Predicting major bleeding in patients with noncardioembolic stroke on antiplatelets: S2TOP-BLEED

Nina A Hilkens; Ale Algra; Hans-Christoph Diener; Johannes B Reitsma; Philip M Bath; Laszlo Csiba; Werner Hacke; L Jaap Kappelle; Peter J Koudstaal; Didier Leys; Jean-Louis Mas; Ralph L Sacco; Pierre Amarenco; Leila Sissani; Jacoba P Greving; Cerebrovascular Antiplatelet Trialists' Collaborative Group

doi:10.1212/WNL.0000000000004289

Predicting major bleeding in patients with noncardioembolic stroke on antiplatelets: S₂TOP-BLEED

Neurology. 2017 Aug 29;89(9):936-943. doi: 10.1212/WNL.0000000000004289. Epub 2017 Aug 2.

Authors

Nina A Hilkens¹, Ale Algra², Hans-Christoph Diener², Johannes B Reitsma², Philip M Bath², Laszlo Csiba², Werner Hacke², L Jaap Kappelle², Peter J Koudstaal², Didier Leys², Jean-Louis Mas², Ralph L Sacco², Pierre Amarenco², Leila Sissani², Jacoba P Greving²; Cerebrovascular Antiplatelet Trialists' Collaborative Group

Collaborators

Cerebrovascular Antiplatelet Trialists' Collaborative Group:
M Gent, D Beaumont, J Blanchard, M G Bousser, J Coffman, J D Easton, J R Hampton, L A Harker, L Janzon, Jje Kusmierek, E Panak, R S Roberts, S Shannon, J Sicurella, G Tognoni, E J Topol, M Verstraete, C Warlow, J M Blard, R Capildeo, H C Diener, B Ersmark, A Escartin, J Ferro, R Galvin, Lah Hogenhuis, C Laterre, L Provincial, U K Rinne, G Bovim, A Lowenthal, H C Diener, J Bogousslavsky, L Brass, C Cimminiello, L Csiba, M Kaste, D Leys, J Matias-Guiu, H J Rupprecht, P B Berger, D L Bhatt, H R Black, W E Boden, P Cacoub, E A Cohen, M A Creager, J D Easton, M D Flather, Kaa Fox, W Hacke, S M Haffner, C W Hamm, G J Hankey, S C Johnston, K H Mak, J L Mas, G Montalescot, T A Pearson, P G Steg, S R Steinhubl, E J Topol, M A Weber, F Aichner, A Algra, J Bogousslavsky, A Chamorro, Cplh Chen, Ellm De Schryver, J M Ferro, J van Gijn, G J Hankey, L I Hertzberger, P J Koudstaal, D Leys, S Ricci, E B Ringelstein, G Vanhooren, G S Venables, G Albers, P Bath, N Bornstein, B Chan, S-T Chen, L Cunha, B Dahlöf, J DeKeyser, H C Diener, G Donnan, C Estol, P Gorelick, M Kaste, C Lu, P Pais, R Roberts, R Sacco, V Skvortsova, P Teal, D Toni, M Weber, B W Yoon, S Yusuf, P Amarenco, M-G Bousser, A Chamorro, M Fisher, I Ford, K M Fox, M G Hennerici, H P Mattle, P Rothwell, L Sissani, J Labreuche, G Steg, E Vicaut

Affiliations

¹ From the Julius Center for Health Sciences and Primary Care (N.A.H., A.A., J.B.R., J.P.G.) and Department of Neurology and Neurosurgery (A.A., L.J.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Department of Neurology (H.-C.D.), University Hospital Essen, Germany; Stroke Trials Unit (P.M.B.), Division of Clinical Neuroscience, University of Nottingham, UK; Department of Neurology (L.C.), University of Debrecen Medical and Health Science Center, Hungary; Department of Neurology (W.H.), University of Heidelberg, Germany; Department of Neurology (P.J.K.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Neurology (D.L.), Roger Salengro Hospital, Lille, France; Department of Neurology (J.-L.M.), Hôpital Sainte-Anne, Université Paris Descartes, France; Department of Neurology (R.L.S.), Miller School of Medicine, University of Miami, FL; and Department of Neurology and Stroke Center (P.A., L.S.), Bichat University Hospital, Paris, France. N.A.Hilkens-3@umcutrecht.nl.
² From the Julius Center for Health Sciences and Primary Care (N.A.H., A.A., J.B.R., J.P.G.) and Department of Neurology and Neurosurgery (A.A., L.J.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Department of Neurology (H.-C.D.), University Hospital Essen, Germany; Stroke Trials Unit (P.M.B.), Division of Clinical Neuroscience, University of Nottingham, UK; Department of Neurology (L.C.), University of Debrecen Medical and Health Science Center, Hungary; Department of Neurology (W.H.), University of Heidelberg, Germany; Department of Neurology (P.J.K.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Neurology (D.L.), Roger Salengro Hospital, Lille, France; Department of Neurology (J.-L.M.), Hôpital Sainte-Anne, Université Paris Descartes, France; Department of Neurology (R.L.S.), Miller School of Medicine, University of Miami, FL; and Department of Neurology and Stroke Center (P.A., L.S.), Bichat University Hospital, Paris, France.

Abstract

Objective: To develop and externally validate a prediction model for major bleeding in patients with a TIA or ischemic stroke on antiplatelet agents.

Methods: We combined individual patient data from 6 randomized clinical trials (CAPRIE, ESPS-2, MATCH, CHARISMA, ESPRIT, and PRoFESS) investigating antiplatelet therapy after TIA or ischemic stroke. Cox regression analyses stratified by trial were performed to study the association between predictors and major bleeding. A risk prediction model was derived and validated in the PERFORM trial. Performance was assessed with the c statistic and calibration plots.

Results: Major bleeding occurred in 1,530 of the 43,112 patients during 94,833 person-years of follow-up. The observed 3-year risk of major bleeding was 4.6% (95% confidence interval [CI] 4.4%-4.9%). Predictors were male sex, smoking, type of antiplatelet agents (aspirin-clopidogrel), outcome on modified Rankin Scale ≥3, prior stroke, high blood pressure, lower body mass index, elderly, Asian ethnicity, and diabetes (S₂TOP-BLEED). The S₂TOP-BLEED score had a c statistic of 0.63 (95% CI 0.60-0.64) and showed good calibration in the development data. Major bleeding risk ranged from 2% in patients aged 45-54 years without additional risk factors to more than 10% in patients aged 75-84 years with multiple risk factors. In external validation, the model had a c statistic of 0.61 (95% CI 0.59-0.63) and slightly underestimated major bleeding risk.

Conclusions: The S₂TOP-BLEED score can be used to estimate 3-year major bleeding risk in patients with a TIA or ischemic stroke who use antiplatelet agents, based on readily available characteristics. The discriminatory performance may be improved by identifying stronger predictors of major bleeding.

Publication types

Validation Study

MeSH terms

Aged
Brain Ischemia / diagnosis*
Brain Ischemia / drug therapy*
Brain Ischemia / epidemiology
Calibration
Female
Hemorrhage / diagnosis*
Hemorrhage / epidemiology
Humans
Male
Models, Cardiovascular
Models, Statistical
Platelet Aggregation Inhibitors / therapeutic use*
Prognosis
Proportional Hazards Models
Randomized Controlled Trials as Topic
Risk Assessment
Stroke / diagnosis*
Stroke / drug therapy*
Stroke / epidemiology

Substances

Platelet Aggregation Inhibitors