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European Journal of Clinical... Mar 2021Direct oral anticoagulants (DOACs) are recommended for stroke prevention in patients with atrial fibrillation (AF) or for treatment of deep vein thrombosis, although... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Direct oral anticoagulants (DOACs) are recommended for stroke prevention in patients with atrial fibrillation (AF) or for treatment of deep vein thrombosis, although some concerns about safety and efficacy were raised on the use of these drugs in patients with advanced liver disease (ALD). We want to investigate the association of DOACs use with the bleeding and ischaemic risk.
MATERIAL AND METHODS
We performed a systematic review and metanalysis of clinical studies retrieved from PubMed (via MEDLINE) and Cochrane (CENTRAL) databases addressing the impact of DOACs therapy on bleeding events including intracranial haemorrhage (ICH), gastrointestinal and major bleeding. Secondary end points were all-cause death, ischaemic stroke/systemic embolism (IS/SE) and recurrence/progression of vein thrombosis (rDVT).
RESULTS
12 studies were included in the meta-analysis: a total of 43 532 patients with ALD or cirrhosis, of whom 27 574 (63.3%) were on treatment with DOACs and 15 958 were in warfarin/low molecular weight heparin. DOACs reduced the incidence of major bleeding by 61% (pooled Hazard Ratio [HR] 0.39, 95% Confidence Interval [CI] 0.21-0.70), ICH by 52% (HR 0.48, 95% CI 0.40-0.59), while no difference in the reduction of any and gastrointestinal bleeding were observed. DOACs reduced also rDVT by 82% (HR 0.18, 95%CI 0.06-0.57), but did not reduce death and IS/SE. No difference was shown according to oesophageal varices and Child Pugh score in the meta-regression analysis between warfarin/heparin and DOACs performed on each outcome.
CONCLUSIONS
DOACs are associated with a lower incidence of bleeding and may be an attractive therapeutic option in patients with cirrhosis.
Topics: Atrial Fibrillation; Embolism; End Stage Liver Disease; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Ischemic Stroke; Liver Cirrhosis; Liver Diseases; Proportional Hazards Models; Severity of Illness Index; Venous Thrombosis
PubMed: 32895926
DOI: 10.1111/eci.13397 -
Revista Da Associacao Medica Brasileira... 2023The aim of this study was to carry out a systematic review of the literature with meta-analysis to evaluate the effect of using oral contraceptive and hormone... (Meta-Analysis)
Meta-Analysis
Does the use of oral contraceptives or hormone replacement therapy offer protection against the formation or rupture of intracranial aneurysms in women?: a systematic review and meta-analysis.
OBJECTIVE
The aim of this study was to carry out a systematic review of the literature with meta-analysis to evaluate the effect of using oral contraceptive and hormone replacement therapy as a protective factor in the formation of intracranial aneurysms and subarachnoid hemorrhage.
METHODS
This is a systematic review of the literature with meta-analysis, using PubMed and Embase as databases and the PRISMA method. Case-control and cohort studies published until December 2022 were included in this review.
RESULTS
Four studies were included in this review; three of which were eligible for meta-analysis. Regarding the use of oral contraceptive and the development of subarachnoid hemorrhage, there was a lower risk of aneurysm rupture with an odds ratio 0.65 (confidence interval 0.5-0.85). In the analysis of patients using hormone replacement therapy and developing subarachnoid hemorrhage, there was also a lower risk of aneurysm rupture with an OR 0.54 (CI 0.39-0.74). Only one article analyzed the formation of intracranial aneurysm and the use of hormone replacement therapy and oral contraceptive, and there was a protective effect with the use of these medications. oral contraceptive: OR 2.1 (CI 1.2-3.8) and hormone replacement therapy: OR 3.1 (CI 1.5-6.2).
CONCLUSION
The use of hormone replacement therapy and oral contraceptive has a protective effect in intracranial aneurysm rupture and formation.
