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Clinician Article

Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data.



  • Bally M
  • Dendukuri N
  • Rich B
  • Nadeau L
  • Helin-Salmivaara A
  • Garbe E, et al.
BMJ. 2017 May 9;357:j1909. doi: 10.1136/bmj.j1909. (Review)
PMID: 28487435
Read abstract Read evidence summary Read full text
Disciplines
  • Public Health
    Relevance - 7/7
    Newsworthiness - 6/7
  • Internal Medicine
    Relevance - 7/7
    Newsworthiness - 5/7
  • Cardiology
    Relevance - 6/7
    Newsworthiness - 5/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 5/7

Abstract

Objective To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs).Design Systematic review followed by a one stage bayesian individual patient data meta-analysis.Data sources Studies from Canadian and European healthcare databases.Review methods Eligible studies were sourced from computerised drug prescription or medical databases, conducted in the general or an elderly population, documented acute myocardial infarction as specific outcome, studied selective cyclo-oxygenase-2 inhibitors (including rofecoxib) and traditional NSAIDs, compared risk of acute myocardial infarction in NSAID users with non-users, allowed for time dependent analyses, and minimised effects of confounding and misclassification bias. Exposure and outcomes Drug exposure was modelled as an indicator variable incorporating the specific NSAID, its recency, duration of use, and dose. The outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date (date of acute myocardial infarction for cases, matched date for controls) versus non-use in the preceding year and the posterior probability of acute myocardial infarction.Results A cohort of 446 763 individuals including 61 460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations.Conclusions All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.


Clinical Comments

Cardiology

1. Observational (vs recent randomized trial suggesting no increased risk). 2. Similar to previous findings. 3. Even if increased risk, may be small in absolute terms for the average patient.

Cardiology

Most physicians are aware of an increased risk for cardiovascular events with NSAIDs. This sophisticated meta-analyses had three findings that I found surprising: 1. the risk seems to have a class effect and the much debated differences between NSAIDs were not evident in this analysis; 2. the magnitude of the risk is high; 3. while there is a dose-response relationship with risk, even short-term NSAID use is associated with substantial risk.

Family Medicine (FM)/General Practice (GP)

More evidence to be cautious with NSAIDs.

General Internal Medicine-Primary Care(US)

I think most of us knew we were kidding ourselves thinking naproxen would be safer. This seems to imply that if a patient wants to take NSAIDs and makes it through the first month, the risk is less after that - like passing a stress test?

General Internal Medicine-Primary Care(US)

This study`s Bayesian meta-analysis methodology is extremely complex, and likely beyond the full understanding of most clinicians. The results demonstrate a consistent increased risk for MI in NSAID and Cox-2 inhibitors. No particular drug was better than the others. The risk was particularly high in the first month of use. The risk was dose-related and higher doses (celecoxib >200mg; diclofenac >100 mg; ibuprofen >1200 mg; naproxen >750 mg;) clearly increased the overall risk.

General Internal Medicine-Primary Care(US)

The article highlights the association between NSAIDs and the risk for myocardial infarction, even at low doses and for less than seven days. Many clinicians are aware of the risk, but this analysis helps quantify the risks in ways that were not done before. After reading this article, I would strongly consider advising patients at an elevated risk for a coronary event to consider another medication for pain relief besides NSAIDs.

Internal Medicine

I think of an acute gout scenario, where this studies' findings of increased myocardial infarction likelihood with all NSAIDS suggests other MI risk factors should temper a decision to prescribe adequate dose NSAID rather than steroid or colchicine. Applying Bayesian method to retrospective data rather than new data collection is probably appropriate. Statistical description and defense of individual patient data use in meta-analyses is elegant, with appraisal of its accuracy deferred to experts in that field. Comment on diminished statistical power from exclusion of redacted IPD by (presumed HIPAA) policy is thought provoking. The huge patient group and granular analysis confirms a class increase of acute myocardial infarction with initial and maintenance NSAID prescription, more important than small differences in likelihood for individual medications.

Internal Medicine

This is useful confirmation that this is, in essence, a class effect.

Public Health

It's important to note that what this adds to the use of NSAIDS and risk of AMI. Practitioners should be more aware of the risks associated with higher dose problems and length of time, as noted, short term use and high dose spell increased risk.

Public Health

Cohort study using prescription/clinical database evaluating the association of NSAIDs use including selective COX inhibitors. The use of NSAIDs, any type, was associated with increased AMI risk especially within the first 1 month of initiation as compared to non-users. Increased doses also associated with increased risk.

Public Health

This IPD-level analysis provides interesting information relevant to practice that recent NSAID use is associated with increased risk for AMI. Are we seeing two different signals? Is the underlying acute exacerbation of an inflammatory condition the reason for plaque rupture or erosion rather than NSAID use at lower doses? Is that why chronic use is not so strongly associated as recent use? Is the second wave and the association with higher dose more related to interference with the balance between the different products of the cyclooxygenase pathway? We know that inflammation is associated with plaque rupture and erosion. The outcome of the trial of MTX in chronic ischemic heart disease may add insight. For now, I would warn patients against high-dose NSAIDs and look carefully at the CAD risk factor optimization when patients have a reason to start NSAIDs. This also raises public health concerns as NSAIDs are available OTC.

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