Research Article

Use of Non-Steroidal Anti-Inflammatory Drugs That Elevate Cardiovascular Risk: An Examination of Sales and Essential Medicines Lists in Low-, Middle-, and High-Income Countries

  • Patricia McGettigan,

    Affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom

  • David Henry mail

    Affiliations: Institute for Clinical Evaluative Sciences, Toronto, Canada, Department of Medicine, University of Toronto, Toronto, Canada, School of Medicine and Public Health, The University of Newcastle, Newcastle, Australia

  • Published: February 12, 2013
  • DOI: 10.1371/journal.pmed.1001388
  • Featured in PLOS Collections

Reader Comments (3)

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Interesting - but needs fleshing out.

Posted by docwheeler on 21 Feb 2013 at 16:39 GMT

Potentially practise changing research - but there is a lack of detail in the findings as presented that hamper clinicians ability to make decisions based on this evidence.

1) It seems astonishing that a paper advocating a widespread change from certain NSAIDS to others makes no mention of GI side effects - with potentially life threatening complication no less serious than cardiovascular events. if (as reported elsewhere) naproxen has a relative risk for GI side effects of 1.83 compared to brufen at 1.19, and diclofenac at 1.73 then some consideration needs to be made as to the relative benefits and harms of widespread change in prescribing practice rather than looking at CVD risks in isolation.

2) Looking at the summary table of evidence it seems that observational studies of what the authors describe in the paper as 'low dose' ibuprofen usage shows a smaller risk of CV problems than with other drugs.

The two RCT papers however - using what is described as 'high dose' ibuprofen show a marked increase in RR (2.26 or 1.51) making it as dangerous - or more so than diclofenac in this respect.

it would have been helpful if the authors had clarified what doses were actually being used in the different studies - and expressing an opinion regarding the relative safety of ibuprofen given that it is one of the most commonly prescribed NSAIDS by GPs in the UK at least - often at a dose of 400mg tds.

No competing interests declared.

RE: Interesting - but needs fleshing out.

PMcGettigan replied to docwheeler on 22 Feb 2013 at 17:43 GMT

Thank you for the comments. In our previous work we addressed the issues raised here and we did not repeat the information. The focus in this paper was the public health issue arising from such widespread use of NSAIDs associated with increased cardiovascular (CVS) risk.
1. Meta-analyses of NSAID-associated serious upper gastrointestinal (GI) events suggest there is no great difference in risk between naproxen & diclofenac (also evident in the RR point estimates quoted here by the writer). Low dose ibuprofen (</=1200mg) is one of the ‘safest’ NSAIDs from the GI risk perspective. There is one big difference between GI risk with NSAIDs and cardiovascular risk - the GI risk can be mitigated greatly using protective agents like proton pump inhibitors. There is no equivalent means yet known to mitigate the CVS risk.
2. The writer is correct. From the CVS perspective, in pairwise comparisons that we undertook in our 2011 meta-analysis (PLOS Medicine, September 2011), diclofenac is associated with a higher risk of events than ibuprofen. We examined dose-risk relationships with individual NSAIDs. Low dose ibuprofen (</= 1200mg/day) was not associated with increased risk; it had a RR for CVS events of 1.05 (95% CI 0.96, 1.15). In higher doses (generally >1200mg/day), the risk was elevated, RR 1.78 (1.35, 2.34). With diclofenac, we found no risk-neutral lower dose. The RCT meta-analyses found CVS risk associated with ibuprofen. The RCTs generally used ibuprofen doses in excess of 1200mg/day (usually 2400mg/day), so the finding here of risk is consistent with the dose-risk relationship evident in our meta-analysis of the observational studies.
Taken as a whole, this suggests that low-dose ibuprofen (</=1200mg/day) is, like naproxen, a reasonable option. We emphasised naproxen because, unlike ibuprofen, at both low doses (</=750mg/day in most of the studies) and high doses, there was no associated increase in CVS risk. In addition, in the pairwise comparisons, naproxen was associated with a lower CVS risk than ibuprofen.

No competing interests declared.