Treatment of Heart Failure

Treatment of Heart Failure Irene Rosen, MD LTC, MC 19 March 2008 Take-home points • HF is a syndrome, not a single disease – Structural or functional defects – Diminished blood flow or tissue oxygenation • Multiple evidence-based treatment options available across dz spectrum – Review 2006 HFSA guidelines • New treatment options are available Heart Failure A Growing Epidemic 12 10 Heart Failure Patients in US (Millions) 10 8 • 4.7 million symptomatic patients, estimated 10 million in 2037 • Incidence: About 550,000 new cases/year 6 4 2 4.7 • More deaths from heart failure than from all forms of cancer combined – 53,000 deaths a year • Prevalence is 1% between the ages of 50 and 59, progressively increasing to >10% over age 80 • ~ $30 billion/year (5% to 7% of total health care cost) 3.5 0 1991 2000 2037* *Rich M. J Am Geriatric Soc. 1997;45:968–974. American Heart Association. 2001 Heart and Stroke Statistical Update. Classification Systems • NYHA based on exercise capacity (functional system) – – – – Class I Class II Class III Class IV • ACC/AHA staging of heart failure (progression) – – – – Stage A Stage B Stage C Stage D New Approach to the Classification of Heart Failure Stage •Patient Description A B C D •High risk for developing heart failure (HF) • • • • • • • • • • • Hypertension CAD Diabetes mellitus Family history of cardiomyopathy Previous MI LV systolic dysfunction, LVH Asymptomatic valvular disease Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized) •Asymptomatic HF •Symptomatic HF •Refractory end-stage HF Modified from Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113. New Classification of Heart Failure ACC/AHA Staging v/s NYHA Functional Class ACC/AHA HF Stage1 NYHA Functional Class2 None AAt high risk for heart failure but without structural heart disease or symptoms of heart failure (eg, patients with HTN or coronary artery disease) BStructural heart disease but without symptoms of heart failure I II Asymptomatic Symptomatic with moderate exertion CStructural heart disease with prior or current symptoms of heart failure III Symptomatic with minimal exertion DRefractory heart failure requiring specialized interventions 1Hunt 2New IV Symptomatic at rest SA et al. J Am Coll Cardiol. 2001;38:2101–2113. York Heart Association/Little Brown and Company, 1964. Adapted from: Farrell MH et al.JAMA.2002;287:890–897. Pathophysiology of HF • Cardiac injury –> depressed cardiac function poor tissue perfusion • Cardiac output must increase – Activation of neurohormonal axis – Norepi, AVP, angiotensin II, endothelin • Chronic NH release is dysfunctional – Alterations in HR, contractility – Myocardial hypertrophy and ischemia Causes of heart failure • Ischemic disease/MI • Cardiomyopathy • Infection • Alcohol • Arrhythmias • Hyperthyroidism • Hypertension • Genetic disorders • Valvular abnormalities • Anemia Classification of HF • Which side of heart is affected – Left (more common) – Right (right-sided MI, pulmonary HTN) • Which heart function is affected – Systolic (↓ contraction and EF, dilated LV) – Diastolic (↓ relaxation,) • Failure of LV filling • Contractile function and EF usually normal 2006 HF Treatment Algorithm by Stage Stage A Stage B Angina Stage C Stage D • nitrate • amlodipine • PCI • CABG AF • warfarin • rate control • cardioversion • stage A, B • ACE-inhibitors • beta-blockers • diuretics • stages A, B, and C • IV inotropes ? • MCS (bridge to Tx) • heart transplantation • treat HTN • smoking cessation • treat lipid disorders • exercise • treat diabetes • stage A • ACE-inhibitors • beta-blockers • ICD ? • spironolactone • digitalis • bivent pacing +/- ICD • ARBs ? • IV inotropes • MCS (permanent) • hospice care Antiendothelin agents, anticytokines, oral inotropes, cardiac support devices, cell and gene Rx The case of Mr. Jones • 32 y/o AA male presents with progressive DOE over the past 3 weeks - unable to walk one flight of stairs without resting. He also complains of severe weight gain over this time period (>15 lbs), feeling bloated, and unable to sleep because he feels like he stops breathing. • No PMH/meds • PE: HR 110s, BP 115/75 • JVD to jaw, pitting edema Signs