DOACs show promise over heparin injections in meta-analysis comparing cancer-associated VTE treatments

Kirtipal Bhatia

A recent meta-analysis found that direct oral anticoagulants (DOACs) appear to be a “reasonable alternative” to low molecular weight heparin (LMWH) for the treatment of venous thromboembolism (VTE) in cancer patients. The study appeared online on 25 July in The American Journal of Cardiology.

Authors Kirtipal Bhatia (Icahn School of Medicine at Mount Sinai, New York, USA) and colleagues write that LMWH is considered the standard anticoagulant therapy for patients with cancer-associated VTE. However, they note that while the efficacy and safety of DOACs in the treatment of VTE in patients without cancer has been validated, their role in cancer-associated VTE is still evolving.

Bhatia et al therefore conducted a meta-analysis of the published randomised controlled trials (RCTs) comparing DOACs with LMWH for the treatment of VTE in cancer patients.

The investigators performed a comprehensive literature search of electronic databases (Embase, MEDLINE, and Cochrane Central) from inception to 30 May 2020 using a predefined search strategy and included all RCTs comparing DOACs with LMWH in cancer associated VTE.

Bhatia and colleagues detail that the principal efficacy outcome was recurrence of VTE, either symptomatic or incidentally discovered. The principal safety outcome was incidence of major bleeding (defined as overt bleeding leading to a decrease in the haemoglobin level of ≥2g/dL, transfusion of two or more units of blood, occurring at a critical site, or fatal bleeding).

They write that secondary outcomes included clinically relevant non-major bleeding (CRNMB) and all-cause mortality. CRNMB was defined as clinically overt bleeding not meeting for criterial for major bleeds, associated with impairment of daily living or requiring medical attention. All outcomes were assessed at six months.

For statistical analysis, the investigators calculated pooled risk ratios (RRs) with 95% confidence intervals (CI) using a random-effect model.

Writing in The American Journal of Cardiology, Bhatia et al state that they included four RCTs in with a total of 2,894 patients in the study-level meta-analysis. Of these 2,894 patients, 1,446 received a DOAC and 1,448 received LMWH. Almost all patients had active cancer (98–100%) and were receiving concurrent cancer treatment (57–73%). Patients with a poor functional status (Eastern Cooperative Oncology Group [ECOG] performance score >2) and those with basal cell or squamous cell skin cancer were excluded.

Bhatia and colleagues report that recurrent VTE at six months was decreased in patients treated with DOACs compared to LMWH (5.2% vs. 8.2%; RR 0.62, 95% CI 0.43–0.91; p=0.01; I2=30%). In addition, CRNMB was higher with DOACs as compared to LMWH (10.3% vs. 6.3%; RR 1.65, 95% CI 1.19–2.28; p=0.002; I2=29%), driven largely by increased gastrointestinal and genitourinary bleeding.

Furthermore, there was no difference between DOACS and LMWH in either major bleeding (4.3% vs. 3.3%; RR 1.31, 95% CI 0.83–2.08; p=0.25; I2=23%) or in all-cause mortality (23.9% vs. 24.2%; RR 0.99, 95% CI 0.83–1.18; p=0.93; I2=37%). The degree of heterogeneity between the studies ranged from low to moderate.

Commenting on the significance of these results, Bhatia and colleagues write: “Our meta-analysis supports the use of DOACs as an effective alternative to LMWH for the treatment of VTE in patients with cancer.”

They continue: “The pooled analysis of study-level data shows a statistically significant reduction in recurrent VTE at six months with DOACs as compared to LMWH.” However, they acknowledge that this decreased in recurrent VTE occurred at the cost of increased bleeding events, largely driven by CRNMB, with no different in major bleeding or mortality.

The authors also consider the place of this study within the literature. They note that the HOKUSAI-VTE and SELECT-D trials compared edoxaban and rivaroxaban, respectively, to LMWH, and that the ADAM-VTE trial was the first to compare apixaban to LMWH in cancer-associated VTE and showed lower risk of recurrent VTE with apixaban. “However,” the authors note, “these individual trials were not powered to detect superiority for efficacy outcomes.”

Subsequently, the CARAVAGGIO study compared apixaban to LMWH for the treatment of VTE in patients with cancer. This trial randomised 1,170 patients, the largest study to date, and demonstrated that apixaban was non-inferior to LMWH for the prevention of cancer-associated recurrent VTE, major bleeding, CRNMB, and all-cause mortality.

“We found low to moderate heterogeneity in these studies, which may be related to the use of different DOACs, varying proportions of underlying cancers, cancer treatment modalities, and subtle differences in the defined outcomes,” Bhatia and colleagues write. “Furthermore, all four studies are limited by their open-label design and small to moderate patients popoulations.”

The senior author of the study, Arman Qamar, (NorthShore University Health System, University of Chicago Pritzker School of Medicine, Chicago, USA) shared with Venous News that DOACS appear to be a “reasonable alternative” to LMWH for the treatment of cancer-associated VTE and should be more frequently prescribed. He also highlighted that the major advantages of DOACs over LMWH include its lower cost and the ease of its administration as compared with LMWH injections.


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