INTRODUCTION: Direct oral anticoagulants (DOACs) effectively prevent recurrent venous thromboembolism (VTE). However, it is unknown which agents should be used to prevent recurrent VTE and which patients with unprovoked VTE should receive extended anticoagulation. We therefore sought to compare the efficacy and safety among DOACs for secondary prevention of VTE. We also determined a risk-adapted threshold for initiating extended anticoagulation based on the likelihood of VTE recurrence (without treatment) and bleeding (with treatment) in patients with unprovoked VTE.
METHODS: Our systematic review of randomized controlled trials compares extended anticoagulation with DOACs to another DOAC, aspirin, or placebo for the prevention of recurrent VTE. We searched PubMed, EMBASE, and Cochrane Registry of Controlled Trials (CENTRAL) in October 2018. Our outcomes of interest were VTE recurrence, major bleeding, and all clinically relevant bleeding. We used network meta-analysis to make indirect comparisons among DOACs. We populated the threshold decision-analytic model with data from our meta-analysis to determine the risk of VTE recurrence above which the benefits of extended anticoagulation outweigh the harms compared with no treatment.
RESULTS: We included four, high-quality, randomized trials comprising 8386 participants. Low-dose apixaban, full-dose apixaban, low-dose rivaroxaban, full-dose rivaroxaban, and dabigatran reduce VTE recurrence compared with placebo (RR = 0.19, 95% CI, 0.12-0.31; RR = 0.20, 95% CI, 0.12-0.32; RR = 0.08, 95% CI, 0.03-0.27; RR = 0.14, 95% CI, 0.06-0.35; RR = 0.19, 95% CI, 0.09-0.40, respectively). No DOACs increased major bleeding risk compared with placebo. A VTE recurrence risk above 0.3% to 0.4% at approximately 1 year is the threshold to treat a patient with unprovoked VTE with extended anticoagulation (with any DOAC).
CONCLUSIONS: All DOACs exhibit comparable efficacy for the prevention of recurrent VTE. Given that the risk of VTE recurrence is much higher than the calculated threshold for treatment, extended thromboprophylaxis should be considered in all patients with unprovoked VTE who do not have increased bleeding risk.
OBJECTIVE: To evaluate efficacy and safety of oral anticoagulant regimens and aspirin for extended venous thromboembolism (VTE) treatment.
METHODS: We searched MEDLINE, Embase, CENTRAL and conference proceedings for randomised controlled trials studying vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or aspirin for secondary prevention of VTE beyond 3 months. ORs (95% credible intervals) between treatments were estimated using random-effects Bayesian network meta-analysis.
RESULTS: Sixteen studies, totaling more than 22 000 patients, were included. Compared with placebo or observation and with aspirin, respectively, the risk of recurrent VTE was lower with standard-intensity VKAs (0.15 (0.08 to 0.24) and 0.23 (0.09 to 0.54)), low-dose factor Xa inhibitors (0.16 (0.06 to 0.38) and 0.25 (0.09 to 0.66)), standard-dose factor Xa inhibitors (0.17 (0.08 to 0.33) and 0.27 (0.11 to 0.65)) and the direct thrombin inhibitor (0.15 (0.04 to 0.37) and 0.23 (0.06 to 0.74)) although the risk of major bleeding was higher with standard-intensity VKAs (4.42 (1.99 to 12.24) and 4.14 (1.17 to 18.86)). Effect estimates were consistent in male patients and those with index pulmonary embolism or with unprovoked VTE and in sensitivity analyses. In addition, compared with placebo or observation, the risk of all-cause mortality was reduced with standard-intensity VKAs (0.44 (0.20 to 0.87)) and low-dose factor Xa inhibitors (0.38 (0.12 to 0.995)).
CONCLUSIONS: Standard-intensity VKAs and DOACs are more efficacious than aspirin for extended VTE treatment. Despite a higher risk of major bleeding, standard-intensity VKAs was associated with a lower risk of all-cause mortality. Since overall efficacy and safety of standard-intensity VKAs and DOACs are in equipoise, patient factors, costs and patient preferences should be considered when recommending extending anticoagulation treatment.
BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) during extended anticoagulation for a VTE remains largely unknown, especially in terms of potential survival benefit. The goal of this study was to assess the effects of VKAs and DOACs on overall mortality and VTE-related mortality, as well as VTE recurrence and safety.
METHODS: PubMed, EMBASE, and the Cochrane Library were searched from January 1990 through September 2018 for randomized controlled trials evaluating the effect of extended anticoagulants as secondary prevention for VTE compared with placebo. The primary outcome was the specific effects of standard-intensity VKAs and DOACs on overall mortality.
RESULTS: Sixteen studies (12,458 patients) were included. DOACs were associated with a reduction in overall (risk ratio [RR], 0.48; 95% CI, 0.27-0.86; P = .01) and VTE-related (RR, 0.36; 95% CI, 0.15-0.89; P = .03) mortality, whereas VKAs were not (P > .50). Although VKAs and DOACs similarly prevented recurrent VTE, only VKAs were associated with an increased risk of major bleeding (RR, 2.67; 95% CI, 1.28-5.60; P < .01), resulting in an improved net clinical benefit for DOACs (RR, 0.25 [95% CI, 0.16-0.39; P < .01] vs 0.46 [95% CI, 0.30-0.72; P < .01]; Pinteraction = .05).
CONCLUSIONS: DOACs for extended anticoagulation were associated with a significant reduction in overall mortality compared with observation alone.
TRIAL REGISTRY: PROSPERO; No.: CRD42018088739; URL: https://www.crd.york.ac.uk/prospero/.
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.
BACKGROUND: Currently, little evidence is available on the length and type of anticoagulation used for extended treatment for prevention of recurrent venous thromboembolism (VTE) in patients with unprovoked VTE who have completed initial oral anticoagulation therapy.
OBJECTIVES: To compare the efficacy and safety of available oral therapeutic options (aspirin, warfarin, direct oral anticoagulants (DOACs)) for extended thromboprophylaxis in adults with a first unprovoked VTE, to prevent VTE recurrence after completion of an acceptable initial oral anticoagulant treatment period, as defined in individual studies.
SEARCH METHODS: For this review, the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (March 2017) as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2). We also searched trials registries (March 2017) and reference lists of relevant articles.
SELECTION CRITERIA: We included randomised controlled trials in which patients with a first, symptomatic, objectively confirmed, unprovoked VTE, who had been initially treated with anticoagulants, were randomised to extended prophylaxis (vitamin K antagonists (VKAs), antiplatelet agents, or DOACs) versus no prophylaxis or placebo. We also included trials that compared one type of extended prophylaxis versus another type of extended prophylaxis.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed quality, and extracted data. We resolved disagreements by discussion.
MAIN RESULTS: Six studies with a combined total of 3436 participants met the inclusion criteria. Five studies compared extended prophylaxis versus placebo: three compared warfarin versus placebo, and two compared aspirin versus placebo. One study compared one type of extended prophylaxis (rivaroxaban) versus another type of extended prophylaxis (aspirin). For extended prophylaxis versus placebo, we downgraded the quality of the evidence for recurrent VTE and all-cause mortality to moderate owing to concerns arising from risks of selection and performance bias in individual studies. For all other outcomes in this review, we downgraded the quality of the evidence to low owing to concerns arising from risk of bias for the studies stated above, combined with concerns over imprecision. For extended prophylaxis versus other extended prophylaxis, we downgraded the quality of the evidence for recurrent VTE and major bleeding to moderate owing to concerns over imprecision. Risk of bias in the individual study was low.Meta-analysis showed that extended prophylaxis was no more effective than placebo in preventing VTE-related mortality (odds ratio (OR) 0.98, 95% confidence