In this study we found that the outcome of a large cohort of cardiovascular high risk patients with osteoarthritis receiving non‐selective NSAIDs or selective COX‐2 inhibitors largely depends on the specific analgesic agent, as well as the presence or absence of low‐dose aspirin treatment. We found that high risk patients not taking aspirin did have a higher cardiovascular event rate with lumiracoxib than with naproxen, but not ibuprofen. In contrast, high risk patients treated with ibuprofen who were taking low‐dose aspirin had a higher incidence of cardiovascular events than patients treated with lumiracoxib, a finding consistent with the hypothesis that ibuprofen interferes with the antiplatelet effects of aspirin. In addition, an increased risk of congestive heart failure events for high risk patients was observed for patients treated with ibuprofen compared with lumiracoxib. These findings, though limited by the post hoc design of the study, and the small number of events in the subgroups of interest suggest that caution is warranted in prescribing ibuprofen to high risk patients.
Evidence from randomised clinical trials to determine the safety of prescribing non‐selective NSAIDs and COX‐2 inhibitors in high risk cardiovascular patients is extremely limited. Two randomised trials of parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery raised concern owing to an excess number of cardiovascular adverse events.14,15
In the second parecoxib/valdecoxib trial, patients randomised to intravenous parecoxib/oral valdecoxib had a higher incidence of cardiovascular events than patients given placebo (2.0% vs 0.5%, p
It should be noted that all patients in these studies received low‐dose aspirin treatment, and, therefore, any observed increase in cardiovascular events can not be attributed to unopposed, “selective” COX‐2 inhibition. These are the only studies aside from ours in which aspirin use was encouraged in a high risk population. Aside from short term clinical studies of the effect of COX‐2 inhibitors on endothelial function,28,29
no other clinical trials of “hard” cardiovascular outcomes have been conducted in the high cardiovascular risk population for commonly prescribed non‐selective NSAIDs or COX‐2 inhibitors.
Limitations of previously published COX‐2 inhibitor clinical trials have been the exclusion of aspirin users and patients at high cardiovascular risk, the short term study duration and the non‐blinded adjudication of cardiovascular end points. The absence of prospective, long term cardiovascular safety data on ibuprofen and naproxen has led to a reliance on retrospective observational studies, frequently from administrative data subject to confounding by both measured and unmeasured variables. In contrast, TARGET included a prespecified recruitment of aspirin users explicitly to employ patients at high cardiovascular risk, which allowed conclusions to be drawn on cardiovascular safety and toxicity relative to aspirin use. Moreover, TARGET was a 12 month study with prespecified cardiovascular end points and independent adjudication.
Three important cardiovascular findings regarding ibuprofen and naproxen should be highlighted from this subanalysis. First, our data suggest that ibuprofen treatment among low‐dose aspirin users is associated with an increased incidence of composite cardiovascular events in patients at high cardiovascular risk in comparison with lumiracoxib. This finding has significant public health implications. Our findings are consistent with previous evidence that ibuprofen can interfere with aspirin acetylation of the COX‐1 binding site on platelets, thereby blocking aspirin‐mediated inhibition of platelet aggregation.13
Further evidence of this interaction was observed by MacDonald and Wei in a retrospective study demonstrating an increase in all‐cause and cardiovascular mortality among patients taking aspirin plus ibuprofen as compared with those taking aspirin alone.11
Similarly, Kurth et al
conducted a subanalysis of the Physicians Health Study and concluded that regular use of non‐selective NSAIDs in combination with low‐dose aspirin is associated with an increased risk of MI relative to low‐dose aspirin users not taking non‐selective NSAIDs.30
However, other studies examining the aspirin interaction with non‐selective NSAIDs found no significant difference in aspirin efficacy in the presence of non‐selective NSAID co‐therapy.6,15
The second principal finding was the relative cardiovascular safety of naproxen 500 mg twice daily relative to supratherapeutic lumiracoxib doses of 400 mg once daily among non‐aspirin users in patients with increased cardiovascular risk. In the overall TARGET population, the risk of the composite cardiovascular end point for lumiracoxib versus naproxen among non‐aspirin users was similar (HR
0.67, 95% CI 0.34 to 1.31, p
Our high risk analysis, however, observed a significant difference in composite cardiovascular events (p
