ARBs in HFrEF (ELITE I & II, CHARM-Alternative, CHARM-Added & Val-HeFT)

ELITE: Pitt B, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349:747-52.

ELITE II: Pitt B, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial-the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-7.

CHARM-Alternative: Granger CB, et al. 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. Lancet 2003;362:772-6.

CHARM-Added: McMurray JJ, et al. Effects of candesartan in patients with chronic heart fialure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767-71.

Val-HeFT: Cohn JN, et al. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-75.

Bottom-line: In patients with HFrEF with suboptimal beta-blocker use, ARBs reduce the risk of death or HF hospitalization (NNT 40-80/year; mainly from reduced HF hospitalizations), whether added to ACEI or used instead in ACEI-intolerant individuals. ARBs increase the risk of discontinuation due to adverse events when added to ACEI (NNH ~20-40), primarily from hypotension, renal dysfunction & hyperkalemia.

Results

Safety

• CHARM-Alternative
  • Any adverse event or lab abnormality: Candesartan 21.5% vs placebo 19.3% (p=0.23)
    • Hypotension leading to D/C: 3.7% vs 0.9% (NNH 36)
    • SCr increase leading to D/C: 6.1% vs 2.7% (NNH 30)
    • Hyperkalemia: 1.9% vs 0.3% (NNH 63)
• CHARM-Added
  • Any adverse event or lab abnormality: Candesartan 24.2% vs placebo 18.3% (NNH 17)
    • Hypotension leading to D/C: 4.5% vs 3.1%
    • SCr increase leading to D/C: 7.8% vs 4.1%
    • Hyperkalemia: 3.4% vs 0.7%
• Val-HeFT
  • Drug D/C: Valsartan 9.9% vs placebo 7.2% (NNH 37)
    • Dizziness 1.6% vs 0.4%
    • Hypotension: 1.3% vs 0.8%
    • Renal impairment: 1.1% vs 0.2%

Generalizability of trials adding ARB to ACEI

• CHARM-Alternative specifically enrolled patients intolerant of ACEI & therefore not receiving these agents, whereas 93% of patients enrolled in Val-HeFT received ACEI therapy
  • Results of CHARM-Added were similar to those of Val-HeFT (HR 0.85 for primary outcome & 0.83 for HF hospital admission)
• Patients in both trials had overall poor optimization of other HF meds (35-55% on beta-blockers, 5-25% on mineralocorticoid receptor antagonist) at baseline.

Internal validity

• Low risk of allocation, performance, detection and attrition bias, as all trials were randomized, allocation concealed, double-blind trials with blinded outcome adjudication, loss-to-follow-up <1% and intention-to-treat analysis.