Case-fatality rate of major bleeding events in patients on dual antiplatelet therapy after percutaneous coronary intervention: A systematic review and meta-analysis.

Background Assessment of the case-fatality rate (CFR) of major bleeding on dual antiplatelet therapy (DAPT) may improve balancing risks and benefits of different durations of DAPT following percutaneous coronary intervention (PCI). Objectives To determine the CFR of major bleeding in patients on DAPT after PCI and to compare rates among different durations of DAPT. Methods Medline, Embase, and CENTRAL were searched from inception to August 2021 for randomized trials that reported fatal bleeding among patients who were randomized to ≥1 month of DAPT following PCI. Summary estimates for CFRs of major bleeding were calculated using the random-effects inverse-variance method. Statistical heterogeneity was evaluated using the I 2 statistic. Results Of 2777 citations obtained by the search, 15 (48%) of 31 potentially eligible studies were excluded because fatal bleeding was not reported, leaving 16 studies that were included in the analysis. Overall, there were 823 major bleeding events including 91 fatal events in 48,884 patients who were assigned to receive DAPT during study follow-up. The CFR of major bleeding was 10.8% (95% confidence interval [CI], 7.1-16.2; I 2 = 50%) in the entire study population, and 13.8% (95% CI, 6.5-27.1; I 2 = 28%), 11.2% (95% CI, 6.7-18.0; I 2 = 0%), and 5.8% (95% CI, 3.0-11.1; I 2 = 0%) in those on short-term (≤6 months; n = 16,553), standard-term (12 months; n = 19,453), and long-term DAPT (>12 months; n = 10,238), respectively. Conclusion Fatal bleeding is not reported in many studies evaluating DAPT after PCI. The CFR of major bleeding on DAPT is substantial and may be higher in the first 12 months of DAPT than during long-term DAPT

An update on the global use of risk assessment models and thromboprophylaxis in hospitalized patients with medical illnesses from the World Thrombosis Day steering committee: Systematic review and meta-analysis

INTRODUCTION Venous thromboembolism (VTE) is a leading cause of cardiovascular morbidity and mortality. The majority of VTE events are hospital-associated. In 2008, the Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) multinational cross-sectional study reported that only approximately 40% of medical patients at risk of VTE received adequate thromboprophylaxis. METHODS In our systematic review and meta-analysis, we aimed at providing updated figures concerning the use of thromboprophylaxis globally. We focused on: (a) the frequency of patients with an indication to thromboprophylaxis according with individual models; (b) the use of adequate thromboprophylaxis; and (c) reported contraindications to thromboprophylaxis. Observational nonrandomized studies or surveys focusing on medically ill patients were considered eligible. RESULTS After screening, we included 27 studies from 20 countries for a total of 137 288 patients. Overall, 50.5% (95% confidence interval [CI]: 41.9-59.1, I$^{2}$ 99%) of patients had an indication to thromboprophylaxis: of these, 54.5% (95% CI: 46.2-62.6, I$^{2}$ 99%) received adequate thromboprophylaxis. The use of adequate thromboprophylaxis was 66.8% in Europe (95% CI: 50.7-81.1, I$^{2}$ 98%), 44.9% in Africa (95% CI: 31.8-58.4, I$^{2}$ 96%), 37.6% in Asia (95% CI: 25.7-50.3, I$^{2}$ 97%), 58.3% in South America (95% CI: 31.1-83.1, I$^{2}$ 99%), and 68.6% in North America (95% CI: 64.9-72.6, I$^{2}$ 96%). No major differences in adequate thromboprophylaxis use were found across risk assessment models. Bleeding, thrombocytopenia, and renal/hepatic failure were the most frequently reported contraindications to thromboprophylaxis. CONCLUSIONS The use of anticoagulants for VTE prevention has been proven effective and safe, but thromboprophylaxis prescriptions are still unsatisfactory among hospitalized medically ill patients around the globe with marked geographical differences

It's time for head-to-head trials with direct oral anticoagulants.

Direct oral anticoagulants (DOACs) have become the recommended first choice anticoagulant agent for treatment of acute venous thromboembolism (VTE) in non-cancer patients and are increasingly prescribed worldwide. They have not only intrinsic advantages, such as rapid onset of action and wide therapeutic windows, but also a lower risk of major, intracranial and fatal bleeding in VTE patients compared to vitamin K antagonists. Even though DOACs are often referred to as uniform drug class, there is growing evidence that each DOAC has a specific risk profile. Indirect comparisons and retrospective cohort studies suggest that apixaban may be associated with a lower risk of major bleeding than other DOACs, but there are no head-to-head trials with DOACs. Therefore, current guidelines do not recommend one DOAC over another and the choice of a specific DOAC is mainly based on physician and patient preferences, reimbursement and availability. Retrospective cohort studies and VTE registries are important to identify potential differences in efficacy and safety between DOACs; but they are methodologically too limited to inform the optimal choice of oral anticoagulant agent. Randomized controlled trials are crucial to inform sound treatment recommendations, because proper randomization is the key to unprejudiced treatment allocation and minimization of unmeasured and unknown confounding. Given increasing evidence of differences in safety profiles of DOACs from indirect comparisons and observational studies, it's time for head-to-head trials with DOACs

Treatment of venous thromboembolism in elderly patients in the era of direct oral anticoagulants.

