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Direct oral anticoagulants in the treatment of acute venous thromboembolism in patients with obesity: A systematic review with meta-analysis.
Mai, V, Marceau-Ferron, E, Bertoletti, L, Lacasse, Y, Bonnet, S, Lega, JC, Provencher, S
Pharmacological research. 2021;:105317
Abstract
BACKGROUND Direct oral anticoagulants' (DOAC) pharmacokinetics are affected by obesity. Their efficacy and safety in obesity (BMI≥30 kg/m2) and morbid obesity (BMI≥40 kg/m2) are still unclear in the treatment of venous thromboembolism (VTE). OBJECTIVES To compare the efficacy/safety of DOAC versus vitamin K antagonist (VKA)/low molecular weight heparin (LMWH) for the treatment of VTE in patients with obesity and morbid obesity. The primary efficacy/safety outcomes were VTE recurrence and major bleeding (MB). Clinically relevant non-MB and mortality were also evaluated. METHODS A systematic literature search (MEDLINE, EMBASE, CENTRAL, Web of Science) identified studies evaluating DOAC in the treatment of VTE in patients with obesity and reporting one of the outcomes. Relative risks (RR) and 95 % confidence intervals (CI) were estimated using the Mantel-Haenszel method. RESULTS We included 21 studies (50,360pts) of which 16,150 patients had a BMI≥30 kg/m2 and 6443 patients had a BMI≥40 kg/m2. VTE recurrence was similar with DOAC compared to VKA/LMWH in patients with obesity (RR 1.03;95 %CI 0.93-1.15;p = 0.55) and morbid obesity (RR 1.06;95 %CI 0.94-1.19;p = 0.35). DOAC were also associated with a reduction in MB (RR 0.57;95 %CI 0.34-0.94;p = 0.03 and RR 0.71;95 %CI 0.50-1.00;p = 0.05 in patients with obesity and morbid obesity, respectively). Subgroup analyses comparing randomized controlled trials to observational studies showed consistent results. No difference was observed in regards of clinically relevant non-MB and mortality. CONCLUSION There is no signal for differences in VTE recurrence in patients with obesity and morbid obesity treated with DOAC compared to VKA/LMWH, while DOAC likely reduce the risk of MB compared to VKA/LMWH.
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Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.
Khan, F, Tritschler, T, Kimpton, M, Wells, PS, Kearon, C, Weitz, JI, Büller, HR, Raskob, GE, Ageno, W, Couturaud, F, et al
Annals of internal medicine. 2021;(10):1420-1429
Abstract
BACKGROUND The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research. (PROSPERO CRD42019128597).
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Association between serum vitamin D levels and venous thromboembolism (VTE): A systematic review and meta-analysis of observational studies.
Wan, J, Yuan, J, Li, X, Bao, Y, Hou, Y, Li, Z, Tan, SC, Low, TY, Chu, Y
Complementary therapies in medicine. 2020;:102579
Abstract
OBJECTIVE Although many studies have attempted to unravel the relationship between vitamin D deficiency and the incidence of VTE, the results remained inconsistent. To address this discrepancy, we performed a systematic review and meta-analysis to precisely disentangle the relationship between serum vitamin D levels and VTE risk. METHODS The Web of Science, Scopus, PubMed/Medline, Embase, and Google Scholar databases were searched for all available observational studies that reported the risk of venous thromboembolism (VTE) based on serum vitamin D levels categories. The search was performed up to March 2020. RESULTS Seven studies were included. The overall analysis showed a significantly increased risk of VTE in subjects with low levels of serum vitamin D compared with those with normal vitamin D levels (RR = 1.34; 95% CI: 1.07-1.69; P = 0.011). In a sensitivity analysis, we did not observe a significant effect of any individual study on the combined effect sizes. Nevertheless, significant heterogeneity was present among the studies (Cochrane Q test, p = 0.018, I2 = 61%). In the stratified analysis, low vitamin D levels were positively associated with an increased risk of VTE in prospective population-based studies (RR = 1.31; 95% CI: 1.06-1.61; P = 0.010) and in subjects below 60 years old (RR = 1.28; 95% CI: 1.07-1.54; P = 0.060). CONCLUSION our systematic review and meta-analysis showed that a low serum vitamin D level was indeed associated with an increased risk of VTE.
