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Non-steroidal anti-inflammatory drugs killThe below papers are free full-texts.

http://pagingdrgupta.blogs.cnn.com/2011/01/11/risks-of-nsaids-backed-in-new-study/

British Journal of Medicine Wayne Ray

[Journal description:]

ResearchCardiovascular safety of NSAIDs

The authors of this network meta-analysis found little evidence that any of the seven investigated non-steroidal anti-inflammatory drugs (NSAIDs) are safe in cardiovascular terms. Naproxen seemed least harmful, but cardiovascular risk needs to be taken into account when prescribing any NSAID, the authors say. In an accompanying editorial, pharmacoepidemiologist Wayne A Ray says that the cardiovascular risks of these drugs should prompt evaluation of a broader range of alternatives.

Relevant Articles:Editorial: Cardiovascular safety of NSAIDs Wayne A RayBMJ 342:doi:10.1136/bmj.c6618 (Published 11 January 2011)http://www.bmj.com/content/342/bmj.c6618.full[Full text of this article]

Millions of patients with chronic musculoskeletal symptoms are long term users of non-steroidal anti-inflammatory drugs (NSAIDs). Unfortunately, these drugs have common and potentially severe adverse effects, including renal impairment, gastrointestinal complications, and as has been shown for selective cyclo-oxygenase-2 inhibitors, cardiotoxicity. The last effect is particularly worrying because many patients have both cardiovascular disease and musculoskeletal disease. Given that both mechanistic and clinical data suggest that individual NSAIDS may have different cardiovascular risk profiles, a natural question is: which NSAID is safest for patients with high cardiovascular risk? In the linked study (doi:10.1136/bmj.c7086), Trelle and colleagues investigate this question by using network meta-analysis to assess the cardiovascular safety of individual NSAIDS.1

All cyclo-oxygenase-2 inhibitors studied in large placebo controlled trials have been found to confer an increased risk of serious cardiovascular disease.2 3 4 Furthermore, rofecoxib increases risk more than naproxen.5 This suggests that patients with a high risk of cardiovascular disease should avoid cyclo-oxygenase-2 inhibitors. Although some trials suggest that celecoxib is safer in lower doses,6 the possibility of dose escalation to improve pain control and the heterogeneity in patient response to a given dose all favour caution.

Several epidemiological investigations have studied the cardiovascular safety of NSAIDs.7 These have confirmed the cardiotoxicity of rofecoxib and suggest that diclofenac has a similar cardiovascular risk.7 Observational studies also indicate that naproxen has the best cardiovascular safety profile, consistent with the more limited data available from clinical trials.8 A large cohort study of the cardiovascular effects of NSAIDs in patients recently admitted to hospital for serious coronary heart disease found that the cardiovascular safety of naproxen was superior to that of ibuprofen, diclofenac, celecoxib, and rofecoxib.9

What does Trelle and colleagues’ study add to this knowledge?1 The authors performed a meta-analysis of randomised trials of NSAIDs with at least 100 person years of follow-up in the studied arms. They used a potentially powerful technique known as network meta-analysis,10 which, when certain assumptions are met, can extract more information from the available data than traditional methods. For example, the analysis was able to compare etoricoxib versus placebo despite there being no large placebo controlled trials. This is because etoricoxib has been compared with diclofenac, which in turn has been compared with both rofecoxib and celecoxib, which themselves have been compared with placebo. From this chain of direct comparisons, the effect of etoricoxib relative to placebo is estimated through an indirect comparison.

This example illustrates both the strengths and weaknesses of network meta-analysis. It uses all of the data, but certain assumptions about homogeneity are necessary for valid estimates of indirect comparisons. Although in theory these assumptions can be checked and uncertainty incorporated into the estimates, this may be difficult in practice with a limited number of comparisons. The usefulness of this technique is limited for NSAIDs because too few adequately powered clinical trials exist. For this reason, the estimates from the meta-analysis that primarily rely on indirect comparisons—such as those for the comparison of etoricoxib with placebo—should be interpreted with caution.

What does this all mean when prescribing NSAIDs for patients at high risk of cardiovascular disease? Current data suggest that selective cyclo-oxygenase-2 inhibitors, particularly in higher doses, should be avoided. With regard to traditional NSAIDs, the most extensive data are available for diclofenac, ibuprofen, and naproxen. Meta-analyses of clinical trials and observational studies have found greater cardiovascular risk for diclofenac,7 8 which suggests that it should be avoided in high risk patients. Ibuprofen may attenuate the antiplatelet effects of aspirin, an important consideration in patients with a high risk of cardiovascular disease.11 In contrast, currently available evidence indicates that naproxen has the best cardiovascular safety. Although the ongoing PRECISION (Prospective Randomised Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen) trial will eventually provide more information on the relative cardiovascular

safety of naproxen, celecoxib, and ibuprofen, until these results become available, naproxen seems to be the best choice with regard to cardiovascular safety. As with any traditional NSAID, it is important to consider coprescription of gastroprotective drugs.12

The controversy and confusion about the cardiovascular safety of drugs to relieve chronic musculoskeletal symptoms provides an important lesson. Drugs for symptomatic relief must be evaluated with regard to the target symptoms as well as less frequent yet serious adverse effects. NSAIDs are not an ideal treatment with respect to efficacy or safety. Perhaps it is time for a larger more systematic evaluation of a broader range of alternatives. In clinical practice, patients with musculoskeletal symptoms receive both paracetamol and low dose opioid analgesics, and new drugs such as tanezumab, are being evaluated. Clearly, each of these has limitations. However, in the absence of large scale comparative trials that consider safety as well as efficacy, we cannot determine which best serves patients.

1. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ2010;341:c7086.http://www.bmj.com/content/342/bmj.c7086.fullhttp://www.bmj.com/content/342/bmj.c7086.full.pdf

Abstract

Objective To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs.

Design Network meta-analysis.

Data sources Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data.

Study selection All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility.

Data extraction The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data.

Data synthesis 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death.

Conclusions Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug. -- Aalt Pater