| Authors |
| McMurray J, Ostergren J, Swedberg K, et al. |
| Title |
| Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial |
| References |
| Lancet 2003;362:767-71 |
| Background |
| ACE inhibitors have been demonstrated to improve morbidity and mortality outcomes in HF but they incompletely inhibit the renin-angiotensin aldosterone system (RAAS). Further RAAS inhibition by addition of an ARB may improve survival. |
| Purpose |
| To determine if the addition of an ARB, candesartan, improves survival rates and clinical outcomes in chronic heart failure patients with reduced left ventricular ejection fraction (≤40%) and already receiving an ACE inhibitor. |
| Design |
- Randomized, double-blind, placebo controlled trial
- 2548 patients, age ≥18 years with NYHA class II-IV symptoms, LVEF ≤40% and treated with ACE inhibitor ≥1 month
|
| 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 41 months |
| Treatment Regimen |
- Candesartan 4 mg or 8 mg once daily, dose doubled every 2 weeks to a target of 32 mg once daily (as tolerated by patient) vs. placebo
- Monitoring of potassium and serum creatinine with each titration and follow-up at week 2, 4, 6, month 6 and then every 4 months
- About 96% of patients in both groups were on optimal doses of enalapril, lisinopril, captopril and ramipril
|
| Results |
Primary Endpoints Death from cardiovascular causes or hospitalization for worsening heart failure: 37.9% (candesartan) vs 42.3% (placebo); hazard ratio 0.85 (0.75-0.96), p=0.011 - individually, CV death (p=0.029) and HF hospitalization (p=0.014) were also significantly reduced in the candesartan group
- rates of first, multiple and total number of HF hospitalizations were significantly lower in the candesartan group
Secondary Endpoints (see study for complete list) Cande-
sartan
n=1276 | Placebo
n=1272 | Hazard Ratio | p |
|---|
| CV death, HF hospitalization, MI |
|---|
| 38.8% | 43.2% | 0.85 (0.76-0.96) | 0.010 | | CV death, HF hospitalization, MI, stroke |
|---|
| 40.1% | 43.9% | 0.87 (0.77-0.98) | 0.020 | | CV death, HF hospitalization, MI, stroke, coronary revascularization |
|---|
| 42.9% | 46.9% | 0.87 (0.77-0.97) | 0.015 | - Rates of candesartan discontinuation significantly higher than in placebo for creatinine increase (p=0.0001) and hyperkalemia (p<0.0001)
- Rates of creatinine increase and hyperkalemia were not significantly higher in patients who were on spironolactone at baseline.
- Reduced risk of CV death or HF hospitalization regardless of beta-blockade.
|
| Summary |
| When added to ACE inhibitor therapy, the ARB candesartan reduces the composite and individual rates of CV death or HF hospitalization in in patients and HF and LVEF. |