NSAIDs post-MI???

A retrospective Danish study evaluated patients post-MI to see if taking NSAIDs influenced subsequent mortality, using their nationwide administrative registries. In Denmark, NSAIDs require prescriptions, except for the lowest dose ibuprofen. (see MI nsaid use inc events jama 2015 in dropbox, or JAMA. 2015;313(8):805-814)​. Guidelines in Denmark advise that all patients with MI have dual antithrombotic therapy (aspirin and clopidogrel) for up to 12 months, then single agent thereafter, and discourage the use of NSAIDs. details:

--61,971 patients (mean age 67.7, 63% men) were analyzed during a median followup of 3.5 years. 2% were not on antithrombotics, 19.7% on only one agent, 64.9% on aspirin plus clopidogrel, and 5% either on oral anticoagulant (OAC) alone or with one other agent, and 8.5% on triple therapy (aspirin, clopidogrel, and OAC). also 78.1% on b-blockers, 49.8% ACE-I/ARB, 75.1% statins, 24.3% PPIs

--34% filled at least 1 NSAID prescription: 23.1% ibuprofen, 9.9% diclofenac, 1.7% naproxen, 2% coxibs

--total number of deaths in the followup period was 18,105 (29.2%).  a total of 5288 (799 fatal) bleeding events occurred (8.5%) as well as 18,568 cardiovascular events (30.0%)

--crude incidence rates were (as events per 100 person-years):

        ​--bleeding: 4.2 for those taking NSAIDs and 2.2 if not. risk even higher when NSAIDs were added to double or triple antihrombotic regimens

        --cardiovascular events: 11.2 for those taking NSAIDs and 8.3 if not​.

--multivariate analysis: adjusting for age; gender; comorbidities of peripheral or cerebral vascular disease, renal failure, COPD, previous bleeding; or concommitant med therapy (b-blockers, statins, ACE-I/ARB, glucose lowering drugs, diuretics, PPIs)

        --increased bleeding with NSAIDs, HR=2.02 (1.81-2.26) --, ie twice the risk

        ​--increased cardiovascular risk, HR=1.40 (1.30-1.49)  -- ie, 40% increase

        --these increases were evident with NSAID use, independent of antithrombotic treatment, types of NSAIDs or duration of use
        --for overall bleeding risk, highest for celecoxib (crude rate 9.1/100 person-yrs), then diclofenac (6.1), rofecoxib (4.6). Naproxen (3.3) and ibuprofen (3.1) were better than average. and no NSAI was 2.2

        --for overall cardiovascular risk, highest for celecoxib (crude rate 25.9/100 person-yrs), then diclofenac (12.0), ibuprofen (10.0), and naproxen (7.4). and no NSAID was 8.3.

a few comments:

--part of the issue may be that taking NSAIDs may decrease the antiplatelet efficacy of aspirin.  for example, a study found that taking aspirin prior to NSAIDs did not block the cyclooxygenase-1 activity of aspirin (as measured by serum thromboxane B levels), BUT taking a single dose of ibuprofen 2 hours before aspirin did block the inhibition of thromboxane B and inhibition of platelet aggregation by aspirin. this was not found with acetaminophen or diclofenac (see aspirin and NSAIDs NEJM 2001 in dropbox, or N Engl J Med. 2001;345:1809)

--Several studies have looked at the different NSAIDs and cardiovascular outcomes, generally finding that naproxen is the safest. a recent network meta-analysis (see nsaid cardiovascular safety bmj 2011 in dropbox, or BMJ. 2011;342:c7086) of 31 trials and >115,000 patient-years of followup found that ibuprofen had the highest risk of stroke, followed by diclofenac (which has somewhat better GI tolerability and is used a lot in Europe, has mixed anti-COX1 and anti-COX-2 effects, though it has stronger anti-COX-2 than most other nonselective NSAIDs, similar to celecoxib). Diclofenac is also associated with high risk of cardiovascular death. and, their conclusion: "Naproxen seemed least harmful".

so, this study adds to several other observational studies finding adverse cardiovascular effects by the use of NSAIDs (with the possible exception of naproxen). but, as well as the known GI adverse effects, NSAIDs in general are associated with increases in blood pressure, heart failure, atrial fibrillation (in a couple of studies), stroke, MI, and cardiovascular death (these outcomes are noted both in patients with and without known cardiovascular disease). i personally think NSAIDs are way overused, especially in the elderly, and should be used sparingly, at the lowest dose and shortest duration possible, and that we should consider using acetaminophen, topical preparations or local injections when possible to treat pain. and, if NSAIDs are necessary, i think the data are pretty consistently better for naproxen.