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

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

Background

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.

Conclusion

References

Find this article online at Circulation