A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke | NEJM

https://www.nejm.org/doi/full/10.1056/NEJMoa1910355

A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke

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• Pierre Amarenco, M.D.,
• Jong S. Kim, M.D.,
• Julien Labreuche, B.S.T.,
• Hugo Charles, B.S.T.,
• Jérémie Abtan, M.D.,
• Yannick Béjot, M.D.,
• Lucie Cabrejo, M.D.,
• Jae-Kwan Cha, M.D.,
• Grégory Ducrocq, M.D., Ph.D.,
• Maurice Giroud, M.D.,
• Celine Guidoux, M.D.,
• Cristina Hobeanu, M.D.,
• Yong-Jae Kim, M.D.,
• Bertrand Lapergue, M.D., Ph.D.,
• Philippa C. Lavallée, M.D.,
• Byung-Chul Lee, M.D.,
• Kyung-Bok Lee, M.D.,
• Didier Leys, M.D.,
• Marie-Hélène Mahagne, M.D.,
• Elena Meseguer, M.D.,
• Norbert Nighoghossian, M.D.,
• Fernando Pico, M.D., Ph.D.,
• Yves Samson, M.D.,
• Igor Sibon, M.D.,
• P. Gabriel Steg, M.D.,
• Sang-Min Sung, M.D.,
• Pierre-Jean Touboul, M.D.,
• Emmanuel Touzé, M.D., Ph.D.,
• Olivier Varenne, M.D., Ph.D.,
• Éric Vicaut, M.D.,
• Nessima Yelles,
• and Eric Bruckert, M.D.
• for the Treat Stroke to Target Investigators^*

Abstract

Background

The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied.

Methods

In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes.

Results

A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P=0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups.

Conclusions

After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.)

QUICK TAKE VIDEO SUMMARYLowering the Target for LDL Cholesterol after Stroke 01:43

Supported by a grant (AOM09002) from the French Ministry of Health, by SOS–Attaque Cérébrale Association, and by grants from Pfizer, AstraZeneca, and Merck for the French sites and from Pfizer for the South Korean sites.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. Amarenco reports receiving grant support, paid to SOS Attaque Cerebrale Association, lecture fees, consulting fees, and fees for serving on an executive committee from AstraZeneca, fees for serving on a steering committee, lecture fees, and consulting fees from Bayer, consulting fees and lecture fees from Daiichi Sankyo, grant support, paid to SOS Attaque Cerebrale Association, lecture fees, and consulting fees from Boston Scientific, fees for serving on an end-point committee from GlaxoSmithKline, consulting fees and fees for serving on an executive committee from Kowa, fees for serving on a data and safety monitoring board from Fibrogen and Shin Poong, grant support, paid to SOS Attaque Cerebrale Association, lecture fees, and advisory board fees from Sanofi, grant support, paid to SOS Attaque Cerebrale Association, lecture fees, and fees for serving on a steering committee from Bristol-Myers Squibb, fees for serving on a steering committee from Portola, and consulting fees from Gilead; Dr. J.S. Kim, receiving grant support from Dong-A Pharmaceutical, Servier, Daiichi Sankyo, and Shin Poong; Dr. Abtan, receiving advisory board fees and lecture fees from AstraZeneca and lecture fees from Bayer and Bristol-Myers Squibb; Dr. Bejot, receiving consulting fees from AstraZeneca and Daiichi Sankyo, consulting fees and lecture fees from Bristol-Myers Squibb, Medtronic, and Boehringer Ingelheim, and lecture fees from Pfizer, Bayer, and Merck Sharp and Dohme; Dr. Cabrejo, receiving lecture fees from Biogen and Teva and advisory board fees from Roche; Dr. Cha, receiving lecture fees and travel support from Bristol-Myers Squibb/Pfizer, lecture fees and consulting fees from Medtronic, and lecture fees from Bayer, Boehringer Ingelheim, and Amgen; Dr. Ducrocq, receiving consulting fees and lecture fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, and Sanofi, and consulting fees from Janssen; Dr. Giroud, receiving training and travel support from Bayer, Boehringer Ingelheim, Pfizer, AstraZeneca, Bristol-Myers Squibb, and Daiichi Sankyo; Dr. Guidoux, receiving consulting fees from Bayer and Boehringer Ingelheim; Dr. Lapergue, receiving grant support and consulting fees from Stryker, grant support from MicroVention and Penumbra, and consulting fees from Bristol-Myers Squibb and Boehringer Ingelheim; Dr. B.-C. Lee, receiving grant support from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Eisai, and AstraZeneca; Dr. K.-B. Lee, receiving grant support from AstraZeneca, Daiichi Sankyo, Boryung, and Shin Poong and consulting fees and advisory board fees from Cheil; Dr. Leys, receiving grant support, paid to his institution, from Pfizer and Bayer Pharma; Dr. Nighoghossian, receiving grant support from Pfizer and Sanofi and consulting fees from Boehringer Ingelheim, Bayer, and Amgen; Dr. Pico, receiving lecture fees and travel support from Bristol-Myers Squibb/Pfizer, lecture fees and consulting fees from Medtronic, and lecture fees from Bayer, Boehringer Ingelheim, and Amgen; Dr. Steg, receiving grant support and fees for serving on a steering committee from Bayer/Janssen, grant support and lecture fees from Merck, grant support, consulting fees, lecture fees, and fees for serving as trial cochair from Sanofi, grant support, consulting fees, and fees for serving on an executive steering committee from Amarin, consulting fees and lecture fees from Amgen, consulting fees, lecture fees, and fees for serving on a critical-event committee from Bristol-Myers Squibb, fees for serving on an executive steering committee from Boehringer Ingelheim, fees for serving on a critical-event committee from Pfizer, consulting fees and fees for serving on an executive steering committee from Novartis, consulting fees and fees for serving as trial cochair from Regeneron, consulting fees from Eli Lilly, consulting fees and lecture fees from AstraZeneca, grant support, fees for serving as chair of a data monitoring committee, and fees for serving as chair of a registry for Servier, consulting fees from Novo Nordisk, and fees for serving on a steering committee from Idorsia; Dr. Sung, receiving lecture fees from Daiichi Sankyo Korea, Korea Otsuka Pharmaceutical, Shin Poong, and Bayer Korea; Dr. Touboul, holding stock in Intelligence in Medical Technologies; Dr. Varenne, receiving grant support from Boston Scientific, lecture fees from Abbott Vascular, AstraZeneca, and Servier, and travel support from Biosensors; Dr. Vicaut, receiving consulting fees from Abbott, Bristol-Myers Squibb, Celgene, LFB Technologies, and Pfizer, lecture fees from Novartis, and grant support, paid to his institution, and consulting fees from Sanofi; and Dr. Bruckert, receiving lecture fees and travel support from Merck Sharp and Dohme, lecture fees and honoraria from Akcea, Servier, Sanofi Aventis, Amgen, and Aegerion Amryt, fees for serving as president of a data and safety monitoring board from Genfit, honoraria from Regeneron, and advisory board fees from Mylan. No other potential conflict of interest relevant to this article was reported.

