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.
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.
BACKGROUND: Cancer is the second leading cause of death in the United States.
PURPOSE: To conduct systematic reviews of aspirin and 1) total cancer mortality and incidence in persons eligible for primary prevention of cardiovascular disease (CVD) and 2) colorectal cancer (CRC) mortality and incidence in persons at average CRC risk.
DATA SOURCES: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials through January 2015 and relevant references from other reviews.
STUDY SELECTION: Trials comparing oral aspirin versus placebo or no treatment in adults aged 40 years or older were included. Two investigators independently reviewed abstracts and articles against inclusion and quality criteria.
DATA EXTRACTION: Data from 20 good- or fair-quality trials were abstracted by one reviewer and checked by another.
DATA SYNTHESIS: In CVD primary prevention trials, cancer mortality (relative risk [RR], 0.96 [95% CI, 0.87 to 1.06]) (10 trials; n = 103 787) and incidence (RR, 0.98 [CI, 0.93 to 1.04]) (6 trials; n = 72 926) were similar in aspirin and control groups over 3.6 to 10.1 years. In CVD primary and secondary prevention trials, 20-year CRC mortality was reduced among persons assigned to aspirin therapy (RR, 0.67 [CI, 0.52 to 0.86]) (4 trials; n = 14 033). Aspirin appeared to reduce CRC incidence beginning 10 to 19 years after initiation (RR, 0.60 [CI, 0.47 to 0.76]) (3 trials; n = 47 464).
LIMITATIONS: Most data were from clinically and methodologically heterogeneous CVD prevention trials. Outcome assessment and follow-up length varied across studies. Data on non-CRC cancer types and subgroups were limited.
CONCLUSION: In CVD primary prevention populations, aspirin's effect on total cancer mortality and incidence was not clearly established. Evidence from CVD primary and secondary prevention studies suggested that aspirin therapy reduces CRC incidence and perhaps mortality approximately 10 years after initiation.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.
BACKGROUND: Historically, warfarin or aspirin have been the recommended therapeutic options for the extended treatment (>3 months) of VTE. Data from Phase III randomised controlled trials (RCTs) are now available for non-VKA oral anticoagulants (NOACs) in this indication. The current systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of anticoagulants for the extended treatment of VTE.
METHODS: Electronic databases (accessed July 2014 and updated April 2016) were systematically searched to identify RCTs evaluating apixaban, aspirin, dabigatran, edoxaban, rivaroxaban, and warfarin for the extended treatment of VTE. Eligible studies included adults with an objectively confirmed deep vein thrombosis, pulmonary embolism or both. A fixed-effect Bayesian NMA was conducted, and results were presented as relative risks (RRs). Sensitivity analyses examining (i) the dataset employed according to the time frame for outcome assessment (ii) the model used for the NMA were conducted.
RESULTS: Eleven Phase III RCTs (examining apixaban, aspirin, dabigatran, rivaroxaban, warfarin and placebo) were included. The risk of the composite efficacy outcome (VTE and VTE-related death) was statistically significantly lower with the NOACs and warfarin INR 2.0-3.0 compared with aspirin, with no significant differences between the NOACs. Treatment with apixaban (RR 0.23, 95% CrI 0.10, 0.55) or dabigatran (RR 0.55, 95% Crl 0.43, 0.71) was associated with a statistically significantly reduced risk of 'major or clinically relevant non-major bleed' compared with warfarin INR 2.0-3.0. Apixaban also showed a significantly reduced risk compared with dabigatran (RR 0.42, 95% Crl 0.18, 0.97) and rivaroxaban (RR 0.23, 95% Crl 0.09, 0.59). Sensitivity analyses indicate that results were dependent on the dataset, but not on the type of NMA model employed.
CONCLUSIONS: Results from the NMA indicate that NOACs are an effective treatment for prevention of VTE or VTE-related death) in the extended treatment setting. However, bleeding risk differs between potential treatments, with apixaban reporting the most favourable profile compared with other NOACs, warfarin INR 2.0-3.0, and aspirin.
INTRODUCTION: The duration of anticoagulation after venous thromboembolic events (VTE) is based on the balance between the risk of recurrent VTE and bleeding. The purpose of this study was to estimate the frequency and case-fatality rate of major bleeding and recurrent VTE during secondary prevention of VTE.