and sxs of HF • • • • • • • DOE, fatigue Orthopnea JVD, enlarged liver Nocturnal cough or DOE S3 gallop Bilateral crackles at lung bases Lower extremity edema What to do with Mr. Jones? • What studies do you want to order? • What medication first? – ACE-I vs. beta blocker – Which ACE-I? Which beta blocker? • Can I start a beta blocker with bad CHF? • When to start diuretics? HF work-up • • • • ECG, CXR, echocardiogram CBC, Chem, LFTs, TSH, lipids Baseline BNP Selected patients: – Iron panel, HIV, ANA – Coronary angiography – Endomyocardial biopsy ACE-inhibitors • First-line treatment • Beneficial across all functional classes of HF • Reduce risk of developing HF in at-risk patients (ALVD, previous MI, > 55 y.o. with vascular disease or DM) • Start low, titrate to target (doses shown effective in clinical trials) ACE Inhibitors in Heart Failure: From Asymptomatic LVD to Severe HF SOLVD Prevention (Asymptomatic LVD) 20% 29% death or HF hosp. death or new HF CONSENSUS (Severe Heart Failure) 40% 31% 27%  mortality at 6 mos. mortality at 1 year mortality at end of study SOLVD Treatment (Chronic Heart Failure) 16% mortality No difference in incidence of sudden cardiac death SOLVD Investigators. N Engl J Med 1992;327:685-91. SOLVD Investigators. N Engl J Med 1991;325:293-302. CONSENSUS Study Trial Group. N Engl J Med 1987;316:1429-35. Mortality Reductions with ACE - I 30 Relative Risk Reduction (%) 25 20 15 10 5 0 CONSENSUS n = 253 SOLVD n = 4228 SAVE n = 2231 AIRE n = 1986 HOPE n = 3577 CONSENSUS: NEJM 1987;316:1429-435, SOLVD: NEJM 1991;325:293-302, SAVE: NEJM 1992;327:669-677 AIRE: Lancet 1993;342:821-828, HOPE: Lancet 2000;355:253-259 How much ACE-I? ACE Inhibitor Enalapril Clinical Trial 18.4 mg/day (CONSENSUS I) 15 mg/day (VHeFT II) 16.6 mg/day (SOLVD) Clinical Practice 2.5 – 5 mg/day (42% of doses) Captopril 150 mg/day 75 mg/day (75% of doses) Lisinopril 20 mg/day 10 mg/day (65% of doses) Beta blockers • Historically contraindicated, but strong evidence now refutes that • Standard therapy in HF • Class effect – most studies with carvedilol and metoprolol • Start when euvolemic and stable • Start low and titrate to max tolerated Effect of Beta Blockade on Outcome in Patients With HF and Post-MI LVD Study US Carvedilol1 CIBIS-II2 MERIT-HF3 COPERNICUS4 CAPRICORN5 Drug carvedilol bisoprolol metoprolol succinate carvedilol carvedilol HF Severity mild/ moderate moderate/ severe mild/ moderate severe post-MI LVD Target Dose (mg) 6.2525 BID 10 QD 200 QD 25 BID 25 BID Outcome ↓48% disease progression (p= .007) ↓34% mortality (p <.0001) ↓34% mortality (p = .0062) ↓35% mortality (p = .0014) ↓23% mortality (p =.031) 4. Packer M et al. N Engl J Med 2001;3441651-8. 1. Colucci WS et al. Circulation 1196;94:2800-6. 5. The CAPRICORN Investigators. Lancet 2001;357:1385-90. 2. CIBIS II Investigators. Lancet 1999;353:9-13. 3. MERIT-HF Study Group. Lancet 1999;353:2001-7. HFSA 2006 Practice Guideline Pharmacologic Therapy: Beta Blocker Overview* General considerations Initiate at low doses Up-titrate gradually, generally no sooner than at 2 week intervals Use target doses shown to be effective in clinical trials Aim to achieve target dose in 8-12 weeks Maintain at maximum tolerated dose If symptoms worsen or other side effects appear If up-titration continues to be difficult Adjust dose of diuretic or concomitant vasoactive med. Continue titration to target after symptoms return to baseline Prolong titration interval Reduce target dose Consider referral to a HF specialist * Consult language of specific recommendations Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. CARMEN: Study Design Echo assessments Carvedilol (blinded) Ealapril (blinded) Enalapril(blinded) Group 1 • n = 572 • Mild CHF • LVEF < 40% Carvedilol (blinded) Placebo (blinded) Placebo (blinded) Enalapril (blinded) Group 2 Group 3 Down-titration Phase Baseline/ screening 0 wk Up-titration Phase A Up-titration Phase B 0 Maintenance Phase 3 6 9 12 15 18 Follow-up (months) LVEF: Change From Baseline Within Treatment-arm Comparison Carvedilol & Enalapril *** *** *** *** *** ** * Carvedilol Enalapril 5 4  LVEF (%) 3 2 1 0 -1 M6 M12 M18 M6 M12 M18 M6 M12 M18 * P < 0.05; ** P < 0.01; *** P < 0.001 Implications of CARMEN • First trial comparing BB monotherapy to ACEI monotherapy – Beta blockers by themselves good enough – Good alternative in ACE-I intolerant patients – Combination therapy is likely best • Consensus supports ACE-I first, if tolerant Effects of Adding -Blockers vs Increasing ACE Inhibitor Dose in HF Symptoms Morbidity Mortality Increase dose of ACE inhibitor1 No effect  10-15% NS Add -blockade2   20-35%  35% No evidence for the need to maximize ACE-I doses before starting -blocker therapy (BB + ACE-I better than high dose ACE alone) 1Packer 2Lechat M et al. Circulation. 