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AbstractObjectivesTo 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.Systematic review registrationPROSPERO CRD42017056309.

This trial showed that the addition of abdominopelvic CT to routine measures in patients with unprovoked venous thrombosis did not detect additional occult cancers. The incidence of cancer in first unprovoked venous thrombosis was 4%, not 10% as had been previously reported. Venous thromboembolism, which comprises deep-vein thrombosis and pulmonary embolism, is the third most common cardiovascular disorder. 1 – 3 It is classified as provoked when it is associated with a transient risk factor (e.g., trauma, surgery, prolonged immobility, or pregnancy or the puerperium) and as unprovoked when it is associated with neither a strong transient risk factor nor overt cancer. Unprovoked venous thromboembolism may be the earliest sign of cancer 4 , 5 ; up to 10% of patients with unprovoked venous thromboembolism receive a diagnosis of cancer in the year after their diagnosis of venous thromboembolism. 6 More than 60% of occult cancers are . . .

Factor V Leiden (FVL) and prothrombin gene mutation (PGM) are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications. A comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1) prospective cohort design; (2) clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3) maternal FVL or PGM carrier status; (4) sufficient data for calculation of odds ratios (ORs). We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2%) was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06-2.19) as compared with women without FVL (absolute risk 3.2%). There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89-1.70) or between FVL and SGA (OR = 1.0, 95% CI 0.80-1.25). PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79-1.99) or SGA (OR 1.25, 95% CI 0.92-1.70). Women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants. Please see later in the article for the Editors' Summary.

Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis. We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249. We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference −8%, 95% CI −17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36–1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications. Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. Canadian Institutes of Health Research.

Venous thromboembolism, comprising both deep vein thrombosis and pulmonary embolism, is a chronic illness that affects nearly 10 million people every year worldwide. Strong provoking risk factors for venous thromboembolism include major surgery and active cancer, but most events are unprovoked. Diagnosis requires a sequential work-up that combines assessment of clinical pretest probability for venous thromboembolism using a clinical score (eg, Wells score), D-dimer testing, and imaging. Venous thromboembolism can be considered excluded in patients with both a non-high clinical pretest probability and normal D-dimer concentrations. When required, ultrasonography should be done for a suspected deep vein thrombosis and CT or ventilation–perfusion scintigraphy for a suspected pulmonary embolism. Direct oral anticoagulants (DOACs) are the first-line treatment for almost all patients with venous thromboembolism (including those with cancer). After completing 3–6 months of initial treatment, anticoagulation can be discontinued in patients with venous thromboembolism provoked by a major transient risk factor. Patients whose long-term risk of recurrent venous thromboembolism outweighs the long-term risk of major bleeding, such as those with active cancer or men with unprovoked venous thromboembolism, should receive indefinite anticoagulant treatment. Pharmacological venous thromboembolism prophylaxis is generally warranted in patients undergoing major orthopaedic or cancer surgery. Ongoing research is focused on improving diagnostic strategies for suspected deep vein thrombosis, comparing different DOACs, developing safer anticoagulants, and further individualising approaches for the prevention and management of venous thromboembolism.

Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov, number NCT00967382, and with Current Controlled Trials, number ISRCTN87441504. Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 [17·1%; 95% CI 11·4–24·2%] vs no dalteparin 27/143 [18·9%; 95% CI 12·8–26·3%]; risk difference −1·8% [95% CI −10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 [19·6%] vs no dalteparin 24/141 [17·0%]; risk difference +2·6% [95% CI −6·4 to 11·6%]). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19·6%]) than in the no dalteparin group (13/141 [9·2%]; risk difference 10·4%, 95% CI 2·3–18·4; p=0·01). Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding. Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.

Whether to continue oral anticoagulant therapy beyond 6 months after an “unprovoked” venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants. In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5–7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p<0.10) with high interobserver reliability to derive a clinical decision rule. We identified 91 confirmed episodes of recurrent venous thromboembolism during follow-up after discontinuing oral anticoagulation therapy (annual risk 9.3%, 95% CI 7.7%–11.3%). Men had a 13.7% (95% CI 10.8%– 17.0%) annual risk. There was no combination of clinical predictors that satisfied our criteria for identifying a low-risk subgroup of men. Fifty-two percent of women had 0 or 1 of the following characteristics: hyperpigmentation, edema or redness of either leg; d-dimer ≥ 250 μg/L while taking warfarin; body mass index ≥ 30 kg/m2; or age ≥ 65 years. These women had an annual risk of 1.6% (95% CI 0.3%–4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%–17.3%). Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men. (http://Clinicaltrials.govtrialregisternumberNCT00261014) Une version française de ce résumé est disponible à l'adresse www.cmaj.ca/cgi/content/full/179/5/417/DC1 CMAJ 2008;179(5):417-26

