Both Selective COX-2 Inhibitors and Non-Selective NSAIDs Increase the Risk of Acute Myocardial Infarction in Patients with Arthritis

Recently, there have been increasing concerns about serious cardiovascular complications with the use of some selective cox-2 inhibitors, especially at high daily doses. Researchers studied the risk of acute myocardial infarction with celecoxib, valdecoxib, rofecoxib, meloxicam and non-selective NSAIDs in a large population of patients with arthritis, many of whom were on concomitant aspirin therapy.

Researchers used data from the Medicaid program in California for a nested case control study of all patients over age 18 with physician-diagnosed arthritis treated with a NSAID between Jan 1, 1999 and June 30, 2004. Cases of acute myocardial infarction (AMI) were risk-set matched with 4 controls on age, gender and date of AMI. Current exposure to cox-2 selective and non-selective NSAIDs was compared to remote exposure to any drug. All analyses were adjusted for 38 confounding risk factors as well as concomitant aspirin treatment.Researchers found that during 2,356,885 person-years of follow-up, 15,343 cases of AMI were identified, of which 8% were fatal. Multivariate-adjusted odds ratios (95% CI) for study drugs compared to remote drug exposure were: celecoxib 1.09 (1.02-1.15, p<0.008), meloxicam 1.37 (95% CI 1.05-1.78, p<0.02), rofecoxib 1.32 (1.22-1.42, p<0.0001), and valdecoxib 0.99 (0.72-1.37, p=0.97). Patients on rofecoxib had a significantly higher risk of AMI compared to patients on celecoxib (OR 1.22, 1.11-1.33, p<0.0001). An increased risk of AMI was seen with many, but not all, non-selective NSAIDs, (eg. indomethacin (OR 1.71, 95% CI 1.35-2.17, p<0.0001), sulindac (OR 1.41, 95% CI 1.01-1.96, p<0.04), ibuprofen (OR 1.11, 95% CI 1.01-1.22, p<0.02), but not nabumetone 0.83, 95% CI 0.60-1.14, p=0.26). There was a strong relationship of the risk of AMI with increasing dose of rofecoxib, with the risk increasing from 1.16 at daily doses of 12.5 mg to 2.4 at daily doses over 50 mg. An increased risk with higher doses was also seen with many NSAIDs - diclofenac 1.02 at <=150 mg and 1.37 at >150 mg, naproxen 1.07 at <=1g and 1.16 at >1g, and celecoxib 1.01 <=200 mg and 1.24 at >200 mg. No cardio-protective effect was seen with naproxen (OR 1.08, 0.95-1.22, p=0.22). As a class, non-coxib NSAIDs increased the risk of AMI modestly compared to remote use (OR 1.12, 1.06-1.19, p<0.0002). Among coxibs, only rofecoxib had a significantly increased risk of AMI compared to non-coxibs (OR 1.18, 1.08-1.29, p=0.0005), consistent with prior clinical trial data comparing coxibs and non-coxibs. High dose valdecoxib could not be studied since most use in our study was at 20 mg or less.Researchers concluded that several selective cox-2 agents and non-selective NSAIDs increase the risk of AMI in patients with arthritis, especially at high doses. Since these drugs have similar efficacy, they should be used on the basis of their relative gastrointestinal and cardiovascular safety profiles in any given patient and not the selectivity of their class.