Clinical Trials Show Direct Oral Anticoagulants Are Safe, Effective for Cancer-Related Venous Thromboembolism

Slightly greater risk of bleeding

One in five cancer patients will get a blood clot at some point during the natural history of their illness. This complication can require hospitalization and interrupt cancer treatments.

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For cancer patients with a clot in the venous system, referred to as venous thromboembolism (VTE), the standard treatment has been low-molecular-weight heparin (LMWH) for six months. Now, however, the results of two clinical trials have shown that a newer class of drugs called direct oral anticoagulants (DOAC) is safe and effective for the majority of cancer patients with this condition.

“In the past year, we’ve had the results of two large randomized trials presented that compared cancer VTE patients treated with direct oral anticoagulants and low-molecular-weight heparin,” says Alok Khorana, MD, of Cleveland Clinic’s Department of Hematology and Medical Oncology. “Patients who took the direct oral anticoagulants had a lower risk of the clot’s coming back, but a slightly greater risk of bleeding.”

Dr. Khorana and colleagues who are on the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH) published a guidance statement in the June issue of the Journal of Thrombosis and Haemostasis describing the result of the trials and offering guidance for physicians treating cancer-related VTE.

Change in treatment paradigm

The researchers looked at two clinical trials, HOKUSAI Cancer and Select-D. In the first, patients were given either LMWH for at least five days followed by oral edoxaban or subcutaneous dalteparin once daily for six months. In the second, patients were given either dalteparin or rivaroxaban, another DOAC.

Both trials showed that treatment with a DOAC worked better at preventing a VTE recurrence than treatment with LMWH. However, both trials showed a higher risk of bleeding among patients — especially those with gastrointestinal cancers and genitourinary cancers — who were treated with DOACs.

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The researchers looked at other studies as well, including a recently published literature review describing all observational studies looking at the use of LMWHs versus DOACs for cancer patients with VTE. Nearly all studies reported lower rates of recurrent VTE for patients receiving DOACs than for those receiving LMWHs.

“This is a big change in the treatment paradigm for cancer-associated VTE,” says Dr. Khorana. “We are moving away from the dominance of low-molecular-weight heparins into a new era of direct oral anticoagulants, which frankly are more convenient to use. It’s a win-win for cancer patients.”

Recommendations for using DOACs

To help physicians navigate the landscape of using DOACs to treat cancer patients with VTE, Dr. Khorana and colleagues from ISTH created the following guidelines:

1. We recommend individualized treatment regimens after shared decision-making with patients.

2. We suggest the use of specific DOACs for cancer patients with an acute diagnosis of VTE, low risk of bleeding, and no drug-drug interactions with current systemic therapy. LMWHs constitute an acceptable alternative. Currently, edoxaban and rivaroxaban are the only DOACs that have been compared with LMWH in RCTs in cancer populations. A final treatment recommendation should be made after shared decision-making with patients regarding a potential reduction in recurrence but higher bleeding rates with specific DOACs, incorporating patient preferences and values.

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3. We suggest the use of LMWHs for cancer patients with an acute diagnosis of VTE and a high risk of bleeding, including patients with luminal gastrointestinal cancers with an intact primary; patients with cancers at risk of bleeding from the genitourinary tract, bladder or nephrostomy tubes; or patients with active gastrointestinal mucosal abnormalities such as duodenal ulcers, gastritis, esophagitis or colitis. Specific DOACs (edoxaban and rivaroxaban) are acceptable alternatives if there are no drug-drug interactions with current systemic therapy. A final treatment recommendation should be made after shared decision-making with patients regarding a potential reduction in recurrence but higher bleeding rates with specific DOACs, incorporating patient preferences and values.

Preventing VTE in cancer patients

Dr. Khorana and colleagues are also turning their attention to studying how to prevent cancer-associated VTE in the first place. He and Keith McCrae, MD, also of Cleveland Clinic’s Department of Hematology and Medical Oncology, recently won a $4.7 million grant from the National Heart, Lung and Blood Institute (NHLBI) to study the prevention of life-threatening, cancer-associated thrombosis.

The grant supports the creation of a new risk-assessment tool to better predict which cancer patients will develop blood clots during treatment.

“One in five cancer patients will get a blood clot, which also means that four in five cancer patients will not,” says Dr. Khorana. “The grant that we received is for identifying which cancer patients are at high risk for getting blood clots and then potentially using that information to target them with prophylactic drugs so we can reduce the overall burden of getting blood clots in the first place.”