > 65 years), family history of premature cardiovascular disease (men < 55 years, women < 65 years) assess for identifiable causes - sleep apnea, drugs (including steroids), chronic kidney disease, primary aldosteronism, renovascular disease, Cushing's syndrome, pheochromocytoma, coarctation of aorta, thyroid disease, parathyroid disease

60 recommendations from expert panels 4 expert panels summarized are Joint National Committee (JNC 7), 2003 European Society of Cardiology, 2004 Canadian Hypertension Education Program and Institute for Clinical Systems Improvement (ICSI) all 4 expert panels recommend –serum potassium and creatinine –fasting blood glucose –fasting lipid panel –hematocrit –urinalysis –ECG

61 in children and adolescents (workup of juvenile hypertension) testing recommended in all children with persistent blood pressure 95th percentile or higher –BUN, creatinine, electrolytes, urinalysis, urine culture –CBC –renal ultrasound –fasting lipid panel, fasting glucose –echocardiogram –retinal exam

62 drug screen if history suggestive polysomnography if history of loud, frequent snoring ambulatory blood pressure monitoring if white-coat hypertension suspected and when other information on blood pressure pattern needed

63 additional testing in young children with stage 1 hypertension and any child or adolescent with stage 2 hypertension plasma renin (also if positive family history of severe hypertension) renovascular imaging –isotopic scintigraphy (renal scan) –magnetic resonance angiography –duplex doppler flow studies –3-dimensional CT –arteriography (DSA or classic) plasma and urine steroid levels plasma and urine catecholamines Reference - Pediatrics 2004 Aug;114(2 Suppl 4th Report):555 full-text, commentary can be found in Pediatrics 2005 Mar;115(3):826Pediatrics 2004 Aug;114(2 Suppl 4th Report):555full-text Pediatrics 2005 Mar;115(3):826

64 Blood Tests persistent hypokalemia and metabolic alkalosis in Conn's syndrome fasting glucose abnormalities in diabetes mellitus, Cushing's syndrome or acromegaly microangiopathic hemolytic anemia renal damage if creatinine > 1.5 no association between serum ionized calcium levels and blood pressure in 3,834 patients from NHANES III study (J Am Geriatr Soc 1998 Sep;46(9):S87,P281) genetic testing may eventually guide selection of antihypertensives; case-control study among HMO patients taking drugs for hypertension with 206 patients with first myocardial infarction, 177 patients with first stroke and 715 controls; among 653 with wild-type adducin genotype, use of diuretics (compared to other antihypertensives) was not associated with increased risk for myocardial infarction and stroke; among 385 carriers of variant adducin allele, use of diuretics was associated with decreased risk (about 50% relative risk) for myocardial infarction and stroke (JAMA 2002 Apr 3;287(13):1680)JAMA 2002 Apr 3;287(13):1680

65 Urine Tests microalbuminuria associated with increased risk for cardiovascular events increasing urine albumin-creatinine ratio associated with increasing cardiovascular risk in cohort of 8,206 patients without diabetes with stage II-III hypertension and left ventricular hypertrophy, with increased risk starting at urine albumin-creatinine ratio > 1.16 mg/mmol (Ann Intern Med 2003 Dec 2;139(11):901), commentary can be found in Ann Intern Med 2004 Aug 3;141(3):244 PDFAnn Intern Med 2003 Dec 2;139(11):901Ann Intern Med 2004 Aug 3;141(3):244PDF microalbuminuria common in hypertension and associated with increased risk for cardiovascular events; in series of 319 patients with newly diagnosed mild-to-moderate essential hypertension, 40% had microalbuminuria (Am J Kidney Dis 1999 Dec;34(6):996); follow-up of 54 patients with microalbuminuria and 87 patients with normal urinary albumin excretion for 7 years found 12 (21%) vs. 2 (2%) with cardiovascular events (p < ) (Am J Kidney Dis 1999 Dec;34(6):973), editorial can be found in Am J Kidney Dis 1999 Dec;34(6);1139 (QuickScan Reviews in Fam Pract 2000 Jul;25(4);3); no evidence that microalbuminuria screening in hypertension affects patient-oriented outcomes (DynaMed commentary)Am J Kidney Dis 1999 Dec;34(6):996Am J Kidney Dis 1999 Dec;34(6):973 no studies to evaluate benefit of screening for microalbuminuria in patients already taking ACE inhibitors or angiotensin II receptor blockers for other indications (J Fam Pract 2003 Mar;52(3):229)J Fam Pract 2003 Mar;52(3):229

66 Imaging CXR (cardiomegaly, rule out CHF) echocardiography for LVH ACC/AHA/ASE 2003 guideline for clinical application of echocardiography can be found in J Am Coll Cardiol 2003 Sep 3;42(5):954, J Am Soc Echocardiogr 2003 Oct;16(10):1091, Circulation 2003 Sep 2;108(9):1146J Am Coll Cardiol 2003 Sep 3;42(5):954J Am Soc Echocardiogr 2003 Oct;16(10):1091Circulation 2003 Sep 2;108(9):1146 American College of Radiology (ACR) Appropriateness Criteria for routine chest radiographs in uncomplicated hypertension can be found in National Guideline Clearinghouse 2006 Sep 11:9606National Guideline Clearinghouse 2006 Sep 11:9606

67 EKG not done if mild and uncomplicated may show left ventricular hypertension (LVH) with strain, ST changes in ischemia, LVH if 35 mm in V1S and V5/6R ECG screening for detecting LVH should use Cornell voltage criteria rather than Sokolow-Lyon voltage criteria Cornell criteria not affected by obesity in study of 380 patients (Am J Cardiol 1996 Apr 1;77(9):739 in Am Fam Physician 1996 Sep 1;54(3);1091)Am J Cardiol 1996 Apr 1;77(9):739 Cornell voltage-duration product criteria for ECG LVH may be more accurate than Sokolow-Lyon voltage criteria in obese patients –based on study of 8,417 patients including 2,519 overweight and 1,573 obese patients –Reference - Hypertension 2000 Jan;35(1 Pt 1):13 in JAMA 2000 Apr 12;283(14):1803Hypertension 2000 Jan;35(1 Pt 1):13 –DynaMed commentary -- suggestion seems reasonable but results not definitive since no gold standard applied to determine diagnosis of LVH, that is, unable to distinguish between underdiagnosis by Sokolow-Lyon criteria or overdiagnosis by Cornell criteria decrease in Cornell product electrocardiographic LVH associated with decreased risk for new-onset heart failure in 8,479 hypertensive patients followed for mean 4.7 years (Ann Intern Med 2007 Sep 4;147(5):311)Ann Intern Med 2007 Sep 4;147(5):311

68 ECG criteria not sufficiently sensitive to rule out LVH in patients with hypertension based on systematic review of 21 studies comparing any of 6 ECG criteria with echocardiography in 5,608 patients with hypertension ECG criteria evaluated were Sokolow-Lyon index, Cornell voltage index, Cornell product index, Gubner index, Romhilt-Estes score 4 points and Romhilt-Estes score 5 points median prevalence of LVH was 33% in primary care settings in 10 studies and 65% in secondary care settings in 11 studies median negative likelihood ratio ranged from 0.85 to 0.91 across ECG criteria negative predictive values (at median prevalence) would be 69% in primary care settings and 37% in secondary care settings Reference - BMJ 2007 Oct 6;335(7622):711 full-text, editorial can be found in BMJ 2007 Oct 6;335(7622):681, commentary can be found in BMJ 2007 Oct 20;335(7624):787BMJ 2007 Oct 6;335(7622):711full-textBMJ 2007 Oct 6;335(7622):681BMJ 2007 Oct 20;335(7624):787

69 American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society (AHA/ACCF/HRS) recommendations and scientific statements for standardization and interpretation of electrocardiograms review of ECG technology and improving accuracy and clinical utility in practice can be found in J Am Coll Cardiol 2007 Mar 13;49(10):1109 or in Heart Rhythm 2007 Mar;4(3):394 or in Circulation 2007 Mar 13;115(10):1306 full-textJ Am Coll Cardiol 2007 Mar 13;49(10):1109 Heart Rhythm 2007 Mar;4(3):394Circulation 2007 Mar 13;115(10):1306full-text statement on diagnostic terms for ECG interpretation can be found in J Am Coll Cardiol 2007 Mar 13;49(10):1128 or in Heart Rhythm 2007 Mar;4(3):413 or in Circulation 2007 Mar 13;115(10):1325 full-textJ Am Coll Cardiol 2007 Mar 13;49(10):1128Heart Rhythm 2007 Mar;4(3):413Circulation 2007 Mar 13;115(10):1325full-text statement on intraventricular conduction disturbances can be found in J Am Coll Cardiol 2009 Mar 17;53(11):976 or in Circulation 2009 Mar 17;119(10):e235 full-textJ Am Coll Cardiol 2009 Mar 17;53(11):976Circulation 2009 Mar 17;119(10):e235full-text statement on T segment, T and U waves, and QT interval can be found in J Am Coll Cardiol 2009 Mar 17;53(11):982 or in Circulation 2009 Mar 17;119(10):e241 full-textJ Am Coll Cardiol 2009 Mar 17;53(11):982Circulation 2009 Mar 17;119(10):e241full-text statement on electrocardiogram changes associated with cardiac chamber hypertrophy can be found in J Am Coll Cardiol 2009 Mar 17;53(11):992 or in Circulation 2009 Mar 17;119(10):e251 full-textJ Am Coll Cardiol 2009 Mar 17;53(11):992 Circulation 2009 Mar 17;119(10):e251full-text statement on acute ischemia/infarction can be found in J Am Coll Cardiol 2009 Mar 17;53(11):1003 or in Circulation 2009 Mar 17;119(10):e262 full- textJ Am Coll Cardiol 2009 Mar 17;53(11):1003Circulation 2009 Mar 17;119(10):e262full- text

70 Pathology tests: renal biopsy may show –hyaline arteriolosclerosis - major characteristic of benign nephrosclerosis, homogeneous pink hyaline thickening, loss of underlying structural detail, narrowing of lumen, leakage of plasma components –hyperplastic arteriolosclerosis - fibroelastic hyperplasia with reduplication of elastic lamina, related to more acute or severe blood pressure elevations, diastolic blood pressure usually > 110 mm Hg, onionskinning, necrotizing arteriolitis (fibrinoid), malignant nephrosclerosis –normal or small kidneys –granular cortical surface –decreased cortex

71 Prognosis of Hypertension hypertension at age 50 years associated with about 5-year reduction in life expectancy compared with normotension, based on 3,128 participants in Framingham Heart Study (Hypertension 2005 Aug;46(2):280)Hypertension 2005 Aug;46(2):280 risk of stroke is much more responsive to treatment than risk of heart disease greater reductions in systolic blood pressure associated with lower risk of stroke, independent of medications used to lower blood pressure (level 1 [likely reliable] evidence); based on meta-analysis of meta-analysis of > 40 randomized trials (Stroke 2004 Mar;35(3):776)level 1 [likely reliable] evidenceStroke 2004 Mar;35(3):776 risk of stroke clearly related to quality of blood pressure control in case- control study in England, consistent maintenance of blood pressure 160/95 mm Hg); compared with non- hypertensive subjects, risk of stroke in hypertensive patients receiving treatment was 1.3 times if BP controlled to < 140 mm Hg, 1.6 times if SBP mm Hg, 2.2 times with SBP mm Hg, 3.2 times if SBP 160 or greater; similar results for diastolic pressure (BMJ 1997 Jan 25;314(7076 ):272)BMJ 1997 Jan 25;314(7076 ):272

72 systolic (but not diastolic) blood pressure is a strong, positive, continuous and independent indicator of mortality risk in the elderly; 10-year follow-up of 3,858 outpatients > 65 years old, 74 patients (1.9%) were lost to follow-up and 1,561 (41.3%) died, 709 (45.4% all deaths) died from cardiovascular causes; positive continuous, graded, strong and independent association observed with both total (P < 0.001) and cardiovascular (P < 0.001) mortality for systolic blood pressure (SBP) but not for diastolic blood pressure (DBP), no J-shaped mortality curve in subjects with lowest SBP and DBP (Arch Intern Med 1999 Jun 14;159(11);1205)Arch Intern Med 1999 Jun 14;159(11);1205 systolic blood pressure predicts cardiovascular events in the elderly cohort of 4,008 persons > 64 years old followed for at least 5 years (mean 11.1 years) elevated systolic blood pressure strongly associated with cardiovascular events, optimal systolic blood pressure < 120 mm Hg diastolic blood pressure not associated with cardiovascular events in subjects < 75 years old diastolic blood pressure mm Hg associated with lowest risk for cardiovascular events in subjects > 75 years old Reference - J Hum Hypertens 2006 Jun;20(6):392J Hum Hypertens 2006 Jun;20(6):392

73 hypertension (and high normal blood pressure to a lesser degree) associated with increased risk for cardiovascular events in women based on prospective cohort study 39,322 women followed for median 10.2 years 982 (2.5%) had major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes) 8,686 (30.1%) without baseline hypertension developed hypertension age-adjusted rate of major cardiovascular events –1.6 per 1,000 person-years in 11,326 women with normal blood pressure ( /75-84 mm Hg) –2.9 per 1,000 person-years in 4,988 women with high normal blood pressure ( /85-89 mm Hg) –4.3 per 1,000 person-years in 10,459 women with baseline hypertension Reference - BMJ 2007 Sep 1;335(7617):432 full-text, editorial can be found in BMJ 2007 Sep 1;335(7617):408BMJ 2007 Sep 1;335(7617):432full-textBMJ 2007 Sep 1;335(7617):408

74 systolic blood pressure (SBP), and not diastolic blood pressure (DBP), predicts outcomes in treated hypertensive men 4,714 hypertensive men treated by their physician were followed for mean 14 years the 85% with uncontrolled hypertension (SBP > 140 mm Hg and/or DBP > 90 mm Hg) had increased risk for cardiovascular disease mortality (risk ratio [RR] 1.66, 95% CI ) and for coronary heart disease mortality (RR 2.35, 95% CI ) compared with the 15% with controlled hypertension after controlling for DBP and risk factors, SBP mm Hg had RR 1.81 (95% CI ) and SBP > 160 mm Hg had RR 1.94 (95% CI ) for cardiovascular disease mortality compared to SBP < 140 mm Hg after controlling for SBP and risk factors, DBP mm Hg and DBP > 100 mm Hg did not have significantly increased risk for cardiovascular disease mortality compared to DBP < 90 mm Hg similar results seen for coronary heart disease mortality Reference - Arch Intern Med 2002 Mar 11;162(5):577, editorial can be found in Arch Intern Med 2002 Mar 11;162(5):506, commentary can be found in Arch Intern Med 2003 Jan 13;163(1):121Arch Intern Med 2002 Mar 11;162(5):577Arch Intern Med 2002 Mar 11;162(5):506Arch Intern Med 2003 Jan 13;163(1):121

75 patients 80 years old with higher blood pressure (up to 139/89 mm Hg) less likely to die than patients with lower blood pressure in retrospective cohort study of 4,071 ambulatory patients 80 years old with hypertension, follow-up 5 years (J Am Geriatr Soc 2007 Mar;55(3):383), commentary can be found in Am Fam Physician 2008 Jan 1;77(1):94, J Am Geriatr Soc 2007 Dec;55(12):2102J Am Geriatr Soc 2007 Mar;55(3):383Am Fam Physician 2008 Jan 1;77(1):94J Am Geriatr Soc 2007 Dec;55(12):2102

76 central systolic blood pressure may predict cardiovascular mortality in patients 65 years (level 2 [mid-level] evidence)level 2 [mid-level] evidence based on prospective cohort study 398 adults 65 years old with normal blood pressure or untreated hypertension had central blood pressure and brachial blood pressure measurements central carotid blood pressure measured by applanation tonometry cardiovascular mortality associated with –elevated carotid SBP (p = 0.029) –history of coronary artery disease (p < 0.001) –male gender (p < 0.001) Reference - J Am Coll Cardiol 2008 Jun 24;51(25):2432, editorial can be found in J Am Coll Cardiol 2008 Jun 24;51(25):2440J Am Coll Cardiol 2008 Jun 24;51(25):2432J Am Coll Cardiol 2008 Jun 24;51(25):2440

77 pulse pressure may be most important contributor to cardiovascular risk in elderly; pooled results from 3 trials with 7,929 patients > 60 with systolic blood pressure mm Hg, increase in pulse pressure associated with increased risk for cardiovascular events (Arch Intern Med 2000 Apr 24;160(8):1085); DynaMed commentary -- results may not be generalizable to younger patients, patients with systolic blood pressure < 160 mm Hg or patients with elevated diastolic blood pressureArch Intern Med 2000 Apr 24;160(8):1085 all-cause mortality and cardiovascular mortality is lower in both men and women who are treated for hypertension (Circulation 1996;93:697)

78 home blood pressure but not office blood pressure predicted cardiovascular mortality in 4,939 treated hypertensive elderly (mean age 70 years) (level 1 [likely reliable] evidence) (JAMA 2004 Mar 17;291(11):1342), commentary can be found in J Fam Pract 2004 Oct;53(10):832, commentary can be found in Am Fam Physician 2004 Oct 15;70(8):1558level 1 [likely reliable] evidenceJAMA 2004 Mar 17;291(11):1342J Fam Pract 2004 Oct;53(10):832Am Fam Physician 2004 Oct 15;70(8):1558 self-measured home blood pressure better than clinic blood pressure for predicting stroke or TIA in cohort of 1,702 Japanese patients > 40 years old followed for mean 10.6 years (Stroke 2004 Oct;35(10):2356 in Evidence-Based Medicine 2005 May- Jun;10(3):92)Stroke 2004 Oct;35(10):2356

79 Treatment JNC 7 treatment overview treat to BP < 140/90 mm Hg or < 130/80 mm Hg in patients with diabetes or chronic kidney disease most patients will require 2 medications to reach goal lifestyle modifications –weight reduction can reduce BP by 5-20 mm Hg per 10 kg lost (see also Obesity in adults)weight reduction –DASH diet (fruits, vegetables, low-fat dairy, reduced fat) can reduce BP by 8-14 mm HgDASH –dietary sodium restriction can reduce BP by 2-8 mm Hgdietary sodium –aerobic physical activity 30 minute/day can reduce BP by 4-9 mm Hgaerobic physical activity –moderate alcohol consumption (1-2 drinks/day) can reduce BP by 2-4 mm Hg –behavioral counseling for comprehensive lifestyle modification can lower blood pressurecounseling

80 initial drug choices if no compelling indications –stage 1 hypertension ( /90-99 mm Hg) - thiazide-type diuretics; may consider ACEI, ARB, BB, CCB or combination –stage 2 hypertension (160/100 mm Hg or higher) - 2-drug combination using thiazide-type diuretic plus ACEI, ARB, BB or CCB compelling indications –heart failure - thiazide diuretic, BB, ACEI, ARB, aldosterone antagonist –post-myocardial infarction - BB, ACEI, aldosterone antagonist –high cardiovascular disease risk - thiazide diuretic, BB, ACEI, CCB –diabetes - thiazide diuretic, BB, ACEI, ARB, CCB –chronic kidney disease - ACEI, ARB –recurrent stroke prevention - thiazide diuretic, ACEI

81 smoking cessation

82 First-line therapy for hypertension Hypertension treatment in elderly patients Hypertension treatment considerations for race and ethnicity Hypertension treatment in patients with diabetes Hypertension treatment in patients with chronic kidney disease Antihypertensive medications overview Diuretics Beta blockers (BB) Angiotensin-Converting Enzyme (ACE) inhibitors (ACEI) Angiotensin II Receptor Blockers (ARBs) Calcium Channel Blockers (CCBs) Alpha-adrenergic antagonists (and centrally acting alpha-2 agonists) Peripheral adrenergic neuron antagonists Combination antihypertensives

83 evidence-based review of cardiovascular risk factors (with focus on decision on treating hypertension) can be found in BMJ 2001 Apr 21;322(7292):967BMJ 2001 Apr 21;322(7292):967 review of using cardiovascular risk profiles to individualize hypertensive treatment can be found in BMJ 2001 May 12;322(7295):1164, correction can be found in BMJ 2001 Oct 27;323(7319):993BMJ 2001 May 12;322(7295):1164BMJ 2001 Oct 27;323(7319):993 guidelines, experts and standards of care may be overtreating hypertension compared with public-based values; 39 consultant physicians, 39 general practitioners, 39 practice nurses, and 100 adult members of the public were asked by postal questionnaire whether or not they would take drugs if one life would be saved for every 12, 33, 50, 100, or 250 people treated for five years; number needed to treat (NNT) thresholds were 100 for consultant physicians, 50 for general practitioners and 33 for practice nurses and the public (BMJ 2000 May 27;320(7247):1446), commentary can be found in BMJ 2000 Oct 21;321(7267):1022BMJ 2000 May 27;320(7247):1446BMJ 2000 Oct 21;321(7267):1022 Other management may include home blood pressure monitoring, self-management programs, alcohol reduction, relaxation and meditation and alternative therapiesOther management

84 Diet dietary salt restriction sodium restriction may not have substantial long-term benefits (level 2 [mid-level] evidence); systematic review of randomized trials of salt restriction in healthy persons lasting 6 months to 7 years; review included 3 trials in 2,326 normotensive people, 5 trials in 387 patients with untreated hypertension, and 3 trials in 801 patients being treated for hypertension; 17 deaths and few cardiovascular events reported overall with no significant differences between groups; intensive interventions (not practical in primary care) reduced blood pressure by mean 1.1/0.6 mm Hg at months; sodium restriction may help patients taking antihypertensives stop medication and maintain blood pressure control; systematic review last updated 2003 Nov 26 (Cochrane Library 2004 Issue 1:CD003656), earlier version published in BMJ 2002 Sep 21;325(7365):628full-text, commentary can be found in Am Fam Physician 2003 Jan 15;67(2):410, commentary can be found in BMJ 2003 Jan 25;326(7382):222full-text, commentary can be found in Lancet 2003 Aug 2;362(9381):403, commentary can be found in Evidence-Based Medicine 2003 Sep-Oct;8(5):139level 2 [mid-level] evidenceCochrane Library 2004 Issue 1:CD003656BMJ 2002 Sep 21;325(7365):628full-text Am Fam Physician 2003 Jan 15;67(2):410BMJ 2003 Jan 25;326(7382):222full-textLancet 2003 Aug 2;362(9381):403

85 dietary changes can have modest effect in lowering blood pressure Dietary Approaches to Stop Hypertension (DASH) diet was healthy diet specifically designed and tested for lowering blood pressure DASH diet is high in dietary fiber, moderate in total fat and protein, and low in saturated fat, dietary cholesterol, and sodium DASH diet emphasizes increased fruits, vegetables, whole grains, low-fat dairy products, legumes, nuts, seeds, and lean meats DASH diet reduces systolic blood pressure by about 8-14 mm Hg and incidence of hypertension (level 3 [lacking direct] evidence), based on randomized trials without clinical outcomes reportedlevel 3 [lacking direct] evidence DASH diet reduces lipid levels and homocysteine levels (level 3 [lacking direct] evidence), based on randomized trials without clinical outcomeslevel 3 [lacking direct] evidence see DASH diet for details slight reduction in saturated fat intake plus use of extra-virgin olive oil significantly lowered daily antihypertensive dosage requirement in randomized 6-month crossover study of 23 hypertensive patients (Arch Intern Med 2000 Mar 27;160(6):837)Arch Intern Med 2000 Mar 27;160(6):837

86 weight loss if obese weight-reducing diets in overweight hypertensive persons can affect modest weight loss of 3-9% body weight and are probably associated with modest blood pressure decreases of about 3 mm Hg systolic and diastolic, weight-reducing diets may decrease dosage requirements of antihypertensive medications, clinical outcomes not reported; systematic review last updated 1998 Jul 20 (Cochrane Library 1999 Issue 1:CD000484)Cochrane Library 1999 Issue 1:CD net weight reduction of 5.1 kg (11.2 lbs) associated with blood pressure reduction of 4.44/3.57 mm Hg; blood pressure reduction proportional to weight loss at systolic blood pressure mm Hg per kg of weight loss and diastolic blood pressure mm Hg per kg of weight loss; based on meta-analysis of 25 randomized trials of weight reduction for blood pressure lowering with 4,874 participants (Hypertension 2003 Nov;42(5):878)Hypertension 2003 Nov;42(5):878 weight loss associated with modest blood pressure reductions but weight loss not generally maintained long-term; in one study, diastolic blood pressure reduced 1.4 mm Hg for 2 lbs of weight loss, but only 13% subjects maintained weight loss at 3 years (Ann Intern Med 2001 Jan 2;134(1):1in BMJ 2001 Jan 13;322(7278):118 and in QuickScan Reviews in Fam Pract 2001 May;26(3):3)Ann Intern Med 2001 Jan 2;134(1):1BMJ 2001 Jan 13;322(7278):118

87 caffeine restriction not likely to improve BP among habitual coffee drinkers with mild hypertension short-term restriction of dietary caffeine not shown to reduce blood pressure in patients with mild hypertension in crossover trial of 4 consecutive dietary caffeine regimens for 2 weeks in patients consuming > 2 cups of coffee daily (BMJ 1991 Nov 16;303(6812):1235)BMJ 1991 Nov 16;303(6812):1235 no difference in BP between drinking vs. abstaining from filter- brewed, caffeinated coffee in trial of 21 normotensive, habitual users over 2 months (J Gen Intern Med 1990 May-Jun;5(3):211)J Gen Intern Med 1990 May-Jun;5(3): mm Hg decline in BP among 45 normotensive habitual users drinking decaffeinated instead of caffeinated coffee over 6 weeks in randomized trial (Hypertension 1989 Nov;14(5):563)Hypertension 1989 Nov;14(5):563 Reference - ACP J Club 1992 Mar-Apr;116(2):38 vitamin C 500 mg orally daily for 4 weeks reduced blood pressure from 142/84 mm Hg to 132/80 mm Hg in randomized placebo-controlled trial of 30 patients aged with type 2 diabetes (Hypertension 2002 Dec;40(6):804)Hypertension 2002 Dec;40(6):804 partial substitution of carbohydrate with protein or monounsaturated fat associated with improvements in blood pressure and lipid levels (level 3 [lacking direct] evidence) in randomized crossover trial with 164 patients with prehypertension or stage 1 hypertension (JAMA 2005 Nov 16;294(19):2455), editorial can be found in JAMA 2005 Novlevel 3 [lacking direct] evidenceJAMA 2005 Nov 16;294(19):2455JAMA 2005 Nov

88 Dietary Alternatives interventions which might reduce blood pressure based on randomized trials without clinical outcomes (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence vitamin D combination antioxidant vitamins vitamin C vitamin E potassium combination of potassium and magnesium omega-6 fatty acids (olive oil) dark chocolate garlic green coffee bean extract guava fruit sour milk (milk fermented with Lactobacillus helveticus, casein hydrosylate) soy milk (but soy protein supplements had inconsistent results) Abana Balsamodendron mukul grape seed polyphenol (but increased blood pressure when combined with vitamin C) hawthorn extract Hibiscus sabdariffa (sour tea) stevia L-arginine coenzyme Q10 melatonin (but increased blood pressure with concomitant nifedipine)

89 interventions which appear ineffective for lowering blood pressure (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence calcium calcium plus vitamin D magnesium combination of calcium plus magnesium combination of calcium plus potassium omega-3 fatty acids (fish oil) tea North American ginseng intervention which may increase blood pressure (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence low potassium diet interventions with no direct evidence for treatment of hypertension folic acid glucomannan olive leaf extract (insufficient evidence)

