Risk of Acute Myocardial Infarction and Sudden Cardiac Death
with Use of COX-2 Selective and Non-Selective NSAIDs
DJ Graham,1 DH Campen,2 C Cheetham,2 R Hui,2 M Spence2 and WA Ray3
1Office of Drug Safety, US Food and Drug Administration; 2Kaiser Permanente, California; 3Vanderbilt University School of Medicine
Rofecoxib use at doses > 25 mg/d increased the risk of an acute cardiac event 3.15-fold (table 3). Risk was also increased at lower rofecoxib doses, but not significantly so. Naproxen use did not decrease risk; rather, it increased risk by 18% (p=0.01). Use of “other
Several studies, including a randomized clinical trial, suggest that higher-dose rofecoxib use increases the risk of acute myocardial
NSAIDs” was associated with a 16% increase in risk (p<0.01). Of note, the 95% CI for rofecoxib ≤ 25 mg/d excluded the point estimate
infarction (AMI). Conflicting studies have found that naproxen use may or may not decrease risk. Celecoxib has not been associated
for celecoxib risk and vice versa. The risk of AMI/ SCD was increased in patients taking lower-dose rofecoxib compared with celecoxib
with AMI. Many of these studies did not include sudden cardiac death (SCD) as an outcome. Objectives
Table 3. Risk of AMI or SCD with current use of celecoxib, ibuprofen, naproxen,
To determine if celecoxib, ibuprofen, naproxen, rofecoxib or other NSAID use increases the risk of AMI and SCD and if risk is similar
rofecoxib or other NSAID, or recent use of a nonsteroidal agent. Setting: Kaiser Permanente (KP) is an integrated managed care organization providing comprehensive health care to over 9 million members nationally. The 6 million members in California were the focus of this study. Computerized eligibility, hospitalization,
outpatient visit, laboratory results, procedure and outpatient drug prescription files are maintained for all members. All patients age
18-84 treated with a COX-2 selective or non-selective NSAID between 1 Jan 1999 and 31 Dec 2001 were entered into the study cohort beginning with their first prescription and followed until the end of the study period, disenrollment, AMI or death. Design: A nested case-control study within this NSAID-exposed study cohort.
Outcome: Hospitalized AMI (from computer files) or out of hospital SCD (from death certificate data).
Cases: All study cohort members with AMI or SCD during the study period.
Controls: Risk-set matched 4:1 on event (index) date, birth year, gender and health plan region (N or S).
Exposure: Current=NSAID use overlapped index date; Recent=NSAID use ended from 1 to 60 days prior to index date;
Remote=NSAID use ended more than 60 days before index date.
Comparison of interest: Current v. remote exposure.
1 Adjusted for age, gender and health plan region; hospitalization for AMI,
Covariates: For the 365 days preceding the index date, data on cardiovascular risk was collected, including hospitalization for a wide
coronary artery revascularization, angina, heart failure, other ischemic heart
variety of cardiac and non-cardiac reasons, emergency room visits, outpatient encounters, same-day hospitalizations and prescription
disease, peripheral vascular disease, cerebrovascular accident, non- cardiac-
drugs including all major classes of agents used to treat cardiovascular diseases.
related disorders and same-day procedures; emergency room visits for cardiac
Cardiovascular risk score (CVRS): Because of the high number of covariates, a CVRS with 10 values (0-9) was created from
and non-cardiac reasons; smoking-related diagnoses; and use of angiotensin
regression models performed on remotely and recently exposed controls, where the regression coefficients determined the weight
converting enzyme inhibitors, angiotensin receptor blockers, anti-arrhythmics,
given to each risk factor in the model. There was a 12-fold difference in AMI/SCD risk between the lowest and highest score.
anticoagulants, ß-blockers, calcium channel blockers, digoxin, insulin, loop
Survey of controls: A random sample of controls exposed to celecoxib, ibuprofen, naproxen or rofecoxib, or remotely exposed to any
diuretics, nitrates, oral hypoglycemic agents, thiazide diuretics, HMG-CoA
NSAID, were surveyed by telephone about their use of low-dose aspirin and OTC-NSAIDs, detailed smoking history and family history
reductase inhibitors, fibrates, niacin, clopidogrel, ticlopidine, hormone
replacement therapy, and high-dose prednisone. Analysis: Conditional logistic regression: odds ratios (ORs) with 95% confidence intervals (CIs); Wald test of coefficients for celecoxib and rofecoxib. Human subjects: Study was approved by the institutional review boards of both the northern and southern divisions of KP.
