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Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer,

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Presentation on theme: "Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer,"— Presentation transcript:

1 Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer, Vice President of Clinical Services Omnicare, Inc., and Adjunct Professor of Pharmacy Practice College of Pharmacy and Health Sciences Wayne State University November 2013

2 Objectives  To identify the key pathophysiologic mechanisms operative in patients with heart failure;  To differentiate characteristics of heart failure in persons older than 80 years of age compared to younger patients;  To select strategies of heart failure management recommended in current evidence-based guideline;  To identify pharmacokinetic and pharmacodynamics features of older persons with heart failure;  To determine important pharmacologic considerations of heart failure medications in older persons;  To select the most common reasons for readmission of heart failure patients to the hospital and strategies to mitigate the risk of rehospitalization; and  Using a case-based approach, to select appropriate interventions to optimize the care of older patients with heart failure. 2 Heart Failure Clinical Program © Omnicare, Inc. 2013

3 Disclosures  Dr. Zarowitz is an employee of Omnicare, Inc., and holds Omnicare stock  She has been awarded numerous research grants for Omnicare Senior Health Outcomes from:  AbbVie  Amgen  Astellas  Avanir  GlaxoSmithKline  Mylan  Optimer  Sanofi-aventis  Savient

4 Case Presentation

5 83 year old Caucasian male, Clcr 63 mL/min, dry weight of 160 lb (72.2 kg) who presented to the nurse practitioner with complaints of shortness of breath and productive coughing for the last 4 weeks  BP-90/64, HR-100, RR-20, T- 98.6   PMH: NYHA stage IV HF, glaucoma, coronary artery disease, hypertension, ocular strokes  HPI: hospitalized the previous year twice for syncope associated with heart failure. Cardiac arrest during one hospitalization following administration of ramipril 2.5 mg  CXR: no infiltrates  Labs: WBC – wnl MedicationDoseFrequency aspirin EC81 mgonce daily clopidogrel75 mgonce daily furosemide40 mgonce daily metoprolol50 mgtwice daily mirtazapine30 mgat bedtime zolpidem5 mgat bedtime simvastatin40 mgat bedtime spironolactone25 mgonce daily digoxin0.0625 mgonce daily Vitamin D31,000 units (2 tabs)once daily Vitamin E400 unitsonce daily latanoprost1 drop each eyeat bedtime furosemide40 mgwt ≤ 162 = no dose 40 mgwt 163 - 167, 1 tab 40 mg (2 tabs)wt 168, 2 tabs 40 mg (2 tabs)wt 169, 2 tabs twice daily 40 mg (4 tabs)wt 170, 2 tabs twice daily

6 Heart Failure Pathophysiology What is Heart Failure? 6

7 7 Definition of HF 7 Inability of the heart to pump blood to the body sufficient to meet the body’s demands Results from structural or functional cardiac disorder – Impaired ability of the ventricle to fill with or eject blood © Omnicare, Inc. 2013

8 Pathophysiology of Heart Failure Causal Factors Myocardial Damage Myocardial Failure  SVR (afterload)  Blood Volume (preload)  Cardiac output  LV end diastolic pressure Compensatory Responses RAA SNSANF Vasopressin

9 9 Pumping and Filling Problems and Heart Failure The enlarged ventricles fill with blood The ventricles fill normally with blood The stiff ventricles fill with less blood than normal The ventricles pump out ~60% of the blood The ventricles pump out less than 40-50% of the blood The ventricles pump out ~60% of the blood, but the amount may be lower than normal NORMAL SYSTOLIC DYSFUNCTION DIASTOLIC DYSFUNCTION Diastole (Filling) Systole (Pumping) © Omnicare, Inc. 2013

10 10 Facts About Heart Failure (HF) (continued)  Prevalence of HF in nursing homes (NHs) is ~20%  HF is the 2 nd most preventable cause of emergency department (ED) visits (19%)  668,000 ED visits and 1,094,000 hospital discharges in 2009  Discharges to someplace other than home have tripled in the past decade  50% of Medicare patients discharged to NHs are rehospitalized within 6 months  Characteristics associated with a high risk for rehospitalization with HF  Higher NYHA stage  Greater functional limitations (ADLs)  Concomitant psychosis  Concomitant renal failure 10 Roger VL et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125:e2–e220. Hutt E et al. J Am Med Dir Assoc 2011; 12:595-601 © Omnicare, Inc. 2013

11 Facts About Heart Failure (HF)  In 2008, 1 in 9 death certificates in the U.S. mentioned HF  An estimated 6.6 million US adults have HF  60-79 years-old: 9% of men and 5.4% of women  80+ years-old: 11.5% of men and 11.6% of women  75% of HF cases had HTN prior to their HF  Lifetime risk for HF is double for those with BP >160/90 mmHg compared to <140/90  More common in the African American population  More common in men than women 11 Roger VL et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125:e2–e220. © Omnicare, Inc. 2013

12 Heart Failure in the Elderly  Persons older than 65 years account for 80% of heart failure hospitalizations  Prevalence doubles with each decade of life over age 75  About 6% to 10% over 65 years have heart failure  88% of newly diagnosed cases occur in patients older than 65 years  49% are older than 80 years

13 Middle Age Elderly (≥ 65 years) Prevalence<1%≈10% GenderM > FF > M EtiologyCoronary artery diseaseHypertension LVEFReducedNormal ComorbiditiesFewMultiple RCTsManyFew TherapyEvidence-basedEmpiric PhysicianCardiologistPrimary care M=male; F=female; LVEF=left ventricular ejection fraction; RCT=randomized clinical trial Features Distinguishing Heart Failure in the Elderly from Heart Failure Occurring During Middle Age Adapted from Rich RW. Drug therapy for heart failure in the elderly. Am J Ger Cardiol 2003;12:235-42.