MATERIALS AND METHODS: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched through September 2014. Two reviewers independently screened citations to identify trials that enrolled patients for secondary prevention of VTE with direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs), aspirin or placebo. Two reviewers independently extracted data onto standardized forms.
RESULTS: Twelve RCTs that enrolled 10,542 patients were included. The rate of major bleeding was 1.6 per 100 patient-years (95% CI, 1.2-2.1), and 0.58 per 100 patient-years (95% CI, 0.24-1.1) on VKAs and DOACs, respectively, with an incidence rate ratio of 0.35 (95% CI, 0.17-0.68, p=0.0023). The case-fatality rates for DOACs and VKAs were not significantly different at 0% (95% CI, 0.0-15.4) and 6.8% (95% CI, 1.4-18.6), respectively. The rate of recurrent VTE was not different between DOACs and VKA, IRR 0.88 (95% CI, 0.15-4.8, p=0.88). Case-fatality rates for recurrent VTE for DOAC and VKAs were 10.8% (95% CI, 4.4-20.9) and 5.6% (95% CI, 1.2-15.4), respectively. Only DOACs showed a significant reduction in the composite outcome of fatal recurrent VTE and fatal bleeding when compared to placebo, IRR 0.40 (95% CI, 0.14-1.0, p=0.03).
CONCLUSION: Case-fatality rates for major bleeding and recurrent VTE for DOACs appear to be similar to those for VKA and the composite of fatal events is lower for DOACs than placebo. Overall, given the favorable safety profile and comparable efficacy of DOAC therapy, the threshold to continue anticoagulation with DOACs after unprovoked VTE should be low if the baseline risk of anticoagulation-related bleeding is not high.
OBJECTIVE: To systematically review the literature and to quantitatively evaluate the efficacy and safety of extended pharmacologic treatment of venous thromboembolism (VTE) through network meta-analysis (NMA).
METHODS: A systematic literature search (MEDLINE, Embase, Cochrane CENTRAL, through September 2014) and searching of reference lists of included studies and relevant reviews was conducted to identify randomized controlled trials of patients who completed initial anticoagulant treatment for VTE and then randomized for the extension study; compared extension of anticoagulant treatment to placebo or active control; and reported at least one outcome of interest (VTE or a composite of major bleeding or clinically relevant non-major bleeding). A random-effects Frequentist approach to NMA was used to calculate relative risks with 95% confidence intervals.
RESULTS: Ten trials (n=11,079) were included. Risk of bias (assessed with the Cochrane tool) was low in most domains assessed across the included trials. Apixaban (2.5mg and 5mg), dabigatran, rivaroxaban, idraparinux and vitamin K antagonists (VKA) each significantly reduced the risk of VTE recurrence compared to placebo, ranging from a 73% reduction with idraparinux to 86% with VKAs. With exception of idraparinux, all active therapies significantly reduced VTE recurrence risk versus aspirin, ranging from a 73% reduction with either apixaban 2.5mg or rivaroxaban to 80% with VKAs. Apixaban and aspirin were the only therapies that did not increase composite bleeding risk significantly compared to placebo. All active therapies except aspirin increased risk of composite bleeding by 2 to 4-fold compared to apixaban 2.5mg, with no difference found between the two apixaban doses.
CONCLUSION: Extended treatment of VTE is a reasonable approach to provide continued protection from VTE recurrence although bleeding risk is variable across therapeutic options. Our results indicate that apixaban, dabigatran, rivaroxaban, idraparinux and VKAs all reduced VTE recurrence when compared to placebo. Apixaban appears to have a more favorable safety profile compared to other therapies.
BACKGROUND: Patients who have had an unprovoked deep venous thrombosis (DVT) or pulmonary embolus (PE) are at a high risk for recurrent venous thromboembolism (VTE). Extended "life-long" anticoagulation has been recommended in these patients. However, the risk benefit ratio of this approach is controversial and the role of the direct oral anticoagulants (DOACs) and aspirin is unclear. Furthermore, in some patients with a "weak provoking factor" there is clinical equipoise regarding continuation or cessation of anticoagulant therapy after treatment of the acute VTE event.
