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HOPE-3 (Stroke Analysis)

Antihypertensives and Statin Therapy for Primary Stroke Prevention: A Secondary Analysis of the HOPE-3 Trial

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Year of Publication: 2021

Authors: Jackie Bosch, PhD; Eva M. Lonn, MD; Gilles R. Dagenais, ..., MD; for the HOPE-3 Investigators

Journal: Stroke

Citation: Stroke. 2021;52:2494-2501.

PDF: https://www.ahajournals.org/doi/epub/10....EAHA.120.030790

Clinical Question

To assess the effect of antihypertensive therapy, statin therapy, and their combination on the risk of first stroke and its subtypes in people at intermediate cardiovascular risk without overt cardiovascular disease.

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.

      

Design

Study Type: Secondary analysis of a randomized, double-blind, placebo-controlled, 2x2 factorial trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: 2007 to 2014

Follow-up Duration: 5.6 years (median)

Centers: 228

Countries: 21 countries

Sample Size: 12705

Analysis: Intention-to-treat analysis. Cox proportional hazards modeling was used to estimate treatment effects (hazard ratios).

Inclusion Criteria

Men aged ≥55 years and women aged ≥65 years (or 60-65 with ≥2 risk factors)
At least one cardiovascular risk factor: elevated waist-to-hip ratio, low HDL-C, current or recent smoking, dysglycemia, family history of premature coronary disease, or mild renal dysfunction
No clinically manifest cardiovascular disease

Exclusion Criteria

Known cardiovascular disease
Indications for or contraindications to the study medications
Moderate or advanced renal dysfunction (eGFR <45 mL/[min·1.73 m²])
Symptomatic hypotension

Baseline Characteristics

Characteristic	Control	Active
Group	Overall Population (N=12,705)
Age, mean (SD), y	65.7 (6.4)
Female, %	46
History of hypertension, %	38
Baseline BP, mmHg, mean (SD)	138 (14.8) / 82 (9.3)
LDL-C, mmol/L (SD)	3.31 (0.93)

Arms

Field	Candesartan/HCTZ + Rosuvastatin Placebo	BP Placebo + Rosuvastatin	Candesartan/HCTZ + Rosuvastatin (Combination)	Control
Intervention	Candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily, and a placebo for rosuvastatin.	Rosuvastatin 10 mg daily, and a placebo for candesartan/hydrochlorothiazide.	Candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily, and rosuvastatin 10 mg daily.	Placebo for candesartan/hydrochlorothiazide and placebo for rosuvastatin.
Duration	5.6 years (median)	5.6 years (median)	5.6 years (median)	5.6 years (median)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
This is a secondary analysis focusing on the outcome of first stroke (any type).	Primary	Placebo: 99/6344 (1.6%)	Rosuvastatin 10 mg: 70/6361 (1.1%)	HR 0.70 (95% CI 0.52-0.95)	P=0.02
Any Stroke: Rosuvastatin vs Placebo	Secondary	99 events	70 events	HR 0.70 (95% CI, 0.52-0.95)	0.02
Any Stroke: BP Lowering vs Placebo	Secondary	94 events	75 events	HR 0.80 (95% CI, 0.59-1.08)	0.14
Any Stroke: Combination vs Double Placebo	Secondary	55 events	31 events	HR 0.56 (95% CI, 0.36-0.87)	0.009
Ischemic Stroke: Rosuvastatin vs Placebo	Secondary	76 events	41 events	HR 0.53 (95% CI, 0.37-0.78)	0.001
Ischemic Stroke: Combination vs Double Placebo	Secondary	41 events	17 events	HR 0.41 (95% CI, 0.23-0.72)	0.002
Muscle pain or weakness	Adverse	296 (4.7%)	367 (5.8%)		0.005
Cataract surgery	Adverse	194 (3.1%)	241 (3.8%)		0.02
Permanent discontinuation for muscle symptoms	Adverse	29 (0.5%)	83 (1.3%)
New-onset diabetes	Adverse	226 (3.8%)	232 (3.9%)	1.02 (0.85-1.23)	0.82
Death from any cause	Adverse	357 (5.6%)	334 (5.3%)	0.93 (0.80-1.08)	0.32
Deep-vein thrombosis or pulmonary embolism	Adverse	31	14	0.45 (0.24-0.84)	0.01

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.

Funding

AstraZeneca and the Canadian Institutes of Health Research (CIHR).

Based on: HOPE-3 (Stroke Analysis) (Stroke, 2021)