1999;100:2312–2318. P et al. Circulation. 1998;98:1184–1191. Back to Mr. Jones… • Echocardiogram – EF 10-20%, global hypokinesis – Idiopathic dilated cardiomyopathy • Carvedilol 3.125mg bid • Lisinopril 5mg qd • Lasix 40mg IV BID due to his LE edema • Mr. Jones now has a dry cough and is uncomfortable • Now what? HFSA 2006 Practice Guideline (7.10) Pharmacologic Therapy: Angiotensin Receptor Blockers ARBs are recommended for routine administration to symptomatic and asymptomatic patients with an LVEF  40% who are intolerant to ACE inhibitors for reasons other than hyperkalemia or renal insufficiency. Strength of Evidence = A Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. CHARM-Alternative Primary outcome of CV death or CHF hospitalization 50 Proportion With CV Death or CHF Hospitalization (%) 40 30 20 Placebo 406 (40.0%) 334 (33.0%) Candesartan 10 0 0 1 HR 0.77 (95% CI 0.67-0.89), P=.0004 Adjusted HR 0.70, P<.0001 2 3 434 427 3.5 122 126 Number at risk Candesartan Placebo Years 1,013 1,015 929 887 831 798 Granger CB, et al. Lancet. 2003;362:772-776. ACE/ARB combination • What if Mr. Jones tolerated the ACE Inhibitor, would it be helpful or harmful add an ARB to his medications? • BP 100/80 HR 72 Cr 1.1 K+ 4.1 CHARM Added Trial CV Mortality or CHF hospitalization 50% 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% 0% 0% HR 0.85 p=0.011 CV Mortality HR 0.84 p=0.02 30% 42.3% 42.3% 23.7% 27.3% 37.9% 37.9% 20% 10% Candesartan Candesartan Placebo Placebo Candesartan Placebo www. Clinical trial results.org 55% on BB European Society of Cardiology 2003 European Society of Cardiology 2003 Poor Mr. Jones… • Titrated up meds – Carvedilol 6.25 mg bid – Lisinopril 10 mg qd – Lasix 80 mg bid • Still NYHA class III, tired of your continued failure to make him better • Now what? HFSA 2006 Practice Guideline (7.14-7.15) Pharmacologic Therapy: Aldosterone Antagonists An aldosterone antagonist is recommended for patients on standard therapy, including diuretics, who have:  NYHA class IV HF (or class III, previously class IV) due to LV systolic dysfunction (LVEF  35%) One should be considered in patients post-MI with clinical HF or diabetes and an LVEF < 40% who are on standard therapy, including an ACE inhibitor or an ARB. Strength of Evidence = A Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. Aldosterone Antagonists in HF RALES (Advanced HF) 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0 3 6 9 12 15 18 21 24 27 30 33 36 1.00 0.90 0.80 EPHESUS (Post-MI) Probability of Survival Epleronone Spironolactone Placebo 0.70 0.60 0.50 0.40 0 3 6 9 12 15 18 21 24 27 30 33 36 Placebo RR = 0.70 P < 0.001 RR = 0.85 P < 0.008 Months Months Pitt B. N Engl J Med 1999;341:709-17. Pitt B. N Engl J Med 2003;348:1309-21. HFSA 2006 Practice Guideline (7.16-7.18) Aldosterone Antagonists and Renal Function Aldosterone antagonists are not recommended when:  Creatinine > 2.5mg/dL (or clearance < 30 mL/min)  Serum potassium> 5.0 mmol/L  Therapy includes other potassium-sparing diuretics Strength of Evidence = A It is recommended that potassium be measured at baseline, then 1 week, 1 month, and every 3 months Strength of Evidence = A Supplemental potassium is not recommended unless potassium is < 4.0 mmol/L Strength of Evidence = A Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. Hail to thee, polypharmacy… • • • • • • So, Mr. Jones is now taking Coreg 6.25mg bid Lisinopril 10mg qd Spironolactone 25mg qd Lasix 80mg bid His BP and HR still stable but had to D/C spironolactone due to severe increase K+ • He is still NYHA Class III • Any other