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Exploring Indications for the Use of Direct Oral Anticoagulants and the Associated Risks of Major Bleeding
Truman J. Milling Jr, MD, and Jennifer Frontera, MD, FNCS

Exploring Indications for the Use of Direct Oral Anticoagulants and the Associated Risks of Major Bleeding

Truman J. Milling Jr, MD, and Jennifer Frontera, MD, FNCS
This supplement to The American Journal of Managed Care® describes the burden of thrombosis in terms of strokes and venous thromboembolism and highlights indications for the use of direct oral anticoagulants (DOACs) for the treatment of these conditions. The burden of DOAC-associated bleeding and unmet needs regarding reversal agents are also discussed.
Ischemic Stroke
In developed nations, ischemic stroke accounts for up to 85% of stroke incidence and approximately 15% to 30% of ischemic strokes are cardioembolic in origin.3,42 Additionally, up to 30% of cryptogenic ischemic strokes may be due to an occult cardiac source.42  AF is associated with an increase in the risk of ischemic stroke by a factor of 4 to 5, and cardiac embolism related to AF accounts for up to 15% of strokes in persons of all ages and 30% in persons older than 80 years.18 The aging population is at a higher risk of developing AF, which may lead to ischemic stroke. The risk of AF increases from 0.1% in adults younger than 55 years to 9% in adults 80 years and older.3 In 2008, the incidence of ischemic stroke was 545 per 100,000 in the Medicare population in the United States.3

Anticoagulant Therapy for Patients With VTE and Patients With AF
Anticoagulant therapy with warfarin and DOACs is approved for patients at risk of thromboembolic complications, such as ischemic stroke, and for prophylaxis and treatment of DVT and PE.10,14 Treating at-risk patients with appropriate anticoagulant therapy may reduce the incidence and frequency of hospital readmissions and thrombosis-related morbidity and mortality.3 In the United States, less than half (48%) of at-risk hospitalized medical patients receive VTE prophylaxis as recommended by evidence-based guidelines, despite the availability of oral and nonoral anticoagulants (eg, low-molecular weight heparin, unfractionated heparin, fondaparinux).28,29 Among patients with nonvalvular AF, 41.3% who require stroke prophylaxis (by CHADS2 [congestive heart failure, hypertension, age, diabetes, stroke (doubled)] stroke risk score) are treated with anticoagulants. This treatment gap leads to approximately 200,000 unnecessary strokes each year in the United States.31

The mechanisms of action of various anticoagulants are shown in Figure 110,21-25,43. Warfarin inhibits vitamin K epoxide reductase, thereby reducing the level of clotting factors II, VII, IX, and X, and proteins C and S.10 In contrast, DOACs specifically target amplification steps in the coagulation cascade by inhibiting FXa or FIIa.21-24

DOACs: Advantages Compared With Warfarin
DOACs have predictable dose-dependent pharmacokinetics and pharmacodynamics and fixed dosing; routine monitoring of their anticoagulant activity is not required.8,19,44,45 Unlike warfarin, DOACs have limited drug interactions and no food interactions. They also have a shorter half-life compared with VKAs and thus a relatively quick onset of anticoagulant activity.8,19,27,45

DOACs: Disadvantages Compared With Warfarin

Lack of Reversal Agent
For patients treated with warfarin, effective reversal agents are available for use (either prothrombin complex concentrates [PCCs] or fresh frozen plasma along with vitamin K).46 A reversal agent (idarucizumab) is also available for dabigatran, a thrombin inhibitor47,48; however, there is no reversal agent currently approved for direct oral FXa inhibitors.46 Reversal agents could be needed in many of the approximately 84,000 cases of oral FXa inhibitor-associated bleeding observed each year,49 a number that is likely to go up. Fueling this growth are the aging of the population (as the risk for thromboembolic conditions increases with age) and the increasing frequency of DOAC use; as the number of patients who are prescribed FXa inhibitors increases, so will the number of patients who need reversal agents.20,33,50

Current strategies to manage life-threatening bleeding in patients receiving oral FXa inhibitors and options for emergent anticoagulation reversal for invasive procedures are limited and will be described in more detail later in this article. Although DOACs may be associated with lower risks of ICH and major hemorrhage compared with warfarin, the inability to reverse these agents may cause providers to be hesitant to prescribe them, particularly in patients at higher risk of bleeding (eg, patients with higher HAS-BLED [hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly] bleeding risk scores).31

Lack of Laboratory Assay for DOAC Activity
Although patients treated with DOACs do not require routine coagulation monitoring, evaluation of anticoagulant activity may be desirable in certain clinical situations.51 For example, knowledge of whether the patient is in an appropriate therapeutic range may be useful when treating patients who cannot provide an accurate history of DOAC use, with suspected noncompliance, and with hepatic or renal insufficiency.52 Similarly, in situations where the degree of drug exposure is unknown and urgent reversal is required, fast and accurate laboratory indicators of coagulation status may be needed.51 Laboratory measures of coagulopathy may also be useful for selecting DOAC dosing regimens, particularly in obese patients for whom optimal dosing is not currently known.51
Chromogenic drug assays are available for dabigatran, apixaban, and rivaroxaban; however, these assays are performed only at select institutions or as part of clinical trials and the results are frequently not available within a clinically meaningful timeframe. Gold standard coagulation studies (ie, dilute thrombin time and ecarin clotting time for dabigatran; drug-specific chromogenic anti-FXa activity for direct oral FXa inhibitors) are expensive and not currently available at most institutions.51,52

Drug Cost
When evaluating patient out-of-pocket drug costs, warfarin is a less expensive treatment compared with DOACs. However, this does not factor in the costs of laboratory tests and office visits associated with warfarin titration. Additionally, DOAC treatment is more effective at preventing thrombosis-related clinical events and thereby reduces overall healthcare costs. Multiple cost-effectiveness studies have favored DOACs relative to treatment with warfarin, although this benefit with DOACs for stroke prevention in nonvalvular AF may be smaller compared with quality warfarin anticoagulation management (ie, longer time spent within the recommended therapeutic INR range of 2-3).53-59

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