| Authors |
| Packer M, Coats AJS, Fowler MB, et al. |
| Title |
| Effect of Carvedilol on Survival in Severe Chronic Heart Failure |
| References |
| N Engl J Med 2001;344:1651-8. |
| Background |
| At the time of initiation of this study, beta-blockers improve survival and decrease hospitalization rates in patients with mild-to-moderate heart failure. Their role in patients with severe HF was not established. |
| Purpose |
| To determine whether carvedilol, when added to conventional therapy, positively affects survival rates in patients with severe chronic heart failure (symptomatic at rest or minimal exertion and LVEF <25%). |
| Design |
- Randomized, double-blind, placebo-controlled trial
- 2289 patients with severe but stable chronic HF (defined as dyspnea or fatigue at rest or on minimal exertion and LVEF <25%) due to ischemic or non-ischemic cardiomyopathy
- Receiving conventional therapy: diuretic and ACEi (or ARB); permitted to use digoxin, nitrates, hydralazine, spironolactone and amiodarone if needed
- Hospitalized patients could be enrolled if without intensive care or continued inpatient care requirements
|
| Exclusion Criteria |
- Contraindications to β-blockers; IV inotropes or vasodilators use within 4 days of screening; use of alpha-blocker, calcium channel blocker, or class I antiarrhythmic drugs in the past 4 weeks or beta-blocker use in the past 2 months
- previous or planned heart transplant; HF due to reversible cardiomyopathy, primary valvular disease; severe primary pulmonary, renal or hepatic disease
- within the last two months: coronary revascularization, MI, CVA, sustained or hemodynamically unstable VT or VF
- SBP <85 mmHg, HR <68 bpm, serum creatinine >247.5 µmol/L, potassium <3.5 or >5.2 mmol/L; >44.2 µmol/L SCr or >1.5 kg increases during screening period
|
| Follow-Up |
| Mean 10.4 months (stopped early, due to survival benefits of carvedilol) |
| Treatment Regimen |
- Carvedilol 3.125 mg twice daily (if tolerated, dose increased every two weeks to 6.25 mg, then 12.5 mg and target of 25 mg twice daily) vs. placebo
|
| Results |
Primary Endpoint Death: - Cumulative risk at 1 year - 18.5% (placebo) vs. 11.4% (carvedilol)
- Risk decreased by 35% with carvedilol vs. placebo, p=0.00013 (unadjusted) and p=0.0014 (after adjustment for interim analyses)
Secondary Endpoint Combined death or hospitalization: 24% decrease with carvedilol vs. placebo, p <0.001
Subgroup analyses: in the very high risk group of patients with recent or recurrent cardiac decompensation or severely depressed cardiac function, cumulative risk of death at one year was 24%; carvedilol reduced this risk by 39% (p=0.009) and decreased combined death or hospitalization by 29% (p=0.003) Safety: discontinuation of treatment due to adverse effects were higher in the placebo group than with carvedilol (p=0.02). |
| Summary |
| In patients with severe chronic heart failure despite diuretic + ACEi (or ARB) therapy, carvedilol significantly increases survival, decreases hospitalizations and is well tolerated as compared to placebo. |