Optimizing the use of DOACs in VTE management
Direct oral anticoagulants (DOACs) are effective and safe alternatives to vitamin K antagonists (VKAs) in venous thromboembolism (VTE) management. At a Daiichi Sankyo-sponsored webinar organized by the Hong Kong Society for Thrombosis and Haemostasis, Professor Harry Buller of the University of Amsterdam, the Netherlands, discussed the advantages of DOACs vs VKAs and low-molecular-weight heparin (LMWH), as shown in the Hokusai VTE and Hokusai VTE Cancer studies, respectively, which support the use of the oral factor Xa inhibitor edoxaban in the management of patients with VTE, including those with cancer-associated VTE.
Advantages of DOACs vs VKAs in VTE management
A meta-analysis of six phase III trials compared DOACs (ie, dabigatran etexilate, rivaroxaban, apixaban, or edoxaban) vs VKAs for the treatment of patients (n=27,023) with symptomatic deep vein thrombosis, pulmonary embolism, or both. Results showed that recurrent VTE occurred in 2.0 percent of DOAC recipients vs 2.2 percent of VKA recipients (relative risk [RR], 0.90; 95 percent confidence interval [CI], 0.77 to 1.06). Importantly, DOACs significantly reduced the risk of major bleeding vs warfarin (RR, 0.61; 95 percent CI, 0.45 to 0.83). [Blood 2014;124:1968-1975]
“Compared with VKAs, DOACs were associated with significantly less intracranial bleeding [RR, 0.37; 95 percent CI, 0.21 to 0.68] and fatal bleeding [RR, 0.36; 95 percent CI, 0.15 to 0.84], as well as less major gastrointestinal [GI] bleeding [RR, 0.78; 95 percent CI, 0.47 to 1.31] and clinically relevant nonmajor [CRNM] bleeding [RR, 0.73; 95 percent CI, 0.58 to 0.93],” said Buller. [Blood 2014;124:1968-1975]
“Thus, DOACs are effective and comparable to VKAs in protecting patients from recurrent VTE, and may be safer alternatives to VKAs,” he added.
Hokusai VTE: Edoxaban noninferior, safer vs warfarin
Included in the aforementioned meta-analysis is the randomized, double-blind Hokusai VTE trial involving patients with acute VTE who initially received heparin followed by either warfarin or oral edoxaban 60 mg QD (or 30 mg QD for those requiring dose reduction [ie, creatinine clearance 30–50 mL/min, body weight ≤60 kg, or receiving concomitant P-glycoprotein inhibitors]) for 3–12 months. [N Engl J Med 2013;369:1406-1415]
Overall efficacy results showed that edoxaban was noninferior to warfarin in preventing recurrent symptomatic VTE, which occurred in 3.2 percent of patients in the edoxaban group vs 3.5 percent of patients in the warfarin group (hazard ratio [HR], 0.89; 95 percent, 0.70 to 1.13; p<0.001 for inferiority).
“Hokusai VTE had the highest external validity due to its unique study design, namely, its follow-up period of 12 months regardless of the duration of treatment, whereas previous studies included on-treatment analyses only,” explained Buller. “This allowed for better understanding of outcomes that may be seen in actual clinical practice.”
Edoxaban also demonstrated significantly less bleeding, with major or CRNM bleeding occurring in 8.5 percent of patients in the edoxaban group vs 10.3 percent of patients in the warfarin group (HR, 0.81; 95 percent CI, 0.71 to 0.94; p=0.004 for superiority).
Edoxaban in East Asian patients
“Hokusai VTE included 1,109 patients from Japan, China, Korea and Taiwan. Subgroup analysis showed that efficacy and safety results in these East Asian patients were consistent with overall results of the main trial,” said Buller. [J Thromb Haemost 2015;13:1606-1614]
Among East Asian patients, symptomatic recurrent VTE occurred in 2.8 percent of those treated with edoxaban vs 4.5 percent of those treated with warfarin (HR, 0.64; 95 percent CI, 0.34 to 1.19; p=0.1601). Clinically relevant bleeding (ie, major and CRNM bleeding) occurred in significantly fewer East Asian patients who received edoxaban vs warfarin (9.9 percent vs 17.3 percent; HR, 0.56; 95 percent CI, 0.40 to 0.78; p<0.001).