0.02) for naproxen compared with lumiracoxib among patients not receiving low‐dose aspirin. In contrast, no significant difference in the rate of composite cardiovascular events was noted in the subanalysis of ibuprofen versus lumiracoxib among non‐aspirin users. In high risk patients not receiving aspirin, naproxen 500 mg twice daily appears to be associated with the lowest cardiovascular risk. This finding is consistent with the ability of naproxen to inhibit platelet aggregation in a similar way to aspirin. However, unlike aspirin, persistent blood levels of naproxen are needed to maintain inhibition of platelet aggregation.18,31
Whether or not naproxen is truly cardioprotective has been of great interest since the VIGOR trial demonstrated higher rates of cardiovascular events for rofecoxib 50 mg daily versus naproxen 500 mg twice daily.2
Recently, Juni et al
conducted a meta‐analysis of 11 observational studies of naproxen compared with control and concluded that naproxen was associated with a small, but statistically significant reduction in risk of MI (combined estimate 0.86, 95% CI 0.75 to 0.99).7
However, many of these studies individually failed to demonstrate a cardioprotective effect for naproxen, and one of the studies reported an increased risk of MI among current naproxen users relative to past users of NSAIDs. Subsequent to this meta‐analysis, Graham et al
published a nested case–control study of patients in the Kaiser Permanente health system and found that naproxen was associated with an increased risk of MI or sudden cardiac death relative to past NSAID users.32
Explanations for the conflicting evidence for naproxen may be related to the naproxen dosage prescribed and whether or not aspirin was co‐administered. Among healthy volunteers, it has been demonstrated that naproxen 500 mg twice daily suppresses thromboxane B2
production, a marker of platelet COX‐1 activity, to a similar level as low‐dose aspirin 100 mg daily.18
However, lower doses of naproxen are frequently prescribed for analgesic treatment that may not provide comparable inhibition of platelet aggregation. In addition, the administration of naproxen to aspirin users has recently been shown to interfere with the effects of aspirin on platelet COX‐1 activity in healthy volunteers.33
Thus, the conflicting nature of the evidence on the effects of naproxen may be due to inadequate platelet inhibition with low‐dose naproxen and/or competition with aspirin for the platelet binding site. Alternatively, depending on the study duration, naproxen may increase cardiovascular risk owing to a sustained rise in blood pressure. Based on our findings, in high risk patients not receiving aspirin, high‐dose naproxen appears to have the lowest cardiovascular risk among the three agents studied in TARGET, although the confidence intervals around these estimates are wide.
The third principal finding from this study was that patients at high cardiovascular risk given ibuprofen (but not naproxen) had a significantly higher incidence of congestive heart failure events than patients administered lumiracoxib. This was primarily owing to events that occurred in patients at high cardiovascular risk receiving aspirin. One possible explanation for this finding may be differences in fluid retention and blood pressure effects among the three agents. In TARGET, Farkouh et al
previously reported that lumiracoxib induced a smaller effect on blood pressure than either ibuprofen or naproxen, although the absolute differences were more pronounced between lumiracoxib and ibuprofen than between lumiracoxib and naproxen.20
However, the mechanism underlying these differences in observed haemodynamic effects remains speculative and requires further study.
As a post hoc subgroup analysis, this study is subject to inherent limitations, and therefore should be interpreted as a hypothesis‐generating study. The risk of bias may be minimal; however, the risk of a type I error due to multiple comparisons is certainly increased. Moreover, the incidence of cardiovascular events was low in both the low and high risk subgroups, thereby affecting the power of the analyses. Although low‐dose aspirin use was recorded at study entry, further information about aspirin use was not collected, and the reason for not using aspirin in high risk patients was not specified. Also, the 1 year duration of the trial may not reflect the longer term risks of non‐selective NSAIDs and selective COX‐2 inhibitors in stable high risk patients. However, clinical trials of NSAIDs and COX‐2 inhibitors typically last for 6–12 weeks, rendering even pooled analyses difficult to interpret owing to low event rates. In contrast, the TARGET trial, along with the VIGOR trial2
and the Celecoxib Long‐term Arthritis Safety Study (CLASS)34
trials, represent the longest duration of arthritis clinical trials to date.