HOPE-3: A Primary Cardiovascular Prevention Trial in People at Intermediate Risk

April 3, 2016

HOPE-3: A Primary Cardiovascular Prevention Trial in People at Intermediate Risk

  1. Allan S. Brett, MD

Rosuvastatin lowered the incidence of CV-related death, myocardial infarction, or stroke by 1 percentage point during 5 years of treatment.

  1. Allan S. Brett, MD

The Heart Outcomes Prevention Evaluation (HOPE)-3 is an international randomized trial conducted in 21 countries; China, India, Colombia, Argentina, and Canada contributed the most participants. The trial included 12,705 people (age, ≥65 for women, and ≥55 for men) without known cardiovascular (CV) disease who were considered to be at intermediate risk by virtue of meeting at least one inclusion criterion: Elevated waist–hip ratio, HDL cholesterol level <39 mg/dL (men) or <50 mg/dL (women), current or recent smoking, prediabetes or diet-controlled diabetes, premature coronary disease in first-degree relatives, or early renal dysfunction. Most participants had at least two risk factors.

In a 2×2 factorial design, each participant received daily rosuvastatin (10 mg) or placebo, plus daily candesartan/hydrochlorothiazide (16 mg/12.5 mg) or placebo. At baseline, mean LDL cholesterol level was 128 mg/dL and mean blood pressure (BP) was 138/82 mm Hg. During median follow-up of 5.6 years, key findings were as follows:

  • Compared with placebo, rosuvastatin lowered mean LDL cholesterol level by 35 mg/dL, and the antihypertensive drugs lowered mean systolic/diastolic BP by 6/3 mm Hg.

  • The first coprimary outcome (CV-related death, nonfatal stroke, or nonfatal myocardial infarction [MI]) occurred significantly less frequently with rosuvastatin than with placebo (3.7% vs. 4.8%); absolute reductions were 0.3%, 0.4%, and 0.5% for CV-related death, MI, and stroke, respectively.

  • Overall, candesartan/hydrochlorothiazide did not significantly lower the incidence of the first coprimary outcome compared with placebo (4.1% vs. 4.4%); however, it did lower the incidence in a subgroup with highest baseline systolic BP (>143 mm Hg; 4.8% vs. 6.5%).

  • Overall, outcomes with rosuvastatin plus candesartan/hydrochlorothiazide were not significantly better than outcomes with rosuvastatin alone.

  • All-cause mortality was not lowered by active therapies compared with placebo.

  • Neither treatment increased risk for diabetes; a small excess of muscle pain was noted with rosuvastatin and dizziness with candesartan/hydrochlorothiazide.

Comment — General Medicine

Interestingly, HOPE-3 had no LDL cholesterol or BP thresholds for enrollment (although people with “symptomatic hypotension” were excluded). For intermediate-risk patients like those in the trial (whose 10-year risk for adverse cardiovascular events is roughly 10%), the subgroup analysis of the trial's antihypertensive arm suggested potential benefit when systolic BP was >143 mm Hg. For the cholesterol-lowering arm, the 1 percentage-point difference in CV-related death, MI, or stroke that favored rosuvastatin (vs. placebo) means that about 100 people were treated for 5 years to benefit 1 person. In the U.S., the retail cost of rosuvastatin (Crestor) — for which a generic form is not available — is about US$3,600 annually. Patient preferences obviously will be important to guide these decisions. HOPE-3 was funded in part by the maker of Crestor.

Comment — Cardiology

  1. Harlan M. Krumholz, MD, SM

In my opinion, this study shows that antihypertensive medications did not benefit this cohort. This finding is certain to unsettle further the ongoing discussion about what patients and their doctors should do about this common risk factor — mildly elevated blood pressure — and runs counter to the findings of the SPRINT trial, albeit with a different population and less-aggressive treatment (NEJM JW Gen Med Dec 15 2015 and N Engl J Med 2015; 373:2174). This study provides little help in determining the threshold to begin treatment. It suggests that the subgroup in the upper tertile of BP (mean BP, 153 mm Hg) might have benefited from BP reduction (which was about 6 mm Hg systolic in this group) — but this secondary analysis with borderline significance is only exploratory.

Editor Disclosures at Time of Publication

  • Disclosures for Allan S. Brett, MD at time of publication Nothing to disclose


Reader Comments (1)


540 different institutions, 12,000 patients: I don't trust the BP data. They did get the cholesterol data right. HRS, MD, FACC

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