Novel oral anticoagulants useful in VTE, but careful decisions required

SAN DIEGO — As the number of available novel oral anticoagulants expands, physicians must consider how best to use these agents in patients with venous thromboembolism.

“For over 50 years, the only oral anticoagulant that was available on the market was warfarin, but since 2010, there have been four different novel oral anticoagulants or direct-acting oral anticoagulants that have been approved for use in VTE,” Satish Madiraju, MD, FSCAI, from the Cardiology Associates of Schenectady, said during a presentation at the Society for Cardiovascular Angiography and Interventions Scientific Sessions.

Reviewing the evidence

These newer treatments, Madiraju noted, have compared favorably with warfarin. For instance, several trials of the novel oral anticoagulants, including RE-COVER, the EINSTEIN program, AMPLIFY and Hokusai-VTE, have shown that dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Janssen), apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and edoxaban (Savaysa, Daiichi Sankyo) are noninferior to warfarin and have comparable or even slightly better safety profiles in terms of bleeding events in patients with VTE, Madiraju noted.

However, questions have arisen about how long patients with VTE should be treated with novel oral anticoagulants. According to data from the EINSTEIN extension study and the AMPLIFY extension study, rivaroxaban and two different doses of apixaban were clearly superior to placebo for reducing recurrent VTE events beyond the initial 6- to 12-month time period, although bleeding rates ranged from 4.2% to 6%, Madiraju said.

As for aspirin, according to Madiraju, the jury is still out. He noted that data are lacking. The ASPIRE study, for example, showed that aspirin reduced vascular events but not VTE events compared with placebo. Moreover, the bleeding terminology used in the study was non-conventional and potentially led to the underrepresentation of the number of bleeding events that occurred in patients with aspirin, he said. In contrast, though, the WARFFASA trial showed that aspirin was superior to placebo and reduced recurrent VTE events with no significant increase in bleeding events.

In terms of length of treatment, the EINSTEIN-CHOICE study, which compared rivaroxaban with aspirin for extended treatment of VTE, showed that two doses of rivaroxaban were superior to aspirin for reducing recurrent VTE events and had comparable safety, Madiraju said, but there was clinical ambiguity as to whether extension of anticoagulation was necessary.

In light of this evidence, the American College of Chest Physicians 2016 guidelines and the European Society of Cardiology 2014 guidelines recommend that the currently available novel oral anticoagulants are preferable to warfarin in patients with deep vein thrombosis or pulmonary embolism, according to Madiraju.

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The ESC guidelines also recommend that all provoked VTE be treated for 3 months and longer anticoagulation therapy may be offered for patients with unprovoked VTE with some caveats. Additionally, patients with unprovoked VTE and low bleeding risk should be considered for extended anticoagulation without a specific end date but accompanied by periodic evaluation to determine the benefits and risks of continuing with the therapy. The guidelines also recommend indefinite anticoagulation in patients with a second unprovoked VTE event and patients with malignancy.

Considerations in DAPT

Madiraju also discussed the use of novel oral anticoagulants for VTE in the setting of dual antiplatelet therapy. Unfortunately, the lack of data in VTE specifically complicates treatment, he said.

To answer questions about the bleeding risks associated with novel oral anticoagulant use for VTE in patients on DAPT, physicians need to review the available data on the use of these agents for secondary prevention in patients with ACS, according to Madiraju. Although one meta-analysis showed that apixaban and rivaroxaban in varied doses along with single antiplatelet therapy or DAPT as secondary prevention reduced MACE but increased bleeding, the PIONEER AF-PCI trial evaluating patients with atrial fibrillation who were stented showed that low-dose rivaroxaban plus DAPT reduced rates of MACE as well as bleeding complications.

“There are no data on novel oral anticoagulants for patients on DAPT who need treatment for VTE, but we can look to the WOEST strategy for coronary interventions, which showed that a strategy of reduced antiplatelet therapy with clopidogrel only and warfarin had less bleeding events and improved MACE events,” Madiraju said.

In light of these data, he suggested avoiding triple therapy if possible. However, for patients who require triple therapy, Madiraju recommended assessing ischemic and bleeding risks using validated risk predictors, such as CHA₂DS₂-VASC and HAS-BLED scores, and keeping the duration of triple therapy as short as possible.

Additionally, when using warfarin, physicians should consider a target international normalized ratio of 2.0 to 2.5. He also noted that clopidogrel is the P2Y12 inhibitor of choice and low-dose aspirin should also be used.

Finally, proton pump inhibitors should be used in patients with a history of gastrointestinal bleeding and can be considered in patients with an increased risk for gastrointestinal bleeding, Madiraju said. – by Melissa Foster

Reference:

Madiraju S. New Frontiers in Acute and Chronic Thromboembolic Pulmonary Disease. Presented at: Society for Cardiovascular Angiography and Interventions Scientific Sessions; April 25-28, 2018; San Diego.

Disclosure: Madiraju reports no relevant financial disclosures.