medications we can add? A-HeFT All-Cause Mortality 100 43% Decrease in Mortality Fixed Dose ISDN/HDZN Survival % 95 90 Placebo P = 0.01 85 0 100 200 300 400 500 600 Days Since Baseline Visit Taylor AL et al. N Engl J Med 2004;351:2049-57. HFSA 2006 Practice Guideline (7.19) Pharmacologic Therapy: Hydralazine and Oral Nitrates A combination of hydralazine and isosorbide dinitrate is recommended as part of standard therapy, in addition to beta-blockers and ACE-inhibitors, for African Americans with LV systolic dysfunction:  NYHA III or IV HF  NYHA II HF Strength of Evidence = A Strength of Evidence = B Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. A-HeFT Outcomes End point Primary end point composite score All-cause mortality (%) 1st HF hospitalization (%) Change in quality-of-life score at 6 months** ISDN-HDZN Placebo (n=518) (n=532) -0.1 6.2 16.4 -5.5 -0.5 10.2 24.4 -2.7 p 0.01 0.02 0.001 0.02 Taylor AL et al. N Engl J Med 2004; 351;2049-2057. How did Mr. Jones do? • Mr. Jones was discharged last week in NYHA class II heart failure, but comes back to the ED after gaining 10 lbs with an increase in fatigue and SOB – he’s having trouble walking up one flight of stairs again. • BP 95/52 HR 58 Cr 1.5 K+ 3.9 • What happened? • Which meds should we hold? • Should we change anything else? Sample Target Behavior: Be Able to Read and Understand Food Labels Labels from cups of soup Diet and nutrition in HF • Sodium restriction (2-3g/day) in all patients with clinical HF • Fluid intake < 2 liters in patients with fluid retention and hyponatremia • Consider daily MVI supplementation • Caloric assessment / supplementation in patients with advanced HF/cachexia A few words about diuretics • • • • Mainstay of symptomatic treatment No clinical trials on mortality effects Thiazide diuretics OK in mild HF Most HF patients will eventually require loop diuretics • Trick: balancing hypervolemia reduction vs. renal function, electrolytes, hemodynamic stability HFSA 2006 Practice Guideline (7.24) Pharmacologic Therapy: Diuretics  Restoration of normal volume status may require multiple adjustments.  Once a diuretic effect is achieved with short-acting loop diuretics, increase frequency to 2-3 times a day if necessary, rather than increasing a single dose. Strength of Evidence = B  Oral torsemide may be considered in patients exhibiting poor absorption of oral medication or erratic diuretic effect. Strength of Evidence = C  IV administration of diuretics may be necessary. Strength of Evidence = A  Diuretic refractoriness may represent patient noncompliance, a direct effect of diuretic use on the kidney, or progression of underlying dysfunction. Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. Diuretic resistance • • • • Progression of heart failure Excessive sodium consumption NSAIDS Tactics to overcome – Increased dose, more frequent dosing – Combine loop and thiazide diuretics – Concurrent ACE-I or aldosterone antag. – Watch renal function carefully! HFSA 2006 Practice Guideline (7.23) Loop Diuretics Agent Initial Daily Dose 20-40mg qd or bid 0.5-1.0 mg qd or bid 10-20 mg qd 25-50 mg qd or bid Max Total Daily Dose 600 mg Elimination: Duration of Renal – Met. Action 65%R-35%M 4-6 hrs Furosemide Bumetanide 10 mg 62%R/38%M 6-8 hrs Torsemide Ethacrynic acid 200 mg 200 mg 20%R-80%M 12-16 hrs 67%R-33%M 6 hrs Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. Digoxin • Limited role in HF • Does not improve mortality in mild to moderate HF • Can reduce hospitalization in poorly controlled patients • Narrow therapeutic window (0.1250.250 mg daily) • Watch for digoxin toxicity HFSA 2006 Practice Guideline Digoxin Recommendation 7.29 Digoxin should be considered for patients with LV systolic dysfunction (LVEF ? 40) who have signs or symptoms of HF while receiving standard therapy, including ACE inhibitors and beta blockers:  NYHA class II-III  NYHA class IV Strength of Evidence = A Strength of Evidence = B Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. HFSA 2006 Practice Guideline Digoxin Recommendation 7.30 It is recommended that:  The dose of digoxin, which should be based on lean body mass, renal function and concomitant medications, should be 0.125 mg daily in the majority of patients.  