90 hypertension treatment considerations for race and ethnicity limited evidence regarding effect of race on clinical response (morbidity and mortality) to antihypertensives –diuretics associated with lower rates of heart failure, stroke and cardiovascular disease than multiple other drug classes –thiazide-type diuretics suggested as initial drug of choice in black patients (grade B recommendation [inconsistent or limited evidence]), based on chlorthalidone having superior outcomes to amlodipine and lisinopril in ALLHAT trialgrade B recommendation [inconsistent or limited evidence] antihypertensive drugs reported to differ in efficacy for lowering blood pressure in black patients (level 3 [lacking direct] evidence) but insufficient evidence to determine effect on clinical outcomeslevel 3 [lacking direct] evidence National Institute for Clinical Excellence (NICE) guidelines recommend first choice for initial therapy in hypertensive black patients of any age should be either calcium-channel blocker or thiazide-type diuretic see Hypertension treatment considerations for race and ethnicity for details

91 comorbidities diabetes - see Hypertension treatment in patients with diabetes chronic kidney disease –target blood pressure in patients with chronic kidney disease < 130/80 mm Hg –most patients with chronic kidney disease should be treated with combination of ACE inhibitor or angiotensin receptor blocker (ARB) diuretic (may need loop diuretic instead of thiazide diuretic if stages 4-5 chronic kidney disease) –recommended parameters for stopping ACE inhibitor are hyperkalemia (serum potassium > 5.6 mmol/L [5.6 mEq/L]) or rise in creatinine > 30% above baseline, even for patients with elevated baseline creatinine > 1.4 mg/dL (123.8 mcmol/L) (grade C recommendation [lacking direct evidence])grade C recommendation [lacking direct evidence]

92 Diabetes

93 Types of Diabetes Diabetes mellitus type 1 Diabetes mellitus type 2 Gestational diabetes (GDM) Diabetes in pregnancy (diabetes that predates the pregnancy) diabetes insipidus –Nephrogenic diabetes insipidus –Central diabetes insipidus

94 Prediabetes, diabetes prevention and screening Prediabetes Risk factors for diabetes mellitus type 2 Diabetes mellitus type 2 screening Diabetes mellitus type 2 prevention

95 treatment targets in patients with diabetes Glycemic goals in patients with type 1 diabetes Glycemic goals in patients with type 2 diabetes Glucose monitoring Hypertension treatment in patients with diabetes Lipid-lowering in patients with diabetes

96 nonpharmacologic management of diabetes Dietary considerations for patients with type 2 diabetes Physical activity for type 2 diabetes Diabetes mellitus type 2 self-management Diabetes alternative treatments

97 Medications for diabetes Glucose lowering medications for type 2 diabetes –Metformin –Sulfonylureas (oral hypoglycemic agents) –Glitazones –Alpha-glucosidase inhibitors –Meglitinide analogs –Dipeptidyl peptidase IV (DPP-4) inhibitors (gliptins) Insulin management Insulin for type 2 diabetes with suboptimal glycemic control Weight loss medications in patients with diabetes Diabetes alternative treatments Oral health care in persons with diabetes

98 Complications of diabetes Diabetic foot ulcer Diabetic nephropathy Diabetic retinopathy Diabetic neuropathy Diabetic ketoacidosis (DKA) in adults Diabetic ketoacidosis (DKA) in children and adolescents Hyperosmolar hyperglycemic crisis Gastroparesis

99 Nephropathy Causes: hyperglycemia leads to diabetic glomerulosclerosis (usually follows year latent period) many patients with diabetes with chronic renal insufficiency may have renal parenchymal disease and not classic diabetic glomerulosclerosis; study of 1,197 adults > 40 years old with diabetes mellitus type 2, 171 (13%) had chronic renal insufficiency defined as glomerular filtration rate < 60 mL/minute/1.73 m2 body surface area; among these 171 subjects, 30% had neither diabetic retinopathy nor albuminuria (including microalbuminuria), suggesting causes other than diabetic glomerulosclerosis (JAMA 2003 Jun 25;289(24):3273), commentary can be found in JAMA 2003 Oct 8;290(14):1855; author reply 1855JAMA 2003 Jun 25;289(24):3273JAMA 2003 Oct 8;290(14):1855; author reply 1855 Pathogenesis: increased mesangial matrix and glomerular basement membrane, hyaline arteriosclerosis of afferent and efferent arterioles, immunoglobulin G (IgG) and albumin deposits lining tubular and glomerular basement membranes hypotheses include protein glycosylation, activation of "polyol" pathway, abnormalities of vascular endothelium and altered capillary blood flow

100 Likely risk factors: hypertension poorly controlled diabetes microalbuminuria –microalbuminuria may be marker for increased mortality and future nephropathy microalbuminuria as marker for increased mortality –microalbuminuria associated with increased risk of mortality »based on systematic review without methodological analysis »11 European cohort studies defined microalbuminuria as albumin excretion g/day »consistent finding across studies showed that presence of microalbuminuria associated with 2 times risk of all cause and cardiovascular mortality »unclear if treating microalbuminuria in type 2 diabetes reduces risk »Reference - Arch Intern Med 1997 Jul 14;157(13):1413 in J Fam Pract 1997 Nov;45(5):379Arch Intern Med 1997 Jul 14;157(13):1413J Fam Pract 1997 Nov;45(5):379

101 microalbuminuria associated with increased risks for overall mortality, major cardiovascular events and hospitalization for heart failure based on cohort study 5,545 persons > 55 years old with cardiovascular disease and 3,498 persons > 55 years old with diabetes followed for median 4.5 years Reference - JAMA 2001 Jul 25;286(4):421, commentary can be found in ACP J Club 2002 Jan-Feb;136(1):34JAMA 2001 Jul 25;286(4):421ACP J Club 2002 Jan-Feb;136(1):34 microalbuminuria and gross proteinuria associated with increased risks for death from all causes, cardiovascular causes, coronary heart disease or stroke cohort study of 840 patients with older-onset diabetes followed 12 years; 43% cardiovascular mortality in cohort, based on death certificates increased risks significant after controlling for known cardiovascular risk factors and diabetes-related variables relative risks were 1.68 to 2.2 for microalbuminuria and 2.33 to 2.73 for gross proteinuria Reference - Arch Intern Med 2000 Apr 24;160(8):1093Arch Intern Med 2000 Apr 24;160(8):1093

102 albumin-to-creatinine ratio > 30 mg/g in random urine specimens predicts development of overt nephropathy study of 439 Pima Indians with diabetes aged years with no overt nephropathy at baseline mean follow-up 4.2 years overt nephropathy defined as protein-to-creatinine ratio > 1 g/g at baseline, 140 patients had albumin/creatinine ratio > 30 mg/g and 299 had ratio < 30 mg/g overt nephropathy developed in 34% with vs. 4% without albumin/creatinine ratio > 30 mg/g other independent predictors of nephropathy were duration of diabetes and 2-hour postload glucose concentration albumin-to-creatinine ratio > 30 mg/g had 80% sensitivity, 76% specificity, 34% positive predictive value and 96% negative predictive value Reference - Arch Intern Med 1991 Sep;151(9):1761, commentary can be found in ACP J Club 1992 Jan-Feb;116(1):19Arch Intern Med 1991 Sep;151(9):1761 microalbuminuria associated with increased risk for diabetic nephropathy but most patients with microalbuminuria do not develop nephropathy based on prospective cohort study 23 patients with diabetes with persistent microalbuminuria and 209 patients with diabetes without microalbuminuria followed for 7 years microalbuminuria regressed in 56% of those with it and developed in 16% of those without it microalbuminuria had 43% positive predictive value and 77% negative predictive value for diabetic nephropathy Reference - Diabetes Care 2001 Sep;24(9):1560Diabetes Care 2001 Sep;24(9):1560

103 Complications and Associated Conditions of Nephropathy Complications: avoid contrast material (intravenous pyelogram [IVP], computed tomography [CT] dye) especially if creatinine > 2, else prior hydration is extremely important papillary necrosis chronic interstitial nephritis Associated conditions: arteriosclerotic disease parallel development of retinopathy

104 Diagnosis of Nephropathy measuring kidney function serum creatinine –high serum creatinine implies poor kidney function –low or normal serum creatinine does not always imply good kidney function –small or elderly patients may not generate as much creatinine due to smaller muscle mass creatinine clearance –measured level more accurate but requires 24-hour urine collection –common ways to estimate creatinine clearance include Cockcroft-Gault equation (based on serum creatinine, age, weight and gender) Modification of Diet in Renal Disease (MDRD) calculator (recommended by National Kidney Foundation for evaluating renal function in patients with chronic kidney disease)Modification of Diet in Renal Disease (MDRD) calculator Reference - Prescriber's Letter 2005 Jul;12(7):38 –MDRD appears more accurate than Cockcroft-Gault formula in elderly patients with diabetes based on diagnostic cohort study 69 patients > 72 years old with diabetes and wide range of renal function (serum creatinine mcmol/L) had measured glomerular filtration rate (GFR) compared with MDRD equation (4-variable version) and Cockcroft-Gault estimation chronic kidney disease defined as measured GFR < 60 mL/minute/1.73 m2 MDRD had 98% sensitivity and 61% specificity for chronic kidney disease Cockcroft-Gault estimation had 82% sensitivity and 44% specificity for chronic kidney disease Reference - J Am Geriatr Soc 2006 Jun;54(6):1007J Am Geriatr Soc 2006 Jun;54(6):1007

105 Rule out: other causes of renal failure, see –Acute renal failure - differential diagnosis –Chronic kidney disease other causes of elevated serum creatinine (blood urea nitrogen [BUN]/creatinine ratio usually < 8) –acute upper gastrointestinal bleeding –malnutrition –liver disease –rhabdomyolysis –laboratory artifact (chemical interference with creatinine determination due to presence of ketones, proteins, sugars) –medication-induced inhibition of tubular secretion of creatinine cimetidine pyrimethamine trimethoprim acetoacetate –Reference - Arch Intern Med 1998 Dec 7-21;158(22):2509Arch Intern Med 1998 Dec 7-21;158(22):2509 causes of falsely elevated serum creatinine –medications (for example, cefoxitin) –toxic ingestion such as methanol poisoning or nitromethane ingestion –ketoacidosis, such as diabetic ketoacidosis (DKA) –see Acute renal failure - differential diagnosis for details

106 Testing to consider: initial testing –blood urea nitrogen, creatinine –urine dipstick –random urine albumin (or protein):creatinine ratio confirmatory testing –24-hour urine collection for albumin (or protein) and creatinine –renal biopsy for all adults with diabetes regardless of degree of urine albumin excretion, measure serum creatinine at least annually for estimation of glomerular filtration rate (grade C recommendation [lacking direct evidence])grade C recommendation [lacking direct evidence] Pathology tests: renal biopsy - 2 patterns –diffuse glomerulosclerosis - eosinophilic thickening of mesangium and basement membrane –50% nodular glomerulosclerosis (Kimmelstiel-Wilson syndrome) - round nodules with homogeneous center and layering of nuclei, specific for diabetes

107 Prognosis of Nephropathy disease process accelerated by hypertension (inconsistent evidence) –systolic blood pressure stronger predictor than diastolic blood pressure of renal outcomes based on randomized trial 1,513 patients with nephropathy, hypertension and type 2 diabetes doubling of serum creatinine, end-stage renal disease, or death Reference - Arch Intern Med 2003 Jul 14;163(13):1555, commentary can be found in Arch Intern Med 2004 Jan 26;164(2):223; author reply 223Arch Intern Med 2003 Jul 14;163(13):1555 Arch Intern Med 2004 Jan 26;164(2):223; author reply 223 –hypoalbuminemia, proteinuria, and black race (but not blood pressure, glycohemoglobin or serum cholesterol) were independent predictors of progression of decline in glomerular filtration rate based on cohort study 343 patients with type 2 diabetes, chronic kidney disease and mean blood pressure 138/72 mm Hg Reference -BMC Nephrol 2005 Jun 28;6(1):8 full-textBMC Nephrol 2005 Jun 28;6(1):8full-text urinary obstruction infection nephrotoxic agents –medication –IV radiocontrast material

108 Treatment of Nephropathy medications angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) –ACE inhibitors appear to reduce mortality in diabetic nephropathy (level 2 [mid-level] evidence) while ARBs have limited evidence for mortality outcomeACE inhibitorslevel 2 [mid-level] evidence –ACE inhibitors decrease albuminuria and may delay onset of nephropathy (level 3 [lacking direct] evidence)decrease albuminurialevel 3 [lacking direct] evidence –ARBs slow progression of diabetic nephropathy and reduce risk for end-stage renal disease (level 1 [likely reliable] evidence)ARBslevel 1 [likely reliable] evidence –addition of ARB to ACE inhibitor may further reduce albuminuria (level 3 [lacking direct] evidence)addition of ARB to ACE inhibitorlevel 3 [lacking direct] evidence combination therapy –combination of perindopril plus indapamide reduces mortality in patients with type 2 diabetes (level 1 [likely reliable] evidence)perindopril plus indapamidelevel 1 [likely reliable] evidence –addition of avosentan to ACE inhibitor/ARB therapy associated with decrease in urine albumin excretion in patients with diabetic nephropathy (level 3 [lacking direct] evidenceavosentanlevel 3 [lacking direct] evidence –addition of aliskiren to losartan may reduce albumin-creatinine ratio in patients with type 2 diabetes and nephropathy (level 3 [lacking direct] evidence)aliskirenlevel 3 [lacking direct] evidence other medications –calcium channels blockers may be effective in treating diabetic nephropathy (level 3 [lacking direct] evidence)calcium channels blockerslevel 3 [lacking direct] evidence –spironolactone may reduce albuminuria (level 3 [lacking direct] evidence)spironolactonelevel 3 [lacking direct] evidence –sulodexide may reduce urinary albumin excretion in patients with diabetes (level 3 [lacking direct] evidence)sulodexidelevel 3 [lacking direct] evidence –EDTA chelation might reduce progression in patients with low-level environmental lead exposure (level 3 [lacking direct] evidence)EDTAlevel 3 [lacking direct] evidence –high-dose B vitamin therapy associated with increased vascular events in patients with diabetic nephropathy (level 2 [mid-level] evidence)high-dose B vitamin therapylevel 2 [mid-level] evidence

109 Dietary Recommendations in patients with any degree of chronic kidney disease, limit protein intake to 0.8 g/kg/day to reduce risk of nephropathy (ADA Grade B) (American Diabetes Association [ADA] 2010 position statement on standards of medical care in diabetes in Diabetes Care 2010 Jan;33 Suppl 1:S11 full-text)ADA Grade B Diabetes Care 2010 Jan;33 Suppl 1:S11full-text

110 Medication for Nephropathy Angiotensin-converting enzyme (ACE) inhibitors: ACE inhibitors appear to reduce mortality in diabetic nephropathy (level 2 [mid-level] evidence) while angiotensin receptor blockers (ARBs) have limited evidence for mortality outcomelevel 2 [mid-level] evidence recommended parameters for stopping ACE inhibitor (grade B recommendation [inconsistent or limited evidence])grade B recommendation [inconsistent or limited evidence] hyperkalemia (serum potassium > 5.6 mmol/L [5.6 mEq/L]) rise in creatinine > 30% above baseline (even for patients with elevated baseline creatinine > 1.4 mg/dL

111 Angiotensin II-receptor blockers (ARBs): angiotensin II receptor blockers (ARBs) slow progression of diabetic nephropathy (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –based on 11 randomized trials –irbesartan (Avapro) and losartan (Cozaar) are first drugs FDA approved for kidney disease in patients with type 2 diabetes and hypertension (Prescriber's Letter 2002 Oct;9(10):60) –losartan slows progression of diabetic nephropathy and reduces risk for end-stage renal disease (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence

112 Other medications: treat hypertension aggressively (see Hypertension treatment in patients with diabetes) spironolactone may reduce albuminuria (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence –based on 2 randomized trials without clinical outcomes –spironolactone may reduce urine albumin-to-creatinine ratio in patients taking lisinopril (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence

113 calcium channel blockers may be effective in treating diabetic nephropathy (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers may have similar efficacy in reducing progression of type 2 diabetes- associated nephropathy –based on small randomized trial without clinical outcomes –52 patients mean age 63 years with type 2 diabetes mellitus randomized to lisinopril, calcium channel blocker (verapamil SR or diltiazem SR), or atenolol and followed for mean of 63 months –lisinopril vs. calcium channel blockers no significant difference in rate of decline of creatinine clearance no significant difference in reduction of proteinuria –rate of decline of creatinine clearance greatest and reduction of proteinuria least affected with atenolol –Reference -Kidney Int 1996 Nov;50(5):1641Kidney Int 1996 Nov;50(5):1641

114 Surgery: transplantation or dialysis within 3 years if renal failure depending on other complications pancreas transplantation can reverse lesions of diabetic nephropathy, but reversal requires > 5 years of normoglycemia, clinical outcomes (need for dialysis, mortality) not assessed, based on serial biopsies of 8 patients with diabetes type 1 (N Engl J Med 1998 Jul 9;339(2):69)N Engl J Med 1998 Jul 9;339(2):69

115 Prevention of Nephropathy National Kidney Foundation recommendations for preserving renal function in adults with hypertension and diabetes: blood pressure (BP) goal < 130/80 mm Hg in patients with diabetes first-line therapy is combination of angiotensin-converting enzyme (ACE) inhibitor and thiazide diuretic additional therapies if BP > 145/90 mm Hg include calcium channel blocker (verapamil or diltiazem if proteinuria), beta blocker (if heart rate > 84 beats/minute), alpha blockers angiotensin receptor blockers may be substituted for ACE inhibitors if adverse effects Reference - Am J Kidney Dis 2000 Sep;36(3):646Am J Kidney Dis 2000 Sep;36(3):646

116 Multiple risk factor management: intensive management of multiple risk factors may reduce microvascular and macrovascular complications in patients with type 2 diabetes and microalbuminuria Antihypertensive treatment: ACE inhibitors –ACE inhibitors decrease albuminuria and may delay onset of nephropathy (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence

117 angiotensin receptor blockers (ARBs) angiotensin II receptor blockers (ARBs) slow progression of diabetic nephropathy (level 1 [likely reliable] evidence) -- see Treatment sectionlevel 1 [likely reliable] evidenceTreatment section ARBs may be beneficial in preventing nephropathy in patients with type 2 diabetes –irbesartan and losartan have been shown to reduce microalbuminuria and slow progression of established renal disease –valsartan has been shown to reduce microalbuminuria –no data to recommend ARBs over ACE inhibitors –Reference - Prescriber's Letter 2001 Jul;8(7):41

118 antihypertensive treatments for patients with diabetes intolerant to ACE inhibitors and ARBs non-dihydropyridine calcium channel blockers (such as verapamil and diltiazem) preferred for pateints with diabetes and proteinuria (grade A recommendation [consistent high-quality evidence])grade A recommendation [consistent high-quality evidence] diuretics effective for reducing risk for cardiovascular disease sustained-release indapamide (a diuretic) appears effective for first-line treatment in of hypertension in patients with diabetes and proteinuria (grade B recommendation [inconsistent or limited evidence])grade B recommendation [inconsistent or limited evidence] atenolol may be as effective as captopril for reducing risk of microvascular and macrovascular complications (grade B recommendation [inconsistent or limited evidence])grade B recommendation [inconsistent or limited evidence] controlling blood pressure in diabetes appears more important than which antihypertensive agents are used Reference - J Fam Pract 2005 Aug;54(8):711J Fam Pract 2005 Aug;54(8):711

119 Reviews: Clinical Evidence Concise review (search date 2004 Nov) can be found in Am Fam Physician 2005 Dec 1;72(11):2299Am Fam Physician 2005 Dec 1;72(11):2299 review of early screening for microalbuminuria can be found in Mayo Clin Proc 2008 Dec;83(12):1373 full-textMayo Clin Proc 2008 Dec;83(12):1373full-text review can be found in Am Fam Physician 2005 Jul 1;72(1):96Am Fam Physician 2005 Jul 1;72(1):96 review can be found in Postgrad Med 2003 May;113(5):35Postgrad Med 2003 May;113(5):35 review can be found in Arch Fam Med 1996 Jun;5(9):513Arch Fam Med 1996 Jun;5(9):513 review can be found in N Engl J Med 1999 Oct 7;341(15):1127 (summarized in Am Fam Physician 2000 Mar 1;61(5):1486), commentary can be found in N Engl J Med 2000 Feb 10;342(6):441N Engl J Med 1999 Oct 7;341(15):1127Am Fam Physician 2000 Mar 1;61(5):1486N Engl J Med 2000 Feb 10;342(6):441 review can be found in N Engl J Med 2002 Apr 11;346(15):1145, commentary can be found in N Engl J Med 2002 Sep 19;347(12):947N Engl J Med 2002 Apr 11;346(15):1145N Engl J Med 2002 Sep 19;347(12):947 review can be found in Lancet 1998 Jul 18;352(9123):213, summarized in Am Fam Physician 1998 Nov 15;58(8):1845Lancet 1998 Jul 18;352(9123):213Am Fam Physician 1998 Nov 15;58(8):1845 review can be found in J Fam Pract 1998 Jan;46(1):21J Fam Pract 1998 Jan;46(1):21 review can be found in Mayo Clin Proc 2000 Jan;75(1):49Mayo Clin Proc 2000 Jan;75(1):49 editorial review can be found in BMJ 2002 Jul 13;325(7355):59BMJ 2002 Jul 13;325(7355):59 American Diabetes Association (ADA) literature review on diabetic nephropathy can be found in Diabetes Rev 1995;3:510

120 Guidelines: American Diabetes Association (ADA) 2010 position statement on standards of medical care in diabetes can be found in Diabetes Care 2010 Jan;33 Suppl 1:S11 full-textDiabetes Care 2010 Jan;33 Suppl 1:S11full-text –ADA grades of evidence for clinical practice recommendations Grade A - clear evidence from well-conducted, generalizable, randomized controlled trials that are adequately powered Grade B - supportive evidence from well-conducted cohort studies Grade C - supportive evidence from poorly controlled or uncontrolled studies Grade E - expert consensus or clinical experience policy statement on nephropathy in diabetes from American Diabetes Association (ADA) can be found in Diabetes Care 2004 Jan;27 Suppl 1:S79full-textDiabetes Care 2004 Jan;27 Suppl 1:S79full-text National Kidney Foundation recommendations for preserving renal function in adults with hypertension and diabetes can be found in Am J Kidney Dis 2000 Sep;36(3):646 Am J Kidney Dis 2000 Sep;36(3):646

121 Diabetic Neuropathy Causes: hyperglycemia Pathogenesis: glucose is converted by aldose reductase to sorbitol which is toxic to endothelium advanced glycosylation end-products atherogenic plaques in vasa nervorum

122 Complications: injury infections amputations Associated conditions: diabetic gastroparesis

123 Chief Concern (CC): paresthesias and pain of feet > hands (symmetric, bilateral, intense burning especially at night) radiculopathy (lancinating pain in single dermatome) mononeuropathy (cranial nerves or proximal motor nerves) weakness erectile dysfunction urinary retention nocturnal diarrhea rarely constipation or diarrhea

124 History of Present Illness (HPI): neuropathic sensory symptoms (numbness of the feet) in patients with diabetes suggest polyneuropathy but are not sensitive for detecting polyneuropathy in patients with type 2 diabetes –588 patients with type 2 diabetes in 26 general practices in the Netherlands had blinded comparison of neuropathic sensory symptom questionnaire and neurologic exam –score > 4 on 0-25 scale on neurologic exam implied diagnosis of diabetic polyneuropathy –32% patients had diabetic polyneuropathy on exam –neuropathic symptoms associated with diabetic polyneuropathy were numbness of the feet, sensory alteration and symptoms of pain –for patients < 68 years old, numbness of feet had 28% sensitivity, 93% specificity, positive likelihood ratio 4 and negative likelihood ratio 0.77 –for patients > 68 years old, numbness of feet had 22% sensitivity, 92% specificity, positive likelihood ratio 2.75 and negative likelihood ratio 0.85 –Reference - Diabet Med 2000 Feb;17(2):105 in ACP J Club 2000 Nov-Dec;133(3):112Diabet Med 2000 Feb;17(2):105

125 Review of Systems (ROS): erectile dysfunction frequent in men with diabetes (normal sexual desire, preserved ejaculation, erection affected, rule out other causes) neurogenic bladder (hesitancy, weak stream, dribbling)

126 General Physical: postural hypotension HEENT: diplopia, abnormal visual fields Extremities: neuropathic ulcers Neuro: decreased reflexes, loss of vibratory sense, loss of pain and temperature sensation, decreased pinprick/light touch/pain sensations, loss of proprioception (causes ataxia), weakness, atrophy of interossei muscles, high steppage gait screening for diabetic peripheral neuropathyscreening –Semmes-Weinstein monofilament exam appears specific for diabetic peripheral neuropathy (level 2 [mid-level] evidence), suggesting diagnosis if positive screenlevel 2 [mid-level] evidence –vibration testing with on-off method is specific for diabetic peripheral neuropathy (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence

127 Diagnosis of Neuropathy Rule out: distal symmetric polyneuropathy of various etiologies autonomic dysfunction (idiopathic, Shy-Drager, Riley-Day) heavy metal poisoning drugs myasthenia gravis Guillain-Barre syndrome sarcoidosis connective tissue disease paraneoplastic syndrome peripheral vascular disease femoral neuropathy tarsal tunnel syndrome spinal stenosis complex regional pain syndrome lymphoma multiple sclerosis spinal tumor alcoholic neuropathy syphilisof

128 Testing to consider: blood tests to consider –complete blood count –electrolytes –blood urea nitrogen (BUN), creatine –glucose –thyroid function tests –syphilis serology

129 nerve conduction studies slowing of nerve conduction velocity segmental demyelination and axonal degeneration point of care device for sural nerve function had 92% sensitivity, 82% specificity, 92% positive predictive value, and 82% negative predictive value for neuropathy on conventional nerve conduction study in 72 patients with diabetes of whom 50 (69%) had neuropathy (Diabetes Care 2006 Sep;29(9):2023)Diabetes Care 2006 Sep;29(9):2023 ankle/brachial index (ABI) > 0.90

130 Treatment of Neuropathy Treatment overview: drugs with efficacy for pain relief in diabetic neuropathy includedrugs with efficacy –anticonvulsants (level 2 [mid-level] evidence) including pregabalin (Lyrica) (level 1 [likely reliable] evidence)anticonvulsantslevel 2 [mid-level] evidence pregabalinlevel 1 [likely reliable] evidence –antidepressants (level 2 [mid-level] evidence)antidepressantslevel 2 [mid-level] evidence –opioids (controlled-release oxycodone [OxyContin], tramadol [Ultram]) (level 2 [mid-level] evidence)opioidslevel 2 [mid-level] evidence –topical capsaicin (level 2 [mid-level] evidence)capsaicinlevel 2 [mid-level] evidence actovegin improves neuropathic symptoms and quality of life in patients with symptomatic diabetic neuropathy (level 1 [likely reliable] evidence)actoveginlevel 1 [likely reliable] evidence dietary supplements have limited evidence but substances which may reduce pain include alpha-lipoic acid and acetyl-L-carnitine (level 2 [mid-level] evidence)alpha-lipoic acidacetyl-L-carnitinelevel 2 [mid-level] evidence

131 Medications: drugs with efficacy for pain relief in diabetic neuropathy include –anticonvulsants (level 2 [mid-level] evidence)level 2 [mid-level] evidence –antidepressants (level 2 [mid-level] evidence)level 2 [mid-level] evidence –opioids (controlled-release oxycodone, tramadol) (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –topical capsaicin (level 2 [mid-level] evidence)level 2 [mid-level] evidence

132 Neuropathy screening Screening: American Diabetes Association (ADA) recommendations for foot care –perform annual testing for loss of protective sensation (LOPS) (10-g monofilament plus testing any one of (ADA grade B)ADA grade B vibration using 128-hertz (Hz) tuning fork pinprick sensation ankle reflexes vibration perception threshold –Reference - American Diabetes Association (ADA) 2010 position statement on standards of medical care in diabetes can be found in Diabetes Care 2010 Jan;33 Suppl 1:S11 full-textDiabetes Care 2010 Jan;33 Suppl 1:S11full-text Semmes-Weinstein monofilament exam appears specific for diabetic peripheral neuropathy (level 2 [mid-level] evidence), suggesting diagnosis if positive screenlevel 2 [mid-level] evidence

