Carvedilol: CARVEDILOL IN CHF(7)

Studies with carvedilol have demonstrated more consistent benefits (hemodynamics, functional class) in patients with heart failure secondary to both IDCM and ischemia (Table 2). The two largest carvedilol trials are from the Australia-New Zealand Heart Failure Research Collaborative Group and the United States Carvedilol Heart Failure Study Group. Although the Australia-New Zealand group found a significant improvement in EF in patients receiving carvedilol, they were unable to demonstrate an improvement in functional class or exercise tolerance. Furthermore, after a mean follow-up of 19 months, there was no difference in overall mortality, although a significant reduction in the combined end-point of death or hospitalization was found. The sample size of this study, however, was designed to detect a difference in EF and exercise duration and, therefore, had inadequate power to detect a significant difference in mortality. buy levaquin online

TABLE 2 Randomized, controlled trials of carvedilol in heart failure

Study (reference) Metraetal Mean doseAll except five patients received 50 mg/day* Samplesize40 Types of patients (cause of CHF)-All IDCM -Mean EF 19.5%– NYHA class II or III Mean duration of follow-up4 months Other therapy (% patients)–    Diuretics -ACEI –    Digoxin Efficacy–    Significant improvement in cardiac index, PCWP, SVR, SWI, SVI and EF–    Significant improvementin NYHA class and quality of life Adverse Effects– Five patients with bradycardia, hypotension or wheezing
Olsen et al 81 mg/day* 60 –    IDCM and ISC–    Mean EF 20%–    NYHA class II or III 4 months –    Diuretics -ACEI –    Digoxin –    Warfarin – Significant improvement in EF, PCWP, SVI and NYHA class in both IDCM and ISC patients – One death and one increased CHF during dose titration on carvedilol
Krum et al Up to 50 mg/day* 56 – IDCM, ISC and valvular heart disease -Mean EF 16%-NYHA class III or IV 14 weeks -ACEI –    Significant improvements in functional class, symptoms and hemodynamics (EF, SVI, PCWP, SVR) in both IDCM and ISC–    Significant decrease in adrenaline concentrations–    Decrease in major cardiovascular events (death, increased CHF, arrhythmias) –    Seven patients failed to complete titration phase (one SCD, two CHF deaths, one wheezing)–    37% dyspnea and fluid retention, 22% dizziness during titration phase
Australia-New Zealand Heart Failure Research Collaborative Group 41 mg/day* 415 –    ISC only–    Mean EF 28.6%-70% NYHA class II or III 19 months –    Diuretics -ACEI –    Digoxin –    Significant increase in EF–    No difference in exercise tolerance or functional class–    No difference in mortality–    Significant decrease in combined end-point of death and hospitalizations –    27 patients withdrawn during titration (eight increased CHF, eight decreased BP, two SCD)–    43 patients withdrawn during trial (30 on carvedilol: increased CHF, bradycardia, AV block, dizziness)
US Carvedilol Heart Failure Study Group 45 mg/day* 1094f –    IDCM and ISC–    Mean EF 22.5%-97% NYHA class II or III 6.5 months* –    Diuretics -ACEI –    Digitalis –    Other vasodilators –    Significant decrease in mortality from 7.8% to 3.2% (65% RR [Cl 39% to 89%], P<0.001)–    Significant decrease in hospitalizations due to CHF – 11 % of patients on carvedilol withdrawn due to increased CHF during titration and trial period

*Open-label phase followed by dosage titration up to maximally tolerated doses;f Stratified into four groups based on exercise capacity: mild, moderate, severe, dose-ranging study in moderate; *Trial terminated early due to beneficial effects of carvedilol on survival. ACEI Angiotensin-converting enzyme inhibitors; A V Atrioventricular; CHF Congestive heart failure; EF Ejection fraction; IDCM Idiopathic dilated cardiomyopathy; ISC Ischemic; NYHA New York Heart Association; PCWP Pulmonary capillary wedge pressure; RR Risk reduction; SCD Sudden cardiac death; SVR Systemic vascular resistance; SWI Stroke work index; SVI Stroke volume index

The United States Carvedilol Heart Failure Study Group studied the effects ofcarvedilol compared with placebo in 1094 patients with heart failure. Patients were stratified, based on exercise capacity, into mild, moderate or severe heart failure. The results of each of these subgroups were also published as separate trials . Patients were stabilized on diuretic and ACE inhibitor therapy, with or without digoxin or other vasodilators. All patients underwent a two-week open-label phase, similar to that of other beta-blocker trials, during which they received carvedilol 6.25 mg orally bid. If patients tolerated this regimen, they were randomly assigned to placebo or active drug, and the dose was titrated up to 50 mg orally bid over a two- to 10-week period. The United States Carvedilol Heart Failure Study Group trial was terminated prematurely based on an interim analysis by the Data and Safety Monitoring Board, which demonstrated a significant reduction in mortality in patients randomly assigned to carvedilol (from 7.8% to 3.2% [65% reduction in risk, P<0.001]). There was also a significant reduction in hospitalizations due to CHF in patients receiving carvedilol. Interestingly, in the individual subgroup trials, there was a significant reduction in mortality only in the dose-ranging study comprising patients with moderate heart failure . Dose-related improvements in EF were also observed consistently in treated patients. However, these improvements did not correspond to benefits in exercise tolerance or quality of life (measured by the Minnesota Living with Heart Failure Questionnaire).

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