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PloS One 2015Anticoagulation with low molecular weight heparin and vitamin K antagonists is the current standard of care (SOC) for venous thromboembolism (VTE) treatment and... (Comparative Study)
Comparative Study Meta-Analysis Review
Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.
BACKGROUND
Anticoagulation with low molecular weight heparin and vitamin K antagonists is the current standard of care (SOC) for venous thromboembolism (VTE) treatment and prevention. Although novel oral anti-coagulants (NOACs) have been compared with SOC in this indication, no head-to-head randomised controlled trials (RCTs) have directly compared NOACs. A systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of NOACs for the initial and long-term treatment of VTE.
METHODS
Electronic databases (accessed July 2014) were systematically searched to identify RCTs evaluating apixaban, dabigatran, edoxaban, and rivaroxaban versus SOC. Eligible patients included adults with an objectively confirmed deep vein thrombosis (DVT), pulmonary embolism (PE) or both. A fixed-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as relative risks (RR) and 95% credible intervals (Crl).
RESULTS
Six Phase III RCTs met criteria for inclusion: apixaban (one RCT; n = 5,395); rivaroxaban (two RCTs; n = 3,423/4,832); dabigatran (two RCTs; n = 2,539/2,568); edoxaban (one RCT; n = 8,240). There were no statistically significant differences between the NOACs with regard to the risk of 'VTE and VTE-related death. Apixaban treatment was associated with the most favourable safety profile of the NOACs, showing a statistically significantly reduced risk of 'major or clinically relevant non-major (CRNM) bleed' compared with rivaroxaban (0.47 [0.36, 0.61]), dabigatran (0.69 [0.51, 0.94]), and edoxaban (0.54 [0.41, 0.69]). Dabigatran was also associated with a significantly lower risk of 'major or CRNM bleed' compared with rivaroxaban (0.68 [0.53, 0.87]) and edoxaban (0.77 [0.60, 0.99]).
CONCLUSIONS
Indirect comparisons showed statistically similar reductions in the risk of 'VTE or VTE-related death for all NOACs. In contrast, reductions in 'major or CRNM bleed' for initial/long-term treatment were significantly better with apixaban compared with all other NOACs, and with dabigatran compared with rivaroxaban and edoxaban. Results from the current analysis indicate that the NOACs offer clinical benefit over conventional therapy while highlighting relative differences in their bleeding profile.
Topics: Administration, Oral; Anticoagulants; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism
PubMed: 26716830
DOI: 10.1371/journal.pone.0144856 -
Journal of the American Heart... Oct 2019Background Inherited thrombophilias are well-established predisposing factors for venous thromboembolism, but their role in arterial thrombosis, such as arterial... (Meta-Analysis)
Meta-Analysis
Background Inherited thrombophilias are well-established predisposing factors for venous thromboembolism, but their role in arterial thrombosis, such as arterial ischemic stroke, remains uncertain. We aimed to evaluate the association between inherited thrombophilia (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency) and risk of arterial ischemic stroke in adults. Methods and Results We searched PubMed, EMBASE, and Cochrane Library Databases from inception to December 31, 2018. We included case-control or cohort studies of adults reporting the prevalence of inherited thrombophilias in those with arterial ischemic stroke and subjects without arterial ischemic stroke. Two reviewers (T.C., E.D.) independently searched the literature and extracted data. Pooled odds ratios (ORs) and 95% CIs were calculated using random-effects model. We identified 68 eligible studies, which collectively enrolled 11 916 stroke patients and 96 057 controls. The number of studies reporting factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency were 56, 45, 15, 17, and 12, respectively. Compared with controls, patients with arterial ischemic stroke were significantly more likely to have the following inherited thrombophilias: factor V Leiden (OR, 1.25; 95% CI, 1.08-1.44; I=0%), prothrombin G20210A mutation (OR, 1.48; 95% CI, 1.22-1.80; I=0%), protein C deficiency (OR, 2.13; 95% CI, 1.16-3.90; I=0%), and protein S deficiency (OR, 2.26; 95% CI, 1.34-3.80; I=8.8%). Statistical significance was not reached for antithrombin deficiency (OR, 1.25; 95% CI, 0.58-2.67; I=8.8%). Conclusions Inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, and protein S deficiency) are associated with an increased risk of arterial ischemic stroke in adults. The implications of these findings with respect to clinical management of patients with ischemic stroke require further investigation.