133 Reviews: review can be found in Am Fam Physician 2005 Jun 1;71(11):2123Am Fam Physician 2005 Jun 1;71(11):2123 review can be found in Mayo Clin Proc 2006 Apr;81(4 Suppl):S3 and Mayo Clin Proc 2006 Apr;81(4 Suppl):S12, correction can be found in Mayo Clin Proc 2006 Jun;81(6):854Mayo Clin Proc 2006 Apr;81(4 Suppl):S3Mayo Clin Proc 2006 Apr;81(4 Suppl):S12 review of diabetic polyneuropathy can be found in JAMA 2009 Oct 7;302(13):1451, commentary can be found in JAMA 2010 Feb 3;303(5):420JAMA 2009 Oct 7;302(13):1451JAMA 2010 Feb 3;303(5):420 review of treatments for diabetic neuropathy can be found in J Fam Pract 2004 May;53(5):403J Fam Pract 2004 May;53(5):403 review can be found in Am Fam Physician 1996 Dec;54(8):2478Am Fam Physician 1996 Dec;54(8):2478 review of managing painful diabetic neuropathy can be found in Hosp Pract (Minneap) 1999 Oct 15;34(11):79Hosp Pract (Minneap) 1999 Oct 15;34(11):79 review of diagnosis and management of neuropathic pain can be found in BMJ 2009 Aug 12;339:b3002, commentary can be found in BMJ 2009 Sep 1;339:b3502BMJ 2009 Aug 12;339:b3002BMJ 2009 Sep 1;339:b3502 review of neuropathic pain can be found in CMAJ 2006 Aug 1;175(3):265 full-textCMAJ 2006 Aug 1;175(3):265full-text review of neuropathic pain can be found in Cleve Clin J Med 2006 Aug;73(8):726Cleve Clin J Med 2006 Aug;73(8):726 review of neuropathic pain can be found in New Zealand Fam Physician 2006 Oct;33(5):323 PDFNew Zealand Fam Physician 2006 Oct;33(5):323 PDF discussion of diabetic polyneuropathy can be found in JAMA 2003 Sep 10;290(10):1371JAMA 2003 Sep 10;290(10):1371 review of primary care management of neuropathic pain can be found in Mayo Clin Proc 2004 Dec;79(12):1533 PDFMayo Clin Proc 2004 Dec;79(12):1533PDF review of autonomic peripheral neuropathy can be found in Lancet 2005 Apr 2;365(9466):1259Lancet 2005 Apr 2;365(9466):1259 American Diabetes Association (ADA) literature review on diabetic autonomic neuropathy can be found in Diabetes Care 2003 May;26(5):1553Diabetes Care 2003 May;26(5):1553

134 Guidelines: American Diabetes Association (ADA) 2010 position statement on standards of medical care in diabetes can be found in Diabetes Care 2010 Jan;33 Suppl 1:S11 full-textDiabetes Care 2010 Jan;33 Suppl 1:S11full-text –ADA grades of evidence for clinical practice recommendations Grade A - clear evidence from well-conducted, generalizable, randomized controlled trials that are adequately powered Grade B - supportive evidence from well-conducted cohort studies Grade C - supportive evidence from poorly controlled or uncontrolled studies Grade E - expert consensus or clinical experience consensus guidelines from 11 pain specialists –explicit methodology not described, all authors have financial relations with pharmaceutical companies –recommended first-line therapies are duloxetine, oxycodone controlled- release, pregabalin, tricyclic antidepressants –recommended second-line therapies are carbamazepine, gabapentin, lamotrigine, tramadol, venlafaxine extended-release –"honorable mention" agents include topical capsaicin, topical lidocaine, bupropion, citalopram, methadone, paroxetine, phenytoin, topiramate –Reference - Mayo Clin Proc 2006 Apr;81(4 Suppl):S12, correction can be found in Mayo Clin Proc 2006 Jun;81(6):854Mayo Clin Proc 2006 Apr;81(4 Suppl):S12

135 Diabetic Retinopathy Pathogenesis: increased capillary permeability, vascular occlusion, weakness of supporting structures erythropoietin and vascular endothelial growth factor levels in vitreous fluid independently associated with proliferative diabetic retinopathy in study of 73 patients with proliferative diabetic retinopathy and 71 patients with ocular disease but no diabetes (N Engl J Med 2005 Aug 25;353(8):782), editorial can be found in N Engl J Med 2005 Aug 25;353(8):839, commentary can be found in N Engl J Med 2005 Nov 17;353(20):2190N Engl J Med 2005 Aug 25;353(8):782N Engl J Med 2005 Aug 25;353(8):839N Engl J Med 2005 Nov 17;353(20):2190

136 main risk factor is duration of diabetes mellitus also poor glycemic control risk factors for diabetic retinopathy were duration of diabetes > 4 years and HbA1c level > 6.9% in study of 260 patients (median age 70 years) with type 2 diabetes (Br J Gen Pract 2002 Mar;52(476):214 in Am Fam Physician 2002 Jun 1;65(11):2349)Br J Gen Pract 2002 Mar;52(476):214Am Fam Physician 2002 Jun 1;65(11):2349 worsens in 15% of pregnancies

137 high blood pressure may be associated with early diabetic retinopathy in adolescents with normal albumin urinary excretion based on prospective cohort of 1,025 adolescent patients with type 1 diabetes and albumin excretion rate < 7.5 mcg/minute followed for median 4.1 years Reference - BMJ 2008 Aug 26;337:a918 full-text, editorial can be found in BMJ 2008 Aug 26;337:a770BMJ 2008 Aug 26;337:a918full-text BMJ 2008 Aug 26;337:a770 younger age at diabetes type 2 onset associated with increased risk for retinopathy based on cohort study 624 patients with diabetes type 2 for years and 852 patients with diabetes type 2 for years analyzed for retinopathy outcomes retinopathy prevalence and severity significantly higher with younger diabetes onset retinopathy risk highest in patients with mean HbA1c > 9% Reference - Diabetes Care 2008 Oct;31(10):1985Diabetes Care 2008 Oct;31(10):1985 review of hypertension as risk factor in ocular disease can be found in Lancet 2007 Feb 3;369(9559):425, correction can be found in Lancet 2007 Jun 23;369(9579):2078 Lancet 2007 Feb 3;369(9559):425

138 Retinopathy Complications Complications: 20% of new blindness in adults, vitreal hemorrhages, fibrous scarring, retinal detachment impaired circulation in microvasculature can lead to ischemia of optic disk and micro neuropathic damage to third, fourth, and sixth cranial nerves insufficient evidence to support use of anti-vascular endothelial growth factor in patients with diabetic retinopathy and macular edema –based on Cochrane review –systematic review of 4 randomized trials evaluating anti-vascular endothelial growth factor in patients with diabetic macular edema –clinical heterogeneity precluded meta-analysis for most comparisons –2 low quality trials reported short-term benefit with bevacizumab in patients with macular edema refractory to photocoagulation (compared to placebo) in previously untreated patients (compared to photocoagulation) –Reference - Cochrane Database Syst Rev 2009 Oct 7;(4):CD007419Cochrane Database Syst Rev 2009 Oct 7;(4):CD Associated conditions: increased frequency of cataracts and glaucoma with diabetes mellitus retinal arteriolar narrowing associated with increased 20-year risk of lower extremity amputation in cohort of 906 patients with diabetes (Arch Intern Med 2003 Nov 10;163(20):2505)Arch Intern Med 2003 Nov 10;163(20): % of patients with diabetic retinopathy had significant stenotic coronary artery disease –based on cohort study of 214 patients with diabetic retinopathy –Reference - J Thorac Cardiovasc Surg 2010 Jan;139(1):92J Thorac Cardiovasc Surg 2010 Jan;139(1):92

139 on funduscopic exam - venous dilatation, exudates, hemorrhages, microaneurysms; rarely preretinal or vitreous hemorrhage may lead to clot retraction and scar formation with retinal detachment microaneurysms generally first clinically detectable sign of diabetic retinopathy

140 Prognosis of Retinopathy nonproliferative retinopathy may improve with intensive multifactorial diabetes control based on 63 patients 65 years with type 2 diabetes and nonproliferative retinopathy 11 (17%) worsened 23 (37%) improved Reference - J Am Geriatr Soc 2007 Apr;55(4):541J Am Geriatr Soc 2007 Apr;55(4):541 diabetic retinopathy may worsen transiently with tighter glycemic control but progresses more slowly in the long term (J Intern Med 1991 Aug;230(2):101, BMJ 1985 Mar 16;290(6471):811 in ACP J Club 1992 Jan-Feb;116(1):5)J Intern Med 1991 Aug;230(2):101BMJ 1985 Mar 16;290(6471):811 black patients with diabetes have greater severity of retinopathy than white patients with diabetes high rate of progression of diabetic retinopathy among African American patients with type 1 diabetes mellitus –cohort of 483 African American patients with type 1 diabetes mellitus who had 2 exams at mean 6 years apart –among 195 without diabetic retinopathy at baseline, 141 (72%) developed diabetic retinopathy –among 419 at risk for progression of diabetic retinopathy at baseline, 235 (56%) had progression of diabetic retinopathy and 63 (15%) had progression to proliferative diabetic retinopathy –among 434 without macular edema at baseline, 69 (16%) developed macular edema –among 393 without vision-threatening diabetic retinopathy at baseline, 85 (22%) developed vision-threatening diabetic retinopathy –Reference - Arch Ophthalmol 2006 Sep;124(9):1297Arch Ophthalmol 2006 Sep;124(9):1297

141 Treatment of Retinopathy American Diabetes Association (ADA) recommendations(2)2 –promptly refer to an ophthalmologist experienced in managing diabetic retinopathy any patient with (ADA Grade A)ADA Grade A any level of macular edema severe nonproliferative diabetic retinopathy (NPDR) any proliferative diabetic retinopathy (PDR) –laser photocoagulation therapy indicated to reduce risk of vision loss in patients with any of (ADA Grade A)ADA Grade A high-risk PDR clinically significant macular edema some cases of severe NPDR –aspirin does not increase the risk of retinal hemorrhage and retinopathy is not a contraindication to aspirin use for cardioprotection (ADA Grade A)ADA Grade A interventions with strong supporting evidence(1)1 –glycemic control –blood pressure control –pan-retinal laser photocoagulation –focal laser photocoagulation interventions with some supporting evidence(1)1 –lipid-lowering therapylipid-lowering therapy –surgical vitrectomy –intravitreal steroids

142 laser therapy laser beam photocoagulation for proliferative retinopathy (obliterates new vessels, reduces rate of vision loss by 50%) macular laser coagulation may improve visual acuity after intravitreal triamcinolone (level 2 [mid-level] evidence)level 2 [mid-level] evidence –86 eyes of 74 patients with diffuse diabetic macular edema were treated with intravitreal injection of triamcinolone acetonide 4 mg then randomized to macular grid laser photocoagulation 3 weeks later vs. no laser –visual acuity significantly better in laser group at 3 and 6 months –Reference - Arch Ophthalmol 2006 May;124(5):653Arch Ophthalmol 2006 May;124(5):653 panretinal photocoagulation in 1 sitting may be as effective as in 4 sittings for diabetic macular edema (level 2 [mid-level] evidence)level 2 [mid-level] evidence –based on nonrandomized trial –155 patients with diabetic macular edema had panretinal photocoagulation in either 1 vs. 4 sittings –no significant differences in visual acuity or central subfield thickness at 34 weeks –Reference - Arch Ophthalmol 2009 Feb;127(2):132Arch Ophthalmol 2009 Feb;127(2):132 vitrectomy may be necessary for complications rapid preoperative glycemic control may increase risk of postoperative progression of diabetic retinopathy and maculopathy (level 2 [mid- level] evidence), based on observational study of 87 patients with type 2 diabetes who had monocular phacoemulsification cataract surgery (Arch Ophthalmol 2006 Jan;124(1):38)level 2 [mid- level] evidenceArch Ophthalmol 2006 Jan;124(1):38

143 Prevention and Screening for Retinopathy control diabetes, hypertension no smoking vitamin B6 intensive management of multiple risk factors reduces microvascular complications in patients with microalbuminuria

144 Screening: American Diabetes Association (ADA) recommendations(2)2 –adults and children aged 10 years old with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist 5 years after onset of diabetes (ADA Grade B)ADA Grade B –patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist soon after the diagnosis of diabetes (ADA Grade B)ADA Grade B –once started, patients should have annual examinations by an ophthalmologist or optometrist (ADA Grade B)ADA Grade B less frequent exams (every 2-3 years) may be considered after one or more normal eye exams if retinopathy progressing, more frequent examinations needed –high-quality retinal fundus photography may serve as a screening tool for retinopathy (ADA Grade E)ADA Grade E interpretation of the images should be performed by a trained eye care provider not a substitute for a comprehensive eye exam –women with preexisting diabetes who are planning pregnancy or who have become pregnant should have (ADA Grade B)ADA Grade B comprehensive eye examination in the first trimester counselling on the risk of development and/or progression of diabetic retinopathy close follow-up throughout pregnancy and for 1 year postpartum –Reference - Diabetes Care 2010 Jan;33 Suppl 1:S62 PDFDiabetes Care 2010 Jan;33 Suppl 1:S62 PDF

145 family physician screening using PanOptic ophthalmoscope may be acceptable for patients who fail to obtain ophthalmologist screening based on case series 11 family physicians assessing 28 standardized patients with diabetes mellitus using PanOptic ophthalmoscope in nonmydriatic exam mean 87% sensitivity and 57% specificity and moderate overall agreement Reference - Ann Fam Med 2004 May-Jun;2(3):218Ann Fam Med 2004 May-Jun;2(3):218 use of mydriatic eye drops for pupil dilation for funduscopy associated with increased detection of diabetic retinopathy and extremely small risk of acute glaucoma (BMJ 2006 Jan 7;332(7532):3), commentary can be found in BMJ 2006 Jan 21;332(7534):179BMJ 2006 Jan 7;332(7532):3BMJ 2006 Jan 21;332(7534):179

146 Reviews: review of screening eye exams in type 2 diabetes can be found in J Fam Pract 2004 Sep;53(9):732J Fam Pract 2004 Sep;53(9):732 Clinical Evidence 2003 Jan review (search date 2002 Sep) can be found in BMJ 2003 May 10;326(7397):1023BMJ 2003 May 10;326(7397):1023 review can be found in N Engl J Med 2004 Jan 1;350(1):48, commentary can be found in N Engl J Med 2004 Jun 10;350(24):2525N Engl J Med 2004 Jan 1;350(1):48N Engl J Med 2004 Jun 10;350(24):2525 review can be found in BMJ 2003 Apr 26;326(7395):924BMJ 2003 Apr 26;326(7395):924 review can be found in Adv Stud Med 2003 Apr;3(4):214Adv Stud Med 2003 Apr;3(4):214 review can be found in Practitioner 2000 Aug;244(1613):696 (Am Fam Physician 2001 Feb 15;63(4):765)Practitioner 2000 Aug;244(1613):696Am Fam Physician 2001 Feb 15;63(4):765 review can be found in N Engl J Med 1999 Aug 26;341(9):667 (author may have conflict of interest [N Engl J Med 2000 Feb 24;342(8):586])N Engl J Med 1999 Aug 26;341(9):667N Engl J Med 2000 Feb 24;342(8):586 discussion can be found in Australian Fam Physician 1997 Apr;26(4):373 in Am Fam Physician 1997 Sep 15;56(4):1208)Australian Fam Physician 1997 Apr;26(4):373 review of systemic management of diabetic retinopathy can be found in BMJ 2009 Feb 12;338:b441BMJ 2009 Feb 12;338:b441 review of ocular emergencies can be found in Am Fam Physician 2007 Sep 15;76(6):829 full-textAm Fam Physician 2007 Sep 15;76(6):829full-text review of management of the visually impaired patient can be found in Am Fam Physician 2008 May 15;77(10):1431, commentary can be found in Am Fam Physician 2009 Oct 1;80(7):668Am Fam Physician 2008 May 15;77(10):1431Am Fam Physician 2009 Oct 1;80(7):668 review of vision loss in older persons can be found in Am Fam Physician 2009 Jun 1;79(11):963Am Fam Physician 2009 Jun 1;79(11):963 review of age-related eye disease and medication safety in elderly can be found in Annals of Long-Term Care 2009 Jun;17(6):17Annals of Long-Term Care 2009 Jun;17(6):17 review of common visual problems in elderly can be found in Annals of Long-Term Care 2005 Sep;13(9):41Annals of Long-Term Care 2005 Sep;13(9):41 review of common causes of vision loss in the elderly can be found in Am Fam Physician 1999 Jul;60(1):99Am Fam Physician 1999 Jul;60(1):99 review of preventing visual loss from chronic eye disease in primary care can be found in JAMA 2004 Mar 24-31;291(12):1487, clinical commentary can be found in JAMA 2004 Mar ;291(12):1497JAMA 2004 Mar 24-31;291(12):1487JAMA 2004 Mar ;291(12):1497 American Diabetes Association (ADA) literature review on diabetic retinopathy can be found in Diabetes Care 1998 Jan;21(1):143 and Diabetic Care 2004 Oct;27(10):2540 Diabetes Care 1998 Jan;21(1):143Diabetic Care 2004 Oct;27(10):2540

147 Guidelines: American Academy of Ophthalmology (AAO) guideline can be found at National Guideline Clearinghouse 2009 Jun 8:13502 National Guideline Clearinghouse 2009 Jun 8:13502 American Diabetes Association (ADA) recommendations for screening and treatment of diabetic retinopathy can be found in Diabetes Care 2010 Jan;33 Suppl 1:S62 full-textDiabetes Care 2010 Jan;33 Suppl 1:S62 full-text guideline for screening for retinopathy in pediatric patient with type 1 diabetes mellitus can be found in Pediatrics 2005 Jul;116(1):270 or at National Guideline Clearinghouse 2005 Sep 12:7427, summary can be found in Am Fam Physician 2005 Oct 1;72(7):1403, commentary can be found in Pediatrics 2006 Feb;117(2):586Pediatrics 2005 Jul;116(1):270 National Guideline Clearinghouse 2005 Sep 12:7427Am Fam Physician 2005 Oct 1;72(7):1403Pediatrics 2006 Feb;117(2):586

148 Hypertension treatment in patients with diabetes Antihypertensive medications overview –Thiazide-type diuretics –Beta blockers –Angiotensin-Converting Enzyme (ACE) inhibitors –Angiotensin II Receptor Blockers –Calcium Channel Blockers –Combination antihypertensives First-line therapy for hypertension Cardiovascular risk prediction DASH diet

149 lifestyle modifications which may lower blood pressure includelifestyle modifications weight reduction Dietary Approaches to Stop Hypertension (DASH) diet (fruits, vegetables, low-fat dairy, reduced fat) dietary sodium restriction aerobic physical activity moderate alcohol consumption most current guidelines recommend target blood pressure < 130/80 mm Hg in patients with diabetesguidelines diastolic blood pressure target < mm Hg in patients with diabetes associated with lower rates of mortality and cardiovascular events (level 2 [mid-level] evidence)diastolic blood pressure target < mm Hglevel 2 [mid-level] evidence systolic blood pressure target < 120 mm Hg does not reduce mortality or myocardial infarction but does reduce nonfatal stroke compared to target < 140 mm Hg (level 1 [likely reliable] evidence)systolic blood pressure target < 120 mm Hglevel 1 [likely reliable] evidence

150 selection of antihypertensive agents guidelines vary but generally recommend angiotensin-converting enzyme (ACE) inhibitor plus thiazide-type diuretic as initial combination therapy or conclude insufficient evidence to recommended specific regimenguidelines vary most patients will require 2 or more drugs to achieve target blood pressure four major antihypertensive classes (diuretics, beta blockers, ACE inhibitors, calcium channel blockers) appear to reduce cardiovascular mortality and morbidity in hypertensive patients with diabetes (level 2 [mid-level] evidence)four major antihypertensive classeslevel 2 [mid-level] evidence angiotensin receptor blockers (ARBs) may not reduce cardiovascular morbidity and mortality (level 2 [mid-level] evidence) but reduce risk for end-stage renal disease (level 1 [likely reliable] evidence)angiotensin receptor blockerslevel 2 [mid-level] evidencelevel 1 [likely reliable] evidence all major antihypertensive regimens (ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, diuretics, beta blockers) appear to have similar short-term and medium-term effects on major cardiovascular events (level 2 [mid-level] evidence)all major antihypertensive regimenslevel 2 [mid-level] evidence insufficient evidence to establish role for beta blockers as first-line therapy for hypertension in patients with diabetesbeta blockers

151 regimens with efficacy for renal outcomes ACE inhibitors appear to reduce all-cause mortality in diabetic nephropathy (level 2 [mid-level] evidence) while angiotensin receptor blockers (ARBs) have limited evidence for mortality outcome – see Diabetic nephropathylevel 2 [mid-level] evidence angiotensin receptor blockers (ARBs) slow progression of diabetic nephropathy and reduce risk for end-stage renal disease (level 1 [likely reliable] evidence)angiotensin receptor blockers (ARBs)level 1 [likely reliable] evidence ACE inhibitors and calcium channel blockers each reported to be effective in reducing progression of type 2 diabetes-associated nephropathy (level 3 [lacking direct] evidence)ACE inhibitors and calcium channel blockerslevel 3 [lacking direct] evidence effect of ACE inhibitors or ARBs on renal outcomes (doubling of creatinine, end-stage renal disease) appears to result from blood pressure lowering and does not clearly differ from other antihypertensives (level 2 [mid-level] evidence)blood pressure loweringlevel 2 [mid-level] evidence combination ACE inhibitor and ARB reported to be more effective than monotherapy for reducing blood pressure and markers of urinary albumin excretion in hypertensive patients with diabetes (level 3 [lacking direct] evidence)combination ACE inhibitor and ARBlevel 3 [lacking direct] evidence

152 Lifestyle Modifications weight reduction can reduce blood pressure by 5-20 mm Hg per 10 kg lost Dietary Approaches to Stop Hypertension (DASH) diet (fruits, vegetables, low-fat dairy, reduced fat) can reduce blood pressure by 8-14 mm Hg dietary sodium restriction can reduce blood pressure by 2-8 mm Hg aerobic physical activity 30 minutes/day can reduce blood pressure by 4-9 mm Hg moderate alcohol consumption (1-2 drinks/day) can reduce blood pressure by 2-4 mm Hg Reference - Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) Reference Card, Express ReportSeventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood PressureReference CardExpress Report summary can be found in JAMA 2003 May 21;289(19):2560, correction can be found in JAMA 2003 Jul 9;290(2):197, considerable commentary can be found in JAMA 2003 Sep 10;290(10):1312JAMA 2003 May 21;289(19):2560JAMA 2003 Sep 10;290(10):1312 summary can be found in Am Fam Physician 2003 Jul 15;68(2):376, editorial can be found in Am Fam Physician 2003 Jul 15;68(2):228Am Fam Physician 2003 Jul 15;68(2):376Am Fam Physician 2003 Jul 15;68(2):228

153 Target Blood pressures American Diabetes Association (ADA) recommended target levels for nonpregnant adults with diabetes mellitus blood pressure < 130/80 mm Hg Reference - American Diabetes Association (ADA) 2010 position statement on standards of medical care in diabetes (Diabetes Care 2010 Jan;33 Suppl 1:S11 full- text)Diabetes Care 2010 Jan;33 Suppl 1:S11full- text most current guidelines recommend target blood pressure < 130/80 mm Hg in patients with diabetes Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) Reference Card, Express ReportSeventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood PressureReference CardExpress Report

154 Evidence: diastolic blood pressure target < mm Hg in patients with diabetes associated with lower rates of mortality and cardiovascular events (level 2 [mid-level] evidence)level 2 [mid-level] evidence

155 3 trials compared target blood pressure levels Hypertension Optimal Treatment (HOT) compared target diastolic blood pressure < 80 mm Hg vs. < 90 mm Hg –subgroup analysis included patients with diabetes –drugs used were felodipine (Plendil), then angiotensin-converting enzyme (ACE) inhibitor or beta blocker –5% absolute risk reduction in total cardiovascular events (NNT 20, 95% CI ) –3% absolute risk reduction in total mortality (NNT 34, borderline statistical significance) –microvascular end points not reported United Kingdom Prospective Diabetes Study (UKPDS) compared target blood pressure < 150/85 mm Hg vs. < 180/105 mm Hg in patients with diabetes –drugs used were captopril (Capoten) or atenolol (Tenormin) –statistically significant reduction in total cardiovascular events but absolute risk reduction not reported –nonsignificant 4% absolute risk reduction in total mortality –5% absolute risk reduction in microvascular end points (NNT 20, 95% CI ) Appropriate Blood Pressure Control in Diabetes (ABCD) compared target diastolic blood pressure 75 mm Hg vs mm Hg in patients with diabetes –drugs used were nisoldipine (Sular) or enalapril (Vasotec) –no significant difference in total cardiovascular events but absolute risk reduction not reported –5% absolute risk reduction in total mortality (NNT 20, borderline statistical significance) –no significant difference in microvascular end points

156 3 trials compared drug vs. no drug and had subgroup analyses for patients with diabetes Systolic Hypertension in the Elderly Program (SHEP) compared thiazide diuretic vs. usual care –8% absolute risk reduction in total cardiovascular events (NNT 13, 95% CI 7-100) –nonsignificant 2% absolute risk reduction in total mortality –microvascular end points not reported Systolic Hypertension in Europe (Syst-Eur) compared calcium channel blocker vs. placebo –8% absolute risk reduction in total cardiovascular events (NNT 13, 95% CI 8-34) –nonsignificant 5% absolute risk reduction in total mortality –microvascular end points not reported Heart Outcomes and Prevention Evaluation (HOPE) compared ACE inhibitor vs. placebo –5% absolute risk reduction in total cardiovascular events (NNT 20, 95% CI 14-50) –3% absolute risk reduction in total mortality (NNT 34, 95% CI ) –3% absolute risk reduction in microvascular end points (NNT 34, borderline statistical significance)

157 2 trials compared angiotensin II receptor blocker vs. placebo in patients with diabetes (primary analysis) Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial found nonsignificant 2% absolute risk reduction in total cardiovascular events, no significant difference in total mortality, and 4% absolute risk reduction in microvascular end points (NNT 25, borderline statistical significance) individualized predictive disease modeling (IPDM) trial did not report total cardiovascular events or total mortality, 10% absolute risk reduction in microvascular end points (NNT 10, 95% CI 6-25) Reference - Ann Intern Med 2003 Apr 1;138(7):593 PDFAnn Intern Med 2003 Apr 1;138(7):593PDF

158 National Kidney Foundation recommends lowering blood pressure goal to < 130/80 mm Hg in patients with diabetes based on consensus statement after review of 12 randomized trials lasting at least 2 years Reference - Am J Kidney Dis 2000 Sep;36(3):646 in Prescriber's Letter 2000 Jul;7(7):37 and in QuickScan Reviews in Fam Pract 2001 Feb;25(12):6Am J Kidney Dis 2000 Sep;36(3):646 systolic blood pressure target < 120 mm Hg does not reduce mortality or myocardial infarction but does reduce nonfatal stroke compared to target < 140 mm Hg (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence

