HOPE, EUROPA, PEACE - ACEIs in CAD & other high-risk patients without HF or LV systolic dysfunction
Bottom line: In patients with stable CAD without clinical HF or reduced LV systolic function, ACE inhibitors reduced the risk of death (NNT ~60-100) and cardiovascular outcomes (NNT 50) over an average 4-5 years. These benefits occurred regardless of concomitant PCI, presence of other medical therapies, or baseline blood pressure.
Patients
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
- HOPE: Ramipril for up to 5 y (median 4.5 y)
- 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)
- Primary outcome (from PEACE, used for pooled analysis): Odds ratio (OR) 0.82, 95% confidence interval 0.76-0.88
- 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