OBJECTIVE: A systematic review and meta-analysis to determine the risks (major bleeding) and benefits (recurrent VTE and mortality) of extended anticoagulation with vitamin k antagonists (VKA), DOACs and aspirin in patients with an unprovoked VTE and in those patients with clinical equipoise regarding continuation or cessation of anticoagulant therapy. In addition, we sought to determine the risk of recurrent VTE events once extended anti-thrombotic therapy was discontinued.
DATA SOURCES: MEDLINE, Cochrane Register of Controlled Trials, citation review of relevant primary and review articles.
STUDY SELECTION: Randomized placebo-controlled trials (RCTs) that compared the risk of recurrent VTE in patients with an unprovoked DVT or PE who had been treated for at least 3 months with a VKA or a DOAC and were then randomized to receive an oral anti-thrombotic agent or placebo for at least 6 additional months. We included studies that included patients in whom clinical equipoise existed regarding the continuation or cessation of anticoagulant therapy.
DATA EXTRACTION: Independent extraction of articles by both authors using predefined data fields, including study quality indicators. Data were abstracted on study size, study setting, initial event (DVT or PE), percentage of patients where the initial VTE event was unprovoked, the number of recurrent VTE events, major bleeds and mortality during the period of extended anticoagulation in the active treatment and placebo arms. In addition, we recorded the event rate once extended treatment was stopped. Meta-analytic techniques were used to summarize the data. Studies were grouped according to the type of anti-thrombotic agent.
DATA SYNTHESIS: Seven studies which enrolled 6778 patients met our inclusion criteria; two studies evaluated the extended use of Coumadin, three studies evaluated a DOAC and two studies evaluated the use of aspirin. The duration of followup varied from 6 to 37 months. In the Coumadin and aspirin studies 100% of the randomized patients had an unprovoked VTE, while in the DOAC studies between 73.5% and 93.2% of the VTE events were unprovoked. In the control group recurrent VTE occurred in 9.7% of patients compared to 2.8% in the active treatment group (OR 0.21; 95% CI 0.11-0.42, p<0.0001). VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with VKA and DOACs being significantly more effective than aspirin. Major bleeding events occurred in 12 patients in the control group (0.4%) and 25 of 3815 (0.6%) patients in the active treatment group (OR 1.64; 95% CI 0.69-3.90, NS). There were 39 (1.3%) deaths in control patients and 33 (0.9%) deaths in the anti-thrombotic group during the treatment period (OR 0.73; 95% CI 0.40-1.33, NS). Patients whose initial VTE event was a PE were more likely to have a recurrent PE than a DVT. The annualized event rate after discontinuation of extended antithrombotic therapy was 4.4% in the control group and 6.5% in the active treatment arm.
CONCLUSIONS: VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with DOACs and VKA being more effective than aspirin. The decision regarding life-long anticoagulation following an unprovoked DVT or PE should depend on the patients' risk for recurrent PE as well as the patients' values and preferences.
BACKGROUND: Cancer is the second leading cause of death in United States. The net benefit for aspirin (ASA) in cardiovascular disease (CVD) primary prevention is controversial due to increased risks from bleeding alongside relatively modest cardiovascular benefits. Consideration of additional cancer prevention effects might clarify whether long-term, low-dose ASA may offer an overall health benefit for the two top causes of mortality in the United States.
PURPOSE: We conducted this review, alongside two companion reviews, to support the U.S. Preventive Services Task Force (USPSTF) in making evidence-based recommendations about the use of ASA for primary prevention in adults and to understand the risks of regular ASA use.
DATA SOURCES: We used a systematic evidence review published in 2012 for cancer-specific and all-cause mortality outcomes and conducted a bridge search of PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials from 2011 to October 2013. For bleeding harms, we used four published systematic evidence reviews and conducted a search of PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials from January 1, 2010 to June 3, 2014 in PubMed and MEDLINE. We also reviewed all studies included and excluded for companion USPSTF reviews on ASA for colorectal cancer and CVD prevention and checked for additional relevant studies by reviewing reference lists of included studies and other published reviews or meta-analyses.