14 Pharmacokinetic and Pharmacodynamic Variants in Older Persons with Heart Failure Absorption  Increased gastric pH, delayed gastric emptying, reduced GI blood flow and slowed intestinal transit  Decreased bioavailability of medications with acid- dependent absorption (iron) and slowed absorption of medications, especially those that are enteric coated Metabolism  20 – 30% reduction in liver mass and hepatic blood flow but hepatocytes remain intact  CYP isozymes may be decreased but do not necessarily result in reduced clearance  first-pass metabolism is reduced with age Elimination  Clcr declines progressively with age- 0.75 mL/min/year 14

15 15 Underlying Causes of Heart Failure Heart Failure HypertensionDrugs Infections Valvular Heart Disease Cardiovascular disease Connective tissue disease Coronary Artery Disease Alcohol Tachycardia Nutritional and metabolic disorders Neuromuscular disease Radiation © Omnicare, Inc. 2013

16 16 Selected Risk Factors for Heart Failure Unmodifiable Modifiable Treatable Myocardial infarction Kidney disease Non-white race Family history Male sex Age Smoking Obesity/Diet Physical inactivity Alcohol consumption Mental stress Depression Sleep disordered breathing Heart disease Hyperlipidemia HYPERTENSION Valve disease Diabetes AFib Kenchaiah S et al. Med Clin N Amer 2004:88;1145-72. © Omnicare, Inc. 2013

17 Risk Factors for Heart Failure Strongly and consistently associated with HF Less consistently associated with HF Age Male sex Hypertension Electrocardiographic LV hypertrophy Myocardial infarction Diabetes Valve disease Overweight/obesity Excessive alcohol consumption Smoking Dyslipidemia Renal insufficiency Sleep-disordered breathing Low physical activity Low socioeconomic status Coffee consumption Dietary sodium intake Increased heart rate Impaired pulmonary function Mental stress and depression Kenchaiah S et al. Med Clin N Amer 2004:88;1145-72.

18 Medications That May Exacerbate Heart Failure AgentsRationale Antiarrhythmic agents (avoid disopyramide and flecanide; amiodarone and dofetilide are acceptable, if necessary, for arrhythmia) Calcium channel antagonists (diltiazem, verapamil) Itraconazole Terbinafine Negative inotropic effects Alcohol (excessive amounts in predisposed patients) Doxorubicin Daunomycin Cyclophosphamide Cardiotoxic Androgens COX-2 inhibitors Estrogens Glucocorticoids Nonsteroidal anti-inflammatory drugs Salicylates (high doses) Sodium-containing drugs (e.g., ticarcillin) Thiazolidinediones (rosiglitazone, pioglitazone) Sodium and water retention Albumin Blood products Osmotic agents

19 19 Signs and Symptoms of Heart Failure SIGNS  Tachycardia  Cachexia and muscle wasting  Third heart sound  Positive hepatojugular reflux  Bilateral rales  Peripheral edema  Laterally displaced apical pulse  Elevated jugular venous distension  Unexpected weight gain SYMPTOMS Shortness of breath Orthopnea Paroxysmal nocturnal dyspnea Reduced exercise tolerance Lethargy, fatigue Unexplained cough Wheeze Edema Loss of appetite Change in urine production © Omnicare, Inc. 2013

20 Congestive Heart Failure 20

21 21 The FACES of Heart Failure 21 F atigue A ctivities limited C hest congestion E dema or ankle swelling S hortness of breath HFSA. Who is the patient with heart failure? 2002. Available at: http://www.hfsa.org/pdf/faces_card.pdf © Omnicare, Inc. 2013

22 22 BNP (B-type natriuretic peptide)  Released in response to pressure overload  Should be measured in patients being evaluated for dyspnea in which the contribution of HF is unknown  Generally as BNP increases, HF worsens, and as HF is successfully treated, BNP decreases  May also be elevated in acute MI, PE, COPD, older age, female gender and renal impairment BNP (pg/mL)Interpretation <100Reliably rules out HF 100-399Possible HF (~75% of cases are HF) >400Suggestive of HF © Omnicare, Inc. 2013

23 BNP Diagnostic Algorithm Dyspnea Physical Examination, Chest XR, ECG, BNP Level BNP 100-400 pg/ml Baseline LV Dysfunction, Underlying Cor Pulmonale, Or Acute Pulmonary Embolism YesNo BNP <100pg/mlBNP >400pg/ml CHF Very Unlikely (2%) Possible Exacerbation of CHF (25%) CHF Likely (75%) CHF Very Likely (95%) Adapted from: Tabbibizar R, Maisel A. Curr Opin Cardiol. 2002;17:343.

