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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.
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.  
Am J Manag Care. 2017;23:S67-S80
 
Expert Opinion

As part of the physiological aging process, the human body experiences age-related changes in the hemostatic system that can lead to an imbalance between the 2 extremes of bleeding and thrombosis. These changes result in a heightened procoagulant state and enhanced risk for thromboembolic conditions. In 1856, Virchow described the mechanisms underlying thrombosis as involving a pathologic triad of stasis, endothelial cell injury, and hypercoagulability.1 Both arterial and venous thromboses are implicated in the pathogenesis of major disorders that include ischemic stroke and venous thromboembolism (VTE, including deep vein thrombosis [DVT] and pulmonary embolism [PE]).2 Thrombosis is a leading cause of morbidity and mortality in the United States and worldwide.3-6

For more than 50 years, oral anticoagulant therapy with warfarin has been used for the treatment and prevention of VTE and for the prophylaxis of stroke in patients with atrial fibrillation (AF). This vitamin K antagonist (VKA), or coumarin class anticoagulant, was first discovered in spoiled sweet clover ingested by Wisconsin cows and then used as a rodenticide. Warfarin was subsequently synthesized and tested in humans starting in the 1950s.7 Although VKAs proved to be very effective drugs, reducing the risk of stroke in patients with AF by two-thirds, they are associated with several clinical limitations.8 Treatment with coumarins requires frequent blood testing (eg, prothrombin time and international normalized ratio [INR]). Warfarin dosage adjustments are needed to maintain patients within the therapeutic INR range.7,9 Medication noncompliance and genetic variations in coumarin metabolism can lead to difficulties in achieving and maintaining therapeutic INR levels. Furthermore, coumarins are associated with multiple drug interactions and dietary restrictions, and alcohol consumption may interfere with warfarin metabolism and availability.10-13
Over the past decade, direct oral anticoagulants (DOACs) have been adopted as alternatives to VKAs because they are more convenient (ie, no requirement for routine blood tests) and maintain their effectiveness in thrombosis reduction.14,15 These novel compounds were discovered through research involving organisms that produce anticoagulants. A factor Xa (FXa) inhibitor was isolated from tick saliva and the first thrombin inhibitor, or inhibitor of factor IIa (FIIa), was isolated from leeches.16 The development of oral forms of these 2 drug classes launched a revolution in anticoagulation. Several clinical trials and meta-analyses showed the DOACs were clinically advantageous and at least as effective as warfarin, the primary VKA used in the United States.9,17-20 The proven efficacy of DOACs led to FDA approval of the direct thrombin inhibitor dabigatran (Pradaxa) and the FXa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis) and edoxaban (Savaysa) for the treatment and prevention of thromboembolic events (Table 121-26).21-24 An additional DOAC (betrixaban) is currently in development.25,26

Compared with warfarin, DOACs are associated with a reduction in the occurrence of intracranial hemorrhage (ICH), a life-threatening complication of anticoagulant therapy.8,19,20,27 In addition, DOACs have the potential to help address an unmet clinical need among patients at risk for thromboembolic events: to advance the quality of anticoagulation therapy by offering an alternative to warfarin. Warfarin is underused, as the risk of thrombosis is often underestimated and treatment is inconvenient. Studies have shown that anticoagulant treatment is used in less than half of patients at risk for thromboembolic events (who have risk stratification scores indicating a need for anticoagulation).28-31

Due to their ease of clinical use, DOACs are increasingly being prescribed instead of warfarin.20,32,33 However, as with all anticoagulants, DOACs are associated with a risk of life-threatening bleeding. Given their rapid adoption and their projected usage within the large patient population affected by thromboembolic conditions, clinicians are increasingly likely to encounter patients with major bleeding events due to DOAC therapy.20,33 And unlike warfarin, there is no approved reversal agent for FXa inhibitors.34 Thus, there is an unmet need for reversal agents to these anticoagulants for the management of life-threatening bleeding or in the case of emergency surgery.20

In this review, we summarize the burden of thrombosis in terms of stroke and VTE and highlight indications for DOAC treatment of these conditions. We also discuss the DOAC-associated bleeding burden and unmet needs for furthering this field of medicine.

Burden of Thrombosis

Venous Thromboembolism/Deep Vein Thrombosis and Pulmonary Embolism


VTE can be manifested as DVT, PE, or both. DVT most commonly presents in the lower extremities, although it can also affect the upper extremities. A PE is a potentially fatal VTE manifestation that results from thrombus embolization and subsequent migration to the lungs.6 VTE poses a substantial burden on healthcare systems worldwide, as it is associated with substantial morbidity and mortality and is the leading cause of preventable hospital death.3-6 Although the exact number of patients affected by VTE is unknown, in the United States, the CDC has estimated that between 350,000 and 900,000 people develop blood clots for the first time each year,35 numbers that exceed the estimated new cases for each of the top 10 cancers in 2016.36 In the United States alone, 60,000 to 180,000 deaths are directly or indirectly a result of DVT or PE. Modeling data suggest that as many as 300,000 VTE-related deaths may occur every year.3,4,35,37 In Europe, however, there are approximately 544,000 VTE-related deaths every year.38 The 30-day mortality rate among patients with VTE in the United States has been estimated at 10% to 30%, and sudden death occurs in 20% to 25% of patients with PE.6

In the United States, 7.7 million to 8 million patients are at risk for developing VTE.28,39 Older patients and those who have been hospitalized are at an especially high risk.6,28 Worldwide, there are approximately 10 million cases of hospital-associated VTE every year, and up to 60% of these cases occur during or after hospitalization.2,3,40 In the United States, up to half of outpatient VTE occurrences can be linked to hospitalization, and the risk among hospitalized patients extends for at least 30 days and up to 3 months post discharge.6,41 Patients with VTE are also at increased risk of recurrence and comorbidities, including chronic thromboembolic pulmonary hypertension, postthrombotic syndrome, and complications of chronic venous insufficiency.6

VTE represents a substantial burden on the healthcare system in the United States: estimated annual healthcare costs for incident and recurrent cases of DVT or PE range from $7594 to $16,644 per patient.6 Given variations in the total projected VTE cases each year, approximations of expenditures in the United States related to VTE range from $2 billion to $10 billion annually.6 Healthcare systems have the potential to reduce the clinical and economic burden associated with VTE by assessing a patient’s risk of thrombosis at the time of hospital admission and initiating antithrombotic therapy as appropriate.



 
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