“Edoxaban may be a safer choice than warfarin, especially for East Asian patients. Among those who received warfarin in Hokusai VTE, clinically relevant bleeding occurred in 9.2 percent of non-East Asian patients vs 17.3 percent of East Asian patients,” he noted.
Edoxaban at 30 mg
“Another subgroup analysis of Hokusai VTE showed that the efficacy and safety of edoxaban were maintained even after dose reduction to 30 mg QD,” said Buller. [Thromb Haemost 2016;116:747-753]
Rates of recurrent VTE were comparable between the 30 mg and 60 mg doses of edoxaban (3.0 percent and 3.2 percent, respectively), while clinically relevant bleeding rates were also similar (7.9 percent and 8.6 percent, respectively). Meanwhile, recurrent VTE and bleeding in warfarin-treated patients meeting the dose-reduction criteria were 4.2 percent and 12.8 percent, respectively. These results demonstrated that the 30 mg dose of edoxaban maintained the efficacy and safety of the 60 mg dose, and was safer than warfarin in patients who met the dose-reduction criteria.
DOACs in cancer-associated VTEs
The open-label Hokusai VTE Cancer trial investigated the role of DOACs in patients with cancer and acute symptomatic or incidental VTE. Patients were randomized to receive either standard LMWH for at least 5 days followed by oral edoxaban (60 mg QD, or 30 mg QD in patients who met the dose-reduction criteria), or subcutaneous dalteparin (200 IU/kg QD for 1 month, then 150 IU/kg QD) for at least 6 months and up to 12 months. [N Engl J Med 2018;378:615-624]
Results showed that edoxaban was noninferior to dalteparin, with the composite primary outcome of recurrent VTE or major bleeding occurring in 12.8 percent of patients in the edoxaban group vs 13.5 percent in the dalteparin group (HR, 0.97; 95 percent CI, 0.70 to 1.36; p=0.006 for noninferiority; p=0.87 for superiority).
“While major bleeding occurred more frequently in the edoxaban vs dalteparin group [6.9 percent vs 4 percent], this was mainly driven by upper GI major bleeding, which occurred primarily in patients with GI cancer,” Buller explained. “Nevertheless, the frequency of severe major bleeding [ie, category 3 or 4] was similar between edoxaban and dalteparin [1.9 percent vs 2.1 percent].”
Other studies assessing the role of DOACs vs LMWH in VTE treatment in cancer patients include the prospective SELECT-D trial, which compares rivaroxaban vs dalteparin, and the CARAVAGGIO trial, which compares apixaban vs dalteparin. These two trials had a treatment and follow-up duration of up to 6 months. [Thromb Res 2016;140(Suppl 1):s172-s173; https://clinicaltrials.gov/ct2/show/NCT03045406]
A systematic review and meta-analysis of the three trials showed that the risk of the composite of recurrent VTE or major bleeding was not significantly lower for DOACs vs LMWHs (RR, 0.86; 95 percent CI, 0.60 to 1.23). “Overall, these trials demonstrated that DOACs are effective treatment options for patients with cancer and acute VTE,” the authors concluded. [Blood 2020;136:1433-1441]
DOACs have emerged as effective and safe alternatives to VKAs for prevention of recurrent VTE. In particular, results of the Hokusai VTE study demonstrated that edoxaban may be more appropriate for East Asian patients than warfarin, and that its efficacy and safety are maintained even after dose reduction. The Hokusai VTE Cancer study demonstrated noninferiority of edoxaban vs the standard LMWH treatment in patients with cancer-associated VTE. (Table)