Editor's Note: Commentary based on The Hokusai-VTE Investigators. Edoxaban versus warfarin for treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Aug 31. [Epub ahead of print].

Introduction

Until recently, standard therapy for venous thromboembolism (VTE) has been comprised of parenteral anticoagulation with either intravenous unfractionated heparin or an injectable anticoagulant with transition to an oral vitamin K antagonist. A number of recent studies have established novel oral anticoagulants (dabigatran, rivaroxaban, and apixaban) as safe and effective alternatives in patients with acute VTE.^1-4 Edoxaban is a direct factor Xa inhibitor that is administered once daily. The Hokusai-VTE study was a randomized, double-blind, double-dummy trial conducted to evaluate edoxaban for treatment of VTE (HOKUSAI).⁵

Methods

In Hokusai-VTE, the investigators compared parenteral anticoagulation (unfractionated heparin or low-molecular weight heparin) followed by edoxaban with parenteral anticoagulation followed by warfarin in patients with acute deep vein thrombosis (DVT), pulmonary embolism (PE), or both. Patients 18 years or older with objectively confirmed acute symptomatic proximal DVT or PE were eligible. Important exclusion criteria included cancer patients planned for long-term therapy with low-molecular weight heparin and those with a creatinine clearance of less than 30 mL/min.

All patients received parenteral anticoagulation for at least five days. Edoxaban was started after discontinuation of parenteral anticoagulation and was administered at a dose of 60 mg daily or a reduced dose at randomization of 30 mg daily if the creatinine clearance was between 30-50 mL/min, body weight was 60 kg or less, or concomitant potent P-glycoprotein inhibitors were used. Warfarin was initiated with parenteral anticoagulation with a target INR range of 2-3. Treatment with edoxaban or warfarin continued for at least three months and a maximum of 12 months, at the discretion of the provider.

The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent VTE, which was defined as a composite of DVT or PE. The primary safety outcome was the incidence of adjudicated clinically relevant bleeding, which was defined as a composite of major bleeding or clinically relevant non-major bleeding.

Hokusai-VTE was an event-driven trial testing the hypothesis that edoxaban would be non-inferior to warfarin with respect to the primary efficacy outcome. Assuming equal efficacy of edoxaban and warfarin, 220 events were estimated to be required for the study to have 85% power to show non-inferiority of edoxaban (two-sided alpha of 0.05). Assuming a 3% incidence of the primary efficacy outcome, the study required at least 7500 patients to be enrolled. All efficacy analyses were performed according to modified intention-to-treat. The primary efficacy analysis included all efficacy outcomes from randomization to 12 months or study closure, regardless of length of therapy. Time to the first primary efficacy outcome was analyzed with the use of a Cox proportional-hazards model with stratification factors as covariates. The same technique was used for the primary safety analysis. Pre-specified subgroup analyses included presence of right ventricular (RV) dysfunction in patients with PE and qualifying diagnosis (DVT or PE).

Results

From January 2010 through October 2012, 8292 patients were enrolled at 439 centers in 37 countries. Baseline characteristics were similar in the two study groups. The proportion of patients with cancer was low (9%). Time within therapeutic range for warfarin patients was 63.5%.

Recurrence of symptomatic VTE occurred in 3.2% of patients in the edoxaban group and 3.5% in the warfarin group (hazard ratio with edoxaban, 0.89; 95% confidence interval [CI], 0.7-1.13; p<0.001 for non-inferiority) (Table 1). The upper limits of the 95% confidence intervals of the hazard ratios in patients who presented with DVT or PE did not exceed the pre-specified margin of 1.5. Among patients with PE and evidence of RV dysfunction (NT-proBNP ≥500 pg/mL), recurrent symptomatic VTE occurred in 3.3% of patients in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52; 95% CI, 0.28-0.98). Among patients receiving the 30 mg daily reduced dose of edoxaban at randomization, there was no significant difference in recurrent symptomatic VTE compared with warfarin.

Clinically relevant bleeding (major and non-major) occurred in 8.5% of patients in the edoxaban group and 10.3% in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71-0.94; p=0.004 for superiority) (Table 1). The difference in the primary safety outcome was largely due to a reduction in clinically relevant non-major bleeding. These findings were consistent among patients whose edoxaban dose was reduced to 30 mg. Rates of other adverse events were similar.

Table 1: Clinical Outcomes
Outcome	Edoxaban	Warfarin	Hazard Ratio with Edoxaban (95% CI)	p-value
First recurrent symptomatic VTE or VTE-related death during overall study period, n (%)	130 (3.2)	146 (3.5)	0.89 (0.7-1.13)	<0.001 (for non-inferiority)
First recurrent symptomatic VTE or VTE-related death during on-treatment period, n (%)	66 (1.6)	80 (1.9)	0.82 (0.6-1.14)	<0.001 (for non-inferiority)
First major or clinical relevant non-major bleed, n (%)	349 (8.5)	423 (10.3)	0.81 (0.71-0.94)	0.004 (for superiority)
Major bleeding, n (%)	56 (1.4)	66 (1.6)	0.84 (0.59-1.21)	0.35 (for superiority)
Clinically relevant non-major bleeding, n (%)	298 (21.7)	368 (8.9)	0.8 (0.68-0.93)	0.004 (for superiority)

Conclusion

In the large, double-blind Hokusai-VTE study, treatment with parenteral anticoagulation followed by edoxaban was non-inferior with respect to prevention of recurrent symptomatic VTE but superior with respect to clinically relevant bleeding compared with parenteral anticoagulation followed by warfarin for patients with acute VTE.

Perspective

Similar to earlier trials of novel oral anticoagulants for initial management of acute VTE, Hokusai-VTE demonstrated the non-inferiority of edoxaban with regard to efficacy and the superiority with regard to safety compared with standard therapy with warfarin.^1-5 Three of these trials tested the hypothesis of whether completely oral monotherapy, without the need for initial parenteral anticoagulation, could be used as a safe and effective alternative to traditional parenteral anticoagulation followed by an oral vitamin K antagonist for patients with acute VTE.^1-3 All three of these trials demonstrated the safety and efficacy of completely oral monotherapy for treatment of acute VTE. The novel oral anticoagulants studied in these trials (rivaroxaban and apixaban) have the potential to change how providers care for patients with acute VTE by reducing the need for lengthy hospitalizations for intravenous unfractionated heparin or painful subcutaneous injections for transition to warfarin.

While Hokusai-VTE required initial parenteral anticoagulation before switching to oral therapy, the study adds considerably to our understanding of how the novel oral anticoagulants may perform in more severe manifestations of VTE, such as PE with right ventricular dysfunction. The use of initial parenteral anticoagulation is well-accepted across the spectrum of VTE severity and allowed the investigators to recruit a large proportion of patients with PE, including high risk with right ventricular dysfunction (approximately one-third). In Hokusai-VTE, edoxaban was associated with a 50% reduction in recurrent symptomatic VTE compared with warfarin in patients with PE and right ventricular dysfunction. These data suggest that edoxaban may be used safely in patients with more severe VTE and should encourage future studies of novel oral anticoagulants to include a greater spectrum of VTE severity.

References

1. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808.
2. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-2510.
3. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-1297.
4. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-2352.
5. The Hokusai-VTE Investigators. Edoxaban versus warfarin for treatment of symptomatic venous thromboembolism. N Engl J Med 2013 Aug 31. [Epub ahead of print].

Keywords: Anticoagulants, Creatinine, Factor Xa, Heparin, Pulmonary Embolism, Venous Thromboembolism, Warfarin

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