Paracetamol, Ibuprofen, and Recurrent Major Cardiovascular and Major Bleeding Events in 19 120 Patients With Recent Ischemic Stroke

Affiliations

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.

PMID: 26979864
DOI: 10.1161/STROKEAHA.115.012091

Free article

Paracetamol, Ibuprofen, and Recurrent Major Cardiovascular and Major Bleeding Events in 19 120 Patients With Recent Ischemic Stroke

Jaime Gonzalez-Valcarcel et al. Stroke. 2016 Apr.

Free article

. 2016 Apr;47(4):1045-52.

doi: 10.1161/STROKEAHA.115.012091. Epub 2016 Mar 15.

Authors

Affiliations

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.

PMID: 26979864
DOI: 10.1161/STROKEAHA.115.012091

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.

Keywords: antiplatelet agent; bleeding; cardiovascular events; ibuprofen; transient ischemic attack.

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Comment in

Letter by Iannuccelli et al Regarding Article, "Paracetamol, Ibuprofen, and Recurrent Major Cardiovascular and Major Bleeding Events in 19 120 Patients With Recent Ischemic Stroke".
Iannuccelli C, Di Franco M, Pulcinelli FM. Iannuccelli C, et al. Stroke. 2016 Sep;47(9):e226. doi: 10.1161/STROKEAHA.116.013868. Epub 2016 Jul 21. Stroke. 2016. PMID: 27444256 No abstract available.

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Paracetamol, Ibuprofen, and Recurrent Major Cardiovascular and Major Bleeding Events in 19 120 Patients With Recent Ischemic Stroke

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Paracetamol, Ibuprofen, and Recurrent Major Cardiovascular and Major Bleeding Events in 19 120 Patients With Recent Ischemic Stroke

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Abstract

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