Exploring indications for the Use of direct oral anticoagulants and the associated risks of major bleeding

Abstract

Thrombosis is a leading cause of morbidity and mortality in the United States. Arterial and venous thromboses are implicated in the pathogenesis of major disorders, including myocardial infarction, ischemic stroke, and venous thromboembolism. Over the past decade, direct oral anticoagulants (DOACs) (eg, direct thrombin inhibitor and factor Xa [FXa] inhibitors) have been adopted as alternatives to warfarin due to their clinical advantages and efficacy for the treatment of thrombosis. As with all anticoagulants, treatment with DOACs is associated with a risk of major bleeding, including life-threatening gastrointestinal bleeds and intracranial hemorrhages (ICHs). In turn, the burden of bleeding associated with DOAC treatment is itself associated with substantial healthcare costs that are amplified by an increased risk of thromboembolic events and mortality following major bleeding events, especially in patients with ICHs. Given the rapid adoption of the DOACs and projected usage in the large patient population affected by thromboembolic conditions, clinicians are increasingly likely to encounter patients with major bleeding events due to DOAC therapy. Unlike warfarin, effective strategies to manage these bleeds are limited. There is an unmet need for reversal agents for use in the management of patients who receive FXa inhibitors and experience life-threatening bleeding or need emergency surgery. Andexanet alfa and ciraparantag are being evaluated as potential antidotes for both direct and indirect FXa inhibitors.

FIGURE 1

Anticoagulation Therapy^,–, I indicates factor I; Ia, factor Ia; II, factor II; IIa, factor IIa; IX, factor IX; IXa, factor IXa; Va, factor Va; VII, factor VII; VIIa, factor VIIa; VIIIa, factor VIIIa; X, factor X; Xa, factor Xa; XI, factor XI; XIa, factor XIa; XII, factor XII; XIIa, factor IIa; XIIIa, factor XIIIa. ^aBetrixaban is an investigational drug.

FIGURE 2

Usage of DOACs Over Time DOAC indicates direct oral anticoagulant. Reprinted from Barnes GD, Lucas EG, Alexander GC, Goldberger ZD. Am J Med. 2015;128(12):1300–1305. doi: 10.1016/j.amjmed.2015.05.044, with permission from Elsevier.

FIGURE 3

Types of DOAC-Associated Major Bleeds^,,,,,–, DOAC indicates direct oral anticoagulant.

FIGURE 4

Increased Mortality and Thromboembolic Risk After a Major Bleed^,,, ICH indicates intracranial hemorrhage; MI, myocardial infarction. ^aThe ROCKET AF trial was designed to compare rivaroxaban with warfarin for the prevention of stroke in patients with atrial fibrillation. Major and nonmajor clinically relevant bleeding events were evaluated as the primary safety end point. ^aMedian time to stroke or systemic embolism, 64 days (range: 16–249 days); median time to myocardial infarction/unstable angina, 282 days (range: 9–485 days).