Long-term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta-analysis

Faizan Khan; Tobias Tritschler; Miriam Kimpton; Philip S Wells; Clive Kearon; Jeffrey I Weitz; Harry R Büller; Gary E Raskob; Walter Ageno; Francis Couturaud; Paolo Prandoni; Gualtiero Palareti; Cristina Legnani; Paul A Kyrle; Sabine Eichinger; Lisbeth Eischer; Cecilia Becattini; Giancarlo Agnelli; Maria Cristina Vedovati; Geert-Jan Geersing; Toshihiko Takada; Benilde Cosmi; Drahomir Aujesky; Letizia Marconi; Antonio Palla; Sergio Siragusa; Charlotte A Bradbury; Sameer Parpia; Ranjeeta Mallick; Anthonie W A Lensing; Martin Gebel; Michael A Grosso; Minggao Shi; Kednapa Thavorn; Brian Hutton; Gregoire Le Gal; Marc Rodger; Dean Fergusson

doi:10.1111/jth.15491

Long-term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta-analysis

J Thromb Haemost. 2021 Nov;19(11):2801-2813. doi: 10.1111/jth.15491. Epub 2021 Aug 22.

Authors

Faizan Khan^{1

2}, Tobias Tritschler³, Miriam Kimpton^{2

4}, Philip S Wells^{2

4}, Clive Kearon⁵, Jeffrey I Weitz⁵, Harry R Büller⁶, Gary E Raskob⁷, Walter Ageno⁸, Francis Couturaud⁹, Paolo Prandoni¹⁰, Gualtiero Palareti¹⁰, Cristina Legnani¹⁰, Paul A Kyrle¹¹, Sabine Eichinger¹¹, Lisbeth Eischer¹¹, Cecilia Becattini¹², Giancarlo Agnelli¹², Maria Cristina Vedovati¹², Geert-Jan Geersing¹³, Toshihiko Takada¹³, Benilde Cosmi¹⁴, Drahomir Aujesky³, Letizia Marconi¹⁵, Antonio Palla¹⁵, Sergio Siragusa¹⁶, Charlotte A Bradbury¹⁷, Sameer Parpia¹⁸, Ranjeeta Mallick², Anthonie W A Lensing¹⁹, Martin Gebel¹⁹, Michael A Grosso²⁰, Minggao Shi²⁰, Kednapa Thavorn^{1

2}, Brian Hutton^{1

2}, Gregoire Le Gal^{2

4}, Marc Rodger^{2

21}, Dean Fergusson^{1

2

4}

Affiliations

¹ School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.
² Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
³ Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁴ Department of Medicine, University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada.
⁵ Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
⁶ Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
⁷ University of Oklahoma Health Sciences Center, Hudson College of Public Health, Oklahoma City, OK, USA.
⁸ Department of Medicine and Surgery, University of Insubria, Varese, Italy.
⁹ Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest, France.
¹⁰ Arianna Foundation on Anticoagulation, Bologna, Italy.
¹¹ Department of Medicine I, Medical University of Vienna, Vienna, Austria.
¹² Internal and Cardiovascular Medicine, Stroke Unit, University of Perugia, Perugia, Italy.
¹³ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
¹⁴ Department of Specialty, Diagnostic and Experimental Medicine, Division of Angiology and Blood Coagulation, S. Orsola Malpighi University Hospital, Bologna, Italy.
¹⁵ Department of Surgical, Medical and Molecular Pathology, and Critical Care, University of Pisa, Pisa, Italy.
¹⁶ Department Pro.Mi.Se., University of Palermo, Palermo, Italy.
¹⁷ School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
¹⁸ Departments of Oncology, and Health Research Methods, Evidence & Impact, McMaster University, Hamilton, ON, Canada.
¹⁹ Bayer AG, Wuppertal, Germany.
²⁰ Daiichi-Sankyo Pharma Development, Basking Ridge, NJ, USA.
²¹ Department of Medicine, McGill University, Montreal, QC, Canada.

PMID: 34379859
DOI: 10.1111/jth.15491

Abstract

Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain.

Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE.

Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results.

Results: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%).

Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE.

Keywords: anticoagulant therapy; prognosis; pulmonary embolism; systematic review; venous thromboembolism.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Anticoagulants / adverse effects
Humans
Prospective Studies
Pulmonary Embolism*
Recurrence
Risk Factors
Venous Thromboembolism* / diagnosis
Venous Thromboembolism* / drug therapy
Venous Thromboembolism* / epidemiology

Substances

Anticoagulants

Grants and funding

CIHR/Canada