Topics: Adult; Aged; Blood Coagulation; Blood Coagulation Disorders, Inherited; Brain Ischemia; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Phenotype; Prognosis; Risk Assessment; Risk Factors; Stroke; Thrombophilia
PubMed: 31549567
DOI: 10.1161/JAHA.119.012877 -
Clinical Laboratory Apr 2023Thrombophilia testing is controversial, not least because of its high cost. Because comprehensive valid testing requires standardized blood collection close by the... (Review)
Review
BACKGROUND
Thrombophilia testing is controversial, not least because of its high cost. Because comprehensive valid testing requires standardized blood collection close by the specialized laboratory, and interpretation of findings together with clinical data, often only part of the necessary laboratory analyses can be performed in remote central laboratories. Restrictive indications for testing, as have been recommended by previous reviews on the topic, have been based on incomplete analytics, studies with small case numbers, or short observation periods, and on an inappropriate, simple risk stratification for venous thromboembolism (VTE), further subdivided into provoked and unprovoked events.
METHODS
The authors reviewed four electronic databases for all peer-reviewed and in-press articles about thrombophilia, VTE, obstetric complications, and arterial thrombosis. After confirmation for relevance to the topic, 201 articles were accepted for inclusion in this article. This review summarizes the studies relevant to the evaluation of thrombophilic conditions, and their combination with each other and with clinical risk factors, to stratify individual risk for thromboembolism and obstetric complications.
RESULTS
Thrombophilia testing requires highly skilled personnel for laboratory analysis and interpretation. Clinical conditions that influence the results as well as special preanalytical, analytical, and postanalytical aspects must be considered if valid results are to be obtained. Tests involved include the natural anticoagulants antithrombin, protein C, and protein S; the procoagulants fibrinogen (dysfibrinogen), prothrombin (mutation G20210A), factor V (Leiden mutation), factor VIII/von Willebrand factor/blood group ABO, factor IX, and factor XI; the anti-phospholipid antibodies to detect an antiphospholipid syndrome and potentially additional uncertain thrombophilic conditions. The risks of thrombophilic conditions and clinical risk factors for VTE are cumulative or even supra-additive. Scores from thrombophilic conditions and other genetic and nongenetic risk factors permit estimation of risk for first and recurrent VTE. Therapeutic strategies can be derived from this risk stratification.
CONCLUSIONS
Thrombophilia testing is indicated when the results have potential to influence the type and duration of treatment. Indications include certain patients after VTE; or patients without previous VTE but with positive family history regarding VTE or thrombophilia before major surgery, pregnancy, combined oral contraceptives, or hormone replacement therapy. Whether or not thrombophilia is present should help determine anticoagulation, hormonal contraception, or hormone replacement.
Topics: Female; Pregnancy; Humans; Venous Thromboembolism; Thrombophilia; Anticoagulants; Risk Factors
PubMed: 37057948
DOI: 10.7754/Clin.Lab.2022.220817 -
BMJ (Clinical Research Ed.) Oct 2017To provide evidence to support updated guidelines for the management of pregnant women with hereditary thrombophilia in order to reduce the risk of a first venous... (Meta-Analysis)
Meta-Analysis Review
To provide evidence to support updated guidelines for the management of pregnant women with hereditary thrombophilia in order to reduce the risk of a first venous thromboembolism (VTE) in pregnancy. Systematic review and bayesian meta-analysis. Embase, Medline, Web of Science, Cochrane Library, and Google Scholar from inception through 14 November 2016. Observational studies that reported on pregnancies without the use of anticoagulants and the outcome of first VTE for women with thrombophilia were eligible for inclusion. VTE was considered established if it was confirmed by objective means, or when the patient had received a full course of a full dose anticoagulant treatment without objective testing. 36 studies were included in the meta-analysis. All thrombophilias increased the risk for pregnancy associated VTE (probabilities ≥91%). Regarding absolute risks of pregnancy associated VTE, high risk thrombophilias were antithrombin deficiency (antepartum: 7.3%, 95% credible interval 1.8% to 15.6%; post partum: 11.1%, 3.7% to 21.0%), protein C deficiency (antepartum: 3.2%, 0.6% to 8.2%; post partum: 5.4%, 0.9% to 13.8%), protein S deficiency (antepartum: 0.9%, 0.0% to 3.7%; post partum: 4.2%; 0.7% to 9.4%), and homozygous factor V Leiden (antepartum: 2.8%, 0.0% to 8.6%; post partum: 2.8%, 0.0% to 8.8%). Absolute combined antepartum and postpartum risks for women with heterozygous factor V Leiden, heterozygous prothrombin G20210A mutations, or compound heterozygous factor V Leiden and prothrombin G20210A mutations were all below 3%. Women with antithrombin, protein C, or protein S deficiency or with homozygous factor V Leiden should be considered for antepartum or postpartum thrombosis prophylaxis, or both. Women with heterozygous factor V Leiden, heterozygous prothrombin G20210A mutation, or compound heterozygous factor V Leiden and prothrombin G20210A mutation should generally not be prescribed thrombosis prophylaxis on the basis of thrombophilia and family history alone. These data should be considered in future guidelines on pregnancy associated VTE risk.