24 BNP for Diagnosis n = 27n = 34n = 36 BNP Concentration (pg/ml) 186 + 22 791 + 165 2013 + 266 BNP concentration for the degree of heart failure severity Maisel A et al. J Am Coll Cardiol 2001;37(2)379-85.

25 Evidence-Based Treatment Guidelines Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines http://content.onlinejacc.org Jessup M, et al. 2009 ACCF/AHA guidelines for the diagnosis and management of heart failure in adults. Circulation. 2009;119:1977–2016. 25

26 Heart Failure with Reduced EF

27 Treatment Approaches for Heart Failure 27

28 28 Goals of Treatment Survival Exercise capacity Quality of life Morbidity Progression of disease Symptoms © Omnicare, Inc. 2013

29 29 Approach to Treatment  Diagnose and Stage HF  Establish patient-centered goals (e.g., BP)  Utilize non-pharmacological interventions and evidence-based medications  Titrate and maximize doses as tolerated  Monitor with vigilance  Dietary considerations  Changes in signs and symptoms (e.g., weight gain)  Medication monitoring (e.g., BMP, pulse, etc) 29 © Omnicare, Inc. 2013

30 30 Classification of HF ACC/AHA Heart Failure StageNYHA Functional Class AAt high risk for HF, but without structural heart disease or symptoms of HF (e.g., HTN, CAD) Not applicable BStructural heart disease but without symptoms of HF IWith cardiac disease but asymptomatic and without limitations of physical activity CStructural heart disease with prior or current symptoms of HF IISymptomatic with ordinary exertion resulting in slight limitation of physical activity (mild HF) IIISymptomatic with less than ordinary exertion resulting in marked limitations of physical activity (moderate HF) DRefractory HF requiring specialized interventions IVSymptomatic at rest resulting in inability to carry on any physical activity without discomfort (severe HF) © Omnicare, Inc. 2013

31 31 Medications That May Cause or Exacerbate HF* AgentsHow they cause/exacerbate HF Antiarrhythmics † [e.g., Multaq (dronedarone), Rythmol (propafenone), Tambocor (flecanide)] Non-dihydropyridine Calcium Channel Blockers [e.g., Calan or Isoptin (verapamil) or Cardizem (diltiazem)] Itraconazole or Terbinafine Negative inotropic effects (decrease the force of the hearts contraction) Alcohol (excessive amounts) Some chemotherapy treatments (e.g., doxorubicin, daunomycin, cyclophosphamide) Cardiotoxic Androgens or Estrogens Aspirin (high doses) NSAIDs (e.g., celecoxib, ibuprofen, meloxicam, naproxen) Glucocorticoids (e.g., prednisone) Thiazolidinediones [e.g., pioglitazone, Avandia (rosiglitazone)] Sodium and water retention Albumin Blood products (e.g., transfusion) Osmotic agents * - not all inclusive † - amiodarone or Tikosyn (dofetilide) are acceptable alternatives if necessary for arrhythmias Avoid or minimize use whenever possible. Monitor closely if must be used.

32 32 Non-Pharmacological Therapies  Modifiable risk reduction (e.g., smoking cessation, stress management)  Dietary modifications  Low sodium, low saturated fat diet  Limit caffeine intake  Limit alcohol intake  Encourage weight loss if BMI > 25  Closely watch fluid intake  Encourage physical activity as tolerated © Omnicare, Inc. 2013

33 33 Pharmacological Therapies Commonly Used  ACE Inhibitors (e.g., lisinopril)  Angiotensin Receptor Blockers [ARBs (e.g., losartan, valsartan)  Beta Blockers (e.g., metoprolol, carvedilol)  Diuretics  Digoxin  Aldosterone Antagonists (e.g., spironolactone, eplerenone)  Hydralazine + Isosorbide 33 ACCF/AHA Guidelines: “It is recommended that evidence-based therapy for HF be used in the elderly patient, with individualized consideration of the elderly patient’s altered ability to metabolize or tolerate standard medications” Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines © Omnicare, Inc. 2013

34 34 ACE Inhibitors (ACEIs) (e.g., lisinopril, enalapril)  Associated with a significant decrease in mortality  “recommended for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated”  Lower blood pressure by causing blood vessels to relax and expand and by reducing sodium and water retention  Monitor for:  Hypotension  Persistent dry cough (~20%)  Angioedema (<1%)  Elevated potassium  Elevated serum creatinine 34 Jessup M, et al. 2009 ACCF/AHA Guidelines. Circulation. 2009;119:1977–2016. Yancy CW, et al. 2013 ACCF/AHA Guidelines. http://content.onlinejacc.org http://content.onlinejacc.org © Omnicare, Inc. 2013

35 VASOCONSTRICTION VASODILATATION Kininogen Kallikrein Inactive Fragments Angiotensinogen Angiotensin I RENIN Kininase II Inhibitor ALDOSTERONE SYMPATHETIC VASOPRESSIN PROSTAGLANDINS tPA ANGIOTENSIN II BRADYKININ ACE-I: Mechanism of Action A.C.E.

