The efficacy and safety of DOACs versus LMWH for cancer-associated thrombosis: A systematic review and meta-analysis

To the Editor:

Venous thromboembolism (VTE) remains the second most common cause of death in cancer patients.¹ Direct oral anticoagulants (DOACs) have revolutionized treatment of VTE, though cancer patients were underrepresented in early trials.^2-4 Low-molecular-weight heparins (LMWH) have been the gold standard for treatment of cancer-associated thrombosis (CAT)^5,6 until publication of several randomized controlled trials (RCT) exploring DOACs for CAT.^7,8 In 2019, two systematic reviews and meta-analyses evaluated two RCTs^7,8 and showed a trend toward reduced VTE recurrence and increased major bleeding with DOACs compared with LMWH.^9,10 We performed an updated systematic review and meta-analysis on the efficacy and safety of DOACs for CAT.

We searched MEDLINE, CENTRAL, and manually searched meeting abstracts to identify all randomized clinical trials comparing DOACs to LMWH for CAT since the previous analysis⁹ (search criteria described in the Supplement). Data were extracted on study design and characteristics, VTE recurrence, major bleeding, clinically relevant non-major bleeding (CRNMB) rates, and mortality. Relative risks (RR) were calculated with a corresponding 95% confidence interval (CI) using a Mantel-Haenszel random-effects model. All analysis was performed with Review Manager (version 5.3 The Cochrane Collaboration, 2014).

In addition to the HOKUSAI VTE Cancer and SELECT-D trials, our systematic review ultimately yielded two new RCTs examining apixaban versus LMWH (ADAM VTE and Caravaggio) for treatment of acute CAT.^11,12 Together, these trials included 2894 patients, with 1446 randomized to DOAC and 1448 randomized to LMWH.

Our updated meta-analysis demonstrated a statistically significant reduction in VTE recurrence in CAT treated with DOACs (75/1446, 5.2%) compared to LMWH (119/1448, 8.2%) (HR 0.62, 95% CI 0.43-0.91, P = .01, I² = 30%), a number needed to treat of 33. The risk of major bleeding was non-significantly higher with DOACs (62/1446, 4.3%) compared with LMWH (48/1448, 3.3%) (HR 1.31, 95% CI 0.83-2.08, P = .27, I² = 23%), number needed to harm (NNH) of 103, while the incidence of CRNMB was significantly higher with DOACs (150/1446, 10.4%) compared with LMWH (92/1448, 6.4%) (HR 1.65, 95% CI 1.19-2.28, P = .002, I² = 29%), NNH of 25. Mortality was comparable with DOACs (346/1446, 23.9%) compared with LMWH (351/1448, 24.2%) (HR 0.99, 95% CI 0.83-1.18, P = .93, I² = 37%). See Figure 1 for full details.

FIGURE 1.

Forest plots of pooled outcome comparisons for DOAC and LMWH for (A) VTE recurrence, (B) major bleeding, (C) clinically relevant non-major bleeding, and (D) overall mortality

To our knowledge, this meta-analysis represents the most up-to-date assessment of pooled efficacy and safety from RCTs specific to cancer patients comparing DOACs to LMWH for treatment of CAT. While prior analyses showed only a trend toward improvement of VTE prevention with DOACs,^9,10,13,14 our analysis integrated recent apixaban studies and showed a significant improvement, but with a trend toward more major bleeding and a significant increase in non-major bleeding. Patient heterogeneity may explain some of the differences in bleeding rates among the included studies with some studies limiting the enrollment of patients with upper GI cancers given concerns for increased rates of bleeding in this population.¹⁵

In summary, these results provide additional support for the effectiveness of DOACs compared to LMWH for preventing recurrent thrombosis in CAT, though a persistently increased bleeding signal requires specific patient considerations including bleeding risks and cancer type before considering the best anticoagulation strategy.