Direct Oral Factor-Xa Inhibitors in Patients with Acute Venous Thromboembolism and Renal Impairment. A randomized controlled trial
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BACKGROUND
In patients with venous thromboembolism (VTE), renal impairment increases the risks for both recurrence and bleeding. Because these patients are underrepresented in clinical trials, we assessed whether standard direct factor Xa inhibitor (DXI) lead-in followed by early dose reduction was noninferior to standard anticoagulation in patients with acute VTE and moderate-to-severe renal impairment.
METHODS
The VERDICT trial was a randomized, prospective, multicenter, open-label, blinded-endpoint, noninferiority trial. Consecutive patients with acute proximal deep-vein thrombosis or pulmonary embolism and chronic renal impairment (creatinine clearance 15–50 mL/min) were randomized 1:1 to an early DXI dose reduction strategy or standard therapy (heparin plus a vitamin K antagonist). Patients allocated to the DXI strategy underwent a second 1:1 randomization to apixaban or rivaroxaban, each administered at an initial standard lead-in dose followed by early dose reduction. The primary outcome was net clinical benefit at 3 months, defined as the composite of major bleeding and symptomatic recurrent VTE.
RESULTS
Due to slow recruitment, the trial was prematurely terminated after enrolling 200 of the planned 800 patients (DXI: n=104; standard: n=96). The median age was 85.9 years, 31% were male, and 29.0% had severe renal impairment. The primary outcome occurred in 8 patients (7.7%) in the DXI group and 9 patients (9.3%) in the standard therapy group (adjusted subhazard ratio [sHR], 0.87; 95% CI, 0.26 to 2.87; P = 0.19 for noninferiority; noninferiority margin 1.30). Major bleeding occurred in 6.7% and 6.2% of patients and recurrent VTE occurred in 1.0% and 3.1% of patients, respectively.
CONCLUSION
In patients with VTE and moderate-to-severe renal impairment, noninferiority of an early DXI dose-reduction strategy versus standard therapy could not be demonstrated for net clinical benefit. Although no major differences in efficacy or safety outcomes were observed between groups, the reduced sample size precludes definitive conclusions.
Clinical Trial Registration
URL: https://clinicaltrials.gov . Unique identifier: NCT02664155
Clinical Perspective
What Is New?
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The VERDICT trial is the first randomized controlled trial specifically designed to assess an initial frontloaded standard dose of oral direct factor Xa inhibitor followed by early dose reduction strategy versus standard anticoagulation therapy for acute venous thromboembolism in patients with moderate-to-severe renal impairment.
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Reflecting real-world clinical practice, the study successfully enrolled an exceptionally elderly and frail population with a median age of 85.9 years.
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A meta-analysis incorporating VERDICT and renal impairment subgroups from previous VTE trials showed a 35% relative reduction in net clinical benefit and a 53% relative reduction in major bleeding with DXI versus standard therapy with heparins/VKA.
What Are the Clinical Implications?
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Although premature trial termination limited statistical power to formally demonstrate noninferiority, the findings did not differ from those observed in renal impairment subgroups of previous randomized VTE trials.
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The available evidence provides a rationale for evaluating an early dose-reduction strategy in frail patients with VTE.