36 ACE Inhibitors  Hypotension  Renal dysfunction  Hyperkalemia  Cough  Angioedema  Neutropenia  Prolonged survival*  Clinical improvement  More stable clinical course  Fewer hospitalizations  Slower disease progression RISKSBENEFITS * Not an indication for all ACEIs

37 ACE Inhibitors: Indications and Doses INDICATION AgentHFLV DysfunctionInitial Dose Maximum Dose captopril (Capoten ® )  (post-MI) 6.25 mg tid50 mg tid enalapril (Vasotec ® )  (asymptomatic) 2.5 mg bid 10 – 20 mg bid fosinopril (Monopril ® )  NA5 - 10 mg qd40 mg qd lisinopril (Prinivil ®, Zestril ® )  NA2.5 - 5 mg qd 20 – 40 mg bid quinapril (Accupril ® )  NA10 mg bid40 mg bid ramipril (Altace ® )  (post-MI) 1.25 – 2.5mg qd10 mg qd trandolapril (Mavik ® )  (post-MI) 1 mg qd4 mg qd ACE = angiotensin-converting enzyme, LV = left ventricular HF = heart failure, MI = myocardial infarction

38 ACE Inhibitors, Heart Failure, and Mortality Reduction STUDYACE-IPatientsDurationResults CONSENSUS Mean age 71 Enalapril 2.5-40 mg/d vs. placebo N=253 Class IV HF 12 months 6 month mortality ↓ 40% 1 year mortality ↓ 31% Death from progressive HF ↓ 50% SOLVD Mean age 60 Enalapril 10 mg bid vs. placebo N=2,589 EF < 35% 42 months 3.5 year mortality ↓ 16% Death or CHF hospitalization ↓26% CV hospitalization ↓ 10% AIRE Mean age 65 Ramipril 2.5-5 mg bid N=2,006 HF post MI 30 months All cause mortality ↓ 17% Risk of 1 st event ↓ 19% SAVECaptopril 12.5-150 mg/d vs. placebo N=2,231 EF < 40% Post MI 42 months All cause mortality ↓ 19% CV death ↓ 21% CHF development ↓ 37% Recurrent MI ↓ 25%

39 ATLAS Trial  Low-dose vs. high dose lisinopril  2.5 to 5 mg QD or 32.5 to 35 mg qd  N = 3,164  Average age 63.6 years  NYHA II-IV  EF ≤ 30%  High dose group had:  12% lower risk of death or hospitalization for any reason (P=0.002) for high  24% fewer hospitalizations for heart failure (P=0.002)  Risk of death reduced 8% in the high dose group (P=0.128) Packer M et al. Circulation 1999;100:2312-8.

40 Placebo Enalapril 12111098765 0.1 0.8 0 0.2 0.3 0.7 0.4 0.5 0.6 p< 0.001 p< 0.002 4321 0 CONSENSUS Trial Probability of death Months CONSENSUS. N Engl J Med 1987;316:1429-35.

41 Placebo Enalapril 0.1 0.8 0 0.2 0.3 0.7 0.4 0.5 0.6 p< 0.001 p< 0.002 SOLVD Trial (Treatment Arm) Percent Survival Months SOLVD. N Engl J Med 1991;325:293-301. p = 0.0036 Enalapril n=1285 Enalapril n=1285 Placebo n=1284 Placebo n=1284 06122418303642 n = 2589 CHF - NYHA II-III - EF < 35

42 ACE Inhibitors: Contraindications/ Risk-Benefit Considerations  Contraindications  Known bilateral renal artery stenosis  History of angioedema  Pregnancy  Risk-benefit considerations  Systolic blood pressure < 90 mm Hg  Serum creatinine > 3 mg/dL  Serum potassium > 5.5 mEq/mL

43 43 Angiotensin Receptor Blockers (ARBs) (e.g., losartan, valsartan)  Similar benefit to ACEIs  “recommended in patients with current or prior symptoms of HF and reduced LVEF who are ACE inhibitor-intolerant”  Routine combined use of ACEI, ARB and aldosterone antagonist is not recommended  Monitor for:  Hypotension  Angioedema (<1%)  Elevated potassium  Elevated serum creatinine 43 Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines Jessup M, et al. 2009 ACCF/AHA guidelines Circulation. 2009;119:1977–2016. © Omnicare, Inc. 2013

44 RENIN Angiotensinogen Angiotensin I ANGIOTENSIN II ACE Other pathways VasoconstrictionProliferative Action Vasodilatation Antiproliferative Action AT1 AT2 AT1 Receptor Blockers AT1 Receptor Blockers RECEPTORS Angiotensin II Receptor Blockers (ARB): Mechanism of Action

45 ACC/AHA Guidelines on the Role of ARBs in HF Therapy  Several clinical trials with ARBs failed to show mortality benefit in heart failure  ARBs should not be considered equivalent or superior to ACE inhibitors in the treatment of HF  ARBs should not be used for the treatment of HF in patients who have had no prior use of an ACE inhibitor  ARBs should be used in patients with angioedema or an intractable cough on an ACE-I. ARBs are as likely as ACE-I to produce hypotension, worsening renal function and hyperkalemia 2013 ACCF/AHA Heart Failure Guidelines. J Am Coll Cardiol. http://content.onlinejacc.org/

46 Val-HeFT: Comparison of Event Rates Event Valsartan (%) Placebo (%)RR*p All-cause mortality17.327.10.670.017 Morbidity/ mortality 24.942.50.56<0.001 Cardiovascular death 15.722.10.760.074 Sudden death with resuscitation 0.51.10.460.529 Hospital admission for HF 13.026.50.47<0.001 Maggioni AP et al. J Am Coll Cardiol 2002;40:1414-21.

