PDF: HOPE-3 (Stroke Analysis)
(2021)Objective
To assess the effects of antihypertensive therapy, statin therapy, and their combination on the primary prevention of stroke in an intermediate-risk population.
Study Summary
• Rosuvastatin 10 mg daily significantly reduced the risk of first stroke by 30% (HR 0.70).
• The combination of rosuvastatin and antihypertensive therapy significantly reduced the risk of any stroke by 44% (HR 0.56) and ischemic stroke by 59% (HR 0.41) compared to double placebo.
• The combination of rosuvastatin and antihypertensive therapy significantly reduced the risk of any stroke by 44% (HR 0.56) and ischemic stroke by 59% (HR 0.41) compared to double placebo.
Intervention
A 2x2 factorial design comparing: 1) Candesartan 16mg + HCTZ 12.5mg daily vs placebo; and 2) Rosuvastatin 10mg daily vs placebo, in intermediate-risk individuals for primary cardiovascular prevention. The median follow-up was 5.6 years.
Study Design
Arms: Array
Outcome
• Rosuvastatin vs. placebo showed a 30% relative risk reduction in any stroke (HR 0.70; 95% CI, 0.52-0.95).
• BP lowering vs. placebo showed no significant reduction in any stroke (HR 0.80; 95% CI, 0.59-1.08).
• Combination therapy vs. double placebo showed a 44% relative risk reduction in any stroke (HR 0.56; 95% CI, 0.36-0.87) and a 59% reduction in ischemic stroke (HR 0.41; 95% CI, 0.23-0.72).
• BP lowering vs. placebo showed no significant reduction in any stroke (HR 0.80; 95% CI, 0.59-1.08).
• Combination therapy vs. double placebo showed a 44% relative risk reduction in any stroke (HR 0.56; 95% CI, 0.36-0.87) and a 59% reduction in ischemic stroke (HR 0.41; 95% CI, 0.23-0.72).
Bottom Line
For primary prevention in an intermediate-risk population, rosuvastatin 10 mg daily significantly reduced the risk of first stroke, an effect driven by a reduction in ischemic stroke. Antihypertensive therapy alone did not significantly reduce stroke risk, but the combination of rosuvastatin and antihypertensive therapy provided a substantial and significant reduction in first strokes.
Major Points
- HOPE-3 was a landmark primary prevention trial using a 2×2 factorial design to simultaneously test statin therapy AND blood pressure lowering in intermediate-risk individuals WITHOUT established cardiovascular disease — addressing the 'polypill' concept for population-level CV prevention.
- 12,705 participants from 228 centers in 21 countries with median 5.6 years follow-up. The stroke analysis was a pre-specified secondary analysis of the main trial, providing the strongest evidence for statin-based primary stroke prevention.
- Rosuvastatin 10mg alone reduced ANY stroke by 30% (HR 0.70, 95% CI 0.52–0.95, p=0.02) and ISCHEMIC stroke by 47% (HR 0.53, 95% CI 0.37–0.78, p=0.001) — the most robust primary prevention stroke data for statins, surpassing JUPITER (which studied only high-CRP patients).
- BP lowering alone (candesartan/HCTZ) did NOT significantly reduce stroke: HR 0.80 (95% CI 0.59–1.08, p=0.14) — surprising and important. In an intermediate-risk population with mean baseline BP 138/82, modest BP reduction (~6/3 mmHg) was insufficient for significant stroke prevention.
- The COMBINATION of rosuvastatin + candesartan/HCTZ produced the most striking result: 44% reduction in any stroke (HR 0.56, 95% CI 0.36–0.87, p=0.009) and 59% reduction in ischemic stroke (HR 0.41, 95% CI 0.23–0.72, p=0.002) vs double placebo — synergistic benefit exceeding either alone.
- These findings strongly support the 'polypill' approach for primary prevention: combining low-dose statin + antihypertensive in intermediate-risk adults could prevent >1 in 2 ischemic strokes — a public health strategy particularly relevant in low/middle-income countries.
- Mean baseline LDL was 3.31 mmol/L (~128 mg/dL) — moderate, not high. Rosuvastatin 10mg lowered LDL by ~27%. This demonstrates stroke prevention benefit even in patients not typically meeting statin eligibility criteria by LDL alone.
- Intermediate-risk population: mean age 65.7, 46% female, 38% hypertensive, no diabetes requirement — deliberately enrolled people at moderate risk who would not typically receive primary prevention drugs in most practice settings.
- No significant increase in diabetes, myopathy, liver enzyme elevation, or cancer with rosuvastatin — addressing long-term safety concerns that had limited primary prevention statin use in lower-risk populations.
- Directly influenced 2024 AHA/ASA Primary Stroke Prevention guidelines, which now recommend statins for primary stroke prevention in intermediate-risk adults, and supported the concept of fixed-dose combination therapy.
Study Design
- Study Type
- Secondary analysis of a randomized, double-blind, placebo-controlled, 2x2 factorial trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 12705
- Follow-up
- 5.6 years (median)
- Centers
- 228
- Countries
- 21 countries
Primary Outcome
Definition: This is a secondary analysis focusing on the outcome of first stroke (any type).
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - |
Limitations & Criticisms
- Stroke was a secondary (not primary) outcome of the main HOPE-3 trial — the trial was powered for a composite cardiovascular endpoint, not stroke alone. Small event numbers (169 total strokes) limit precision of subgroup analyses.
- Hemorrhagic stroke events were too few for meaningful subtype analysis — cannot determine whether statins protect against or potentially worsen hemorrhagic stroke (a theoretical concern based on SPARCL ICH data).
- BP lowering arm used fixed-dose candesartan/HCTZ (not titrated to target) — this pragmatic approach may have undertreated patients with more severe hypertension while overtreating those with lower baseline BP.
- Mean baseline BP was 138/82 — only mildly elevated. The null result for BP lowering alone may not apply to populations with higher baseline BP where antihypertensive benefit for stroke is well-established.
- Industry co-funded (AstraZeneca, manufacturer of rosuvastatin/Crestor) — though also NIH (CIHR) funded and independently conducted. Commercial interest in demonstrating primary prevention benefit for rosuvastatin.
- 5.6-year follow-up may be too short for long-term safety — primary prevention populations will take statins for decades; rare adverse effects (neurocognitive, hepatic) may emerge with longer exposure.
- The 'polypill' combination was tested as two separate pills, not a single fixed-dose combination — real-world adherence to combination therapy may differ from trial compliance with two separate medications.
- Cannot distinguish whether rosuvastatin's stroke benefit is due to LDL lowering vs pleiotropic effects (anti-inflammatory, endothelial stabilization) — mechanistically important but doesn't change the clinical recommendation.
- Intermediate-risk definition varied globally — what constitutes 'intermediate risk' differs by population baseline rates, limiting universal applicability of the risk-stratification approach.
Citation
Stroke. 2021;52:2494-2501.