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Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta-analysis.
Elsebaie, MAT, van Es, N, Langston, A, Büller, HR, Gaddh, M
Journal of thrombosis and haemostasis : JTH. 2019;(4):645-656
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Abstract
Essentials We investigated direct oral anticoagulant (DOAC) use in venous thromboembolism and thrombophilia. A comprehensive search identified 10 studies, 8 of which were included in a meta-analysis. DOACs were overall safe and effective in patients with venous thromboembolism and thrombophilia. Efficacy/safety of DOACs was maintained in low-risk antiphospholipid syndrome patient subgroup. SUMMARY Background Direct oral anticoagulants (DOACs) are increasingly used in acute and long-term treatment of venous thromboembolism (VTE). However, their role in management of thrombophilia-associated VTE is controversial. Methods Through a comprehensive search on MEDLINE, Cochrane Library, and Clinicaltrials.gov, we identified 10 eligible studies, 8 of which reporting data on 1994 thrombophilia patients were included in a random-effects meta-analysis. Eligible studies were phase 2 to 3 randomized controlled trials comparing DOACs to vitamin K antagonists (VKAs) in patients with VTE, including those with thrombophilia. Results Of eight studies included in meta-analysis, four evaluated rivaroxaban, three dabigatran, and one edoxaban. No results could be obtained on apixaban use. The rates of VTE recurrence (RR, 0.70; 95% CI, 0.34-1.44; I2 = 0%) and major/clinically relevant non-major bleeding events (RR, 0.92; 95% CI, 0.62-1.36; I2 = 23%) were similar between thrombophilia patients treated with DOACs compared to VKAs. Results were comparable to findings in patients without known thrombophilia: RR, 1.02; 95% CI, 0.80-1.30; I2 = 46% for VTE recurrence and RR, 0.72; 95% CI, 0.57-0.90; I2 = 84% for major/clinically relevant non-major bleeding events. Conclusions Rates of VTE recurrence and bleeding events were both low and comparable in patients with various thrombophilias receiving either treatment, suggesting that DOACs are an appropriate treatment option in this population. Due to limited data, it is unclear whether these findings apply to specific subgroups such as high-risk antiphospholipid syndrome, uncommon thrombophilias, or the use of apixaban.
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Efficacy and Safety of Genotype-Guided Warfarin Dosing in the Chinese Population: A Meta-analysis of Randomized Controlled Trials.
Wang, F, Guo, J, Zhang, A
Journal of cardiovascular pharmacology. 2019;(3):127-135
Abstract
AIMS: To evaluate the efficacy and safety of using genetic information to guide warfarin dosing in the Chinese population. METHODS This meta-analysis was conducted among the published, randomized, controlled trials (RCTs) in the Chinese population comparing genotype-guided warfarin dosing (PG group) with clinical or standard warfarin dosing (STD group). RCTs published on or before January 2018 were identified using the PubMed, Embase, Cochrane Library, CNKI, Chinese VIP database, and Chinese Wanfang database. RESULT Intotal, 2137 participants from 14 RCTs were included in the meta-analysis. Primary analysis showed that both bleeding events [odds ratio (OR) = 0.24; 95% confidence interval (CI), 0.11-0.52; P = 0.0003] and adverse events (OR = 0.60; 95% CI, 0.43-0.83; P = 0.002) were significantly lower in the genotype-guided group than in the clinical or standard group. The percentage of patients who received a warfarin-stable therapeutic dose during follow-up was increased in the genotype-guided group compared with the percentage in the clinical or standard group (OR = 2.68; 95% CI, 1.82-3.95; P < 0.00001). In the genotype-guided group, the time to a stable therapeutic dose (mean difference = -7.98; 95% CI, -9.08 to -6.87; P < 0.00001) and the time to the first target value (mean difference = -1.87; 95% CI, -3.41 to -0.32; P = 0.02) were shortened compared with those of the clinical or standard group, but there was no difference for international normalized ratio >4, between the 2 groups (OR = 0.42; 95% CI, 0.14-1.25; P = 0.12). CONCLUSIONS Genotype-guided warfarin-dosing algorithms could improve the efficacy and safety of warfarin anticoagulation in the Chinese population.
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Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.
Sabater-Lleal, M, Huffman, JE, de Vries, PS, Marten, J, Mastrangelo, MA, Song, C, Pankratz, N, Ward-Caviness, CK, Yanek, LR, Trompet, S, et al
Circulation. 2019;(5):620-635
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Abstract
BACKGROUND Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. METHODS We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. RESULTS We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. CONCLUSIONS The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
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Extended anticoagulation for the secondary prevention of venous thromboembolic events: An updated network meta-analysis.
Mai, V, Bertoletti, L, Cucherat, M, Jardel, S, Grange, C, Provencher, S, Lega, JC
PloS one. 2019;(4):e0214134
Abstract
BACKGROUND Extended treatment is preconized in a significant proportion of patients with unprovoked venous thromboembolism (VTE). However, limited direct/indirect comparisons are available to appropriately weight the benefit/risk ratio of the diverse treatments available. We aimed to compare the rate of symptomatic recurrent VTE and major bleeding (MB), the net clinical benefit (VTE+MB) and death on vitamin-K antagonist (VKA), direct oral anticoagulants (DOAC) and antiplatelet drugs for extended anticoagulation. METHODS A systematic literature search through September 2018 identified randomized trials studying these pharmacologic therapies for extended anticoagulation following VTE. Treatment effects were calculated using network meta-analysis with frequentist fixed-effects model. RESULTS 18 trials (18,221 patients) were included in the analysis. All treatments reduced the risk of recurrence compared to placebo/observation. Nonetheless, VKA (RR 0.22; 95%CI 0.13-0.39) and DOAC (RRs ranging from 0.25-0.32; 95%CI ranging from 0.13-0.52) were more effective than aspirin, whereas low-dose VKA was less effective than standard-dose VKA (RR 2.47; 95%CI 1.34-4.55). The efficacy of DOAC was globally comparable to standard-adjusted dose VKA. Low- (RR 3.13; 95%CI 1.37-7.16) and standard-dose (RR 3.23; 95%CI 1.16-8.99) VKA also increased the risk of MB, which was not the case for any DOAC. Low-dose VKA and low-dose DOAC had similar effects on MB compared to standard-doses. Although there was a trend for reduced MB and enhanced net clinical benefit for DOAC compared to VKA, this was not statistically significant. The specific anticoagulant therapies had no significant effects on deaths. CONCLUSION Standard-dose VKA and low/standard-dose DOAC share similar effects on VTE recurrence and MB, whereas aspirin and low-dose VKA were associated with lower benefit/risk ratio.