1. Hypertension: Case Studies Michael Soung, MD, FACP Virginia Mason Medical Center General Internal Medicine

2. JNC 8?  Current NHLBI guideline in development: JNC 8 (Hypertension) JNC 8 (Hypertension) ATP IV (Cholesterol) ATP IV (Cholesterol) Obesity 2 Obesity 2 “Integrated Cardiovascular Risk Reduction Guideline” “Integrated Cardiovascular Risk Reduction Guideline”  Why the delay? Intensified focus on evidence-based recommendations Intensified focus on evidence-based recommendations IOM 2011 reports on systematic reviews and guideline development IOM 2011 reports on systematic reviews and guideline development http://www.nhlbi.nih.gov/guidelines/http://www.nhlbi.nih.gov/guidelines/ -- Accessed Oct 2012 http://www.nhlbi.nih.gov/guidelines/

3. JNC 8? 3 clinical questions:  When to initiate drug treatment?  How low should BP be lowered?  How do you get there? http://www.ahdbonline.com/node/1009http://www.ahdbonline.com/node/1009-- Accessed Oct 2012 http://www.ahdbonline.com/node/1009 -- Accessed Oct 2012 http://www.ahdbonline.com/node/1009

4. Question #1  60 yo man w/ PMH HTN, hyperlipidemia, smoking. Meds include lisinopril 40mg qAM, HCTZ 25mg qAM, amlodipine 10mg qAM. Average bp 145/90.  Which of the following is the next best step in management? A) Add losartan 25mg daily B) Increase HCTZ to 50mg daily C) Increase Lisinopril to 80mg daily D) Switch lisinopril dosing to bedtime E) No change in medications

5. MAPEC study  2156 patients w/ untreated or resistant HTN (not well-controlled w/ ≥ 3 anti-HTsives)  Intervention: Untreated: monotherapy -- morning vs. bedtime Untreated: monotherapy -- morning vs. bedtime Resistant: (Replace 1 drug and take all BP meds in morning) vs. (Shift ≥ 1 BP med to bedtime dosing) Resistant: (Replace 1 drug and take all BP meds in morning) vs. (Shift ≥ 1 BP med to bedtime dosing)  Primary composite CV outcome at 5.6y: Bedtime dosing: RR 0.39 (0.29-0.51) Bedtime dosing: RR 0.39 (0.29-0.51) 16 fewer CV events per 1000 patient-years 16 fewer CV events per 1000 patient-years 2 fewer deaths per 1000 patient-years 2 fewer deaths per 1000 patient-years Chronobiol Int 2010;27:1629-1651

6. MAPEC study Chronobiol Int 2010;27:1629-1651

7. MAPEC study  Single-center (Spain), open-label, choice of meds left up to providers, use of ambulatory BP monitoring  No difference in clinic BPs or awake ambulatory BP monitoring  Lower sleep-time ambulatory BP monitoring  Similar results in DM and CKD subgroup analyses Ann Intern Med 2012;156:JC6-8 Chronobiol Int 2010;27:1629-1651 Diabetes Care 2011;34:1270-1276 J Am Soc Nephrol 2011;22:2313-21 J Fam Pract 2012;61:153-155 Answer: D

8. Question #2  52 yo man, initial clinic visit. Long history of inconsistently treated HTN. No current meds. Average BP over the last 6 months: 150/85. Trace LE edema on exam. Serum creatinine 3.1 (eGFR 21). Cr 3 months ago was 2.9. K 4.5 Serum creatinine 3.1 (eGFR 21). Cr 3 months ago was 2.9. K 4.5 Urine albumin/creatinine ratio = 600 mg/g. Urine albumin/creatinine ratio = 600 mg/g. Fasting glucose 98, HbA1c = 5.4%. Fasting glucose 98, HbA1c = 5.4%. Renal Ultrasound: medical renal disease, no hydronephrosis. Renal Ultrasound: medical renal disease, no hydronephrosis.

