Two novel agents for extended treatment of venous thromboembolism

Published - Written by Jamie Colbert

Venous thromboembolic disease (VTE) and pulmonary embolism have been major causes of human morbidity and mortality for thousands of years, yet our understanding of the pathobiology of this disease was rudimentary until the 1840s when German pathologist Rudolf Virchow discovered that blood clots in large veins of the lower legs could travel through the right side of the heart and into the lungs where they would obstruct pulmonary blood flow and lead to hypoxemia and often death. Virchow termed this phenomenon “embolia.” Virchow went on to describe the three main factors that contribute to venous thromboembolism: vessel injury, venous stasis, and hypercoagulability. Unfortunately for patients at the time, Virchow’s medical discoveries did not immediately lead to any effective treatment for this disease.

German surgeon Friedrich Trendelenburg spent the early decades of the 20th century experimenting with surgical removal of pulmonary emboli. He tried the technique on three patients, but none survived the surgery. In 1924 Trendelenburg’s student, Martin Kischner, performed the first successful pulmonary artery thrombectomy on a 38-year-old female with a pulmonary embolus. The technique never achieved widespread usage because the surgery carried a high risk of mortality and required a high degree of technical expertise.

The discovery of heparin in 1918 by researchers at Johns Hopkins University paved the way for medical treatment of blood clots. However, it was another 20 years after heparin’s discovery before the drug began to be widely used by physicians to treat VTE. The current standard of care for VTE involves initial treatment with IV heparin overlapping with oral vitamin K antagonist, followed by a prolonged course of vitamin K antagonist therapy. By the 1990s IV heparin was replaced by subcutaneous injection of low molecular weight heparin, which offered the advantage of weight based dosing without the need for frequent dose monitoring as well as a decreased risk of heparin induced thrombocytopenia.

Patients with VTE due to transient risk factors such as immobility or recent surgery can safely discontinue treatment after three months of anticoagulant therapy. However, patients with unprovoked VTE have recurrence rates as high as 40% at 5 years and therefore benefit from long term anticoagulation. Up until now, the main option for long term anticoagulation in such patients has been warfarin, an oral vitamin K antagonist which can be taken once daily. However, long term use of warfarin is far from ideal: warfarin interacts with many other medications and foods, it requires frequent monitoring of clotting factors, and it has a very narrow therapeutic index. Aspirin has recently emerged as a potential option for those who do not want to take warfarin, and a 2012 randomized trial of low dose aspirin for extended treatment after VTE showed that aspirin could modestly reduce the yearly risk of recurrent VTE from 6.5% to 4.8%.

This week’s NEJM presents the results of randomized clinical trials of two novel oral anticoagulant medications: apixaban, a direct factor Xa inhibitor, and dabigatran, a direct thrombin inhibitor. Both trials used the anticoagulants as extended treatment for unprovoked VTE. The AMPLIFY-EXT trial was a double blind, randomized trial comparing two doses of apixaban with placebo for extended treatment of DVT after a patient had already been treated with 6-12 months of anticoagulation. Patients receiving apixaban at either study dose had a reduction in risk of recurrent deep vein thrombosis (DVT) from 9% to just under 2% after 12 months of treatment. Furthermore, there was a lower rate of all-cause mortality in the two treatment groups as compared with placebo. Rates of adverse events did not differ between the two groups. The REMEDY /RESONATE trial compared dabigatran, a direct thrombin inhibitor, at a dose of 150mg twice daily, with warfarin as well as placebo for patients with VTE who had completed at least three months of anticoagulation therapy. The study showed that dabigatran is as effective as warfarin in preventing recurrent VTE with a lower risk of clinically relevant bleeding.

Although these data are interesting, a big question remains unanswered: Which patients would benefit most from these novel medications as compared with warfarin or aspirin? As Dr. Jean Connors writes in an accompanying editorial, “Direct comparison of these agents, and with warfarin and aspirin, is needed to determine which confers the greatest protection from recurrent venous thromboembolism with the lowest rate of bleeding complications.” Such studies could also help further elucidate potential adverse effects of apixaban and dabigatran such as the possibility of increased risk of cardiac events.  Furthermore, while these new agents are both much more expensive than warfarin, they offer the potential for cost savings in the form of fewer blood draws and physician visits. Going forward, a rigorous analysis of the cost-effectiveness of these medications is essential to inform both clinicians and payers as they consider the multiple anticoagulants available. Until then, physicians and patients will need to make informed decisions together by weighing the risks and benefits of each of the various options for treatment following VTE.

Connect with Dr. Colbert on Twitter: @jcolbertMD

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