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
- 1The 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
- 2Cardiovascular Clinical Research Center, New York University School of Medicine, New York, NY, USA
- 3New York University Hospital for Joint Diseases, New York, NY, USA
- 4Cardiology Department, University Medical Centre, Nijmegen, The Netherlands
- 5Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- 6Division of Cardiology, Mayo Clinic, Jacksonville, Florida, USA
- 7Department of Neurology, St Luke’s-Roosevelt Hospital Center, New York, NY, USA
- 8Department of Neurology and Rehabilitation, University of Illinois at Chicago, Illinois, USA
- 9Novartis Pharma, Basel, Switzerland
- 10Novartis 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;
- Accepted 21 January 2007
- Published Online First 5 April 2007
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.
- 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
- coronary disease
- anti-inflammatory agents
- non-steroidal anti-inflammatory drugs
- COX-2 inhibitors
Published Online First 5 April 2007
Funding: Source of support: Novartis AG, Basel, Switzerland.
Conflict of interest: MEF has received speaking and consulting honoraria from Novartis, Bristol Myers Squibb and Sanofi. JDG has received speaking and consulting honoraria from Pfizer and was supported by a Physician Scientist Development Award from the American College of Rheumatology/Arthritis Foundation. RVJ was supported by the AstraZeneca Scholarship of the Swiss Society of Hypertension; the Freiwillige Akademische Gesellschaft Basel, Switzerland; and the Fund for the Promotion of a new Generation of Academics at the University of Basel, Switzerland. FWAV has received educational and research grants from Bayer, Roche, Eli Lilly, and Boehringer Ingelheim; and has received consulting honoraria from Pharmacia Upjohn, Eli Lilly, Merck, and Bayer. HK has acted as a consultant for Novartis, Wyeth, Sanofi-Synthelabo, Bristol Myers Squibb, and AstraZeneca; as a study investigator for Pfizer, Bristol Myers Squibb, Sanofi-Synthelabo, Boehringer Ingelheim, ONO, Fujisawa and AstraZeneca; and is a member of the speakers’ bureau for Pfizer, Novartis, Janssen, Forest, Boehringer Ingelheim, Sanofi Synthelabo, Bristol Myers Squibb, AstraZeneca and Wyeth. JSH has received clinical trial research support from Arginox and has consulted for GlaxoSmithKline, Sanofi and Datascope. CLL has received speaking and consulting honoraria from Ortho-McNeil, Pfizer, Allergan, and GlaxoSmithKline. SR has received consulting honoraria from Novartis, Boehringer Ingelheim, Bristol Myers Squibb, Solvay and ESP Pharma. BM and PTM are employees of Novartis. VF has acted as a consultant to GlaxoSmithKline, Kereos and Vasogen. SBA has received speaking and consulting honoraria from Pfizer, GlaxoSmithKline, Merck, NicOX, Eli Lilly and Novartis.