47 CHARM Trial  3 studies in one  CHARM-Alternative: LVEF ≤ 40% and could not tolerate an ACE inhibitor  CHARM-Added: LVEF ≤ 40% who were currently taking an ACE inhibitor, with or without a beta-blocker  CHARM-Preserved: LVEF > 40%  Overall-- showed ARB beneficial in terms of morbidity and mortality in heart failure

48 Background Therapy ACEI +, Beta Blocker - 3034 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 N P=0.009 Test for heterogeneity Relative Risk of Death Valsartan BetterPlacebo Better Combination of ACEI and ARB in Heart Failure Management ACEI +, Beta Blocker + 1610 ACEI -, Beta Blocker - 228 ACEI -, Beta Blocker + 140 Cohn JN et al. NEJM 2001;345:1667-75

49 All-Cause Mortality in the VALIANT Study Group All-cause mortality (%) Hazard ratio (95% CI) compared with captopril p value Captopril (n=4909) 19.5-- Valsartan (n=4909) 19.9 1 (0.90-1.11) 0.98 Combination (n=4885) 19.3 0.98 (0.89-1.09) 0.73 Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906.

50 VALIANT: Cardiovascular Death, Recurrent MI, or Heart Failure Hospitalization Group CV death, re-MI, or heart-failure hospitalization (%) Hazard ratio (95% CI) compared with captoprilp value Captopril (n=4909) 31.9-- Valsartan (n=4909) 31.10.95 (0.88-1.03) 0.20* Combination (n=4885) 31.10.97 (0.89-1.05) 0.37* *Not significant Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906. Secondary End Point

51 VALIANT: Incidence of Adverse Events Group Any adverse event (%) Any ADE leading to permanent study drug discontinuation (%) Captopril28.47.7 Valsartan29.45.8* Combination34.8*9.0* Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906. * Significant difference from captopril (p<0.05)

52 52 Beta-Blockers (BBs) (bisoprolol, carvedilol, or metoprolol succinate XL)  Prevent the speeding up of the damaged heart  “recommended for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated”  Start only if patients have stable fluid status and gradually increase the dose as tolerated  Titrate no sooner than every 2 weeks  May initially worsen HF and may need to adjust diuretics to maintain pre- treatment weight  Monitor heart rate and blood pressure  Typically held if pulse <60 beats per minute  Monitor for hypoglycemia if diabetic  May block symptoms of hypoglycemia except sweating  Carefully assess risk vs. benefit for patients with:  Reactive airway disease (e.g., asthma)  COPD  Peripheral vascular disease 2013 ACCF/AHA guidelines. http://content.onlinejacc.org/http://content.onlinejacc.org/

53 Dosages of Beta-Blockers in Heart Failure Drug Starting DosageTitration Sequence* Maximum Dosage Bisoprolol (Zebeta ® ) 1.25 mg/dayIncrease to 2.5 mg/day in 2-4 weeks, then increase to 5.0 mg/day in 2-4, weeks, then increase to maximum 10 mg/day Carvedilol (Coreg ® ) 3.125 mg twice daily Increase to 6.25 mg bid in 2-4 weeks, then increase to 12.5 mg bid in 2-4 weeks, then increase to maximum 25 mg twice daily (50 mg twice daily if > 85 kg) Metoprolol extended release (Toprol XL ® ) 12.5 mg/dayIncrease to 25 mg/day in 2-4 weeks, then Increase to 50 mg/day in 2-4 weeks, then increase to 100 mg/day in 2-4 weeks, then increase to maximum 200 mg/day ACC/AHA Heart Failure Guidelines, 2001; Farrell MH et al. JAMA 2002;287:890-97. *Doses should only be increased if resident tolerates current dose. Some residents will not tolerate higher doses or may require slower titration.

