Extended anticoagulation in provoked VTE with persistent risk factors: A meta-analysis of randomised trials

Mohsin Raj Mantoo; Saadat Raj Mantoo; Mir Wajid Majeed; Anushka Kulkarni; Haziq Parveez Lone; Mazin Mansoor; Ambuj Roy

doi:10.2478/rjc-2026-0014

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Extended anticoagulation in provoked VTE with persistent risk factors: A meta-analysis of randomised trials

Romanian Journal of Cardiology

AHEAD OF PRINT

By: Mohsin Raj Mantoo, Saadat Raj Mantoo, Mir Wajid Majeed, Anushka Kulkarni, Haziq Parveez Lone, Mazin Mansoor and Ambuj Roy

Open Access

|Jun 2026

Figures & Tables

PRISMA flow diagram. PRISMA flowchart illustrating the identification, screening, eligibility assessment and inclusion of RCTs evaluating extended DOAC therapy in patients with provoked VTE and persistent non-malignant risk factors. DOAC, direct oral anticoagulant; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCTs, randomised controlled trials; VTE, venous thromboembolism.

Risk-of-bias assessment for included RCTs using the ROB2 tool. Traffic light plot summarising domain-level and overall risk-of-bias assessment for three RCTs (EINSTEIN-Extension, EINSTEIN CHOICE and HI-PRO) included in the meta-analysis. All studies were graded as low risk of bias across the five domains: D1 (randomisation process), D2 (deviations from intended interventions), D3 (missing outcome data), D4 (outcome measurement) and D5 (selection of reported results). Green circles denote low risk of bias in each domain. The overall risk of bias for each study is shown in the far-right column. RCTs, randomised controlled trials; RoB2, Risk of Bias 2.0.

Efficacy of continued DOAC therapy on recurrent VTE. Forest plot of RCTs comparing extended DOAC therapy (therapeutic or reduced dose) with placebo or aspirin for the outcome of recurrent VTE. Results are shown as RRs with 95% CIs under both fixed-and random-effects models. CIs, confidence intervals; DOAC, direct oral anticoagulant; RCTs, randomised controlled trials; RRs, risk ratios; VTE, venous thromboembolism.

Recurrent VTE stratified by comparator type. Forest plot showing the effect of extended DOAC therapy on recurrent VTE stratified by comparator type (placebo-controlled vs aspirin-controlled trials). Pooled estimates are presented with 95% CIs for each subgroup, and tests for subgroup differences are displayed. CIs, confidence intervals; DOAC, direct oral anticoagulant; VTE, venous thromboembolism.

Efficacy of reduced-dose DOAC therapy on symptomatic recurrent VTE. Forest plot of RCTs evaluating reduced-dose DOAC regimens (apixaban 2.5 mg twice daily or rivaroxaban 10 mg OD) versus control (placebo or aspirin) for recurrent VTE. RRs and 95% CIs are shown. CIs, confidence intervals; DOAC, direct oral anticoagulant; OD, once daily; RCTs, randomised controlled trials; RRs, risk ratios; VTE, venous thromboembolism.

Risk of major bleeding with extended DOAC therapy. Forest plot depicting the risk of major bleeding associated with extended DOAC therapy compared with placebo or aspirin. Effect estimates are presented as RRs with 95% CIs using fixed- and random-effects models. CIs, confidence intervals; DOAC, direct oral anticoagulant; RRs, risk ratios.

Major bleeding stratified by comparator type. Forest plot showing major bleeding outcomes stratified by comparator group (placebo vs aspirin). No statistically significant interaction between treatment effect and comparator type was observed.

Summary of the studies included in this SRMA evaluating continued and reduced dose DOAC therapy in provoked VTE with persistent non-malignant risk factors_

Study (year), design	EINSTEIN CHOICE (2017), RCT	EINSTEIN Extension (2018), RCT	HI-PRO (2025), RCT
Sample size (subgroup included)	3365(1404)	1196(494)	600
DOAC dose	Rivaroxaban 20 mg and10 mg OD	Rivaroxaban 20 mg	Apixaban 2.5 mg BD
Comparator	Aspirin 100 mg	Placebo	Placebo
Mean age (years)	58.5	58.3	59.5
% Male	55.4	57.9	43
Index event (DVT/PE/Both, %)	50.7/35.3/15.3	62/38	48/23.3/28.7
Duration of initial anticoagulation(months)	6–12(<9 months in 75.8%)	6–12(<9 months in 67.4%)	≥3(Median 6.6)
Persistent risk factors^* (Commonest)%	BMI > 30 kg/m²: 68.6Thrombophilia: 13.1Creatinine clearance <50 mL/min: 10.8		BMI > 30 kg/m²: 48.2Chronic inflammatory or autoimmunedisease: 52.2ASCVD: 29.3CKD: 10.7%
Follow up (months)	12	12	12
Primary efficacy outcome	Symptomatic recurrent VTE	Symptomatic recurrent VTE	Symptomatic recurrent VTE
Major bleeding definition	ISTH guidelines	ISTH guidelines	ISTH guidelines

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DOI: https://doi.org/10.2478/rjc-2026-0014 | Journal eISSN: 2734-6382 | Journal ISSN: 1220-658X

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Language: English

Published on: Jun 1, 2026

Published by: Romanian Society of Cardiology

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

venous thromboembolism,

direct oral anticoagulants,

persistent risk factors,

secondary prevention,

Related subjects:

Surgery,

Pediatrics and juvenile medicine,

Paediatric cardiology

© 2026 Mohsin Raj Mantoo, Saadat Raj Mantoo, Mir Wajid Majeed, Anushka Kulkarni, Haziq Parveez Lone, Mazin Mansoor, Ambuj Roy, published by Romanian Society of Cardiology
This work is licensed under the Creative Commons Attribution 4.0 License.

AHEAD OF PRINT

Extended anticoagulation in provoked VTE with persistent risk factors: A meta-analysis of randomised trials

Figures & Tables

Figure 1

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Summary of the studies included in this SRMA evaluating continued and reduced dose DOAC therapy in provoked VTE with persistent non-malignant risk factors_

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