Topics: Bayes Theorem; Evidence-Based Medicine; Female; Humans; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Hematologic; Risk Factors; Thrombolytic Therapy; Thrombophilia; Venous Thrombosis
PubMed: 29074563
DOI: 10.1136/bmj.j4452 -
Journal of Thrombosis and Haemostasis :... Jul 2016Essentials We performed a meta-analysis on thrombosis risk in thrombophilic oral contraceptive (COC)-users. The results support discouraging COC-use in women with a... (Meta-Analysis)
Meta-Analysis Review
UNLABELLED
Essentials We performed a meta-analysis on thrombosis risk in thrombophilic oral contraceptive (COC)-users. The results support discouraging COC-use in women with a natural anticoagulant deficiency. Contrary, additive risk of factor V Leiden (FVL) or prothrombin-G20210A (PT) mutation is modest. Women with a FVL/PT-mutation as single risk factor can use COCs if alternatives are not tolerated.
SUMMARY
Background Combined oral contraceptives (COCs) are associated with an increased risk of venous thromboembolism (VTE), which is shown to be more pronounced in women with hereditary thrombophilia. Currently, WHO recommendations state that COC-use in women with hereditary thrombophilias (antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden and prothrombin-G20210A mutation) is associated with an unacceptable health risk. Objective To perform a meta-analysis evaluating the additional risk of VTE in COC-users with thrombophilia. Methods The MEDLINE and EMBASE databases were searched on 10 February 2015 for potential eligible studies. A distinction was made between 'mild' (factor V Leiden and prothrombin-G20210A mutation) and 'severe' thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). Results We identified 12 case-control and three cohort studies. In COC-users, mild and severe thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95% confidence interval [CI], 4.21-8.23) and 7-fold (RR, 7.15; 95% CI, 2.93-17.45), respectively. The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). Conclusion These results support discouraging COC-use in women with severe hereditary thrombophilia. By contrast, additive VTE risk of mild thrombophilia is modest. When no other risk factors are present, (e.g. family history) COCs can be offered to these women when reliable alternative contraceptives are not tolerated.
Topics: Adolescent; Adult; Aged; Anticoagulants; Case-Control Studies; Cohort Studies; Contraceptives, Oral, Combined; Factor V; Female; Heterozygote; Humans; Middle Aged; Mutation; Protein C Deficiency; Protein S Deficiency; Prothrombin; Risk Factors; Thrombophilia; Venous Thromboembolism; Young Adult
PubMed: 27121914
DOI: 10.1111/jth.13349 -
Clinical Drug Investigation Apr 2021BACKGROUND AND OBJECTIVE: Systematic reviews and meta-analyses of direct oral anticoagulants (DOACs) for patients with chronic kidney disease (CKD) or dialysis patients... (Comparative Study)
Comparative Study Meta-Analysis
UNLABELLED
BACKGROUND AND OBJECTIVE: Systematic reviews and meta-analyses of direct oral anticoagulants (DOACs) for patients with chronic kidney disease (CKD) or dialysis patients are lacking. We aimed to compare the efficacy and safety of DOACs and warfarin in patients with CKD requiring anticoagulation therapy.
METHODS
We performed a systematic review and meta-analysis of six randomized controlled trials and 19 observational studies, with the inclusion criteria being a comparative study between DOACs and warfarin in patients with CKD or dialysis patients from database inception until August 2020. The efficacy outcomes were stroke, systemic embolism (SE), or venous thromboembolism (VTE), and the safety outcome was major bleeding.
RESULTS
Compared with warfarin, DOACs significantly reduced the risk of stroke/SE/VTE by 22% (hazard ratio [HR] = 0.78, 95% confidence interval [CI] 0.64-0.95) and major bleeding by 17% (HR = 0.83, 95% CI 0.71-0.97). On comparing factor Xa inhibitors and dabigatran with warfarin separately, factor Xa inhibitors significantly reduced the risk of stroke/SE/VTE (HR = 0.78, 95% CI 0.62-0.98) and major bleeding (HR = 0.76, 95% CI 0.64-0.91) overall in patients. Comparing each DOACs with warfarin separately, apixaban was associated with a significantly better risk reduction of stroke/SE/VTE (25% risk reduction) and major bleeding (35% risk reduction) than warfarin. Compared with warfarin, DOACs significantly reduced the risk of stroke, SE, or VTE by 19% (HR = 0.81, 95% CI 0.68-0.97) in patients with CKD stage 3 and significantly lowered the risk of major bleeding by 31% (HR = 0.69, 95% CI 0.56-0.85) in patients with CKD stages 4-5.
