Bd1e Management Of Heart Failure

Management of Chronic Heart Failure DR.SAMEER AMBAR DEPT OF CARDIOLOGY JNMC BELGAUM, INDIA [email_address]

Asses the functional class BP <130/80 mm of Hg Good glycaemic control LIPIDS LDL < 100 (IHD) <70 (DM) Avoid smoking, alcohol Sodium restriction <2gms /day Fluid restriction ,2 Litres/day

ACEI MECHANISM OF ACTION VASOCONSTRICTION VASODILATATION Kininogen Kallikrein Inactive Fragments Angiotensinogen Angiotensin I RENIN Kininase II Inhibitor ALDOSTERONE SYMPATHETIC VASOPRESSIN PROSTAGLANDINS tPA ANGIOTENSIN II BRADYKININ A.C.E.

SAVE ( NEJM 1992 327:669-677) 2231 pts EF<40%, 3-16d post MI , without sx of heart failure , Up to 50 mg Captopril tid for 42 mo AIRE (Lancet 1993:342:821) 2006 patients 3-10 days post MI with any evidence of post infarct clinical HF, Up to 5 mg Ramipril bid for 15 mos TRACE (NEJM 1995; 333: 1670-1676) 1749 pts 3-7 days post MI with EF<=35%, with or without symptomatic HF trandolapril for 24-50 mos ACEI IN POST MI HF

Mortality SAVE: 25% (placebo) vs 20% (captopril) - 19% RRR AIRE: 23% (placebo) vs 17% (ramipril) - 27% RRR TRACE: 42.3% (placebo) vs 34.7% (trandolapril)- 24% RRR

ARBs Clinical Study: 1.Elite-II. Study: Enrolled Target: CHF P’t Drug: losartan v.s. captopril Primary Endpoint:CHF Improvement Result: losartan is not better than captopril 2.Va-HeFT Study: Enrolled Target: CHF P’t Drug: valsartan + Usual Group v.s. Usual Group Primary Endpoint: CHF Event-Free Probability Result: Reduce M/M by 13.3%

Granger CB, et al. Lancet . 2003;362:772-776. CHARM-Alternative Number at risk Candesartan 1,013 929 831 434 122 Placebo 1,015 887 798 427 126 0 1 2 3 Years 0 10 20 30 40 50 Placebo Candesartan HR 0.77 (95% CI 0.67-0.89), P =.0004 Adjusted HR 0.70, P <.0001 3.5 406 (40.0%) 334 (33.0%) Proportion With CV Death or CHF Hospitalization (%) Primary outcome of CV death or CHF hospitalization

When to use Angiotensin receptor blockers 1. There has been no definite mortality or morbility advantage of ARBs over ACE inhibitors demonstrated 2. Consider ARB in patient who is ACE inhibitor eligible if the patient is intolerant of ACE inhibitors because of cough, renal insufficiency, or hyperkalemia

When to use Angiotensin receptor blockers 3. In the patient who is apparently ACE inhibitor intolerant, rule out other causes of presumed side effect: a. Cough-evaluate for pulmonary edema b. Hyperkalemia-concurrent potassium supplementation, potassium-sparing diuretic use c. renal insufficiency-evaluate for prerenal azotemia, NSAID use 4. The incidence of cough and hyperkalemia is lower with ARBs versus ACE inhibitors There does not appear to be a significant difference in incidence of renal insufficiency

Beta blockade in Heart failure Beta receptor levels in heart failure Normal Heart B1 80 : B2 20 Severe Heart Failure B1 60 : B2 40 B1 receptors to selectively down-regulate secondary to high levels of catecholamine B2 agonists retain full inotropic activity mediated through a B2 population that is not significantly decreased

Effect of Sympathetic Activation in Heart Failure CNS Sympathetic Outflow Sympathetic activity to kidneys & blood vessels Activation of RAS Vasoconstriction Sodium retention Disease Progression Cardiac sympathetic Activity 1 Receptors 2 Receptors 1 Receptors Myocyte death Increased arrhythmias

Benefit Of Beta Blockers Improve symptoms and clinical status Increase LV ejection fraction Little effect on exercise tolerance Reduce frequency of hospitalizations for heart failure Decrease mortality

Action Time dependant improvement in LV remodelling Reduce cetecholamine myocyte toxicity Improved B1 signaling Antiapoptosis antiarrthymic RAAS inhibition

Sympathetic Activation B1 Receptors B2 Receptors A1 Receptors Cardiotoxicity Carvedilol Metoprolol Propranolol

Clinical Trials Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise (PRECISE) 278 patients with chronic stable symptomatic heart failure EF<35% despite diuretics and ACE Carvedilol group was associated with greater improvement in NYHA Class 39% reduction in combined risk of death/hospitalization for any reason 46% reduction in risk of hospitalization for cardiovascular reason Circulation 1996;94:2793-2799

