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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.
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Effects of Non-Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: A Systematic Review and Meta-Analysis.
Pan, KL, Singer, DE, Ovbiagele, B, Wu, YL, Ahmed, MA, Lee, M
Journal of the American Heart Association. 2017;(7)
Abstract
BACKGROUND The original non-vitamin K antagonist oral anticoagulant (NOAC) trials in nonvalvular atrial fibrillation (AF) enrolled patients with native valve pathologies. The object of this study was to quantify the benefit-risk profiles of NOACs versus warfarin in AF patients with native valvular heart disease (VHD). METHODS AND RESULTS Trials were identified by exhaustive literature search. Trial data were combined using inverse variance weighting to produce a meta-analytic summary hazard ratio (HR) and 95% confidence interval (CI) of efficacy and safety of NOACs versus warfarin. Our final analysis included 4 randomized controlled trials that enrolled 71 526 participants, including 13 574 with VHD. Pooling results from included trials showed that NOACs versus warfarin reduced stroke or systemic embolism (HR: 0.70; 95% CI, 0.60-0.82) and intracranial hemorrhage (HR: 0.47; 95% CI, 0.24-0.92) in AF patients with VHD. However, risk reduction of major bleeding and intracranial hemorrhage was driven by apixaban, edoxaban, and dabigatran (HR for major bleeding: 0.79 [95% CI, 0.69-0.91]; HR for intracranial hemorrhage: 0.33 [95% CI, 0.25-0.45]) but not rivaroxaban (HR for major bleeding: 1.56 [95% CI, 1.20-2.04]; HR for intracranial hemorrhage: 1.27 [95% CI, 0.77-2.10]). CONCLUSIONS Among patients with AF and native VHD, NOACs reduce stroke and systemic embolism compared with warfarin. Evidence shows that apixaban, dabigatran, and edoxaban also reduce bleeding in this patient subgroup, whereas major bleeding (but not intracranial hemorrhage or mortality rate) is significantly increased in VHD patients treated with rivaroxaban. NOACs are a reasonable alternative to warfarin in AF patients with VHD.
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Maternal and Fetal Outcomes of Anticoagulation in Pregnant Women With Mechanical Heart Valves.
Steinberg, ZL, Dominguez-Islas, CP, Otto, CM, Stout, KK, Krieger, EV
Journal of the American College of Cardiology. 2017;(22):2681-2691
Abstract
BACKGROUND Anticoagulation for mechanical heart valves during pregnancy is essential to prevent thromboembolic events. Each regimen has drawbacks with regard to maternal or fetal risk. OBJECTIVES This meta-analysis sought to estimate and compare the risk of adverse maternal and fetal outcomes in pregnant women with mechanical heart valves who received different methods of anticoagulation. METHODS Studies were identified using a Medline search including all publications up to June 5, 2016. Study inclusion required reporting of maternal death, thromboembolism, and valve failure, and/or fetal spontaneous abortion, death, and congenital defects in pregnant women treated with any of the following: 1) a vitamin K antagonist (VKA) throughout pregnancy; 2) low-molecular-weight heparin (LMWH) throughout pregnancy; 3) LMWH for the first trimester, followed by a VKA (LMWH and VKA); or 4) unfractionated heparin for the first trimester, followed by a VKA (UFH and VKA). RESULTS A total of 800 pregnancies from 18 publications were included. Composite maternal risk was lowest with VKA (5%), compared with LMWH (16%; ratio of averaged risk [RAR]: 3.2; 95% confidence interval [CI]: 1.5 to 7.5), LMWH and VKA (16%; RAR: 3.1; 95% CI: 1.2 to 7.5), or UFH and VKA (16%; RAR: 3.1; 95% CI: 1.5 to 7.1). Composite fetal risk was lowest with LMWH (13%; RAR: 0.3; 95% CI: 0.1 to 0.8), compared with VKA (39%), LMWH and VKA (23%), or UFH and VKA (34%). No significant difference in fetal risk was observed between women taking ≤5 mg daily warfarin and those with an LMWH regimen (RAR: 0.9; 95% CI: 0.3 to 2.4). CONCLUSIONS VKA treatment was associated with the lowest risk of adverse maternal outcomes, whereas the use of LMWH throughout pregnancy was associated with the lowest risk of adverse fetal outcomes. Fetal risk was similar between women taking ≤5 mg warfarin daily and women treated with LMWH.
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Prediction Score for Anticoagulation Control Quality Among Older Adults.