interval (CI) 0.14 to 6.98; 1862 participants; 4 studies; P = 0.98; low-quality evidence), recurrent VTE (OR 0.63, 95% CI 0.38 to 1.03; 2043 participants; 5 studies; P = 0.07; moderate-quality evidence), major bleeding (OR 1.84, 95% CI 0.87 to 3.85; 2043 participants; 5 studies; P = 0.86; low-quality evidence), all-cause mortality (OR 1.00, 95% CI 0.63 to 1.57; 2043 participants; 5 studies; P = 0.99; moderate-quality evidence), clinically relevant non-major bleeding (OR 1.78, 95% CI 0.59 to 5.33; 1672 participants; 4 studies; P = 0.30; low-quality evidence), stroke (OR 1.15, 95% CI 0.39 to 3.46; 1224 participants; 2 studies; P = 0.80; low-quality evidence), or myocardial infarction (OR 1.00, 95% CI 0.35 to 2.87; 1495 participants; 3 studies; P = 1.00; low-quality evidence).One study showed that the novel oral anticoagulant rivaroxaban was associated with fewer recurrent VTEs than aspirin (OR 0.28, 95% CI 0.15 to 0.54; 1389 participants; P = 0.0001; moderate-quality evidence). Data show no clear differences in the incidence of major bleeding between rivaroxaban and aspirin (OR 3.06, 95% CI 0.37 to 25.51; 1389 participants; P = 0.30; moderate-quality evidence) nor in the incidence of clinically relevant non-major bleeding (OR 0.84, 95% CI 0.37 to 1.94; 1389 participants; 1 study; P = 0.69; moderate-quality evidence). Data on VTE-related mortality, all-cause mortality, stroke, and myocardial infarction were not yet available for participants with unprovoked VTE and will be incorporated in future versions of the review.
AUTHORS' CONCLUSIONS: Evidence is currently insufficient to permit definitive conclusions concerning the effectiveness and safety of extended thromboprophylaxis in prevention of recurrent VTE after initial oral anticoagulation therapy among participants with unprovoked VTE. Additional good-quality large-scale randomised controlled trials are required before firm conclusions can be reached.
Direct oral anticoagulants (DOACs) effectively prevent recurrent venous thromboembolism (VTE). However, it is unknown which agents should be used to prevent recurrent VTE and which patients with unprovoked VTE should receive extended anticoagulation. We therefore sought to compare the efficacy and safety among DOACs for secondary prevention of VTE. We also determined a risk-adapted threshold for initiating extended anticoagulation based on the likelihood of VTE recurrence (without treatment) and bleeding (with treatment) in patients with unprovoked VTE.
METHODS:
Our systematic review of randomized controlled trials compares extended anticoagulation with DOACs to another DOAC, aspirin, or placebo for the prevention of recurrent VTE. We searched PubMed, EMBASE, and Cochrane Registry of Controlled Trials (CENTRAL) in October 2018. Our outcomes of interest were VTE recurrence, major bleeding, and all clinically relevant bleeding. We used network meta-analysis to make indirect comparisons among DOACs. We populated the threshold decision-analytic model with data from our meta-analysis to determine the risk of VTE recurrence above which the benefits of extended anticoagulation outweigh the harms compared with no treatment.
RESULTS:
We included four, high-quality, randomized trials comprising 8386 participants. Low-dose apixaban, full-dose apixaban, low-dose rivaroxaban, full-dose rivaroxaban, and dabigatran reduce VTE recurrence compared with placebo (RR = 0.19, 95% CI, 0.12-0.31; RR = 0.20, 95% CI, 0.12-0.32; RR = 0.08, 95% CI, 0.03-0.27; RR = 0.14, 95% CI, 0.06-0.35; RR = 0.19, 95% CI, 0.09-0.40, respectively). No DOACs increased major bleeding risk compared with placebo. A VTE recurrence risk above 0.3% to 0.4% at approximately 1 year is the threshold to treat a patient with unprovoked VTE with extended anticoagulation (with any DOAC).
CONCLUSIONS:
All DOACs exhibit comparable efficacy for the prevention of recurrent VTE. Given that the risk of VTE recurrence is much higher than the calculated threshold for treatment, extended thromboprophylaxis should be considered in all patients with unprovoked VTE who do not have increased bleeding risk.
Systematic Review Question»Systematic review of interventions