CONCLUSIONS
In pooled, analyzed randomized controlled trials and observational studies, DOACs were associated with better efficacy in early CKD, as well as similar efficacy and safety outcomes to warfarin in patients with CKD stages 4-5 or dialysis patients. The results of patients with CKD stages 4-5 and dialysis patients were from observational studies. Well-designed randomized controlled trials focused on DOAC use in patients with CKD and dialysis patients are needed. PROSPERO register number: CRD42020150599, 6 February, 2020.
Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Stroke; Venous Thromboembolism; Warfarin
PubMed: 33709339
DOI: 10.1007/s40261-021-01016-7 -
Future Cardiology May 2022To compare real-world effectiveness/safety of non-vitamin K antagonist oral anticoagulants and vitamin K antagonists among patients with non-valvular atrial... (Meta-Analysis)
Meta-Analysis Review
To compare real-world effectiveness/safety of non-vitamin K antagonist oral anticoagulants and vitamin K antagonists among patients with non-valvular atrial fibrillation. A systematic review of electronic databases yielded 7661 citations published from January 2013 to January 2020. Fifty-five studies were included in Bayesian network meta-analyses of hazard ratios. In comparison with vitamin K antagonists, apixaban, dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, ischemic stroke, intracranial hemorrhage and all-cause mortality. Apixaban, dabigatran and edoxaban, but not rivaroxaban, were associated with a reduced risk of major bleeding. This study confirmed the effectiveness and safety of non-vitamin K antagonist oral anticoagulants for the treatment of non-valvular atrial fibrillation in real-world settings, consistent with clinical trial evidence.
Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Bayes Theorem; Dabigatran; Fibrinolytic Agents; Humans; Network Meta-Analysis; Pyridones; Rivaroxaban; Stroke; Vitamin K
PubMed: 35360925
DOI: 10.2217/fca-2021-0120 -
Stroke Jan 2018The use of oral anticoagulant therapy for stroke prevention in atrial fibrillation has been transformed by the availability of the nonvitamin K antagonist oral... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND PURPOSE
The use of oral anticoagulant therapy for stroke prevention in atrial fibrillation has been transformed by the availability of the nonvitamin K antagonist oral anticoagulants. Real-world studies on the use of nonvitamin K antagonist oral anticoagulants would help elucidate their effectiveness and safety in daily clinical practice. Apixaban was the third nonvitamin K antagonist oral anticoagulants introduced to clinical practice, and increasing real-world studies have been published. Our aim was to summarize current evidence about real-world studies on apixaban for stroke prevention in atrial fibrillation.
METHODS
We performed a systematic review and meta-analysis of all observational real-world studies comparing apixaban with other available oral anticoagulant drugs.
RESULTS
From the original 9680 results retrieved, 16 studies have been included in the final meta-analysis. Compared with warfarin, apixaban regular dose was more effective in reducing any thromboembolic event (odds ratio: 0.77; 95% confidence interval: 0.64-0.93), but no significant difference was found for stroke risk. Apixaban was as effective as dabigatran and rivaroxaban in reducing thromboembolic events and stroke. The risk of major bleeding was significantly lower for apixaban compared with warfarin, dabigatran, and rivaroxaban (relative risk reduction, 38%, 35%, and 46%, respectively). Similarly, the risk for intracranial hemorrhage was significantly lower for apixaban than warfarin and rivaroxaban (46% and 54%, respectively) but not dabigatran. The risk of gastrointestinal bleeding was lower with apixaban when compared with all oral anticoagulant agents (<0.00001 for all comparisons).
CONCLUSIONS
Use of apixaban in real-life is associated with an overall similar effectiveness in reducing stroke and any thromboembolic events when compared with warfarin. A better safety profile was found with apixaban compared with warfarin, dabigatran, and rivaroxaban.
Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Female; Humans; Intracranial Hemorrhages; Male; Polymers; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Saliva, Artificial; Stroke; Vitamin K; Warfarin
PubMed: 29167388
DOI: 10.1161/STROKEAHA.117.018395 -
Journal of Clinical Oncology : Official... Jun 2023To conduct an update of the ASCO venous thromboembolism (VTE) guideline.
