Coxibs and cardiovascular harm in arthritis
Clinical bottom line
Meta-analyses of randomised trials, and large randomised trials, show no convincing evidence for increased heart attacks, strokes, or cardiovascular death in patients treated with coxibs for arthritis. NNH estimates for an APTC endpoint were much larger (better) than those seen in cancer prevention trials with coxibs or aspirin.
References
MR Weir et al. Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program. American heart Journal 2003 146: 591-604.
WB White et al. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. American Journal of cardiology 2003 92: 411-418.
WB White et al. Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. American Journal of Therapeutics 2004 11: 244-250.
S Curtis et al. Cardiovascular safety summary associated with the etoricoxib development programme. Arthritis & Rheumatism 2003 48 Suppl, S616.
ME Farkouh et al. Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004 364: 675-684.
Background
Whether coxibs cause cardiovascular adverse events (myocardial infarction, stroke, unstable angina, sudden cardiac death) as opposed to congestive heart failure (a known effect of NSAIDs and coxibs) is a hot topic. Most RCTs and high-quality observational studies find no increase in individual studies.
But some studies do find an increase, albeit with small numbers of events. Plausible mechanisms have been proposed for Cox-2 inhibitors to cause thrombosis [1] and animal experiments can demonstrate increases firm platelet adhesion in arterioles, with faster occlusion of microvessels [2], as least in hamsters.
So this is an appropriate time to examine the evidence. There are a number of issues that make this a very complicated area, even for randomised trials with tens of thousands of patients enrolled:
- The number of events is small even though the number of patients in all the trials is large. As the number of events becomes smaller, the possibility of random chance effects becomes higher.
- Cardiovascular events are rarely a prime outcome, so even RCTs actually become high-quality observational studies.
- The duration of trials varied from two weeks to three years. Event rates in the trials will vary because of this, though the number of events expressed in terms of person years may be similar.
- In arthritis, placebo-controlled trials may be limited to 6-12 weeks and the longest trial will be 12 months. In other conditions like Alzheimer's disease or cancer trials are as long as three years.
- The duration of exposure may vary between treatments used in the trials. Patients tended to take coxibs for longer than they took NSAIDs. The consequence is greater exposure to coxibs than NSAIDs, even with the same number of patients in each group of an RCT. Analysis using crude events may be different from that using events per 100 patient years.
- Trials use different patients. Most of the trials are in OA, RA or back pain. Because inhibition of cyclooxygenase-2 enzyme has been thought of as being helpful in other areas based on observational studies, coxibs have also been used in patients with Alzheimer's, and following colorectal cancer surgery to prevent recurrence.
- Trials use different comparators. Some comparisons are with placebo. Others are with NSAIDs, but some NSAIDs, like naproxen, are theoretically capable of themselves reducing cardiovascular events (much like aspirin). Comparisons with naproxen and non-naproxen NSAIDs have led to much sub-group analysis.
Studies
The evidence we have comes from four analyses of clinical trial data of coxibs, and from one large randomised trial. Briefly, the details are:
- Rofecoxib: Analysis of all arthritis trials and Alzheimer's trials, using APTC endpoint (cardiovascular, haemorrhagic, and unknown death, and nonfatal myocardial infarction and stroke). Comparison with placebo, naproxen and non-naproxen NSAID. Doses of rofecoxib were 12.5 to 50 mg daily.
- Celecoxib: APTC endpoint from all completed trials of four weeks or longer in arthritis. Comparison with placebo, naproxen and non-naproxen NSAID. Doses of celecoxib were 200 to 800 mg daily.
- Valdecoxib: APTC endpoint from completed trials of 6-52 weeks or longer in arthritis. Comparison with placebo, naproxen and non-naproxen NSAID. Doses of valdecoxib were 10-80 mg daily.
- Etoricoxib: Thrombotic cardiovascular serious adverse experiences endpoint from all completed trials of four weeks or longer in arthritis. Comparison with placebo, naproxen and non-naproxen NSAID. Doses of etoricoxib were 60 mg daily or greater.