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Physical activity and risk of venous thromboembolism: systematic review and meta-analysis of prospective cohort studies.
Kunutsor, SK, Mäkikallio, TH, Seidu, S, de Araújo, CGS, Dey, RS, Blom, AW, Laukkanen, JA
European journal of epidemiology. 2020;(5):431-442
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Abstract
The inverse association between physical activity and arterial thrombotic disease is well established. Evidence on the association between physical activity and venous thromboembolism (VTE) is divergent. We conducted a systematic review and meta-analysis of published observational prospective cohort studies evaluating the associations of physical activity with VTE risk. MEDLINE, Embase, Web of Science, and manual search of relevant bibliographies were systematically searched until 26 February 2019. Extracted relative risks (RRs) with 95% confidence intervals (CIs) for the maximum versus minimal amount of physical activity groups were pooled using random effects meta-analysis. Twelve articles based on 14 unique prospective cohort studies comprising of 1,286,295 participants and 23,753 VTE events were eligible. The pooled fully-adjusted RR (95% CI) of VTE comparing the most physically active versus the least physically active groups was 0.87 (0.79-0.95). In pooled analysis of 10 studies (288,043 participants and 7069 VTE events) that reported risk estimates not adjusted for body mass index (BMI), the RR (95% CI) of VTE was 0.81 (0.70-0.93). The associations did not vary by geographical location, age, sex, BMI, and methodological quality of studies. There was no evidence of publication bias among contributing studies. Pooled observational prospective cohort studies support an association between regular physical activity and low incidence of VTE. The relationship does not appear to be mediated or confounded by BMI.
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Host-related factors for venous thromboembolism following total joint replacement: A meta-analysis of 89 observational studies involving over 14 million hip and knee replacements.
Barrett, MC, Whitehouse, MR, Blom, AW, Kunutsor, SK
Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 2020;(2):267-275
Abstract
BACKGROUND Venous thromboembolism, a potential complication of total joint replacement, is associated with preventable mortality and morbidity and is likely to be influenced by host-related factors such as sociodemographic characteristics, body mass index, medical and surgical histories, as well as circulating biomarkers. We conducted a systematic review and meta-analysis to assess the associations between host-related factors and venous thromboembolism risk following total hip and knee replacements. METHODS We searched MEDLINE, Embase, Web of Science, and Cochrane Library to March 2018 for longitudinal studies reporting these associations. Summary measures of association were relative risks (95% confidence intervals). RESULTS We identified 89 studies with data on 14,763,963 joint replacements and 150,086 venous thromboembolism events. Comparing males to females, age ≥70 to <70 years, and blacks to whites, relative risks for venous thromboembolism were 0.83 (0.75-0.91), 1.24 (1.03-1.50), and 1.26 (1.20-1.31) respectively. Comparing body mass indices ≥25 vs. <25; ≥30 vs. <30; and ≥50 vs. <50 kg/m2, relative risks were 1.40 (1.24-1.57); 1.65 (1.23-2.22); and 1.72 (1.10-2.67) respectively. Histories of venous thromboembolism; cardiovascular disease; congestive heart failure; cardiac arrhythmia; chronic pulmonary disease; renal disease; neurological disease; fluid & electrolyte imbalance; bariatric surgery; and comorbidity indices were associated with increased venous thromboembolism risk. Comparing a total knee with a hip replacement, the relative risk for venous thromboembolism was 1.69 (1.32-2.15). CONCLUSIONS Enhanced venous thromboembolism prophylaxis should be considered in those with nonmodifiable risk factors such as older black female knee replacement patients. Modifiable risk factors such as high body mass index and fluid & electrolyte imbalance should be addressed prior to elective surgery. SYSTEMATIC REVIEW REGISTRATION PROSPERO 2018: CRD42018089625.
