Jaime Gonzalez-Valcarcel1, Leila Sissani1, Julien Labreuche1, Marie-Germaine Bousser1, Angel Chamorro1, Marc Fisher1, Ian Ford1, Kim M Fox1, Michael G Hennerici1, Heinrich P Mattle1, Peter M Rothwell1, Philippe Gabriel Steg1, Eric Vicaut1, Pierre Amarenco2. 1. From the Université Paris Diderot, Paris, France (J.G.-V., M.-G.B., P.G.S., E.V., P.A.); INSERM LVTS (Laboratory for VascularTranslational Sciences) 1148 and Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation, Remodelling), Paris, France (L.S., J.L., P.G.S., P.A.); Department of Neurology and Stroke Centre, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris France (J.G.-V., L.S., J.L., P.A.); Université de Lille, CHU Lille, EA 2694-Santé publique: épidémiologie et qualité des soins, Lille, France (J.L.); Department of Neurology, hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France (M.-G.B.); Department of Neurology, Hospital Clinic de Barcelona, University of Barcelona, Barcelona, Spain (A.C.); Department of Neurology, Harvard University, Brigham and Women Hospital, MA (M.F.); Robertson Centre for Biostatistics, Department of Biostatistics, University of Glasgow, Glasgow, UK (I.F.); Department of Cardiology, NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK (K.M.F.; P.G.S.); Department of Neurology, University of Heidelberg, UMM, Mannheim, Germany (M.G.H.); Neurologische Klinik und Poliklinik, Universität Bern, Inselspital, Bern (H.P.M.); Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK (P.M.R.); and Department of Biostatistics, Hôpital Fernand Widal, Assistance Publique-Hôpitaux de Paris, Paris France (E.V.). 2. From the Université Paris Diderot, Paris, France (J.G.-V., M.-G.B., P.G.S., E.V., P.A.); INSERM LVTS (Laboratory for VascularTranslational Sciences) 1148 and Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation, Remodelling), Paris, France (L.S., J.L., P.G.S., P.A.); Department of Neurology and Stroke Centre, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris France (J.G.-V., L.S., J.L., P.A.); Université de Lille, CHU Lille, EA 2694-Santé publique: épidémiologie et qualité des soins, Lille, France (J.L.); Department of Neurology, hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France (M.-G.B.); Department of Neurology, Hospital Clinic de Barcelona, University of Barcelona, Barcelona, Spain (A.C.); Department of Neurology, Harvard University, Brigham and Women Hospital, MA (M.F.); Robertson Centre for Biostatistics, Department of Biostatistics, University of Glasgow, Glasgow, UK (I.F.); Department of Cardiology, NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK (K.M.F.; P.G.S.); Department of Neurology, University of Heidelberg, UMM, Mannheim, Germany (M.G.H.); Neurologische Klinik und Poliklinik, Universität Bern, Inselspital, Bern (H.P.M.); Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK (P.M.R.); and Department of Biostatistics, Hôpital Fernand Widal, Assistance Publique-Hôpitaux de Paris, Paris France (E.V.). pierre.amarenco@aphp.fr.
Abstract
BACKGROUND AND PURPOSE: The presumed safety of paracetamol in high-cardiovascular risk patients has been questioned. We determined whether paracetamol or ibuprofen use is associated with major cardiovascular events (MACE) or major bleeding in 19 120 patients with recent ischemic stroke or transient ischemic attack of mainly atherothrombotic origin included in the Prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) trial. METHODS: We performed 2 nested case-control analysis (2153 cases with MACE during trial follow-up and 4306 controls matched on Essen stroke risk score; 809 cases with major bleeding matched with 1616 controls) and a separate time-varying analysis. RESULTS: 12.3% were prescribed paracetamol and 2.5% ibuprofen. Median duration of treatment was 14 (interquartile range 5-145) days for paracetamol and 9 (5-30) days for ibuprofen. Paracetamol, but not ibuprofen, was associated with increased risk of MACE (odds ratio 1.21, 95% confidence interval [CI] 1.04-1.42) or a major bleeding (odds ratio 1.60, 95% CI 1.26-2.03), with no impact of daily dose and duration of paracetamol treatment. Time-varying analysis found an increased risk of MACE with both paracetamol (hazard ratio 1.22, 95% CI 1.05-1.43) and ibuprofen (hazard ratio 1.47, 95% CI 1.06-2.03) and of major bleeding with paracetamol (hazard ratio 1.95, 95% CI 1.45-2.62). CONCLUSIONS: There was a weak and inconsistent signal for association between paracetamol or ibuprofen and MACE or major bleeding, which may be related to either a genuine but modest effect of these drugs or to residual confounding. CLINICAL TRIAL REGISTRATION: http://www.isrctn.com. Unique identifier: ISRCTN66157730.
BACKGROUND AND PURPOSE: The presumed safety of paracetamol in high-cardiovascular risk patients has been questioned. We determined whether paracetamol or ibuprofen use is associated with major cardiovascular events (MACE) or major bleeding in 19 120 patients with recent ischemic stroke or transient ischemic attack of mainly atherothrombotic origin included in the Prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) trial. METHODS: We performed 2 nested case-control analysis (2153 cases with MACE during trial follow-up and 4306 controls matched on Essen stroke risk score; 809 cases with major bleeding matched with 1616 controls) and a separate time-varying analysis. RESULTS: 12.3% were prescribed paracetamol and 2.5% ibuprofen. Median duration of treatment was 14 (interquartile range 5-145) days for paracetamol and 9 (5-30) days for ibuprofen. Paracetamol, but not ibuprofen, was associated with increased risk of MACE (odds ratio 1.21, 95% confidence interval [CI] 1.04-1.42) or a major bleeding (odds ratio 1.60, 95% CI 1.26-2.03), with no impact of daily dose and duration of paracetamol treatment. Time-varying analysis found an increased risk of MACE with both paracetamol (hazard ratio 1.22, 95% CI 1.05-1.43) and ibuprofen (hazard ratio 1.47, 95% CI 1.06-2.03) and of major bleeding with paracetamol (hazard ratio 1.95, 95% CI 1.45-2.62). CONCLUSIONS: There was a weak and inconsistent signal for association between paracetamol or ibuprofen and MACE or major bleeding, which may be related to either a genuine but modest effect of these drugs or to residual confounding. CLINICAL TRIAL REGISTRATION: http://www.isrctn.com. Unique identifier: ISRCTN66157730.
Authors: Paulus Kirchhof; Sylvia Haas; Pierre Amarenco; Susanne Hess; Marc Lambelet; Martin van Eickels; Alexander G G Turpie; A John Camm Journal: J Am Heart Assoc Date: 2020-02-21 Impact factor: 5.501