36. 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
37. 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
38. 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
39. 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
40. 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
41. 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
42. 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%
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44.
45.
46. 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
47.
48.
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52.
53. 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 )
FIGURE 25–6 Stages of heart failure and treatment options for systolic heart failure. Patients with stage A heart failure are at high risk for heart failure but do not have structural heart disease or symptoms of heart failure. This group includes patients with hypertension, diabetes, coronary artery disease, previous exposure to cardiotoxic drugs, or a family hisotry of cardiomyopathy. Patients with stage B heart failure have structural heart disease but have no symptoms of heart failure. This group includes patients with left ventricular hypertrophy, previous myocardial infarction, left ventricular systolic dysfunction, or valvular heart disease, all of whom would be considered to have New York Heart Association (NYHA) class I symptoms. Patients with stage C heart failure have known structural heart disease and current or previous symptoms of heart failure. Their symptoms may be classified as NYHA class I, II, III, or IV. Patients with stage D heart fialure have refractory symptoms of heart failure at rest despite maximal medical therapy, are hospitalized, and require specialized interventions or hospice care. All such patients would be considered to have NYHA class IV symptoms. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; VAD = ventricular assist device. (Reprinted from Jessup M, Brozena S: Heart failure. N Eng J Med 348:2007-2018, 2003) .
FIGURE 25–17 Treatment algorithm for patients with chronic heart failure (HF) with a reduced ejection fraction (EF). After the clinical diagnosis of HF is made, it is important to treat the fluid retention that the patient experienced before starting an angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin receptor blocker (ARB) if the patient is ACE intolerant). Beta blockers should be started after the fluid retention has been treated and/or the ACE inhibitor has been uptitrated. If the patient remains symptomatic, an ARB, aldosterone antagonist, or digoxin can be added as triple therapy. The fixed-dose combination of hydralazine–isosorbide dinitrate should be added to an ACE inhibitor and beta blocker in African American patients with New York Heart Association (NYHA) Class II, II, or IV HF. Device therapy should be considered in addition to pharmacological therapy for appropriate patients. CRT = cardiac resynchronization therapy; ICD = implantable cardioverter-defibrillator. (From Mann DL: Heart failure and cor pulmonale. In Kasper DL, Braunwald E, Fauci AS, et al (eds): Harrison’s Principles of Internal Medicine. 17th ed. New York, McGraw-Hill, 2007 [in press].)
TABLE 25–5 Pharmacological and Device Therapy in Patients with Chronic Heart Failure (HF). (Modified from Swedberg K, Cleland J, Dargie H, et al: Guidelines for the diagnosis and treatment of chronic heart failure: Executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 26:1115, 2005.)
TABLE 25–9 Drugs for the Prevention and Treatment for Chronic Heart Failure. (Modified from Mann DL: Heart failure and cor pulmonale. In Kasper DL, Braunwald E, Fauci AS, et al (eds): Harrison’s Principles of Internal Medicine. 17th ed. New York, McGraw-Hill, 2007 (in press).)
TABLE 25–10 Mortality Rates in Placebo-Controlled Trials of Patients with Chronic Heart Failure (EF <40%), with Acute Myocardial Infarction, or at Risk for Heart Failure. (Modified from Bristow MR, Linas S, Port DI: Drugs in the treatment of heart failure. In Zipes DP, Libby P, Bonow RO, Braunwald E (eds): Braunwald’s Heart Disease. 7th ed. Philadelphia, Elsevier, 2004, pp 569-601.)
TABLE 23-7 Crude, Annualized Mortality Rates in Renin-Angiotensin-Aldosterone System Inhibitor Placebo-Controlled Trials Conducted in Chronic Heart Failure (HF) from Systolic Dysfunction, Left Ventricular (LV) Dysfunction after Myocardial Infarction, or in Patients Without LV Dysfunction at Risk for HF
TABLE 23-8 Properties of Widely Used Angiotensin-Converting Enzyme Inhibitors
Candesartan in ACE-I intolerant patients Another study, Val-HeFT looked at valsartan in HF and found: The primary outcomes of the Val-HeFT study was all-cause mortality, and combined all-cause mortality plus morbidity, which included hospitalization for heart failure, cardiac arrest with resuscitation, or need for intravenous support for worsening heart failure. 30 After 2 years of follow up, analysis of the data showed no effect of valsartan on all-cause mortality. However, there was a statistically significant risk reduction of 0.87 (95% confidence interval 0.79, 0.96) in the combined outcome of all-cause morbidity and mortality, or a 13% decline ( P = 0.009).
