CONSENSUS - Enalapril in severe HF

in

The Consensus Trial Study Goup. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-35.

Bottom line: In patients with NYHA class IV HF (presumably with reduced EF), enalapril reduced the risk of death (NNT 6-7) & reduced symptom burden at 6 & 12 months.

 

Patients (n=253)

  • Inclusion
    • Clinical diagosis of HF
      • Hx of heart disease
      • Symptoms of dyspnea and/or fatigue
      • Signs of fluid retention
    • Symptomatic at rest (NYHA functional class IV)
    • Cardiomegaly on CXR, defined as heart size
      • Men: >600 mL/m^2
      • Women: >550 mL/m^2
    • No assessment of myocaridal function performed (? LVEF)
  • Exclusion
    • NYHA <IV after optimization with diuretics & digoxin
    • Hemodynamically important aortic/mitral stenosis
    • MI <2 months
    • Unstable angina
    • Planned cardiac surgery
    • 1o pulmonary disease or right HF due to pulmonary disease
    • SCr >300 umol/L
  • "Average" patient
    • Age 70
    • Female 30%
    • HF duration: <18 months (25%), 18 months to 4 y (~25%), >4 y (50%)
    • PMHx
      • CAD 73%, previous MI 48%
      • Cardiomyopathy 15%
      • Valvular heart disease ~20%
      • AF ~50%
    • BP 120/75 mm Hg
    • SCr 130 umol/L
    • K 4.0 mmol/L
    • Meds
      • Furosemide 90% (mean dose 200 mg)
      • Spironolactone 55% (mean dose 80 mg)
      • Digoxin 93%
      • Nitrate 45%, hydralazine 2%
      • Anticoagulant 33%

Interventions & co-interventions

  • I: Enalapril
    • Initial dose 5 mg PO BID (started in hospital)
    • Then increased to 10 mg PO BID after 1 week
    • Then the dose could be increased up to 20 mg PO BID
    • Mean dose @ end of study: 18.4 mg/day (~10 mg PO BID)
  • C: Matching placebo
  • Co-interventions
    • Optimized on diuretics +/- digoxin at start of trial
    • Other non-ACEI vasodilators permitted, including nitrates, alpha-1 blockers, hydralazine

Results @ 6 months

  • Death, statistically significant reduction
    • @ 6 months (primary outcome): 26% vs 44% (NNT 6 - relative risk reduction (RRR) 40%)
    • @ 1 year: 36% vs 52% (NNT 7 - RRR 31%)
  • Improvement in NYHA functional class: 42% vs 22% (NNT 5)
  • Study drug discontinuation: 17% vs 14% (NSS)

Issues with internal validity?

  • Possible exaggeration of benefit due to early termination for mortality in enalapril group in unplanned interim analysis
  • Otherwise well-designed: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up analyzed according to the intention-to-treat principle