Edoxaban noninferior to warfarin for cancer, VTE

Edoxaban may more effectively treat venous thromboembolism and produce less clinically relevant bleeding than warfarin in patients with cancer, according to a subgroup analysis of a randomized, double blind, double-dummy, open-label trial.

VTE is a common adverse event in patients with cancer. Direct oral anticoagulants, such as edoxaban (Savaysa, Daiichi Sankyo), have been proven noninferior to conventional anticoagulation treatments.

Gary E. Raskob, PhD, dean and regents professor at University of Oklahoma Health Sciences Center’s College of Public Health, and colleagues surmised that edoxaban may serve as a better treatment platform for cancer-associated VTE than traditional anticoagulation.

The researchers conducted a subgroup analysis of the Hokusai-VTE trial, which consisted of patients with cancer and acute symptomatic deep vein thrombosis or acute symptomatic pulmonary embolism.

The subgroup analysis focused on patients with a history of cancer, as well as those deemed to have active cancer at study entry.

The study included data from 771 adult patients assigned to 60 mg daily edoxaban (n = 378) or warfarin (n = 393). The most common solid tumors in the population were breast (enoxaban, 18%; warfarin, 15%), prostate (14%, 10%) and colorectal (10% for both) cancers; the most common hematologic malignancies were lymphoma (3%, 5%) and leukemia (3%, 2%).

All patients received edoxaban or unfractionated heparin for 5 days; edoxaban treatment commenced after discontinuation of initial heparin and warfarin began concurrently.

The incidence of symptomatic recurrent VTE during the study period served as the trial’s primary efficacy endpoint. Clinically relevant bleeding among patients who received at least one dose of the study drug served as the primary safety endpoint.

Fourteen patients (4%) assigned edoxaban experienced recurrent VTE, compared with 28 patients (7%) assigned warfarin (HR = 0.53; 95% CI, 0.28-1).

The upper limit of the 95% CI did not exceed the trial’s prespecified noninferiority margin of 1.5.

Major or nonmajor clinically relevant bleeding occurred in 47 patients (12%) assigned edoxaban and 74 patients (19%) assigned warfarin (HR = 0.64; 95% CI, 0.45-0.92).

Among patients with active cancer while on study (edoxaban, n = 109; warfarin, n = 99), 10 patients (3%) assigned edoxaban and 13 (3%) patients assigned warfarin experienced major bleeding (HR = 0.8; 95% CI, 0.35-1.83).

Eighty patients (n = 40 for each group) died during the study period, 57 of whom were deemed to have active cancer (edoxaban, n = 31; warfarin, n = 26).

The researchers acknowledged several study limitations. They noted that many patients with active cancer were probably not enrolled in the initial trial due to guidelines recommending extended low–molecular-weight heparin for treatment.

The researchers further noted that drug interactions between edoxaban and other direct oral anticoagulants have not been completely clarified.

“The ultimate role of edoxaban for treatment of patients with cancer with VTE requires further research, because low–molecular-weight heparin, not warfarin, is the anticoagulant recommended for such patients based on evidence-based practice guidelines,” Raskob and colleagues wrote. “Despite this recommendation, some patients receive warfarin for long-term anticoagulation either because of patient preference for oral therapy, or because of an absence of private insurance or health-system coverage of low–molecular-weight heparin, which is more expensive than warfarin. Our results suggest that edoxaban could be a useful alternative for such patients.”

Additional data are needed before direct oral anticoagulants become a standard of care in this patient population, Simon I.R. Noble, MBBS, MD, FRCP, of Cardiff University and Royal Gwent Hospital in Wales, wrote in an accompanying editorial.

“The use of direct-acting oral anticoagulants is restricted with some chemotherapy drugs, especially those that interact with P-glycoprotein and cytochrome P450 3A4,” Noble wrote. “Real-world data suggest that at least 60% of cancer-associated VTE is precipitated during chemotherapy, yet for these patients use of direct-acting oral anticoagulants might be restricted according to particular chemotherapy regimen.

“Renal clearance of direct-acting oral anticoagulants will be of concern until we can identify whether they accumulate during renal impairment,” Noble continued. “Therefore, the challenges that direct-acting oral anticoagulants present in the cancer setting will not be addressed by the demonstration of noninferiority alone.” – by Cameron Kelsall

 

Disclosure: Daiichi Sankyo funded this research. Raskob reports honoraria from and consultant roles with Bayer HealthCare, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Janssen, Johnson & Johnson, Pfizer, and Portola. Please see the full study for a list of all other researchers’ relevant financial disclosures. Noble reports unpaid advisory board and speakers bureau positions with Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma and Pfizer.