TY - JOUR
T1 - Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event
T2 - systematic review and meta-analysis
AU - Khan, Faizan
AU - Rahman, Alvi
AU - Carrier, Marc
AU - Kearon, Clive
AU - Weitz, Jeffrey I.
AU - Schulman, Sam
AU - Couturaud, Francis
AU - Eichinger, Sabine
AU - Kyrle, Paul A.
AU - Becattini, Cecilia
AU - Agnelli, Giancarlo
AU - Brighton, Timothy A.
AU - Lensing, Anthonie W. A.
AU - Prins, Martin H.
AU - Sabri, Elham
AU - Hutton, Brian
AU - Pinede, Laurent
AU - Cushman, Mary
AU - Palareti, Gualtiero
AU - Wells, George A.
AU - Prandoni, Paolo
AU - Buller, Harry R.
AU - Rodger, Marc A.
AU - MARVELOUS Collaborators
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to.
PY - 2019/7/24
Y1 - 2019/7/24
N2 - OBJECTIVESTo 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.DESIGNSystematic review and meta-analysis.DATA SOURCESMedline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019).STUDY SELECTIONRandomised 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 SYNTHESISTwo 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.RESULTS18 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%).CONCLUSIONSIn 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.
AB - OBJECTIVESTo 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.DESIGNSystematic review and meta-analysis.DATA SOURCESMedline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019).STUDY SELECTIONRandomised 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 SYNTHESISTwo 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.RESULTS18 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%).CONCLUSIONSIn 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.
KW - DEEP-VEIN THROMBOSIS
KW - PULMONARY-EMBOLISM
KW - ORAL ANTICOAGULATION
KW - EXTENDED TREATMENT
KW - THERAPY
KW - EPISODE
KW - WARFARIN
KW - ASPIRIN
KW - RIVAROXABAN
KW - PREVENTION
U2 - 10.1136/bmj.l4363
DO - 10.1136/bmj.l4363
M3 - (Systematic) Review article
SN - 1756-1833
VL - 366
JO - BMJ
JF - BMJ
M1 - l4363
ER -