Topics: Humans; Female; Intracranial Aneurysm; Contraceptives, Oral; Subarachnoid Hemorrhage; Hormone Replacement Therapy; Cohort Studies; Risk Factors
PubMed: 37556637
DOI: 10.1590/1806-9282.2023S118 -
Canadian Journal of Gastroenterology &... 2019Anticoagulants carry a significant risk of gastrointestinal bleeding. With the increase in use and availability of direct oral anticoagulants ("DOACs") more data are...
BACKGROUND
Anticoagulants carry a significant risk of gastrointestinal bleeding. With the increase in use and availability of direct oral anticoagulants ("DOACs") more data are available regarding the risks of these medications. With diverticular bleeds being common, and hospitalization associated with gastrointestinal bleed increasing 30-day mortality, it is paramount to better understand the potential risks of using DOACs in this population.
METHODS
A systematic review of the literature was undertaken, using the databases PubMed, EMBASE, Cochrane Library, and CINAHL. Two reviewers independently searched the literature, and initial screening was performed through title and abstract reading. Search terms included "direct" AND "anticoagulant" AND "diverticular bleed" OR "diverticular hemorrhage". The references of the selected studies were manually reviewed for any further relevant articles.
RESULTS
Literature search across the databases garnered 182 articles-157 unique abstracts after duplicate removal. Based on inclusion and exclusion criteria, 6 studies were deemed relevant. The selected studies' reference lists yielded no further relevant articles.
DISCUSSION
Across the 6 studies, the incidence of diverticular bleeding in patients using DOACs was extremely low. Of 23,990 patients taking DOACs identified from two separate institutions, only 60 were found to have diverticular hemorrhage. Similarly, among 15,056 patients with diverticular hemorrhage, only 246 (1.6%) among them were taking DOACs. Generally, the studies found no increased diverticular bleeding rate between patients taking DOACs and those who were taking other anticoagulants, such as warfarin, or the general population. The studies also did not find an increased risk of rebleeding with DOAC continuation.
CONCLUSION
The evidence suggests the risk of diverticular bleed among DOAC users is equivocal to those not taking DOACs, and the overall incidence of diverticular bleed in the DOAC population is low. As it stands, the risk of thrombotic events from not starting DOACs apparently outweighs the risk of diverticular bleed.
Topics: Administration, Oral; Anticoagulants; Diverticulum; Gastrointestinal Hemorrhage; Humans; Risk Factors
PubMed: 31316948
DOI: 10.1155/2019/9851307 -
Community Dentistry and Oral... Dec 2022To systematically evaluate the association of individual and contextual social capital with oral health outcomes in children and adolescents. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To systematically evaluate the association of individual and contextual social capital with oral health outcomes in children and adolescents.
METHODS
Electronic searches were performed in PubMed/Medline, Embase, Web of Science and Scopus databases for articles published from 1966 up to June 2021. Two calibrated reviewers screened and critically appraised the identified papers. Observational studies that evaluated the relationship of individual or/and contextual social capital or their proxies with oral health outcomes in children and adolescents using validated methods were included. Quality assessment was conducted using the Newcastle-Ottawa Scale. Data were extracted for narrative synthesis and meta-analysis followed by a meta-regression model. Meta-analysis using random effects method was used to estimate pooled prevalence ratio (PR) and 95% confidence intervals (CI).
RESULTS
Of the 3060 studies initially retrieved, 31 were included in the systematic review and 21 in the meta-analysis, totalling 81 241 individuals. The clinical outcomes included dental caries and gingival bleeding and subjective outcomes were oral health-related quality of life (OHRQoL) and self-rated oral health (SROH). Individuals with lower levels of individual social capital had a higher prevalence of poor clinical (PR 1.11; 95%CI 1.02-1.22) and subjective (PR 1.25; 95%CI 1.09-1.45) oral health conditions. The prevalence of worse clinical (PR 1.34; 95%CI 1.11-1.61) and subjective (PR 1.56; 95%CI 1.13-2.16) oral health outcomes were also associated with lower levels of contextual social capital. In general, the contextual level of social capital exerted more impact, and the subjective oral health outcomes were the more affected.
CONCLUSIONS
Contextual and individual social capital were positively related to oral health outcomes, such as dental caries, gingival bleeding, SROH and OHRQoL in children and adolescents.