9. Question #2  Which of the following is the most appropriate anti-hypertensive? A) Hydrochlorothiazide B) Benazepril C) Diltiazem D) Amlodipine E) Metoprolol

10. HTN and Chronic Kidney Disease  JNC 7: urinalysis in patients w/ HTN (consider urinary albumin)  NKF K/DOQI guidelines: Assess for proteinuria in patients with CKD Assess for proteinuria in patients with CKD Proteinuria is strong predictor of both CKD progression and cardiovascular disease Proteinuria is strong predictor of both CKD progression and cardiovascular disease Proteinuria as a target of therapy Proteinuria as a target of therapy JAMA 2003;289:2560-2572 Am J Kidney Dis 2004;43:S1-S290

11. HTN and Chronic Kidney Disease  ACE inhibitors for nondiabetic CKD: Meta-analysis of 11 RCTs Meta-analysis of 11 RCTs RR 0.70 (13.2% vs 20.5%) for renal outcomes (doubling of serum Cr or ESRD) RR 0.70 (13.2% vs 20.5%) for renal outcomes (doubling of serum Cr or ESRD) Strongest benefit if proteinuria >0.5 g/ day Strongest benefit if proteinuria >0.5 g/ day  No major differences between individual ACE-inhibitors and ARBs Ann Intern Med 2001;135:73-87 Am J Kidney Dis 2004;43:S1-S290

12. HTN and Chronic Kidney Disease  What about advanced CKD? Largely excluded from earlier ACE-I trials Largely excluded from earlier ACE-I trials  ACE-I in advanced, nondiabetic, proteinuric CKD 224 patients, serum Cr 3.1-5.0 mg/dL, Uprot > 0.3g/d 224 patients, serum Cr 3.1-5.0 mg/dL, Uprot > 0.3g/d Benazepril 20mg daily, 3.4 year f/u Benazepril 20mg daily, 3.4 year f/u Primary outcome: doubling of Cr, ESRD, death Primary outcome: doubling of Cr, ESRD, death RR 0.57 (41% vs 60%) for benazepril group RR 0.57 (41% vs 60%) for benazepril group ***Started low (10mg), checked weekly labs (Cr, K)***  ACE-I: check Cr and K in 1-2 wks Up to 30-35% increase in serum Cr is okay (beneficial), unless hyperkalemia (> 5.6) develops Up to 30-35% increase in serum Cr is okay (beneficial), unless hyperkalemia (> 5.6) develops NEJM 2006;354:131-140 Arch Intern Med 2000;160:685-693 Answer: B

13. Question #3  66yo woman w/ PMH HTN, CKD w/ proteinuria. Meds include lisinopril 40mg daily and amlodipine 10mg daily. Average BP 150/90. No S3, lungs clear, trace BLE edema on exam. Serum Cr 1.2, Urine alb/Cr ratio: 1400 mg/g.  Which of the following is the most appropriate anti-hypertensive? A) Metoprolol B) Hydralazine C) Losartan D) Hydrochlorothiazide E) Doxazosin

14. ACE-inhibitors plus ARBs  ONTARGET (NEJM 2008;358:1547-59 / Lancet 2008;372:547-53.) Ramipril vs telmisartan vs dual-therapy Ramipril vs telmisartan vs dual-therapy 25,620 pts w/ CVD or high-risk DM 25,620 pts w/ CVD or high-risk DM No improvement in primary CV outcome No improvement in primary CV outcome Improved urinary albumin Improved urinary albumin Worsened major renal outcomes (~1% ARI) Worsened major renal outcomes (~1% ARI)  VALIANT (NEJM 2003;349:1893-906) Captopril vs valsartan vs dual-therapy Captopril vs valsartan vs dual-therapy 14,808 pts w/ recent MI c/b CHF 14,808 pts w/ recent MI c/b CHF No difference in mortality or CV outcomes No difference in mortality or CV outcomes 1-3% ARI in drug discontinuation (hypotension, renal) 1-3% ARI in drug discontinuation (hypotension, renal)

15. ACE-inhibitors plus ARBs  CHARM-Added (Lancet 2003;362:767-71) Candesartan vs placebo Candesartan vs placebo 2548 pts w/ CHF on ACE-inhibitors 2548 pts w/ CHF on ACE-inhibitors 4.8% ARR in CV death or CHF hospitalization 4.8% ARR in CV death or CHF hospitalization 7% ARI in drug discontinuation 7% ARI in drug discontinuation  Val-HeFT (NEJM 2001;345:167-75) Valsartan vs placebo Valsartan vs placebo 5010 pts w/ CHF (93% on ACE-inhibitors) 5010 pts w/ CHF (93% on ACE-inhibitors) 4.4% ARR in CHF hospitalization (mortality unchanged) 4.4% ARR in CHF hospitalization (mortality unchanged) 2.2% ARI in drug discontinuation 2.2% ARI in drug discontinuation Worse outcome if already on both ACE-I and β-blocker Worse outcome if already on both ACE-I and β-blocker

