BACKGROUND: Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately one in 1000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTIs) and oral factor Xa inhibitors, which have characteristics that may be favourable compared to conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or dose adjustment and few known drug interactions. DOACs are now commonly being used for treating DVT: recent guidelines recommended DOACs over conventional anticoagulants for both DVT and PE treatment. This Cochrane Review was first published in 2015. It was the first systematic review to measure the effectiveness and safety of these drugs in the treatment of DVT. This is an update of the 2015 review. OBJECTIVES: To assess the effectiveness and safety of oral DTIs and oral factor Xa inhibitors versus conventional anticoagulants for the long-term treatment of DVT.
SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 1 March 2022.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which people with a DVT, confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor compared with conventional anticoagulation or compared with each other for the treatment of DVT. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were recurrent venous thromboembolism (VTE), recurrent DVT and PE. Secondary outcomes included all-cause mortality, major bleeding, post-thrombotic syndrome (PTS) and quality of life (QoL). We used GRADE to assess the certainty of evidence for each outcome.
MAIN RESULTS: We identified 10 new studies with 2950 participants for this update. In total, we included 21 RCTs involving 30,895 participants. Three studies investigated oral DTIs (two dabigatran and one ximelagatran), 17 investigated oral factor Xa inhibitors (eight rivaroxaban, five apixaban and four edoxaban) and one three-arm trial investigated both a DTI (dabigatran) and factor Xa inhibitor (rivaroxaban). Overall, the studies were of good methodological quality. Meta-analysis comparing DTIs to conventional anticoagulation showed no clear difference in the rate of recurrent VTE (odds ratio (OR) 1.17, 95% confidence interval (CI) 0.83 to 1.65; 3 studies, 5994 participants; moderate-certainty evidence), recurrent DVT (OR 1.11, 95% CI 0.74 to 1.66; 3 studies, 5994 participants; moderate-certainty evidence), fatal PE (OR 1.32, 95% CI 0.29 to 6.02; 3 studies, 5994 participants; moderate-certainty evidence), non-fatal PE (OR 1.29, 95% CI 0.64 to 2.59; 3 studies, 5994 participants; moderate-certainty evidence) or all-cause mortality (OR 0.66, 95% CI 0.41 to 1.08; 1 study, 2489 participants; moderate-certainty evidence). DTIs reduced the rate of major bleeding (OR 0.58, 95% CI 0.38 to 0.89; 3 studies, 5994 participants; high-certainty evidence). For oral factor Xa inhibitors compared with conventional anticoagulation, meta-analysis demonstrated no clear difference in recurrent VTE (OR 0.85, 95% CI 0.71 to 1.01; 13 studies, 17,505 participants; moderate-certainty evidence), recurrent DVT (OR 0.70, 95% CI 0.49 to 1.01; 9 studies, 16,439 participants; moderate-certainty evidence), fatal PE (OR 1.18, 95% CI 0.69 to 2.02; 6 studies, 15,082 participants; moderate-certainty evidence), non-fatal PE (OR 0.93, 95% CI 0.68 to 1.27; 7 studies, 15,166 participants; moderate-certainty evidence) or all-cause mortality (OR 0.87, 95% CI 0.67 to 1.14; 9 studies, 10,770 participants; moderate-certainty evidence). Meta-analysis showed a reduced rate of major bleeding with oral factor Xa inhibitors compared with conventional anticoagulation (OR 0.63, 95% CI 0.45 to 0.89; 17 studies, 18,066 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: The current review suggests that DOACs may be superior to conventional therapy in terms of safety (major bleeding), and are probably equivalent in terms of efficacy. There is probably little or no difference between DOACs and conventional anticoagulation in the prevention of recurrent VTE, recurrent DVT, pulmonary embolism and all-cause mortality. DOACs reduced the rate of major bleeding compared to conventional anticoagulation. The certainty of evidence was moderate or high.
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.
