Millions of elderly people take nonsteroidal antiinflammatory drugs (NSAIDs), selective and nonselective, because of their analgesic and antiinflammatory benefits (1). However, many questions remain about the cardiovascular safety of selective cyclooxygenase 2 inhibitors (coxibs) as well as nonselective NSAIDs, particularly in older adults. Despite a recent Food and Drug Administration requirement that the labels of all NSAIDs contain a boxed warning (2), few studies have estimated the cardiovascular risk of NSAIDs. The time course of cardiovascular events associated with coxibs is also controversial, and may reveal some information about their mechanism of cardiovascular risk. It is possible that the risk of cardiovascular events with these drugs may be based on a patient's underlying cardiovascular risk, but there is little published evidence on this. While appropriately designed randomized controlled trials would help answer these questions, results from such trials are not imminent. In the absence of trial data, nonexperimental epidemiologic studies provide the best alternative source of information for patients, doctors, and regulators.
Epidemiologic studies of drug safety can be conducted using previously collected, readily available data sources to allow for quicker and less expensive analyses than randomized controlled trials. These data sets contain information on patients with a broad range of comorbid conditions who use the drugs of interest in a typical manner; this may differ from the constrained patterns of use reflected in a clinical trial. However, nonexperimental studies of the cardiovascular safety of coxibs and NSAIDs have important potential limitations, including the nonrandom assignment of treatment, lack of information regarding important covariates such as aspirin use and body mass index, misclassification of drug exposure due to the availability of over-the-counter NSAIDs, and difficulty ascertaining the cause of out-of-hospital sudden death.
With these caveats in mind, we set out to examine the cardiovascular risk associated with the 3 coxibs marketed in the US during the study period—celecoxib, rofecoxib, and valdecoxib—and several commonly used NSAIDs, including diclofenac, ibuprofen, naproxen, and a combined group of other NSAIDs. The primary aims of these analyses were 1) to examine the risk of cardiovascular events in users of coxibs and NSAIDs compared with users of other drugs, 2) to assess the time course of risk, and 3) to determine whether baseline cardiovascular risk modifies the risk of future events. These study aims were pursued using a large health care utilization database with older at-risk adults, many of whom would not be included in trials but actually represent the target population for these medications.
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We identified 74,838 new users of coxibs or NSAIDs. These subjects were compared with new users of thyroid hormones or glaucoma medications who were not new users of coxibs or NSAIDs (n = 23,532). Characteristics of these subjects are compared in Table 2. All groups were quite similar with respect to age, sex, and race distribution and most diagnoses. Users of ibuprofen and naproxen and the nonusers were less likely to have received a diagnosis of osteoarthritis.
Table 2. Baseline characteristics of study subjects during the 6 months before starting medication*
|All patients included|| || || || || || || || |
| Age, mean ± SD years||80 ± 7||80 ± 7||79 ± 7||78 ± 7||78 ± 7||77 ± 7||78 ± 7||80 ± 7|
| Female||22,323 (85)||15,311 (85)||2,616 (85)||2,239 (84)||5,974 (81)||4,998 (82)||8,863 (79)||19,950 (85)|
| Race, white||24,970 (95)||17,145 (95)||2,929 (96)||2,474 (93)||6,406 (86)||5,455 (89)||10,360 (92)||22,062 (94)|
|Patients from 2003§|| || || || || || || || |
| Hospitalized||149 (5)||126 (5)||81 (5)||12 (4)||59 (5)||39 (4)||68 (5)||236 (6)|
| Nursing home residence||170 (6)||150 (6)||70 (4)||11 (3)||55 (5)||21 (2)||49 (3)||330 (8)|
| Physician visits, mean ± SD||5 ± 4||5 ± 4||5 ± 4||4 ± 4||4 ± 4||4 ± 4||5 ± 4||5 ± 4|
| No. of generic preparations taken, mean ± SD||7 ± 4||7 ± 4||7 ± 4||6 ± 4||7 ± 4||6 ± 4||7 ± 4||6 ± 4|
