PDF: HOPE-3
(2016)Objective
To determine whether rosuvastatin 10 mg daily reduces major cardiovascular events in individuals at intermediate risk without known cardiovascular disease.
Study Summary
• The benefit was consistent across LDL levels, hsCRP, BP, and ethnicity.
• Rosuvastatin did not significantly increase diabetes but slightly increased muscle symptoms and cataract surgeries.
Intervention
Randomized, double-blind, placebo-controlled, 2x2 factorial trial across 228 centers in 21 countries. • 12,705 participants with intermediate CV risk randomized to rosuvastatin 10 mg vs. placebo. • Primary outcomes: (1) CV death, MI, or stroke; (2) CV death, MI, stroke, revascularization, heart failure, or cardiac arrest. • Median follow-up: 5.6 years.
Inclusion Criteria
Men ≥55 years or women ≥65 years (or women ≥60 years with ≥2 risk factors) with at least one cardiovascular risk factor: elevated waist-to-hip ratio, low HDL, smoking, dysglycemia, family history of premature CHD, or mild renal dysfunction
Study Design
Arms: Rosuvastatin group (n=6361) vs Placebo group (n=6344)
Patients per Arm: 6361 rosuvastatin, 6344 placebo
Outcome
• Second coprimary outcome: 4.4% vs. 5.7%; HR 0.75; 95% CI 0.64–0.88; p<0.001
• Stroke: 1.1% vs. 1.6%; HR 0.70; p=0.02
• MI: 0.7% vs. 1.1%; HR 0.65; p=0.02
• Revascularization: 0.9% vs. 1.3%; HR 0.68; p=0.01
• No significant difference in all-cause mortality or new-onset diabetes
• Adverse events: slight increase in muscle symptoms (5.8% vs. 4.7%, p=0.005) and cataract surgery (3.8% vs. 3.1%, p=0.02)
Bottom Line
Rosuvastatin 10 mg daily significantly reduced cardiovascular events by 24-25% in an ethnically diverse, intermediate-risk population without cardiovascular disease, demonstrating benefit regardless of baseline lipid levels.
Major Points
- Large international trial with 12,705 participants from 21 countries across 6 continents
- 2x2 factorial design evaluating both cholesterol lowering and blood pressure lowering
- Ethnically diverse population: 20% white, 49.1% Asian, 27.5% Hispanic, 3.3% black/other
- Rosuvastatin reduced LDL cholesterol by 26.5% compared to placebo
- First coprimary outcome reduced by 24% (HR 0.76, 95% CI 0.64-0.91, p=0.002)
- Second coprimary outcome reduced by 25% (HR 0.75, 95% CI 0.64-0.88, p<0.001)
- Benefits consistent across all ethnic groups and risk levels
- Fixed-dose approach without routine monitoring was effective
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind with patients, investigators, and others involved in treatment or data analysis masked to treatment allocation
- Sample Size
- 12705
- Follow-up
- Median 5.6 years
- Centers
- 228
- Countries
- Germany, Italy, Spain, UK, Poland, Czech Republic, Russia, India, China, Malaysia, Philippines, Thailand, Brazil, Colombia, Argentina, Canada, USA, Australia, South Africa, Ukraine, Israel
Primary Outcome
Definition: First coprimary outcome: composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 304/6344 (4.8%) | 235/6361 (3.7%) | 0.76 (0.64-0.91) | 0.002 |
Limitations & Criticisms
- 2x2 factorial design makes it complex to isolate effects of cholesterol lowering alone
- Adherence declined over time (75.5% at 5 years vs 88.0% at 1 year)
- Some participants in placebo group initiated open-label statins (5.6% at 5 years)
- Muscle symptoms were more common with rosuvastatin
- Increased risk of cataract surgery not previously reported in trials
- Relatively short follow-up may underestimate long-term benefits and risks
Citation
N Engl J Med 2016;374:2021-31. DOI: 10.1056/NEJMoa1600176