Topics: Child; Adolescent; Humans; Oral Health; Dental Caries; Social Capital; Quality of Life; Gingival Hemorrhage
PubMed: 34951711
DOI: 10.1111/cdoe.12714 -
Clinical Cardiology Jul 2021Several observational studies have compared the effectiveness and safety outcomes between nonvitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists... (Meta-Analysis)
Meta-Analysis Review
Non-vitamin K antagonist oral anticoagulants versus vitamin K antagonists in atrial fibrillation patients with previous stroke or intracranial hemorrhage: A systematic review and meta-analysis of observational studies.
Several observational studies have compared the effectiveness and safety outcomes between nonvitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients with a history of either stroke/transient ischemic attack (TIA) or intracranial hemorrhage. Therefore, our current meta-analysis aimed to address this issue. The Cochrane Library, PubMed, and Embase databases were systematically searched until December 2020 for all relevant observational studies. We applied a random-effects model to pool adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for this meta-analysis. A total of 10 studies were included. Among patients with a history of stroke/TIA, the use of NOACs versus VKAs was associated with decreased risks of stroke (HR, 0.82, 95% CI 0.69-0.97), systemic embolism (HR, 0.73, 95% CI 0.61-0.87), all-cause death (HR, 0.87, 95% CI 0.81-0.94), major bleeding (HR, 0.77, 95% CI 0.64-0.92) and intracranial hemorrhage (HR, 0.54, 95% CI 0.38-0.77). Among patients with a history of intracranial hemorrhage, the use of NOACs versus VKAs was associated with reduced risks of stroke (HR, 0.81, 95% CI 0.68-0.95), all-cause death (HR, 0.68, 95% CI 0.49-0.94), and intracranial hemorrhage (HR, 0.66, 95% CI 0.51-0.84). Compared with VKAs, the use of NOACs exhibited superior efficacy and safety outcomes in AF patients with previous stroke/TIA, and the use of NOACs was associated with reduced risks of stroke, all-cause death, and intracranial hemorrhage in patients with a history of intracranial hemorrhage.
Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Intracranial Hemorrhages; Stroke; Vitamin K
PubMed: 34013988
DOI: 10.1002/clc.23647 -
Annals of Palliative Medicine Oct 2022Use of oral anticoagulants (OACs) among atrial fibrillation (AF) patients surviving intracranial hemorrhage (ICH) represents a challenge due to the difficult balance... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Use of oral anticoagulants (OACs) among atrial fibrillation (AF) patients surviving intracranial hemorrhage (ICH) represents a challenge due to the difficult balance between thrombosis and hemorrhage.
METHODS
We performed a systematic review and meta-analysis to evaluate the effectiveness and safety of OACs resumption in AF patients with a history of ICH during long-term follow-up. The outcome measures were ischemic stroke (IS), IS or systemic embolism (SE), all-cause death, recurrent ICH and major bleeding. Meta-analyses of pooled odds ratios (ORs) were conducted with random-effects models.
RESULTS
A total of 2 randomized controlled trials (RCTs) and 9 observational studies were included, covering 18,115 patients with AF and a history of ICH. The risk of IS was not statistically different between the group of patients receiving OAC therapy and the no-OAC group (OR: 0.41, 95% CI: 0.16 to 1.0, P=0.05). The rate of IS or SE (OR: 0.42, 95% CI: 0.27 to 0.70, P=0.0008), all-cause death (OR: 0.54, 95% CI: 0.41 to 0.70, I2=42%, P<0.00001) were significantly decreased in patients receiving OAC therapy compared to those with no-OAC therapy. The pooled OR estimates for ICH recurrence (OR: 1.46, 95% CI: 0.94 to 2.26, P=0.09) and major bleeding (OR: 1.35, 95% CI: 0.86 to 2.11, P=0.19) were not significantly increased in the OAC therapy group. There was heterogeneity between the results of observational studies and RCTs in terms of all-cause death (I2=83.4%).
CONCLUSIONS
Considering the heterogeneity in results between observational studies and RCTs, as well as the limited number and small size of RCTs, high grade evidences are needed. Pooled analysis is required when more RCTs are completed in the future to resolve this therapeutic dilemma.
