Cardiovascular outcomes in high-risk patients with osteoarthritis treated with Ibuprofen, Naproxen, or Lumiracoxib

Michael E. Farkouh ^1*, Jeffrey D. Greenberg ², Raban V. Jeger ³, Krishnan Ramanathan ³, Freek W. A. Verheugt ⁴, James H. Cheseboro ⁵, Howard Kirshner ⁶, Judith S. Hochman ³, Christine L. Lay ⁷, Sean Ruland ⁸, Bernhard Mellein ⁹, Patrice T. Matchaba ¹⁰, Valentin Fuster ¹ and Steven B. Abramson ²

¹ Mount Sinai School of Medicine, United States
² NYU Hospital for Joint Diseases, United States
³ NYU School of Medicine, United States
⁴ University Medical Center, Nijmegen, United States
⁵ Mayo Clinic, United States
⁶ Vanderbilt University School of Medicine, United States
⁷ St. Luke's-Roosevelt Hospital Center, United States
⁸ University of Chicago at Illinois, United States
⁹ Novartis Pharmaceuticals, Switzerland
¹⁰ Novartis Pharmaceuticals, United States

^* To whom correspondence should be addressed. E-mail: michael.farkouh{at}mssm.edu.

Accepted 21 January 2007

Abstract

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

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

Results: In high risk patients among aspirin users, patients in the ibuprofen sub-study had more primary events with ibuprofen than lumiracoxib (2.14% vs. 0.25%, p=0.038), whereas in the naproxen sub-study 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 versus lumiracoxib (0% vs. 1.57%, p=0.027), but not 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. Our study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non-aspirin users. Our data should be interpreted as hypothesis-generating.

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

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