The incidence of venous thromboembolism (VTE) and VTE-related morbidity and mortality increase with advancing age. Over the past decade, substantial advances in treatment of VTE have been made, most notably the introduction of direct oral anticoagulants (DOACs) which offer simple treatment regimens across a broad spectrum of VTE patients and have become the first-choice anticoagulants in many VTE patients. Even though elderly patients are underrepresented in clinical trials, extrapolation of overall study results to the elderly subpopulation appears justified for acute VTE treatment and for the choice of anticoagulant agent. In the elderly, DOACs are not only associated with a lower risk of bleeding but they even appear to be more efficacious than vitamin K antagonists in preventing recurrent VTE during the acute treatment period. The most challenging aspect of VTE management in elderly patients is determination of optimal treatment duration. The risk of bleeding increases with advancing age but also several risk factors for recurrent VTE after stopping anticoagulation are more frequent in the elderly. Clinical decision rules estimating risk of recurrent VTE and bleeding have limited utility in elderly patients. Shared decision making considering patient preferences and values is therefore crucial to help determine individual treatment duration in elderly patients

Major Bleeding during Secondary Prevention of Venous Thromboembolism in Patients who have Completed Anticoagulation: A Systematic Review and Meta-Analysis.

International audienceBACKGROUND: The risk of major bleeding in patients who have completed anticoagulation therapy for unprovoked venous thromboembolism (VTE) is unknown. OBJECTIVE: To report the major bleeding and fatal bleeding rates in patients randomized to placebo or observation (i.e. no anticoagulation therapy) for the secondary prevention of recurrent VTE. PATIENTS/METHODS: We performed a systematic review and meta-analysis of the literature to summarize the rates of major bleeding and fatal bleeding in patients randomized to placebo or observation during the secondary prevention of VTE. Unrestricted searches of Medline (1950 to August 31, 2013), Embase (1980 to August 31, 2013), and the Cochrane Register of Controlled Trials using the OVID interface were conducted. Publications from potentially relevant journals were also searched by hand. We used a random-effects model to pool study results and I(2) testing to assess for heterogeneity. RESULTS: The analysis included 11 studies and 3,965 patients who were followed for a median of 24 months. The overall pooled major bleeding rate was 0.45 per 100 patient-years (95% CI: 0.29 to 0.64; I(2) : 0%), and the overall pooled fatal bleeding rate was 0.14 per 100 patient-years (95% CI: 0.057 to 0.26; I(2) : 0%). CONCLUSIONS: Patients not receiving anticoagulant therapy for the secondary prevention of VTE experience major bleeding events and this may impact recommendations for extended treatment in this patient population. This article is protected by copyright. All rights reserved

Defining time in therapeutic range for busy clinicians: frequency of dose changes is a good surrogate marker to identify patients with suboptimal anticoagulation with warfarin.

International audiencePatients on warfarin with sub-optimal time-in-therapeutic-range (TTR) are more likely to have adverse events. Target-specific oral anticoagulants (TSOACs) are approved and can be used as an alternative to warfarin for a number of indications. Further, the efficacy and safety profiles of the TSOACs compared to warfarin are more favourable when the TTR is ≤65% for certain indications. We aimed to determine simple, sensitive and specific diagnostic tools to identify TTR ≤ 65% during the initial three months of warfarin therapy. A cross-sectional study including patients newly initiated on warfarin without any interruption for three months was conducted. TTR was calculated using the Rosendaal method. Patients were stratified by TTR (≤ 65% or >65%). Number of INR measurements, dose changes and INR measurements of ≤ 1.7 or ≥ 4.0 were evaluated as potential diagnostic tools to identify TTR ≤ 65%. 670 patients were included. The most common indication for anticoagulation was venous thromboembolism. The mean TTR in the first three months was 68 ± 21% (Range: 10 to 100%). Three or more dose changes identified TTR ≤ 65% and demonstrated a sensitivity and specificity of 90% (95%CI 86 to 93%) and 56% (95%CI 51 to 61%), respectively. Three or more INR measurements of ≤ 1.7 during the initial three months of anticoagulation showed a sensitivity and specificity of 37% (95%CI 32 to 43%) and 98% (95%CI 96 to 99%), respectively. Three or more dose changes and three or more INR measurements of ≤ 1.7 could identify patients with a TTR ≤ 65% in the first three months of warfarin therapy

Treatment of venous thromboembolism in elderly patients in the era of direct oral anticoagulants

The incidence of venous thromboembolism (VTE) and VTE-related morbidity and mortality increase with advancing age. Over the past decade, substantial advances in the treatment of VTE have been achieved. Most notably, direct oral anticoagulants (DOACs) were introduced, which offer simple treatment regi- mens across a broad spectrum of patients with VTE and have become the first-choice anticoagulants in many individuals in this population. Even though elderly patients are underrepresented in clinical trials, the extrapolation of overall study results to the elderly subpopulation can be considered justified regarding acute VTE treatment and the choice of anticoagulant agent. In the elderly, DOACs are not only associated with a lower bleeding risk but they also appear to be even more efficacious than vitamin K antagonists in preventing recurrent VTE during the acute treatment period. Determining the optimal treatment duration is the most challenging aspect of VTE management in elderly patients. The risk of bleeding increases with advancing age, and several risk factors for recurrent VTE after stopping anticoagulation are also more frequent in the elderly. Clinical decision rules estimating the risk of recurrent VTE and bleeding have limited utility in elderly patients. Shared decision making considering patients' preferences and values is therefore crucial to help determine individual treatment duration in these patients

Extended treatment of venous thromboembolism: A systematic review and network meta-analysis

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