Summary Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at an increased risk of developing VTE and are more likely to have a recurrence ...of VTE and bleeding while taking anticoagulants. Management of VTE in patients with cancer is a major therapeutic challenge and remains suboptimal worldwide. In 2013, the International Initiative on Thrombosis and Cancer (ITAC-CME), established to reduce the global burden of VTE in patients with cancer, published international guidelines for the treatment and prophylaxis of VTE and central venous catheter-associated thrombosis. The rapid global adoption of direct oral anticoagulants for management of VTE in patients with cancer is an emerging treatment trend that needs to be addressed based on the current level of evidence. In this Review, we provide an update of the ITAC-CME consensus recommendations based on a systematic review of the literature ranked according to the Grading of Recommendations Assessment, Development, and Evaluation scale. These guidelines aim to address in-hospital and outpatient cancer-associated VTE in specific subgroups of patients with cancer.
SummaryVenous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The ...International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer.
Summary Background Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to ...prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. Methods We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov , number NCT00143598 , and Current Controlled Trials, number ISRCTN71334751. Findings From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73–1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. Interpretation ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. Funding Canadian Institutes of Health Research.
Abstract Background We aimed to evaluate health-related quality of life (QOL), dyspnea and functional exercise capacity during the year following the diagnosis of a first episode of pulmonary ...embolism. Methods Prospective multicenter cohort study of 100 patients with acute pulmonary embolism recruited at 5 Canadian hospitals from 2010-2013. We measured the outcomes QOL (by SF-36 and PEmb-QOL measures), dyspnea (by the University of California San Diego Shortness of Breath Questionnaire (SOBQ)) and six-minute walk distance at Baseline, 1, 3, 6, and 12 months after acute pulmonary embolism. CT pulmonary angiography was performed at baseline, echocardiogram was performed within 10 days, and cardiopulmonary exercise testing was performed at 1 and 12 months. Predictors of change in QOL, dyspnea, and six-minute walk distance were assessed by repeated measures mixed effects models analysis. Results Mean age was 50.0 years, 57% were male, and 80% were treated as out-patients. Mean scores for all outcomes improved during 1 year follow-up: from baseline to 12 months, mean SF-36 physical component score improved by 8.8 points, SF-36 mental component score by 5.3 points, PEmb-QoL by -32.1 points, and SOBQ by -16.3 points, and six-minute walk distance improved by 40 m. Independent predictors of reduced improvement over time were female sex, higher BMI and percent-predicted VO2 peak <80% on 1 month cardiopulmonary exercise test for all outcomes; prior lung disease and higher pulmonary artery systolic pressure on 10-day echocardiogram for the outcomes SF-36 physical component score and dyspnea score; and higher main pulmonary artery diameter on baseline CT pulmonary angiography for the outcome PEmb-QoL score. Conclusions On average, QOL, dyspnea, and walking distance improve during the year after pulmonary embolism. However, a number of clinical and physiological predictors of reduced improvement over time were identified, most notably female sex, higher BMI and exercise limitation on 1- month cardiopulmonary exercise test. Our results provide new information on patient-relevant prognosis after pulmonary embolism.
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 > or = 250 microg/L while taking warfarin; body mass index > or = 30 kg/m(2); or age > or = 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.
Summary Background 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. Methods 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. Findings 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). Interpretation 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. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.
The optimal duration of oral anticoagulant therapy after a first, unprovoked venous thromboembolism is controversial due to tightly balanced risks and benefits of indefinite anticoagulation. Risk ...stratification tools may assist in decision making.
We sought to determine the relationship between residual pulmonary embolism assessed by baseline ventilation-perfusion scan after completion of 5–7months of oral anticoagulant therapy and the risk of recurrent venous thromboembolism in patients with the first episode of unprovoked pulmonary embolism.
We conducted a multicentre prospective cohort study of participants with a first, unprovoked venous thromboembolism enrolled after the completion of 5–7months of oral anticoagulation therapy. The participants completed a mean 18-month follow-up. Participants with pulmonary embolism had baseline ventilation-perfusion scan before discontinuation of oral anticoagulant therapy and the percentage of vascular obstruction on baseline ventilation-perfusion scan was determined. During follow-up after discontinuation of oral anticoagulant therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated with reference to baseline imaging.
During follow-up, 24 of 239 (10.0%) participants with an index event of isolated pulmonary embolism or pulmonary embolism associated with deep vein thrombosis and central assessment of percentage of vascular obstruction on baseline ventilation-perfusion scan had confirmed recurrent venous thromboembolism. As compared to participants with no residual pulmonary embolism on baseline ventilation-perfusion scan, the hazard ratio for recurrent venous thromboembolism was 2.0 (95% CI 0.5–7.3) for participants with percentage of vascular obstruction of 0.1%–4.9%, 2.1 (95% CI 0.5–7.8) for participants with percentage vascular obstruction of 5.0%–9.9% and 5.3 (95% CI 1.8–15.4) for participants with percentage vascular obstruction greater than or equal to 10%.
