Prevention of stroke with the addition of ezetimibe to statin therapy in patients with acute coronary syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)
Abstract
Background: Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization. Methods: Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years. Results: Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73–1.00; P =0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67–0.94; P =0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93–2.04; P =0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70–0.98; P =0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63–0.91; P =0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38–0.95; P =0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31–0.86; P =0.011) with ezetimibe added to simvastatin therapy. Conclusions: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.
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ASCEND found no significant impact on serious vascular events (HR 0.97, 95% CI 0.87-1.08) among 15,480 people randomized to omega-3 supplements versus placebo over a mean 7.4 years.
“Among 15 480 people randomized to omega-3 fatty acid supplements vs. placebo over a mean follow-up of 7.4 years, there was no significant effect (HR 0.97, 95% CI 0.87-1.08) on serious vascular events [nonfatal MI, non-fatal stroke, transient ischaemic attack (TIA), or vascular death] [329,424-426].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [425]
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- Authors
- Bohula, E. A., Wiviott, S. D., Giugliano, R. P., Blazing, M. A., Park, J.-G., Murphy, S. A., White, J. A., Mach, F., Van de Werf, F., Dalby, A. J., White, H. D., Tershakovec, A. M., Cannon, C. P., & Braunwald, E.
- Affiliations
- Brigham and Women's Hospital (US)
- Duke Clinical Research Institute (US)
- Cardiology Dvision, Geneva University Hospital, Switzerland (F.M.)
- Departments of Cardiovascular Medicine and Cardiovascular Sciences, University of Leuven, Belgium (F.V.d.F.)
- Milpark Hospital (ZA)
- Auckland City Hospital (NZ)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- TIMI Study Group, Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (E.A.B., S.D.W., R.P.G., J.-G.P., S.A.M., C.P.C., E.B.)
- ORCID
- Venue
- Circulation
- Published
- 2017-12-19
- Volume
- 136
- Issue
- 25
- Pages
- 2440-2450
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2757304856
- Cited by
- 142
- References
- 24
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 12 · 2023: 19 · 2022: 18 · 2021: 20 · 2020: 21 · 2019: 17 · 2018: 11 · 2017: 1
- FWCI
- 14.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- GlaxoSmithKline
- Sanofi
- Alnylam Pharmaceuticals
- Regeneron Pharmaceuticals
- Medicines Company
- Kowa Company
- Daiichi-Sankyo
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Keywords
- ezetimibe, simvastatin, acute coronary syndrome, stroke prevention, ischemic stroke, hemorrhagic stroke, IMPROVE-IT trial, LDL cholesterol lowering, cardiovascular risk factors, stroke recurrence, secondary prevention, statin therapy, lipid-lowering therapy, atrial fibrillation, diabetes mellitus, renal dysfunction, congestive heart failure, myocardial infarction
- MeSH terms
- Ezetimibe, Aged, Anticholesteremic Agents, Atrial Fibrillation, Double-Blind Method, Female, Humans, Cholesterol, LDL, Male, Middle Aged, Myocardial Infarction, Recurrence, Risk Factors, Placebo Effect, Proportional Hazards Models, Treatment Outcome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Stroke, Acute Coronary Syndrome
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