Anti-Xa Activity of Enoxaparin for Prevention of Venous Thromboembolism in Severe Nephrotic Syndrome—A Single Center Prospective Study

Abstract

Severe nephrotic syndrome (NS) is associated with high risk of venous thromboembolic events (VTE), as well as presumably altered heparin pharmacokinetics and pharmacodynamics. Although prophylactic anticoagulation is recommended, the optimal dose is not established. The aim of the study was to test two co-primary hypotheses: of reduced enoxaparin effectiveness and of the need for dose-adjustment in NS. Forty two nephrotic patients with serum albumin ≤2.5 g/dL were alternately assigned to a standard fixed-dose of enoxaparin (NS-FD: 40 mg/day) or ideal body weight (IBW)-based adjusted-dose (NS-AD: 1 mg/kg/day). Twenty one matched non-proteinuric individuals (C-FD) also received fixed-dose. Co-primary outcomes were: the achievement of low- and high-VTE risk threshold of antifactor-Xa activity (anti-FXa) defined as 0.2 IU/mL and 0.3 IU/mL, respectively. Low-VTE-risk threshold was achieved less often in NS-FD than C-FD group (91 vs. 62%, p = 0.024), while the high-VTE-risk threshold more often in NS-AD than in NS-FD group (90 vs. 38%, p < 0.001). Two VTE were observed in NS during 12 months of follow-up (incidence: 5.88%/year). In both cases anti-FXa were 0.3 IU/mL implying the use of anti-FXa >0.3 IU/mL as a target for dose-adjustment logistic regression models. We determined the optimal dose/IBW cut-off value at 0.8 mg/kg and further developed bivariate model (termed the DoAT model) including dose/IBW and antithrombin activity that improved the diagnostic accuracy (AUC 0.85 ± 0.06 vs. AUC 0.75 ± 0.08). Enoxaparin efficacy is reduced in severe NS and the dose should be adjusted to ideal body weight to achieve target anti-FXa activity.

Efficacy and safety of prophylactic anticoagulation in patients with primary nephrotic syndrome: a systematic review and meta‐analysis

“…Among the 88 remaining articles, a total of 83 papers were excluded because they were duplicated (6), reviews or commentaries (11), did not provide clinical outcomes (19), did not investigate prophylactic anticoagulation (44) or did not have full text available but only an abstract (3). Five studies were finally included in our review (Matyjek 2021, 30 Welander 2021, 31 Kelddal 2019, 32 Medjeral-Thomas 2014 33 and Rostoker 1995 [32][33][34] ).…”

“…Three of the five studies were retrospective, [31][32][33] and two were prospective. [30][31][32][33][34] No RCTs were published. Only two studies were multicentre (two Danish and three Sweden centres), 31,32 whereas the other three were conducted in a European single centre (Poland, United Kingdom and France).…”

“…Only two studies were multicentre (two Danish and three Sweden centres), 31,32 whereas the other three were conducted in a European single centre (Poland, United Kingdom and France). 30,33,34 No study included children.…”

“…The enrolled populations were heterogenous and included few patients with secondary or unspecified NS. Matyjek et al 30 34 included two (3.6%) patients with secondary NS caused by systemic lupus erythematosus, six (10.9%) unspecified glomerulonephritis and three (5.5%) unspecified glomerulopathies.…”

“…Matyjek et al 30 administered enoxaparin at fixed or adjusted for ideal body weight (IBW) dose. IBW was calculated with a formula that included height.…”