PURPOSE
To conduct an update of the ASCO venous thromboembolism (VTE) guideline.
METHODS
After publication of potentially practice-changing clinical trials, identified through ASCO's signals approach to updating, an updated systematic review was performed for two guideline questions: perioperative thromboprophylaxis and treatment of VTE. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) published between November 1, 2018, and June 6, 2022.
RESULTS
Five RCTs provided information that contributed to changes to the 2019 recommendations. Two RCTs addressed direct factor Xa inhibitors (either rivaroxaban or apixaban) for extended thromboprophylaxis after surgery. Each of these postoperative trials had important limitations but suggested that these two oral anticoagulants are safe and effective in the settings studied. An additional three RCTs addressed apixaban in the setting of VTE treatment. Apixaban was effective in reducing the risk of recurrent VTE, with a low risk of major bleeding.
RECOMMENDATIONS
Apixaban and rivaroxaban were added as options for extended pharmacologic thromboprophylaxis after cancer surgery, with a weak strength of recommendation. Apixaban was also added as an option for the treatment of VTE, with high quality of evidence and a strong recommendation.Additional information is available at www.asco.org/supportive-care-guidelines.
Topics: Humans; Venous Thromboembolism; Rivaroxaban; Anticoagulants; Hemorrhage; Neoplasms
PubMed: 37075273
DOI: 10.1200/JCO.23.00294 -
Drugs Aug 2022High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or... (Meta-Analysis)
Meta-Analysis
BACKGROUND
High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD.
METHODS
A systematic search was conducted to identify randomized controlled trials. The primary endpoints were major adverse cardiovascular events (MACE) and major bleedings. Secondary endpoints were major adverse limb events (MALE) and acute limb ischaemia (ALI). For each outcome, a frequentist network meta-analysis was used to compare relative risks (RRs) between medication and ASA. ASA was the universal comparator since a majority of studies used ASA as in the reference group.
RESULTS
Twenty-four randomized controlled trials were identified including 48,759 patients. With regard to reducing MACE, clopidogrel [RR 0.78, 95% confidence interval (CI) 0.66-0.93], ticagrelor (RR 0.79, 95% CI 0.65-0.97), ASA plus ticagrelor (RR 0.79, 95% CI 0.64-0.97), and ASA plus low-dose rivaroxaban (RR 0.84, 95% CI 0.76-0.93) were more effective than ASA, and equally effective to one another. As compared to ASA, major bleedings occurred more frequently with vitamin K antagonists, rivaroxaban, ASA plus vitamin K antagonists, and ASA plus low-dose rivaroxaban. All regimens were similar to ASA concerning MALE, while ASA plus low-dose rivaroxaban was more effective in preventing ALI (RR 0.67, 95% CI 0.55-0.80). Subgroup analysis in patients undergoing peripheral revascularization revealed that ≥ 3 months after intervention, evidence of benefit regarding clopidogrel, ticagrelor, and ASA plus ticagrelor was lacking, while ASA plus low-dose rivaroxaban was more effective in preventing MACE (RR 0.87, 95% CI 0.78-0.97) and MALE (RR 0.89, 95% CI 0.81-0.97) compared to ASA. ASA plus clopidogrel was not superior to ASA in preventing MACE ≥ 3 months after revascularization. Evidence regarding antithrombotic treatment strategies within 3 months after a peripheral intervention was lacking.
CONCLUSION
Clopidogrel, ticagrelor, ASA plus ticagrelor, and ASA plus low-dose rivaroxaban are superior to ASA monotherapy and equally effective to one another in preventing MACE in PAD. Of these four therapies, only ASA plus low-dose rivaroxaban provides a higher risk of major bleedings. More than 3 months after peripheral vascular intervention, ASA plus low-dose rivaroxaban is superior in preventing MACE and MALE compared to ASA but again at the cost of a higher risk of bleeding, while other treatment regimens show non-superiority. Based on the current evidence, clopidogrel may be considered the antithrombotic therapy of choice for most PAD patients, while in patients who underwent a peripheral vascular intervention, ASA plus low-dose rivaroxaban could be considered for the long-term (> 3 months) prevention of MACE and MALE.
Topics: Aspirin; Clopidogrel; Fibrinolytic Agents; Hemorrhage; Humans; Network Meta-Analysis; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban; Ticagrelor; Vitamin K
PubMed: 35997941
DOI: 10.1007/s40265-022-01756-6