16. ACE-inhibitors plus ARBs  Meta-analysis of dual-therapy in CHF: Worsened renal function: RR 2.17 Worsened renal function: RR 2.17 Hyperkalemia: RR 4.87 Hyperkalemia: RR 4.87 Symptomatic Hypotension: RR 1.50 Symptomatic Hypotension: RR 1.50  Meta-analysis of dual-therapy in proteinuria No difference in mortality or CV events No difference in mortality or CV events Hypotension: RR 2.21 Hypotension: RR 2.21 Arch Intern Med 2007;167:1930-1936 Nephrol Dial Transplant 2011;26:2827-2847

17. ACE-inhibitors plus ARBs Pros:  Improves albuminuria and blood pressure  Possible benefit in heart failure Cons:  May worsen hard renal outcomes  More hyperkalemia  More symptomatic hypotension  Generally avoid dual-therapy w/ ACE-I and ARB

18. HTN and Chronic Kidney Disease  Diuretics recommended in CKD and HTN NKF K/DOQI Grade A recommendation for most pts w/ CKD and HTN NKF K/DOQI Grade A recommendation for most pts w/ CKD and HTN Thiazides if GFR ≥ 30 mL/min Thiazides if GFR ≥ 30 mL/min Loop diuretics if GFR < 30 mL/min Loop diuretics if GFR < 30 mL/min Combination for volume overload / edema Combination for volume overload / edema  Non-dihydropyridine calcium-channel blockers also reduce proteinuria Am J Kidney Dis 2004;43:S1-S290 Answer: D

19. Question #4  67 yo woman w/ PMH of DM II, HTN, and hyperlipidemia, on metformin 1000mg BID, lisinopril 10mg daily, and atorvastatin 20mg daily. Average BP:135/85. HbA1c 7.8%, Cr 0.9, Urine alb/cr ratio 16 mg/g.  What of the following is the most appropriate next step in her blood pressure management? A) Add diltiazem B) Add amlodipine C) Add hydrochlorothiazide D) Increase the dose of lisinopril E) No change in blood pressure meds

20. Blood pressure targets in diabetes JNC 7:  Goal blood pressure < 140/90  Exceptions: Diabetes Mellitus Diabetes Mellitus Chronic Kidney Disease Chronic Kidney Disease  goal blood pressure < 130/80 JAMA 2003;289:2560-2572

21. Blood pressure targets in diabetes  ACCORD BP trial 4733 pts w/ high-risk DM, HbA1c ≥ 7.5% 4733 pts w/ high-risk DM, HbA1c ≥ 7.5% SBP goals of <120 vs <140 mmHg SBP goals of <120 vs <140 mmHg SBPs achieved: 119 vs 133.5 mmHg SBPs achieved: 119 vs 133.5 mmHg No change in primary CV outcome at 4.7y No change in primary CV outcome at 4.7y reduction in CVA: 0.32% vs 0.53%reduction in CVA: 0.32% vs 0.53% SBP <120: ↑ serious adverse events (ARI 2%) SBP <120: ↑ serious adverse events (ARI 2%)  No difference for microvascular outcomes NEJM 2010;362:1575-85 Kidney Int 2012;81:586-594

22. Blood pressure targets in diabetes  2011 meta-analysis (broad inclusion): 13 RCTs, 37,736 pts, BP <135 vs <140 13 RCTs, 37,736 pts, BP <135 vs <140 No difference in overall macro/microvacular outcomes No difference in overall macro/microvacular outcomes ↓ mortality by 10% (BP 130-135), ↓ CVA by 17% ↓ mortality by 10% (BP 130-135), ↓ CVA by 17% ↑ serious adverse effects by 20% ↑ serious adverse effects by 20%  2012 meta-analysis (strict inclusion): 5 RCTs, 7312 pts, DBP <75-80 vs <90, + ACCORD 5 RCTs, 7312 pts, DBP <75-80 vs <90, + ACCORD No difference in mortality or MI No difference in mortality or MI ↓ CVA by 35% (1% ARI) ↓ CVA by 35% (1% ARI) Circulation 2011;123:2799-2810 Arch Intern Med 2012;172:1296-1303 Answer: E