54 54 Diuretics (furosemide, bumetanide, hydrochlorothiazide,metolazone)  Reduce fluid volume to decrease workload of the heart  Loop diuretics (e.g., furosemide) are generally more effective than thiazide diuretics (e.g., hydrochlorothiazide)  Thiazides are less effective with declining kidney function  Assess edema and monitor weight frequently  Often requires use/adjustment of potassium supplementation  Monitor electrolytes and kidney function routinely  Monitor for rash/photosensitivity  Combination therapy with a loop and thiazide diuretic may be necessary in the presence of diuretic resistance 54 2013 ACCF/AHA guidelines. http://content.onlinejacc.org/http://content.onlinejacc.org/

55 Action of Diuretics Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle K-sparing Inhibit reabsorption of Na in distal convoluted and collecting tubule Loop Diuretics Inhibit exchange of Cl-Na-K in thick segment of the ascending loop of Henle Collecting Tubule Loop of Henle MEDULLA CORTEX

56 Loop Diuretics  Mechanism of action  Act on the ascending limb of loop of Henle  Increase potassium, magnesium and calcium excretion  More effective than thiazide diuretics  Adverse reactions  Electrolyte/metabolic disturbances  hypokalemia, hypomagnesemia, hyperglycemia, hyperuricemia  Metabolic alkalosis  Azotemia  Hypotension, including orthostasis  Ototoxicity  Other (rash, photosensitivity)

57 Thiazide Diuretics  Mechanism of action  No dose response  Increase potassium, magnesium and calcium excretion more than with loop diuretics  Increase renal vasoconstriction  Increase uric acid excretion  Adverse reactions  Electrolyte/metabolic disturbances  hypokalemia, hypomagnesemia, hyperglycemia, hyperuricemia  Metabolic alkalosis  Azotemia  Hypotension, including orthostasis  Other (rash, photosensitivity)

58 Torsemide  Loop diuretic  Consistent absorption  Reduced fatigue  Fewer hospitalizations  Lower cost of care Murray MD, Deer MM, Ferguson JA et al. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513-20.

59 Diuretic Resistance: Causes  Delayed absorption of the diuretic  Reduced secretion of the diuretic into the tubular lumen (its site of action)  Compensatory retention of sodium after the effective period of the diuretic  Hypertrophy and hyperplasia of epithelial cells of the distal convoluted tubule

60 Diuretic Resistance: Management  Rule out non-compliance  Dose adjustment  Intravenous bolus injection or continuous infusion of a loop diuretic  Combination diuretic therapy  Metolazone use in combination with loops  Given 30 minutes prior to loop administration  Monitor closely for hypokalemia

61 61 Digoxin  Increases the force and velocity of cardiac contraction while also reducing the heart rate  “can be beneficial in patients with current or prior symptoms of HF and reduced LVEF to decrease hospitalizations for HF”  2012 Updated Beers Criteria list 0.125 mg/day as the maximum recommended dose  Monitor pulse prior to giving each dose  Monitor for signs/symptoms of toxicity (nausea, anorexia, visual disturbances, electrolyte abnormalities, impaired cognition, weakness, dizziness, hallucinations, etc)  Monitor BMP and digoxin concentration routinely  Serum drug concentration of 0.5-0.8 ng/mL is the recommended therapeutic range 2013 ACCF/AHA guidelines. http://content.onlinejacc.org/http://content.onlinejacc.org/

62 Digoxin  Inhibits sodium-potassium adenosine triphosphatase  Promotes calcium influx via sodium-calcium exchange mechanism  Results in an increase in the contractile state of the heart  Stroke volume and cardiac output increase  Indirect increase in parasympathetic tone  Results in decrease in heart rate  Direct and indirect decrease in sympathetic tone  Secondary to impaired cardiac output  Indirectly decreases sympathetic vasoconstriction

63 Na + K+K+K+K+ K+K+K+K+ Ca ++ Na-K ATPase Na-Ca Exchange Myofilaments Digoxin CONTRACTILITY Digoxin: Mechanism of Action -

64 Digoxin: Clinical Use  Therapy is initiated at dose of 0.125 mg for heart failure  Lower doses such as every other day  Some elderly  Impaired renal function  Caution in patients with significant sinus or atrioventricular block  Not indicated for stabilization of acute decompensated heart failure

65 Serum Digoxin Concentrations  Are lower digoxin concentrations effective?  Methods  Data from PROVED and RADIANCE  Both were randomized, multi-center, double-blind clinical trials  PROVED – diuretic vs. diuretic + digoxin  RADIANCE – ACEI+diuretic vs. ACEI+diuretic+digoxin  Compared digoxin withdrawal vs. continuation for worsening heart failure  Serum drug concentration (SDCs) obtained at baseline, 4, 8, and 20 weeks Adams KF et al. J Am Coll Cardiol 2002;39:946-53.

66 Risk of Treatment Failure Based on Randomization SDC Group Treatment Group Relative Risk95% CIP Value Digoxin concentration (SDC) < 0.9 ng/ml0.090.01-0.66 0.018 > 0.9-1.2 ng/ml0.220.08-0.61 0.004 > 1.2 ng/ml0.170.06-0.44 <0.001 Relative risk and p values are based on the adjusted Cox proportional hazards analysis. CI = confidence interval; SDC = serum digoxin concentration Adams KF et al. J Am Coll Cardiol 2002;39:946-53.