This article was published on November 18, 2019, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Author Affiliations

From the Department of Neurology and Stroke Center (P.A., J.L., H.C., L.C., C.G., C.H., P.C.L., E.M., P.-J.T.) and the Department of Cardiology (J.A., G.D., P.G.S.), Assistance Publique–Hôpitaux de Paris (APHP), Bichat Hospital, Laboratory for Vascular Translational Science, INSERM Unité 1148, Département Hospitalo Universitaire–Fibrose Inflammation Remodelage, and the Department of Cardiology, Cochin Hospital (O.V.), University of Paris, the Department of Neurology, Foch Hospital (B.L.), Urgences Cerebrovasculaires (Y.S.), Centre de Pharmacoépidémiologie de l'APHP (N.Y.), and the Department of Endocrinology (E.B.), Hôpital de la Pitié–Salpêtrière, the Department of Biostatistics, APHP, Université Paris Diderot, Sorbonne Paris Cité, Fernand Widal Hospital (É.V.), and the Department of Endocrinology, Sorbonne University (E.B.), Paris, Équipe d'Accueil EA2694, Santé Publique: Epidémiologie et Qualité des Soins (J.L.), and the Department of Neurology, Stroke Unit, University of Lille, Centre Hospitalier Universitaire (CHU) de Lille (D.L.), Lille, the Department of Neurology, University Hospital of Dijon, University of Burgundy, Dijon (Y.B., M.G.), the Stroke Unit, Pasteur Hospital, Nice (M.-H.M.), Hospices Civils de Lyon, Department of Neurology and Stroke Center, Lyon University, Lyon (N.N.), the Department of Neurology, Versailles University Hospital, Versailles (F.P.), the Department of Vascular Neurology, Pellegrin Tripode Hospital, University of Bordeaux, Bordeaux (I.S.), and the Department of Neurology, Université Caen Normandie, CHU Caen Normandie, INSERM Unité 1237, Cyceron, Caen (E.T.) — all in France; Asan Medical Center (J.S.K.), the Department of Neurology, Eunpyeong St. Mary's Hospital, Catholic University of Korea (Y.-J.K.), and the Department of Neurology, Soonchunhyang University College of Medicine (K.-B.L.), Seoul, Dong-a University Hospital (J.-K.C.) and the Department of Neurology and Stroke Center, Pusan National University Hospital (S.M.S.), Busan, and the Department of Neurology, Hallym University Sacred Heart Hospital, Anyang (B.-C.L.) — all in South Korea; and the National Heart and Lung Institute–Imperial College and the Institute of Cardiovascular Medicine and Science–Royal Brompton Hospital, London (P.G.S.).

Address reprint requests to Dr. Amarenco at the Department of Neurology and Stroke Center, Bichat Hospital, 46 rue Henri Huchard, Paris 75018, France, or at pierre.amarenco@aphp.fr.

A complete list of the Treat Stroke to Target investigators is provided in the Supplementary Appendix, available at NEJM.org.