23. Blood pressure targets in CKD?  JNC 7 & NKF K/DOQI: < 130/80  Extrapolated from recommendations for other high-risk groups (e.g. diabetes)  Annals 2011 systematic review: 3 RCTs, 2272 patients 3 RCTs, 2272 patients No clear benefit from lower BP targets No clear benefit from lower BP targets Possible benefit in proteinuric patients Possible benefit in proteinuric patients Await SPRINT (2018) and HALT-PKD (2013) Await SPRINT (2018) and HALT-PKD (2013) Am J Kidney Dis 2004;43:S1-S290 Ann Intern Med 2011;154:541-548

24. Question #5  62 yo man w/ long history of HTN on max doses of lisinopril, hydrochlorothiazide, and amlodipine. Average bp: 155/95. No JVD, lungs clear, no LE edema. Serum electrolytes, glucose, creatinine, EKG normal. Negative secondary HTN workup.  Which of the following is the most appropriate next step in management? A) Hydralazine B) Metoprolol C) Spironolactone D) Doxazosin E) Clonidine

25. Resistant Hypertension = failure to reach goal BP w/ full doses of appropriate 3-drug regimen including a diuretic  Multiple potential causes Secondary HTN (e.g. 1° hyperaldo, RAS) Secondary HTN (e.g. 1° hyperaldo, RAS) Improper measurement (e.g. cuff too small) Improper measurement (e.g. cuff too small) Nonadherence, inadequate doses Nonadherence, inadequate doses Drug-induced: NSAIDs, decongestants, OCPs, steroids, cocaine, amphetamines Drug-induced: NSAIDs, decongestants, OCPs, steroids, cocaine, amphetamines Excessive alcohol use, obesity Excessive alcohol use, obesity JAMA 2003;289:2560-2572

26. Resistant Hypertension  ASCOT-BPLA Uncontrolled, nonrandomized ASCOT cohort Uncontrolled, nonrandomized ASCOT cohort 1411 pts who received spironolactone as fourth-line anti-hypertensive 1411 pts who received spironolactone as fourth-line anti-hypertensive Exclusions: hyperaldosteronism or receipt for another indication (CHF, liver failure) Exclusions: hyperaldosteronism or receipt for another indication (CHF, liver failure) Median dose = 25mg Median dose = 25mg Mean bp reduction: 22 / 10 mmHg Mean bp reduction: 22 / 10 mmHg  Dosing: 12.5 - 50mg daily  Side effects: gynecomastia (6%), hyperkalemia (monitor closely!) Hypertension 2007;49:839-845 Answer: C

27. Question #6  85 yo woman w/ PMH HTN and chronic stable angina on ASA and metoprolol. No CP, SOB, edema, HAs, lightheadedness. Healthy diet, regular exercise. Average BP: 165/85. HR 60, nl CV exam, no edema. Cr 0.9, K 4.2, UA neg.  Which of the following is the most appropriate next step in management? A) Add indapamide B) Add lisinopril C) Add amlodipine D) Increase metoprolol dose E) No change in blood pressure meds

28. HTN in the very elderly  Few patients >80yo included in previous HTN trials  JNC 7 recommends same management for elderly (but w/ lower initial drug doses)  Previous meta-analysis of HTN treatment in pts >80yo suggested reduced CVA risk but trend towards increase mortality JAMA 2003;289:2560-2572 NEJM 2008;358:1887-98

29. HTN in the very elderly  HTN in the Very Elderly Trial (HYVET) 3845 healthy pts, age 80+, SBP ≥ 160 mmHg 3845 healthy pts, age 80+, SBP ≥ 160 mmHg Indapamide +/- perindopril vs placebo Indapamide +/- perindopril vs placebo Target blood pressure: 150/80 Target blood pressure: 150/80 2y f/u: 48% of Rx group reached target (vs 20% placebo); mean difference 16/6 mmHg 2y f/u: 48% of Rx group reached target (vs 20% placebo); mean difference 16/6 mmHg CVA: 5.3 fewer per 1000 pt-yrs CVA: 5.3 fewer per 1000 pt-yrs Death (any cause): 12.4 fewer per 1000 pt-yrs Death (any cause): 12.4 fewer per 1000 pt-yrs Fewer serious adverse events in Rx group Fewer serious adverse events in Rx group NEJM 2008;358:1887-98