| Myocardial infarction||173 (6)||171 (7)||93 (6)||12 (4)||59 (5)||48 (5)||92 (6)||316 (7)|
| Congestive heart failure||787 (27)||660 (27)||416 (26)||71 (22)||251 (23)||202 (21)||426 (28)||1,199 (28)|
| Coronary revascularization||47 (2)||64 (3)||34 (2)||4 (1)||19 (2)||22 (2)||29 (2)||79 (2)|
| Angina||223 (8)||239 (9)||148 (9)||27 (8)||96 (9)||72 (7)||135 (9)||394 (9)|
| Diabetes||447 (15)||371 (15)||246 (15)||42 (13)||174 (16)||167 (17)||207 (14)||574 (13)|
| Hypertension||1,808 (62)||1,483 (61)||1,020 (63)||186 (57)||661 (61)||559 (57)||918 (61)||2,367 (55)|
| Statin use||892 (31)||756 (31)||517 (32)||106 (33)||359 (33)||317 (33)||482 (32)||1,156 (27)|
| Clopidogrel use||246 (8)||196 (8)||137 (8)||21 (6)||84 (8)||66 (7)||106 (7)||353 (8)|
| Peripheral vascular disease||313 (11)||255 (11)||151 (9)||36 (11)||106 (10)||84 (9)||126 (8)||473 (11)|
| Stroke||210 (7)||182 (8)||98 (6)||15 (5)||70 (6)||61 (6)||90 (6)||357 (8)|
| Carotid revascularization||6 (0.2)||7 (0.3)||3 (0.2)||0 (0)||2 (0.2)||2 (0.2)||2 (0.1)||13 (0.3)|
| Chronic renal disease||84 (3)||88 (4)||60 (4)||10 (3)||41 (4)||30 (3)||71 (5)||267 (6)|
| Rheumatoid arthritis||61 (2)||35 (1)||41 (3)||8 (2)||16 (1)||10 (1)||23 (2)||67 (2)|
| Osteoarthritis||747 (26)||590 (24)||502 (31)||61 (19)||169 (15)||160 (16)||315 (21)||572 (13)|
| Malignancy||75 (3)||76 (3)||36 (2)||5 (2)||39 (4)||20 (2)||32 (2)||132 (3)|
The number of new use periods, person-time, and events are shown for all users of each coxib and NSAID in Table 3. There were large numbers of events for each drug. Table 3 displays the incidence rate, rate differences between users of each agent and glaucoma or thyroid drug users, and the unadjusted and adjusted rate ratios for cardiovascular events, comparing users of each drug with nonusers. Rofecoxib was associated with an increased rate difference and rate ratio, but the other 2 coxibs were not. This result was quite uniform across MI and stroke (Table 4). None of the NSAIDs was associated with an increased rate ratio, and naproxen was associated with a reduced rate ratio. Diclofenac did appear to be associated with an increased rate ratio of MI (Table 4), but not with the composite end point. In secondary analyses comparing each agent with ibuprofen as the reference group, the results were similar to those from the primary analyses (rofecoxib RR 1.19, 95% CI 1.00–1.41; celecoxib RR 1.03, 95% CI 0.87–1.22; valdecoxib RR 0.97, 95% CI 0.75–1.25; and naproxen (RR 0.79, 95% CI 0.62–1.01). The results obtained when the reference group included only glaucoma medication users (and not thyroid medication users) were also very similar (rofecoxib RR 1.27, 95% CI 1.11–1.44; celecoxib RR 1.09, 95% CI 0.96–1.24; valdecoxib RR 1.05, 95% CI 0.84–1.31; and naproxen RR 0.84, 95% CI 0.67–1.04).
Table 3. Cardiovascular events among all users of coxibs or NSAIDs*
|Treatment||n||Myocardial infarction or stroke|
|Events||Person-years||Incidence rate per 100 person-years||Unadjusted rate difference||Unadjusted rate ratio (95% CI)||Adjusted rate ratio (95% CI)|
|Celecoxib||26,366||1,342||11,768||11.4||0.58 (−00.20, 1.37)||1.05 (0.98, 1.13)||0.99 (0.92, 1.07)|
|Rofecoxib||17,967||912||6,746||13.5||2.70 (1.69, 3.70)||1.25 (1.15, 1.35)||1.15 (1.06, 1.25)|
|Valdecoxib||3,060||112||985||11.4||0.55 (−1.61, 2.71)||1.05 (0.87, 1.27)||0.96 (0.78, 1.17)|
|Diclofenac||2,673||86||736||11.7||0.86 (−1.66, 3.38)||1.08 (0.87, 1.34)||1.10 (0.89, 1.37)|
|Ibuprofen||7,421||151||1,244||12.1||1.32 (−0.68, 3.31)||1.12 (0.95, 1.32)||0.96 (0.81, 1.14)|
|Naproxen||6,130||108||1,254||8.6||−2.21 (−3.91, 0.51)||0.80 (0.66, 0.97)||0.75 (0.62, 0.92)|
|Other NSAIDs†||11,221||292||2,615||11.2||0.34 (−1.03, 1.72)||1.03 (0.91, 1.17)||0.95 (0.84, 1.08)|
Table 4. Myocardial infarctions and strokes among users of coxibs or NSAIDs*
| ||n||Myocardial infarction||Stroke|
|Events||Person-years||Adjusted RR (95% CI)||Events||Person-years||Adjusted RR (95% CI)|
|Celecoxib||26,366||424||12,135||0.99 (0.87–1.13)||988||11,861||1.00 (0.92–1.09)|
|Rofecoxib||17,967||290||6,952||1.16 (1.01–1.34)||660||6,797||1.15 (1.04–1.26)|
|Valdecoxib||3,060||37||1,006||1.06 (0.75–1.50)||80||989||0.93 (0.74–1.18)|