Candesartan added to background therapy (ACE-I and BB) – resulted in statistically significant reduction in CV mortality and HF hospitalization
TABLE 23-9 Properties of Widely Used Angiotensin Receptor Blockers
TABLE 23-10 Biological Responses Mediated by Adrenergic Receptors in the Human Heart
FIGURE 23-6 Schematic representation of selected components of the cardiac myocyte beta 1 - and beta 2 -adrenergic receptor pathways. The beta 1 -adrenergic receptor is illustrated with direct coupling through G αs to voltage-sensitive Ca 2+ channels as well as to Ca 2+ channels by cyclic adenosine monophosphate (cAMP-dependent protein kinase A (PKA) phosphorylation. AC = adenylyl cyclase; AR = adrenergic receptor; ATP = adenosine triphosphate; CAMK = calmodulin-activated kinase; PDE = phosphodiesterase; PHLMBN = phospholamban; SR = sarcoplasmic reticulum.
TABLE 23-11 Adrenergic Receptor Blocking Affinities of Beta-Blocking Agents in Human Receptors
TABLE 23-13 Beta Blocker Trials Conducted in Chronic Heart Failure, with 12-Month Mortality Rates Taken from Survival Curves When Data Not Directly Available in Published Material
TABLE 25–10 Mortality Rates in Placebo-Controlled Trials of Patients with Chronic Heart Failure (EF <40%), with Acute Myocardial Infarction, or at Risk for Heart Failure. (Modified from Bristow MR, Linas S, Port DI: Drugs in the treatment of heart failure. In Zipes DP, Libby P, Bonow RO, Braunwald E (eds): Braunwald’s Heart Disease. 7th ed. Philadelphia, Elsevier, 2004, pp 569-601.)
TABLE 23-12 Starting and Target Doses for Beta Blockers
Slide 27 The results of the MERIT-HF study indicate that treatment with TOPROL-XL added to standard heart failure therapy reduces the risk of mortality and morbidity. 1,2 The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup and women, overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. 2 Slide and Notes References 1. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet . 1999:353:2001-2007. 2. TOPROL-XL Prescribing Information. AstraZeneca. Wayne, PA. 27
FIGURE 25–16 Kaplan-Meier analysis of the probability of survival in patients in the placebo and beta blocker groups in the MERIT-HF (top), CIBIS II (middle), and COPERNICUS (bottom) trials. CHF = chronic heart failure; CI = confidence interval; RR = relative risk. (Data from The Cardiac Insufficiency Bisoprolol Study II [CIBIS II]: A randomised trial. Lancet 353:9, 1999; Effect of metoprolol in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure [MERIT-HF]. Lancet 353:2001, 1999; and Packer M, Coats AJ, Fowler MB, et al; Carvedilol Prospective Randomized Cumulative Survival Study [COPERNICUS] Group: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344:1651, 2001.)
TABLE 25–8 Diuretics for Treating Fluid Retention in Chronic Heart Failure*. (Modified from Hunt SA, Abraham WT, Chin MH, JL, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 112:e154, 2005.)
FIGURE 25–9 Sites of action of diuretics in the kidney. AVP = arginine vasopressin.
TABLE 25–9 Drugs for the Prevention and Treatment for Chronic Heart Failure. (Modified from Mann DL: Heart failure and cor pulmonale. In Kasper DL, Braunwald E, Fauci AS, et al (eds): Harrison’s Principles of Internal Medicine. 17th ed. New York, McGraw-Hill, 2007 (in press).)
FIGURE 23-5 Changes from baseline in pulmonary capillary wedge pressure in patients in decompensated heart failure treated with placebo, nitroglycerin, or nesiritide. (From Publication Committee for the VMAC Investigators: Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure. A randomized controlled trial. JAMA 287:1531, 2002.)
TABLE 25–7 Possible Precipitating Factors for Acute Decompensation in Patients with Chronic Heart Failure (HF). (From Mann DL: Heart failure and cor pulmonale. In Kasper DL, Braunwald E., Fauci AS, et al (eds): Harrison’s Principles of Internal Medicine. 17th ed. New York, McGraw-Hill, 2007 (in press).)
![Management of Chronic Heart Failure DR.SAMEER AMBAR DEPT OF CARDIOLOGY JNMC BELGAUM, INDIA [email_address]](https://image.slidesharecdn.com/bd1emanagementofheartfailure-090624165708-phpapp02/85/Bd1e-Management-Of-Heart-Failure-1-320.jpg)
