Clinician Article

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

  • Bhala N
  • Emberson J
  • Merhi A
  • Abramson S
  • Arber N
  • Baron JA, et al.
Lancet. 2013 Aug 31;382(9894):769-79. doi: 10.1016/S0140-6736(13)60900-9. Epub 2013 May 30. (Review)
PMID: 23726390
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  • Public Health
    Relevance - 7/7
    Newsworthiness - 6/7
  • Special Interest - Pain -- Physician
    Relevance - 7/7
    Newsworthiness - 6/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 7/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 7/7
    Newsworthiness - 5/7
  • Gastroenterology
    Relevance - 6/7
    Newsworthiness - 6/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 6/7
  • Cardiology
    Relevance - 6/7
    Newsworthiness - 4/7


BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials.

METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed).

FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001).

INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making.

FUNDING: UK Medical Research Council and British Heart Foundation.

Clinical Comments


We've heard this before, but it doesn't hurt to hear it again.

Family Medicine (FM)/General Practice (GP)

Extensive meta-analysis of hundreds of RCTs. Coxibs, diclofenac, and probably ibuprofen, increase vascular risks, and naproxen does not. There are limitations, of course, but useful information.


Thorough and rigorous review of a complicated literature with high clinical relevance. Should definitely be reviewed.

General Internal Medicine-Primary Care(US)

Good review of existing data suggesting that most non-selective NSAIDs (except naproxen) confer similar risk to COX-2 inhibitors. Don't think this is all that new, but better than average quality data. Interesting that RR for UGI complications is increased for COX 2 although not as much as other NSAIDs.

Internal Medicine

What most practitioners do not know is the absence of vascular diseases with naproxen. Everything else must be well known to all. If this "fact" about naproxen is so, it would be a great boon to pain sufferers and the manufacturers of the drug. Of course we must not, in our excitement, forget the adverse renal effects of all NSAIDS, including the interference with treatment of hypertension.

Public Health

An important and useful article quantifying the cardiovascular and gastrointestinal side effects of the NSAIDs, allowing the practitioner to select the appropriate drug for patients at increased risk for cardiovascular or gastrointestinal complications.

Special Interest - Pain -- Physician

Great reminder even if a doc has some prior knowledge of this.

Special Interest - Pain -- Physician

Timely and important meta-analysis of NSAID side effects.

Special Interest - Pain -- Physician

This meta-analysis examined the vascular and upper gastrointestinal effects of NSAIDs. The manuscript is well written and confirms previous studies. The study suggests that high-dose naproxen may not have the same vascular hazard. Furthermore, the study reinforced that the risk varies depending upon certain patient factors.

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