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Direct Oral Anticoagulants vs. Conventional Anticoagulants for Pulmonary Embolism

No difference in death, recurrent VTE, or major bleeding when compared to conventional anticoagulation

Benefits in NNT

No difference in rate of adverse events (death, recurrent VTE, or major bleeding)
No difference in rate of adverse events (death, recurrent VTE, or major bleeding)

Harms in NNT

No difference in harms
No difference in harms
View As:

Efficacy Endpoints

Rate of recurrent VTE, DVT, PE, all-cause mortality, and major bleeding

Harm Endpoints

Adverse treatment reactions

Narrative

Pulmonary embolism (PE) has an incidence ranging from four to 12 per 10,000 annually and is a leading cause of cardiovascular mortality in the United States, contributing to nearly 300,000 deaths per year.1, 2, 3, 4 Conventional treatment includes heparins, fondaparinux, or vitamin K antagonists (VKAs), but recent data suggest treatment with oral direct thrombin inhibitors (DTIs) or oral factor Xa inhibitors, collectively known as direct oral anticoagulants (DOACs), is effective and safe.5, 6, 7, 8, 9 DOACs can be administered orally and have a more predictable effect without the need for monitoring. Here we summarize a recent update to a prior Cochrane review,10 adding 1484 new participants to meta-analyzed data on the subject.11

The Cochrane review included 10 randomized trials comprising 13,073 participants with confirmed PE allocated to treatment with a DOAC or conventional anticoagulation.11 The authors excluded trials not administering oral DOACs, trials not using conventional treatment with heparin and/or VKAs as the comparison, and trials with treatment less than 3 months. Confirmation of PE included computed tomography pulmonary angiography, ventilation/perfusion scan, or pulmonary angiography. DTIs included dabigatran and ximelagatran; factor Xa inhibitors included rivaroxaban, apixaban, betrixaban, and edoxaban; and control agents included low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), or VKAs. Two trials evaluated dabigatran (2553 patients) and eight trials evaluated factor Xa inhibitors (three with apixaban [3307 patients], three with rivaroxaban [2548 patients], and two with edoxaban [2172 patients]).

The primary outcome of the review included recurrent venous thromboembolism (VTE), defined variably as clinically overt new deep vein thrombosis (DVT), PE, or either, confirmed by standard imaging during the period after PE diagnosis. Secondary outcomes included all-cause mortality, major bleeding (fatal bleeding, symptomatic bleeding in a critical area, bleeding causing a fall of hemoglobin ≥2 g/dL or requiring transfusion of ≥2 units, or any combination of these), and health-related quality of life.

Compared to conventional anticoagulation, DTIs led to a similar rate of recurrent PE (two trials, 1602 participants; moderate-certainty evidence), recurrent VTE (two trials, 1602 participants; moderate-certainty evidence), recurrent DVT (two trials, 1602 participants; moderate-certainty evidence), and major bleeding (two trials, 1527 participants; moderate-certainty evidence). Factor Xa inhibitors were also similar to conventional anticoagulation for recurrent PE (three trials, 8186 participants; moderate-certainty evidence), recurrent VTE (eight trials, 11,416 participants; moderate-certainty evidence), recurrent DVT (two trials, 8151 participants; moderate certainty evidence), all-cause mortality (one trial, 4817 participants; moderate-certainty evidence), and major bleeding (eight trials, 11,447 participants; low-certainty evidence). Authors did not evaluate quality of life.

Caveats

There are several important limitations to this systematic review. First, overall outcome event rates were low resulting in wide confidence intervals. While the included trials were mostly of good methodological quality, the certainty of evidence was considered moderate or low. The authors downgraded certainty for both imprecision and heterogeneity in the data. Second, the duration of treatment varied among the studies, ranging from 3 months to 1 year. Third, health-related quality of life was not reported. Fourth, while overall risk of bias was low in eight trials, two trials were at high risk of reporting bias, and six were open label.

Current guidelines incorporate treatment of VTE with DOACs due to efficacy, ease of use, and no need for monitoring. The American College of Chest Physicians guidelines recommend DOACs over VKAs for treatment of VTE, and these guidelines also recommend oral factor Xa inhibitors over LMWH for VTE associated with cancer.12, 13 The 2019 European Society of Cardiology also recommends DOACs over VKAs in those requiring treatment for VTE,2 while the NICE 2020 guidelines recommend apixaban or rivaroxaban as the initial anticoagulant of choice.4

Based on these data, there seems to be little or no outcome difference between DOACs and conventional anticoagulation for PE; however, DOACs provide several practical advantages including ease of use, fixed dosing, ability to initiate in the ED without the need for LMWH injections or UFH infusions, and no need for routine laboratory monitoring. Thus, we have provided a color recommendation of green (benefits > harms) for the use of DOACs in treatment of PE. It is difficult to directly compare prices due to variations in dosages, treatment regimens, and local cost data for DOACs versus warfarin14, 15, 16; however, in general, DOACs are significantly more expensive than conventional anticoagulation. For example, a 1-month supply of dabigatran costs more than $400, and a 1-month supply of rivaroxaban costs more than $500, though this depends on each individual patient's insurance.17, 18 In contrast, a 1-month supply of 5-mg tablets of warfarin (a traditional VKA) is about $11, though warfarin does require laboratory monitoring, which increases the price of use.19 Also of note, DOAC reversal may be more expensive (idarucizumab for dabigatran and prothrombin complex concentrate [PCC] or andexanet alpha for factor Xa inhibitors) compared to warfarin (vitamin K with fresh-frozen plasma or PCC).20 More studies are necessary to compare DOACs to each other, as well as to evaluate adherence, mortality, safety, quality of life, cost-effectiveness, and tolerability.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

Author

Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD

Published/Updated

August 10, 2023

References:

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