The Hematologist

March-April 2019, Volume 16, Issue 2

Treatment of Renally Impaired Patients With Venous Thromboembolism: Awaiting the VERDICT

Lori-Ann Linkins, MD, MSc(Clin Epi), FRCPC Associate Professor
McMaster University, Hamilton, ON, Canada

Published on: February 13, 2019

Study Title: Venous Thromboembolism in Renally Impaired Patients With Direct Oral Anticoagulants (VERDICT) Identifier: NCT02664155

Sponsor: Centre Hospitalier Universitaire de Saint Etienne

Participating Centers: Multiple sites in France

Study Design: Randomized, open-label, non-inferiority

Accrual Goal: 800

Study Synopsis: This is a phase III, randomized, open-label study comparing reduced doses of apixaban and rivaroxaban with standard-of-care in adult patients with symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) and either moderate (creatinine clearance [CrCl], 30-50 mL/min by Cockcroft-Gault equation) or severe (CrCl, 15-29 mL/min) renal insufficiency. The primary outcome measure is net clinical benefit (recurrent venous thromboembolism [VTE] and major bleeding) at three months. Key exclusion criteria include high risk of bleeding, CrCl less than 15 mL/min, need for dialysis, or requirement for concomitant use of strong CYP 3A4 inducers or inhibitors.

Participants randomly assigned to the experimental arm will receive either apixaban 10 mg twice daily (bid) for seven days followed by apixaban 2.5 mg bid for three months or rivaroxaban 15 mg bid for 21 days followed by rivaroxaban 15 mg once daily for three months. Participants randomly assigned to the control arm will receive heparin or low–molecular-weight heparin for a minimum of five days followed by a vitamin K antagonist (VKA) for three months.

Rationale: Direct oral anticoagulants (DOACs) have been approved for treatment of VTE in patients with moderate to severe renal insufficiency in many countries, despite limited clinical evidence.

Comment: This study has the potential to provide much-needed high-quality clinical data. Less than 20 percent of participants in the large randomized clinical trials comparing these agents with VKA had CrCl 30 to 50 mL/min, and none had CrCl less than 25 mL/min.1-6

A meta-analysis by Dr. Nick van Es and colleagues, including more than 27,000 patients with VTE, showed that DOACs were noninferior to standard of care for recurrent VTE and superior for major bleeding.7 These findings were consistent in the subgroup with moderate renal insufficiency (CrCl, 30-49 mL/min; n = 898); however, both VTE recurrence (2.9% vs. 2.0%) and major bleeding rates (1.8% vs. 1.1%) were higher in the renally impaired subgroup compared with the general study population.

All of the DOACs are renally cleared to different degrees (i.e., apixaban 27%, rivaroxaban 33%), therefore the plasma concentration rises as CrCl drops.8 For example, apixaban 5 mg twice daily given to a patient with CrCl 15 to 29 mL/min results in a 44 percent increase in plasma level compared to patients with normal renal function.9 For this reason, reduced doses of DOACs are recommended for patients with atrial fibrillation with CrCl less than 50 mL/min (plus body weight less than 60 kg or age older than 80 years). Surprisingly, dose reduction has not been recommended for renally impaired patients with VTE.

Because of the issues described above, one of the strengths of the VERDICT study is the use of net clinical benefit as the primary outcome measure. Afterall, it would not be surprising that DOACs are noninferior to VKA at reducing recurrent VTE, but this benefit easily could be outweighed by increased harm due to bleeding.

Limitations of this study include short duration of follow up, exclusion of patients on dialysis, and a clinical trial environment that is not quite the same as “real-world” exposure. That being said, the VERDICT from this study is keenly awaited.


  1. Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-1415.
  2. EINSTEIN-PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.
  3. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.
  4. 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.
  5. 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.
  6. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764-772.
  7. van Es N, Coppens M, Schulman S, et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124:1968-1975.
  8. Lutz J, Jurk K, Schinzel H. Direct oral anticoagulants in patients with chronic kidney disease: patient selection and special considerations. Int J Nephrol Renovasc Dis. 2017;10:135-143.
  9. Chang M, Yu Z, Shenker A, et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol. 2016;56:637-645.

Conflict of Interests

Dr. Linkins indicated no relevant conflicts of interest. back to top