159 Choice of Antihypertensive guidelines vary but generally recommend angiotensin-converting enzyme (ACE) inhibitor plus thiazide-type diuretic as initial combination therapy or conclude insufficient evidence to recommended specific regimenguidelines vary most patients will require 2 or more drugs to achieve target blood pressure four major antihypertensive classes (diuretics, beta blockers, ACE inhibitors, calcium channel blockers) appear to reduce cardiovascular mortality and morbidity in hypertensive patients with diabetes (level 2 [mid-level] evidence)four major antihypertensive classeslevel 2 [mid-level] evidence angiotensin receptor blockers (ARBs) may not reduce cardiovascular morbidity and mortality (level 2 [mid-level] evidence) but reduce risk for end-stage renal disease (level 1 [likely reliable] evidence)angiotensin receptor blockerslevel 2 [mid-level] evidencelevel 1 [likely reliable] evidence all major antihypertensive regimens (ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, diuretics, beta blockers) appear to have similar short-term and medium-term effects on major cardiovascular events (level 2 [mid-level] evidence)all major antihypertensive regimenslevel 2 [mid-level] evidence

160 Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) most patients will require 2 medications to reach goal (< 130/80 mm Hg) initial drug choices –stage 1 hypertension ( /90-99 mm Hg) - thiazide-type diuretics and/or angiotensin-converting enzyme (ACE) inhibitor; may consider angiotensin receptor blocker (ARB), beta blocker, calcium channel blocker –stage 2 hypertension (160/100 mm Hg or higher) - 2-drug combination using thiazide-type diuretic plus ACE inhibitor, ARB, beta blocker or calcium channel blocker Reference - Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) Reference Card, Express ReportSeventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood PressureReference CardExpress Report –summary can be found in JAMA 2003 May 21;289(19):2560, correction can be found in JAMA 2003 Jul 9;290(2):197, considerable commentary can be found in JAMA 2003 Sep 10;290(10):1312JAMA 2003 May 21;289(19):2560JAMA 2003 Sep 10;290(10):1312 –summary can be found in Am Fam Physician 2003 Jul 15;68(2):376, editorial can be found in Am Fam Physician 2003 Jul 15;68(2):228Am Fam Physician 2003 Jul 15;68(2):376Am Fam Physician 2003 Jul 15;68(2):228

161 National Kidney Foundation recommends ACE inhibitor plus thiazide diuretic based on consensus statement after review of 12 randomized trials lasting at least 2 years recommended first-line therapy is combination of ACE inhibitor and thiazide diuretic recommended additional therapies if blood pressure > 145/90 mm Hg include calcium channel blocker (verapamil [Calan] or diltiazem [Cardizem] if proteinuria), beta blocker if heart rate > 84 beats/minute, alpha blockers angiotensin receptor blockers may be substituted for ACE inhibitors if adverse effects Reference - Am J Kidney Dis 2000 Sep;36(3):646 in Prescriber's Letter 2000 Jul;7(7):37 and in QuickScan Reviews in Fam Pract 2001 Feb;25(12):6Am J Kidney Dis 2000 Sep;36(3):646

162 Reviews: review can be found in N Engl J Med 2006 Jul 27;355(4):385, commentary can be found in N Engl J Med 2006 Nov 2;355(18):1934N Engl J Med 2006 Jul 27;355(4):385N Engl J Med 2006 Nov 2;355(18):1934 review can be found in Arch Intern Med 2004 Sep 27;164(17):1850Arch Intern Med 2004 Sep 27;164(17):1850 review can be found in Adv Stud Med 2003 Jun;3(6):326Adv Stud Med 2003 Jun;3(6):326 review can be found in Am Fam Physician 2002 Oct 1;66(7):1209, editorial can be found in Am Fam Physician 2002 Oct 1;66(7):1151, correction can be found in Am Fam Physician 2003 Mar 15;67(6):1195, commentary can be found in Am Fam Physician 2003 Jul 1;68(1):41Am Fam Physician 2002 Oct 1;66(7):1209Am Fam Physician 2002 Oct 1;66(7):1151Am Fam Physician 2003 Jul 1;68(1):41 review of pharmacologic management of hypertension in patients with diabetes can be found in Am Fam Physician 2008 Dec 1;78(11):1277Am Fam Physician 2008 Dec 1;78(11):1277 review of treatment of hypertension in patients with diabetes can be found in Mayo Clin Proc 1996 Jan;71(1):53 Mayo Clin Proc 1996 Jan;71(1):53 evidence-based discussion of treatment of hypertension in patients with diabetes can be found in JAMA 2000 Jun 28;283(24):3177JAMA 2000 Jun 28;283(24):3177 review of calcium channel blockers and evidence for benefit and harm can be found in Arch Intern Med 2001 May 13;161(9):1145Arch Intern Med 2001 May 13;161(9):1145 American Diabetes Association (ADA) literature review on hypertension in adults with diabetes can be found in Diabetes Care 2002 Jan;25(1):134Diabetes Care 2002 Jan;25(1):134

163 Guidelines: American Diabetes Association (ADA) –2010 position statement on standards of medical care in diabetes can be found in Diabetes Care 2010 Jan;33 Suppl 1:S11 full-textDiabetes Care 2010 Jan;33 Suppl 1:S11full-text –policy statement on management of hypertension in adults with diabetes can be found in Diabetes Care 2004 Jan;27 Suppl 1:S65 full-text Diabetes Care 2004 Jan;27 Suppl 1:S65full-text –guidelines on prevention and management of diabetes complications in Diabetes Care 2007 Jan;30 Suppl 1:S4full-text or at National Guideline Clearinghouse 2008 Jun 2:12185Diabetes Care 2007 Jan;30 Suppl 1:S4full-textNational Guideline Clearinghouse 2008 Jun 2:12185 American Society of Hypertension position paper on treatment of hypertension in patients with diabetes can be found in J Clin Hypertens (Greenwich) 2008 Sep;10(9):707J Clin Hypertens (Greenwich) 2008 Sep;10(9):707 American Association of Clinical Endocrinologists (AACE) guidelines on management of diabetes mellitus: hypertension management can be found in Endocr Pract 2007 May-Jun;13(Suppl 1):35 or at National Guideline Clearinghouse 2007 Nov 26:11095National Guideline Clearinghouse 2007 Nov 26:11095 American Heart Association/American College of Cardiology –2007 scientific statement for primary prevention of cardiovascular diseases in people with diabetes can be found in Circulation 2007 Jan 2;115(1):114 full-textCirculation 2007 Jan 2;115(1):114full-text –2006 guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease (endorsed by National Heart, Lung, and Blood Institute [NHLBI]) can be found in Circulation 2006 May 16;113(19):2363 full-text or at National Guideline Clearinghouse 2006 Oct 9:9373Circulation 2006 May 16;113(19):2363full-textNational Guideline Clearinghouse 2006 Oct 9:9373 American College of Physicians guidelines for treatment of hypertension in patients with type 2 diabetes can be found in Ann Intern Med 2003 Apr 1;138(7):587, supporting evidence-based review in Ann Intern Med 2003 Apr 1;138(7):593, commentary can be found in Ann Intern Med 2004 Mar 16;140(6):487Ann Intern Med 2003 Apr 1;138(7):587Ann Intern Med 2003 Apr 1;138(7):593Ann Intern Med 2004 Mar 16;140(6):487 Canadian Diabetes Association 2008 guideline on diabetes mellitus can be found at CDA PDF CDAPDF Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure can be found at JNC 7 Reference Card, Express Report, summary can be found in JAMA 2003 May 21;289(19):2560 and Am Fam Physician 2003 Jul 15;68(2):376JNC 7Reference CardExpress ReportJAMA 2003 May 21;289(19):2560Am Fam Physician 2003 Jul 15;68(2):376

164 Lipid Management in Diabetes Overview: American Diabetes Association (ADA) guidelines and American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend LDL cholesterol target < 100 mg/dL (< 2.6 mmol/L)LDL cholesterol target < 100 mg/dL (< 2.6 mmol/L) –AHA/ACC also suggests optional target < 70 mg/dL (< 1.8 mmol/L) –additional lipid targets recommended by ADA for non-pregnant adults triglycerides < 150 mg/dL (< 1.7 mmol/L) HDL cholesterol > 40 mg/dL (> 1.0 mmol/L) in men, or > 50 mg/dL (1.3 mmol/L) in women lipid-lowering therapy (primarily with statins) recommended for most patients with diabetes (grade A recommendation [consistent high- quality evidence])grade A recommendation [consistent high- quality evidence] –lipid-lowering drug therapy effective for primary and secondary prevention of major coronary events in patients with and without diabetes (level 1 [likely reliable] evidence)lipid-lowering drug therapy effectivelevel 1 [likely reliable] evidence –cholesterol and blood pressure lowering appear more effective than glucose lowering for preventing cardiovascular events (level 2 [mid- level] evidence)cholesterol and blood pressure lowering appear more effective than glucoselevel 2 [mid- level] evidence –lipid-lowering therapy in patients with diabetes with other cardiac risk factors reduces risk of major cardiovascular events at ANY initial LDL cholesterol level (level 1 [likely reliable] evidence)lipid-lowering therapy in patients with diabetes with other cardiac risk factors reduces risklevel 1 [likely reliable] evidence

165 Target lipid levels: American Diabetes Association (ADA) recommended target levels for non-pregnant adults with diabetes mellitus –LDL cholesterol < 100 mg/dL (< 2.6 mmol/L) –triglycerides < 150 mg/dL (< 1.7 mmol/L) –HDL cholesterol > 40 mg/dL (> 1.0 mmol/L), or > 50 mg/dL (1.3 mmol/L) in women –Reference - American Diabetes Association (ADA) 2010 position statement on standards of medical care in diabetes (Diabetes Care 2010 Jan;33 Suppl 1:S11 full-text)Diabetes Care 2010 Jan;33 Suppl 1:S11 full-text 2006 American Heart Association/American College of Cardiology (AHA/ACC) secondary prevention guidelines recommend –LDL cholesterol 20% –LDL cholesterol < 70 mg/dL (< 1.8 mmol/L) as an alternative goal –Reference - Circulation 2006 May 16;113(19):2363Circulation 2006 May 16;113(19):2363 NO valid evidence found to support assumption that degree of LDL cholesterol lowering with statins independently predicts cardiovascular risk reduction in patients with LDL cholesterol levels < 130 mg/dL (3.36 mmol/L) (Ann Intern Med 2006 Oct 3;145(7):520, full-text)Ann Intern Med 2006 Oct 3;145(7):520,full-text

166 cholesterol lowering could save years of life in men and years of life in women with type 2 diabetes, based on decision analysis (Am J Med 2003 Aug 1;115(2):122), commentary can be found in Am Fam Physician 2004 Jan 15;69(2):395, J Fam Pract 2004 Feb;53(2):102Am J Med 2003 Aug 1;115(2):122Am Fam Physician 2004 Jan 15;69(2):395J Fam Pract 2004 Feb;53(2):102 glycemic optimization reduced incidence of LDL cholesterol > 100 mg/dL (2.6 mmol/L) from 78% to 66% (NNT 9) in uncontrolled study (Arch Intern Med 2000 Oct 9;160(18):2756), commentary can be found in Arch Intern Med 2001 Jun 11;161(11):1461Arch Intern Med 2000 Oct 9;160(18):2756Arch Intern Med 2001 Jun 11;161(11):1461 statin therapy recommended for all patients with type 2 diabetes who have coronary artery disease (grade A recommendation [consistent high-quality evidence])grade A recommendation [consistent high-quality evidence] age > 40 years plus other cardiovascular risk factors and unable to achieve LDL < 100 mg/dL (2.6 mmol/L) by lifestyle modification (grade A recommendation [consistent high-quality evidence])grade A recommendation [consistent high-quality evidence] no clear evidence to support routine use of statins in other patients with type 2 diabetes (grade C recommendation [lacking direct evidence])grade C recommendation [lacking direct evidence] Reference - Am Fam Physician 2005 Sep 1;72(5):866Am Fam Physician 2005 Sep 1;72(5):866

167 Reviews: review can be found in J Fam Pract 2007 Aug;56(8):634, commentary can be found in J Fam Pract 2007 Nov;56(11):886J Fam Pract 2007 Aug;56(8):634 review can be found in J Fam Pract 2007 Apr;56(4):294J Fam Pract 2007 Apr;56(4):294 review of cholesterol lowering in diabetes can be found in Postgrad Med 2005 Apr;117(4):17Postgrad Med 2005 Apr;117(4):17 review of management of dyslipidemia in patients with type 2 diabetes mellitus can be found in Adv Stud Med 2005 Jan;5(1):28 PDF, commentary can be found in Adv Stud Med 2005 Nov-Dec;5(10):546 PDFAdv Stud Med 2005 Jan;5(1):28 PDFAdv Stud Med 2005 Nov-Dec;5(10):546 PDF review of use of statins for prevention of coronary heart disease can be found in Am Fam Physician 2001 Jan 15;63(2):309Am Fam Physician 2001 Jan 15;63(2):309

168 Guidelines: synthesis of 3 guidelines (UMHS 2009, USPSTF 2008, VA/DoD 2006) on screening for lipid disorders in adults can be found at National Guideline Clearinghouse 2010 Mar 8:LIPSCREEN7National Guideline Clearinghouse 2010 Mar 8:LIPSCREEN7 American Diabetes Association (ADA) 2010 position statement on standards of medical care in diabetes can be found in Diabetes Care 2010 Jan;33 Suppl 1:S11 full-textDiabetes Care 2010 Jan;33 Suppl 1:S11full-text Canadian Diabetes Association 2008 guideline on diabetes mellitus can be found at CDA PDFCDAPDF American Diabetes Association (ADA) guidelines on prevention and management of diabetes complications in Diabetes Care 2007 Jan;30 Suppl 1:S4full-text or at National Guideline Clearinghouse 2008 Jun 2:12185Diabetes Care 2007 Jan;30 Suppl 1:S4full-textNational Guideline Clearinghouse 2008 Jun 2:12185 American College of Physicians evidence-based guideline on lipid control in management of type 2 diabetes mellitus –lipid-lowering therapy recommended for all patients with type 2 diabetes with known coronary artery disease or other cardiovascular risk factors –once lipid-lowering therapy started, patients with type 2 diabetes should be taking at least moderate doses of a statin –for patients with type 2 diabetes taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances –Reference - Ann Intern Med 2004 Apr 20;140(8):644 full-text, supporting systematic review can be found in Ann Intern Med 2004 Apr 20;140(8):650 full- text, summary can be found in Am Fam Physician 2004 Aug 15;70(4):775, commentary can be found in ACP J Club 2004 Nov-Dec;141(3):65, Am Fam Physician 2005 Feb 1;71(3):588, Ann Intern Med 2005 Nov 1;143(9):673 PDFAnn Intern Med 2004 Apr 20;140(8):644full-textAnn Intern Med 2004 Apr 20;140(8):650full- textAm Fam Physician 2004 Aug 15;70(4):775ACP J Club 2004 Nov-Dec;141(3):65Am Fam Physician 2005 Feb 1;71(3):588Ann Intern Med 2005 Nov 1;143(9):673PDF

169 Congestive Heart Failure

170 Types: American College of Cardiology/American Heart Association (ACC/AHA) staging of development of heart failure(1,2)1,2 –stage A - persons with risk factors that predispose toward development of heart failure (coronary artery disease, hypertension, diabetes mellitus, prior treatment with cardiotoxic drugs, rheumatic fever, or family history of cardiomyopathy) but who do not yet have impaired left ventricular function, hypertrophy or geometric chamber disorientation –stage B - asymptomatic patients with left ventricular hypertrophy and/or impaired left ventricular function –stage C - patients with current or past symptoms of heart failure associated with underlying structural heart disease –stage D - patients with refractory heart failure New York Heart Association (NYHA) functional classification(2)2 –class I - symptoms of heart failure only at levels of exertion that would limit normal individuals –class II - symptoms of heart failure on ordinary exertion –class III - symptoms of heart failure on less-than-ordinary exertion –class IV - symptoms of heart failure at rest Killip Classification of Heart Failure –Class I - no clinical heart failure –Class II - rales bilaterally up to 50% lung fields –Class III - pulmonary edema with rales in all lung fields –Class IV - pulmonary edema, cardiogenic shock, stuporous, SBP < 90 mm Hg, cold clammy skin, decreased urine

171 types of left ventricular dysfunction systolic dysfunction - primary impairment of pumping of left ventricle, decrease in systolic wall motion, described in this topic diastolic dysfunction - primary impairment of filling of left ventricle, elevated end-diastolic pressure in chamber of normal size, not well understood, see Diastolic heart failure types of heart failure among 844 patients with initial diagnosis of heart failure in Soweto, South Africa in 2006 dilated cardiomyopathy in 35% hypertensive heart failure in 33% right heart failure in 27% ischemic cardiomyopathy in 9% valvular heart failure in 8% Reference - Lancet 2008 Mar 15;371(9616):915, editorial can be found in Lancet 2008 Mar 15;371(9616):876Lancet 2008 Mar 15;371(9616):915 Lancet 2008 Mar 15;371(9616):876

172 Incidence/Prevalence: 400,000 new cases/year, affecting estimated 3 million Americans 200,000 deaths, nearly 1 million hospitalizations and costs > $7 billion/year incidence in US 3 per 1,000 person-years (Arch Intern Med 1999 Jan 11;159(1):29)Arch Intern Med 1999 Jan 11;159(1):29 CHF affects at least 4.8 million people in US, leading cause of hospital admissions for patients > 65 years, annual mortality 5-30% (Am J Cardiol 1999;83:2A in J Fam Pract 1999 Apr;48(4):247)J Fam Pract 1999 Apr;48(4):247 incidence of heart failure in United States stable from –10,311 persons years old without heart failure at baseline (1948) were followed up to 50 years in Framingham cohort, 1,075 developed heart failure –age-adjusted incidence of heart failure for each decade higher in men than women, and higher in than (statistically significant only in women) –age-adjusted incidence of heart failure in was 564 per 100,000 person-years in men and 327 per 100,000 person-years in women –Reference - N Engl J Med 2002 Oct 31;347(18):1397, editorial can be found in N Engl J Med 2002 Oct 31;347(18):1442, commentary can be found in N Engl J Med 2003 Feb 13;348(7):660N Engl J Med 2002 Oct 31;347(18):1397N Engl J Med 2002 Oct 31;347(18):1442N Engl J Med 2003 Feb 13;348(7):660

173 20% lifetime risk for CHF 3,757 men and 4,472 women were followed over 25 years (124,262 person- years), 583 developed CHF at age 40 years, lifetime risk for CHF was 21% for men and 20.3% for women at age 80 years, lifetime risk was 20.2% for men and 19.3% for women lifetime risk for CHF increased with blood pressure > 160/100 mm Hg and with myocardial infarction Reference - Circulation 2002 Dec 10;106(24):3068, commentary can be found in Am Fam Physician 2003 Mar 15;67(6):1339Circulation 2002 Dec 10;106(24):3068Am Fam Physician 2003 Mar 15;67(6):1339 about 3% of adults > 45 years old have heart failure based on large representative sample of adults in England, 6,286 randomly selected patients > 45 years from 16 randomly selected general practices, 3,960 (63%) participated 72 (1.8%) had left ventricular systolic dysfunction defined as ejection fraction < 40% (95% CI %), 139 (3.5%) had borderline left ventricular function defined as ejection fraction 40-50% (95% CI 3-4.1%) 124 (3.1%) had definite or probable heart failure (95% CI %) definite heart failure in 92 patients associated with ejection fraction < 40%, atrial fibrillation and valve disease Reference - Lancet 2001 Aug 11;358(9280):439, editorial can be found in Lancet 2001 Aug 11;358(9280):432Lancet 2001 Aug 11;358(9280):439 Lancet 2001 Aug 11;358(9280):432

174 2.2% prevalence of congestive heart failure (CHF) based on clinical criteria in study of 2,042 persons > 45 years old, 44% of whom had ejection fraction (EF) > 50% among this population, 6% had systolic dysfunction (EF < 50%), 2% had moderate or severe systolic dysfunction (EF < 40%), 20.8% had mild diastolic dysfunction (impaired relaxation without increased filling pressures), 6.6% had moderate diastolic dysfunction (impaired relaxation with moderately elevated filling pressures or pseudonormal filling), and 0.7% had severe diastolic dysfunction (advanced reduction in compliance or restrictive filling) systolic dysfunction and diastolic dysfunction each increased risk of CHF but most patients with moderate or severe systolic or diastolic dysfunction did not have CHF Reference - JAMA 2003 Jan 8;289(2):194, commentary can be found in ACP J Club 2003 Sep-Oct;139(2):51JAMA 2003 Jan 8;289(2):194 ACP J Club 2003 Sep-Oct;139(2):51 higher prevalence with increasing age study of 1,275 persons aged years in Canberra, Australia who had history and exam by cardiologist and echocardiography 6.3% had clinical heart failure (5.6% previously diagnosed, 0.6% previously undiagnosed), persons aged years had 4.4 times higher prevalence of clinical heart failure than persons aged years 75 persons (5.9%) had left ventricular systolic dysfunction, including 44 (3.5%) in preclinical stage of disease Reference - Med J Aust 2006 Feb 20;184(4):151 full-textMed J Aust 2006 Feb 20;184(4):151full-text

175 heart failure common among patients with coronary disease or diabetes study of 1,062 patients with previous myocardial infarction, angina, hypertension, or diabetes left ventricular systolic ejection fraction < 40% was found in 22.1% patients with previous myocardial infarction, 8.1% patients with angina, 1.8% patients with hypertension, and 5.8% patients with diabetes heart failure (defined as dyspnea plus either systolic dysfunction, atrial fibrillation or clinically significant valve disease) was found in 16% patients with previous myocardial infarction, 8.4% patients with angina, 2.8% patients with hypertension, and 7.7% patients with diabetes Reference - BMJ 2002 Nov 16;325(7373):1156BMJ 2002 Nov 16;325(7373):1156

176 Causes: coronary artery disease is most common cause - ischemic cardiomyopathy, myocardial infarction systemic hypertension valvular heart disease including aortic stenosis, aortic regurgitation, mitral regurgitation severe renal failure constrictive pericarditis other causes of heart failure include alcoholic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, infiltrative disorders (sarcoidosis, hemochromatosis, amyloidosis), peripartum cardiomyopathy myocarditis infectious endocarditis arrhythmia tachycardia-induced heart failure

177 beriberi chemotherapy AIDS muscular dystrophy causes of right ventricular failure #1 cause is left ventricular failure (right-sided failure usually late in course) mitral stenosis pulmonary hypertension (COPD, pulmonary embolism) right-sided infectious endocarditis right ventricular infarction high output cardiac failure - anemia, thyrotoxicosis, arteriovenous fistula, Paget's disease pheochromocytoma other precipitating factors noncompliance with medications - digitalis, diuretics, ACE inhibitor excess dietary sodium diastolic heart failure

178 drugs alcohol, propanolol and other beta blockers, cardiotoxic drugs (daunorubicin), NSAIDs, antiarrhythmics (disopyramide), corticosteroids, androgens, estrogens, tricyclic antidepressants (for example, nortriptyline), glitazones tumor necrosis factor antagonists (etanercept and infliximab) associated with new or worsening heart failure in 47 cases reported to US FDA Medwatch (Ann Intern Med 2003 May 20;138(10):807)Ann Intern Med 2003 May 20;138(10):807 imatinib (Gleevec) associated with occasional occurrence of severe congestive heart failure and left ventricular dysfunction, mostly in patients with history of cardiac disease (FDA MedWatch 2006 Oct 19); imatinib associated with severe congestive heart failure in 10 patients (Nat Med 2006 Aug;12(8):908)FDA MedWatch 2006 Oct 19Nat Med 2006 Aug;12(8):908 review of drug-induced heart failure can be found in J Am Coll Cardiol 1999 Apr;33(5):1141 (QuickScan Reviews in Fam Pract 1999 Nov;24(8):7)J Am Coll Cardiol 1999 Apr;33(5):1141 high output states with increased metabolic demands - fever, hypothyroidism, anemia, AV fistula, infections, pregnancy, cocaine bilateral renovascular disease may lead to fluid retention (BMJ 2003 Mar 1;326(7387):489 full-text)BMJ 2003 Mar 1;326(7387):489full-text renal AV malformation in case report (Lancet 2009 Dec 5;374(9705):1944)Lancet 2009 Dec 5;374(9705):1944

179 reversible causes of congestive heart failure - anemia, hyperthyroidism, atrial myxoma, arteriovenous fistula, surgically correctable valvular heart disease, surgically correctable congenital heart disease, cardiac arrhythmias in otherwise normal heart, thiamine deficiency, alcohol, cocaine, carnitine deficiency, hemochromatosis, hypocalcemia, hypophosphatemia, infectious disease, pheochromocytoma, sarcoidosis, uremia hypocalcemia reported as cause of reversible cardiomyopathy with ventricular tachycardia in case report (Ann Intern Med 2007 Apr 3;146(7):541)Ann Intern Med 2007 Apr 3;146(7):541 causes of HF in children without congenital heart disease in United Kingdom and Ireland dilated cardiomyopathy myocarditis occult arrhythmia anthracycline toxicity metabolic disease left ventricular noncompaction Reference - based on cohort of 104 children in United Kingdom and Ireland (Circulation 2008 Jan 1;117(1):79), editorial can be found in Circulation 2008 Jan 1;117(1):11, commentary can be found in Circulation 2008 Jun 10;117(23):e481Circulation 2008 Jan 1;117(1):79Circulation 2008 Jan 1;117(1):11Circulation 2008 Jun 10;117(23):e481

180 Pathogenesis of CHF impairment of ability to fill or empty left ventricle most cases are due to systolic dysfunction (low left ventricular ejection fraction [LVEF]), usually left ventricular dysfunction for example, post-MI, cardiomyopathy, myocarditis, valvular heart disease some cases are due to diastolic dysfunction (normal LVEF), for example, ischemic and infiltrative diseases, hypertensive cardiovascular disease, valvular heart disease, restrictive cardiomyopathy –patients with diastolic heart failure have abnormal active relaxation and high passive stiffness, based on prospective study comparing 47 such patients (heart failure signs and symptoms, normal ejection fraction, and increased left ventricular end-diastolic pressure) with 10 controls (N Engl J Med 2004 May 6;350(19):1953), commentary can be found in N Engl J Med 2004 Sep 9;351(11):1143, summary can be found in Am Fam Physician 2005 Jan 15;71(2):374N Engl J Med 2004 May 6;350(19):1953N Engl J Med 2004 Sep 9;351(11):1143Am Fam Physician 2005 Jan 15;71(2):374 high-output failure is seen in chronic severe anemia, Paget's disease, beriberi and arteriovenous fistulae

181 symptoms due to congestion due to elevated ventricular filling pressure fatigue and organ system dysfunction due to inadequate cardiac output ventricular remodeling change in chamber volume and shape not related to preload-mediated increase in sarcomere length myocardium dilates and lowers ejection fraction to avoid excess cardiac output does not cause symptoms directly, but data suggests adverse effect on prognosis in patients after myocardial infarction

182 risk factors include hypertension, left ventricular hypertrophy, smoking, hyperlipidemia, diabetes mellitus, microalbuminuria, decreased vital capacity, higher resting heart rate, obesity and asymptomatic left ventricular dysfunction (BMJ 1999 May 22;318(7195):1400 full-text)BMJ 1999 May 22;318(7195):1400full-text

183 hypertension - especially elevated systolic blood pressure and pulse pressure systolic blood pressure, pulse pressure, and body mass index each associated with risk for incident heart failure –based on cohort of 3,362 participants in Framingham Heart Study with 67,240 person-years of follow-up –518 developed heart failure –Reference - Hypertension 2007 Nov;50(5):869Hypertension 2007 Nov;50(5):869 systolic blood pressure and pulse pressure were each better risk predictors than diastolic blood pressure for congestive heart failure –2,040 persons in Framingham Heart Study followed for mean 17.4 years, 234 (11.8%) developed heart failure –increasing SBP, DBP and pulse pressure were each associated with increasing risk for heart failure after controlling for multiple variables

