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Circulation. 2019 Dec 17;140(25):2054-2062. doi: 10.1161/CIRCULATIONAHA.119.043826. Epub 2019 Nov 11.

Effect of Alirocumab on Stroke in ODYSSEY OUTCOMES.

Author information

1
Department of Cardiology, Leiden University Medical Center, The Netherlands (J.W.J., L.E.Z.).
2
Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts (D.L.B.).
3
Division of Cardiovascular Disease, University of Alabama at Birmingham (V.A.B.).
4
Estudios Cardiológicos Latinoamérica, Instituto Cardiovascular de Rosario, Rosario, Argentina (R.D.).
5
Landeskrankenhaus Feldkirch, Austria (H.D.).
6
Division of Angiology, Swiss Cardiovascular Center, University of Bern, Switzerland (H.D.).
7
Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada (S.G.G.).
8
St. Michael's Hospital, University of Toronto, Ontario, Canada (S.G.G.).
9
Sanofi, Paris, France (Y-U.K.).
10
Regeneron Pharmaceuticals Inc., Tarrytown, New York (R.P.).
11
University Hospital Center Zagreb, School of Medicine, University of Zagreb, Croatia (Z.R.).
12
Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina (M.T.R.).
13
Queen Mary Hospital, The University of Hong Kong (H-F.T.).
14
Unidad de Diagnostico Cardiologico, Guatemala City, Guatemala (P.C.M.V.).
15
Hospital General San Juan de Dios, Guatemala City, Guatemala (P.C.M.V.).
16
Green Lane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand (H.D.W.).
17
Department of Medicine III, Goethe University, Frankfurt am Main, Germany (A.M.Z.).
18
State University of New York, Downstate School of Public Health, Brooklyn (M.S.).
19
Division of Cardiology, University of Colorado School of Medicine, Aurora (G.G.S.).
20
Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Université de Paris, FACT (French Alliance for Cardiovascular Trials), INSERM U1148, Paris (P.G.S.).
21
National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom (P.G.S.).

Abstract

BACKGROUND:

Lowering of atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), reduces the risk of ischemic stroke. However, concerns have been raised about very low LDL-C levels and a potential increased risk of hemorrhagic stroke. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, despite intensive statin therapy, targeting LDL-C levels of 25 to 50 mg/dL and avoiding sustained LDL-C <15 mg/dL. This prespecified analysis was designed to assess the effect of alirocumab on ischemic and hemorrhagic stroke. We hypothesized that for patients treated with alirocumab there would be a reduction in risk of ischemic stroke without increasing hemorrhagic stroke, irrespective of baseline LDL-C and of history of cerebrovascular disease.

METHODS:

Patients were randomized to alirocumab or placebo 1 to 12 months after acute coronary syndrome. The risk of nonfatal or fatal ischemic or hemorrhagic stroke was evaluated, stratified by baseline LDL-C concentration and history of cerebrovascular disease. A potential association of very low achieved LDL-C with alirocumab treatment at month 4 and subsequent hemorrhagic stroke was assessed.

RESULTS:

Median follow-up was 2.8 years. In total, 263 ischemic and 33 hemorrhagic strokes occurred. Alirocumab reduced the risk of any stroke (HR, 0.72 [95% CI, 0.57-0.91]) and ischemic stroke (HR, 0.73 [95% CI, 0.57-0.93]) without increasing hemorrhagic stroke (HR, 0.83 [95% CI, 0.42-1.65]). In total, 7164 (37.9%), 6128 (32.4%), and 5629 (29.7%) patients had a baseline LDL-C of <80, 80 to 100, and >100 mg/dL, respectively. The treatment effect on stroke appeared numerically greater for patients with higher baseline LDL-C, but there was no formal evidence of heterogeneity (Pinteraction=0.31). The effect of alirocumab on stroke was similar among 944 patients (5.0%) with a history of previous cerebrovascular disease and among those without a history of cerebrovascular disease (Pinteraction=0.37). There was no apparent adverse relation between lower achieved LDL-C and incidence of hemorrhagic stroke in the alirocumab group.

CONCLUSIONS:

In patients with recent acute coronary syndrome and dyslipidemia despite intensive statin therapy, alirocumab decreased the risk of stroke, irrespective of baseline LDL-C and history of cerebrovascular disease, over a median follow-up of 2.8 years. Furthermore, risk of hemorrhagic stroke did not depend on achieved LDL-C levels within the alirocumab group.

CLINICAL TRIAL REGISTRATION:

URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.

KEYWORDS:

acute coronary syndrome; cerebrovascular disorders; lipoprotein, LDL; stroke

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