Residual pulmonary embolism assessed by pulmonary vascular obstruction on baseline ventilation-perfusion performed after 5–7months of oral anticoagulant therapy for the first episode of unprovoked pulmonary embolism was associated with a statistically significant higher risk of subsequent recurrent venous thromboembolism. Percentage of pulmonary vascular obstruction assessment by ventilation-perfusion scans maybe a useful tool to help guide the duration of oral anticoagulant therapy after a first unprovoked pulmonary embolism.
Registered at www.clinicaltrials.gov identifier: NCT00261014.
•Optimal duration of OAT after a first, unprovoked VTE is controversial.•Better prediction of the risk of recurrent VTE after OAT discontinuation is necessary.•Residual PE can be assessed by percentage of vascular obstruction (PVO).•PVO after 5–7months OAT was associated with a higher risk of recurrent VTE.•PVO assessment by V/Q scans maybe a useful tool to help guide the duration of OAT.
CONTEXT When unfractionated heparin is used to treat acute venous thromboembolism, it is usually administered by intravenous infusion with coagulation monitoring, which requires hospitalization. ...However, subcutaneous administration of fixed-dose, weight-adjusted, unfractionated heparin may be suitable for inpatient and outpatient treatment of venous thromboembolism. OBJECTIVE To determine if fixed-dose, weight-adjusted, subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for treatment of venous thromboembolism. DESIGN, SETTING, AND PATIENTS Randomized, open-label, adjudicator-blinded, noninferiority trial of 708 patients aged 18 years or older with acute venous thromboembolism from 6 university-affiliated clinical centers in Canada and New Zealand conducted from September 1998 through February 2004. Of the randomized patients, 11 were subsequently excluded from the analysis of efficacy and 8 from the analysis of safety. INTERVENTIONS Unfractionated heparin was administered subcutaneously as an initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours (n = 345). Low-molecular-weight heparin (dalteparin or enoxaparin) was administered subcutaneously at a dose of 100 IU/kg every 12 hours (n = 352). Both treatments could be administered out of hospital and both were overlapped with 3 months of warfarin therapy. MAIN OUTCOME MEASURES Recurrent venous thromboembolism within 3 months and major bleeding within 10 days of randomization. RESULTS Recurrent venous thromboembolism occurred in 13 patients in the unfractionated heparin group (3.8%) compared with 12 patients in the low-molecular-weight heparin group (3.4%; absolute difference, 0.4%; 95% confidence interval, −2.6% to 3.3%). Major bleeding during the first 10 days of treatment occurred in 4 patients in the unfractionated heparin group (1.1%) compared with 5 patients in the low-molecular-weight heparin group (1.4%; absolute difference, −0.3%; 95% confidence interval, −2.3% to 1.7%). Treatment was administered entirely out of hospital in 72% of the unfractionated heparin group and 68% of the low-molecular-weight heparin group. CONCLUSION Fixed-dose subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin in patients with acute venous thromboembolism and is suitable for outpatient treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00182403
Background We aimed to determine the frequency and predictors of exercise limitation after pulmonary embolism (PE) and to assess its association with health-related quality of life (HRQoL) and ...dyspnea. Methods One hundred patients with acute PE were recruited at five Canadian hospitals from 2010 to 2013. Cardiopulmonary exercise testing (CPET) was performed at 1 and 12 months. Quality of life (QoL), dyspnea, 6-min walk distance (6MWD), residual clot burden (perfusion scan, CT pulmonary angiography), cardiac function (echocardiography), and pulmonary function tests (PFTs) were measured during follow-up. The prespecified primary outcome was percent predicted peak oxygen uptake (Vo2 peak) < 80% at 1-year CPET. Results At 1 year, 40 of 86 patients (46.5%) had percent predicted Vo2 peak < 80% on CPET, which was associated with significantly worse generic health-related QoL (HRQoL), PE-specific HRQoL and dyspnea scores, and significantly reduced 6MWD at 1 year. Predictors of the primary outcome included male sex (relative risk RR, 3.2; 95% CI, 1.3-8.1), age (RR, 0.98; 95% CI, 0.96-0.99 per 1-year age increase), BMI (RR 1.1; 95% CI, 1.01-1.2 per 1 kg/m2 BMI increase), and smoking history (RR, 1.8; 95% CI, 1.1-2.9), as well as percent predicted Vo2 peak < 80% on CPET at 1 month (RR, 3.8; 95% CI,1.9-7.2), and 6MWD at 1 month (RR, 0.82; 95% CI, 0.7-0.9 per 30-m increased walking distance). Baseline or residual clot burden was not associated with the primary outcome. Mean PFT and echocardiographic results (pulmonary artery pressure, right and left ventricular systolic function) at 1 year were similarly within normal limits in both patients with exercise limitations and those without such limitations. Conclusions Almost half of patients with PE have exercise limitation at 1 year that adversely influences HRQoL, dyspnea, and walking distance. CPET or 6MWD testing at 1 month may help to identify patients with a higher risk of exercise limitation at 1 year after PE. Based on our results, we believe that the deconditioning that occurs after acute PE could underlie this exercise limitation, but we cannot exclude the fact that this may have been present before PE. Trial Registry ClinicalTrials.gov; No.: NCT01174628 ; URL: www.clinicaltrials.gov.
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