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Effects of sodium-glucose cotransporter 2 inhibitors on risk of venous thromboembolism in patients with type 2 diabetes: A systematic review and meta-analysis.
Wang, A, Yang, K, Wang, T, Zhang, N, Tang, H, Feng, X
Diabetes/metabolism research and reviews. 2020;(1):e3174
Abstract
It has been reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors could increase blood viscosity, which may further increase risk of venous thromboembolism (VTE). Therefore, we conducted this meta-analysis to evaluate the association between SGLT2 inhibitors and risk of VTE in patients with type 2 diabetes. We systematically searched electronic databases up to April 2019 to identify randomized trials that reported the events of VTE in SGLT2 inhibitors group and control group (placebo or other active antidiabetic drugs). The primary outcome was VTE, and secondary outcomes included deep venous thrombosis (DVT) and pulmonary embolism (PE). A fixed-effects meta-analysis was performed to calculate the risk ratio (RR) with 95% CI. In total, 29 randomized trials involving 56 035 patients with type 2 diabetes were included. Incidence of VTE was not significantly different between SGLT2 inhibitors group and control group (128/32 038 vs 92/23 997), yielding an RR of 0.98 (95% CI, 0.75-1.28). Similarly, null associations were observed in the subgroup analyses. Our cumulative meta-analysis demonstrated the stability of our overall result over time. There was no significant association between SGLT2 inhibitors and risk of both DVT (17 trials; 31/17 442 vs 15/10 930; RR, 1.06; 95% CI, 0.60-1.89) and PE (19 trials; 56/26 118 vs 41/19 517; RR, 0.99; 95% CI, 0.67-1.46). Low statistical heterogeneity and no evidence of publication bias were observed. Current evidence from randomized trials found no association between SGLT2 inhibitors and risk of VTE among patients with type 2 diabetes.
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Editor's Choice - A Systematic Review and Meta-Analysis of the Efficacy and Safety of Anticoagulation in the Treatment of Venous Thromboembolism in Patients with Cancer.
Kirkilesis, GI, Kakkos, SK, Tsolakis, IA
European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2019;(5):685-701
Abstract
OBJECTIVE/BACKGROUND The aim was to review the relative efficacy and safety of anticoagulation for managing venous thromboembolism (VTE) in patients with cancer. METHODS A systematic review and meta-analysis was carried out. On 17 May 2018 the MEDLINE and Scopus databases were searched for randomised controlled trials (RCTs). Eligible RCTs had to be performed in patients with cancer exclusively or to report results on a subset of patients with cancer. The main study outcomes (efficacy/recurrent VTE and safety/bleeding events) were expressed as risk ratios (RR) with a 95% confidence interval (CI). The quality of evidence was assessed following the GRADE method. RESULTS Twenty-three RCTs with 6980 patients were identified. Low molecular weight heparins (LMWHs) were more effective than vitamin K antagonists (VKAs) in preventing recurrent VTE (RR 0.58, 95% CI 0.45-0.75) and deep vein thrombosis (RR 0.44, 95% CI 0.29-0.69) but not pulmonary embolism (PE), bleeding, or overall mortality. Direct oral anticoagulants (DOACs) were more effective than VKAs in preventing recurrent VTE (RR 0.65, 95% CI 0.45-0.95) but not DVT, PE, overall mortality, or bleeding. However, anti-Xa DOACs were more effective (RR for VTE 0.64, 95% CI 0.42-0.97) and caused less bleeding than VKAs, although major bleeding was reduced only with DOACs not requiring initial parenteral anticoagulation (RR 0.45, 95% CI 0.21-0.97). In a direct comparison, DOACs were more effective than LMWHs in preventing VTE recurrence (RR 0.64, 95% CI 0.45-0.90) but caused more major bleeding (RR 1.75, 95% CI 1.10-2.77), with no difference in fatal bleeding and overall mortality. Quality of evidence, where sufficient, was mostly moderate or high. CONCLUSION Compared with VKAs, LMWHs and DOACs are more effective in treating VTE, but the former caused less bleeding. DOACs are more effective than LMWHs in preventing VTE recurrence but may carry a higher risk of major bleeding, pending additional information by ongoing trials.
