Edoxaban Approved to Reduce Stroke Risk in Nonvalvular AF and to Treat VTE

January 8, 2015—Daiichi Sankyo Company, Limited announced that the US Food and Drug Administration (FDA) has approved the company’s Savaysa (edoxaban) tablets, an oral, once-daily selective factor Xa inhibitor, to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). The FDA also approved Savaysa for the treatment of deep vein thrombosis and pulmonary embolism after 5 to 10 days of initial therapy with a parenteral anticoagulant.

According to Daiichi Sankyo, the FDA-approved indications for Savaysa are based on data from the ENGAGE AF-TIMI 48 and Hokusai-VTE studies. In ENGAGE AF-TIMI 48, Savaysa was noninferior to warfarin in the overall study population for the primary efficacy endpoint of stroke or SE.

The full ENGAGE AF-TIMI 48 results were presented at the AHA Scientific Sessions 2013 in Dallas and published in the New England Journal of Medicine (2013;369:2093–2104). The full Hokusai-VTE results were presented at the ESC Congress 2013 in Amsterdam and published in the New England Journal of Medicine (2013;369:1406­­–1415).

In ENGAGE AF-TIMI 48, Savaysa had significantly less major bleeding in patients with NVAF, both in the overall study population (HR, 0.8; 95% confidence interval [CI], 0.7 to 0.91; P < .001) and in patients with creatinine clearance (CrCL) ≤ 95 mL/min (HR, 0.84; 95% CI, 0.73 to 0.97). In addition, in the approved population, there were lower rates of intracranial hemorrhage with Savaysa compared to warfarin in patients with NVAF (0.5% vs 1% per year, respectively; HR, 0.44, 95% CI, 0.32 to 0.61). In ENGAGE AF-TIMI 48, there was a significant increase in gastrointestinal bleeding events in the approved population compared to warfarin of 1.8% versus 1.3% per year, respectively (HR, 1.4; 95% CI, 1.13 to 1.73). 

In the overall Hokusai-VTE study population, once-daily Savaysa 60 mg was noninferior to warfarin for the primary efficacy endpoint of recurrence of symptomatic venous thromboembolism (VTE) (3.2% vs 3.5%, respectively; HR, 0.89; 95% CI, 0.7 to 1.13). In addition, Savaysa demonstrated a significant 19% lower rate of clinically relevant bleeding in patients with VTE compared to warfarin (8.5% vs 10.3%, respectively; HR, 0.81; 95% CI, 0.71 to 0.94; P = .004).

The company advised that the most common side effects observed in clinical trial participants were bleeding and anemia. Savaysa increases the risk of bleeding and can cause serious and potentially fatal bleeding.

As stated in the United States label, Savaysa should not be used in NVAF patients with CrCL levels > 95 mL/min because in that population there is an increased risk of ischemic stroke compared to warfarin. Patients with CrCL ≤ 95 mL/min represented 77% of the patients studied. In those patients, Savaysa 60 mg (30 mg dose reduced) reduced the risk of stroke and SE when compared to warfarin (hazard ratio [HR], 0.68; 95% CI, 0.55 to 0.84), and the rates of cardiovascular death with Savaysa and warfarin were 2.95% per year versus 3.59% per year, respectively.

On September 26, 2014, Daiichi Sankyo announced that it received approval from the Ministry of Health, Labour and Welfare in Japan for edoxaban under the brand name Lixiana for the prevention of ischemic stroke and SE in patients with NVAF and for the treatment and recurrence prevention of VTE (deep vein thrombosis and pulmonary thromboembolism). Edoxaban was approved in Japan in April 2011 for the prevention of VTE after major orthopedic surgery and was launched in July 2011.