Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysisBMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4363 (Published 24 July 2019) Cite this as: BMJ 2019;366:l4363
- Faizan Khan, doctoral student1 2,
- Alvi Rahman, doctoral student3,
- Marc Carrier, professor1 2 4,
- Clive Kearon, professor5,
- Jeffrey I Weitz, professor5,
- Sam Schulman, professor5 6,
- Francis Couturaud, professor7,
- Sabine Eichinger, professor8,
- Paul A Kyrle, professor8,
- Cecilia Becattini, professor9,
- Giancarlo Agnelli, professor9,
- Timothy A Brighton, professor10,
- Anthonie W A Lensing, professor11,
- Martin H Prins, professor12,
- Elham Sabri, statistician2,
- Brian Hutton, professor12,
- Laurent Pinede, investigator13,
- Mary Cushman, professor14,
- Gualtiero Palareti, professor15,
- George A Wells, professor1 16,
- Paolo Prandoni, professor15,
- Harry R Büller, professor17,
- Marc A Rodger, professor of medicine and epidemiology1 2 4
- for the MARVELOUS Collaborators
- 1School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada
- 2Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- 3Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada
- 4Ottawa Blood Disease Centre, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
- 5Department of Medicine, McMaster University, and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- 6Department of Obstetrics and Gynaecology, The First I.M. Sechenov Moscow State Medical University, Moscow, Russia
- 7Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest, France
- 8Department of Medicine I, Medical University of Vienna, Vienna, Austria
- 9Internal and Cardiovascular Medicine, Stroke Unit, University of Perugia, Perugia, Italy
- 10Department of Haematology, Prince of Wales Hospital, Sydney, Australia
- 11Bayer, Leverkusen, Germany
- 12Department of Epidemiology and Technology Assessment, University of Maastricht, Maastricht, Netherlands
- 13Department of Internal Medicine, Infirmerie Protestante, Caluire-Lyon, France
- 14Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, USA
- 15Arianna Foundation on Anticoagulation, Bologna, Italy
- 16Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada
- 17Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
- Correspondence to: M A Rodger, Ottawa Blood Disease Centre, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
- Accepted 4 June 2019
Objectives To determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, and the cumulative incidence for recurrent VTE up to 10 years.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019).
Study selection Randomised controlled trials and prospective cohort studies reporting symptomatic recurrent VTE after discontinuation of anticoagulant treatment in patients with a first unprovoked VTE event who had completed at least three months of treatment.
Data extraction and synthesis Two investigators independently screened studies, extracted data, and appraised risk of bias. Data clarifications were sought from authors of eligible studies. Recurrent VTE events and person years of follow-up after discontinuation of anticoagulant treatment were used to calculate rates for individual studies, and data were pooled using random effects meta-analysis. Sex and site of initial VTE were investigated as potential sources of between study heterogeneity.
Results 18 studies involving 7515 patients were included in the analysis. The pooled rate of recurrent VTE per 100 person years after discontinuation of anticoagulant treatment was 10.3 events (95% confidence interval 8.6 to 12.1) in the first year, 6.3 (5.1 to 7.7) in the second year, 3.8 events/year (95% confidence interval 3.2 to 4.5) in years 3-5, and 3.1 events/year (1.7 to 4.9) in years 6-10. The cumulative incidence for recurrent VTE was 16% (95% confidence interval 13% to 19%) at 2 years, 25% (21% to 29%) at 5 years, and 36% (28% to 45%) at 10 years. The pooled rate of recurrent VTE per 100 person years in the first year was 11.9 events (9.6 to 14.4) for men and 8.9 events (6.8 to 11.3) for women, with a cumulative incidence for recurrent VTE of 41% (28% to 56%) and 29% (20% to 38%), respectively, at 10 years. Compared to patients with isolated pulmonary embolism, the rate of recurrent VTE was higher in patients with proximal deep vein thrombosis (rate ratio 1.4, 95% confidence interval 1.1 to 1.7) and in patients with pulmonary embolism plus deep vein thrombosis (1.5, 1.1 to 1.9). In patients with distal deep vein thrombosis, the pooled rate of recurrent VTE per 100 person years was 1.9 events (95% confidence interval 0.5 to 4.3) in the first year after anticoagulation had stopped. The case fatality rate for recurrent VTE was 4% (95% confidence interval 2% to 6%).
Conclusions In patients with a first episode of unprovoked VTE who completed at least three months of anticoagulant treatment, the risk of recurrent VTE was 10% in the first year after treatment, 16% at two years, 25% at five years, and 36% at 10 years, with 4% of recurrent VTE events resulting in death. These estimates should inform clinical practice guidelines, enhance confidence in counselling patients of their prognosis, and help guide decision making about long term management of unprovoked VTE.
Systematic review registration PROSPERO CRD42017056309.
Contributors: FK and MAR conceived the study. FK, AR, BH, GAW, and MAR developed the design and methodology of the study. All authors were involved in the acquisition, analysis, or interpretation of data. FK and MAR drafted the manuscript and all authors critically revised the manuscript for important intellectual content. All authors gave final approval of the version to be published. FK and MAR are guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding: MC, CK, SS, JIW, and MAR are investigators of the CanVECTOR Network; the Network receives grant funding from the Canadian Institutes of Health Research (CDT-142654). FK was supported by the Canada Graduate Scholarship from the Canadian Institutes of Health Research (CIHR), the CIHR Drug Safety and Effectiveness Cross-Disciplinary Training award, the Queen Elizabeth II Graduate Scholarship in Science and Technology, and is supported by the CIHR Fredrick Banting and Charles Best Doctoral Research Award. CK is supported by the Jack Hirsh Fellowship in Thromboembolism, McMaster University. MAR is supported by a Heart and Stroke Foundation Career Investigator Award and a University of Ottawa, Faculty of Medicine Tier 1 Clinical Research Chair. The funding organisations did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare: MC has received grants from Leo Pharma, Bristol-Myers Squibb, Bayer, Octapharma, personal fees from Sanofi Aventis, Pfizer, Boehringer Ingelheim, Leo Pharma, Bayer Pfizer, Servier, and been on the advisory board for Leo Pharma and Sanofi Aventis, outside the submitted work; CK has received grants from Bayer, outside the submitted work. JIW has received personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Pfizer, and Portola, outside the submitted work; SS has received grants from Boehringer Ingelheim and Octapharma, personal fees from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Octapharma, Sanofi, Alnylam, and Bristol-Myers-Squibb, outside the submitted work; FC has received grants from Pfizer, and personal fees from Bayer, BMS, Aztra Zeneca, leopharma, outside the submitted work; CB has received personal fees from Bayer HealthCare, Daiichi Sankyo, Bristol Myers Squibb, and Servier, outside the submitted work; GA has received personal fees from Bristol-Myers-Squibb, Bayer Healthcare, Boehringer Ingelheim, and Daiichi Sankyo, outside the submitted work; AWAL reports being an employee of Bayer HealthCare; MHP has received personal fees from Pfizer and Daiichi Sankyo, outside the submitted work; BH reports past research from Cornerstone Research Group for methodologic advice related to the conduct of systematic reviews and meta-analysis, outside the submitted work; GP has received personal fees from Alfasigma, Pfizer, BMS, Roche, and Werfen, outside the submitted work. There are no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: Not required.
Data sharing: No additional data available.
Transparency: The lead author (FK) and senior author (MAR) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
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