Cardiology · 2000
HOPE (Heart Outcomes Prevention Evaluation)
ACE inhibitors had established roles in heart failure and in patients with reduced ejection fraction after myocardial infarction, where their benefit was attributed to reducing afterload and attenuating ventricular remodeling. The question that HOPE asked was different: whether ACE inhibition could reduce cardiovascular events in high-risk patients who did not have heart failure or depressed LV function, and whose indication for the drug would be vascular protection rather than hemodynamic support. If true, the eligible population was vastly larger than any prior indication.
HOPE enrolled 9,297 patients aged 55 or older with established vascular disease or diabetes plus at least one additional cardiovascular risk factor, specifically excluding patients with heart failure or low ejection fraction. Patients were randomized to ramipril 10 mg daily or placebo and followed for a mean of five years. The composite primary endpoint of cardiovascular death, myocardial infarction, and stroke occurred in 14.0% of the ramipril group and 17.8% of the placebo group, a relative risk reduction of 22%. Each component of the composite was reduced individually. Salim Yusuf at McMaster University was the principal investigator.
The observed fall in blood pressure during the trial was modest, approximately 3 mmHg systolic and 2 mmHg diastolic. The magnitude of the cardiovascular benefit was difficult to attribute entirely to antihypertensive effect at that level; modeling from the established relationship between blood pressure and cardiovascular events predicted a smaller reduction than was observed. This discrepancy generated substantial discussion and hypothesis about direct vascular, anti-inflammatory, or anti-atherosclerotic effects of ACE inhibition operating independently of pressure lowering. The debate was never fully resolved, but the clinical conclusion was straightforward: ramipril reduced events in this population.
The MICRO-HOPE substudy, with Eva Lonn as lead author, examined the 3,577 diabetic patients within the trial and found comparable or larger relative risk reductions in that group, including a 24% reduction in nephropathy. MICRO-HOPE provided a specific evidence base for using ACE inhibitors in diabetic patients with any vascular risk factor, regardless of whether hypertension or albuminuria was present. That finding was incorporated into diabetes management guidelines alongside the UKPDS data from the same year.
HOPE expanded ACE inhibitor prescribing beyond its prior indications into broad secondary prevention. The trial also influenced subsequent study design by demonstrating that adding a drug to existing standard therapy in a multimorbid population could yield detectable outcome differences with sample sizes around ten thousand patients followed for five years. ONTARGET, which tested the same hypothesis with telmisartan and a combination arm, followed in the same methodologic tradition and enrolled over 25,000 patients.
Key People
- Salim Yusuf — Principal investigator, HOPE trial, McMaster University
- Eva Lonn — Co-investigator and lead author of the MICRO-HOPE substudy
- Jackie Bosch — McMaster co-investigator; contributed to HOPE trial management and analysis
N Engl J Med. 2000;342(3):145-153.