Resource File

Arthritis & Rheumatism 2001;44:S372;S230;S266

[1916] Cardiovascular Safety Profile of Rofecoxib: A Meta-Analysis.
A Reicin, E Barr, D Shapiro Rahway, NJ

Objectives: To evaluate the cardiovascular (CV) safety profile of rofecoxib, a selective COX-2 inhibitor.

Background: Non-selective NSAIDs, selective COX-2 inhibitors, and aspirin each exhibit different patterns of inhibition of platelet COX-1, and chronic use of these agents is likely to be associated with differential risks of platelet-mediated vascular events. Aspirin, which induces irreversible inhibition of platelet COX-1, can be cardioprotective. NSAIDs that mediate near complete inhibition of platelet function throughout their entire dosing cycle may be similar to aspirin and reduce the risk of vascular events; other compounds with less substantial platelet inhibition may have no impact on vascular events.

Methods: A meta-analysis of all Phase IIb-V clinical trials was conducted using individual patient data and focusing on the relative risk of CV thrombotic serious adverse experiences in patients taking rofecoxib as compared to placebo, naproxen (an NSAID with near complete inhibition of platelet function throughout its dosing interval), and non-selective NSAIDs that lack potent sustained inhibition of platelet function (diclofenac, ibuprofen, and nabumetone). The primary metric utilized was the Antiplatelet Trialists' Collaboration (APTC) combined endpoint of cardiovascular or unknown death, stroke, or myocardial infarction.

Results: Over 28,000 patients in 19 studies (Osteoarthritis, Rheumatoid Arthritis, Alzheimer's, and Chronic Low Back Pain trials) representing over 14,000 patient-years at risk were included in the meta-analysis. The relative risk (95% CI) for an APTC combined endpoint was: 0.59 (0.37, 0.94) when comparing naproxen (n=7870) vs. rofecoxib (n=9083); 1.27 (0.64, 2.50) when comparing non-naproxen NSAIDs (n=2755) vs. rofecoxib (n=4549); 1.19 (0.73, 1.96) when comparing placebo (n=3482) vs. rofecoxib (n=6290); and, 1.31 (0.86, 2.01) when comparing non-naproxen NSAIDs or placebo (n=6017) vs. rofecoxib (n=7675).

Conclusions: (1) The risk of sustaining a thrombotic cardiovascular event was similar in patients treated with rofecoxib, placebo, or non-selective NSAIDs without sustained effects on platelet function and, (2) the risk of sustaining a thrombotic cardiovascular event was reduced in patients treated with naproxen compared to rofecoxib. This reduction in events on naproxen is likely due to its ability to maintain near complete inhibition of platelet function throughout its dosing interval.
Disclosure: A Reicin, E Barr, and D Shapiro are employees of Merck & Co., Inc.

[1066] The Relationship Between Nsaids And Myocardial Infarction.
Daniel H Solomon, Robert J Glynn, Raisa Levin, Jerry Avorn Boston, MA

Background: While aspirin has been shown to protect patients from myocardial infarction (MI), it is not clear whether non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) have a similar effect. We examined the association between NSAID use and subsequent MI.

Methods: We performed a case-control study in a large health care database containing all prescription, diagnosis, and procedure information for patients in the New Jersey Medicare and Medicaid programs. We examined data on 22,125 persons during a study period of 1991 to 1995; 4,425 (20%) had an MI during this time. Multivariable models were constructed to control for demographic and clinical characteristics that might confound the relationship between NSAID use and subsequent MI.

Results: A quarter of both the cases and the controls filled a prescription for an NSAID in the 6 months prior to their MI (cases) or a randomly assigned index date (controls), and 9% had filled a prescription for an NSAID in effect at the time of their MI or index date. In adjusted analyses, when all NSAID preparations were studied as a group, NSAID users had the same risk of MI as non-users, whether such use was measured on the index date (OR = 1.04, 95% CI 0.92 - 1.18; P = 0.55) or at any time in the prior 6 months (OR = 1.00, 95% CI 0.92 - 1.08; P = 0.92). However, use of naproxen was associated with a significant reduction in the risk of MI (OR = 0.84, 95% CI 0.72 - 0.98; P = 0.027). This effect was consistent across several subgroups of the population.

Conclusions: These findings do not support a relationship between the use of NSAIDs as a group and MI. Use of one specific NSAID, naproxen, did appear to be associated with a reduced rate of MI, but the mechanism of such an effect is not clear.

[1278] Association Of Conventional Non-Aspirin Nonsteroidal Antiinflammatory Drugs (Nsaids) With Hospitalizations For Myocardial Infarction.
Elham Rahme, Louise Pilote, Jacques Lelorier Montreal, PQ, Canada

Introduction: The association between non-aspirin NSAIDs and acute myocardial infarction (AMI) is unclear. It has been proposed that NSAIDs vary in their antithrombotic properties, with naproxen having a particularly effective antithrombotic potential.

Objective: We evaluated the association between naproxen and AMI in an elderly population.

Methods: This was a population-based, 1-1 matched, case-control study. Cases were elderly patients with AMI between 1992-94 identified from the Government of Quebec hospital discharge summary database. The date of admission for AMI was the index date. Controls were selected randomly from the drugs/physician claims database. Controls were matched with cases for age, sex and index date. Cases and controls were required to have one year of pharmaceutical/medical records prior to the index date. Three conditional logistic regression analyses were used to adjust for potential confounders. The main analysis evaluated concurrent chronic exposures (at least 2 prescriptions and a total 60 consecutive exposure days and exposure at the index date); the secondary analyses evaluated interrupted chronic exposures (at least 2 prescriptions and a total 60 consecutive exposure days but not exposed at the index date) and concurrent exposures (exposure at the index date).

Results: 14,163 cases and 14,160 controls were included. The main analysis showed that determinants of AMI (odds ratio (OR), 95%CI) included: use in the prior year of anticoagulants (0.75, 0.63-0.89), nitrates (2.02, 1.87-2.18), antidiabetic agents (1.72, 1.56-1.90), antihypertensive agents (1.36, 1.28-1.45), lipid lowering agents (0.83, 0.75-0.91); and chronic disease score > 3 (1.73, 1.60-1.87). The risk of AMI in concurrent chronic users of naproxen was significantly lower than that of concurrent chronic users of other NSAIDs (0.65, 0.48-0.87). Secondary analyses showed that the OR of AMI in interrupted chronic users of naproxen versus interrupted chronic users of other NSAIDs were (0.98, 0.72-1.32); and (0.79, 0.63-1.00) in concurrent users of naproxen versus concurrent users of other NSAIDs.

Conclusions: This study showed that naproxen has a protective effect against AMI. This effect seemed only to be present with a concurrent naproxen prescription, and was strongest in chronic users. This would be consistent with the fact that naproxen anti-platelet effect is mainly short-term in duration and would suggest that chronic persistent usage is required for cardioprotection. In an elderly population such as the one included in this study physicians should weigh the cardiac benefit of naproxen versus its gastrointestinal toxicity.

Disclosure: This study was supported by Merck & Co. Inc.