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Circulation. 2017 Sep 30. pii: CIRCULATIONAHA.117.029095. doi: 10.1161/CIRCULATIONAHA.117.029095. [Epub ahead of print]

Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients with Acute Coronary Syndrome in IMPROVE-IT.

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TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Duke Clinical Research Institute, Durham, NC.
Cardiology Dvision, Geneva University Hospital, Geneva, Switzerland.
Department of Cardiovascular Medicine, Department of Cardiovascular Sciences, University of Leuven, Belgium.
Milpark Hospital, Johannesburg, South Africa.
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand.
Merck & Co., Inc, Kenilworth, NJ.


Background -Patients who experience an acute coronary syndrome (ACS) are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after ACS. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT, with a focus on patients with a stroke prior to randomization. Methods -Post-ACS patients were randomized to placebo/simvastatin or ezetimibe/simvastatin 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 endpoints of stroke of any etiology, stroke subtypes, and the primary trial endpoint at 7 years. Results -Of 18,144 patients, 641 (3.5%) experienced at least one stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes, MI, and renal dysfunction. There was a non-significant reduction in the first event of stroke of any etiology (4.2% vs 4.8%; HR 0.86, 0.73-1.00; p=0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% vs 4.1%; HR 0.79, 0.67-0.94; p=0.008) and a non-significant increase in hemorrhagic stroke (0.8% vs 0.6%; HR 1.38, 0.93-2.04; p=0.11). Evaluating total events, including the first stroke and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR 0.83, 0.70-0.98; p=0.029) and ischemic stroke (HR 0.76, 0.63-0.91; p=0.003). Patients who had experienced a stroke prior to randomization were at higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% vs 18.8%; NNT=12; HR 0.60, 0.38-0.95; p=0.030) and 7.6% for ischemic stroke (8.7% vs 16.3%; NNT=13; HR 0.52, 0.31-0.86; p=0.011) with ezetimibe added to simvastatin therapy. Conclusions -The addition of ezetimibe to simvastatin in patients stabilized after ACS reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. Clinical Trial Registration -URL: Unique Identifier: NCT00202878.


Ezetimibe; acute coronary syndrome; low-density lipoprotein cholesterol; secondary prevention; stroke

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