Cholesterol absorption inhibitor plus statin as secondary prevention protects against ischemic stroke

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

Literature - Bohula EA, Wiviott SD, Giugliano RP, et al. - Circulation 2017; published online ahead of print


It has been shown that lipid lowering therapy with statins results in a 22% reduction in major vascular events per 1 mmol/L reduction in LDL-C, including a 21% RRR in ischemic stroke per 1 mmol/L reduction in LDL-C [1]. In the IMPROVE-IT study, the addition of the non-statin lipid-lowering drug ezetimibe on top of simvastatin, in the long-term treatment of stabilized post-ACS patients, led to a significant reduction in CV events [2,3].

In this posthoc analysis of the multi-national, double-blind, placebo-controlled IMPROVE-IT study, the incidence and predictors of stroke post-ACS were evaluated. Furthermore, the efficacy of ezetimibe on top of simvastatin was evaluated for the prevention of stroke and other CV events, particularly in patients with a history of prior stroke. Of the 18144 post-ACS patients, 3.5% experienced at least one stroke during a median follow-up of 6 years. 89% were first events and 11% were recurrent events. Out of the first strokes, 82% were ischemic and 16% were hemorrhagic, whereas 2% were of unknown type, and 15% were fatal.

Main results

  • A history of prior stroke was the most potent independent predictor of recurrent stroke of any etiology, with a more than 3-fold increased risk in patients with a prior stroke compared to those without a prior stroke (7-year KM rate of 18.8% vs 4.3%; HR: 3.06; 2.40-3.92; P<0.001). Other independent predictors of stroke were: age ≥ 75 years, AF, DM, prior MI, renal dysfunction and HF. The independent predictors of ischemic stroke were the same with the exception of HF. A history of AF, HF and hypertension predicted hemorrhagic stroke during follow-up.
  • In the overall population, there was a non-significant reduction in the first event of stroke of any type with the addition of ezetimibe to simvastatin compared to simvastatin monotherapy with rates of 4.2% vs. 4.8%, respectively (HR: 0.86; 0.73-1.00; P=0.052).
  • Ischemic stroke as a first event was significantly reduced by 21% with ezetimibe/simvastatin compared to placebo/simvastatin (7-year KM rate of 3.4% versus 4.1%; HR: 0.79; 0.67-0.94; P=0.008).
  • There was a non-significant, but numerically greater number of hemorrhagic strokes with ezetimibe/simvastatin vs placebo/simvastatin (KM rates of 0.8% vs 0.6%; HR: 1.38; 0.93-2.04; P=0.11).
  • There were 20 fewer subsequent strokes with ezetimibe/simvastatin compared to placebo/simvastatin. When adding the recurrent strokes to the first strokes, there was a significant 17% reduction in total strokes (325 vs 394; RR: 0.83; 0.70-0.98; P=0.029), and a significant 24% reduction in total ischemic strokes (258 vs 338; RR: 0.76; 0.63-0.91; P=0.003).
  • Compared to patients without a history of prior stroke, there were greater relative reductions in total stroke (RR: 0.54; 0.33-0.90; P=0.019 versus RR: 0.88; 0.74-1.05; P=0.16; P-interaction<0.001) and total ischemic stroke (RR: 0.45; 0.26-0.80; P=0.006 versus RR: 0.82; 0.68-1.00; P=0.045; P-interaction<0.001) in patients with a prior stroke.


In the IMPROVE-IT study, the addition of ezetimibe to simvastatin in stabilized post-ACS patients reduced the frequency of ischemic stroke, particularly in patients with a history of prior stroke. These data support the addition of ezetimibe to a moderate-high intensity statin regimen for the prevention of ischemic stroke in stabilized post-ACS patients, particularly if they had a history of stroke prior to their ACS event.


1. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681.

2. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372:2387-2397.

3. Murphy SA, Cannon CP, Blazing MA, et al. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. J Am Coll Cardiol. 2016;67:353-361.

Find this article online at Circulation

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