184 several ECG findings associated with increased risk of CHF left ventricular hypertrophy on ECG associated with higher risk of CHF in prospective study of 2,638 older persons (J Am Geriatr Soc 1998 Oct;46(10):1280)J Am Geriatr Soc 1998 Oct;46(10):1280 –ECG strain associated with further increased risk of CHF among patients with left ventricular hypertrophy 8,696 patients with hypertension and left ventricular hypertrophy on ECG but no CHF were randomized to atenolol-based vs. losartan-based antihypertensive regimen for mean 4.7 years 923 (10.6%) had ECG strain at baseline defined as downsloping convex ST segment with inverted asymmetrical T wave opposed QRS axis in lead V5 or V6 265 (3%) had new-onset CHF, 26 had CHF-related death ECG strain predicted new-onset heart failure with hazard ratio 3.27 (95% CI ) and adjusted hazard ratio 1.8 (95% CI ) ECG strain predicted heart failure mortality with hazard ratio 4.74 (95% CI ) and adjusted hazard ratio 2.78 (95% CI ) –Reference - Circulation 2006 Jan 3;113(1):67Circulation 2006 Jan 3;113(1):67 5 ECG findings associated with > 2 times risk of incident CHF in 9- year follow-up of 38,283 postmenopausal women in Women's Health Initiative –wide QRS/T angle –STV5 depression –high TV1 amplitude –QRS non-dipolar voltage –myocardial infarction on ECG –Reference - Circulation 2006 Jan 31;113(4):481Circulation 2006 Jan 31;113(4):481

185 increased left ventricular mass, especially eccentric left ventricular hypertrophy on echocardiography, associated with increased risk of new development of depressed left ventricular ejection fraction in prospective study of 3,042 persons > 65 years old followed mean 5 years (J Am Coll Cardiol 2004 Jun 16;43(12):2207 in J Watch Online 2004 Jul 30)J Am Coll Cardiol 2004 Jun 16;43(12):2207 wall-motion abnormalities on echocardiography associated with increased risk of cardiovascular events based on prospective cohort study 2,864 patients (mean age 60 years) without clinically evident cardiovascular disease at baseline followed for mean 8 years on baseline echocardiography, 5% had focal hypokinesia and 1.5% had wall-motion abnormalities comparing patients with vs. without segmental wall-motion abnormalities –42.1% vs. 18% had cardiovascular events –11.4% vs. 5.4% had myocardial infarction –4.3% vs. 2.4% had stroke –18.6% vs. 8.8% had coronary heart disease –11.4% vs. 4% had heart failure –18.6% vs. 5.6% had cardiovascular mortality Reference - Circulation 2007 Jul 10;116(2):143Circulation 2007 Jul 10;116(2):143

186 chronic anemia associated with increased risk of heart failure study of Medicare claims data for 1,179,700 persons > 65 years old in 1999 and 2000, 5% prevalence of chronic anemia in 1999 incidence of heart failure in 2000 (no heart failure in 1999) was 12.4% among patients with and 5.9% among patients without chronic anemia in 1999 Reference - AGS 2003 annual meeting in J Am Geriatr Soc 2003 Apr;51(4 Suppl):S131,P262 elevated atrial natriuretic peptide (ANP) level associated with increased risk of developing congestive heart failure in 7-month prospective study of 256 nursing home patients aged years without history of CHF (J Am Geriatr Soc 1999 Apr;47(4):407)J Am Geriatr Soc 1999 Apr;47(4):407

187 obesity associated with increased risk of heart failure 5,881 persons (mean age 55 years, 54% women) in Framingham Hearth Study followed for mean 14 years, 496 (8.4%) developed heart failure after adjustment for risk factors, risk of heart failure increased for each increment of 1 in body mass index obese subjects had 2 times greater risk for heart failure compared to subjects with normal body mass index Reference - N Engl J Med 2002 Aug 1;347(5):305, editorial can be found in N Engl J Med 2002 Aug 1;347(5):358, commentary can be found in N Engl J Med 2002 Dec 5;347(23):1887N Engl J Med 2002 Aug 1;347(5):305N Engl J Med 2002 Aug 1;347(5):358N Engl J Med 2002 Dec 5;347(23):1887 waist circumference stronger risk factor for congestive heart failure than body mass index in cohort of 2,435 persons aged years followed median 6.1 years (J Am Geriatr Soc 2006 Mar;54(3):413)J Am Geriatr Soc 2006 Mar;54(3):413 metabolic syndrome associated with increased risk for heart failure 2,314 men aged 50 years free from heart failure followed for 20 years metabolic syndrome associated with adjusted hazard ratio 1.66 for heart failure Reference - Heart 2006 Oct;92(10):1409Heart 2006 Oct;92(10):1409 retinopathy associated with 2 times adjusted relative risk of congestive heart failure (unadjusted rates 15.1% vs. 4.8%) in 7-year prospective follow-up of 11,612 US persons aged years (JAMA 2005 Jan 5;293(1):63)JAMA 2005 Jan 5;293(1):63 some medications may be associated with increased risk for CHF -- see History section, Meds subsection

188 Possible risk factors: higher dietary sodium intake may increase risk for CHF in overweight persons; 5,233 nonoverweight and 5,129 overweight persons followed mean 19 years, 413 nonoverweight and 679 overweight persons developed CHF based on medical records and death certificates (Arch Intern Med 2002 Jul 22;162(14):1619), commentary that underlying data is not valid can be found in Arch Intern Med 2003 Apr 14;163(7):851Arch Intern Med 2002 Jul 22;162(14):1619Arch Intern Med 2003 Apr 14;163(7):851 egg consumption 1 per day may be associated with increased risk of heart failure –based on a prospective cohort study of 21,275 US male physicians –Reference - Circulation 2008 Jan 29;117(4):494Circulation 2008 Jan 29;117(4):494 increased intake of eggs and high-fat dairy may be associated with increased risk for heart failure –based on prospective cohort study of 14,153 African-American and white adults in United States followed for mean 13 years –1,140 (8%) developed heart failure –incident heart failure associated with increased egg intake (adjusted hazard ratio [HR] 1.23, 95% CI ) increased high-fat dairy intake (HR 1.08, 95% CI ) –Reference - J Am Diet Assoc 2008 Nov;108(11):1881J Am Diet Assoc 2008 Nov;108(11):1881

189 Complications: weak skeletal and respiratory muscles from heart failure related myopathy (Eur Heart J 1999;20:1191 PDF in BMJ 1999 Aug 28;319(7209):586)Eur Heart J 1999;20:1191PDF BMJ 1999 Aug 28;319(7209):586 left ventricular failure associated with 2.1 times increased risk for stroke in case-control study (J Epidemiol Community Health 2002;56(suppl 1):i8 in BMJ 2002 Feb 9;324(7333):374)J Epidemiol Community Health 2002;56(suppl 1):i8BMJ 2002 Feb 9;324(7333):374 heart failure associated with increased risk of dementia and Alzheimer disease in community-based cohort of 1,301 persons > 75 years old in Sweden followed for up to 9 years (mean 5 years) (Arch Intern Med 2006 May 8;166(9):1003), commentary can be found in Arch Intern Med 2006 Nov 13;166(20):2286Arch Intern Med 2006 May 8;166(9):1003Arch Intern Med 2006 Nov 13;166(20):2286 hypoxic liver injury (Mayo Clin Proc 2006 Sep;81(9):1232)Mayo Clin Proc 2006 Sep;81(9):1232

190 Associated conditions: depression –clinically significant depression reported in 21.5% of heart failure patients based on systematic review of 36 studies prevalence was 19.3% in studies using diagnostic interview and 33.6% in studies using questionnaires prevalence ranged from 11% in NYHA class I to 42% in NYHA class IV heart failure Reference - J Am Coll Cardiol 2006 Oct 17;48(8):1527, commentary can be found in Am Fam Physician 2007 Jun 1;75(11):1711J Am Coll Cardiol 2006 Oct 17;48(8):1527Am Fam Physician 2007 Jun 1;75(11):1711 –heart failure associated with depression cross-sectional study of 6,125 persons > 70 years old criteria for syndromic depression were met by 11% of 199 persons with self-reported heart failure, 4.8% of 1,856 persons with other heart conditions, and 3.2% of 4,070 persons with no heart conditions Reference - J Am Geriatr Soc 2002 Dec;50(12):2003J Am Geriatr Soc 2002 Dec;50(12):2003 –depression but not antidepressant use associated with increased mortality in patients with heart failure based on prospective cohort study 1,006 patients 18 years old with heart failure and ejection fraction 35% were followed for mean 2.7 years 30% of patients depressed (Beck Depression Inventory 10) 24.2% taking antidepressants mortality 42.7% depression independently associated with increased mortality (odds ratio 1.34, 95% CI ) neither use of any antidepressant nor use of SSRI antidepressants associated with increased mortality after adjustment for depression and other confounders Reference - Arch Intern Med 2008 Nov 10;168(20):2232Arch Intern Med 2008 Nov 10;168(20):2232 –depression common in heart failure and associated with worsening health status at 6 weeks prospective cohort study of 460 outpatients with heart failure and left ventricular ejection fraction < 30%, 30% had depression at baseline at 6 weeks, depressed patients had declines in health status, physical status (6-minute walk distance), social status and quality of life Reference - J Am Coll Cardiol 2003 Nov 19;42(10):1811 in QuickScan Reviews in Fam Pract 2004 Dec 6;30(6):20J Am Coll Cardiol 2003 Nov 19;42(10):1811 –depression associated with risk of death or cardiovascular hospitalization over 3 years based on cohort of 204 outpatients with heart failure and ejection fraction 40% or lower who were followed for median 3 years Beck Depression Inventory score at baseline associated with risk of death or cardiovascular hospitalization (p < 0.001) Reference - Arch Intern Med 2007 Feb 26;167(4):367Arch Intern Med 2007 Feb 26;167(4):367

191 cognitive impairment associated with congestive heart failure based on case-control study 62 patients with congestive heart failure were compared to 53 controls with cardiovascular disease but not heart failure (cardiac controls) and 43 healthy controls cognitive impairment in –25% of patients with congestive heart failure –15% of cardiac controls –4% of healthy controls –differences statistically significant (p = 0.04) patients with congestive heart failure had pattern of general cognitive impairment including impairment in executive function, memory, language, attention and mental speed Reference - J Am Geriatr Soc 2007 Nov;55(11):1764J Am Geriatr Soc 2007 Nov;55(11):1764

192 sleep-disordered breathing sleep apnea associated with congestive heart failure –based on study of 81 patients with stable heart failure 41 (51%) met criteria for sleep apnea patients with sleep apnea had higher resting PO2 levels, oxygen desaturations during sleep (average low level 76%), lower average ejection fractions (22% vs. 27%), higher prevalence of atrial fibrillation (22% vs. 5%) and higher rate of nocturnal ventricular tachycardia (51% vs. 37%) Reference - Circulation 1998 Jun 2;97:2154 full-text in J Watch 1998 Jul 1;18(13):103Circulation 1998 Jun 2;97:2154full-text –untreated obstructive sleep apnea (OSA) associated with increased mortality in heart failure based on prospective study of 164 heart failure patients with left ventricular ejection fraction 45% or lower followed for up to 7.3 years (mean 2.9 years) death rate was –8.7 per 100 patient-years in 37 patients with untreated OSA (apnea-hypopnea index at least 15/hour of sleep) –4.2 per 100 patient-years in 113 patients with mild or no OSA (apnea-hypopnea index < 15/hour of sleep) –0 in 14 patients with OSA treated with continuous positive airway pressure (CPAP) Reference - J Am Coll Cardiol 2007 Apr 17;49(15):1625J Am Coll Cardiol 2007 Apr 17;49(15):1625 –review of sleep apnea and congestive heart failure can be found in Minerva Med 2004 Aug;95(4):257Minerva Med 2004 Aug;95(4):257 –see also Cardiovascular disease and obstructive sleep apnea nocturnal desaturation common in patients with treated heart failure, low ejection fraction related to dip frequency (Heart 1998;79:394 full-text in Mayo Clin Proc 1998 Oct;73(10):963)Heart 1998;79:394full-text sleep-disordered breathing occurs in about 60% patients with heart failure –manifesting as Cheyne-Stokes respiration in 36%, obstructive sleep apnea in 12% and combination of central and obstructive abnormal breathing in 12% –studies of prognostic value of nocturnal Cheyne-Stokes respiration have been contradictory but recent studies suggest poor prognosis –clinical trials of CPAP should be conducted, home pulse oximetry may be cheap screening test for selection of trial participants –Reference - Lancet 1999 Aug 14;354(9178):531Lancet 1999 Aug 14;354(9178):531

193 bundle branch block on ECG may be a marker of myocardial progressive degenerative disease and associated with congestive heart failure, in study of 855 men > 50 years old followed for 30 years 10% (82) developed bundle branch block (BBB), 36% with BBB vs. 14% controls had congestive heart failure (Circulation 1998;98:2494 full-text in Family Practice Alert 1999 Feb;2(10):74)Circulation 1998;98:2494full-text

194 risk for any orthopedic fracture, and hip fracture specifically, may be increased in patients with heart failure based on 2 cohort studies cohort study of 31,936 Swedish twins born from 1914 to 1944 and followed up to age 50 years –hip fracture after age 50 years diagnosed in 1,442 twins –crude absolute rate of hip fractures (per 1,000 person-years) 12.6 after diagnosis of heart failure 12.6 after stroke 6.6 after diagnosis of peripheral atherosclerosis 5.2 after diagnosis of ischemic heart disease 1.2 for patients without cardiovascular disease diagnosis –multivariable-adjusted hazard ratio of hip fracture 4.4 (95% CI ) after diagnosis of heart failure 5.09 (95% CI ) after stroke 3.2 (95% CI ) after diagnosis of peripheral atherosclerosis 2.32 (95% CI ) after ischemic heart disease event –increased risk of hip fracture in identical twins without heart failure or stroke if their co-twins had either respective disease –Reference - JAMA 2009 Oct 21;302(15):1666, commentary can be found in JAMA 2010 Feb 24;303(8):731JAMA 2009 Oct 21;302(15):1666JAMA 2010 Feb 24;303(8):731 population-based cohort study of 16,294 consecutive patients 65 years old presenting to emergency room with cardiovascular disease from 1998 to 2001 evaluated for orthopedic fracture in first year after emergency room visit –2,041 patients newly diagnosed with heart failure –14,253 patients had non-heart failure cardiovascular diagnosis –comparing patients with heart failure vs. non-heart failure cardiovascular patients orthopedic fracture occurred in 4.6% vs. 1% (p < 0.001) hip fracture occurred in 1.3% vs. 0.1% (p < 0.001) –heart failure independently associated with increased risk for any orthopedic fracture (adjusted odds ratio 4 [95% CI ]) and hip fracture (adjusted odds ratio 6.3 [95% CI ]) –Reference - Circulation 2008 Nov 4;118(19):1946Circulation 2008 Nov 4;118(19):1946

195 risk for any orthopedic fracture, and hip fracture specifically, may be increased in patients with heart failure based on 2 cohort studies cohort study of 31,936 Swedish twins born from 1914 to 1944 and followed up to age 50 years –hip fracture after age 50 years diagnosed in 1,442 twins –crude absolute rate of hip fractures (per 1,000 person-years) 12.6 after diagnosis of heart failure 12.6 after stroke 6.6 after diagnosis of peripheral atherosclerosis 5.2 after diagnosis of ischemic heart disease 1.2 for patients without cardiovascular disease diagnosis –multivariable-adjusted hazard ratio of hip fracture 4.4 (95% CI ) after diagnosis of heart failure 5.09 (95% CI ) after stroke 3.2 (95% CI ) after diagnosis of peripheral atherosclerosis 2.32 (95% CI ) after ischemic heart disease event –increased risk of hip fracture in identical twins without heart failure or stroke if their co-twins had either respective disease –Reference - JAMA 2009 Oct 21;302(15):1666, commentary can be found in JAMA 2010 Feb 24;303(8):731JAMA 2009 Oct 21;302(15):1666JAMA 2010 Feb 24;303(8):731

196 Chief Concern (CC): dyspnea, orthopnea, paroxysmal nocturnal dyspnea, nocturia, edema, lethargy, nocturnal angina, fatigue, decreased exercise tolerance, congestion

197 some medications which may worsen heart failure include anti-inflammatory medications - corticosteroids (case series), NSAIDs (case series) cardiovascular medications - class I and III antiarrhythmics (randomized trials), calcium channel blockers (randomized trials), minoxidil (randomized trial) diabetes medications - metformin (case series), thiazolidinediones (open-label trial) hematologic medications - anagrelide (randomized trial), cilostazol (randomized trial) neuropsychiatric medications - amphetamines (randomized trial), carbamazepine (anecdotal), clozapine (case series), ergot alkaloids (case reports), pergolide (case reports), tricyclic antidepressants (case reports) miscellaneous - beta-2 agonists (case series), itraconazole (case series), licorice (open-label trial) Reference - Arch Intern Med 2004 Apr 12;164(7):709, correction can be found in Arch Intern Med 2004 Jul 12;164(13):1464, commentary can be found in Arch Intern Med 2005 Jan 10;165(1):118Arch Intern Med 2004 Apr 12;164(7):709Arch Intern Med 2005 Jan 10;165(1):118

198 Family History (FH): parental heart failure associated with increased risk of heart failure in cross- sectional study of 1,497 participants in Framingham Offspring Study and prospective study of 2,214 offspring (N Engl J Med 2006 Jul 13;355(2):138)N Engl J Med 2006 Jul 13;355(2):138 Social History (SH): smoking and/or alcohol use associated with increased risk for multiple hospital admissions for heart failure –retrospective case-control study comparing 533 patients with 1 hospital admission for heart failure to 220 patients with multiple heart failure admissions over a 2-year period at a veterans hospital –smoking associated with 2 times risk and alcohol use associated with 5 times risk for multiple admissions –Reference - Am J Cardiol 2000 Dec 15;86:1339 in Am Fam Physician 2001 Jun 15;63(12):2449Am J Cardiol 2000 Dec 15;86:1339Am Fam Physician 2001 Jun 15;63(12):2449 Review of Systems (ROS): anorexia (correlates with hepatic congestion and right heart failure) thorough history should address physical functioning, mental health, sleep disturbance, sexual function, cognitive function and ability to perform usual work and social activities, grade B evidence in AHCPR clinical practice guideline (J Am Geriatr Soc 1998 Apr;46(4):525)J Am Geriatr Soc 1998 Apr;46(4):525 ileus present in 14% of older CHF patients in study of 109 patients (mean age 74 years) admitted with CHF compared to 3% of 114 controls admitted with hip fracture (J Am Geriatr Soc 1999 Feb;47(2):258)J Am Geriatr Soc 1999 Feb;47(2):258

199 General Physical: tachycardia, tachypnea (LHF), Cheynes-Stokes respiration, dyspnea with rapid shallow breathing, pink frothy sputum elderly often present without typical findings (discussion in J Am Geriatr Soc 1997 Sep;45(9):1128), commentary can be found in J Am Geriatr Soc 1998 Aug;46(8):1053J Am Geriatr Soc 1997 Sep;45(9):1128J Am Geriatr Soc 1998 Aug;46(8):1053 technique to differentiate between cardiac and pulmonary disease in acute dyspnea –Valsalva maneuver with BP cuff inflated to 15 mm Hg over SBP (with auscultation in antecubital fossa) –normal response is disappearance of Korotkoff sounds during sustained Valsalva maneuver with reappearance after release –patients with chronic heart disease have abnormal response with lack of reappearance of Korotkoff sounds after release of Valsalva maneuver or maintenance of beats throughout maneuver –80-85% sensitive, 86-91% specific –Reference - Chest 1990;97:772Chest 1990;97:772 increased Valsalva blood pressure response may be an early warning sign of recurrent CHF after furosemide withdrawal, based on very small study of older CHF patients (J Am Geriatr Soc 1998 Sep;46(9):S71,P219, J Am Geriatr Soc 1999 Nov;47(11):1384)J Am Geriatr Soc 1999 Nov;47(11):1384

200 Neck: jugular venous distension (JVD) –suggests right heart failure –jugular venous distension approximates right atrial pressure, add 4 cm to height above angle of Louis (i.e. junction of manubrium and body of sternum), normal is 0-6 cm –anecdotal suggestion to use dorsal hand veins to estimate jugular venous pressure when jugular venous pulses not visible (Cortlandt Forum 1997 Sep;10(9):146,115-37) –jugular venous distention has 55-65% sensitivity and 74-80% specificity for increased filling pressure; based on review of 11 studies (JAMA 1997 Jun 4;277:1712 in Evidence-Based Medicine 1998 Jan/Feb;3(1):22)JAMA 1997 Jun 4;277:1712 –elevated jugular venous pressure and third heart sound are each independently associated with adverse outcomes in patients with heart failure retrospective study of 2,479 patients with symptomatic heart failure or history of symptomatic heart failure enrolled in SOLVD trial which randomized them to enalapril vs. placebo, mean follow-up 32 months 280 (11%) had elevated jugular venous pressure at entry, this group had increased risk of hospitalization for heart failure (relative risk [RR] 1.32, 95% confidence interval [CI] ), death or hospitalization for heart failure (RR 1.3, 95% CI ), and death from pump failure (RR 1.37, 95% CI ) 597 (24%) had third heart sound at entry, this group had similar increased risks Reference - N Engl J Med 2001 Aug 23;345(8):574, editorial can be found in N Engl J Med 2001 Aug 23;345(8):612, commentary can be found in N Engl J Med 2001 Dec 27;345(26):1912N Engl J Med 2001 Aug 23;345(8):574N Engl J Med 2001 Aug 23;345(8):612N Engl J Med 2001 Dec 27;345(26):1912 hepatojugular reflux (RHF) Chest: bilateral breast swelling due to congestive heart failure in case report (BMJ 2007 Sep 8;335(7618):520)

201 Cardiac: palpation of precordial apical impulse –palpation of precordial apical impulse in left lateral decubitus position for point of maximal impulse (PMI) –localized, sustained, outward thrust suggests hypertrophy –displaced, diffuse heave suggests dilatation –abnormal apical impulse has 31-36% sensitivity and 89-95% specificity for ejection fraction < 40%, based on review of 12 studies assessing systolic dysfunction (JAMA 1997 Jun 4;277:1712 in Evidence-Based Medicine 1998 Jan/Feb;3(1):22)JAMA 1997 Jun 4;277:1712

202 S3 and S4 heart sounds S3 ventricular gallop (third heart sound) –found in left heart failure, most reliable sign in patients > 40, may also be found in young healthy athletes –elevated jugular venous pressure and third heart sound are each independently associated with adverse outcomes in patients with heart failure retrospective study of 2,479 patients with symptomatic heart failure or history of symptomatic heart failure enrolled in SOLVD trial which randomized them to enalapril vs. placebo, mean follow-up 32 months 280 (11%) had elevated jugular venous pressure at entry, this group had increased risk of hospitalization for heart failure (relative risk [RR] 1.32, 95% confidence interval [CI] ), death or hospitalization for heart failure (RR 1.3, 95% CI ), and death from pump failure (RR 1.37, 95% CI ) 597 (24%) had third heart sound at entry, this group had similar increased risks Reference - N Engl J Med 2001 Aug 23;345(8):574, editorial can be found in N Engl J Med 2001 Aug 23;345(8):612, commentary can be found in N Engl J Med 2001 Dec 27;345(26):1912N Engl J Med 2001 Aug 23;345(8):574N Engl J Med 2001 Aug 23;345(8):612N Engl J Med 2001 Dec 27;345(26):1912 S4 atrial gallop (fourth heart sound, may also be caused by decreased left ventricular compliance with age)

203 S2 paradoxical splitting or increased P2 intensity murmurs (AS, AR, MR) all patients with angina and/or congestive heart failure with a systolic murmur should be suspected of having significant aortic stenosis, aortic stenosis can present without left ventricular hypertrophy on ECG and no history of syncope, patients will often have atrial fibrillation (Am J Cardiol 1995 Oct 1;76:728 in QuickScan Reviews in Fam Pract 1996 Mar;10)Am J Cardiol 1995 Oct 1;76:728

204 Lungs: rales (pulmonary edema in LHF) Abdomen: ascites (RHF), hepatomegaly (RHF, distended liver from passive congestion) ileus present in 14% of older CHF patients in study of 109 patients (mean age 74) admitted with CHF compared to 3% of 114 controls admitted with hip fracture (J Am Geriatr Soc 1999 Feb;47(2):258)J Am Geriatr Soc 1999 Feb;47(2):258 Extremities: edema (RHF, lower extremity and presacral) Beau's lines - transverse nail ridging or depressions of nail plates –usually bilateral from temporary cessation of growth during severe systemic illness –picture can be found in N Engl J Med 1997 Jul 17;337(3):168 full-textN Engl J Med 1997 Jul 17;337(3):168full-text –picture can be found in BMJ 2002 Aug 31;325(7362):502, dissenting commentary can be found in BMJ 2003 Jan 11;326(7380):105BMJ 2002 Aug 31;325(7362):502BMJ 2003 Jan 11;326(7380):105 Terry's nails are proximal white nail beds with distal pink transverse band; associated with cirrhosis, diabetes mellitus type 2, congestive heart failure and chronic renal failure (Am Fam Physician 2004 Jun 15;69(12):2903 full-text)Am Fam Physician 2004 Jun 15;69(12):2903full-text case report of elephantiasis nostras verrucosa can be found in CMAJ 2008 Sep 23;179(7):673 CMAJ 2008 Sep 23;179(7):673

205 Making the diagnosis: see acute heart failure for diagnostic considerations in patients presenting with acute symptoms chest x-ray findings of cardiomegaly and pulmonary congestion capillary wedge pressure > 20 (normal 12) left ventricular systolic dysfunction (LVSD) difficult to diagnose based on history and physical exam alone –study of 259 adult British patients with suspected congestive heart failure referred by general practitioner to assess whether they would be candidates for treatment with ACE inhibitor –each patient underwent complete history and physical exam by single examiner then echocardiography by blinded cardiologist, some patients were already treated empirically at time of study –LVSD defined as fractional shortening < 25% or systolic function "significantly impaired" when quantitative measures unobtainable; echocardiogram revealed LVSD in 16% –absence of dyspnea on exertion effectively ruled out LVSD, while displaced cardiac apical impulse and S3 gallop strongly supported diagnosis of LVSD; presence of jugular veinous distension, history of diabetes mellitus and history of myocardial infarction predicted LVSD –given pretest probability in this study of LVSD of 16%, positive predictive values were 64% for JVD, 77% for S3 gallop, 75% for displaced cardiac apical impulse and 89% for combination of prior MI and displaced cardiac apical impulse –Reference - QJM 1997 May;90(5):335 in J Fam Pract 1997 Sep;45(3):197, commentary can be found in BMJ 2004 Jul 24;329(7459):209QJM 1997 May;90(5):335J Fam Pract 1997 Sep;45(3):197BMJ 2004 Jul 24;329(7459):209

206 history, physical, ECG and chest x-ray all have low predictive value in differentiating normal from decreased systolic function in patients with CHF 225 consecutive patients hospitalized with CHF were evaluated, 104 (46%) had normal left ventricular systolic function defined as ejection fraction (EF) > 45% and 121 (54%) had EF < 45% on echocardiogram rales had 89% sensitivity, 20% specificity, 57% positive predictive value and 62% negative predictive value electrocardiographic left ventricular hypertrophy had 42% sensitivity, 78% specificity, 69% positive predictive value and 54% negative predictive value cephalization of blood flow on chest x-ray had 91% sensitivity, 21% specificity, 13% positive predictive value and 57% negative predictive value Reference - Am J Med 2002 Apr 15;112(6):437 in QuickScan Reviews in Fam Pract 2002 Jul;27(6):5Am J Med 2002 Apr 15;112(6):437 history and physical exam alone has low predictive value for heart failure study of 5,434 Portuguese patients attending 365 primary care centers, echocardiography done in 1,058 patients who met study screening criteria, 551 (10%) had cardiac dysfunction at rest history findings with high positive likelihood ratios (high specificity for heart failure) had sensitivity < 36% and included prior use of digoxin, prior use of diuretics, history of coronary artery disease, history of pulmonary edema, current paroxysmal nocturnal dyspnea, current orthopnea, and current breathlessness when walking on the flat physical exam findings with high positive likelihood ratios had sensitivity 6 cm with hepatic enlargement, edema of lower limbs, ventricular gallop, heart rate > 110 bpm, and pulmonary rales Reference - Eur J Heart Fail 2004 Oct;6(6):795Eur J Heart Fail 2004 Oct;6(6):795

