Antihypertensives and Statin Therapy for Primary Stroke Prevention

A Secondary Analysis of the HOPE-3 Trial

Jackie Bosch, PhD; Eva M. Lonn, MD; Gilles R. Dagenais, MD; Peggy Gao, MSc; Patricio Lopez-Jaramillo, MD, PhD; Jun Zhu, MD; Prem Pais, MD; Alvaro Avezum, MD, PhD; Karen Sliwa, MD, PhD; Irina E. Chazova, MD, PhD; Ron J.G. Peters, MD, PhD; Claes Held, MD, PhD; Khalid Yusoff, MD; Basil S. Lewis, MD; William D. Toff, MD; Kamlesh Khunti, MD, PhD; Christopher M. Reid, PhD; Lawrence A. Leiter, MD; Salim Yusuf, MBBS, DPhil; Robert G. Hart, MD


Stroke. 2021;52(8):2494-2501. 

In This Article

Abstract and Introduction


Background and Purpose: The HOPE-3 trial (Heart Outcomes Prevention Evaluation–3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups.

Methods: Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed.

Results: Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59–1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55–1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34–1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41–2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52–0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37–0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59–2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57–2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36–0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23–0.72]).

Conclusions: Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated.

Registration: URL:; Unique identifier: NCT00468923.


About 75% of all clinical strokes are first strokes rather than recurrent events.[1,2] A first stroke can result in permanent disability or death and significant health care and societal costs, so focusing on secondary stroke prevention is too late for many patients. To substantially decrease the burden of stroke in the community, efforts must be aimed at primary prevention (ie, preventing stroke among people without a previous clinical stroke). Primary stroke prevention is challenging, requiring treatment of large numbers of relatively low-or average-risk people, in contrast to secondary prevention where one can readily identify those at higher risk and, therefore, have a lower number-needed-to-treat.[1] Consequently, interventions for primary stroke prevention must be safe, widely applicable, and require minimal medical monitoring to be effective and to be globally applicable.

The HOPE-3 trial (Heart Outcomes Prevention Evaluation–3) tested blood pressure (BP) lowering and statin therapy, as well as their combination, for primary prevention of cardiovascular events in 12 705 moderate-risk people without clinically manifest cardiovascular disease, using drugs with well-established safety profiles and medical monitoring similar to usual practice in primary prevention. The results for the primary trial outcome of myocardial infarction, stroke, or cardiovascular death have been published.[3–5] Here, we report secondary analyses of predefined stroke outcomes for each randomized intervention, by stroke subtype, independent predictors, treatment effects in key subgroups, and absolute risk reductions.