Clinical Trials Merit-HF Trial( metaprolol randomised interventional trial in CHF) 3991 patients with an ischemic or nonischemic cardiomyopathy (NYHA Class II or III) randomized to either Metoprolol XL up to 200mg/day or placebo. Metoprolol XL was associated with a 35% reduction in mortality Amer J Cardiol 1997;80:54J-58J

MERIT-HF METOPROL-XL: Mortality and Morbidity MERIT-HF Study Group. Lancet. 1999;353:2001-2007

NYHA III/IV EF <0.25 Post-MI Patients with Severe Heart Failure (n= 384) Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF

Total Mortality Months of follow-up Per cent 20 15 10 5 0 Placebo Metoprolol CR/XL p = 0.0004 Risk reduction = 40% 0 3 6 9 12 15 18 Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF Post-MI Patients

Per cent 12 9 6 3 0 Risk reduction = 50% Sudden Death Placebo Metoprolol CR/XL p = 0.0004 0 3 6 9 12 15 18 Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF Post-MI Patients Months of follow-up

Per cent 5 4 3 1 0 Risk reduction = 49% Death from Worsening Heart Failure Placebo Metoprolol CR/XL p = 0.021 2 0 3 6 9 12 15 18 Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF Post-MI Patients Months of follow-up

Total Number of Hospitalizations Heart failure p=0.006 -32% All-cause ns -8% CV cause p=0.037 -17% MERIT-HF Post-MI Patients Jánosi A et al, Am Heart J 2003;146:721-8

Post-MI severe CHF Total mortality Cardiac death/nonfatal MI History of revasc. (PTCA or CABG) 40% 45% Risk reduction Events Plac/Beta 122/74 44/24 37/26 132/74 46/22 42/27 All Post-MI patients Post-MI severe CHF All Post-MI patients Relative risk and 95% CI 0.0 1.0 History of revasc. (PTCA or CABG) Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF Post-MI Patients

Effect of metoprolol and placebo treatment on survival and hospitalization risk in class III and IV HF MERIT-HF Goldstein S et al. J Am Coll Cardiol 2001; 38(4):932-8 Endpoint Metoprolol (N) Placebo (N) Risk reduction (%) p value Total mortality 45 72 39% 0.0086 CV mortality 40 70 44% 0.0028 Sudden death 22 39 45% 0.024 Death from worsening HF 13 28 55% 0.015 Total hospitalizations 273 363 27% 0.0037 Total hospitalizations due to worsening HF 105 187 45% <0.0001

Comparison of findings in subanalysis and entire MERIT-HF cohort MERIT-HF Goldstein S et al. J Am Coll Cardiol 2001; 38(4):932-8 Endpoint Reductions in entire MERIT-HF cohort Reductions in class III and IV MERIT-HF subset Total mortality -34% -39% Sudden death -41% -45% Death due to worsening HF -49% -55%

40% reduction in Total Mortality 50% reduction in Sudden Death 32% reduction in number of hospitalizations for Worsening Heart Failure Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF Post-MI Patients Mortality/Hospitalizations Summary

Enrolled 2289 patients with severe HF (LVEF <25%) Randomized to carvedilol in a target dose of 25 mg bid for up to 29 months Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS) 35% reduction in the risk of all-cause mortality among patients with severe congestive heart failure (CHF) treated with carvedilol compared to placebo

COPERNICUS: Effect of carvedilol on the combined risk of morbidity and mortality Death or hospitalization for HF 0.000004 p value Endpoint COPERNICUS and CAPRICORN 0.00004 31% Death or hospitalization for a CV reason 0.76 Death or hospitalization for any reason Relative risk reduction 24% 0.00002 Odds ratio 27% 0.73 0.69

Beta Blockers Post MI LV dysfunction CAPRICORN( carvedilol post infarct survival control in LVD) 1959 pts post MI LVEF<40% Randomized to carvedilol or placebo Results: Lower all cause mortality (12% vs. 15%) Lower non-fatal MI Lancet 2001; 357: 1385–90

CAPRICORN All-Cause Mortality 0 0.5 1 1.5 2 2.5 Carvedilol n=975 Placebo n=984 Years Proportion Event-free 23% (2%, 40%) Risk reduction 0 0.90 0.70 0.60 0.80 The CAPRICORN Investigators. Lancet . 2001;357:1385-1390. Mortality Rates: Placebo 15%; Carvedilol 12% Carvedilol Post-Infarct Survival Control in LV Dysfunction 1.00

Clinical Use Of Beta Blockers Recommended for patients with NYHA class II-IV General contraindications: Decompensated heart failure Severe claudication Bronchospasm Advanced heart block Use with caution if patient requires inotropes for support of circulatory function

Beta-Blockade Cardiac Output Renal Blood Flow Sodium Retention Worsening Heart Failure