30. HTN in the very elderly  2010 Cochrane review on anti-HTsive drug treatment in the very elderly: CV mortality / morbidity: RR 0.75 (0.65-0.87) CV mortality / morbidity: RR 0.75 (0.65-0.87) Total mortality: RR 1.01 (0.90-1.13) Total mortality: RR 1.01 (0.90-1.13) Withdrawals due to adverse effects: RR 1.71 (1.45-2.00) Withdrawals due to adverse effects: RR 1.71 (1.45-2.00) Cochrane Database of Systematic Reviews 2010 Answer: A

31. Question #7  63 yo man w/ PMH of HTN, CHF, asthma, gout. Meds include lisinopril, fluticasone / salmeterol INH, allopurinol. Average BP 145/90, HR 68, lungs are clear, no S3, trace BLE edema, a few gouty tophi.  Which of the following is the most appropriate anti-hypertensive? A) Diltiazem B) Amlodipine C) Doxazosin D) Hydrochlorothiazide E) Metoprolol

32. Βeta-blockers and lung disease Cochrane reviews on cardioselective beta-blockers in:  COPD: 22 RCTs in pts w/ COPD 22 RCTs in pts w/ COPD No change in FEV1 or symptoms No change in FEV1 or symptoms No change in response to β2-agonists No change in response to β2-agonists  Reversible airway disease (asthma/COPD): 29 RCTs in pts w/ reversible airway disease 29 RCTs in pts w/ reversible airway disease No change in FEV1 or symptoms No change in FEV1 or symptoms No change in response to β2-agonists No change in response to β2-agonists Cochrane Database of Systematic Reviews 2008

33. Anti-HTsives in systolic heart failure DrugsWho? ↓ mortality? ↓ morbidity? ACE-I/ARBAll Carvedilol / metoprolol ER All Aldosterone antagonists Class III or IV Diuretics Class II - IV Hydralazine / Nitrates ACE-I/ARB intolerant Ann Intern Med 2010;152:ITC61-15 Answer: E

34. Question #8  37 yo woman w/ 5-year history of HTN comes for pre-pregnancy counseling. Stopped her OCP and lisinopril 3 weeks ago. Average BP since: 160/90. No edema on exam, serum electrolytes, Cr, UA all normal.  Which of the following is the most appropriate next step in management? A) Hydrochlorothiazide B) Losartan C) Labetalol D) Atenolol E) No medication

35. Chronic Hypertension in Pregnancy  Prevalence in U.S.: 3% and rising  ↑ risk for preeclampsia, placental abruption, fetal growth restriction, preterm birth, C-section  Treatment reduces risk for severe HTN (but not the above outcomes)  BP typically falls late 1 st trimester, rises to pre- pregnacy values during 3 rd trimester  Cochrane: insufficient evidence to determine appropriate BP targets in pregnancy  Recommendations for starting therapy range from >150-180/100-110, variable targets NEJM 2011;365:439-46 Cochrane Database of Systematic Reviews 2011

36. Chronic Hypertension in Pregnancy  First-line: Methyldopa: longest safety record, somnolence limits tolerability Methyldopa: longest safety record, somnolence limits tolerability Labetalol: better tolerated, good safety data Labetalol: better tolerated, good safety data (Atenolol: fetal-growth restriction)(Atenolol: fetal-growth restriction)  Second-line: Long-acting CCBs: less safety data but appears safe Long-acting CCBs: less safety data but appears safe Diuretics: previously considered unsafe but review of 9 RCTs  no difference in pregnancy outcomes Diuretics: previously considered unsafe but review of 9 RCTs  no difference in pregnancy outcomes  Contraindicated: ACE-I / ARBs: teratogenic, oligohydramnios ACE-I / ARBs: teratogenic, oligohydramnios NEJM 2011;365:439-46 Answer: C

37. Question #9  72 yo woman w/ PMH of HTN, atrial fibrillation (EF 60%), and hyperlipidemia. Medications include HCTZ 25mg daily, digoxin 0.125mg daily, warfarin 5mg daily, and simvastatin 40mg daily. Average BP 135/85, HR 90-110.  Which of the following is the most appropriate next step in management? A) Start metoprolol B) Start diltiazem C) Start amiodarone D) Start amlodipine E) Increase digoxin dose