207 possible prediction rule for diagnosing heart failure in elderly patients with stable COPD rule derived in study of 405 patients at least 65 years old with COPD, chronic bronchitis or emphysema –20.5% had heart failure based on expert consensus panel using clinical findings and echocardiography –no external validation study points for rule –history of ischemic disease 2 points –body mass index > 30 kg/m2 3 points –laterally displaced apex beat 3 points –heart rate > 90 beats/minute 2 points –NT-proBNP > pmol/L (125 pg/mL) 4 points –abnormal ECG (abnormal Q waves, left bundle branch block, left ventricular hypertrophy, atrial fibrillation, ST and/or T wave abnormalities, sinus tachycardia) 3 points

208 risk interpretation very low risk if 0 points; 4 (5%) of 81 patients with 0 points had heart failure low risk if 2-5 points –15 (11%) of 142 patients with 2-5 points had heart failure –risk score 2 or higher had 95% sensitivity, 24% specificity, 24% positive predictive value and 95% negative predictive value medium risk if 6-9 points –32 (25%) of 126 patients with 6-9 points had heart failure –risk score 6 or higher had 77% sensitivity, 63% specificity, 35% positive predictive value and 91% negative predictive value high risk if points –32 (57%) of 56 patients with points had heart failure –risk score 10 or higher had 39% sensitivity, 93% specificity, 57% positive predictive value and 85% negative predictive value Reference - BMJ 2005 Dec 10;331(7529):1379 full-textBMJ 2005 Dec 10;331(7529):1379full-text

209 Testing to consider: American College of Cardiology/American Heart Association (ACC/AHA) guidelines on heart failure: Initial assessment in patients presenting with heart failure: thorough history and physical exam (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C careful history of current and past use of alcohol, illicit drugs, "alternative therapies" and chemotherapy drugs (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C assessment of ability to perform routine and desired activities of daily living (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C exam including volume status, orthostatic blood pressure changes, weight, height and calculation of body mass index (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C laboratory evaluation (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C –complete blood count –electrolytes including calcium and magnesium –blood urea nitrogen –serum creatinine –fasting blood glucose –glycohemoglobin (HbA1c) –lipid profile –liver function tests –thyroid-stimulating hormone (TSH) –urinalysis measurement of natriuretic peptides (BNP and NT-proBNP) (ACC/AHA Class IIa, Level of Evidence A)ACC/AHA Class IIa, Level of Evidence A –useful in urgent care setting if clinical diagnosis of heart failure uncertain –useful in risk stratification –see Brain natriuretic peptide (BNP) testing for details

210 screening or diagnostic testing for specific conditions in selected patients (ACC/AHA Class IIa, Level of Evidence C)ACC/AHA Class IIa, Level of Evidence C hemochromatosis sleep-disturbed breathing (obstructive sleep apnea (OSA)) human immunodeficiency virus (HIV infection) rheumatologic diseases amyloidosis pheochromocytoma

211 12-lead electrocardiogram (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C chest x-ray (posterior to anterior [PA] and lateral) (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C 2-dimensional echocardiography with Doppler (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C to assess left ventricular ejection fraction, left ventricular size, wall thickness and valve function radionuclide ventriculography can be done to assess left ventricular ejection fraction and volumes

212 measurement of left ventricular ejection fraction can be done by –echocardiography –equilibrium radionuclide angiocardiography (multiple gated acquisition scanning [MUGA]) –ventriculography consider ECG before echocardiography, may make echocardiography unnecessary –use of EKG may be reasonable as a screening test to determine if an echocardiography is indicated; in a study of 534 patients who underwent echo for suspected left ventricular dysfunction, a normal EKG would reduce the number of echo's performed by about 50% without missing any of the 96 patients with left ventricular systolic dysfunction seen on echo (BMJ 1996 Jan 27;312(7025):222 in J Watch 1996 Mar 1;16(5):39)BMJ 1996 Jan 27;312(7025):222 –study suggests that normal ECG reduces likelihood of left ventricular systolic dysfunction to 2% 2,158 patients > 40 years old were screened, 126 with any past or present signs or symptoms of heart disease were studied, 15 (12%) had left ventricular systolic dysfunction Reference - BMJ 2000 Jan 22;320(7229):220, commentary can be found in BMJ 2000 Jul 8;321(7253):111, ACP J Club 2000 Nov-Dec;133(3):114BMJ 2000 Jan 22;320(7229):220BMJ 2000 Jul 8;321(7253):111 only 1 of 60 patients with normal ECG had systolic dysfunction (J Watch 2000 Mar 15;20(6):50) with only 126 patients actually studied, validity for clinical application questionable (DynaMed commentary) –in series of 300 inpatients referred for echocardiographic assessment of left ventricular function, 124 (41%) had left ventricular systolic dysfunction (LVSD) defined as ejection fraction < 45%, only 2 patients with LVSD (1.6%) had a normal electrocardiogram (Am Heart J 2000 Mar;139(3):394), editorial can be found in Am Heart J 2000 Mar;139(3):388, commentary can be found in J Fam Pract 2000 Jul;49(7):655Am Heart J 2000 Mar;139(3):394Am Heart J 2000 Mar;139(3):388J Fam Pract 2000 Jul;49(7):655 American College of Radiology (ACR) Appropriateness Criteria for suspected cardiac origin in shortness of breath can be found at National Guideline Clearinghouse 2006 Aug 21:9591, previous version can be found in Radiology 2000 Jun;215 Suppl:23National Guideline Clearinghouse 2006 Aug 21:9591Radiology 2000 Jun;215 Suppl:23

213 Blood tests: ABG may show respiratory and metabolic acidosis (but may have respiratory alkalosis initially) - decreased PaO2, increased PCO2, decreased pH increased uric acid, may be due to increased proximal tubule resorption as nephron perceives hypovolemic state (Cortlandt Forum 1996 Jan;9(1):109,95-30) brain natriuretic peptide (BNP) levels potentially useful in primary care for ruling out heart failure –N-terminal pro-BNP improved diagnostic accuracy in primary care by ruling out heart failure in 1 randomized trial –see Brain natriuretic peptide (BNP) testing for details

214 chest x-ray (CXR) may show pulmonary venous congestion (fluffy perihilar infiltrates in early stages, Kerley-B lines), cardiomegaly, pleural effusions radiographic redistribution has 10-58% sensitivity and % specificity for increased filling pressure; based on review of 11 studies (JAMA 1997 Jun 4;277:1712 in Evidence-Based Medicine 1998 Jan/Feb;3(1):22)JAMA 1997 Jun 4;277:1712 radiographic cardiomegaly or redistribution has 4-33% sensitivity and % specificity for ejection fraction < 40%, based on review of 12 studies assessing systolic dysfunction (JAMA 1997 Jun 4;277:1712 in Evidence-Based Medicine 1998 Jan/Feb;3(1):22)JAMA 1997 Jun 4;277:1712 cardiothoracic ratio on CXR not useful for estimating left ventricular ejection fraction in study of 7,476 CHF patients, although weak negative correlation exists (Arch Intern Med 1998 Mar 9;158(5):501)Arch Intern Med 1998 Mar 9;158(5):501

215 echocardiogram especially useful to show mitral valve disease use of Doppler to evaluate VHD or intracardiac shunts bedside thoracic ultrasound alone or in combination with N- terminal pro-brain-type natriuretic peptide (NT-ProBNP) may help differentiate CHF from COPD in dyspneic adults in the emergency department (level 2 [mid-level] evidence)level 2 [mid-level] evidence –based on prospective convenience sample of 100 adults seeking emergency department care for shortness of breath –positive thoracic ultrasound positive likelihood ratio 3.88 (p < 0.05) negative likelihood ratio 0.5 (p < 0.05) –NT-ProBNP had positive likelihood ratio 2.3 (p < 0.05) negative likelihood ratio 0.24 (P < 0.05) –Reference - Acad Emerg Med 2009 Mar;16(3):201Acad Emerg Med 2009 Mar;16(3):201 review of stress echocardiography in heart failure can be found in Cardiovascular Ultrasound 2004 Jul 30;2:11 Cardiovascular Ultrasound 2004 Jul 30;2:11 review of basic transthoracic echocardiography can be found in BMJ 2005 Jun 18;330(7505):1432BMJ 2005 Jun 18;330(7505):1432 ACC/AHA/ASE 2003 guideline for clinical application of echocardiography can be found in J Am Coll Cardiol 2003 Sep 3;42(5):954, J Am Soc Echocardiogr 2003 Oct;16(10):1091, Circulation 2003 Sep 2;108(9):1146J Am Coll Cardiol 2003 Sep 3;42(5):954J Am Soc Echocardiogr 2003 Oct;16(10):1091 Circulation 2003 Sep 2;108(9):1146 see Cardiac stress testing for additional information

216 review of cardiovascular MRI can be found in CMAJ 2006 Oct 10;175(8):911 full-textCMAJ 2006 Oct 10;175(8):911full-text coronary angiography - cardiac catheterization most accurate but invasive American College of Radiology (ACR) Appropriateness Criteria for congestive heart failure can be found at National Guideline Clearinghouse 2006 Sep 4:9604 National Guideline Clearinghouse 2006 Sep 4:9604

217 EKG: almost always abnormal if substantial left ventricular dysfunction; frequently nonspecific but may detect ischemia, arrhythmia, infarction or hypertrophy anterior Q waves has 32-44% sensitivity and 89% specificity for ejection fraction < 40%, based on review of 12 studies assessing systolic dysfunction (JAMA 1997 Jun 4;277:1712 in Evidence-Based Medicine 1998 Jan/Feb;3(1):22)JAMA 1997 Jun 4;277:1712 left bundle branch block has 18% sensitivity and 95% specificity for ejection fraction < 40%, based on review of 12 studies assessing systolic dysfunction (JAMA 1997 Jun 4;277:1712 in Evidence-Based Medicine 1998 Jan/Feb;3(1):22)JAMA 1997 Jun 4;277:1712 American College of Cardiology/American Heart Association guidelines for ambulatory ECG can be found in Circulation 1999 Aug 24;100(8):886 full-text or J Am Coll Cardiol 1999 Sep;34(3):912 (summarized in Am Fam Physician 2000 Feb 1;61(3):884)Circulation 1999 Aug 24;100(8):886full-textJ Am Coll Cardiol 1999 Sep;34(3):912Am Fam Physician 2000 Feb 1;61(3):884 T wave alternans on ECG may be predictive of future arrhythmic events, based on study of 107 CHF patients (Lancet 2000 Aug 19;356(9230):651)Lancet 2000 Aug 19;356(9230):651

218 Prognosis of CHF 7-item risk score may predict mortality in elderly patients based on prospective cohort of 282 elderly (mean age 79 years) with heart failure followed for up to 14 years 269 patients (95%) died with median survival 894 days risk score based on 1 point each for –age > 75 years –sodium < 135 mEq/L –coronary artery disease –dementia –peripheral vascular disease –systolic blood pressure < 120 mm Hg –serum urea nitrogen 30 mg/dL or higher all-cause mortality stratified by risk score –0-1 point (89 patients) - mortality 8% at 6 months, 9% at 1 year, 57% at 5 years –2-3 points (153 patients) - mortality 10% at 6 months, 22% at 1 year, 79% at 5 years –4-7 points (137 patients) - mortality 59.5% at 6 months, 73% at 1 year, 100% at 5 years Reference - Arch Intern Med 2006 Sep 25;166(17):1892Arch Intern Med 2006 Sep 25;166(17):1892

219 7-item risk score may predict mortality in elderly patients based on prospective cohort of 282 elderly (mean age 79 years) with heart failure followed for up to 14 years 269 patients (95%) died with median survival 894 days risk score based on 1 point each for –age > 75 years –sodium < 135 mEq/L –coronary artery disease –dementia –peripheral vascular disease –systolic blood pressure < 120 mm Hg –serum urea nitrogen 30 mg/dL or higher all-cause mortality stratified by risk score –0-1 point (89 patients) - mortality 8% at 6 months, 9% at 1 year, 57% at 5 years –2-3 points (153 patients) - mortality 10% at 6 months, 22% at 1 year, 79% at 5 years –4-7 points (137 patients) - mortality 59.5% at 6 months, 73% at 1 year, 100% at 5 years Reference - Arch Intern Med 2006 Sep 25;166(17):1892Arch Intern Med 2006 Sep 25;166(17):1892

220 asymptomatic left ventricular dysfunction with ejection fraction < 35% had 30% 3-year risk of symptomatic heart failure in Studies of Left Ventricular Dysfunction (SOLVD) Prevention Trial (N Engl J Med 1992 Sep 3;327(10):685, correction in N Engl J Med 1992 Dec 10;327(24):1768)N Engl J Med 1992 Sep 3;327(10):685 risk factors for exacerbation of heart failure based on prospective study of 768 patients with ejection fraction < 40% participating in 2 randomized trials over 43 weeks noncompliance with salt restriction (22% episodes) other noncardiac causes (20%, especially pulmonary infectious processes) use of antiarrhythmic agents in prior 48 hours (15%) arrhythmias (13%) calcium channel blockers (13%) inappropriate reductions in heart failure therapy (10%) Reference - Arch Intern Med 2001 Oct 22;161(19):2337Arch Intern Med 2001 Oct 22;161(19):2337

221 Treatment of CHF American College of Cardiology and American Heart Association (ACC/AHA) guidelines on heart failure in adults recommendations for patients with symptomatic heart failure (Stage C) and reduced left ventricular ejection fraction –follow all Class I recommendations for Stage A and Stage B (patients at risk but without symptomatic heart failure) treat risk factors in accordance with contemporary guidelines –control systolic and diastolic hypertension (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A –treat lipid disorders (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A –control blood sugar in patients with diabetes (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C –provide secondary prevention measures for patients with known atherosclerotic vascular disease (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C counsel patients to avoid behaviors that may increase risk of heart failure (such as smoking, excessive alcohol consumption and illicit drug use) (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C control ventricular rate or restore sinus rhythm in patients with supraventricular tachyarrhythmias (ACC/AHA Class I, Level of Evidence B)ACC/AHA Class I, Level of Evidence B treat thyroid disorders in accordance with contemporary guidelines (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C evaluate periodically for signs and symptoms of heart failure (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C

222 medications diuretics and salt restriction indicated in patients who have evidence of fluid retention (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C –furosemide (Lasix) mg once or twice daily initially, maximum 600 mg/day –bumetanide (Bumex) mg once or twice daily initially, maximum 10 mg/day –torsemide (Demadex) mg/day initially, maximum 200 mg/day ACE inhibitors recommended for all patients unless contraindicated (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A –captopril (Capoten) 6.25 mg three times daily initially, maximum 50 mg three times daily –enalapril (Vasotec) 2.5 mg twice daily initially, maximum mg twice daily –fosinopril (Monopril) 5-10 mg/day initially, maximum 40 mg/day –lisinopril (Prinivil, Zestril) mg/day initially, maximum mg/day –perindopril (Aceon) 2 mg/day initially, maximum 8-16 mg/day –quinapril (Accupril) 5 mg twice daily initially, maximum 20 mg twice daily –ramipril (Altace) mg/day initially, maximum 10 mg/day –trandolapril (Mavik) 1 mg/day initially, maximum 4 mg/day beta blockers proven to reduce mortality (bisoprolol, carvedilol or sustained release metoprolol succinate) recommended for all stable patients unless contraindicated (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A –start at very low doses and increase gradually as tolerated –bisoprolol (Zebeta) 1.25 mg/day initially, maximum 10 mg/day –carvedilol (Coreg) mg twice daily initially, maximum 25 mg twice daily (maximum 50 mg twice daily if > 85 kg) –metoprolol extended release (Toprol XL) mg/day initially, maximum 200 mg/day

223 angiotensin II receptor blockers (ARBs) recommended in patients who are ACE inhibitor- intolerant (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A ARBs are reasonable to use as alternatives to ACE inhibitors as first-line therapy for patients with mild to moderate heart failure, especially for patients taking ARBs for other indications (ACC/AHA Class IIa, Level of Evidence A)ACC/AHA Class IIa, Level of Evidence A addition of ARB may be considered in persistently symptomatic patients on conventional therapy (ACC/AHA Class IIb, Level of Evidence B)ACC/AHA Class IIb, Level of Evidence B specific ARBs may include –candesartan (Atacand) 4-8 mg/day initially, maximum 32 mg/day –losartan (Cozaar) mg/day initially, maximum mg/day –valsartan (Diovan) mg twice daily initially, maximum 160 mg twice daily

224 addition of aldosterone antagonist recommended in selected patients with moderately severe to severe symptoms of heart failure who can be carefully monitored for preserved renal function and normal potassium concentration (ACC/AHA Class I, Level of Evidence B)ACC/AHA Class I, Level of Evidence B maintain creatinine 2.5 mg/dL (221 mcmol/L) in men and 2 mg/dL (176.8 mcmol/L) in women maintain potassium < 5 mEq/L (5 mmol/L) risks may outweigh benefits in patients where monitoring for hyperkalemia or renal dysfunction is not feasible risk for hyperkalemia increased with –risk increases progressively when serum creatinine > 1.6 mg/dL (141.4 mcmol/L), or creatinine clearance < 30 mL/minute –concomitant use of higher doses of ACE inhibitors (captopril 75 mg/day, enalapril or lisinopril 10 mg/day or higher doses) –nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors –potassium supplements initial dose of spironolactone 12.5 mg or eplerenone 25 mg recommended, dose may then increase to spironolactone 25 mg or eplerenone 50 mg if appropriate closely monitor serum potassium, check at 3 days and 1 week after initiation of therapy and at least monthly for first 3 months emergently address diarrhea or other causes of dehydration

225 combination of hydralazine plus nitrates recommended for patients self-described as African- Americans with moderate-severe symptoms on optimal therapy with ACE inhibitors, beta blockers and diuretics (ACC/AHA Class I, Level of Evidence B)ACC/AHA Class I, Level of Evidence B reasonable addition for patients with persistent symptoms despite taking an ACE inhibitor and beta- blocker (ACC/AHA Class IIa, Level of Evidence B)ACC/AHA Class IIa, Level of Evidence B might be reasonable for patients who cannot take ACE inhibitor or ARB because of drug intolerance, hypotension or renal failure (ACC/AHA Class IIb, Level of Evidence C)ACC/AHA Class IIb, Level of Evidence C digitalis can be beneficial to decrease hospitalizations for heart failure (ACC/AHA Class IIa, Level of Evidence B)ACC/AHA Class IIa, Level of Evidence B avoid or withdraw drugs known to adversely affect clinical status whenever possible (e.g. NSAIDs, most antiarrhythmic drugs, most calcium channel blocking drugs) (ACC/AHA Class I, Level of Evidence B)ACC/AHA Class I, Level of Evidence B

226 implantable cardioverter-defibrillator recommended as secondary prevention to prolong survival in patients with history of cardiac arrest, ventricular fibrillation or hemodynamically destabilizing ventricular tachycardia (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A as primary prevention of sudden cardiac death to reduce mortality in patients with nonischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-myocardial infarction, left ventricular ejection function 35%, New York Heart Association (NYHA) functional Class II or III symptoms while undergoing chronic optimal medical therapy and reasonable expectation of survival with good functional status for > 1 year (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A

227 cardiac resynchronization therapy (biventricular pacing or atriobiventricular pacing) recommended (with or without implantable cardioverter-defibrillator) (unless contraindicated) for patients with left ventricular ejection fraction 35%, sinus rhythm and NYHA functional Class III or ambulatory Class IV symptoms despite recommended optimal medical therapy and who have cardiac dyssynchrony (currently defined as QRS duration > 120 milliseconds) (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A reasonable (with or without implantable cardioverter-defibrillator) for patients with left ventricular ejection fraction 35%, QRS duration 0.12 seconds, atrial fibrillation, and NYHA functional Class III or ambulatory class IV symptoms despite recommended optimal medical therapy (ACC/AHA Class IIa, Level of Evidence B)ACC/AHA Class IIa, Level of Evidence B reasonable for patients with left ventricular ejection fraction 35% and NYHA functional Class III or ambulatory Class IV symptoms despite recommended optimal medical therapy and who have frequent dependence on ventricular pacing (ACC/AHA Class IIa, Level of Evidence C)ACC/AHA Class IIa, Level of Evidence C

228 reasonable to treat patients with atrial fibrillation with strategy to maintain sinus rhythm or with strategy to control ventricular rate alone (ACC/AHA Class IIa, Level of Evidence A)ACC/AHA Class IIa, Level of Evidence A treatments NOT recommended routine combined use of ACE inhibitor, ARB and aldosterone antagonist (ACC/AHA Class III, Level of Evidence C)ACC/AHA Class III, Level of Evidence C calcium channel blockers as routine treatment (ACC/AHA Class III, Level of Evidence A)ACC/AHA Class III, Level of Evidence A long-term use of infusion of positive inotropic drug, except as palliation for patients with end-stage disease who cannot be stabilized with standard medical treatment (ACC/AHA Class III, Level of Evidence C)ACC/AHA Class III, Level of Evidence C use of nutritional supplements (ACC/AHA Class III, Level of Evidence C)ACC/AHA Class III, Level of Evidence C hormonal therapies other than to replete deficiencies (ACC/AHA Class III, Level of Evidence C)ACC/AHA Class III, Level of Evidence C

229 meticulous identification and control of fluid retention (ACC/AHA Class I, Level of Evidence B)ACC/AHA Class I, Level of Evidence B referral to heart failure program with expertise in management of refractory heart failure (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A referral for cardiac transplantation in potentially eligible patients (ACC/AHA Class I, Level of Evidence B)ACC/AHA Class I, Level of Evidence B absolute indications for cardiac transplantation in appropriate patients –hemodynamic compromise due to heart failure refractory cardiogenic shock documented dependence on intravenous inotropic support peak oxygen consumption (VO2) < 10 mL/kg/minute with achievement of anaerobic metabolism –severe symptoms of ischemia that consistently limit routine activity and are not amenable to revascularization –recurrent symptomatic ventricular arrhythmias refractory to all therapeutic modalities relative indications –peak VO mL/kg/minute (or 55% predicted) and major limitation of patient's daily activities –recurrent unstable ischemia not amenable to other intervention –recurrent instability of fluid balance or renal function not due to patient noncompliance

230 discuss options for end-of-life care with patient and family when severe symptoms persist despite all recommended therapies (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C provide information about option to inactivate defibrillation in patients with implantable defibrillators (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C consider left ventricular assist device as permanent or "destination" therapy for end-stage heart failure patients who (ACC/AHA Class IIa, Level of Evidence B)ACC/AHA Class IIa, Level of Evidence B are not candidates for transplantation do not respond to standard therapy have predicted 1-year survival < 50% considerations with insufficient evidence for guidance (ACC/AHA Class IIb, Level of Evidence C)ACC/AHA Class IIb, Level of Evidence C pulmonary artery catheter placement to guide therapy in patients with persistently severe symptoms mitral valve repair or replacement for severe secondary mitral regurgitation continuous intravenous infusion of positive inotropic agent for palliation of symptoms treatments NOT recommended partial left ventriculectomy in patients with non-ischemic cardiomyopathy (ACC/AHA Class III, Level of Evidence C)ACC/AHA Class III, Level of Evidence C routine intermittent infusions of vasoactive and positive inotropic agents (ACC/AHA Class III, Level of Evidence A)ACC/AHA Class III, Level of Evidence A

231 Diet: Fluid restriction: fluid restriction not advisable unless hyponatremia present, grade C evidence (i.e. expert opinion with no evidence) in AHCPR clinical practice guideline (J Am Geriatr Soc 1998 Apr;46(4):525)J Am Geriatr Soc 1998 Apr;46(4):525 Sodium restriction: normal sodium diet with high diuretic doses and fluid intake restriction associated with reduced readmission rate for patients with compensated heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence –based on randomized trial without blinding –410 patients aged years with NYHA class II-IV (compensated) heart failure randomized to 8 different levels of fluid/sodium intake and diuretic doses; followed for 180 days –patients taking 1,000 mL fluid per day, 120 mmol sodium per day, furosemide 250 mg twice daily had 7.69% readmission rate compared to other groups with readmission rate range 29.4% to 78.4% (p < 0.001) –Reference - Am J Cardiol 2009 Jan 1;103(1):93Am J Cardiol 2009 Jan 1;103(1):93

232 Alcohol: reduction of alcohol intake to < 60 g daily may be associated with significant improvement in ejection fraction in men with alcoholic cardiomyopathy (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence –based on prospective cohort study without clinical outcomes –55 men with history of alcohol consumption > 100 g daily for at least 10 years and known alcoholic cardiomyopathy followed prospectively for 4 years –mean improvements of ejection fractions after 1 year of observation complete abstinence (95% CI ) < 60 g ethanol daily (95% CI ) –most patients who consumed > 80 g of ethanol/day had significant decrease in ejection fraction –trend of improvement continued after 4 years of observation for subjects who abstained or had moderate alcohol consumption; all patients with continued heavy alcohol consumption were dead by the end of the four- year observation period –Reference - Ann Intern Med 2002 Feb 5;136(3):192 PDFAnn Intern Med 2002 Feb 5;136(3):192PDF

233 Nutrition: heart failure patients may need to increase protein intake –prospective study of 57 nonobese heart failure patients and 49 age- and BMI-matched sedentary controls using 7-day food diaries, urine and blood samples, and calorimetry –31 (54%) heart failure patients had malnutrition, 22 with protein malnutrition and 9 with combined protein-calorie malnutrition –heart failure patients had more nutritional deficits than controls despite similar calorie intake, nitrogen intake and total energy expenditure –heart failure patients on average had negative calorie balance and negative nitrogen balance, while controls had positive calorie balance and positive nitrogen balance –Reference - J Am Coll Cardiol 2003 Oct 1;42(7):1218 in J Watch Online 2003 Nov 14J Am Coll Cardiol 2003 Oct 1;42(7):1218 see also nutritional supplements (below)nutritional supplements

234 Activity: exercise training safe in patients with heart failure (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –systematic review of 81 controlled comparisons of exercise training vs. no exercise training in patients with ejection fraction < 40% –no exercise-related death reported with > 60,000 hours of exercise training in 2,387 patients –30 parallel-group randomized trials included 1,197 patients, follow-up ranged from 4 weeks to 192 weeks, no significant differences in adverse events or all-cause mortality, non- significant trend (p = 0.06) toward reduction in all-cause mortality with exercise –exercise training increased maximum oxygen uptake by 17% in 57 trials

235 Medications: Angiotensin-converting enzyme (ACE) inhibitors: indicated for all patients with reduced left ventricular ejection fraction regardless of symptomatic state, unless ACE inhibitors contraindicated or not tolerated (grade A recommendation [consistent high-quality evidence])grade A recommendation [consistent high-quality evidence] ACE inhibitors can improve symptoms, exercise tolerance and enhance functional status, usually takes 4-12 weeks; early circulatory instability does not preclude long-term benefit contraindicated with hyperkalemia, hypotension, elevated creatinine, severe aortic stenosis start at low doses and increase gradually ACE inhibitors lower rates of mortality, myocardial infarction, and hospital admission for heart failure in patients with left ventricular dysfunction or heart failure (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence ACE inhibitors may be ineffective in black patients and in patients with creatinine > 2 mg/dL (176.8 mol/L) (level 2 [mid-level] evidence)level 2 [mid-level] evidence side effects include hypotension, azotemia, hyperkalemia, cough, and angioneurotic edema severe hyperkalemia can occur with concomitant spironolactone different ACE inhibitors appear to have similar rates of mortality and hospital admission for heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence see ACE inhibitors for heart failure for details

