Oral Anticoagulants Show Benefit for Cancer Patients at High Risk of Venous Thromboembolism

Venous thromboembolism (VTE) is the second leading cause of death for cancer patients after cancer itself. To prevent it, the American Society of Clinical Oncology (ASCO) guidelines recommend prescribing low-molecular heparin (LMWH).

Using LMWH to prevent VTE in cancer patients, however, is complicated. LMWH clinical trials were not risk-adapted, so physicians don’t know how well they work in high-risk patients. In addition, because most cancer patients today are not hospitalized while receiving treatment, cancer patients who are prescribed an LWMH must inject themselves at home.

“Daily self-injection is a barrier to patient compliance,” says Alok Khorana, MD, Hematology and Medical Oncology, Cleveland Clinic. “In addition, physicians don’t know how well LWMH works in high-risk VTE cancer patients, which is who you want to focus on because taking blood thinners also carries a risk of bleeding.”

Now a new multicenter trial — that was risk-adapted — shows oral anticoagulants might be a better way to treat high-risk VTE cancer patients. Results of the CASSINI trial showed that the oral anticoagulant rivaroxaban significantly reduced VTE and VTE-related deaths for outpatient, at-risk cancer patients.

“This could potentially signal a change in the prevention approaches to cancer-associated VTE,” says Dr. Khorana, who was co-chair of the steering committee of the trial and presented the results as a late-breaking abstract at the 2018 American Society of Hematology meeting. The results were also published in the New England Journal of Medicine in February 2019.

He also presented another just published study in the journal Research and Practice in Thrombosis and Haemostasis showing that using lower extremity ultrasonography screening on high-risk VTE cancer patients prior to cancer treatment can identify patients with pre-existing, subclinical, deep-vein thrombosis (DVT).

Fewer blood clots

CASSINI included 841 patients, of which 274 (32.6 percent) had pancreatic cancer; 698 (83 percent) were white and 428 (50.9 percent) were male. Patients were randomized 1:1 to rivaroxaban 10 mg once daily or a placebo for 180 days.

Each patient’s risk of blood clots was identified at the time of chemotherapy initiation by the Khorana Score, previously designed by Dr. Khorana and colleagues. The score predicts blood clots based on simple variables: cancer type, body mass index and complete blood count (platelet, leukocyte, hemoglobin). Patients with a Khorana score of 2 or greater are considered at higher risk for developing blood clots, and were included in the trial.

Only 2.62 percent of patients who took rivaroxaban developed blood clots compared with 6.41 percent of the placebo group. In addition, those taking rivaroxaban were less likely to die — 23.1 percent, compared with 29.5 percent in the placebo group. Less than 2 percent of patients suffered major bleeding, a side effect of anticoagulants — on par with what would be expected with prophylactic anticoagulation in cancer patients.

Procoagulant state persists

After the patients stopped taking rivaroxaban, trial investigators continued to observe them for an additional 180 days. The gap between the two groups narrowed with 5.95 percent of the previous rivaoxaban patients developing blood clots during this period compared with 8.79 percent of the placebo patients. This led to the primary analysis period of 180 days not being statistically significant.

“It shows that the procoagulant state in cancer is persistent,” says Dr. Khorana. “If you get a knee or hip replacement, the clotting state lasts for a few weeks after surgery then it goes away. But in patients with advanced cancer, it’s pretty clear based on this trial that the risk of getting a blood clot doesn’t go away.”

Screen prior to cancer treatment

Eighteen months ago, Dr. Khorana and colleagues began a study in which they created an electronic health record alert that identified high-risk VTE cancer patients on the Khorana score (score of 3 or higher for this project). The alert also prompted physicians to screen those patients’ lower extremities for blood clots before initiating cancer treatment.

The study had an initial silent phase — from Aug. 2016 through Jan. 2017 — that involved 194 patients. Fourteen (7.2 percent) developed subsequent DVT or pulmonary embolism (PE) over 90-day follow-up, with a median of 27 days.

During the active phase — from June 2017 through Dec. 2017— an alert occurred when a physician opened a high-risk patient’s electronic records and suggested a bilateral, lower-extremity screening ultrasound. It fired only once per provider for each patient, with the option to accept, ignore or to repeat at a later time.

During this phase, 197 alerts met the inclusion criteria, and 40 patients (20.3 percent) received a screening ultrasound. Five (12.5 percent) had a DVT and were started on therapeutic anticoagulation. Of patients with alerts who had screening deferred, 13 (8.3 percent) were later diagnosed with DVT (median 50.5 days) and seven (4.5 percent) with PE.

“This prescreening for blood clots in high-risk cancer patients is something we’re doing at Cleveland Clinic that’s very unique,” Dr. Khorana says. “And we’re seeing a lot of potential benefits for patients.”