Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta‐analysis

Abstract

We investigated direct oral anticoagulant (DOAC) use in venous thromboembolism and thrombophilia. A comprehensive search identified 10 studies, 8 of which were included in a meta‐analysis. DOACs were overall safe and effective in patients with venous thromboembolism and thrombophilia. Efficacy/safety of DOACs was maintained in low‐risk antiphospholipid syndrome patient subgroup. Summary BackgroundDirect oral anticoagulants (DOACs) are increasingly used in acute and long‐term treatment of venous thromboembolism (VTE). However, their role in management of thrombophilia‐associated VTE is controversial. MethodsThrough a comprehensive search on MEDLINE, Cochrane Library, and Clinicaltrials.gov, we identified 10 eligible studies, 8 of which reporting data on 1994 thrombophilia patients were included in a random‐effects meta‐analysis. Eligible studies were phase 2 to 3 randomized controlled trials comparing DOACs to vitamin K antagonists (VKAs) in patients with VTE, including those with thrombophilia. ResultsOf eight studies included in meta‐analysis, four evaluated rivaroxaban, three dabigatran, and one edoxaban. No results could be obtained on apixaban use. The rates of VTE recurrence (RR, 0.70; 95% CI, 0.34–1.44; I2 = 0%) and major/clinically relevant non‐major bleeding events (RR, 0.92; 95% CI, 0.62–1.36; I2 = 23%) were similar between thrombophilia patients treated with DOACs compared to VKAs. Results were comparable to findings in patients without known thrombophilia: RR, 1.02; 95% CI, 0.80–1.30; I2 = 46% for VTE recurrence and RR, 0.72; 95% CI, 0.57–0.90; I2 = 84% for major/clinically relevant non‐major bleeding events. ConclusionsRates of VTE recurrence and bleeding events were both low and comparable in patients with various thrombophilias receiving either treatment, suggesting that DOACs are an appropriate treatment option in this population. Due to limited data, it is unclear whether these findings apply to specific subgroups such as high‐risk antiphospholipid syndrome, uncommon thrombophilias, or the use of apixaban.

Diagnosis and management of congenital thrombophilia in the era of direct oral anticoagulants

“…1, panel D). In a systematic review by Elsebaie et al, including mostly patients with factor V Leiden mutation and antiphospholipid antibodies, the risk reduction for thrombosis recurrence with anti-IIa vs VKAs (RR, 0.50; 95% CI, 0.19 to 1.34) appeared greater than that observed for anti-Xa vs VKAs (RR, 1.02; 95% CI, 0.35 to 2.97), although not statistically significant [10]. Although not definitive, these results open the possibility that certain patients with CT may derive better protection from thrombosis with specific agents.…”

Differential effects of direct factor IIa and factor Xa inhibitors in protein C‐deficient plasma detected using thrombin generation and viscoelastometry assays

“…Experience of DOACs or LMWH in severe PC deficiency is restricted to single case reports . The use of selective direct inhibitors of FIIa or FXa in other severe prothrombotic disorders such as antiphospholipid syndrome remains controversial because of incomplete efficacy in some studies …”

“…14 There are limited data describing the efficacy and safety of DOACs in rare heritable thrombophilias such as PC deficiency. 15 In a subgroup analysis of patients with mild PC deficiency with VTE in the RE-MEDY trial, the FIIa inhibitor dabigatran was noninferior to VKA for preventing recurrent VTE. 16 Similarly, in the EINSTEIN-DVT, EINSTEIN-PE and Hokusai-VTE trials, [17][18][19] a subgroup meta-analysis showed no difference in efficacy between the FXa inhibitors rivaroxaban or edoxaban, and VKA.…”

“…16 Similarly, in the EINSTEIN-DVT, EINSTEIN-PE and Hokusai-VTE trials, [17][18][19] a subgroup meta-analysis showed no difference in efficacy between the FXa inhibitors rivaroxaban or edoxaban, and VKA. 15 However, these analyses included patients only with mild PC deficiency. Experience of DOACs or LMWH in severe PC deficiency is restricted to single case reports.…”

“…[20][21][22][23][24][25] The use of selective direct inhibitors of FIIa or FXa in other severe prothrombotic disorders such as antiphospholipid syndrome remains controversial because of incomplete efficacy in some studies. 15,26 The aim of this study was to evaluate the in-vitro effects of direct FIIa and FXa inhibitors, alongside the indirect dual FXa/FIIa inhibitor enoxaparin in PC-deficient plasma using modified thrombin generation and viscoelastometry assays that were sensitive to PC anticoagulant activity.…”