236 Angiotensin receptor blockers (ARB): angiotensin II receptor blockers (ARBs) also called angiotensin II inhibitors established role of ARBs is substitution of ACE inhibitor for patients intolerant of ACE inhibitors, for example, cough or angioneurotic edema ARBs reduce mortality and heart failure hospitalization compared with placebo, no differences compared with ACE inhibitors (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence addition of ARBs to ACE inhibitors –reduces heart failure hospitalization but not mortality (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –increases rate of medication discontinuation due to adverse effects, symptomatic hypotension and worsening renal function compared to ACE inhibitor alone (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence SEVERE HYPERKALEMIA can occur when spironolactone given with ACE inhibitors or angiotensin receptor blockers for heart failure see Angiotensin II inhibitors for heart failure for details combination of ACE inhibitor and angiotensin receptor blocker reduces hospitalization rate but not mortality compared to ACE inhibitor alone –based on MEDLINE search for randomized trials and meta-analyses –addition of ARB to ACEI did not affect mortality in meta-analysis of 6 trials with nearly 6,000 patients or more recent trial with 2,548 patients, addition of ARB to ACEI in these studies reduced hospitalization rates (NNT 21 over 2 years) –limited number of studies evaluated symptoms, exercise capacity, functional capacity or quality of life with larger trials finding no benefit –Reference - Am Fam Physician 2003 Nov 1;68(9):1795, commentary can be found in Am Fam Physician 2004 Jul 15;70(2):261Am Fam Physician 2003 Nov 1;68(9):1795Am Fam Physician 2004 Jul 15;70(2):261

237 Beta blockers: useful in class II, III and IV congestive heart failure (CHF) beta blockers proven effective for heart failure include –bisoprolol, a beta-1 selective blocker –carvedilol, a nonselective beta-blocker and alpha-1 blocker –sustained-release metoprolol, a beta-1 selective blocker choice of beta blocker not clear –only carvedilol and sustained-release metoprolol FDA approved for CHF –carvedilol improved survival compared to immediate-release metoprolol in large randomized trial –4 small randomized trials have compared carvedilol vs. metoprolol, 2 found no difference, 2 found differences in ejection fraction or left ventricular size favoring carvedilol adverse effects include worsening of heart failure, symptomatic hypotension, bradycardia, heart block use not advised in patients with asthma or severe bradycardia starting with low doses and titrating dose based on tolerance can reduce risk of side effects

238 addition of carvedilol to digoxin may reduce symptoms in patients with heart failure and atrial fibrillation (level 2 [mid- level] evidence)level 2 [mid- level] evidence 47 patients with heart failure and persistent atrial fibrillation for at least 1 month and were taking digoxin were randomized to add carvedilol vs.placebo for 4 months carvedilol improved symptom control and left ventricular ejection fraction and reduced heart rate Reference - J Am Coll Cardiol 2003 Dec 3;42(11):1944 in Am Fam Physician 2004 Jul 15;70(2):386J Am Coll Cardiol 2003 Dec 3;42(11):1944Am Fam Physician 2004 Jul 15;70(2):386

239 Timing of starting beta blocker and ACE inhibitor: starting beta blocker before ACE inhibitor and starting ACE inhibitor before beta blocker may have similar outcomes (level 2 [mid-level] evidence)level 2 [mid-level] evidence –1,010 patients with mild to moderate CHF and ejection fraction 35% or lower were randomized to open-label monotherapy with bisoprolol (target dose 10 mg once daily) vs. enalapril (target dose 10 mg twice daily) for 6 months then combined therapy for 6-24 months –no significant difference sin all-cause mortality or hospitalization –study underpowered to definitively demonstrate lack of clinically significant differences –Reference - Circulation 2005 Oct 18;112(16):2426Circulation 2005 Oct 18;112(16):2426 starting carvedilol before perindopril may improve symptoms (level 2 [mid-level] evidence)level 2 [mid-level] evidence –78 patients with New York Heart Association (NYHA) functional class II or III heart failure were randomized to open-label carvedilol vs. perindopril for 6 months then combination therapy, study drugs titrated to maximum tolerable doses –comparing carvedilol-first vs. perindopril-first groups at 12 months, carvedilol-first associated with higher tolerable dose of carvedilol achieved (43 mg vs. 33 mg, p = 0.03) lower furosemide dose (p < 0.05) better improvements in NYHA functional class (p < 0.002) better improvements in ejection fraction (15% vs. 6%, p < 0.05) –Reference - J Am Coll Cardiol 2004 Nov 2;44(9):1825J Am Coll Cardiol 2004 Nov 2;44(9):1825

240 Diuretics: for heart failure –diuretics recommended for patients with current or recent history of fluid overload, but not in patients without fluid overload –strong evidence that diuretics relieve symptoms, reduce episodes of decompensation and improve exercise capacity (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –weak evidence that diuretics reduce mortality and worsening heart failure compared to placebo (level 2 [mid-level] evidence)level 2 [mid-level] evidence –typical doses for recommended loop diuretics furosemide (Lasix) mg once or twice daily initially, maximum 600 mg/day bumetanide (Bumex) mg once or twice daily initially, maximum 10 mg/day torsemide (Demadex) mg/day initially, maximum 200 mg/day –addition of spironolactone to ACE inhibitor and loop diuretic shown to reduce mortality in patients with severe heart failure monitor electrolytes, BUN and creatinine –hypokalemia may require potassium supplements or potassium-sparing diuretics –hyperkalemia may occur with potassium-sparing diuretics, especially with concomitant ACE inhibitors –excessive diuresis, particularly before or with ACE inhibitors, can potentiate hypotension or renal insufficiency loop diuretics (and possibly metolazone and indapamide) more effective than thiazides if renal insufficiency potassium-sparing diuretics include amiloride (Midamor) and triamterene (Dyrenium) –potassium-sparing diuretics which also have aldosterone antagonist activity include spironolactone and eplerenone –used as adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents to prevent hypokalemia –rarely used alone due to weak diuretic and antihypertensive effects –contraindicated if anuria, acute or chronic renal insufficiency, or diabetic nephropathy –risk for hyperkalemia, especially with renal impairment or use of ACE inhibitors, angiotensin II receptor antagonist, cyclosporine, or tacrolimus

241 Aldosterone antagonists: Spironolactone: aldosterone antagonist, potassium-sparing diuretic available in generic or brand name Aldactone addition of aldosterone antagonist recommended in selected patients with moderately severe to severe symptoms of heart failure who can be carefully monitored for preserved renal function and normal potassium concentration (grade B recommendation [inconsistent or limited evidence])grade B recommendation [inconsistent or limited evidence] addition of spironolactone to ACE inhibitor and loop diuretic shown to reduce mortality in patients with severe heart failure based on Randomized Aldactone Evaluation Study (RALES) –initial dose 25 mg orally once daily –increased to 50 mg/day after 8 weeks if progression of heart failure without hyperkalemia or renal insufficiency –decreased to 25 mg every other day if hyperkalemia developed US FDA Pregnancy Category C contraindicated with hyperkalemia (potassium > 5.5 mEq/L [5.5 mmol/L]) or renal impairment (creatinine > 2.5 mg/dL [221 µmol/L]) SEVERE HYPERKALEMIA can occur when spironolactone given with ACE inhibitors or angiotensin receptor blockers for heart failure avoid concomitant potassium-sparing diuretics, potassium supplements and lithium gynecomastia occurred in 10% of men in RALES study see Spironolactone for heart failure for details

242 Digoxin: digoxin (Lanoxin) is inotropic but also vagotonic limited value with mild heart failure and normal sinus rhythm no increased survival if asymptomatic heart failure beneficial if atrial fibrillation, severe heart failure, ejection fraction (EF) < 20% –dramatic effectiveness in symptomatic heart failure –withdrawal studies (digoxin replaced with placebo) have shown increased progression of heart failure; PROVED and RADIANCE trials with and without ACE inhibitors ( J Am Coll Cardiol 1993;22:955, N Engl J Med 1993;329:1, discussion in Cortlandt Forum 1996 Sep;9(9):69, 103-8)J Am Coll Cardiol 1993;22:955N Engl J Med 1993;329:1 –can decrease symptoms, increase exercise tolerance and decrease hospitalization frequency can be added to diuretics and ACE inhibitors digoxin loading dose 0.5 mg intravenously or orally then 0.25 mg every 4-6 hours for 4 doses then mg orally once daily –optimal dose unclear –most studies used mg/day, but many physicians prescribe mg/day as initial and target dose –reduce dose in elderly and renal failure patients –monitor level (therapeutic ng/mL); higher levels may increase mortality –digoxin toxicity more likely with quinidine, verapamil, hypokalemia, hypomagnesemia adverse effects - conduction disturbances, cardiac arrhythmias, nausea, vomiting, confusion, visual disturbances; risk of digitalis toxicity increased with hypokalemia or renal insufficiency Reference - Treatment Guidelines from The Medical Letter 2006 Jan;4(41):91Treatment Guidelines from The Medical Letter 2006

243 Antiplatelet therapy/anticoagulants: role of aspirin for heart failure has not been established –aspirin may increase hospitalization rates in patients with heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence –aspirin may increase heart failure hospitalization and non-fatal stroke compared to warfarin in patients with heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence –aspirin may reduce efficacy of ACE inhibitors (based on surrogate markers) in patients with heart failure (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence –see Aspirin use in patients with heart failure for details role of warfarin for heart failure has not been established –warfarin decreases heart failure hospitalization and non-fatal stroke compared to aspirin in patients with heart failure (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence

244 Hydralazine plus isosorbide dinitrate (BiDil): BiDil (hydralazine plus isosorbide dinitrate) FDA approved for heart failure in self-identified black patients; hydralazine is an antihypertensive which causes arterial vasodilation and reduced cardiac workload, isosorbide dinitrate is an anti-anginal with venous and arterial vasodilation; neither hydralazine alone nor isosorbide dinitrate alone is FDA approved for heart failure (FDA Press Release 2005 Jun 23)FDA Press Release 2005 Jun 23 recommendations from The Medical Letter –recommended for patients with persistent symptoms despite taking an ACE inhibitor and a beta-blocker; consider in patients intolerant of an ACE inhibitor or ARB –no data available for use in addition to standard therapy in populations other than black patients –improves left ventricular ejection fraction –dosing initial isosorbide dinitrate/hydralazine 20 mg/37.5 mg 3 times daily target dose isosorbide dinitrate/hydralazine 40 mg/75 mg 3 times daily –avoid BiDil with concurrent phosphodiesterase inhibitors - sildenafil (Viagra, Revatio), vardenafil (Levitra), or tadalafil (Cialis) because of risk of additive hypotension –adverse effects of BiDil include frequent headache and dizziness –hydralazine alone can cause tachycardia, peripheral neuritis, and a lupus-like syndrome –Reference - Treatment Guidelines from The Medical Letter 2006 Jan;4(41):91Treatment Guidelines from The Medical Letter 2006

245 Nitrates (nitroglycerin): transdermal nitroglycerin improves exercise tolerance in some patients but no differences shown in patient-oriented outcomes –29 patients with CHF and symptoms despite ACE inhibitor therapy randomized to nitroglycerin mg/day vs. placebo as transdermal patches daily for 12 hours for 12 weeks in crossover fashion with 4-week washout period, exercise treadmill testing done every 4 weeks –increase in exercise tolerance (by seconds) occurred with nitroglycerin but not with placebo –most common adverse effects were headache and patch site irritation, 23% nitroglycerin vs. 11% placebo discontinuation rates, no differences in quality of life or need for additional diuretics or hospitalizations for CHF –Reference - Circulation 1999 May 25;99(20):2652 full-textCirculation 1999 May 25;99(20):2652full-text

246 Statins: –atorvastatin may decrease all-cause mortality and hospitalization for worsening heart failure (level 2 [mid-level] evidence), but these benefits not found with simvastatin (level 2 [mid-level] evidence) or rosuvastatin (level 1 [likely reliable] evidence)level 2 [mid-level] evidence level 1 [likely reliable] evidence based on systematic review of trials with methodologic limitations systematic review of 10 randomized trials comparing statins to placebo in 10,192 patients with heart failure 3 trials of rosuvastatin, 1 trial of simvastatin, and 6 trials of atorvastatin trials had varied follow-up (3-47 months) and possible publication bias all individual trials had methodologic limitations affecting blinding, allocation concealment, or sample size except one large rosuvastatin trial heterogeneity in overall analysis so meta-analysis combining statins not appropriate in meta-analyses of atorvastatin –significantly decreased all-cause mortality (odds ratio 0.39, p = 0.004) in analysis of 6 trials with 471 patients –significantly decreased hospitalization for worsening heart failure (odds ratio 0.3, p < ) in analysis of 6 trials with 472 patients –increase in left ventricular ejection fraction (weighted mean difference +5.49%, p < ) in analysis of 4 trials in meta-analyses of rosuvastatin –no significant effect on all-cause mortality in analysis of 3 trials with 9,670 patients –no significant effect on hospitalization for worsening heart failure in analysis of 3 trials with 9,670 patients –decrease in left ventricular ejection fraction (mean difference -3.07%, p = 0.002) in 1 trial simvastatin trial had only 51 patients Reference - Am J Cardiol 2009 Dec 15;104(12):1708Am J Cardiol 2009 Dec 15;104(12):1708

247 Dobutamine: long-term intermittent dobutamine infusion may improve survival in refractory CHF (level 2 [mid-level] evidence)level 2 [mid-level] evidence –30 patients with end-stage CHF refractory to standard medical therapy who could be weaned from dobutamine after initial 72-hour infusion were randomized to dobutamine 10 mcg/kg/minute vs. placebo IV for 8 hours every 14 days –all patients received standard medical therapy and oral amiodarone 400 mg/day (800 mg/day if implanted defibrillator) starting at least 2 weeks before randomization –comparing dobutamine vs. placebo, 1-year survival 69% vs. 28% (NNT 3), 2-year survival 44% vs. 21% (NNT 5), median survival 574 vs. 144 days –Reference - Chest 2004 Apr;125(4):1198 in Am Fam Physician 2004 Aug 15;70(4):756Chest 2004 Apr;125(4):1198Am Fam Physician 2004 Aug 15;70(4):756

248 Medical therapy in patient subgroups: among the oldest old, ACE inhibitors appear beneficial while digoxin may not be; retrospective study of 19,492 nursing home residents > 85 years old with CHF taking ACE inhibitor or digoxin, patients taking ACE inhibitor had lower mortality and lower rates of functional decline than patients taking digoxin (Arch Intern Med 2000 Jan 10;160(1):53); comparison with entire group of 64,637 nursing home residents > 85 years old with CHF would make data more convincing (DynaMed commentary), commentary can be found in Arch Intern Med 2000 Sep 11;160(16):2550Arch Intern Med 2000 Jan 10;160(1):53 Arch Intern Med 2000 Sep 11;160(16):2550 limited evidence regarding treatment for heart failure patients with renal failure –ACE inhibitors reduce mortality if moderate renal insufficiency (glomerular filtration rate mL/minute/1.73 m2) but little evidence for more severe renal failure –beta blockers unlikely affected by renal function –spironolactone associated with increased risk of hyperkalemia if renal failure –Reference - Ann Intern Med 2003 Jun 3;138(11):917 PDF, commentary can be found in Ann Intern Med 2004 Apr 6;140(7):584, Ann Intern Med 2004 Jun 1;140(11):931Ann Intern Med 2003 Jun 3;138(11):917PDFAnn Intern Med 2004 Apr 6;140(7):584Ann Intern Med 2004 Jun 1;140(11):931

249 Iron/erythropoietin: Iron: intravenous iron (ferric carboxymaltose) improves quality of life and functional status in patients with heart failure and iron deficiency even if no anemia present (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –based on randomized trial –459 patients with heart failure of NYHA functional class II-III, iron deficiency (ferritin level < 100 mcg/L, or mcg/L if transferrin saturation < 20%) and hemoglobin level g/dL were randomized to IV ferric carboxymaltose 4 mL (elemental iron 200 mg) vs. saline –dosing was weekly until iron repletion achieved and then once every 4 weeks (beginning at week 8-12) –patients had left ventricular ejection fraction 40% (for patients with NYHA class II) or 45% (for NYHA class III) at baseline –withdrawal before 24-week follow-up in 6.9% with iron and 10.3% with placebo –comparing iron vs. placebo self-reported "much or moderately improved" on Patient Global Assessment in 50% vs. 28% (p < 0.001, NNT 5) NYHA functional class I or II in 47% vs. 30% (p < 0.001, NNT 6) –iron associated with improvements in 6-minute walk test and quality-of-life (p < 0.001) –no significant differences in death, adverse events, or serious adverse events –similar findings in subgroups of patients with or without anemia –Reference - FAIR-HR trial (N Engl J Med 2009 Dec 17;361(25):2436), editorial can be found in N Engl J Med 2009 Dec 17;361(25):2475N Engl J Med 2009 Dec 17;361(25):2436N Engl J Med 2009 Dec 17;361(25):2475

250 Erythropoietin: erythropoietin treatment may reduce hospitalization but not mortality in patients with anemia and chronic heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence –based on systematic review of moderate quality trials –systematic review of 7 randomized trials comparing the effect erythropoietin stimulating proteins vs. placebo or usual care in 650 patients with anemia and heart failure –erythropoietin stimulating proteins associated with reduced heart failure hospitalization (relative risk 0.59, 95% CI ) –no significant difference between treatments in mortality risk (relative risk 0.69, 95% CI ) –Reference - Heart 2009 Aug;95(16):1309, editorial can be found in Heart 2009 Aug;95(15):1278Heart 2009 Aug;95(16):1309Heart 2009 Aug;95(15):1278 treatment of mild anemia with subcutaneous erythropoietin and intravenous iron associated with marked improvement in patients with severe CHF –based on small randomized trial –32 patients with moderate to severe CHF (NYHA class III-IV), ejection fraction < 40% despite maximal medical therapy and hemoglobin g/dL were randomized to subcutaneous erythropoietin and intravenous iron to attain hemoglobin 12.5 g/dL vs. no treatment of anemia –comparing erythropoietin and iron vs. no treatment at mean follow-up 8 months 0 vs. 25% death from CHF-related causes ejection fraction increased 5.5% vs. decreased 5.4% NYHA class improved vs. worsened need for furosemide decreased vs. increased number of days of hospitalization decreased vs. increased –Reference - J Am Coll Cardiol 2001 Jun 1;37(7):1775 in Prescriber's Letter 2001 Jul;8(7):38J Am Coll Cardiol 2001 Jun 1;37(7):1775

251 Estrogen: estrogen use associated with reduced mortality in RETROSPECTIVE study; retrospective study of 1,134 women > 50 years old with symptomatic CHF and left ventricular ejection fraction < 30%; comparing estrogen users vs. nonusers, 15% vs. 27% overall mortality (J Am Coll Cardiol 2000 Aug;36:529 in Am Fam Physician 2001 Feb 15;63(4):728)J Am Coll Cardiol 2000 Aug;36:529Am Fam Physician 2001 Feb 15;63(4):728 Testosterone: testosterone replacement therapy may improve symptoms in men (level 2 [mid- level] evidence)level 2 [mid- level] evidence –76 men with heart failure were randomized to testosterone replacement therapy (Androderm 5 mg) vs. placebo with maximum follow-up of 12 months 42 (55%) completed 12 months of follow-up 19 (25%) dropped out due to skin reaction –exercise capacity significantly improved with testosterone therapy –13 (35%) testosterone vs. 3 (8%) placebo group improved symptoms by at least 1 functional class (NNT 4) –Reference - Eur Heart J 2006 Jan;27(1):57Eur Heart J 2006 Jan;27(1):57 long-acting testosterone therapy may improve metabolic parameters in men with chronic heart failure (level 3 [lacking direct] evidence)level 3 [lacking direct] evidence –based on randomized trial without clinical outcomes –70 men with stable chronic heart failure (median age 70 years) were randomized to testosterone undecanoate 1,000 mg vs. placebo intramuscularly every 6 weeks for 12 weeks –91% completed trial –testosterone associated with improvements in body mass index, aerobic capacity, peak work load, 6-minute walking test, maximal voluntary contraction, isokinetic power torque, ventilation/carbon dioxide output and insulin sensitivity (all p < 0.05) –Reference - J Am Coll Cardiol 2009 Sep 1;54(10):919, commentary can be found in J Am Coll Cardiol 2009 Sep 1;54(10):928J Am Coll Cardiol 2009 Sep 1;54(10):919J Am Coll Cardiol 2009 Sep 1;54(10):928

252 Additional medications: morphine has been suggested for late-stage, refractory, severely symptomatic CHF (Mayo Clin Proc 1998 Feb;73(2):194)Mayo Clin Proc 1998 Feb;73(2):194 theophylline may reduce apnea and oxygen desaturation during sleep in patients with stable heart failure who have central apnea study of 15 men with compensated heart failure, EF 10 episodes of apnea and hypopnea per hour crossover study of theophylline orally 2 times daily for 5 days vs. placebo episodes with theophylline, placebo and baseline were 18, 37 and 47, number of episodes of central apnea (cessation of inspiratory flow for 10 seconds, without rib cage or abdominal excursions) were 6, 26 and 26 theophylline also reduced % sleep time with O2 saturation < 90% alternative treatment of nasal oxygen mentioned as safest approach but somewhat inconvenient Reference - N Engl J Med 1996 Aug 22;335(8):562N Engl J Med 1996 Aug 22;335(8):562

253 sildenafil (Viagra) sildenafil may improve exercise capacity and quality of life in patients with symptomatic heart failure and pulmonary hypertension (level 2 [mid-level] evidence)level 2 [mid-level] evidence –based on small randomized trial –34 patients with symptomatic heart failure and pulmonary hypertension randomized to oral sildenafil (25-75 mg 3 times/day) vs. placebo for 12 weeks –comparing sildenafil vs. placebo 29-meter improvement in 6-minute walking distance (p = 0.047) improved quality of life score (p = 0.01) decreased pulmonary vascular resistance and increased cardiac output with exercise (p < 0.05) –Reference - Circulation 2007 Oct 2;116(14):1555Circulation 2007 Oct 2;116(14):1555 sildenafil may improve breathlessness scores in stable CHF patients (level 2 [mid-level] evidence)level 2 [mid-level] evidence –based on small randomized trial –23 stable CHF patients randomized to sildenafil 50 mg vs. placebo twice daily for 6 months –breathlessness score reduced from baseline at 3 and 6 months in sildenafil group (p < 0.01) but not in placebo group –Reference - J Am Coll Cardiol 2007 Nov 27;50(22):2136J Am Coll Cardiol 2007 Nov 27;50(22):2136

254 Nutritional supplements: Omega-3 (n-3) fatty acids: n-3 polyunsaturated fatty acids reduce all-cause mortality in patients with chronic heart failure (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –based on randomized trial in 357 cardiology or internal medicine centers in Italy –7,046 patients (mean age 67 years) with chronic heart failure (New York Heart Association [NYHA] class II-IV) randomized to n-3 polyunsaturated fatty acids 1 g vs. placebo once daily –n-3 polyunsaturated fatty acids 1 g contains mg of eicosapentaenoic acid plus docosahexaenoic acid as ethyl esters in average ratio 1.2:1 –median follow-up 3.9 years –71 (1%) patients from 1 site not analyzed due to inadequate data –comparing n-3 polyunsaturated fatty acids vs. placebo death from any cause in 27.3% vs. 29.1% (p = 0.041, NNT 56) death from cardiovascular cause in 20.4% vs. 22% (p = 0.045, NNT 63) hospital admission for cardiovascular reasons in 46.8% vs. 48.5% (p = 0.026, NNT 59) –no significant differences in rates of sudden cardiac death, myocardial infarction, or admission for heart failure, but non-significant trends toward reduced rates with n-3 polyunsaturated fatty acids –no significant differences in rates of stroke –similar rate of patients no longer taking study drug by trial end (29% with treatment vs. 30% with placebo) –gastrointestinal disorders reported as most frequent adverse reaction (3% in both groups) –Reference - GISSI-HF trial (Lancet 2008 Oct 4;372(9645):1223) (correction in Lancet 2009 Jan 31;373(9661):382), editorial can be found in Lancet 2008 Oct 4;372(9645):1195, Ann Intern Med 2009 Jan 20;150(2):JC1Lancet 2008 Oct 4;372(9645):1223Lancet 2008 Oct 4;372(9645):1195Ann Intern Med 2009 Jan 20;150(2):JC1 –DynaMed commentary -- study funded by drug manufacturer, drug used in study appears similar to (but not same as) prescription drug with brand name Lovaza

255 Coenzyme Q10: may be beneficial as adjunctive therapy, but should not replace conventional therapy coenzyme Q10 also called ubiquinone or Co-Q10 coenzyme Q10 beneficial in most rigorous randomized, placebo-controlled trial –651 patients with NYHA class III or IV heart failure given coenzyme Q10 2 mg/kg/day vs. placebo for 1 year –comparing coenzyme Q10 vs. placebo 23% vs. 37% hospitalization (NNT 7) 6% vs. 30% pulmonary edema (NNT 4) 30% vs. 61% cardiac asthma (NNT 3) –no adverse effects found –Reference - Clin Investig 1993;71(8 Suppl);S134Clin Investig 1993;71(8 Suppl);S134 coenzyme Q10 might improve symptoms in end-stage heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence –32 patients with end-stage heart failure awaiting heart transplantation were randomized to Ultrasome--CoQ10 60 mg/day vs. placebo for 3 months –27 patients (84%) completed the study –no significant differences in echocardiography parameters, or atrial natriuretic factor or tumor necrosis factor levels –intervention group had significant improvement in 6-minute walk test and decreases in dyspnea, nocturia, fatigue and NYHA classification –Reference - Clin Cardiol 2004 May;27(5):295Clin Cardiol 2004 May;27(5):295

256 Phosphodiesterase inhibitors: phosphodiesterase inhibitors include amrinone, milrinone, vesnarinone phosphodiesterase inhibitors increase mortality in chronic heart failure (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –systematic review of 21 randomized placebo-controlled trials with 8,408 patients followed at least 3 months –phosphodiesterase inhibitors also increase risk of cardiac death, sudden death, arrhythmias and vertigos –Reference - systematic review last updated 2004 Jul 20 (Cochrane Library 2005 Issue 1:CD002230)Cochrane Library 2005 Issue 1:CD long-term oral milrinone increases morbidity and mortality in severe congestive heart failure –patients with dyspnea and left ventricular ejection fraction < 35% despite conventional therapy (diuretics, digoxin and ACE inhibitor at least 4 weeks) given milrinone 10 mg orally 4 times daily vs. placebo –lack of functional improvement, increased hospitalization and increased mortality in milrinone group resulted in early termination of trial

257 Medical therapies which appear ineffective for chronic heart failure: calcium channel blockers –calcium channel blockers not associated with significant effect on mortality based on systematic review of 18 randomized trials with 3,128 patients with moderate to advanced heart failure Reference - Am J Cardiol 2001 Feb 15;87(4):487Am J Cardiol 2001 Feb 15;87(4):487 –amlodipine (Norvasc) studied in PRAISE-1 trial amlodipine may be safe in severe heart failure but efficacy not shown –based on trial of 1,153 chronic heart failure patients given amlodipine (5 mg orally once daily for 2 weeks then 10 mg orally once daily) vs. placebo for 6-33 months, all patients given ACE inhibitor –no significant negative inotropy, no effects on conduction –trend toward mortality reduction from 38.3% to 33.2% (p = 0.07), no adverse effects –no trend in patients with ischemic cardiomyopathy –421 patients with non-ischemic (idiopathic) cardiomyopathy had statistically significant decrease in all-cause mortality from 34.9% to 21.5% (p = 0.001), decrease in fatal or nonfatal cardiovascular events from 37% to 28%, decrease in cardiovascular mortality from 31% to 18% –amlodipine increased incidence of pulmonary edema from 10% to 15% (mainly on chest x-ray and not clinically significant) –Reference - N Engl J Med 1996 Oct 10;335(15):1107, commentary in N Engl J Med 1997 Apr 3;336(14):1023N Engl J Med 1996 Oct 10;335(15):1107N Engl J Med 1997 Apr 3;336(14):1023

