Mulder FI, Bosch FTM, Young AM, et al. Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis. Blood. 2020 Sep 17;136(12):1433-1441. doi: 10.1182/blood.2020005819. (Systematic review)

Direct oral anticoagulants (DOACs) are an emerging treatment option for patients with cancer and acute venous thromboembolism (VTE), but studies have reported inconsistent results. This systematic review and meta-analysis compared the efficacy and safety of DOACs and low-molecular-weight heparins (LMWHs) in these patients. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and conference proceedings were searched to identify relevant randomized controlled trials. Additional data were obtained from the original authors to homogenize definitions for all study outcomes. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively. Other outcomes included the composite of recurrent VTE and major bleeding, clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Summary relative risks (RRs) were calculated in a random effects meta-analysis. In the primary analysis comprising 2607 patients, the risk of recurrent VTE was nonsignificantly lower with DOACs than with LMWHs (RR, 0.68; 95% CI, 0.39-1.17). Conversely, the risks of major bleeding (RR, 1.36; 95% CI, 0.55-3.35) and CRNMB (RR, 1.63; 95% CI, 0.73-3.64) were nonsignificantly higher. The risk of the composite of recurrent VTE or major bleeding was nonsignificantly lower with DOACs than with LMWHs (RR, 0.86; 95% CI, 0.60-1.23). Mortality was comparable in both groups (RR, 0.96; 95% CI, 0.68-1.36). Findings were consistent during the on-treatment period and in those with incidental VTE. In conclusion, DOACs are an effective treatment option for patients with cancer and acute VTE, although caution is needed in patients at high risk of bleeding.

Discipline Area Score
Physician 7 / 7
Comments from MORE raters

Physician rater

This is a carefully performed meta-analysis of 4 studies comparing a DOAC to a LMWH in patients with active cancer. The studies themselves were of high quality. All showed lower incidence of recurrent VTE; 2 showed higher major bleeding, while one showed significantly lower, and another showed somewhat lower major bleeding. Two showed higher, two showed lower overall mortality. In summary, recurrent VTE rates were 32% lower with DOACs, and major bleeding was 36% higher (note these are non-comparable percent differences, as the n's were different). In none of the categories were the differences statistically significant, except (barely) in risk of recurrent VTE. The judgement remains with treating oncologists/hematologists, hospitalists, internists, and family physician to balance risk vs benefit. I conclude that DOACs offer a suitable alternative to an injectable agent, depending on clinician assessment of risk and evaluation of patient preferences.

Physician rater

This interesting article provides evidence that the discomfort of long-term heparin administration can be avoided also in cancer patients.

Physician rater

This formal meta-analysis confirms what was apparent from the individual study results: DOACs vs LMWH for cancer associated thrombosis are associated with less recurrent VTE, more major and CRNM bleeding and the same overall net clinical benefit (composite of recurrent VTE and major bleeding). Caveat: patients with luminal GI are at a higher risk for DOAC-related bleeding than other oncologic patients. Society guidelines already reflect the results of this paper which lends them credence.
Comments from CLOT+ subscribers

Dr. John Blakely (9/27/2020 1:36 PM)

The SPORTIF trials demonstrate that NOAC trials must be double-blind to be valid. Although I have not checked the designs of all these trials, I am aware that at least three were not blinded. It would be fine to do a meta-analysis of the double-blind (and double-dummy) trials and it would be nice if patients with malignancy and VTE could be spared needles, but this is not the conclusion of the trials. The methodology is key.