Lin, KJ, Singer, DE, Glynn, RJ, Blackley, S, Zhou, L, Liu, J, Dube, G, Oertel, LB, Schneeweiss, S
Journal of the American Heart Association. 2017;(10)
Abstract
BACKGROUND Time in the therapeutic range (TTR) is associated with the effectiveness and safety of vitamin K antagonist (VKA) therapy. To optimize prescribing of VKA, we aimed to develop and validate a prediction model for TTR in older adults taking VKA for nonvalvular atrial fibrillation and venous thromboembolism. METHODS AND RESULTS The study cohort comprised patients aged ≥65 years who were taking VKA for atrial fibrillation or venous thromboembolism and who were identified in the 2 US electronic health record databases linked with Medicare claims data from 2007 through 2014. With the predictors identified from a systematic review and clinical knowledge, we built a prediction model for TTR, using one electronic health record system as the training set and the other as the validation set. We compared the performance of the new models to that of a published prediction score for TTR, SAMe-TT2R2. Based on 1663 patients in the training set and 1181 in the validation set, our optimized score included 42 variables and the simplified model included 7 variables, abbreviated as PROSPER (Pneumonia, Renal dysfunction, Oozing blood [prior bleeding], Staying in hospital ≥7 days, Pain medication use, no Enhanced [structured] anticoagulation services, Rx for antibiotics). The PROSPER score outperformed SAMe-TT2R2 when predicting both TTR ≥70% (area under the receiver operating characteristic curve 0.67 versus 0.55) and the thromboembolic and bleeding outcomes (area under the receiver operating characteristic curve 0.62 versus 0.52). CONCLUSIONS Our geriatric TTR score can be used as a clinical decision aid to select appropriate candidates to receive VKA therapy and as a research tool to address confounding and treatment effect heterogeneity by anticoagulation quality.
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Clinical Impact of Heparin Kinetics During Catheter Ablation of Atrial Fibrillation: Meta-Analysis and Meta-Regression.
Briceno, DF, Villablanca, PA, Lupercio, F, Kargoli, F, Jagannath, A, Londono, A, Patel, J, Otusanya, O, Brevik, J, Maraboto, C, et al
Journal of cardiovascular electrophysiology. 2016;(6):683-93
Abstract
INTRODUCTION Appropriate activated clotting time (ACT) during catheter ablation of atrial fibrillation (CA-AF) is essential to minimize periprocedural complications. METHODS AND RESULTS An electronic search was performed using major databases. Outcomes were thromboembolic (TE) and bleeding complications according to ACT levels (seconds). Heparin dose (U/kg) and time (minutes) to achieve the target ACT was compared among patients receiving vitamin K antagonist (VKA) versus non-VKA oral anticoagulants (NOAC). Nineteen studies involving 7,150 patients were identified. Patients with ACT > 300 had less TE (OR, 0.51; 95% CI 0.35-0.74) and bleeding (OR, 0.70; 95% CI 0.60-0.83) compared to ACT < 300, when using any type of oral anticoagulation. The use of VKA was associated with reduced heparin requirements (mean dose: 157 U/kg vs. 209 U/kg, P < 0.03; SDM -0.86 [95% CI -1.39 to -0.33]), and with lower time to achieve the target ACT (mean time: 24 minutes vs. 49 minutes, P < 0.03; SDM -11.02 [95% CI -13.29 to -8.75]) compared to NOACs. No significant publication bias was found. CONCLUSIONS Performing CA-AF with a target ACT > 300 decreases the risk of TE without increasing the risk of bleeding. Patients receiving VKAs required less heparin and reached the target ACT faster compared to NOACs.
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Interaction Between Dietary Vitamin K Intake and Anticoagulation by Vitamin K Antagonists: Is It Really True?: A Systematic Review.
Violi, F, Lip, GY, Pignatelli, P, Pastori, D
Medicine. 2016;(10):e2895
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Abstract
Educational advice is often given to patients starting treatment with vitamin K Antagonists (VKAs). A great emphasis is made on nutritional information. Common belief is that dietary vitamin K intake could counteract the anticoagulant effect by VKAs and for many years, patients have been discouraged to consume vitamin-K-rich foods, such as green leafy vegetables.The objective of this study is to summarize the current evidence supporting the putative interaction between dietary vitamin K intake and changes in INR with the VKAs.Data sources are MEDLINE via PubMed and Cochrane database.All clinical studies investigating the relationship between dietary vitamin K and measures of anticoagulation were included. We excluded all studies of supplementation of vitamin K alone.We performed a systematic review of the literature up to October 2015, searching for a combination of "food," "diet," "vitamin K," "phylloquinone," "warfarin," "INR," "coagulation," and "anticoagulant."Two dietary interventional trials and 9 observational studies were included. We found conflicting evidence on the effect of dietary intake of vitamin K on coagulation response. Some studies found a negative correlation between vitamin K intake and INR changes, while others suggested that a minimum amount of vitamin K is required to maintain an adequate anticoagulation. Median dietary intake of vitamin K1 ranged from 76 to 217 μg/day among studies, and an effect on coagulation may be detected only for high amount of vitamin intake (>150 μg/day).Most studies included patients with various indications for VKAs therapy, such as atrial fibrillation, prosthetic heart valves, and venous thromboembolism. Thus, INR target was dishomogeneous and no subanalyses for specific populations or different anticoagulants were conducted. Measures used to evaluate anticoagulation stability were variable.The available evidence does not support current advice to modify dietary habits when starting therapy with VKAs. Restriction of dietary vitamin K intake does not seem to be a valid strategy to improve anticoagulation quality with VKAs. It would be, perhaps, more relevant to maintain stable dietary habit, avoiding wide changes in the intake of vitamin K.
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Testing the therapeutic equivalence of novel oral anticoagulants for thromboprophylaxis in orthopedic surgery and for prevention of stroke in atrial fibrillation.
Messori, A, Fadda, V, Maratea, D, Trippoli, S, Marinai, C
International journal of clinical pharmacology and therapeutics. 2015;(3):211-9
Abstract
BACKGROUND In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to-head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered. OBJECTIVES The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation. METHODS Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials. RESULTS Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses. CONCLUSIONS Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings.