There are no randomized clinical trial results comparing the relative safety and efficacy of different direct oral anticoagulants (DOACs) for patients with atrial fibrillation, and findings from observational studies have conflicted. Arnar B. Ingason, MD, PhD, of the University of Iceland in Reykjavik, pointed out that previously performed observational studies have had important limitations. Dr. Ingason and colleagues published results of their observational cohort study in Blood Advances, showing a higher risk of major bleeding events for rivaroxaban and suggesting it may carry a lower risk of myocardial infarction compared to dabigatran.
“While all four pivotal randomized clinical trials comparing warfarin and DOACs in patients with atrial fibrillation used the [International Society on Thrombosis and Haemostasis] criteria to define major bleeding, none of the previous large observational studies have used this definition,” he said.
Dr. Ingason and colleagues did use these criteria, instead of defining major bleeding as bleeding leading to hospitalization like most previous observational studies. Their nationwide propensity-weighted cohort study followed 4,670 patients with atrial fibrillation who were newly prescribed apixaban, dabigatran, or rivaroxaban from 2014 to 2019. Of these, 1,787 received apixaban, 420 received dabigatran, and 2,463 received rivaroxaban over an average follow-up period ranging from 1.3 years (apixaban) to 1.9 years (dabigatran).
Previous large observational studies have used only the International Classification of Diseases, 10th Edition (ICD-10) codes to identify safety events without additional verification. However, Dr. Ingason’s group additionally searched the Icelandic national death registry and examined results from endoscopic procedures and computed tomography scans of the head and pulmonary arteries.
“We manually reviewed and confirmed each diagnosis, thereby greatly increasing the accuracy of the data,” he added.
The researchers compared outcomes from the groups using Cox regression. Rivaroxaban was associated with higher major bleeding rates compared to both apixaban and dabigatran (2.9 events/100 person-years vs. 1.8 and 1.4 events, respectively). This higher rate is in line with trends from most other observational studies, which have also demonstrated a somewhat higher bleeding risk from rivaroxaban.
The authors did not find a difference in the rates of stroke or systemic embolism. However, they did find that dabigatran was associated with twofold higher rates of myocardial infarction compared to both rivaroxaban and apixaban (1.4 events/100 person years vs. 0.7 and 0.7 events, respectively).
“There is actually pretty strong evidence from randomized controlled trials that dabigatran is associated with higher myocardial infarction rates than warfarin,” Dr. Ingason noted.
He speculated that these higher rates of myocardial infarction may not have been found in some previous observational studies, at least partly, because they did not manually verify their outcomes.
“These findings must be interpreted in the context of a relatively small dabigatran group [compared to some other studies], leading to wide confidence intervals,” he added.
The researchers noted an additional limitation: although they used inverse probability weighting to obtain balanced study groups, they were unable to control for certain potentially confounding factors, such as socioeconomic status, smoking history, certain baseline laboratory values, or over-the-counter medications such as nonsteroidal anti-inflammatory drugs.
“Given that the effectiveness of DOACs seem to be similar, it may be reasonable to guide oral anticoagulant selection based on the safety profile of the drugs,” Dr. Ingason said. “Rivaroxaban may be less suitable for patients with high bleeding risk.”
Dr. Ingason added, “The results do suggest that dabigatran should potentially be avoided in patients at high risk of [myocardial infarction], [for example] patients with known coronary artery disease or multiple risk factors for myocardial infarction.”
Randomized clinical trials comparing the safety and efficacy of DOACs may help further clarify these issues.
Any conflicts of interest declared by the authors can be found in the original article.
Ruth Jessen Hickman, MD, is a freelance medical and science writer based in Bloomington, Indiana.
Reference
Ingason AB, Hreinsson JP, Agustsson AS, et al. Comparison of the effectiveness and safety of direct oral anticoagulants: nationwide propensity score-weighted study [published online ahead of print, 2022 Dec 23]. Blood Adv. doi: 10.1182/bloodadvances.2022009099.
