Does inhibition of the renin-angiotensin-aldosterone system reduce the risk of cardiovascular events? A discussion of HOPE

Original Citation

The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of an angiotensin- converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.

Study Question

The HOPE study was designed to test the theory that inhibition of the renin-angiotensin-aldosterone system would reduce the risk of cardiovascular events.  Patients were included in the study if they were 55 years or older, had a history of coronary artery disease, stroke, peripheral vascular disease, or had diabetes plus one or more other cardiovascular risk factors.  These patients are considered to be at high risk for cardiovascular events.  The primary outcome was a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

Yes. Patients meeting the inclusion criteria were randomly assigned to one of four treatment groups.  The study was a two-by-two factorial design that simultaneously compared the efficacy of ramipril and vitamin E.  Randomization was undertaken using a computer-generated sequence and was managed at a central office.  Patients were assigned to receive either: 1) ramipril 10 mg and vitamin E 400 IU, 2) ramipril 10 mg and placebo, 3) placebo and vitamin E 400 IU, or 4) placebo for both ramipril and vitamin E.  A sub study compared patients who were randomized to receive 2.5 mg of ramipril, 10 mg of ramipril, or placebo.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes.  10,576 patients met the inclusion criteria and entered a run-in phase.  All patients received 2.5 mg of ramipril for 7 to 10 days, then placebo for 10 to 14 days.  1035 patients were excluded during the run-in phase due to poor adherence (<80% of pills taken), adverse effects, abnormal serum creatinine or potassium levels, or withdrawal of consent.  The remaining patients were randomly assigned to receive ramipril 10 mg (4645 patients), placebo (4652 patients), or ramipril 2.5 mg (244 patients).  Vital status was known for 99.9% of the patients at the end of the study.  Data were analyzed according to intention-to-treat.  The study was terminated early after an independent data and safety monitoring committee found clear evidence of a beneficial effect for ramipril at one of the planned interim analyses.

3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?

Yes.  Patients and clinicians were blinded to treatment assignment.  An expert committee adjudicated all reported endpoints using standardized definitions.

4. Were the groups similar at the start of the trial?

Yes.  The baseline characteristics between the ramipril and placebo groups were similar.  It is noteworthy that 26.7% were female, 80.4% had a history of coronary artery disease and 38.5% had diabetes.

5. Aside from the experimental intervention, were the groups treated equally?

Yes.  All patients were followed in a similar fashion.  Follow-up visits occurred at 1 month, then every 6 months.  The study was initially planned for a mean of 3.5 years follow-up.  However, after a blinded interim analysis revealed a lower than expected event rate, the steering committee decided to extend follow-up to 5 years.  Standardized data forms were used to record outcome events, compliance rates and adverse events.

6. Overall, are the results of the study valid?

Yes.

What were the Results?

1. How large was the treatment effect?

The primary endpoint for the HOPE trial was a composite of myocardial infarction, stroke, or death from cardiovascular causes.  Patients treated with ramipril had a significantly lower risk of reaching the primary endpoint as compared to patients treated with placebo.

Cardiovascular mortality, stroke or myocardial infarction: ramipril = 14.0%; placebo = 17.8%; RRR = 22% (95% CI 14 to 30%), p<0.001; ARR = 3.8%.  This translates to an NNT of 26 (95% CI 19 to 40).

Secondary endpoints included each of the individual components of the primary endpoint, all cause mortality, need for revascularization, hospitalization for unstable angina or heart failure, and complications related to diabetes.  Treatment with ramipril significantly reduced the risk of each of the secondary endpoints except hospitalization.

There was no information provided regarding the frequency or nature of adverse effects.

2. How precise was the estimate of the treatment effect?

The confidence intervals were relatively narrow, which could be due to the large sample size of the trial.  However, treatment with ramipril could reduce the risk of the primary endpoint as much as 5.3% ARR or as “poorly” as 2.5% ARR, which is still considered clinically significant.

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

Yes.  The results of this trial can be applied to a wide range of patients who are at high risk for cardiovascular events.  The treatment effect was retained in a number of predefined subgroups controlling for presence of diabetes, gender, presence of cardiovascular disease, age (cut point of 65 years old), presence of hypertension, and presence of microalbuminuria.

2. Were all clinically important outcomes considered?

Yes.  Major clinical events were considered, including total and cardiovascular mortality, and various forms of morbidity including hospitalization, need for revascularization, and diabetes-related complications.  However, clinically important adverse events, such as renal insufficiency and hypotension were not reported.

3. Are the likely treatment benefits worth the potential harms and costs?

Yes.  The number needed to treat is similar to that for other currently accepted secondary prevention measures such as beta-blockers, acetylsalicylic acid, and lipid-lowering medications.  An economic impact of these results is planned.

Commentary

The beneficial effects of  angiotensin- converting enzyme inhibitors have been proven in patients with symptomatic and asymptomatic heart failure.  With the results of the HOPE trial, use of these agents could be expanded to secondary prevention of cardiovascular events.  One finding that warrants further investigation is the reduction in diabetic-related complications, even in patients who do not have diabetes.

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