67 Digoxin: Clinical Trials  Digitalis Investigation Group (DIG Trial)  6,800 patients with ischemic and non-ischemic cardiomyopathy  Mild to moderate heart failure  Randomized to placebo or digoxin  Digoxin has no effect on mortality  Digoxin was associated with decreased risk of hospitalization (28% CHF, 6% all cause)  Digoxin level investigation (post-hoc of DIG Trial)  SDCs of 1.2 ng/mL and higher may be harmful  SDCs of ~ 1.0 ng/mL may not provide any clinical benefit vs. placebo  SDC of 0.5 to 0.8 ng/mL likely the optimal therapeutic range The Digitalis Investigation Group. N Engl J Med 1997;336:525-33.

68 50 40 30 20 10 0 48 0 122436 DIG Clinical Trial The Digitalis Investigation Group. N Engl J Med 1997;336:525-33. Months Percent Mortality n = 6800 NYHA II-III P=0.8 Placebo N=3403 Digoxin N=3397

69 Digoxin Concerns in the Elderly  Narrow therapeutic index  Age related decrease in renal function  Results in increased serum digoxin concentrations  May cause delirium  Drug-drug interactions  Affect digoxin bioavailability or excretion  Increase risk of digoxin toxicity  Reduced skeletal mass  Reduced volume of digoxin distribution Aronow WS. J Am Geriatr Soc 1997;45:1252-8.

70 Digoxin and Women Outcome Women digoxin (%) Women Placebo (%)p Absolute diff. between sexes (%)* Death from any cause 33.128.90.078 5.8 Death from CV causes 27.824.10.098 4.3 Death from worsening HF 12.411.90.750 2.8 Hospitalization for worsening HF 30.234.40.079 4.7 *Absolute difference between the effect of digoxin compared with the effect of placebo among women vs the same comparative effect in men; p was significant for death from any cause (p=0.034) and marginally significant for hospitalization for worsening HF (p=0.053). Rathore SS et al. N Engl J Med 2002;347:1403-11.

71 71 Aldosterone Antagonists (AAs) (e.g., spironolactone, eplerenone)  Block aldosterone-induced increases in vasoconstriction and sodium reabsorption  “Addition of an aldosterone antagonist is reasonable in selected patients with moderately severe to severe symptoms of HF and reduced LVEF who can be carefully monitored for preserved renal function and normal potassium concentration.”  SCr should be  2.5 mg/dL for men and  2.0 mg/dL in women  K+ should be  5.0 mEq/L  Eplerenone is NOT suggested for those over 75 years of age due to lack of survival benefit  Monitor BMP and kidney function routinely  Minimize concomitant use of potassium supplements, especially in combination with an ACEI or ARB  Monitor for endocrine disturbances (e.g., gynecomastia) 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org

72 ALDOSTERONE Retention Na + Retention Na + Retention H 2 O Retention H 2 O Excretion K + Excretion K + Excretion Mg 2+ Excretion Mg 2+ Collagen Collagen deposition deposition Fibrosis Fibrosis - myocardium - myocardium - vessels - vessels Spironolactone Edema Edema Arrhythmias Arrhythmias Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Aldosterone Antagonists: Mechanism of Action

73  Recent or current symptoms despite ACEI, diuretics, digoxin, and beta-blockers  Recommended in advanced heart failure (II-IV), LVEF of ≤ 35%, in addition to ACEI and diuretics  Hypokalemia -ESC HF guidelines 2001 Spironolactone: Indications 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org

74 Background – The RALES Study  Pts with NYHA Class III & IV HF on ACEI’s and loop diuretics were randomized to either 25 mg of spironolactone or placebo (avg dose = 26 mg)  Spironolactone group had a 30% reduction in risk of death and 35% reduction in hospitalization for worsening HF Pitt B, et al. N Engl J Med 1999;341:709-17.

75 Aldactone Placebo Survival 1.0 0.9 0.8 0.7 0.6 0.5 0612 18 243036 months p < 0.0001 Annual Mortality Aldactone 18%; Placebo 23% N = 1663 NYHA III-IV Mean follow-up 2 y RALES Trial: Spironolactone RALES. N Engl J Med 1999;341:709

76 RALES Results – patients with HF Before RALES After RALES Early 1994 (per 1000) Early 1999 (per 1000) Late 2001 (per 1000) Spiro Rx’s3430149 * Hyper K + adms 2.44.011 * Hyper K + deaths 0.30.72.0 * (* p<0.001)

77 Spironolactone: Contraindications/ Risk-Benefit Considerations  Contraindications  Potassium concentration > 5.5 mEq/L  Risk-benefit considerations  Concomitant use with potassium supplements  Life threatening hyperkalemia when used with ACE inhibitors or ARBs

78 Eplerenone  Potassium-sparing diuretic  Lower affinity than spironolactone for progesterone and androgen receptors  Ephesus trial showed statistically significant reduction in death versus placebo  More expensive than spironolactone  Those over 75 years did not respond to treatment Pitt B et al. N Engl J Med 2003; 348:1309-21. Pitt B 2003. Circulation 2003;108:1790

79 79 Hydralazine/Isosorbide Dinitrate  Hydralazine is a peripheral arterial vasodilator  Isosorbide is a peripheral venous vasodilator  Working together they mimic vasodilating action of ACEIs  “recommended to improve outcomes for patients self-described as African-Americans, with moderate-severe symptoms on optimal therapy with ACE inhibitors, beta blockers, and diuretics.”  “patients with reduced LVEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency.”  Monitor closely for hypotension, worsening edema, or headaches 79 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org