|Diclofenac||2,673||34||751||1.43 (1.01–2.03)||56||739||0.98 (0.75–1.29)|
|Ibuprofen||7,421||47||1,253||1.02 (0.75–1.38)||111||1,247||0.95 (0.78–1.16)|
|Naproxen||6,130||28||1,272||0.67 (0.45–0.98)||89||1,257||0.83 (0.67–1.04)|
|Other NSAIDs†||11,221||72||2,667||0.77 (0.60–0.99)||229||2,625||1.02 (0.88–1.17)|
As illustrated in Figure 1, the rate ratios observed in the first 60 days were very similar to those in the next 60 days for all medications. All interaction terms between the exposures of interest and the time receiving therapy were nonsignificant (all P values > 0.8). The time course of events was further explored in Kaplan-Meier survival analyses stratified on the cardiovascular disease risk score. Among the low-risk subgroup (Figure 2a), the probability of cardiovascular events rose within the first year for rofecoxib, but not celecoxib. This elevation persisted throughout 3 years for rofecoxib users. The time course of events among high-risk patients (Figure 2b) was similar, but the probability of event was much higher. Celecoxib was not associated with an elevated probability of event in either low- or high-risk patients.
Figure 1. Adjusted rate ratio of myocardial infarction or ischemic stroke by duration of use of selective cyclooxygenase 2 inhibitors (a) or nonselective nonsteroidal antiinflammatory drugs (NSAIDs) (b). All estimates were derived from Cox proportional hazards models, stratified on year, that included age, sex, race, hospitalizations, physician visits, number of other medications, nursing home residence, prior myocardial infarction, prior stroke, angina, congestive heart failure, peripheral vascular disease, revascularization procedures, diabetes, hypertension, use of a statin, use of clopidogrel, renal disease, rheumatoid arthritis, osteoarthritis, and malignancy. The reference group was users of glaucoma or thyroid medications. Vertical lines show the 95% confidence intervals. No significant interactions between drug exposure and duration of medication use were observed (all P values > 0.8).
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Figure 2. Kaplan-Meier survival curves illustrating the cumulative probability of a myocardial infarction or stroke during the first 3 years after starting treatment with a selective cyclooxygenase 2 inhibitor, among subjects who were at low risk (a) and subjects who were at high risk (b) of future cardiovascular events (see Methods for description of the different risk groups). Only drug exposures with at least 25 subjects followed up for at least 36 months were included in these analyses.
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We then explored whether a patient's baseline cardiovascular risk modified the effects of a given agent (Figures 3a and b). None of the interaction terms for the exposures of interest and a baseline cardiovascular risk indicator were significant (all P values > 0.7). An elevated rate ratio with rofecoxib was observed in both low- and high-risk patients, while both low- and high-risk naproxen users experienced a reduction in cardiovascular events. We found a similar consistency of results among low- and high-dose users.
Figure 3. Adjusted rate ratio of myocardial infarction or ischemic stroke by baseline cardiovascular risk among users of selective cyclooxygenase 2 inhibitors (a) or nonselective nonsteroidal antiinflammatory drugs (NSAIDs) (b). All estimates were derived from Cox proportional hazards models, stratified on year, that included age, sex, race, hospitalizations, physician visits, number of other medications, nursing home residence, prior myocardial infarction, prior stroke, angina, congestive heart failure, peripheral vascular disease, revascularization procedures, diabetes, hypertension, use of a statin, use of clopidogrel, renal disease, rheumatoid arthritis, osteoarthritis, and malignancy. The reference group was users of glaucoma or thyroid medications. Vertical lines show the 95% confidence intervals. No significant interactions between drug exposure and baseline risk of cardiovascular disease were observed (all P values > 0.7).
