| Posted: July 24 2006 at 12:30am
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| July, 2006 - CRA Journal Club Review by Dr. PAUL DAVIS | Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal
anti-inflammatory drugs increase the risk of atherothrombosis?
Meta-analysis of randomized trials.
Kearney P M, et al
BMJ 2006;332;1302-1308
PAUL DAVIS
M.D., FRCPC |
Editorial:
By Dr. Paul Davis
The enthusiasm that greeted the development of cyclo-oxygenase-2 inhibitors (COXIBs) and their superior gastrointestinal safety profile over traditional non-steroidal anti inflammatory drugs (NSAIDs) has been tempered by concerns over cardiovascular side effects associated with this new class of medication. The withdrawal of two widely prescribed COXIBs in light of this has led to significant confusion amongst physicians and their patients alike. The recently published meta-analysis by Kearney et al is therefore very timely.
The study was undertaken to assess the effects of COXIBs and NSAIDs and their possible cardiovascular risk profile. The method was a traditional meta-analysis although, of interest, it included not only published but also unpublished data made available to the authors from pharmaceutical companies involved in COXIB development and marketing. 138 RCTs involving over 145,000 patients were included. | The analysis concentrated on vascular complications including myocardial infarction and/or vascular death. This study did not address issues related to other potential toxicities associated with these drugs such as gastrointestinal and renal complications. The results are of value in that they provide some clarification in an area where there has been considerable confusion due to differences in interpretation of already published data.
In summary there was no significant heterogeneity amongst COXIBs with relationship to myocardial infarction and other vascular risks. Although the increased incidence of serious events was small in the treatment versus placebo groups it did achieve statistical significance. Vascular events, 1.42(1.13 to 1.78) p = 0.003, myocardial infarction, 1.86(1.33 to 2.59) p = 0.0003. Of potential concern and somewhat surprisingly the data also indicated that similar cardiovascular risks existed with other traditional NSAIDs although Naproxen appears to be superior to both COXIBs and other traditional NSAIDs in this regard with similar risks compared to patients enrolled in the placebo groups.
This paper is of significant importance to physicians with respect to the use of COXIBs and NSAIDs in patients at cardiovascular risk. Does this paper answer all the questions that exist concerning this potential problem? No, but it certainly helps.
It is now clear that physicians must be as equally alerted to potential cardiovascular risk factors in patients receiving these medications in exactly the same way that we have for years been alerted to the identification of potential gastrointestinal risk factors. Thus increasing vigilance is required when contemplating the use of both COXIBs and traditional NSAIDs in all patients and has implications in terms of patient information and informed consent prior to use of these drugs. The study however does not definitively answer the issue concerning a hierarchy amongst available COXIBs and traditional NSAIDs, notwithstanding the recent withdrawal of two COXIBs from the market.
With respect to cardiovascular toxicity, if any drug appears to be a “best buy” it would appear to be Naproxen. If such is true this does nothing but add fuel to the fire over the controversy that developed from inappropriate comparisons of the CLASS and VIGOR studies that resulted from the different comparator NSAIDs used.
The other issue which is not resolved by this analysis is an evaluation of the comparative risk of cardiovascular toxicity versus GI safety, and visa versa, when comparing traditional NSAIDs to COXIBs. Unfortunately therefore physicians are still left in a quandary as to whether the potential benefits of one selected anti inflammatory drug is out weighed by the potential toxicity of another. (gastrointestinal safety, versus cardiovascular risk). It is the opinion of this reviewer that we must have a heightened awareness of cardiovascular risk with all anti inflammatory drugs in the same way as we have been sensitized to gastrointestinal toxicity and it would be judicious to screen patients appropriately. This has significant implications for patient information and awareness of risk/benefit ratios when selecting a drug for management of musculoskeletal symptoms.
Learning Objectives:
- Selective cyclo-oxygenase 2 inhibitors (COXIBs) have been shown by meta-analysis to have increased cardiovascular risk when compared to placebo drugs.
- Similar risks may be seen with some traditional nonsteroidal anti inflammatory drugs (NSAIDs) although this risk does not appear to apply to Naproxen.
- Increasing vigilance is required when assessing patients for the use of these drugs with respect to cardiovascular risks in the same way that we currently assess gastrointestinal risk.
ABSTRACT
Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials.
- Kearney PM,
- Baigent C,
- Godwin J,
- Halls H,
- Emberson JR,
- Patrono C.
Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford OX3 7LF.
OBJECTIVE: To assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events.
DESIGN: Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs.
DATA SOURCES: Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck.
REVIEW METHODS: Eligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks' duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group.
RESULTS: In placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year's duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9%/year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac.
CONCLUSIONS: Selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.
PMID: 16740558 [PubMed - indexed for MEDLINE]
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Click HERE for the full version of the article (PDF)
Edited by elisia - July 24 2006 at 1:03am
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