NOACs Carry Lower MI Risk vs Warfarin in Real-world Study

The risk of MI is lower in patients with A-fib starting treatment with a direct non-vitamin K antagonist oral anticoagulant (NOAC) rather than a vitamin K antagonist (VKA) for stroke prevention, Danish researchers report, adding fodder to a debate about MI risks that has been ongoing since the RE-LY trial results were first reported back in 2009.

Overall, the standardized risk of MI in the year after initiating treatment was 1.1% to 1.2% with dabigatran, rivaroxaban, and apixaban and 1.6% with a VKA, with lower absolute risks of 0.4% to 0.5% with the newer agents, according to Christina Ji-Young Lee, MD (Aalborg University, Denmark), and colleagues.

There were no differences in MI risk across the three NOACs, the investigators report in a study published online ahead of the July 3, 2018, issue of the Journal of the American College of Cardiology.

“Presently, there are no results from randomized clinical trials directly comparing the direct oral anticoagulants head-to-head, although current evidence has not shown superiority of one [of these drugs] over the other,” they write. “Present evidence from supporting biological studies remains insufficient, and studies in sizeable cohorts comparing the effects of direct oral anticoagulants and VKAs on platelet function and reactivity continue to be wanted.”

Commenting for TCTMD, T. Jared Bunch, MD (Intermountain Heart Institute Heart Rhythm Specialists, Murray, UT), said he was not surprised to see the NOACs fare well against VKAs in a real-world setting because outside of clinical trials controlling patients on warfarin can be challenging and NOACs have greater ease of use and more predictable effects.

The findings seem to bear out the hypothesis “that predictable anticoagulants can lower risk of heart attack in patients with atrial fibrillation,” he said.

Oral anticoagulants in general tend to perform worse out in the community than in clinical trials, Bunch added, but “what happens is if you take one drug that needs very tight control and needs very careful follow-up in the community and one that needs less, the drug that needs less control and less follow-up is likely going to look better.”

The Long-Running MI Debate

Though pivotal trials have shown the NOACs to be at least as good as warfarin for preventing stroke, with a lower bleeding risk, patients with A-fib remain at risk for MI, and there has been some question ever since the release of results from the first NOAC trial, RE-LY, as to whether there may be an excess MI risk with dabigatran (Pradaxa; Boehringer Ingelheim).

In RE-LY, there were numerically more MIs with both doses of dabigatran than with warfarin, a difference that reached marginal statistical significance for the higher, 150-mg dose of the NOAC. A subsequent post hoc analysis did not, however, find a significant difference in MI specifically or overall myocardial ischemic events more broadly.

But the debate has continued because of conflicting results from further studies. Several meta-analyses have found a higher risk of MI with dabigatran versus warfarin, whereas meta-analyses of the other NOACs—rivaroxaban (Xarelto; Bayer/Janssen), apixaban (Eliquis; Bristol-Myers Squibb), and edoxaban (Savaysa; Daiichi Sankyo)—have not. Newer studies also don’t agree, with some pointing to no difference in MI risk or a lower risk with the newer agents and others supporting a higher MI risk with the NOACs.

The US Food and Drug Administration has weighed in on this with its own analysis, finding no difference in MI between dabigatran and warfarin.

Still, questions about MI risk in patients receiving oral anticoagulation in real-world practice linger.

It’s in that context that Lee et al performed an analysis of patients starting treatment for A-fib for the first time within the Danish healthcare system. Using national registries, the investigators identified 31,739 patients (median age 74 years; 47% women) who started taking a VKA (28%), apixaban (27%), dabigatran (23%), or rivaroxaban (22%) between January 2013 and June 2016.

The NOACs performed favorably versus VKA therapy in terms of MI risk in the main analysis and in a number of sensitivity analyses, including one looking at patients with or without prior ischemic heart disease.

Although MI risk did not differ across NOACs, some differences emerged when looking at composite endpoints. For MI or all-cause mortality, dabigatran had a lower risk than apixaban, and rivaroxaban had a higher risk than both of the other NOACs. For MI or cardiovascular mortality, rivaroxaban carried a significantly higher risk versus apixaban and dabigatran.

Bunch said those findings are consistent with other observational data pointing to somewhat higher risks with rivaroxaban compared with its NOAC competitors, adding that there is no clear explanation for the disparity.

Is the Debate Settled?

Selection bias could be playing a role in the findings of the study, Bunch acknowledged, saying that patients who receive NOACs—which remain under patent protection and thus are more expensive—tend to be healthier because they have better access to healthcare compared with those who can’t afford the newer agents or who have insurance that doesn’t pay for them.

Still, the study “does help give evidence that there’s not a perceived higher risk of heart attack with [the NOACs],” he said. “The study is a large population study with long-term follow-up, so I think it does point to the fact that they do not increase risk.”

Bunch added that he would have liked to have seen an analysis looking at women and men separately because prior studies have found a higher risk of MI—particularly NSTEMI—in women. A community-based study in the works by Bunch’s group will address that issue, he said.

In an accompanying editorial, Stefan Hohnloser, MD (J. W. Goethe University, Frankfurt, Germany), and John Eikelboom, MD, MBBS (McMaster University, Hamilton, Canada), say 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 (and specifically dabigatran) for stroke prevention in AF.

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