| Authors |
| Granger CB, McMurray J, Yusuf S, et al. |
| Title |
| Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial |
| References |
| Lancet 2003;362:772-6 |
| Background |
| ACE inhibitor reduces mortality and morbidity in patients with HF and systolic dysfunction. However, intolerance to ACE inhibitors prevents these patients from receiving their benefits. The ARB may be an alternative but their effects have yet to be demonstrated. |
| Purpose |
| To determine whether the ARB, candesartan, improves survival rates and clinical outcomes in symptomatic left ventricular systolic heart failure patients who are intolerant to ACE inhibitor therapy. |
| Design |
- Randomized, double-blind, placebo-controlled trial
- 2028 patients, age ≥18 years with NYHA class II-IV symptoms, LVEF ≤40% and intolerance to ACE inhibitors
- other medications for heart failure such as diuretics, digoxin, beta-blockers and spironolactone permitted
|
| Exclusion Criteria |
- serum creatinine ≥265 µmol/L, serum potassium ≥5.5 mmol/L
- symptomatic hypotension, known bilateral renal artery stenosis
- critical mitral or aortic stenosis; recent MI, CVA or CABG
- ARB therapy in the previous 2 weeks
- women with childbearing potential and not on contraception
- other co-morbidities preventing completion of study duration
|
| Follow-Up |
| Median of 33.7 months |
| Treatment Regimen |
- candesartan 4 mg or 8 mg once daily, dose doubled every 2 weeks to target of 32 mg once daily (as tolerated by patient) vs. placebo
- Potassium and creatinine level monitoring with each titration. Patient follow-up at week 2, 4, 6, month 6 and then every 4 months.
|
| Results |
Primary Endpoints Death from cardiovascular causes or hospitalization for worsening heart failure: 33% (candesartan) vs. 40% (placebo); unadjusted hazard ratio 0.77 (0.67-0.89), p=0.0004.
Secondary Endpoints (see study for complete list) Cande-
sartan
n=1013 | Placebo
n=1015 | Hazard Ratio | p |
|---|
| CV death, HF hospitalization, MI |
|---|
| 34.8% | 41.4% | 0.78 (0.68-0.90) | 0.0007 | | CV death, HF hospitalization, MI, stroke |
|---|
| 36.4% | 42.6% | 0.78 (0.68-0.90) | 0.001 | | CV death, HF hospitalization, MI, stroke, coronary revascularization |
|---|
| 39.1% | 44.9% | 0.78 (0.68-0.90) | 0.002 | - Rates of candesartan discontinuation significantly higher than in placebo for hypotension (p<0.0001), creatinine increase (p<0.0001), hyperkalemia (p=0.0005)
|
| Summary |
| Candesartan therapy is an acceptable alternative for patients with systolic heart failure, NYHA class II-IV symptoms who are intolerant to ACE inhibitors. |