EXTENDED REPORT

Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib

M E Farkouh¹, J D Greenberg³, R V Jeger², K Ramanathan², F W A Verheugt⁴, J H Chesebro⁶, H Kirshner⁵, J S Hochman², C L Lay⁷, S Ruland⁸, B Mellein⁹, P T Matchaba¹⁰, V Fuster¹, S B Abramson³

¹ The Zena and Michael A Wiener Cardiovascular Institute and The Marie-Josée and Henry R Kravis Center for Cardiovascular Health, Mount Sinai Medical Center, New York, NY, USA
² Cardiovascular Clinical Research Center, New York University School of Medicine, New York, NY, USA
³ New York University Hospital for Joint Diseases, New York, NY, USA
⁴ Cardiology Department, University Medical Centre, Nijmegen, The Netherlands
⁵ Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
⁶ Division of Cardiology, Mayo Clinic, Jacksonville, Florida, USA
⁷ Department of Neurology, St Luke’s-Roosevelt Hospital Center, New York, NY, USA
⁸ Department of Neurology and Rehabilitation, University of Illinois at Chicago, Illinois, USA
⁹ Novartis Pharma, Basel, Switzerland
¹⁰ Novartis Pharmaceuticals, East Hanover, NJ

Correspondence to:
Dr M E Farkouh
Mount Sinai Cardiovascular Institute, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1074, New York, New York 10029, USA; michael.farkouh{at}mssm.edu

Background: Evidence suggests that both selective cyclooxygenase (COX)-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX-2 inhibitors and non-selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin.

Objective: To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib.

Methods: The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX-2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low-dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non-fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF).

Results: In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib.

Conclusions: These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non-aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis-generating study.

Abbreviations: CCSC, Cardiovascular and Cerebrovascular Safety Committee; CI, confidence interval; COX, cyclooxygenase; HOPE, Heart Outcomes Prevention Evaluation; HR, hazard ratio; MI, myocardial infarction; NSAIDs, non-steroidal anti-inflammatory drugs; TARGET, Therapeutic Arthritis Research and Gastrointestinal Event Trial; VIGOR, Vioxx Gastrointestinal Outcomes Research

Keywords: coronary disease; osteoarthritis; anti-inflammatory agents; non-steroidal anti-inflammatory drugs; COX-2 inhibitors; aspirin

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