DOACs in AF: Observational and Randomized Studies Don't Always Agree

October 30, 2018

A new review has identified discrepancies between randomized controlled trials (RCTs) and observational studies in how direct oral anticoagulants (DOAC) compare with warfarin in terms of efficacy and safety in patients with atrial fibrillation (AF).

For example, in contrast to combined RCT findings, observational data did not show a reduction in all-cause mortality using the factor Xa inhibitor DOACs, as opposed to warfarin, in the survey based on 220 publications related to 117 separate studies.

The new report, published October 29 in the Annals of Internal Medicine, also confirmed that the DOACs overall performed as well in a broad range of patient subgroups as in the broad cohorts included in their respective RCT comparisons with warfarin.

Overall, the survey concurred with the major DOAC trials in finding that "each of the DOACs provide either similar or superior thromboembolic prevention and bleeding outcomes," lead author Angela Lowenstern, MD, Duke University School of Medicine, Durham, North Carolina, told theheart.org | Medscape Cardiology.

"In patients with renal impairment and across many different patient subgroups, we found the same outcomes," she said.

The DOACs include the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) and three factor Xa inhibitors: apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), edoxaban (Savaysa/Lixiana, Daiichi Sankyo), and rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals).

Some subgroup differences stood out, Lowenstern said. Whereas all the factor Xa inhibitors were effective and safe relative to warfarin in patients with diabetes or previous stroke and regardless of glomerular filtration rate (GFR), apixaban showed an especially steep reduction in bleeding risk when GFR was below 50 mL/min per 1.73 m² (= .003).

Also, the report notes, the risk of major bleeding on apixaban, compared with warfarin, was significantly reduced in patients without diabetes but not among diabetics.

Observational Studies vs RCTs

When observational studies arrived at conclusions that differed from RCT results, it could for some findings have the effect of weakening the strength of evidence that contributed to treatment recommendations in the guidelines, observed the report's senior author Gillian D. Sanders, PhD, also from Duke University.

"There were a few inconsistencies between what we saw in RCTs and what we saw in observational studies," she said. "Observational studies showed a benefit in all-cause mortality for patients on dabigatran, compared with warfarin, while the RCTs did not. Also, observational studies showed a difference in MI while the RCT studies suggested an increase with dabigatran."

Factor Xa inhibitor RCTs, considered together, showed a benefit for the drugs, compared with warfarin, with respect to all-cause and cardiovascular death and hemorrhagic stroke. In contrast, observational studies did not point to an overall survival benefit with the drugs, but did suggest a reduction in stroke or systemic embolism with rivaroxaban.

Differences Among DOACs

Dabigatran hasn't been compared with the factor Xa inhibitors in RCTs, but observational studies suggest the two classes of agents are comparable for stroke and systemic embolism, the analysis found.

They also point to an increased risk for intracranial hemorrhage with the factor Xa inhibitors compared with the direct thrombin inhibitor (hazard ratio [HR], 1.63; 95% CI, 1.14 - 2.34).

Also in observational studies, the risk of major bleeding, compared with dabigatran, was significantly reduced for apixaban (HR, 0.67; 95% CI, 0.47 - 0.94) and significantly elevated for rivaroxaban (HR, 1.32; 95% CI, 1.02 - 1.70).

Nor have there been RCTs comparing the factor Xa inhibitors. A number of observational studies suggested that apixaban and rivaroxaban, at least, are similar with respect to stroke or systemic embolism and for ischemic and hemorrhagic stroke on their own. And when combined, some saw a reduced risk of major bleeding with apixaban compared with rivaroxaban (HR, 0.51; 95% CI, 0.38 - 0.68).

"I don't know if there's a need for more observational studies or more RCTs of just the individual therapies, but certainly studies that make direct comparisons could add a lot to the field," Sanders said. RCT comparisons of the DOACs are probably unlikely, "but if there were a need for future studies, that would be it."

Lowenstern and Sanders reported no conflicts. Disclosures for the other authors are in the report.

Ann Intern Med. Published online October 29, 2018. Article

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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