Treatment Options for Venous Thromboembolism in Patients Receiving Dialysis

Venous thromboembolic disease includes deep vein thrombosis and pulmonary embolism, and it is a common problem among patients with CKD. The incidence of venous thromboembolic disease in CKD has been studied in several observational cohort studies, and it is estimated at 4.5 events per 1000 patient-years in CKD stages 3 and 4 (1) and 5.3 events per 1000 patient-years in kidney failure (2). This represents a significantly higher disease burden compared with patients with preserved kidney function. In addition to higher disease burden, patients with CKD have worse clinical outcomes, including higher incidence of recurrent venous thromboembolism and higher incidence of treatment-associated major bleeding complications (3). Anticoagulation is the mainstay of management for patients with venous thromboembolic disease. It includes three distinct phases (Figure 1): a first acute phase of at least 5 days in duration aiming at stabilization of the thrombotic burden and prevention of acute extension and subsequent high-risk/fatal pulmonary embolism, a second phase of a total duration of at least 3 months to complete treatment of the acute event and for the secondary prevention of venous thromboembolism recurrence, and a third phase (after the first 3 months) with long-term/indefinite anticoagulation considered in selected patients at high risk of recurrence (4).Figure 1.: Conventional and apixaban-based management of venous thromboembolic disease in patients with preserved kidney function or moderate CKD (creatinine clearance ≥25 ml/min and creatinine ≤2.5 mg/dl). bid, twice daily; INR, international normalized ratio; VKA, vitamin K antagonist. *In selected patients at high risk of recurrence; †if there is clinical equipoise about continuation or cessation of anticoagulation.The treatment paradigm for venous thromboembolic disease gradually shifted over the last 10 years from parenteral anticoagulation followed by vitamin K antagonists to direct oral anticoagulants (DOACs) (Figure 1). Advantages of the DOACs include fixed dose regimen, no need for laboratory monitoring, and a predictable profile with less drug and food interactions. Apixaban is a direct factor Xa inhibitor, and it is a less kidney-excreted DOAC (4). In the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial in patients with acute deep venous thrombosis and/or pulmonary embolism, apixaban was found to be noninferior to conventional therapy (subcutaneous enoxaparin followed by warfarin) for the outcome of recurrent symptomatic venous thromboembolism or death related to venous thromboembolism (5). In addition, apixaban was superior to conventional therapy for the outcome of major bleeding. There were no dose adjustment criteria for apixaban in this study; all patients in the apixaban arm were treated with 10 mg twice daily for the first week and then 5 mg twice daily for 6 months. Patients with serum creatinine >2.5 mg/dl or with an estimated creatinine clearance <25 ml/min were excluded from this study. In the subgroup of patients with a creatinine clearance between 25 and 60 ml/min, the relative risk of recurrent venous thromboembolism or death related to venous thromboembolism was 0.93 (95% confidence interval [95% CI], 0.34 to 2.61), and the relative risk of major bleeding was 0.52 (95% CI, 0.18 to 1.51). The AMPLIFY extension trial included patients who had completed 6–12 months of anticoagulation or participants who had completed the AMPLIFY trial and for whom there was clinical equipoise about continuation or cessation of anticoagulation (6). Extended anticoagulation with the therapeutic dose (5 mg twice daily) or the prophylactic dose (2.5 mg twice daily) of apixaban compared with placebo reduced the risk of recurrent venous thromboembolism, but it did not increase the risk of major bleeding. There is a particular interest in apixaban in the kidney community due to the limitations of traditional anticoagulants in kidney failure, including very low time in therapeutic range and higher risk of accelerated vascular calcification with warfarin. Although apixaban has been further studied in large observational cohorts of patients with advanced CKD who have atrial fibrillation and who are receiving anticoagulation for stroke prevention, little data exist on apixaban in patients with advanced kidney disease or kidney failure who are treated with this agent for venous thromboembolic disease. Six small observational, single-center studies in patients with eGFR<30 ml/min per 1.73 m2 or creatinine clearance <25 ml/min did not show any difference between apixaban and warfarin with respect to the outcome of recurrent venous thromboembolism (7). In this issue of CJASN, Wetmore et al. (8) report their findings on apixaban for patients on maintenance dialysis with a diagnosis of venous thromboembolism (compared with warfarin). They used a large administrative claims database (the United States Renal Data System) and included 3130 incident users of apixaban and 9086 incident