HOPE, EUROPA, PEACE - ACEIs in CAD & other high-risk patients without HF or LV systolic dysfunction

Generalizability: Who do these results apply to?

  • HOPE represents a population of patients at high risk of CVD, the majority of whom had stable CAD
  • EUROPA and PEACE represent a stable CAD population
  • All 3 trials specifically excluded patient with clinical HF or LVEF <40% (though HOPE went to lesser lengths to obtain objective evidence of preserved EF)

Interventions

  • I: ACEI
    • HOPE: Ramipril for up to 5 y (median 4.5 y)
      • Initial: 2.5 mg PO HS x1 week,
      • Then increased to 5 mg PO HS x1 week,
      • Then increased to 10 mg PO HS for the duration of the trial
      • Adherence: 79% still taking at final follow-up visit
    • EUROPA: Perindopril for a mean 4.2 years
      • Initial: 4 mg PO daily x2 weeks (started @ 2 mg if age 70+ y),
      • Then increased to 8 mg PO daily
      • Dose could be reduced to 4 mg daily if higher dose not tolerated
      • Adherence: 81% still taking at 3 y follow-up visit
    • PEACE: Trandolapril for a median 4.8 years
      • Initial: 2 mg PO daily x6 months,
      • Then increased to 4 mg PO daily if tolerated
      • Adherence: 74% still taking at 3 y follow-up visit
  • C: Matching placebo

Results

Individually, HOPE and EUROPA demonstrated statistically significant results in their primary outcome, whereas PEACE did not. Results of PEACE originally seemed contradictory, however, a pooled analysis of these trials demonstrated consistent benefits.

Note: The following results are approximately calculated using the pooled relative risks & absolute risk in each study's placebo group.

  • Statistically significant reduction in:
    • Primary outcome (from PEACE, used for pooled analysis): Odds ratio (OR) 0.82, 95% confidence interval 0.76-0.88
      • 10.7% vs 12.8% (NNT 48)
    • All-cause mortality: OR 0.86 (0.79-0.94)
      • HOPE: 10.5% vs 12.2% (NNT 59)
      • EUROPA: 5.9% vs 6.9% (NNT 100)
      • PEACE: 7.0% vs 8.1% (NNT 91)
    • Non-fatal MI: OR 0.82 (0.75-0.91)
      • HOPE: 6.1% vs 7.5% (NNT 72)
      • EUROPA: 5.1% vs 6.2% (NNT 91)
      • PEACE: 4.3% vs 5.3% (NNT 100)
    • Stroke (fatal or non-fatal): OR 0.77 (0.66-0.89)
      • HOPE: 3.8% vs 4.9% (NNT 91)
      • EUROPA: 1.3% vs 1.7% (NNT 250)
      • PEACE: 1.7% vs 2.2% (NNT 200)
    • Hospital admission for HF: OR 0.77 (0.67-0.90)
      • HOPE: 2.6% vs 3.4% (NNT 125)
      • EUROPA: 1.3% vs 1.7% (NNT 250)
      • PEACE: 2.5% vs 3.2% (NNT 143)
    • Revascularization with CABG: OR 0.87 (0.79-0.96)
      • HOPE: 8.2% vs 9.4% (NNT 84)
      • EUROPA: 4.1% vs 4.7% (NNT 167)
      • PEACE: 6.2% vs 7.1% (NNT 112)
  • No statistically significant difference in revascularization with PCI: OR 0.97 (0.89-1.06)
  • Subgroup analyses showed consistent benefit with no significant difference in relative risk reduction between the following subgroups:
    • Low vs high annual CV risk
    • Revascularized or not (p=0.078 for interaction, both groups statistically significantly beneficial)
    • Optimal medical management (ASA+statin+beta-blocker), partially optimized, or not (p=0.357)
    • BP >140/90 vs <140/90

Issues with internal validity?

  • No; all 3 trials were randomized, allocation concealed, double-blind trials with low loss-to-follow-up (<2%) that adhered to the intention-to-treat principle
  • Run-in phase: All 3 trials had a run-in phase prior to randomization lasting 2-4 weeks