Cardiology Express Report

Based on data presented at the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) 67th Annual Scientific Meeting Orlando, Florida

Publication date: 2004-01-29

Cardiovascular Complications Associated with COX-2 Selective Inhibitor Use

This report was reviewed for medical and scientific accuracy by Ronald S. Freudenberger, MD, Director, Heart Failure and Transplant Cardiology, Associate Professor of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

According to the results of studies presented at the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) 67th Annual Scientific Meeting in Orlando, Florida, the use of a cyclooxygenase (COX)-2 selective inhibitor in elderly patients (≥65 years of age) results in an increased risk of cardiovascular complications. In an observational study of 54,475 Medicare beneficiaries,¹ the use of rofecoxib (Vioxx) was associated with an increased adjusted relative risk of acute myocardial infarction compared with celecoxib (Celebrex) and with no nonsteroidal anti-inflammatory drug (NSAID) use. Dosages of rofecoxib greater than 25 mg were associated with the highest risk. Utilizing a subset of the same patient database, investigators assessed the relative risk of new-onset hypertension in 17,844 patients who had used rofecoxib or celecoxib compared to patients taking either the other COX-2 selective inhibitor, a nonselective NSAID, or no NSAID.² Patients who had taken rofecoxib were at a significantly increased relative risk for new-onset hypertension compared with patients taking celecoxib, taking a nonselective NSAID, or taking no NSAID. In patients with a history of chronic renal disease, liver disease, or congestive heart failure, the relative risk of new-onset hypertension associated with rofecoxib use was twice as high as compared with celecoxib.

Perspective
An association between COX-2 selective inhibitor and cardiovascular complications was first suggested in the Vioxx Gastrointestinal Outcomes Research (VIGOR) Study.³ The results of VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% Confidence Interval (CI), 1.39-4.00; P<.001).⁴ The concern for cardiovascular complications is not limited to rofecoxib. The annualized myocardial infarction rates for both the VIGOR³ and the Celecoxib Long-term Arthritis Safety Study (CLASS) trial⁵ were significantly higher (0.74% with rofecoxib, P = .04; 0.80% with celecoxib, P = .02) compared with the annualized myocardial infarction rate for placebo-treated patients (0.52%) in a recent meta-analysis of 4 primary prevention aspirin trials.⁶

Rofecoxib and celecoxib have been known to increase systolic blood pressure,^7,8 and exacerbate existing hypertension.^9,10 In one study, systolic blood pressure increased significantly in 17% of rofecoxib-treated patients compared with 11% of celecoxib-treated patients (P = .032).⁷ Moreover, nearly twice as many rofecoxib-treated patients compared with celecoxib-treated patients experienced edema (9.5% vs 4.9%, respectively; P = .014). Although in some cases, the average increases in systolic blood pressure may be considered small (a few mm Hg), evidence indicates that mean increases of systolic blood pressure of 1 to 5 mm Hg are associated with 7,100 to 35,700 additional ischemic heart disease and stroke events over one year, with corresponding medical and economic costs of $114 to $569 million.¹¹

Respectively, clinically important differences between rofecoxib and celecoxib are related to oral bioavailability (92-93% vs 22-40%), half-life (10-17 hours vs 11), extent of plasma protein binding (86% vs >97%), and main pathways of hepatic metabolism (cytosolic reduction vs oxidation by cytochrome P-450).