STUDY SELECTION: Two investigators independently reviewed 4,393 abstracts and 336 articles against previously established inclusion and exclusion criteria and critically appraised studies for risk of bias using USPSTF methods, supplemented by the Newcastle-Ottawa Scale for cohort studies and the Assessment of Multiple Systematic Reviews for systematic reviews. We included fair- or good-quality trials evaluating the effect of 75 mg or greater ASA at least every other day for 12 months or longer versus no ASA, in the absence of other antithrombotic medications, on cancer mortality, all-cause mortality, cancer incidence, and harms, primarily related to serious bleeding. We also included cohort studies meeting these criteria to evaluate potential harms of ASA.
DATA EXTRACTION AND ANALYSIS: For fair- and good-quality studies, one investigator abstracted study characteristics and outcomes into structured tables and a second verified accuracy. We assessed trials for heterogeneity using I(2) statistics and pooled trial-level results when appropriate using Mantel-Haenszel fixed effects to calculate relative risks (RRs) and Peto's odds ratios (OR). We focused on cancer effects and bleeding harms in CVD primary prevention trials, but also assessed results after including secondary CVD and colorectal adenoma prevention trials. Expected outcome rates with ASA intervention were calculated by multiplying simulated control group event rates for benefits as well as harms from the CVD primary prevention trials by the pooled RR estimate (and bounds of 95% confidence interval [CI]). The expected outcome rates were subtracted from the simulated control group rate to calculate the absolute risk reduction with 95% CI. We calculated expected outcomes using the minimum, maximum, and median control group rate for a given outcome to examine the range of results suggested by the primary studies.
RESULTS: When restricting analyses to 10 CVD primary prevention trials with a median of 6.0 years of followup, we found a nonsignificantly reduced mortality due to cancer among 103,787 individuals randomized to ASA or no ASA over 3.7 to 10.1 years (RR, 0.96 [95% CI, 0.87 to 1.06]), corresponding to 0.14 fewer cancer deaths (95% CI, 0.21 more to 0.45 fewer) per 1,000 person-years. Effects on all cancer mortality remained nonstatistically significant in sensitivity analyses exploring the effect of excluding trials of greater than 100 mg per day, of average length of scheduled treatment less than 5 years, or of every other day dosing. Only when including trials of both primary and secondary CVD prevention with doses up to 1,200 mg per day and requiring daily dosing within a scheduled treatment duration of 4 years or more could we find a statistically significant cancer mortality benefit (RR, 0.83 [95% CI, 0.70 to 0.98]) as reported by others. All-cause mortality in 10 CVD primary prevention trials was statistically significantly reduced (RR, 0.94 [95% CI, 0.88 to 0.99]), corresponding to 0.57 fewer deaths (95% CI, 0.10 fewer to 1.15 fewer) per 1,000 person-years, but was sensitive to including longer-term followup results from one trial and some other changes in inclusion or exclusion criteria. When also including CVD secondary prevention trials, all-cause mortality was similarly reduced and remained statistically significant when requiring daily dosing, dosages of 100 mg or less, or at least 4 years of followup, but not when substituting longer-term followup results. Few reduced deaths were cardiovascular and reduced nonvascular noncancer deaths appeared to play a prominent role, but this deserves further exploration. Among 72,926 participants in six CVD primary prevention trials, cancer incidence was similar between ASA and no ASA groups (RR, 0.98 [95% CI, 0.93 to 1.04]), corresponding to 0.20 fewer incident cases (95% CI, 0.39 more to 0.69 fewer) per 1,000 person-years, and was only statistically significantly reduced when including both primary and secondary CVD prevention trials and restricting to daily dose interventions with at least 4 years of followup with doses ranging from 75 to 500 mg per day (RR, 0.86 [95% CI, 0.74 to 0.99]). Data from primary prevention populations are currently too sparse to robustly examine cancer incidence or mortality for any cancer type other than colorectal cancer, which is examined in a companion report. Among 10 CVD primary prevention trials, the risk of major GI bleeding was increased (OR, 1.59 [95% CI, 1.32 to 1.91]), corresponding to 0.29 more cases of bleeding (95% CI, 0.44 more to 0.16 more) per 1,000 person-years. Sensitivity analyses showed little variation, except nonsignificantly increased risk with daily dosing and nonsignificantly decreased risk with alternate-day dosing. Risk of hemorrhagic stroke or other intracranial bleeding tended to be increased in primary prevention trials (OR, 1.27 [95% CI, 0.98 to 1.66]), corresponding to 0.11 more cases (95% CI, 0.28 more to 0.01 fewer) per 1,000 person-years, with statistically significant effects only when both primary and secondary prevention trials were combined (OR, 1.43 [95% CI, 1.12 to 1.81]). When restricted to all trials of 100 mg or less, the risk tended to decrease (OR, 1.32 [95% CI, 1.00 to 1.75]). Relatively rare events limited analyses. Data from cohort studies indicated that baseline rates of serious bleeding are higher than suggested from trials, and data from trials as well as cohorts indicated considerable baseline bleeding rate variation according to age, sex, diabetes, hypertension, and perhaps other selected cardiovascular risk factors. Comedications such as nonsteroidal anti-inflammatory drugs appeared to modify baseline rates in cohort studies, as well as bleeding risks with low-dose ASA, although data adjusted for other risk factors suggested a more modest combined effect than earlier estimates. These and other bleeding risk factors could potentially have a large impact on the absolute number of excess cases of bleeding and therefore net benefit considerations.
