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Rheumatology Advance Access originally published online on February 17, 2009
Rheumatology 2009 48(4):425-432; doi:10.1093/rheumatology/kep005
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cardiovascular safety and gastrointestinal tolerability of etoricoxib vs diclofenac in a randomized controlled clinical trial (The MEDAL study)

Bernard Combe1, Gary Swergold2, James McLay3, Timothy McCarthy4, Cristiano Zerbini5, Paul Emery6, Laurine Connors2, Amarjot Kaur2, Sean Curtis2, Loren Laine7 and Christopher P. Cannon8

1Service d’Immuno-Rhumatologie, Hopital Lapeyronie, Montpellier, France, 2Merck Research Laboratories, Rahway, NJ, USA, 3Departments of Medicine and Therapeutics, University of Aberdeen Polwarth Buildings, Aberdeen, Scotland, 4Manitoba Clinic, Manitoba, Canada, 5Serviço de Reumatologia, Hospital Heliópolis, São Paulo, Brazil, 6Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK, 7Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA and 8TIMI Study Group, Brigham and Women's Hospital, Boston, MA, USA.

Correspondence to: Bernard Combe, Immuno-Rhumatologie, Hopital Lapeyronie, CHU Montpellier, Université Montpellier 1, Montpellier F-34000, France. E-mail: b-combe{at}chu-montpellier.fr


  Abstract

Objective. To compare cardiovascular (CV) and other safety and efficacy parameters of etoricoxib 60 and 90 mg, and diclofenac 150 mg.

Methods. This double-blind study randomized OA patients to etoricoxib 90 mg, then to 60 mg once daily vs diclofenac 75 mg twice daily; RA patients were randomized to etoricoxib 90 mg once daily or diclofenac 75 mg twice daily. The primary endpoint was non-inferiority of etoricoxib vs diclofenac for thrombotic CV events (95% CI upper bound of hazard ratio <1.30). Other safety and efficacy parameters were evaluated in cohorts of patients based on etoricoxib dose and disease.

Results. A total of 23 504 patients were randomized with mean treatment duration from 19.4 to 20.8 months. The thrombotic CV risk hazard ratio (HR) (etoricoxib to diclofenac) was 0.96 (95% CI 0.81, 1.15), consistent with non-inferiority of etoricoxib to diclofenac. The cumulative gastrointestinal (GI)/liver adverse events (AEs) discontinuation rate was significantly lower for etoricoxib than diclofenac in each patient cohort; HR (95% CI) of 0.46 (0.39, 0.54), 0.52 (0.42, 0.63) and 0.49 (0.39, 0.62) for the 60 mg OA, 90 mg OA and RA cohorts. The maximum average change in systolic blood pressure (BP) with etoricoxib was 3.4–3.6 mmHg (diastolic BP: 1.0–1.5 mmHg), while diclofenac produced a maximum average change of 0.9–1.9 mmHg (diastolic BP: 0.0–0.5 mmHg). Both agents resulted in similar efficacy regardless of etoricoxib dose.

Conclusion. Long-term etoricoxib use is associated with a risk of thrombotic CV events comparable with that of diclofenac. Compared with diclofenac, etoricoxib demonstrated a greater risk of renovascular AEs, but a more favourable GI/liver tolerability profile.

KEY WORDS: NSAIDs, Rheumatoid arthritis, Osteoarthritis, COX-2 inhibitors, Cardiovascular safety, Gastrointestinal safety, Analgesia

Submitted 22 January 2008; revised version accepted 7 January 2009.
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