Efficacy and safety of direct oral anticoagulants (DOACs) for preventing primary and recurrent venous thromboembolism (VTE) in patients with cancer remain unclear. In this study, we conducted a systematic review to summarize the most up-to-date evidence from randomized controlled trials (RCTs). Our primary outcomes included the benefit outcome (VTE) and safety outcome (major bleeding). A random-effects model was used to pool the relative risks (RRs) for data syntheses. The Grading of Recommendations Assessment, Development and Evaluation tool was used to evaluate the quality of the entire body of evidence across studies. We included 11 RCTs with a total of 3741 patients with cancer for analyses. The DOACs were significantly related with a reduced risk of VTE when compared with non-DOACs: RR = 0.77, 95% confidence interval [CI]: 0.61-0.99, P = .04. Nonsignificant trend towards a higher risk of major bleeding was found in DOACs: RR = 1.28 95% CI: 0.81-2.02, P = .29. The quality of the entire body of evidence was graded as moderate for risk of VTE, and low for risk of major bleeding. To summarize, DOACs were found to have a favorable effect on risk of VTE but a nonsignificant higher risk of major bleeding compared with non-DOACs in patients with cancer. The safety effect of DOACs in patients with cancer requires further evaluation in adequately powered and designed studies.
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: Direct oral anticoagulants (DOACs) have emerged as promising alternatives to vitamin K antagonists (VKAs) for patients with non-valvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). Few meta-analyses have included all DOACs that have received FDA approval for these cardiovascular indications, and their overall comparisons against VKAs have shortcomings in data and methods. We provide an updated overall assessment of the efficacy and safety of those DOACs at dosages currently approved for NVAF or VTE, in comparison with VKAs.
METHODS: We used data from Phase 3 randomized trials that compared an FDA-approved DOAC with VKA for primary prevention of stroke in patients with NVAF or for treatment of acute VTE.
RESULTS: Among trial participants with NVAF, DOAC recipients had a lower risk of stroke or systemic embolism [Pooled Odds Ratio (OR) 0.76, 95% Confidence Interval (CI) (0.68-0.84)], any stroke (0.80, 0.73-0.88), systemic embolism (0.56, 0.34-0.93), and total mortality (0.89, 0.84-0.95). Safety outcomes also showed a lower risk of fatal, major, and intracranial bleeding but higher risk for gastrointestinal bleeding (GIB). Patients with acute VTE randomized to DOACs had comparable risk of recurrent VTE and death (OR 0.88, 95% CI 0.75-1.03), recurrent DVT (0.83, 0.66-1.05), recurrent non-fatal PE (0.97, 0.75-1.25), and total mortality (0.94, 0.79-1.12). Safety outcomes for DOACs showed a lower risk of major, fatal, and intracranial bleeding, but similar risk of GIB.
CONCLUSIONS: Patients receiving DOACs for NVAF had predominantly superior efficacy and safety. Patients who were treated with DOACs for acute VTE had non-inferior efficacy, but an overall superior safety profile.
Venous thromboembolism (VTE) is highly prevalent in patients with cancer. Non-vitamin K antagonist oral anticoagulants (NOACs), directly targeting the enzymatic activity of thrombin or factor Xa, have been shown to be as effective as and safer than traditional anticoagulation for VTE prophylaxis in no-cancer patients. However, related studies that focused on the anticoagulation in cancer patients are lacked, and almost no net clinical benefit (NCB) analyses that quantified both VTE events and bleeding events have been addressed in this fragile population. Therefore, we aim to investigate this issue using a systematic review and NCB analysis. A comprehensive search of Medline, Embase, and Cochrane Library were performed for randomized controlled trials (RCTs) that reported the VTE events and major bleeding of NOACs and traditional anticoagulants in patients with or without cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) of VTE and bleeding events were calculated using a random-effects model. The primacy outcome of narrow NCB was calculated by pooling ORs of VTE and major bleeding, with a weighting of 1.0. Similarly, the broad NCB was calculated by pooling ORs of VTE and clinically relevant bleeding. Heterogeneity was assessed through I2 test and Q statistic, and subgroup analyses were performed on the basis of different patients (VTE patients or acutely ill patients), comparators (vitamin-K antagonists or low-molecular-weight heparin), and follow-up duration (≤6 months or >6 months). Overall, 9 RCTs including 41,454 patients were enrolled, of which 2,902 (7%) were cancer patients, and 38,552 (93%) were no-cancer patients; 20,712 (50%) were administrated with NOACs and 20,742 (50%) were administrated with traditional anticoagulants. The use of NOACs had a superior NCB than traditional anticoagulation in both cancer patients (OR: 0.68, 95%CI: 0.50-0.85 for narrow NCB; OR: 0.76, 95%CI: 0.61-0.91 for broad NCB) and no-cancer patients (OR: 0.75, 95%CI: 0.54-0.96 for narrow NCB; OR: 0.85, 95%CI: 0.67-1.04 for broad NCB), with the estimates mainly from VTE patients receiving long-term warfarin treatment. In conclusion, NOACs may represent a better NCB property compared to traditional anticoagulants in cancer patients who need long-term anticoagulation treatment.