Topics: Humans; Atrial Fibrillation; Administration, Oral; Intracranial Hemorrhages; Anticoagulants; Hemorrhage; Risk Factors
PubMed: 35948473
DOI: 10.21037/apm-22-582 -
Journal of the American College of... Jun 2021Delayed intracranial hemorrhage (ICH) after a negative initial head cat scan (CT) is a recognized complication after blunt trauma but the risk of this condition is... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Delayed intracranial hemorrhage (ICH) after a negative initial head cat scan (CT) is a recognized complication after blunt trauma but the risk of this condition is unknown. Due to theoretical increased risk in patients on direct oral anticoagulants (DOACs) and inability to monitor degree of anticoagulation, there is a lack of consensus regarding need for additional observation or routine repeat head CT. We hypothesized that patients on DOACs would have a low risk of delayed ICH after blunt head trauma.
METHODS
In June 2020, an electronic literature search of MEDLINE (Ovid), Embase (Elsevier), and Cochrane Library was performed by a medical librarian (TH) using a combination of keywords and subject headings. Databases were searched from inception through June 2020. Included studies reported outcome data on trauma patients greater than 18 years old who were taking anticoagulants and were observed after initial normal head CT. A meta-analysis was performed using a random effects model. The Newcastle-Ottawa Scale (NOS) was utilized for assessing the quality of nonrandomized studies in meta-analyses.
RESULTS
Our electronic search returned 5719 papers and after removal of duplications, 72 underwent full review, and 12 met final inclusion/exclusion criteria. Four thousand eight hundred ninety one of 5289 (92%) patients suffered a ground level fall. Four studies reported routine repeat CT scans on all patients while the remaining only repeated CT scans for symptoms. Overall, 5289 patients were studied and 1263 (23.9%) were on a DOAC. Sixty-nine patients suffered delayed intracranial hemorrhage, 25 on DOAC and 44 on warfarin. The pooled weighted proportion for delayed ICH on DOAC was 2.43% (95% CI, 1.31 – 3.88%) compared to 2.31% (95% CI, 1.26 – 3.66%) on warfarin. Eighty six percent of patients (59/69) who suffered delayed ICH had no clinical consequences while 0.16% (2/1263) of those on DOAC and 0.48% (8/1788) of those on warfarin died from complications following delayed ICH. The overall crude risk of death from delayed ICH while on DOAC or Warfarin was 0.36% (11/3051).
CONCLUSIONS
The risk of delayed ICH following low energy blunt head trauma for patients on DOACs is low, and the risk of a clinically significant bleed is even lower. The practice of routinely observing or systematically repeating head CT in patients on DOACs after low energy blunt head trauma with initially negative head CT may not be warranted.
Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Head Injuries, Closed; Humans; Intracranial Hemorrhages; Risk Assessment; Time Factors; Tomography, X-Ray Computed; Venous Thromboembolism
PubMed: 33766725
DOI: 10.1016/j.jamcollsurg.2021.02.016 -
Journal of the American Heart... Dec 2023Intravenous thrombolysis (IVT) is an effective stroke therapy that remains underused. Currently, the use of IVT in patients with recent direct oral anticoagulant (DOAC)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Intravenous thrombolysis (IVT) is an effective stroke therapy that remains underused. Currently, the use of IVT in patients with recent direct oral anticoagulant (DOAC) intake is not recommended. In this study we aim to investigate the safety and efficacy of IVT in patients with acute ischemic stroke and recent DOAC use.