258 Surgery: Left ventricular assist device (LVAD) : general information left ventricular assist device improves survival and quality of life in advanced heart failure in patients ineligible for cardiac transplantation –based on randomized trial –129 patients with end-stage heart failure (NYHA class IV) who were ineligible for cardiac transplantation randomized to left ventricular assist device (LVAD) vs. optimal medical management –comparing LVAD vs. medical management 1-year survival 52% vs. 25% (p = 0.002, NNT 4) 2-year survival 23% vs. 8% (p = 0.09, NNT 6.7) quality of life significantly improved in device group at 1 year –device use associated with increased serious adverse events including infection, bleeding, and device malfunction; rate of serious adverse events 6.45 vs per patient-year –Reference - N Engl J Med 2001 Nov 15;345(20):1435, editorial can be found in N Engl J Med 2001 Nov 15;345(20):1490, commentary can be found in N Engl J Med 2002 Mar 28;346(13):1023, ACP J Club 2002 May-Jun;136(3):88N Engl J Med 2001 Nov 15;345(20):1435N Engl J Med 2001 Nov 15;345(20):1490N Engl J Med 2002 Mar 28;346(13):1023ACP J Club 2002 May-Jun;136(3):88

259 left ventricular assist device placement before heart transplant not associated with increased survival based on retrospective cohort study 2,786 adults 18 years old in status 1A or 1B had heart transplantation 1,354 patients (48.6%) received left ventricular assist device prior to transplantation no significant difference in survival with or without left ventricular assist device (even after data stratified by propensity score) Reference - BMJ 2010 Feb 10;340:c392 full-textBMJ 2010 Feb 10;340:c392full-text

260 device approvals HeartMate left ventricular assist device FDA approved for use as bridge to heart transplant and for permanent use in certain terminally ill patients ineligible for heart transplant (FDA Press Release 2002 Nov 6) HeartMate II left ventricular assist system FDA approved as –first compact heart assist device (FDA Press Release 2008 Apr 21)FDA Press Release 2008 Apr 21 –support for severe heart failure patients not acceptable as candidates for heart transplantation (FDA Press Release 2010 Jan 20)FDA Press Release 2010 Jan 20 DeBakey VAD Child is first ventricular assist device FDA approved for children ages 5-16 years awaiting heart transplant (FDA Talk Paper 2004 Feb 26FDA Talk Paper 2004 Feb 26

261 Cardiac transplantation: consider in class III-IV, age < 65 years, no major medical problems post-transplant survival rates 85-87% at 1 year, 65-75% at 5 years, median survival 7-8 years; survival has improved with use of cyclosporine

262 Consultation and referral: Structured management and education: heart failure-specific patient education and postdischarge follow-up after hospitalization for heart failure reduces readmission rates but not mortality (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence comprehensive discharge planning with postdischarge support reduces readmission rates in heart failure patients (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence self-management may reduce readmission rate after hospitalization for heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence nurse-based case management has inconsistent evidence multidisciplinary disease management programs may reduce mortality and hospitalizations (level 2 [mid-level] evidence)level 2 [mid-level] evidence collaborative care including pharmacist (but not pharmacist-directed care) may reduce all-cause and heart failure hospitalizations (level 2 [mid-level] evidence)level 2 [mid-level] evidence telephonic case management or support for heart failure may reduce mortality and hospital admission rates (level 2 [mid-level] evidence)level 2 [mid-level] evidence home nurse visits after hospital discharge may reduce readmission rates (level 2 [mid-level] evidence)level 2 [mid-level] evidence see Heart failure structured management and education for details

263 Reviews of pacing for heart failure: review of pacing for heart failure can be found in Lancet 2001 Apr 21;357(9264):1277Lancet 2001 Apr 21;357(9264):1277 review of ventricular pacing in congestive heart failure can be found in Mayo Clin Proc 2001 Aug;76(8):803Mayo Clin Proc 2001 Aug;76(8):803 review of pacemaker therapy can be found in Am Fam Physician 2005 Apr 15;71(8):1563Am Fam Physician 2005 Apr 15;71(8):1563 review of cardiac pacing can be found in Lancet 2004 Nov 6;364(9446):1701Lancet 2004 Nov 6;364(9446):1701 review of pacing for heart failure can be found in BMJ 2003 May 17;326(7398):1073BMJ 2003 May 17;326(7398):1073

264 Implanted cardioverter-defibrillator (ICD): implanted cardioverter-defibrillator (ICD) may prevent sudden cardiac death in multiple patient populations –single-lead, shock-only ICD reduces mortality in patients with NYHA class II heart failure, and in patients with class III heart failure and ejection fraction < 31% (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –ICD reduces mortality in patients with prior myocardial infarction and left ventricular ejection fraction < 30% –ICD reduces risk of sudden death from arrhythmia in nonischemic dilated cardiomyopathy, left ventricular ejection fraction 120/minute) (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –ICD may reduce mortality in patients prone to ventricular fibrillation based on electrophysiologic testing (level 2 [mid-level] evidence)level 2 [mid-level] evidence –implantable cardioverter-defibrillator (ICD) appears superior to antiarrhythmic drugs for increasing survival (level 2 [mid-level] evidence) for patients with history of ventricular fibrillation or sustained ventricular tachycardia (spontaneous or induced)level 2 [mid-level] evidence –see Implantable cardioverter-defibrillator (ICD) for details

265 Hospice care: 4-item risk score may predict 6-month mortality in older patients with heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence –based on derivation cohort study without validation –282 patients > 70 years old admitted to hospital with heart failure –43 (15%) died within 6 months –4 independent risk factors for 6-month mortality serum urea nitrogen (BUN) 30 mg/dL systolic blood pressure < 120 mm Hg peripheral arterial disease serum sodium < 135 mEq/L –6-month mortality 3.7% with 0 risk factors 16.3% with 1 risk factor 41% with 2 risk factors 66.7% with 3-4 risk factors –Reference - J Am Geriatr Soc 2008 Jun;56(6):1111J Am Geriatr Soc 2008 Jun;56(6):1111

266 smoking cessation –retrospective study of > 6,700 patients in trials found that current smoking was associated with increased risks for overall mortality and combined endpoint of death, myocardial infarction or recurrent hospitalization for heart failure compared with never- smokers or ex-smokers –increased risk disappeared within 2 years after quitting smoking –Reference - J Am Coll Cardiol 2001 May;37(6):1677 in J Watch 2001 Jul 1;21(13):105, editorial can be found in J Am Coll Cardiol 2001 May;37(6):1683J Am Coll Cardiol 2001 May;37(6):1677J Am Coll Cardiol 2001 May;37(6):1683

267 Continuous positive airway pressure (CPAP): CPAP does not prevent mortality or hospitalization in heart failure patients with central sleep apnea (level 1 [likely reliable] evidence)level 1 [likely reliable] evidence –258 patients with heart failure (mean ejection fraction 24.5%) and central sleep apnea (mean 40 apnea and hypopnea episodes per hour of sleep) were randomized to continuous positive airway pressure (CPAP) vs. no CPAP for mean 2 years –CPAP (vs. no CPAP) improved multiple intermediate outcomes mean reductions in hourly apnea and hypopnea episodes 21 vs. 2 (p < 0.001) mean nocturnal oxygen saturation increased 1.6% vs. 0.4% (p < 0.001) mean ejection fraction increased 2.2% vs. 0.4% (p = 0.02) mean six-minute walk distance increased 20 vs meters (p = 0.016) –CPAP did not significantly affect most important outcomes number of hospitalizations quality of life overall survival survival without heart transplantation –Reference - N Engl J Med 2005 Nov 10;353(19):2025, editorial can be found in N Engl J Med 2005 Nov 10;353(19):2070, (correction can be found in N Engl J Med 2005 Dec 8;353(23):2523), commentary can be found in N Engl J Med 2006 Mar 9;354(10):1086N Engl J Med 2005 Nov 10;353(19):2025N Engl J Med 2005 Nov 10;353(19):2070N Engl J Med 2006 Mar 9;354(10):1086

268 Follow-up: Monitoring: routine echocardiography or maximal exercise testing for monitoring not recommended, grade B evidence in AHCPR clinical practice guideline (J Am Geriatr Soc 1998 Apr;46(4):525)J Am Geriatr Soc 1998 Apr;46(4):525 patients should record daily weights and call practitioner if unexplained weight gain of 3-5 lbs, grade C evidence (i.e. expert opinion with no evidence) in AHCPR clinical practice guideline (J Am Geriatr Soc 1998 Apr;46(4):525)J Am Geriatr Soc 1998 Apr;46(4):525 implantable hemodynamic monitoring (Chronicle IHM System) not clearly shown to reduce health care utilization (level 2 [mid- level] evidence)level 2 [mid- level] evidence –based on systematic review of limited evidence –remote monitoring for ambulatory heart failure patients transmits data from implantable device for continuous assessment –5 prospective observational studies funded by Medtronic suggest reduced hospitalizations with right ventricle implantable hemodynamic monitoring –1 randomized trial in 277 patients (COMPASS-HF) did not show significant reduction in composite outcome of hospital admissions, emergency department or urgent clinic visits –Reference - Canadian Agency for Drugs and Technologies in Health (CADTH) Health Technology Assessment 2008 Jan PDFCanadian Agency for Drugs and Technologies in Health (CADTH) Health Technology Assessment 2008 Jan PDF

269 Prevention and Screening of CHF Prevention: American College of Cardiology/American Heart Association (ACC/AHA) guidelines on heart failure in adults –for patients with risk factors (hypertension, coronary artery disease, diabetes, prior treatment with cardiotoxic drugs, rheumatic fever, or family history of cardiomyopathy) treat hypertension and lipid disorders (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A control blood sugar in patients with diabetes (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C secondary prevention measures if known atherosclerotic vascular disease (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C avoid smoking, excessive alcohol consumption and illicit drug use (ACC/AHA Class I, Level of Evidence C)ACC/AHA Class I, Level of Evidence C control ventricular rate or restore sinus rhythm if supraventricular tachyarrhythmia (ACC/AHA Class I, Level of Evidence B)ACC/AHA Class I, Level of Evidence B

270 additional recommendations for asymptomatic patients with cardiac structural abnormalities or remodeling (for example, reduced left ventricular ejection fraction) if recent or remote history of myocardial infarction –add beta blockers (ACC/AHA Class I, Level of Evidence A ) and ACE inhibitors (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence A –angiotensin II receptor blockers may be beneficial if low left ventricular ejection fraction and intolerant of ACE inhibitor (ACC/AHA Class I, Level of Evidence B)ACC/AHA Class I, Level of Evidence B if reduced left ventricular function –add beta blockers (ACC/AHA Class I, Level of Evidence C ) and ACE inhibitors (ACC/AHA Class I, Level of Evidence A)ACC/AHA Class I, Level of Evidence CACC/AHA Class I, Level of Evidence A –angiotensin II receptor blockers may be beneficial if intolerant of ACE inhibitor (ACC/AHA Class IIa, Level of Evidence C)ACC/AHA Class IIa, Level of Evidence C if hypertension and left ventricular hypertrophy - ACE inhibitors or angiotensin II receptor blockers (ACC/AHA Class IIa, Level of Evidence B)ACC/AHA Class IIa, Level of Evidence B implantable cardioverter-defibrillator reasonable in patients with ischemic cardiomyopathy who are at least 40 days post-myocardial infarction, have left ventricular ejection fraction 30%, are New York Heart Association functional Class I on chronic optimal medical therapy and have reasonable expectation of survival with good functional status for > 1 year (ACC/AHA Class IIa, Level of Evidence B)ACC/AHA Class IIa, Level of Evidence B

271 antihypertensives associated with reduced incidence of heart failure diuretic treatment of elderly patients with isolated systolic hypertension may reduce incidence of heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence beta blockers similar to other antihypertensive agents for prevention of heart failure in hypertensive patients (level 2 [mid-level] evidence)level 2 [mid-level] evidence ACE inhibitors appear effective for prevention of heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence angiotensin receptor blockers (ARBs) may not be effective for prevention of heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence calcium channel blockers (CCBs) may not be as effective as other antihypertensives for prevention of heart failure (level 2 [mid-level] evidence)level 2 [mid-level] evidence

272 Screening: current evidence inadequate to support community- wide screening for asymptomatic left ventricular systolic dysfunction, either with echocardiography or with natriuretic peptide assays; estimated prevalence 3%-6%, prognosis of mild disease in community settings not established (Ann Intern Med 2003 Jun 3;138(11):907)Ann Intern Med 2003 Jun 3;138(11):907 plasma natriuretic peptides not useful for general population screening –study of 3,177 subjects from Framingham cohort –neither brain natriuretic peptide (BNP) nor N-terminal proatrial natriuretic peptide (NT-ANP) had adequate sensitivity for elevated left ventricular mass or left ventricular systolic dysfunction to be useful for screening –Reference - JAMA 2002 Sep 11;288(10):1252JAMA 2002 Sep 11;288(10):1252

273 BNP may be sensitive enough for screening if use limited to high-risk patients, based on high blood pressure or abnormal ECG random sample of 1,257 persons age years from general population in Glasgow had blood pressure measurement, ECG, BNP measurement and echocardiography 140 subjects with symptomatic heart disease had 19% prevalence of left ventricular systolic dysfunction and 71% had BNP > 8 pg/mL, BNP had 92% sensitivity with 95.1% negative predictive value, 34% specificity with 24% positive predictive value 269 subjects with blood pressure > 160/95 mm Hg or abnormal ECG had 6% prevalence of left ventricular systolic dysfunction and 64% had BNP > 8 pg/mL, BNP had 94% sensitivity with 99% negative predictive value, 38% specificity with 8.7% positive predictive value 823 subjects with no risk factors had 0.7% prevalence of left ventricular systolic dysfunction and 41% had BNP > 8 pg/mL, BNP had 83% sensitivity with 99.8% negative predictive value, 59% specificity with 1.5% positive predictive value Reference - J Am Coll Cardiol 2003 Jan 1;41(1):113 in Am Fam Physician 2003 Jun 15;67(12):2599J Am Coll Cardiol 2003 Jan 1;41(1):113Am Fam Physician 2003 Jun 15;67(12):2599

274 General references used: 1. Jessup M, Abraham WT, Casey DE, et al. Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009 Apr 14;119(14):1977 PDF Circulation 2009 Apr 14;119(14):1977PDF 2. Hunt SA; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol Sep 20;46(6):e1-82. PDF or Circulation 2005 Sep 20;112(12):e154 full-text (correction can be found in Circulation 2006 Apr 4;113(13):e684) or at National Guideline Clearinghouse 2005 Dec 5:7664J Am Coll Cardiol Sep 20;46(6):e1-82.PDFCirculation 2005 Sep 20;112(12):e154full-textCirculation 2006 Apr 4;113(13):e684National Guideline Clearinghouse 2005 Dec 5:7664 American College of Cardiology/American Heart Association (ACC/AHA) guideline classification: Classification of Recommendations: Class I - evidence and/or general agreement that procedure or treatment is beneficial, useful and effective and should be done Class II - conflicting evidence and/or divergence of opinion about usefulness or efficacy of procedure or treatment –Class IIa - weight of evidence or opinion in favor of usefulness or efficacy, so reasonable to do –Class IIb - usefulness or efficacy less well established by evidence or opinion, so may be considered Class III - evidence and/or general agreement that procedure or treatment is not useful or effective, and may be harmful, so should not be done Level of Evidence: Level of Evidence A - data derived from multiple randomized trials or meta-analyses Level of Evidence B - data derived from single randomized trial or non-randomized studies Level of Evidence C - only consensus opinion of experts, case studies or standard of care

275 General reviews: review can be found in Lancet 2009 Mar 14;373(9667):941Lancet 2009 Mar 14;373(9667):941 Clinical Evidence Concise review (search date 2005 Feb) can be found in Am Fam Physician 2006 Aug 1;74(3):467Am Fam Physician 2006 Aug 1;74(3):467 review can be found in Lancet 2005 May 28;365(9474):1877Lancet 2005 May 28;365(9474):1877 review can be found in N Engl J Med 2003 May 15;348(20):2007, commentary can be found in N Engl J Med 2003 Sep 4;349(10):1002, Am Fam Physician 2004 Jan 15;69(2):405N Engl J Med 2003 May 15;348(20):2007N Engl J Med 2003 Sep 4;349(10):1002Am Fam Physician 2004 Jan 15;69(2):405 review based on new ACC/AHA guidelines can be found in Adv Stud Med 2003 Jan;3(1):14 PDFAdv Stud Med 2003 Jan;3(1):14 PDF review can be found in Postgrad Med 2003 Mar;113(3):36Postgrad Med 2003 Mar;113(3):36 Clinical Evidence review can be found in Am Fam Physician 2002 Jan 1;65(1):99Am Fam Physician 2002 Jan 1;65(1):99 review can be found in BMJ 2002 Aug 24;325(7361):422BMJ 2002 Aug 24;325(7361):422 review of systolic heart failure can be found in N Engl J Med 2010 Jan 21;362(3):228N Engl J Med 2010 Jan 21;362(3):228 review of advanced heart failure can be found in JAMA 2002 Feb 6;287(5):628, commentary can be found in JAMA 2002 May 1;287(17):2209JAMA 2002 Feb 6;287(5):628JAMA 2002 May 1;287(17):2209 review can be found in Am Fam Physician 2000 Mar 1;61(5):1319Am Fam Physician 2000 Mar 1;61(5):1319 review can be found in BMJ 2000 Mar 4;320(7235):626BMJ 2000 Mar 4;320(7235):626 multiple articles on heart failure can be found in Lancet 1998 Aug 29;352(suppl 1); summary of review article can be found in Am Fam Physician 1999 Jan 15;59(2):443Am Fam Physician 1999 Jan 15;59(2):443 review can be found in Am Fam Physician 1996 Jul;54(1):245, commentary can be found in Am Fam Physician 1997 Apr;55(5):1561Am Fam Physician 1996 Jul;54(1):245Am Fam Physician 1997 Apr;55(5):1561 review of CHF in elderly patients can be found in Mayo Clin Proc 1997 May;72(5):453 (summary in Am Fam Physician 1997 Oct 1;56(5):1448 or in J Am Geriatr Soc 1997 Oct;45(10):1252), commentary can be found in J Am Geriatr Soc 1998 Aug;46(8):1053Mayo Clin Proc 1997 May;72(5):453J Am Geriatr Soc 1997 Oct;45(10):1252J Am Geriatr Soc 1998 Aug;46(8):1053 review of diastolic ventricular dysfunction in the elderly can be found in J Am Geriatr Soc 1995 Sep;43(9):1035J Am Geriatr Soc 1995 Sep;43(9):1035 review of diastolic heart failure can be found in Postgrad Med 2003 Mar;113(3):51Postgrad Med 2003 Mar;113(3):51

276 Diagnosis reviews: review of evaluation of chronic dyspnea can be found in Am Fam Physician 2005 Apr 15;71(8):1529 Am Fam Physician 2005 Apr 15;71(8):1529 review of diagnosis of heart failure in adults can be found in Am Fam Physician 2004 Dec 1;70(11):2145Am Fam Physician 2004 Dec 1;70(11):2145 Applied Evidence review of evaluation of suspected left ventricular systolic dysfunction can be found in J Fam Pract 2002 May;51(5):466J Fam Pract 2002 May;51(5):466 review of clinical features and complications can be found in BMJ 2000 Jan 22;320(7229):236BMJ 2000 Jan 22;320(7229):236 case-based discussion of heart failure can be found in JAMA 1999 Jun 23/30;281(24):2321, commentary can be found in JAMA 2000 Feb 23;283(8):1054 JAMA 1999 Jun 23/30;281(24):2321JAMA 2000 Feb 23;283(8):1054 review of pulmonary artery wedge pressure can be found in Am Fam Physician 1996 Sep 1;54(3):1039, correction can be found in Am Fam Physician 1996 Dec;54(8):2377Am Fam Physician 1996 Sep 1;54(3):1039

277 Treatment reviews: Applied Evidence review of outpatient treatment can be found in J Fam Pract 2002 Jun;51(6):519J Fam Pract 2002 Jun;51(6):519 review of management strategies can be found in BMJ 2000 Feb 26;320(7234):559BMJ 2000 Feb 26;320(7234):559 review of outpatient treatment of systolic heart failure can be found in Am Fam Physician 2004 Dec 1;70(11):2157, commentary can be found in Am Fam Physician 2005 Oct 1;72(7):1172Am Fam Physician 2004 Dec 1;70(11):2157Am Fam Physician 2005 Oct 1;72(7):1172 review of treatment can be found in Am Fam Physician 2001 Apr 15;63(8):1593, editorial can be found in Am Fam Physician 2001 Apr 15;63(8):1483, correction can be found in Am Fam Physician 2002 Jan 15;65(2):172Am Fam Physician 2001 Apr 15;63(8):1593Am Fam Physician 2001 Apr 15;63(8):1483Am Fam Physician 2002 Jan 15;65(2):172 review of treatment checklist for advanced heart failure in elderly can be found in Annals of Long-Term Care 2007 Aug;15(8):21, commentary can be found in Annals of Long-Term Care 2008 Jan;16(1):17Annals of Long-Term Care 2007 Aug;15(8):21Annals of Long-Term Care 2008 Jan;16(1):17 review of treatment of edema can be found in Am Fam Physician 2005 Jun 1;71(11):2111, commentary can be found in Am Fam Physician 2006 Feb 15;73(4):589Am Fam Physician 2005 Jun 1;71(11):2111Am Fam Physician 2006 Feb 15;73(4):589

278 Pharmacological: review with focus on drug therapy can be found in Arch Intern Med 2001 Feb 12;161(3):342Arch Intern Med 2001 Feb 12;161(3):342 review of drug treatment can be found in Adv Stud Med 2005 Feb;5(2):81 PDFAdv Stud Med 2005 Feb;5(2):81 PDF review of newer drug therapy can be found in Arch Intern Med 1999 Jun 14;159(11):1177Arch Intern Med 1999 Jun 14;159(11):1177 review of drug treatment can be found in BMJ 2000 Apr 29;320(7243):1188, correction can be found in BMJ 2000 Jul 15;321(7254):161, commentary can be found in BMJ 2000 Sep 16;321(7262):706BMJ 2000 Apr 29;320(7243):1188BMJ 2000 Jul 15;321(7254):161BMJ 2000 Sep 16;321(7262):706 review of pharmacotherapy for chronic heart failure can be found in Ann Intern Med 2005 Jan 18;142(2):132Ann Intern Med 2005 Jan 18;142(2):132 review of pharmacologic management of heart failure caused by systolic dysfunction can be found in Am Fam Physician 2008 Apr 1;77(7):957, commentary can be found in Am Fam Physician 2009 Mar 15;79(6):454Am Fam Physician 2008 Apr 1;77(7):957Am Fam Physician 2009 Mar 15;79(6):454 review of diuretics, ACE inhibitors and nitrates can be found in BMJ 2000 Feb 12;320(7232):428BMJ 2000 Feb 12;320(7232):428 review of inotropes, beta blockers, antithrombotics and antiarrhythmics can be found in BMJ 2000 Feb 19;320(7233):495BMJ 2000 Feb 19;320(7233):495

279 Non-pharmacological: review of nutrition and heart failure can be found in Nutr Clin Pract 2009 Feb-Mar;24(1):60Nutr Clin Pract 2009 Feb-Mar;24(1):60 review of nonpharmacologic treatment can be found in BMJ 2000 Feb 5;320(7231):366BMJ 2000 Feb 5;320(7231):366 review of non-pharmacologic therapy for chronic heart failure can be found in Adv Stud Med 2006 Jan;6(1):16 PDFAdv Stud Med 2006 Jan;6(1):16 PDF review of surgery for chronic heart failure can be found in Postgrad Med 2001 Mar;109(3):61Postgrad Med 2001 Mar;109(3):61 Palliative: review of palliative care for heart failure patients can be found in JAMA 2004 May 26;291(20):2476, follow-up can be found in JAMA 2004 Oct 13;292(14):1744 JAMA 2004 May 26;291(20):2476JAMA 2004 Oct 13;292(14):1744 review of palliative care in heart failure can be found in Adv Stud Med 2003 Sep;3(8):456 PDF, commentary can be found in Adv Stud Med 2003 Nov-Dec;3(10):580 PDFAdv Stud Med 2003 Sep;3(8):456 PDFAdv Stud Med 2003 Nov-Dec;3(10):580 PDF review of integrating palliative care into heart failure care can be found in Arch Intern Med 2005 Feb 28;165(4):374Arch Intern Med 2005 Feb 28;165(4):374

280 Guidelines: synthesis of 3 guidelines (HFSA 2006, NHFA/CSANZ 2006, SIGN 2007) on diagnosis and evaluation of chronic heart failure can be found at National Guideline Clearinghouse 2009 May 18:CHF1National Guideline Clearinghouse 2009 May 18:CHF1

281 United States guidelines: American College of Cardiology/American Heart Association (ACC/AHA) heart failure guidelines –American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2009 focused update on guidelines for diagnosis and management of heart failure in adults can be found in Circulation 2009 Apr 14;119(14):1977 PDF or J Am Coll Cardiol 2009 Apr 14;53(15):e1Circulation 2009 Apr 14;119(14):1977 PDFJ Am Coll Cardiol 2009 Apr 14;53(15):e1 –ACC/AHA 2005 guideline update for diagnosis and management of chronic heart failure in the adult can be found in J Am Coll Cardiol Sep 20;46(6):e1 PDF or Circulation 2005 Sep 20;112(12):e154 full-text (correction can be found in Circulation 2006 Apr 4;113(13):e684) or at National Guideline Clearinghouse 2005 Dec 5:7664, summary can be found in Am Fam Physician 2007 Mar 1;75(5):742 full-textJ Am Coll Cardiol Sep 20;46(6):e1PDFCirculation 2005 Sep 20;112(12):e154full-text Circulation 2006 Apr 4;113(13):e684National Guideline Clearinghouse 2005 Dec 5:7664Am Fam Physician 2007 Mar 1;75(5):742full-text –updates ACC/AHA 2001 guidelines for evaluation and management of chronic heart failure in adult which can be found in J Am Coll Cardiol 2001;38:2101 full- text, summary can be found in J Am Geriatr Soc 2003 Jan;51(1):123J Am Coll Cardiol 2001;38:2101full- textJ Am Geriatr Soc 2003 Jan;51(1):123 American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) 2006 guidelines for management of patients with ventricular arrhythmias and prevention of sudden cardiac death can be found in J Am Coll Cardiol 2006 Sep 5;48(5):e247 full-text or at National Guideline Clearinghouse 2007 Jun 25:9725J Am Coll Cardiol 2006 Sep 5;48(5):e247full-textNational Guideline Clearinghouse 2007 Jun 25:9725 Advisory Council to Improve Outcomes Nationwide in Heart Failure (ACTION HF) guidelines published in Am J Cardiol 1999 Jan 21 can be found in Am Fam Physician 1999 Jun;59(11):3265 or in J Am Geriatr Soc 2000 Nov;48(11):1521Am Fam Physician 1999 Jun;59(11):3265J Am Geriatr Soc 2000 Nov;48(11):1521 University of Michigan Health System guidelines on heart failure- systolic dysfunction can be found at National Guideline Clearinghouse 2007 Feb 5:10179National Guideline Clearinghouse 2007 Feb 5:10179

282 The primary source of information, data and links are from DynaMed medical database


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