The goal of management of venous thromboembolic disease is to prevent thrombus extension or embolisation and to prevent early and late episodes of recurrence. Armando Mansilha, Porto, Portugal, explains how our approach has changed and what obstacles still face physicians and patients in achieving best outcomes.
Anticoagulation is the cornerstone of venous thromboembolism (VTE) treatment, usually divided into two phases: active treatment for three months and extended treatment for a longer period that has to be defined case by case. Traditionally, treatment occurs in two overlapping steps. It starts with a rapidly-acting parenteral anticoagulant, usually low-molecular-weight heparin (LMWH), which is overlapped with a vitamin K antagonist such as warfarin. When the anticoagulant response with warfarin is therapeutic, as evidenced by an international normalised ratio (INR) between 2 and 3, LMWH is stopped and warfarin is continued as a long-term therapy for a minimum of three months. The subsequent anticoagulation aims to prevent recurrent episodes of thrombosis, and the decision to stop or continue treatment depends on the balance between the risk of recurrence and the risk of bleeding. Patients who are treated for indefinite period of time should be reviewed at least annually. The risk of venous thromboembolism recurrence decreases with time following the incident event, and the risk of bleeding also may vary over time. Consequently, the benefits and risks of secondary prophylaxis must be continually re-evaluated.
Although this therapy with vitamin K antagonist is effective and safe, these conventional anticoagulants present several disadvantages, including unpredictable response, the need for routine monitoring, frequent dose adjustments due to multiple interactions with other drugs and food, and a narrow therapeutic window. These limitations led to the development of new direct oral anticoagulants (DOACs or NOACs), which reversibly inhibit specific coagulation proteins and produce a more predictable anticoagulant response. DOACs offer a convenient and attractive approach to the treatment of venous thromboembolism since they are given orally in a fixed dose, do not require routine laboratory monitoring, have fewer drug-to-drug interactions than oral vitamin K antagonist and there are no dietary restrictions. Because of their rapid onset of action, the DOACs have the potential to enable all-oral regimens, which can replace parenteral anticoagulants and warfarin for active and extended thromboembolism treatment, thereby simplifying it.
The four main DOACs currently approved for the treatment of venous thromboembolism are dabigatran (a direct thrombin inhibitor), rivaroxaban, apixaban and edoxaban (all direct factor Xa inhibitors). All four agents have been compared with conventional anticoagulant therapy for the treatment of acute symptomatic venous thromboembolism, in the RE-COVER I and II, EINSTEIN-DVT and PE, AMPLIFY, and Hokusai-VTE trials, respectively. Overall, DOACs are, at least, as effective as conventional treatment for venous thromboembolism and are associated with less bleeding. Rivaroxaban, apixaban, and dabigatran were also evaluated for extended treatment and compared with placebo in the double-blind EINSTEIN-Extension, AMPLIFY-Extension, and RE-SONATE trials, respectively. All trials demonstrated superiority of the DOACs over placebo for the prevention of recurrent venous thromboembolism and are associated with low rates of major bleeding. Dabigatran was also compared with warfarin for extended treatment in the RE-MEDY trial, and demonstrated non-inferiority compared with warfarin and major bleeding was reduced by 50% with dabigatran. The use of DOACs represents an important step forward in the management of venous thromboembolism and may therefore reduce the significant burden on patients.
However, the utility of the DOACs in some specific populations remain to be established (cancer, high-risk thrombophilias, pregnancy, severe renal impairment or severe liver disease). Due to the limited number of patients with high-risk inherited or acquired thrombophilia included in the clinical trials and uncertainty regarding the efficacy of DOACs in these settings, it might be prudent to use vitamin K antagonist in patients with antiphospholipid syndrome (APS), antithrombin deficiency or multiple defects. In the particular population of APS patients, until the results of ongoing trials of DOACs for APS are presented, these agents should be reserved for exceptional cases and not recommended for all APS patients. Decision to use a DOAC for APS should be balanced and discussed on an individual basis.
The DOACs are now licensed for venous thromboembolism treatment and secondary prevention of recurrent events. Although more expensive than warfarin, these drugs are likely to provide a cost-effective option. The efficacy of DOACs are at least similar to warfarin and the safety profile is superior to warfarin. They are easier to use and do not need routine monitoring.
More studies are now needed to evaluate DOACs in specific populations like patients with cancer or high-risk thrombophilias.
Armando Mansilha is at the University of Porto, Portugal