| Authors |
| Packer M, O’Connor CM, Ghali JK, et al. |
| Title |
| Effect of amlodipine on morbidity and mortality in severe chronic heart failure |
| References |
| N Engl J Med 1996;335:1107-14. |
| Background |
| Use of calcium-channel blockers have been avoided in patients with severe HF as they may worsen HF and increase risk of death. However, an improvement in clinical status has been noted in small trials with amlodipine specifically. |
| Purpose |
| To determine if the addition of amlodipine to standard HF treatment affects the clinical outcomes in patients with severe heart failure (NYHA Class IIIB or IV) |
| Design |
- Randomized, placebo controlled, double-blind trial
- 1153 patients with NYHA class IIIB or IV symptoms and LVEF ≤30%
- after randomization, also stratified to ischemic heart disease vs. nonischemic dilated cardiomyopathy
- receiving conventional treatment, including digitalis, diuretic and ACEi
- nitrates permitted, but other vasodilators were not (eg hydralazine)
|
| Exclusion Criteria |
- Cardiac: uncorrected 1° valvular disease, myocarditis (active), constrictive pericarditis; recent cardiac arrest, SVT/fibrillation, UA/MI, cardiac revascularization or stroke
- Other: severe pulmonary, renal or hepatic disease; SBP <85 mmHg or >159 mmHg, DBP >89 mmHg, SCr >270 µmol/L, K <3.5 or >5.5 mmol/L or treatment with β-blockers, calcium-channel blockers or class IC antiarrhythmics
|
| Follow-Up |
| Median 13.8 months (ranged from 6-33 months) |
| Treatment Regimen |
- Amlodipine 5 mg daily for two weeks, then 10 mg daily (if tolerated) vs. placebo
- Dose was reduced or discontinued for side effects, but restarted at a later time if able; adjustment of concomitant medications also permitted but no open-label amlodipine use
|
| Results |
| For all patients and in ischemic & nonischemic stratum Primary Endpoint = Combined death from all causes and CV morbidity - CV morbidity: ≥24 hr hospitalization for acute pulmonary edema, severe hypoperfusion, MI, or sustained or hemodynamically unstable VT or fibrillation)
Secondary Endpoint = Death from all causes | All patients | Ischemic | Nonischemic |
|---|
| 1° Endpoint |
|---|
| 39% (amlodipine) vs. 42% (placebo); risk reduction 9% (24% lower to 10% higher), p=0.31 | 45% (amlodipine) vs. 45% (placebo); HR 1.04 (0.83-1.29); no significant difference | 28% (amlodipine) vs. 37% (placebo); risk reduction 31% (2-51% reduction), p=0.04 | | 2° Endpoint |
|---|
| 33% (amlodipine) vs. 38% (placebo); risk reduction 16% (31% lower to 2% higher), p=0.07 | 40% (amlodipine) vs. 40% (placebo); HR 1.02 (0.81-1.29); no significant difference | 74 deaths (amlodipine) vs. 45 deaths (placebo); risk reduction 46% (21-63% reduction), p<0.001 | - Effect on subgroups: Amlodipine did not have any adverse effects on the defined subgroups (age, sex, EF, NYHA class, serum sodium, presence of angina, hypertension), but did demonstrate a beneficial effect in patients without angina (p=0.002, as compared to angina patients).
- Safety & Adverse Reactions: Peripheral edema (27% vs. 18%, p<0.001) and pulmonary edema (15% vs. 10%, p=0.01) was more frequent in the amlodipine vs. placebo group. Worsening heart failure was not significant (42% amlodipine vs. 41% placebo). Uncontrolled hypertension (<1% vs 2%, p=0.03) and chest pain/angina (25% vs. 31%, p=0.07) was lower in the amlodipine vs. placebo group.
|
| Summary |
| When added to standard HF therapy in patients with severe HF, amlodipine does not increase morbidity and mortality rates. Amlodipine may also have a beneficial effect for patients with nonischemic dilated cardiomyopathy. |