38. Atrial Fibrillation management 2006 ACC/AHA/ESC Guidelines:  Recommended equally for rate control: Beta-blockers Beta-blockers Nondihydropyridine calcium channel blockers Nondihydropyridine calcium channel blockers  Digoxin: Slows HR at rest, but not w/ exercise, in Afib Slows HR at rest, but not w/ exercise, in Afib Not generally recommended for monotherapy Not generally recommended for monotherapy Circulation 2006; 114:700-752

39. Drug interactions  SEARCH trial Simvastatin 20mg vs 80mg w/ hx of MI Simvastatin 20mg vs 80mg w/ hx of MI Non-significant 6% RRR in CV events Non-significant 6% RRR in CV events 80mg dose: ↑↑ myopathy 80mg dose: ↑↑ myopathy Excess rate: 4/1000 in 1 st year, 1/1000 thereafterExcess rate: 4/1000 in 1 st year, 1/1000 thereafter Increased risk in women and elderly Increased risk in women and elderly Risk doubled w/ calcium channel blocker (particularly diltiazem) Risk doubled w/ calcium channel blocker (particularly diltiazem) Lancet 2010;376:1658–1669 www.fda.gov/Drugs/DrugSafety/ucm256581.htm

40. Drug interactions 2011 FDA simvastatin warning:  Do not exceed 10mg simvastatin daily with: Diltiazem, Verapamil Diltiazem, Verapamil  Do not exceed 20mg simvastatin daily with: Amlodipine, Amiodarone Amlodipine, Amiodarone 2012 FDA lovastatin warning:  Do not exceed 20mg lovastatin daily with: Diltiazem, Verapamil Diltiazem, Verapamil www.fda.gov/Drugs/DrugSafety/ucm256581.htmwww.fda.gov/Drugs/DrugSafety/ucm283137.htmwww.fda.gov/Drugs/DrugSafety/ucm293101.htm Answer: A

41. Question #10  50 yo man w/ hx of difficult-to-control HTN and recurrent headaches. Average BP 165/95 on HCTZ 25mg daily, felodipine 10mg daily, metoprolol 100mg BID, and lisinopril 40mg daily. Taking all meds as prescribed, no supplements, checking BPs appropriately. On exam, he is obese, HR 80, funduscopic exam shows AV nicking, trace leg edema. Labs show K 3.0 and Cr 1.0 prior to starting lisinopril. Since then, stable K 3.2 and Cr 1.3. UA trace protein.

42. Question #10  Which of the following is the most appropriate test? A) Sleep study B) Serum aldosterone / renin ratio C) Plasma free metanephrines D) MRA of renal arteries E) 24-hour urinary cortisol

43. Secondary Hypertension  Consider workup if: Severe or resistant hypertension Severe or resistant hypertension New-onset HTN at age <25 New-onset HTN at age <25 Malignant HTN Malignant HTN Signs / symptoms of a specific secondary cause Signs / symptoms of a specific secondary cause  Rule out other causes of resistant HTN (see previous slide; e.g. med nonadherence, other meds, improper measurement, etc) Ann Intern Med 2008;149:ITC61-16 JAMA 2003;289:2560-2572 UpToDate 2011

44. Secondary Hypertension (By ascending age:)  Coarctation of the aorta: Children, young adults Children, young adults >20mmHg difference between arm & leg SBP >20mmHg difference between arm & leg SBP Diminished / delayed femoral pulses Diminished / delayed femoral pulses Initial test: Echocardiogram Initial test: Echocardiogram  Fibromuscular dysplasia (Renal artery stenosis): Young adults, typically women Young adults, typically women Acute, >30-35% increase in serum Cr w/ ACE-I / ARB Acute, >30-35% increase in serum Cr w/ ACE-I / ARB Renal bruits Renal bruits Initial test: CTA, MRA, Duplex U/S of renal arteries Initial test: CTA, MRA, Duplex U/S of renal arteries Am Fam Physician 2010;82:1471-1478 UpToDate 2011