Considerations in selecting a beta-blocker Patients should be clinically stable and euvolemic before initiating beta-blocker therapy Start at low doses and titrate upward gradually (doubling every 2-4 weeks) Patients may experience an initial exacerbation of heart failure symptoms because of transient worsening of cardiac output

Clinical Use Cont . . . Clinical response may not be seen until 2 to 3 months after initiation of therapy Abrupt withdrawal can lead to dramatic deterioration Patient education paramount

Outcome in Post-MI Patients with Heart Failure CAPRICORN and MERIT-HF 1 Time to first event CAPRICORN All-cause mortality All-cause mortality/CV hosp. 1 MERIT-HF 23% 8% Risk reduction p- value p=0.03 Plac/Beta 151/116 122/74 40% p=0.0004 CAPRICORN MERIT-HF 367/340 326/258 ns 22% p=0.002 The CAPRICORN Investigators, Lancet 2001;357:1385-90 Jánosi A et al, Am Heart J 2003;146:721-8 Relative risk and 95% CI 0.0 1.0 Metoprolol CR/XL  1 Metoprolol CR/XL  1 Carvedilol  1  2 (  1 ) Carvedilol  1  2 (  1 )

LVEF: Change From Baseline Within Treatment-arm Comparison * P < 0.05; ** P < 0.01; *** P < 0.001 Enalapril Carvedilol & Enalapril Carvedilol -1 0 1 2 3 4 5  LVEF (%) *** *** *** *** *** ** * M6 M12 M18 M6 M18 M12 M6 M12 M18

RALES(randomised aldactone evaluation study) 1663 patients Class 3-4 CHF, LVEF<35% on ACE-inhibitor/diuretic/dig randomized to 25 mg spironolactone vs. placebo issues: only 10% of patients on beta blockers NEJM 1999:341:709-17

RALES Results: 46% mortality placebo vs 35% spironolactone (30% RRR) adverse effects: 10% of pts in spironolactone group developed gynecomastia. -serious hyperkalemia (K>6) 14% vs 10% (not statist sig)

EPHESUS(eplerenone post AMI HF efficacy and survival study) 6642 patients: a) 3-14 days post MI , b) EF<40, c) CHF (rales, pulm venous congestion seen on CXR, 3rd heart sound) OR Diabetes randomized to 25 mg eplerenone titrated up to 50 mg po qd NEJM 2003;348:1309-21

Results: One year mortality: 15% risk reduction (11.8% vs 13.6%) CV death or cardiovascular hospitalizations (26% vs 30.0%) (75% of patients on beta blockers) adverse effects: serious hyperkalemia (K>6) Epler- 5.5% vs plac- 3.9% (p=.002) serious hypokalemia (K<3.5) Epler- 8.4% plac- 13.1% (p<.001) gynecomastia- 0.5% vs 0.6% EPHESUS

Criteria for treatment with spironolactone New York heart Association class 3-4 Left ventricular ejection fraction <35% Serum creatinine <2.5 mg/dL Serum potassium <5 mmol/L Baseline treatment with ACE inhibitor (or other vasodilator if ACE inhibitor intolerance), loop diuretic, and digoxin as indicated

Digoxin Digoxin has a significant role in improving symptoms and rehospitalization rate No impact on the total and cardiovascular mortality Usually used only in severe CHF or in patients who remain symptomatic with optimal treatment Digoxin is useful in CHF with atrial fibrillation

Digoxin DIG trial 6800 pts EF <45% 0.25 mg/day 22% reduction in hospitalisation No mortlity benefit 28% RRR of death in post hoc analysis

Nesiritide Identical to human BNP Causing vasodilation and decrease LV filling pressure Decrease pulmonary capillary wedge pressure Improves patients’ symptoms Improvement in hemodynamics VMAC trial 5.8 mm of hg decrease on PCW

Nesiritide 2 mcg/kg bolus infusion 0.01-0.03 mcg/kg/min for 3 hrs Improved safety profile compared with dobutamine with fewer arrhythmias and better outcomes It should not be used in patients who are overdiuresed, hypotensive, or present with other signs of inadequate perfusion - Worsening of renal failure (45%)

Inotropes Inotropes: direct adrenergic agonists, phosphodiesterase inhibitors, and dopaminergic agonists Inotropes improve short term hemodynamics, they do not improve and in several cases may worsen long-term survival Oral inotropic agents have resulted in excess mortality in patients with HF

Amiodarone Antiarrhythmic effect Low dose amiodarone was safe and significantly reduced 2-year mortality (33.5% vs 41.4%, p=0.02) in patients with moderate to severe HF (GESICA trial) Another trial did not demonstrate mortality benefit, either all-cause or sudden death

Anticoagulation LVEF < 30% LV thrombus Atrial fibrillation INR 2-3

Bd1e Management Of Heart Failure

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