users of warfarin with an inpatient or outpatient diagnosis of venous thromboembolic disease between 2014 and 2018. The authors used inverse probability of treatment and inverse probability of censoring weights to create a pseudocohort that was well balanced for all baseline characteristics. The primary efficacy outcome was hospitalization for recurrent venous thromboembolism, and the primary safety outcome was major bleeding. They found that apixaban was associated with lower risk of recurrent venous thromboembolism (hazard ratio, 0.58; 95% CI, 0.43 to 0.77) and lower risk of major bleeding (hazard ratio, 0.78; 95% CI, 0.62 to 0.98) compared with warfarin. Most of the major bleeding events were gastrointestinal (70%–74%), whereas cerebral bleeding represented <11% and 13% of all events in the apixaban and warfarin arms, respectively. There was no difference in all-cause mortality between the two treatment groups. Results were similar in various sensitivity analyses and in different clinical settings, including patients with cancer or patients with trauma/surgery. The authors concluded that apixaban may be a safer and more effective treatment for venous thromboembolic disease in patients on maintenance dialysis compared with warfarin. This is the largest cohort study comparing apixaban with warfarin in patients with venous thromboembolic disease and kidney failure. The large sample size, rigorous statistical approach, and similar findings in different sensitivity analyses constitute unique strengths of the study. However, as the authors acknowledge, residual confounding, inherent in all observational studies, may be explaining at least in part the identified differences between the two treatment options. In addition, patients at low risk of death might have been treated as outpatients, and some recurrent events might have been missed. Moreover, the authors did not report which apixaban dosage was used and did not present outcomes by apixaban dosage. Several important questions remain to be answered. First, how should patients with kidney failure be treated during the acute phase? Use of apixaban from day 1 implies a higher dosage of 10 mg twice daily for 1 week. This dose has never been studied in patients with creatinine clearance <25 ml/min. A safer alternative might be using a low molecular weight heparin with appropriate dose adjustment during the first week of treatment before switching to apixaban. Second, what is the optimal maintenance dose for apixaban in kidney failure? In contrast to patients with atrial fibrillation, the reduced apixaban dose of 2.5 mg twice daily has never been studied in the venous thromboembolic disease setting and may be associated with subtherapeutic anticoagulation and recurrence on therapy. On the other hand, the standard dose of 5 mg twice daily might be associated with a disproportionally high bleeding risk in patients on maintenance dialysis. Third, would drug monitoring help with dose adjustment? A calibrated anti-Xa assay is now available in several tertiary care centers, but therapeutic intervals have not been well established; also, drug levels may not be associated with clinical outcomes. In addition, whether the use of trough or peak levels is preferable to guide anticoagulation remains unclear. Fourth, how do we approach patients with unprovoked venous thromboembolism who might have been considered for long-term/indefinite anticoagulation? Does the benefit from extended anticoagulation outweigh bleeding risk, and what would be the optimal long-term dose? Could a lower apixaban dose, as studied in the AMPLIFY extension trial, prove beneficial in this setting? Fifth, how should patients at high risk of recurrence be treated? This group includes but is not limited to patients with active malignancy or recurrent unprovoked venous thromboembolic disease. Finally, use of antiplatelet agents in patients receiving therapeutic anticoagulation requires particular attention as these drugs might disproportionately increase risk of bleeding. In summary, this important observational study provides preliminary evidence suggesting that apixaban might be a safer and more effective treatment for venous thromboembolic disease in patients with kidney failure. However, many questions remain to be answered before such a recommendation can be made. Until we can be better informed, treatment approaches should be individualized, and expert advice should be sought. An interventional study using a noninferiority design comparing apixaban with conventional treatment would be needed to address this important question. As with other indications of anticoagulation in kidney failure, the challenge for the nephrology community is still ahead. Disclosures T.A. Mavrakanas received honoraria from BMS Canada, Daiichi Sankyo, Janssen, and Pfizer and has served on advisory boards for Boehringer Ingelheim outside the submitted work. Funding T.A. Mavrakanas is supported by a Fonds de Recherche du Québec - Santé Junior 1 Clinician Scholar Award.

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