Wednesday, May 9, 2012

Dabigatran and the Risk of MI - Another Way to Keep the ED Busy?

The Gist:  Dabigatran, while more convenient than standard warfarin therapy in non-valvular atrial fibrillation, may have more complications than originally touted, including an increased incidence of myocardial infarction (MI).  Exercise caution in patients with dabigatran (for multiple reasons).

I'm wary of dabigatran.  There's no good test to determine the degree of anticoagulation, although apparently the response is "predictable," and there's presently no available reversal agent for this drug.  Unfortunately, many patients take their medications in unpredictable fashion (or are predictably non-compliant, which we can sometimes deduce in warfarin patients upon seeing a sub-therapeutic INR).  Bleeding complications from this direct thrombin inhibitor are surfacing with unnerving frequency and severity... However, the plot thickens...

Earlier this year, the Archives of Internal Medicine published a  a meta-analysis of the dabigatran non-inferiority trials.  Out of seven trials with a pooled n=30514 individuals, dabigatran was associated with a greater risk of MI with an odds ratio (OR) of 1.33 (95% CI 1.03-1.71).  The paper assessed these rates when shorter studies were included or excluded in the analysis.
The original RE-LY trial demonstrated 34% reduction in incidence of stroke and PE in patients on dabigatran compared with warfarin.  Increased risk of MI in the cohort receiving dabigatran? A whopping 38% compared with warfarin.  The statistical significance of the increase MI incidence disappeared in the revised data (1).

What explanation underlies this increase in MI?  I'm not really sure, but here are some possibilities:
  • Concomitant aspirin use.  Not tracked by most of the studies (neither was CAD)
    • Protective benefit with MI
  • On dabigitran there's increased excretion of 11-dehydrothromboxane B2, a metabolite of thromboxane A2, possibly demonstrating increased platelet activation/aggregation (which would be offset by the aspirin inhibition of TXA2 in patients taking both medications) (2).  This would explain the point mentioned above.
  • Some protective effect conferred by warfarin
The convenience of dabigatran, proffered by the lack of dietary restriction and freedom from anticoagulation clinics, may entice patients but we should still exercise caution utilizing this drug.  Patients are excited to switch to this medication (excluding the financial burden) without necessarily understanding the uncertainty associated with trauma, bleeding, and ACS risk.  It's difficult for providers to undertake these risk versus benefit conversations without elucidation of the actual adverse effects of the drug.

Bottom Line:  You can bet I'm going to keep close tabs on patients I see on dabigatran.

1.  Uchino K, Hernandez AV. Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of Noninferiority Randomized Controlled Trials. Arch Intern Med. 2012 Jan 9.
2.  Ezekowitz MD, Reilly PA, Nehmiz G, et al.  Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study).Am J Cardiol. 2007 Nov 1;100(9):1419-26. Epub 2007 Aug 17.

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