45. Secondary Hypertension  Pheochromocytoma: Rare. Middle-aged adults Rare. Middle-aged adults Paroxysms of elevated BPs, esp w/ HA, palpitations, sweats, flushing Paroxysms of elevated BPs, esp w/ HA, palpitations, sweats, flushing Initial test: plasma free metanephrines Initial test: plasma free metanephrines  Cushing’s Syndrome: Middle-aged adults (depending on cause) Middle-aged adults (depending on cause) Moon facies, buffalo hump, central obesity, dark abdominal striae Moon facies, buffalo hump, central obesity, dark abdominal striae Initial test: 24-hour urine cortisol, late-night salivary cortisol, low-dose dexamethasone suppresion test Initial test: 24-hour urine cortisol, late-night salivary cortisol, low-dose dexamethasone suppresion test Am Fam Physician 2010;82:1471-1478 UpToDate 2011

46. Secondary Hypertension  Primary hyperaldosteronism: Middle-aged adults Middle-aged adults Hypokalemia (though >1/2 are normokalemic) Hypokalemia (though >1/2 are normokalemic) Common: 6% of pts w/ HTN Common: 6% of pts w/ HTN Initial test: serum aldosterone / renin ratio Initial test: serum aldosterone / renin ratio  Obstructive Sleep Apnea: Middle-aged (and younger) adults Middle-aged (and younger) adults Snoring, apneic events, daytime somnolence Snoring, apneic events, daytime somnolence Initial test: sleep study Initial test: sleep study Am Fam Physician 2010;82:1471-1478 UpToDate 2011

47. Secondary Hypertension  Renal artery stenosis (atherosclerotic) Older, vascular disease Older, vascular disease Acute, >30-35% increase in serum Cr w/ ACE-I / ARB Acute, >30-35% increase in serum Cr w/ ACE-I / ARB Renal bruits Renal bruits Initial test: CTA, MRA, Duplex U/S of renal arteries Initial test: CTA, MRA, Duplex U/S of renal arteries Medical management as effective as revascularization without clear indications Medical management as effective as revascularization without clear indications  Other causes: Thyroid dysfunction Thyroid dysfunction 1° hyperPTH 1° hyperPTH Renal parenchymal disease Renal parenchymal disease Am Fam Physician 2010;82:1471-1478 UpToDate 2011 Answer: B

48. Question #11  42 yo man w/ new diagnosis of HTN, average BP 145/90 after intensive lifestyle improvements. Normal serum electrolytes and creatinine, UA negative, EKG wnl. Otherwise healthy.  Which of the following is the most appropriate next step in management? A) Lisinopril B) Chlorthalidone C) Amlodipine D) Hydrochlorothiazide E) Atenolol F) No medication, continued monitoring

49. Initial Therapy in HTN  JNC 7: Thiazide diuretics for most patients  Hydrochlorothiazide = most common But not widely used in studies at current doses But not widely used in studies at current doses HCTZ 12.5-25mg: weaker reduction in BP vs all other drug classes HCTZ 12.5-25mg: weaker reduction in BP vs all other drug classes No CV morbidity or mortality outcomes data at low doses (except in combo w/ triamterene or amiloride) No CV morbidity or mortality outcomes data at low doses (except in combo w/ triamterene or amiloride) JAMA 2003;289:2560-2572 J Am Coll Cardiol 2011;57:590-600 Hypertension 2009;54:951-953 Cochrane Database of Systematic Reviews 2009

50. Initial Therapy in HTN  Some recommend chlorthalidone: Longer half life, 1.5-2x as potent (vs HCTZ) Longer half life, 1.5-2x as potent (vs HCTZ) (12.5mg chlorthalidone ≈ 25mg HCTZ) Used in ALLHAT, SHEP Used in ALLHAT, SHEP 2012 network meta-analysis of CTD vs HCTZ: greater CV benefit w/ similar BP reduction 2012 network meta-analysis of CTD vs HCTZ: greater CV benefit w/ similar BP reduction  Caveats: Less available (few combo pills, higher cost) Less available (few combo pills, higher cost) No 12.5mg dose (need to halve a 25mg pill) No 12.5mg dose (need to halve a 25mg pill) More hypokalemia More hypokalemia Hypertension 2009;54:951-953 Hypertension 2011;57:689;694 Hypertension 2012;59:1110-1117