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A revised systematic review and meta-analysis on the effect of statins on D-dimer levels.
Schol-Gelok, S, Morelli, F, Arends, LR, Boersma, E, Kruip, MJHA, Versmissen, J, van Gelder, T
European journal of clinical investigation. 2019;(8):e13130
Abstract
BACKGROUND D-dimers are generated during endogenous fibrinolysis of a blood clot and have a central role in diagnostic algorithms to rule out venous thromboembolism. HMG-CoA reductase inhibitors, more commonly called statins, are known to have effects independent of LDL-cholesterol lowering, including antithrombotic properties. An effect of statins on D-dimer levels has been reported in a prior systematic review and meta-analysis, but methodological shortcomings might have led to an overestimated effect. To re-evaluate the association between statins and D-dimer levels, we systematically reviewed all published articles on the influence of statins on D-dimer levels and conducted a novel meta-analysis (PROSPERO registration number CRD42017058932). MATERIALS AND METHODS We electronically searched EMBASE, Medline Epub, Cochrane, Web of Science and Google Scholar (100 top relevance) (date of last search: 5 October 2017). We included randomized controlled trials, cohort studies and cross-sectional studies. Two reviewers independently screened all articles retrieved and extracted data on study and patient characteristics, study quality and D-dimer levels. RESULTS Study-level meta-analysis involving 18,052 study participants showed lower D-dimer levels in those receiving statin treatment than controls (SMD: -0.165, 95% CI -0.234; -0.096, P = <0.001). Sensitivity analyses and additional analyses on treatment duration (<12 weeks vs ≥12 weeks) and type of statin (lipophilic or hydrophilic) did not modify this overall result. CONCLUSION This meta-analysis suggests an association between use of statins and reduction of D-dimer levels, independent of treatment duration and type of statin used. This effect is small but robust, and should be interpreted with caution.
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Risk of intracranial hemorrhage associated with therapeutic anticoagulation for venous thromboembolism in cancer patients: a systematic review and meta-analysis.
Rojas-Hernandez, CM, Oo, TH, García-Perdomo, HA
Journal of thrombosis and thrombolysis. 2017;(2):233-240
Abstract
Intracranial hemorrhage (ICH) in cancer patients can result from tumor bleeding and from antitumor and anticoagulation therapy. The effect of anticoagulation on the incidence of ICH in cancer patients has not been quantified. Our objective was to determine the risk of intracranial hemorrhage associated with anticoagulation therapy for cancer-associated venous thromboembolism (VTE). Systematic review and meta-analysis of studies assessing the safety of anticoagulation therapy in patients with cancer-associated VTE. The primary endpoint of interest was the incidence of ICH and secondary outcomes included all major bleeding, and the time to ICH and major bleeding. After identifying 595 studies, five studies and 2089 patients were included in the analyses. We found that the relative risk (RR) for ICH was 0.494, 95 % CI (0.105-2.331) when low molecular weight heparin (LMWH) with vitamin K antagonist (VKA) anticoagulants were compared. No statistically significant differences in risk were measured. The risk of major bleeding using any type of anticoagulation therapy in patients with cancer-associated VTE was RR 0.853, 95 % CI (0.549, 1.327). After meta-analytic review of data published through August 2015, we conclude that therapeutic anticoagulation with LMWH given ≤6 months does not increase the risk of ICH in cancer patients compared to VKA. The risk of ICH in cancer patients is also similar to that of non-cancer patients. Available data were insufficient to determine if the ICH risk increase changes when the duration of anticoagulation is >6 months.
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Effectiveness and Safety of Non-vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillation and Venous Thromboembolism: A Systematic Review and Meta-analyses.
Almutairi, AR, Zhou, L, Gellad, WF, Lee, JK, Slack, MK, Martin, JR, Lo-Ciganic, WH
Clinical therapeutics. 2017;(7):1456-1478.e36
Abstract
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.