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Long B, Gottlieb M. Direct oral anticoagulants versus conventional anticoagulants for deep vein thrombosis. Academic Emergency Medicine. Published online June 23, 2023:acem.14763.

Study Population: 21 trials comprising 30,895 participants with confirmed DVT

Efficacy Endpoints

Recurrent VTE, all-cause mortality, and major bleeding

Harm Endpoints

N/A

Narrative

Deep vein thrombosis (DVT) has an incidence of approximately five per 10,000 annually.1^, 2^, 3 If DVT is not appropriately managed, the thrombus may progress or dislodge leading to pulmonary embolism (PE). DVT was traditionally treated with heparin and vitamin K antagonists (VKAs).2^, 3^, 4 However, oral direct thrombin inhibitors (DTIs) and oral factor Xa inhibitors, broadly known as direct oral anticoagulants (DOACs), demonstrate several characteristics that may be favorable to heparin and VKAs. DOACs can be administered orally, have a predictable effect without the need for frequent monitoring or dose adjustment, and have few medication interactions.5^, 6 Current guidelines have incorporated DOACs for management of DVT based on recent literature, suggesting that DOACs are safe and efficacious.7^, 8^, 9^, 10^, 11^, 12^, 13^, 14 A prior Cochrane systematic review evaluated 11 randomized controlled trials (RCTs) comprising 27,945 participants15; however, the publication of several new RCTs required an updated evaluation of DOACs in the treatment of DVT.10^, 11^, 12^, 13^, 14

This updated Cochrane review published in 2023 included RCTs of participants with confirmed DVT allocated to treatment with a DOAC or conventional anticoagulation.2 They did not include studies evaluating these treatments by other routes, trials not using conventional treatment with heparin and/or VKAs as the comparison, and trials with treatment less than 3 months. Confirmation of DVT was based on standard imaging (venography, impedance plethysmography, whole-leg compression ultrasound, proximal compression ultrasound). DTIs included dabigatran and ximelagatran; factor Xa inhibitors included rivaroxaban, apixaban, and edoxaban; and comparisons included low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), or VKAs (warfarin, acenocoumarol, phenprocoumon, and fluindione).

The Cochrane review utilized three primary outcomes. The first included recurrent venous thromboembolism (VTE), which was defined as a clinically overt DVT confirmed by standard imaging such as proximal leg vein ultrasound scan and/or D-dimer test or a clinically overt PE confirmed by imaging including computed tomography pulmonary angiography (CTPA) and/or ventilation/perfusion scan. The second was a recurrent DVT confirmed by standard imaging including proximal leg ultrasound or D-dimer. The third primary outcome included PE (fatal and nonfatal) confirmed by imaging. Secondary outcomes included all-cause mortality, major bleeding (fatal bleeding, symptomatic bleeding in a critical area/organ, bleeding causing a fall of hemoglobin ≥2 g/dL or requiring transfusion of ≥2 units, or any combination), post-thrombotic syndrome (PTS), and health-related quality of life (as reported by the individual studies).

The systematic review included 21 trials (n = 30,895 participants).2 Three studies investigated DTIs (two dabigatran and one ximelagatran), 17 studies investigated factor Xa inhibitors (eight rivaroxaban, five apixaban, and four edoxaban), and one trial with three arms investigated both a DTI (dabigatran) and a factor Xa inhibitor (rivaroxaban).

DTIs compared to conventional anticoagulation did not reduce the rate of recurrent VTE (odds ratio [OR] 1.17, 95% confidence interval [CI] 0.83–1.65; three studies, 5994 participants; moderate-certainty evidence), recurrent DVT (OR 1.11, 95% CI 0.74–1.66; three trials, 5994 participants; moderate-certainty evidence), fatal PE (OR 1.32, 95% CI 0.29–6.02; three trials, 5994 participants; moderate-certainty evidence), nonfatal PE (OR 1.29, 95% CI 0.64–2.59; three trials, 5994 participants; moderate-certainty evidence), or all-cause mortality (OR 0.66, 95% CI 0.41–1.08; one trial, 2489 participants; moderate-certainty evidence).16^, 17^, 18 However, DTIs reduced the risk of major bleeding (OR 0.58, 95% CI 0.38–0.89; absolute risk difference [ARD] 0.80%; number needed to treat [NNT] 125; three studies, 5994 participants; high-certainty evidence) compared to conventional anticoagulation.

Factor Xa inhibitors compared to conventional anticoagulation did not reduce rate of recurrent VTE (OR 0.85, 95% CI 0.71–1.01; 13 trials, 17,505 participants; moderate-certainty evidence), recurrent DVT (OR 0.70, 95% CI 0.49–1.01; nine trials, 16,439 participants; moderate-certainty evidence), fatal PE (OR 1.18, 95% CI 0.69–2.02; 6 trials, 15,082 participants; moderate-certainty evidence), nonfatal PE (OR 0.93, 95% CI 0.68–1.27; seven trials, 15,166 participants; moderate-certainty evidence), or all-cause mortality (OR 0.87, 95% CI 0.67 to 1.14; nine trials, 10,770 participants; moderate-certainty evidence). However, factor Xa inhibitors reduced the risk of major bleeding (OR 0.63, 95% CI 0.45–0.89; ARD 0.86%; NNT 116; 17 studies, 18,066 participants; high-certainty evidence). Only one trial evaluated PTS, and one study evaluated health-related quality of life, preventing the systematic review from drawing clear conclusions regarding these outcomes.

Caveats

There are several limitations to the findings of this systematic review.2 The overall outcome event rates were low, resulting in wide CIs and limited precision, though heterogeneity was low for all reported outcomes. The Cochrane review only included patients with DVT, so it is difficult to draw conclusions regarding treatment failures or mortality in patients with PE. Importantly, the Cochrane review included D-dimer for diagnosis of DVT or PE as part of the primary outcome, which may have led to incorrect diagnoses in some cases, as D-dimer test should only be used to exclude the diagnosis of VTE, and imaging is necessary for VTE diagnosis. The duration of treatment varied among the studies, ranging from 3 months to 1 year. Almost all participants had DVT of the lower extremities, and thus authors did not address DVT of the upper extremities. Of note, ximelagatran was withdrawn from the market in 2006 due to safety issues, though only one study evaluated this medication.18 While it is difficult to compare prices due to various dosages and treatment regimens, 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 $500.19^, 20 In contrast, a 1-month supply of 5-mg tablet of warfarin (a traditional VKA) is approximately $11.21 However, warfarin requires regular monitoring, which is inconvenient for patients and associated with increased cost, and the medication has numerous dietary restrictions and medication interactions.

Based on the existing data, DOACs have similar efficacy but a better safety profile (lower risk of major bleeding) than conventional anticoagulation for treatment of DVT. Additionally, DOACs provide a practical benefit with ease of use, fewer medication interactions, and no requirement for frequent laboratory monitoring. Thus, we have assigned a color recommendation of green (benefits > harms) for the use of DOACs in treatment of DVT. Of note, DOACs are renally excreted and may require dose adjustment in those with chronic kidney disease (CKD). Further studies should include subjects with CKD and those with DVT in unusual sites (e.g., upper extremities) as well as those with specific health conditions such as subjects who have obesity and malignancy.

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

July 18, 2023