HOPE-3
Heart Outcomes Prevention Evaluation-3: Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease
Year of Publication: 2016
Authors: S. Yusuf, J. Bosch, G. Dagenais, ..., for the HOPE-3 Investigators
Journal: New England Journal of Medicine
Citation: N Engl J Med 2016;374:2021-31. DOI: 10.1056/NEJMoa1600176
PDF: Clinical Question
Does rosuvastatin reduce cardiovascular events in intermediate-risk persons without cardiovascular disease, regardless of lipid levels, inflammatory markers, hypertension, or diabetes status?
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
Design
Study Type: Randomized, double-blind, placebo-controlled trial
Randomization: 1
Blinding: Double-blind with patients, investigators, and others involved in treatment or data analysis masked to treatment allocation
Enrollment Period: April 2007 to November 2010
Follow-up Duration: 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
Sample Size: 12705
Analysis: Intention-to-treat analysis using Cox proportional-hazards model stratified according to the opposite group of the factorial design
Inclusion Criteria
- Men ≥55 years and women ≥65 years with at least one cardiovascular risk factor
- Women ≥60 years with at least two cardiovascular risk factors
- Risk factors: elevated waist-to-hip ratio, history of low HDL cholesterol, current/recent tobacco use, dysglycemia, family history of premature coronary disease, mild renal dysfunction
- No cardiovascular disease at baseline
- Intermediate risk (defined as annual risk of major cardiovascular events of approximately 1%)
Exclusion Criteria
- Cardiovascular disease
- Indication for or contraindication to statins
- Indication for or contraindication to angiotensin-receptor blockers, ACE inhibitors, or thiazide diuretics
- Trial did not mandate specific lipid or blood pressure levels for entry
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Mean age | 65.7 years | 65.8 years |
| Female | 46.1% | 46.4% |
| Elevated waist-to-hip ratio | 86.6% | 87.1% |
| Current/recent smoking | 28.1% | 27.4% |
| Low HDL cholesterol | 35.4% | 36.8% |
| Impaired glucose tolerance/diabetes | 18.3% | 18.6% |
| Family history premature CHD | 26.2% | 26.3% |
| Hypertension | 38.0% | 37.8% |
| Mean LDL cholesterol | 127.9 mg/dL | 127.8 mg/dL |
| Mean total cholesterol | 201.3 mg/dL | 201.5 mg/dL |
| INTERHEART Risk Score | 14.4 | 14.5 |
Arms
| Field | Rosuvastatin group | Control |
|---|---|---|
| Intervention | Rosuvastatin 10 mg once daily (fixed dose without adjustment or lipid targets) | Matched placebo tablets once daily |
| Duration | Median 5.6 years | Median 5.6 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| First coprimary outcome: composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke | Primary | 304/6344 (4.8%) | 235/6361 (3.7%) | 0.76 | 0.002 |
| Second coprimary outcome (first coprimary + resuscitation, heart failure, revascularization) | Secondary | 363/6344 (5.7%) | 277/6361 (4.4%) | 0.75 | <0.001 |
| Stroke (fatal or nonfatal) | Secondary | 99/6344 (1.6%) | 70/6361 (1.1%) | 0.7 | 0.02 |
| Myocardial infarction (fatal or nonfatal) | Secondary | 69/6344 (1.1%) | 45/6361 (0.7%) | 0.65 | 0.02 |
| Death from cardiovascular causes | Secondary | 171/6344 (2.7%) | 154/6361 (2.4%) | 0.89 | Not significant |
| Death from any cause | Secondary | 357/6344 (5.6%) | 334/6361 (5.3%) | 0.93 | 0.32 |
| Muscle symptoms | Adverse | 296/6344 (4.7%) | 367/6361 (5.8%) | 0.005 | |
| Cataract surgery | Adverse | 194/6344 (3.1%) | 241/6361 (3.8%) | 0.02 | |
| New-onset diabetes | Adverse | 226/6344 (3.8%) | 232/6361 (3.9%) | 1.02 | 0.82 |
| Cancer | Adverse | 286 cases | 267 cases | Not significant |
Subgroup Analysis
Benefits of rosuvastatin were consistent across subgroups defined by cardiovascular risk, LDL cholesterol level, blood pressure, C-reactive protein level, age, sex, and race/ethnic group. Particularly notable benefit demonstrated in Chinese, other Asian, and Hispanic populations.
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
Funding
Canadian Institutes of Health Research and AstraZeneca
Based on: HOPE-3 (New England Journal of Medicine, 2016)
Authors: S. Yusuf, J. Bosch, G. Dagenais, ..., for the HOPE-3 Investigators
Citation: N Engl J Med 2016;374:2021-31. DOI: 10.1056/NEJMoa1600176
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