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Because of concerns regarding unmeasured confounders in our study database, we examined educational attainment, smoking, body mass index, and aspirin use in a large survey of Medicare beneficiaries. As noted in Table 5, coxib users were more likely than nonusers to have had lower educational attainment, to be obese, and to be current smokers. These differences result in a small (2%) bias away from the null hypothesis in our primary health care utilization data analyses in which such factors were not considered. However, in the analyses with ibuprofen users as the reference group, the coxib analyses were biased up to 6% toward the null hypothesis.
Table 5. Prevalence of potential unmeasured confounders in a separate survey of 9,501 Medicare beneficiaries*
| ||n||Female||Age, years||High school education or less||Obese (body mass index ≥30 kg/m2)||Aspirin use||Smoking status|
| Celecoxib only||677||70.6||39.1||60.9||62.8||23.7||5.9||9.6||43.5||46.6|
| Rofecoxib only||488||66.8||46.3||53.7||59.8||27.5||6.4||6.6||50.7||42.2|
| Valdecoxib only||57||70.2||50.9||49.1||68.4||28.1||3.5||5.3||49.1||45.6|
|Nonselective NSAIDs only‡||702||59.1||53.9||46.2||63.1||25.1||9.8||10.1||49.6||40.1|
| Ibuprofen only||204||56.4||58.8||41.2||67.7||21.8||10.3||11.9||50.0||37.1|
| Naproxen only||210||56.7||54.3||45.7||61.4||26.8||12.9||11.0||50.7||38.3|
| Diclofenac only||51||62.8||43.1||56.9||60.8||34.0||2.0||4.0||56.0||40.0|
| Other NSAIDs only||252||61.5||50.8||49.2||62.7||24.4||8.7||8.8||48.0||43.2|
|Glaucoma or thyroid drugs only (nonusers)||1,272||71.1||32.5||67.5||40.4||18.4||5.4||6.2||46.6||47.1|
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In this study of patients ages 65 and older, we found that rofecoxib, but not celecoxib, valdecoxib, diclofenac, ibuprofen, or naproxen, was associated with an increased rate ratio of cardiovascular events compared with other medications. Naproxen was associated with a modest reduction in the rate ratio of cardiovascular events. The increased rate among rofecoxib users was observed in the first 60 days and persisted. Kaplan-Meier curves indicated that the risk with rofecoxib rose early and continued through 3 years. The rate ratio elevation was evident in patients at either low or high risk for future cardiovascular events.
While the rate ratios that we estimated for rofecoxib were smaller than those determined in several trials (10, 11), the increase in cardiovascular event rate with rofecoxib in this study was somewhat higher than that observed in the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial (10). In our study, rofecoxib was associated with an excess event rate of 2.70 per 100 patient-years compared with nonusers, while in the APPROVe trial there were 0.72 excess events per 100 patient-years (95% CI 0.19–1.25). One potential explanation for the smaller rate ratios we observed may be the greater cardiovascular risk of our study population, with a mean age of nearly 80 years; 7% had had an MI and 6% a stroke in the 6 months prior to starting the study medication. This is very different from findings in the APPROVe or Vioxx Gastrointestinal Outcomes Research (VIGOR) study trial populations (10, 11). Others have noted that relative risks in high-risk groups often are lower than in low-risk groups (12, 13). Most often this can be explained by the accumulation of competing risks, diminishing the relative effect of any one factor.
In addition, we observed that the risk associated with rofecoxib began early after initiation of treatment, unlike what has been suggested based on data from the APPROVe trial (10). A crucial advantage of our study is the superior power for detecting small differences. We observed 499 events in the first 60 days of rofecoxib use, whereas in the APPROVe trial there were only 46 events observed in the full 3 years, and perhaps 20 in the first 18 months. Furthermore, rofecoxib 50 mg daily was associated with increased cardiovascular risk compared with naproxen 500 mg twice daily in the 12 months of the VIGOR trial (11).
It is important to place our findings in the context of earlier studies. In 2 randomized controlled trials, valdecoxib was found to be associated with a 2–4-fold increased risk of cardiovascular events compared with placebo, immediately after coronary artery bypass graft surgery (14, 15). In relatively short-term trials among patients with arthritis, valdecoxib was not associated with an increased risk of MI or stroke compared with placebo or with nonselective NSAIDs (16). Rofecoxib at 25 mg and 50 mg daily for 1–3 years was found to be associated with a 2-fold increased risk of thrombotic cardiovascular events compared with placebo or naproxen (10, 11). Several, but not all, observational studies have shown a similar increase in risk associated with rofecoxib (17–20). In one study, celecoxib at 200 mg and 400 mg twice daily was associated with a 2.5–3.5-fold increased risk of cardiovascular events compared with placebo (21), whereas most observational studies have shown no increased cardiovascular risk with low- or high-dose celecoxib (17–20).