LIMITATIONS: Data on cancer benefits were limited by few trials—particularly of low-dose ASA and in CVD primary prevention populations—with adequate length of followup, which also limited analyses for cancer site-specific effects. Few analyses adjusted for combined impact of risk factors on bleeding risks; intracranial bleeding/hemorrhagic strokes are relatively rare and thus incompletely studied, and other potential risks of long-term ASA use are also understudied. Most currently available trial data are from older studies not specifically designed for outcomes beyond CVD and major bleeding, and not considering contemporary medications such as statins. In-progress research will be very valuable in updating these findings.
CONCLUSIONS: Low-dose ASA use may eventually be shown to provide modest cancer mortality benefits in CVD primary prevention populations, but effects are not clearly established since current estimates are imprecise and relatively unstable. Modest reductions in all-cause mortality effect are more stable, but cannot be completely explained through cancer and/or CVD mortality reduction. Rates of serious bleeding, with and without ASA, are higher than previously suggested in clinical trial populations, and are very important when assessing the likely net benefit of low-dose ASA use as a chemopreventive agent in a more individualized or subpopulation-specific manner.
BACKGROUND: In patients with a first unprovoked venous thromboembolism (VTE) the risk of recurrent VTE remains high after anticoagulant treatment is discontinued. The Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials showed that aspirin reduces this risk, but they were not individually powered to detect treatment effects for particular outcomes or subgroups. METHODS AND RESULTS: An individual patient data analysis of these trials was planned, before their results were known, to assess the effect of aspirin versus placebo on recurrent VTE, major vascular events (recurrent VTE, myocardial infarction, stroke, and cardiovascular disease death) and bleeding, overall and within predefined subgroups. The primary analysis, for VTE, was by intention to treat using time-to-event data. Of 1224 patients, 193 had recurrent VTE over 30.4 months' median follow-up. Aspirin reduced recurrent VTE (7.5%/yr versus 5.1%/yr; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51-0.90; P=0.008), including both deep-vein thrombosis (HR, 0.66; 95% CI, 0.47-0.92; P=0.01) and pulmonary embolism (HR, 0.66; 95% CI, 0.41-1.06; P=0.08). Aspirin reduced major vascular events (8.7%/yr versus 5.7%/yr; HR, 0.66; 95% CI, 0.50-0.86; P=0.002). The major bleeding rate was low (0.4%/yr for placebo and 0.5%/yr for aspirin). After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR, 0.58; 95% CI, 0.40-0.85; P=0.005). Prespecified subgroup analyses indicate similar relative, but larger absolute, risk reductions in men and older patients. CONCLUSIONS: Aspirin after anticoagulant treatment reduces the overall risk of recurrence by more than a third in a broad cross-section of patients with a first unprovoked VTE, without significantly increasing the risk of bleeding. CLINICAL TRIAL REGISTRATION URL: www.anzctr.org.au. Unique identifier: ACTRN12611000684921.
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.
Systematic Review Question»Systematic review of interventions