51. Initial Therapy in HTN  BMJ 2009 meta-analysis: All classes similar efficacy for reducing CHD events and CVA All classes similar efficacy for reducing CHD events and CVA Beta-blockers extra protection first few years post-MI Beta-blockers extra protection first few years post-MI CCBs slight advantage for CVA prevention CCBs slight advantage for CVA prevention  Cochrane 2009 meta-analysis: Low-dose thiazides (HCTZ <50mg/day, chlorthalidone <50mg/day): strongest evidence Low-dose thiazides (HCTZ <50mg/day, chlorthalidone <50mg/day): strongest evidence ACE-I: similar benefit, less evidence ACE-I: similar benefit, less evidence CCBs: insufficient evidence CCBs: insufficient evidence β-blockers (atenolol) and high-dose thiazides: inferior β-blockers (atenolol) and high-dose thiazides: inferior BMJ 2009;338:b1665 Cochrane Database of Systematic Reviews 2009

52. Initial Therapy in HTN  ACCOMPLISH trial: 11,506 pt w/ high-risk HTN 11,506 pt w/ high-risk HTN Benazepril plus (amlodipine or HCTZ) Benazepril plus (amlodipine or HCTZ) Target BP <140/90 (<130/80 for DM or CKD) Target BP <140/90 (<130/80 for DM or CKD) Similar BPs achieved Similar BPs achieved Primary composite CV outcome at 3y: Primary composite CV outcome at 3y: Benazepril-amlodipine: 9.6%Benazepril-amlodipine: 9.6% Benazepril-hydrochlorothiazide: 11.8%Benazepril-hydrochlorothiazide: 11.8% NEJM 2008;359:2417-2428

53. Initial Therapy(?) in HTN  Cochrane 2012: mild hypertension BP 140-159 / 90-99, primary prevention BP 140-159 / 90-99, primary prevention 4 RCTs, 8912 patients, 4-5y f/u 4 RCTs, 8912 patients, 4-5y f/u No change in mortality, CHD, CVA, CV events No change in mortality, CHD, CVA, CV events 9% ARI of withdrawals due to adverse effects 9% ARI of withdrawals due to adverse effects  Caveats: Low event rates, mostly driven by a single trial (MRC), half on propranolol-based Rx Low event rates, mostly driven by a single trial (MRC), half on propranolol-based Rx Wide confidence intervals Wide confidence intervals Long enough follow-up? Long enough follow-up? Cochrane Database Syst Rev 2012;8 :CD006742

54. Anti-HTsives in normotension  JAMA 2011 meta-analysis: Anti-HTsives in normotensive patients w/ CVD Anti-HTsives in normotensive patients w/ CVD 25 RCTs, 64,000 patients 25 RCTs, 64,000 patients ↓ mortality, CVA, MI, CHF, total CVD events ↓ mortality, CVA, MI, CHF, total CVD events  Eur Heart J 2012 meta-analysis: ACE-I or ARB in normotensive patients w/ CVD or CVD risk factors ACE-I or ARB in normotensive patients w/ CVD or CVD risk factors 13 RCTs, 80,000 patients 13 RCTs, 80,000 patients ↓ composite CV endpoint, CV mortality ↓ composite CV endpoint, CV mortality JAMA 2011;305:913-922 Eur Heart J 2012;33:505-514

55. Initial Therapy in HTN  Sigh…  Consider overall CV risk when managing mild HTN  Really push lifestyle changes  My current approach to meds: 1 st line: Lisinopril, HCTZ/triam, or chlorthalidone (depending on potassium level), or no med if low risk 1 st line: Lisinopril, HCTZ/triam, or chlorthalidone (depending on potassium level), or no med if low risk Still using lisinopril-HCTZ due to low cost and convenience -- dosing qhs or BID Still using lisinopril-HCTZ due to low cost and convenience -- dosing qhs or BID Amlodipine before beta-blockers Amlodipine before beta-blockers  JNC 8?? Answer: A, B, C, D, F?

56. Take home points  Dose ≥1 BP med at bedtime  Use ACE-inhibitors for proteinuric CKD (even with very high Cr)  Avoid combining ACE-I & ARB  No benefit from tight BP control in DM (or CKD?)  Add spironolactone for resistant HTN  Treat systolic HTN in octogenarians (with caution)

57. Take home points  Beta-blockers okay with chronic asthma & COPD  Use labetolol in pregnancy  Avoid CCBs with ≥10-20mg of simvastatin or lovastatin (or switch statins)  Watch for clues suggesting secondary causes of HTN (hypoK & hyperaldo)  First-line Rx: variety of reasonable options Not atenolol Not atenolol Consider chlorthalidone over HCTZ Consider chlorthalidone over HCTZ No clear benefit from meds in low-risk mild HTN No clear benefit from meds in low-risk mild HTN