PURPOSE: The findings from the observational studies comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) for atrial fibrillation (AF) and venous thromboembolism (VTE) are inconsistent. We conducted separate meta-analyses examining the efficacy/effectiveness and safety of NOACs versus VKAs by disease (AF vs VTE), study design (randomized controlled trials [RCTs] vs observational studies), and NOAC (dabigatran, rivaroxaban, apixaban, and edoxaban).
METHODS: The main data sources included PubMed/MEDLINE, EMBASE, Web of Science, CINAHL, and Scopus from January 1, 2005, to February 15, 2016. We searched for Phase III RCTs and observational studies comparing NOACs versus VKAs. The primary outcomes were stroke/systemic embolism (SE) for AF; recurrent VTE/fatal pulmonary embolism (PE) for VTE; and major bleeding for both conditions. Secondary outcomes included stroke and myocardial infarction (MI) for AF, recurrent deep vein thrombosis (DVT)/PE for VTE, and mortality, intracranial hemorrhage (ICH), and gastrointestinal bleeding for both conditions. Pooled hazard ratios (HRs) were reported by using inverse variance-weighted random effects models.
FINDINGS: A total of 13 RCTs and 27 observational studies (AF, n = 32; VTE, n = 8) were included. For AF, dabigatran and VKAs were comparable for stroke/SE risk in 1 RCT (HR, 0.77 [95% CI, 0.57-1.03]) and 6 observational studies (HR, 1.03 [95% CI, 0.83-1.27]). Rivaroxaban had a 20% decreased risk of stroke/SE in 3 RCTs (HR, 0.80 [95% CI, 0.67-0.95]) compared with VKA, but the effect was nonsignificant in 3 observational studies (HR, 0.78 [95% CI, 0.59-1.04]). Apixaban decreased stroke/systemic embolism risk (HR, 0.79 [95% CI, 0.66-0.95]) compared with VKA in 1 RCT, but edoxaban was comparable to VKA (HR, 0.99 [95% CI, 0.77-1.28]) in 1 RCT (no observational studies available for apixaban/edoxaban). Dabigatran, apixaban, and edoxaban decreased the risk of hemorrhagic stroke, mortality, major bleeding, and ICH by 10% to 71% compared with VKAs but not rivaroxaban. For VTE, NOACs and VKAs were comparable for recurrent VTE/fatal PE/DVT/PE risk in 7 RCTs and 1 observational study. The 7 RCTs demonstrated a 32% to 69% decreased risk of major bleeding for dabigatran, rivaroxaban, and apixaban compared with VKAs. No difference was shown in 1 rivaroxaban observational study (HR, 0.77 [95% CI, 0.40-1.49]) and 1 edoxaban RCT (HR, 0.84 [95% CI, 0.59-1.20]). Except for dabigatran, the NOACs had a 61% to 86% decreased risk of ICH and gastrointestinal bleeding.
IMPLICATIONS: Overall, NOACs were comparable or superior to VKAs. Although no observational studies are currently available for apixaban/edoxaban, a few notable inconsistencies exist for dabigatran (ischemic stroke, MI) and rivaroxaban (stroke/SE, major bleeding in VTE) between RCTs and observational studies. Individualizing NOAC/VKA therapy based on benefit/safety profiles and patient characteristics is suggested.
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.
Data on all-cause mortality in patients with venous thromboembolism (VTE) and prolonged anticoagulation are inconclusive. The aim of this study was to compare the incidence of all-cause mortality in patients with VTE at intermediate risk of recurrence, i.e. without transient risk factors or cancer, exposed to shorter (at least three months) or longer anticoagulation. We did a systematic revue and meta-analysis of randomized clinical trials searching MEDLINE and COCHRANE bibliographic databases. A random-effects model was used to pool study results. I2 testing was used to test for heterogeneity. Six studies (5920 patients) entered in the final analysis. Mean course of anticoagulation was 7.5months in the shorter and 18.6months in the longer treatment arm. Prolonged anticoagulation was associated with a statistically significant reduction in all-cause mortality (RR 0.47, 95% CI 0.29 to 0.75; 0.8% vs 1.8%). Pulmonary embolism-related death was also lowered in the longer anticoagulation arm (RR 0.32, 95% CI 0.12 to 0.83; 0.2% vs 0.6%). Longer compared with shorter anticoagulation significantly reduced all-cause mortality in patients with VTE at intermediate risk of recurrence.
Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately one in 1000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTIs) and oral factor Xa inhibitors, which have characteristics that may be favourable compared to conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or dose adjustment and few known drug interactions. DOACs are now commonly being used for treating
DVT:
recent guidelines recommended DOACs over conventional anticoagulants for both DVT and PE treatment. This Cochrane Review was first published in 2015. It was the first systematic review to measure the effectiveness and safety of these drugs in the treatment of DVT. This is an update of the 2015 review.
OBJECTIVES:
To assess the effectiveness and safety of oral DTIs and oral factor Xa inhibitors versus conventional anticoagulants for the long-term treatment of DVT.
SEARCH METHODS:
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 1 March 2022.
SELECTION CRITERIA:
We included randomised controlled trials (RCTs) in which people with a DVT, confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor compared with conventional anticoagulation or compared with each other for the treatment of DVT.
DATA COLLECTION AND ANALYSIS:
We used standard Cochrane methods. Our primary outcomes were recurrent venous thromboembolism (VTE), recurrent DVT and PE. Secondary outcomes included all-cause mortality, major bleeding, post-thrombotic syndrome (PTS) and quality of life (QoL). We used GRADE to assess the certainty of evidence for each outcome.
MAIN RESULTS:
We identified 10 new studies with 2950 participants for this update. In total, we included 21 RCTs involving 30,895 participants. Three studies investigated oral DTIs (two dabigatran and one ximelagatran), 17 investigated oral factor Xa inhibitors (eight rivaroxaban, five apixaban and four edoxaban) and one three-arm trial investigated both a DTI (dabigatran) and factor Xa inhibitor (rivaroxaban). Overall, the studies were of good methodological quality. Meta-analysis comparing DTIs to conventional anticoagulation showed no clear difference in the rate of recurrent VTE (odds ratio (OR) 1.17, 95% confidence interval (CI) 0.83 to 1.65; 3 studies, 5994 participants; moderate-certainty evidence), recurrent DVT (OR 1.11, 95% CI 0.74 to 1.66; 3 studies, 5994 participants; moderate-certainty evidence), fatal PE (OR 1.32, 95% CI 0.29 to 6.02; 3 studies, 5994 participants; moderate-certainty evidence), non-fatal PE (OR 1.29, 95% CI 0.64 to 2.59; 3 studies, 5994 participants; moderate-certainty evidence) or all-cause mortality (OR 0.66, 95% CI 0.41 to 1.08; 1 study, 2489 participants; moderate-certainty evidence). DTIs reduced the rate of major bleeding (OR 0.58, 95% CI 0.38 to 0.89; 3 studies, 5994 participants; high-certainty evidence). For oral factor Xa inhibitors compared with conventional anticoagulation, meta-analysis demonstrated no clear difference in recurrent VTE (OR 0.85, 95% CI 0.71 to 1.01; 13 studies, 17,505 participants; moderate-certainty evidence), recurrent DVT (OR 0.70, 95% CI 0.49 to 1.01; 9 studies, 16,439 participants; moderate-certainty evidence), fatal PE (OR 1.18, 95% CI 0.69 to 2.02; 6 studies, 15,082 participants; moderate-certainty evidence), non-fatal PE (OR 0.93, 95% CI 0.68 to 1.27; 7 studies, 15,166 participants; moderate-certainty evidence) or all-cause mortality (OR 0.87, 95% CI 0.67 to 1.14; 9 studies, 10,770 participants; moderate-certainty evidence). Meta-analysis showed a reduced rate of major bleeding with oral factor Xa inhibitors compared with conventional anticoagulation (OR 0.63, 95% CI 0.45 to 0.89; 17 studies, 18,066 participants; high-certainty evidence).
AUTHORS' CONCLUSIONS:
The current review suggests that DOACs may be superior to conventional therapy in terms of safety (major bleeding), and are probably equivalent in terms of efficacy. There is probably little or no difference between DOACs and conventional anticoagulation in the prevention of recurrent VTE, recurrent DVT, pulmonary embolism and all-cause mortality. DOACs reduced the rate of major bleeding compared to conventional anticoagulation. The certainty of evidence was moderate or high.