Exercise training may have the potential to improve post-thrombotic syndrome, a frequent, chronic complication of deep venous thrombosis. We conducted a randomized controlled two-centre pilot trial to assess the feasibility of a multicentre-based evaluation of a six-month exercise training program to treat post-thrombotic syndrome and to obtain preliminary data on the effectiveness of such a program. Patients were randomized to receive exercise training (a six-month trainer-supervised program) or control treatment (an education session with monthly phone follow-ups). Levels of eligibility, consent, adherence and retention were used as indicators of study feasibility. Primary outcomes were change from baseline to six months in venous disease-specific quality of life (as measured using the Venous Insufficiency Epidemiological and Economic Study Quality of Life [VEINES-QOL] questionnaire) and severity of post-thrombotic syndrome (as measured by scores on the Villalta scale) in the exercise training group versus the control group, assessed by t tests. Secondary outcomes were change in generic quality of life (as measured using the Short-Form Health Survey-36 [SF-36] questionnaire), category of severity of post-thrombotic syndrome, leg strength, leg flexibility and time on treadmill. Of 95 patients with post-thrombotic syndrome, 69 were eligible, 43 consented and were randomized, and 39 completed the study. Exercise training was associated with improvement in VEINES-QOL scores (exercise training mean change 6.0, standard deviation [SD] 5.1 v. control mean change 1.4, SD 7.2; difference 4.6, 95% CI 0.54 to 8.7; p = 0.027) and improvement in scores on the Villalta scale (exercise training mean change −3.6, SD 3.7 v. control mean change −1.6, SD 4.3; difference −2.0, 95% CI −4.6 to 0.6; p = 0.14). Most secondary outcomes also showed greater improvement in the exercise training group. Exercise training may improve post-thrombotic syndrome. It would be feasible to definitively evaluate exercise training as a treatment for post-thrombotic syndrome in a large multicentre trial. (Trial registered at www.controlled-trials.com, no. ISRCTN56430072.)

Objective To prospectively validate the HERDOO2 rule (Hyperpigmentation, Edema, or Redness in either leg; D-dimer level ≥250 μg/L; Obesity with body mass index ≥30; or Older age, ≥65 years), which states that women with none or one of the criteria can safely discontinue anticoagulants after short term treatment.Design Prospective cohort management study.Setting 44 secondary or tertiary care centres in seven countries.Participants Of 3155 consecutive eligible participants with a first unprovoked venous thromboembolism (VTE, proximal leg deep vein thrombosis or pulmonary embolism) who completed 5-12 months of short term anticoagulant treatment, 370 declined to participate, leaving 2785 enrolled participants. 2.3% were lost to follow-up.Interventions Women with none or one of the HERDOO2 criteria were classified as at low risk of recurrent VTE and discontinued anticoagulants (intervention arm), whereas anticoagulant management for high risk women (≥2 HERDOO2 criteria) and men was left to the discretion of the clinicians and patients (observation arm).Main outcome measure Recurrent symptomatic VTE (independently and blindly adjudicated) over one year of follow-up.Results Of 1213 women, 631 (51.3%) were classified as low risk and 591 discontinued oral anticoagulant treatment. In the primary analysis, 17 low risk women who discontinued anticoagulants developed recurrent VTE during 564 patient years of follow-up (3.0% per patient year, 95% confidence interval 1.8% to 4.8%). In 323 high risk women and men who discontinued anticoagulants, 25 had VTE during 309 patient years of follow-up (8.1%, 5.2% to 11.9%), whereas in 1802 high risk women and men who continued anticoagulants 28 had recurrent VTE during 1758 patient years of follow-up (1.6%, 1.1% to 2.3%).Conclusions Women with a first unprovoked VTE event and none or one of the HERDOO2 criteria have a low risk of recurrent VTE and can safely discontinue anticoagulants after completing short term treatment.Trial registration clinicaltrials.gov NCT00967304.