Real-World MI Risk Lower With NOACs vs Warfarin in AFib

Patrice Wendling

June 29, 2018

Danish registry data show a lower risk for myocardial infarction (MI) in patients with atrial fibrillation (AF) initially treated with a non–vitamin K antagonist oral anticoagulant (NOAC) vs a vitamin K antagonist (VKA).

The standardized 1-year absolute risk for MI in the nationwide cohort was 1.56% with a VKA, 1.16% with apixaban (Eliquis, Bristol-Myers Squibb), 1.20% with dabigatran (Pradaxa, Boehringer Ingelheim), and 1.07% with rivaroxaban (Xarelto, Bayer). Risk differences were significant for all NOACs compared with VKA.

Further, the risk for MI was not significantly different between NOACs, Christina Ji-Young Lee, MD, Aalborg University, Denmark, and colleagues reported in a study, published online June 25 in the Journal of the American College of Cardiology.

"There have been other smaller studies investigating the risk of MI with the use of NOACs as well, however, our study is one of the largest including both the frail and the older [patient] and we also did a direct comparison of the NOACs and the risk of MI, which hasn't been done before," Lee told | Medscape Cardiology.

Although NOACs have been shown to be similar to VKA treatment in preventing stroke, the 2009 RE-LY trial prompted debate after finding an increased incidence of MI in patients with AF treated with dabigatran vs warfarin. The absolute difference was low, at just 0.2%/year, and reached statistical significance only at the 150-mg dose.

A subsequent RE-LY subanalysis and a US Food and Drug Administration review found no link between dabigatran and MI, but conflicting results from other analyses have kept the debate simmering.

Commenting on the Danish analysis to | Medscape Cardiology, RE-LY investigator Stuart Connolly, MD, McMaster University, Hamilton, Ontario, Canada, said, "There was an MI signal at one point, but increasingly this has not been reproduced in so-called real-world or cohort studies. So this is just one more reassuring bit of evidence that there is no overt risk of MI with dabigatran. Does it prove it? No. These studies have their own weaknesses," including many potential confounders.

Using national healthcare registries, investigators identified 31,339 patients (median age, 74 years; 47% female) with nonvalvular AF who were first-time users of oral anticoagulants and were treated with a VKA (28%), apixaban (27%), dabigatran (23%), and rivaroxaban (22%) between January 2013 and June 2016.

One year after start of treatment, the standardized risk for the combined endpoint of MI or all-cause mortality was highest with VKA therapy (12.2%), followed by rivaroxaban (12.0%), apixaban (10.9%), and dabigatran (9.3%).

Among the NOACs, dabigatran had a lower risk than apixaban (–1.59%) and rivaroxaban had a higher risk than apixaban (1.16%) and dabigatran (2.75%).

"We did find a lower risk with the use of apixaban and dabigatran compared to vitamin K for the composite endpoint and with no differences between rivaroxaban. However, our study is observational, and this might show that we're not afraid of using the NOACs in the older or frail," Lee said.

For the composite of MI or cardiovascular mortality, the standardized 1-year risk was highest for rivaroxaban (9.04%), followed by VKA (8.61%), apixaban (6.25%), and dabigatran (5.75%).

Rivaroxaban had a numerically higher risk for the outcome vs VKA (0.44%; P = .512) that rose to statistical significance vs apixaban (2.79%; P < .001) and dabigatran (3.29%; P < .001).

"We have less data of the cardiovascular risk because the data only went to 2015, so I would not conclude anything out of that," Lee cautioned.

"Our study did not show that rivaroxaban was the best, neither that it showed it was less. I think the important message here is that we did not find any difference between the NOACs," she added.

Connolly echoed those remarks, saying, "What I would take from this is no safety signal for dabigatran; that's a useful thing and probably fairly reliable. To try and parse this further, you're getting into dangerous territory and a significant risk of overinterpreting the data."

Although the study shows that dabigatran does not have a safety signal for MI, it doesn't provide nearly as good information about any benefit of dabigatran against MI, which is available for rivaroxaban, he noted. Results of the COMPASS, and to some extent the ATLAS trial, have established rivaroxaban as a NOAC that is beneficial in patients with coronary disease, a condition that's quite common in those with AF at about 1 in 5.

"If rivaroxaban at the dose of 2.5 [mg] bid on top of aspirin reduces cardiovascular outcomes and to some extent reduces MI in patients with coronary disease, I think it's an increasingly interesting option for the patient who has both Afib and coronary artery disease to consider rivaroxaban-based strategies," Connolly said. "The problem is what dose of rivaroxaban, because the Afib dose is a lot higher than the dose that was used in coronary disease."

In an accompanying editorial, Stefan Hohnloser, MD, JW Goethe University, Frankfurt, Germany, and John Eikelboom, MD, MBBS, McMaster University, point out that the primary results were consistent in secondary and sensitivity analyses that included patients with or without prior ischemic heart disease or concomitant antiplatelet therapy.

The study "helps to settle the dust around an 8-year-old debate concerning the risk of MI in patients receiving [direct oral anticoagulant therapy] DOACs (and specifically dabigatran) for stroke prevention in AF," they write.

"Based on the large and consistent body of evidence now available, clinicians can use dabigatran with even greater confidence in AF patient, including those with a history of coronary artery disease and prior MI," Hohnloser and Eikelboom conclude.

The study was supported by Aalborg University, Department of Health Science and Technology. Lee reports no relevant financial relationships. Hohnloser reports receiving consulting fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Boston Scientific, Cardiome, Daiichi-Sankyo, Gilead, Johnson & Johnson, Medtronic, Pfizer, Portola, Sanofi, Servier, Abbott SJM, and Zoll; and lecture fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, Sanofi, St Jude Medical, and Medtronic. Eikelboom reports receiving consulting fees and/or honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, and Sanofi and grants and/or in-kind support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Janssen, and Sanofi.

J Am Coll Cardiol. 2018;72:17-26, 27-28. Abstract, Editorial

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