The serum digoxin level should be < 1.0 ng/mL. Strength of Evidence = C Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. Mr. Jones redux • You started IV lasix 80mg TID and Mr. Jones is not responding – urine output < 1L a day • Symptoms worsen to NYHA Class IV • JVD to earlobes, bilateral rales • Vital signs 95/50 HR 103 • Cr still 1.5 K+ stable • Any suggestions? Recombinant Human B-type Natriuretic Peptide – Pharmacologic Effects • NATRECOR® (nesiritide) has the same 32 amino acid sequence as the R I SS D S endogenous peptide1 M S • Human BNP increases K G intracellular cGMP, which R L serves as second G H G messenger to dilate veins F R 1 S CK L R and arteries C S V G • Systemic Hemodynamic S P KMV Q G S 1,2,3 Effects – preload and afterload reduction – increased cardiac index – no significant increase in heart rate References: 1. NATRECOR® Full Prescribing Information. 2. Colucci WE et al. N Engl J Med. 2000;343:246 3. Abraham WT et al. J Card Fail. 1998;4:37 Nesiritide Efficacy: Dyspnea Improvement in VMAC Trial Significant improvement§ in patient-reported dyspnea at 3 hours Reference: NATRECOR® Full Prescribing Information. Effect of Nesiritide on Serum Creatinine: VMAC Nesiritide plus standard care Serum creatinine (mg/dL) 3.5 3.1 2.7 2.3 Nitroglycerin plus standard care Patients with renal insufficiency (n=104) 1.9 1.5 All patients (n=489) Baseline Day 2 Day 5 Day 14 Day 30 Renal insufficiency defined as serum creatinine ≥2.0 mg/dL Study drug discontinued following 24–48 hr of treatment in majority of patients in VMAC Reference: Butler J et al. Nephrol Dial Transplant. 2004;19:391 Acute Decompensated Heart Failure: Nesiritide and Mortality • No short-term therapy for ADHF has been proven to improve short- or long-term mortality rates. • Nesiritide is the only approved ADHF therapy which has been shown in large, randomized trials to provide both significant symptomatic and hemodynamic improvement when added to standard care. • Nesiritide has not been studied in a trial powered to evaluate an effect on mortality. • Follow dosing instructions and patient exclusion criteria carefully Other last-ditch options • Cardiac resynchronization therapy (CRT) • ICD placement • Biventricular pacing HFSA 2006 Practice Guideline (9.1, 9.4) Device Therapy: Prophylactic ICD Placement In patients on optimal medical therapy (ideally 3-6 months) with or without concomitant coronary artery disease (including a prior MI > 1 month ago):   Prophylactic ICD placement should be considered in those with NYHA II-III HF (LVEF  30%) Prophylactic ICD placement may be considered in those with NYHA II-III HF (LVEF 31-35%) Strength of Evidence = A Concomitant placement should be considered in NYHA IIIIV patients undergoing implantation of a biventricular pacing device. Strength of Evidence = B Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. MADIT II: Prophylactic ICD in Ischemic LVD (LVEF 30%) 1.0 Probability of Survival .9 .8 .7 .6 0 0 1 503 (.91) 329 (.90) Defibrillator Conventional Therapy 2 3 110 (.78) 65 (.69) 4 9 3 Number at Risk Defibrillator Conventional Year 742 490 274 (.84) 170 (.78) Moss AJ et al. N Engl J Med 2002;346:877-83. HFSA 2006 Practice Guideline (9.7) Device Therapy: Biventricular Pacing Biventricular pacing therapy should be considered for patients with all of the following:  Sinus rhythm  A widened QRS interval (120 ms)  Severe LV systolic dysfunction (LVEF  35% with LV dilation > 5.5 cm)  Persistent, moderate-to-severe HF (NYHA III) despite optimal medical therapy. Strength of Evidence = A Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. When to hospitalize? • Severely decompensated CHF – hypotension, AMS, ↓ renal function • Dyspnea at rest, O2 sat < 90% • Hemodynamically significant arrhythmia • New onset atrial fibrillation • Acute coronary syndrome • Comorbid conditions – PE, DKA, CVA Evidence-Based Treatment Across the Continuum of Systolic LVD and HF Control Volume Diuretics Renal Replacement Therapy* Improve Clinical Outcomes Aldosterone ACEI -Blocker Antagonist or ARB or ARB CRT  an ICD* HDZN/ISDN* *In selected patients Treat Residual Symptoms Digoxin QUESTIONS?