80 80 Inotropic Support [e.g., Dopamine, Dobutamine, Milrinone (Primacor ® )  Increase force of cardiac contraction  May provide symptom improvement but result in overall increase in mortality  Central line access required  Monitor for:  Hypotension  Arrhythmias  Dizziness/Headache  Adequate fluid intake  Peripheral blood perfusion 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org

81 2013 Guidelines for Inotropic Support  Until definitive therapy (e.g. coronary revascularization, mechanical circulatory support (MCS), heart transplantation) or resolution of the acute precipitating problems.  Patients with cardiogenic shock should receive temporary intravenous inotropic support to maintain systemic perfusion and preserve end-organ performance  Continuous inotropic support reasonable as “bridge therapy” in patients with Stage D refractory to medication therapy and device therapy who are eligible for and awaiting MCS or cardiac transplantation  Palliative therapy in stage D despite optimal medication therapy and device therapy who are not eligible for MCS or transplantation  Potentially Harmful – absence of specific indications noted above 81 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org

82 Therapeutic Concerns When Treating HF 82

83 83 Therapeutic Concerns with HF in the Elderly ProblemSuggestions HypotensionStart therapies at lower doses and titrate upward slowly as tolerated Hyperkalemia (with ACEIs, ARBs, AAs) Avoid concomitant potassium supplements when possible Adjust diuretic use Monitor BMP routinely Other electrolyte abnormalities (e.g., hypokalemia) Monitor BMP routinely Monitor fluid status closely Adjust dietary intake as necessary © Omnicare, Inc. 2013

84 84 Therapeutic Concerns with HF in the Elderly ProblemSuggestions Digoxin toxicityMonitor closely for signs and symptoms (e.g., nausea, visual disturbances) Maintain serum drug concentration at 0.5-0.8 ng/mL Monitor kidney function and electrolytes BradycardiaAvoid other drugs that affect heart fate Titrate beta blocker dose slowly Gradually get out of bed/chair Monitor pulse routinely © Omnicare, Inc. 2013

85 85 Actions for Monitoring Heart Failure  Routine assessment of vital signs (BP, pulse)  Frequent assessment of weight (e.g., 3 times per week)  Establish “dry weight”  Establish threshold for notifying the prescriber (e.g., increase of 3 lbs)  Monitor for signs of congestion and/or edema  Increased cough or shortness of breath (especially at night or while lying down)  Abdominal or lower extremity swelling  Monitor for decreased blood perfusion  Cool extremities  Resting tachycardia  Increased confusion  BUN:Cr ratio 20:1 or greater (dehydration) © Omnicare, Inc. 2013

86 Heart Failure Clinics  Dedicated clinics to heart failure  Nurse practitioner trained in heart failure  Greater access to a clinician  “Brittle” patients need periodic medication adjustments  Cheaper  Reduces repeat hospitalizations  Reduces morbidity and mortality

87 87 Ouslander JG, et al. INTERACT® Licensed Materials. http://www.interact2.net/index.aspxhttp://www.interact2.net/index.aspx

88 Back to the Case 88

89 83 year old Caucasian male, Clcr 63 mL/min, dry weight of 160 lb (72.2 kg) who presented to the nurse practitioner with complaints of shortness of breath and productive coughing for the last 4 weeks  BP-90/64, HR-100, RR-20, T- 98.6   PMH: NYHA stage IV HF, glaucoma, coronary artery disease, hypertension, ocular strokes  HPI: hospitalized the previous year twice for syncope associated with heart failure. Cardiac arrest during one hospitalization following administration of ramipril 2.5 mg  CXR: no infiltrates  Labs: WBC – wnl MedicationDoseFrequency aspirin EC81 mgonce daily clopidogrel75 mgonce daily furosemide40 mgonce daily metoprolol50 mgtwice daily mirtazapine30 mgat bedtime zolpidem5 mgat bedtime simvastatin40 mgat bedtime spironolactone25 mgonce daily digoxin0.0625 mgonce daily Vitamin D31,000 units (2 tabs)once daily Vitamin E400 unitsonce daily latanoprost1 drop each eyeat bedtime furosemide40 mgwt ≤ 162 = no dose 40 mgwt 163 - 167, 1 tab 40 mg (2 tabs)wt 168, 2 tabs 40 mg (2 tabs)wt 169, 2 tabs twice daily 40 mg (4 tabs)wt 170, 2 tabs twice daily

90 Response of BP and Weight to Furosemide Therapy 90 Zarowitz, BJ, Heart failure management and the war between evidence-based guidelines and common sense. Geriatr Nurs 2013; 34: 230 – 2.

91 91 Summary  HF is associated with a high rate of emergency department visits, rehospitalizations, and overall morbidity and mortality  Vigilance in monitoring for signs and symptoms of HF is essential  Evidence-based medications and non-pharmacological interventions are an important part of improving the care of HF patients  Early intervention in exacerbations can reduce rehospitalizations © Omnicare, Inc. 2013

92 Questions Thank you for this opportunity!


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