A secondary analysis of the “other NSAID” category was performed for those NSAIDs with more than 50 exposed cases and controls. The risk of AMI/SCD was increased with indomethacin (OR=1.33, 95% CI 1.09-1.63, p=0.005) and possibly diclofenac
(OR=1.69, 95% CI 0.97-2.93, p=0.06). There were only 21 cases and 54 controls currently exposed to diclofenac and use within the study cohort was low (table 1).
1,394,764 patients contributed 2,295,168 person-years of observation time to the study cohort and included 40,405 patients treated with celecoxib and 26,748 treated with rofecoxib (table 1).
Of 1028 randomly selected controls, 831 (80.8%) agreed to complete a brief telephone survey. The control groups with current exposure to COX-2 selective and non-selective NSAIDs were generally comparable to each other and to remotely exposedcontrols with respect to potential cardiovascular risk factors that could not be measured using automated data sources (table 4).
Table 1. Exposure to Specific NSAIDs within
Table 4. Aspirin use (≤ 325 mg/day), OTC-NSAID use, smoking history and family history of AMI among 831
randomly selected controls with current exposure to celecoxib, ibuprofen, naproxen or rofecoxib or remote
Aspirin use, %
† Use ≥2d/wk for ≥1year‡ Age at first AMI: males ≤ 55, females ≤ 60
There were 8,199 acute cardiac events within the study cohort (6,675 AMI; 1,524 SCD), with available enzyme confirmation (CK-MB or troponin I) for 5,836 (87.4%) hospitalized AMIs. As expected, the prevalence of prior cardiovascular disease, emergency room
visits and drug use was uniformly increased among cases (table 2). Main findings
• Higher-dose rofecoxib (> 25 mg/d) conferred a 3.15-fold increased risk of AMI and SCD compared with remote use of any NSAID.
Table 2. Characteristics of cases of AMI or SCD and matched controls from the study cohort of 1,394,764
• Risk was also increased with lower-dose rofecoxib (≤ 25 mg/d) but not significantly so, compared with remote NSAID use.
patients with any exposure to COX-2 selective or non-selective NSAIDs.
• Risk of AMI and SCD was increased with lower-dose rofecoxib compared with celecoxib (p=0.04).
• Naproxen use did not confer a protective effect; rather it increased risk by 18%. Secondary findings
• Indomethacin and possibly diclofenac increased the risk of AMI and SCD. Study strengths
• Case-control, nested in a well-defined inception cohort of selective and non-selective NSAID users.
• Large number of users for many NSAIDs, including the COX-2 selective agents.
Cardiovascular hospitalization in past year
• Very large number of cases of hospitalized AMI, with 87.4% having computerized enzyme confirmation available.
Myocardial infarction or revascularization
• Included cases of SCD, the presenting expression of AMI in ~20% of cases.
• Covariate data collected for the 365 days preceding index date.
• Telephone survey of a random sample of exposed controls showed no important differences in the distribution of aspirin or OTC-
NSAID use, smoking history or family history of AMI among different groups of NSAID users, suggesting that these factors did notconfound the study results.
• Diverse base population; no barriers to health care access. Study limitations
• Use of higher-dose rofecoxib in this health plan was very low, resulting in a wide 95% CI for the OR estimate.
• Low-dose aspirin and OTC-NSAID use was not captured in electronic files.
Survey of controls suggests these are not confounders.
• Medical record review of hospitalized AMI cases not performed.
Previous studies suggest high validity of hospitalized AMI diagnosis.
Documented enzyme confirmation of AMI available electronically for most cases. Conclusions
• Rofecoxib use at a dose > 25 mg/d increased the risk of AMI and SCD.
This and other studies cast serious doubt on the safety of rofecoxib > 25 mg/d and its use by physicians and patients.
• For patients treated with a COX-2 selective NSAID, rofecoxib ≤ 25 mg/d conferred an increased risk of AMI and SCD compared with
From a cardiovascular perspective, celecoxib may be safer than rofecoxib.
Additional research comparing rofecoxib to celecoxib is needed.
Cardiovascular safety of other coxibs should not be assumed.
• Current use of several other NSAIDs appears to increase the risk of AMI and SCD. Disclaimer: The views expressed are the authors’ and do not necessarily reflect those of the US Food and Drug Administration. Funding: FDA contract with Kaiser Permanente. Disclosures: Drs. Graham, Campen, Cheetham, Hui and Spence have no potential conflicts to disclose. Dr. Ray has served as a consultant to Pfizer and plaintiffs’ attorneys re: rofecoxib.
1 Visits not resulting in hospitalization
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