- Lumiracoxib: APTC endpoint from randomised trial in osteoarthritis up to one year. Comparison with naproxen and ibuprofen. Dose of lumiracoxib was 400 mg daily.
Results
None of the five reviews found any overall difference between coxib or NSAID for thrombotic events, or between coxib and placebo. All the reviews used analyses based on patient-years of exposure. Some of the analyses looked at different NSAIDs, especially naproxen or other non-naproxen NSAIDs, and some looked at patients taking or not taking aspirin. There was no significant difference for any of these, and the number of APTC events per 100 patient years for coxib compared with placebo and NSAID are shown in Table 1.
Table 1: APTC events with coxib, placebo, and NSAID
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| Rofecoxib |
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| Celecoxib |
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| Valdecoxib |
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| Etoricoxib |
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| Lumiracoxib |
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These analyses all take into account the propensity in some studies for patients taking coxibs to discontinue less often than those taking NSAIDs. This means that those on coxibs have more time on the drug, and can therefore accumulate more, possibly unrelated, adverse events. So all the meta-analyses have been corrected for duration.
If we take the worse case, and just take the crude results form the meta-analyses and trial, we can sum the overall risk for all coxibs, and all doses, in arthritis trials (plus some in Alzheimer's disease). These are shown in Table 2. For the comparison with placebo there were about 30,000 patients, in mainly short-term studies, with no significant difference. For the comparison with NSAIDs with over 80,000 patients, in shorter and longer term studies, there was a bare statistical significance, with an NNH of over 1,000 at the point estimate, but with a confidence interval that includes no effect.
Table 2: Overall results for all coxibs versus all NSAIDs, and all placebo
(95% CI) |
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| All coxibs vs placebo (four coxibs) | ||||
| All coxibs versus NSAIDs (five coxibs) | ||||
Comment
Some will see these data as there being no smoke without fire, while others will wonder whether this is all smoke and mirrors emanating from different agendas. The overall picture from cardiovascular events observed in randomised trials is relatively benign, with no difference between coxibs and placebo, and at worst a small difference between coxibs and NSAIDs and point estimate for NNH for an APTC event of about 1000. This contrasts with studies in colorectal polyp prevention studies, where the NNH for one APTC event over three years was 70. It is difficult to reconcile this order of magnitude difference.
Points of view, and questions, abound:
- Is there a duration effect, with more problems after longer times? If there was, it didn't show in a trial comparing rofecoxib with placebo over three years in elderly patients with Alzheimer's disease and high cardiovascular risk, but perhaps this cannot entirely be ruled out.
- Is there greater risk in people with arthritis who usually take these drugs? Not from these data. One cautionary note comes from use of coxibs in a surgical setting [3,4], where more serious adverse events, including heart attacks and strokes, occurred in patients treated with per- and post-operative coxibs. Another is that aspirin appears to cause heart attacks and strokes in people in a cancer prevention trial. We may not know all about cyclo-oxygenase inhibitors that we should.
- Are important data being hidden from us? This is unlikely, given the involvement of so many people, including regulatory authorities. And observational studies generally support that (more of which in a future issue).
If pain were well treated, this would be less of a problem. But pain is badly treated, it affects a huge proportion of elderly people. What we really need is more research in how better to deliver the effective analgesics we have, in the most effective and the safest way. Pragmatic rather than explanatory trials. The problem isn't what intervention is best, but rather how best to use the interventions available to best effect. Agonising about safety of coxibs might be seen as a distraction from that goal.
References:
- GA Fitzgerald. Cox-2 and beyond: approaches to prostaglandin inhibition in human disease. Nature Reviews: Drug Discover 2003 2: 879-890.
- MA Buerkle et al. Selective inhibition of cyclooxygenase-2 enhances platelet adhesion in hamster arterioles in vivo. Circulation 2004 110: 2053-2059.
- E Ott et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. Journal of Thoracic and cardiovascular Surgery 2003 125: 1481-1492.
- N Nussmeier et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. NEJM 2005 352:1081-1091.