There are no long-term randomized controlled trials comparing NSAIDs with placebo with regard to cardiovascular outcomes. However, results of several nonexperimental studies have suggested a reduced cardiovascular risk associated with naproxen compared with other agents (22–24). Ibuprofen may block the cardioprotective benefits of aspirin (25), and several (but not all) observational studies have suggested that ibuprofen may be associated with increased cardiovascular risk in patients taking aspirin (26–29). There are even fewer data regarding other specific NSAIDs and cardiovascular risk.
The lack of cardiovascular risk associated with valdecoxib or celecoxib in this study is notable. In contrast to the Adenoma Prevention with Celecoxib (APC) trial (21), in which an increased risk of cardiovascular events was observed among subjects taking twice-daily doses of celecoxib 200 mg or 400 mg, very few patients in our study (70 of 26,366 users of celecoxib) took ≥400 mg daily. In addition, our study population was primarily female (84%), whereas two-thirds of the members of the APC trial cohort were men. The 2 randomized trials that showed a cardiovascular risk associated with short-term valdecoxib use were conducted in patients who had just undergone coronary artery bypass grafting (14, 15), a period when the endothelium is highly thrombophilic (30). In the present study, few new users of valdecoxib had undergone coronary or carotid revascularization in the 6 months prior to starting treatment (37 of 3,060 users of valdecoxib), making our study population unlike that of either the Coronary Artery Bypass Grafting study I (CABG I) or the CABG II (14, 15).
Much of the current debate about coxibs and NSAIDs focuses on their use among specific patient groups, raising the question of whether there are subgroups of patients in which their use is especially dangerous or safe. Our results do not support the contention that the rate ratio of any of these agents differs by baseline cardiovascular risk. However, these analyses were exploratory, and more work is needed to determine whether there are differences in risk among certain patient groups.
It is important to note the limitations of our study methods. Observational drug studies are plagued by the potential for channeling of certain types of patients to use specific drugs. These patient characteristics may themselves influence cardiovascular risk, and thus could cause confounding bias if not controlled for in the analyses. Our analyses did control for many important factors such as age, sex, race, prior cardiovascular events, angina, congestive heart failure, hypertension, and use of relevant medications. However, large health care utilization databases do not contain information on other potential confounders, including smoking, aspirin use, body mass index, and socioeconomic status. These unmeasured factors could introduce bias into our analyses. We examined the potential bias (Table 5) and found that the comparisons between coxib users and nonusers may have caused minimal bias against coxibs, while the comparisons between coxib users and ibuprofen users may have produced bias against ibuprofen.
Another potential limitation is the lack of information on out-of-hospital sudden cardiac death, which was not included in our study end point. Only if this were to occur differentially across exposure groups would it lead to bias. Many NSAIDs are available over the counter, and thus there may be some misclassification of exposure. This is less problematic among low-income elderly persons with a complete drug benefit, for whom most NSAIDs are likely obtained through prescriptions with very small copayments. Some may consider the old age of our population (mean 79 years) as a limitation. Since older adults are the target population for coxibs, however, they are a very relevant study population.
Strengths of this study include the new use design (31), the definition of exposure in a time-varying manner, the large size and relative heterogeneity of the study sample, and the examination of how confounders may have biased our results. It is also important to note that the numbers of events we observed among the coxib users (n = 2,366) is 8 times larger than what has been observed in all long-term coxib clinical trials combined (n = 295) (32).
In this observational study, we have confirmed the findings of prior studies that showed an increased rate of cardiovascular events associated with rofecoxib and a decreased rate associated with naproxen. Celecoxib, valdecoxib, diclofenac, and ibuprofen were not associated with an increased rate of cardiovascular events in these analyses. The Kaplan-Meier curves, as well as the multivariable models, suggest that rofecoxib users have an increased rate of cardiovascular events soon after starting treatment. The elevated rate of events with rofecoxib appears to persist and is observed in both low and high cardiovascular risk groups. Our data do not focus on the potential cause of this increased cardiovascular risk, but the early divergence in the risk curves suggests that abrupt elevations in blood pressure, thrombosis, and/or vasoconstriction all might contribute. These analyses support the contention that most of these agents are not associated with a significant increase in cardiovascular risk in typical clinical settings.