METHODS AND RESULTS
A systematic review and meta-analysis of proportions evaluating IVT with recent DOAC use was conducted. Outcomes included symptomatic intracranial hemorrhage, any intracranial hemorrhage, serious systemic bleeding, and 90-day functional independence (modified Rankin scale score 0-2). Additionally, rates were compared between patients receiving IVT using DOAC and non-DOAC by a random effect meta-analysis to calculate pooled odds ratios (OR) for each outcome. Finally, sensitivity analysis for idarucizumab, National Institutes of Health Stroke Scale, and timing of DOAC administration was completed. Fourteen studies with 247 079 patients were included (3610 in DOAC and 243 469 in non-DOAC). The rates of IVT complications in the DOAC group were 3% (95% CI, 3-4) symptomatic intracranial hemorrhage, 12% (95% CI, 7-19) any ICH, and 0.7% (95%CI, 0-1) serious systemic bleeding, and 90-day functional independence was achieved in 57% (95% CI, 43-70). The rates of symptomatic intracranial hemorrhage (3.4 versus 3.5%; OR, 0.95 [95% CI, 0.67-1.36]), any intracranial hemorrhage (17.7 versus 17.3%; OR, 1.23 [95% CI, 0.61-2.48]), serious systemic bleeding (0.7 versus 0.6%; OR, 1.27 [95% CI, 0.79-2.02]), and 90-day modified Rankin scale score 0-2 (46.4 versus 56.8%; OR, 1.21 [95% CI, 0.400-3.67]) did not differ between DOAC and non-DOAC groups. There was no difference in symptomatic intracranial hemorrhage rate based on idarucizumab administration.
CONCLUSIONS
Patients with acute ischemic stroke treated with IVT in recent DOAC versus non-DOAC use have similar rates of hemorrhagic complications and functional independence. Further prospective randomized trials are warranted.
Topics: Humans; Stroke; Fibrinolytic Agents; Ischemic Stroke; Thrombolytic Therapy; Brain Ischemia; Hemorrhage; Intracranial Hemorrhages; Treatment Outcome; Anticoagulants
PubMed: 38108256
DOI: 10.1161/JAHA.123.031669 -
Supportive Care in Cancer : Official... Dec 2022The efficacy and safety of direct oral anticoagulants (DOACs), including dabigatran, apixaban, rivaroxaban, and edoxaban, for preventing and treating venous... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The efficacy and safety of direct oral anticoagulants (DOACs), including dabigatran, apixaban, rivaroxaban, and edoxaban, for preventing and treating venous thromboembolism (VTE) in patients with cancer is unclear.
METHODS
We searched the PubMed, Embase, Web of Science, and Cochrane Library databases from the establishment to November 30, 2021. In the frequency-based network meta-analysis, the odds ratio with a 95% confidence interval was reported. The relative ranking probability of each group was generated based on the surface under the cumulative ranking curve (SUCRA).
RESULTS
We included 15 randomized controlled trials involving a total of 6162 patients. Apixaban reduced the risk of VTE compared with low-molecular heparin [OR = 0.53, 95% CI (0.32, 0.89)]. The efficacy of drugs was ranked from highest to lowest as follows: apixaban (SUCRA, 81.0), rivaroxaban (73.0), edoxaban (65.9), dabigatran (51.4), warfarin (30.8), and low-molecular-weight heparin (LMWH) (27.4). Edoxaban increased the risk of major bleeding compared with LMWH [OR = 1.83, 95% CI (1.04, 3.22)]. The safety of drugs was ranked from highest to lowest as follows: major bleeding-apixaban (SUCRA, 68.5), LMWH (55.1), rivaroxaban (53.0), warfarin (35.9), dabigatran (29.2), edoxaban (16.5) and clinically relevant non-major bleeding-LMWH (73.0), apixaban (57.8), edoxaban (45.8), rivaroxaban (35.3), and warfarin (10.8).
CONCLUSIONS
For preventing and treating VTE, in terms of VTE occurrence and major bleeding, apixaban had the lowest risk; in terms of clinically relevant non-major bleeding, LMWH had the lowest risk, followed by apixaban. Generally, apixaban is the most efficient and safest DOAC and presents better efficacy and relatively low bleeding risk among the VTE prevention and treatment drugs for patients with cancer.
Topics: Humans; Venous Thromboembolism; Dabigatran; Rivaroxaban; Warfarin; Heparin, Low-Molecular-Weight; Network Meta-Analysis; Administration, Oral; Anticoagulants; Hemorrhage; Neoplasms
PubMed: 36318341
DOI: 10.1007/s00520-022-07433-4 -
The Cochrane Database of Systematic... Nov 2017Chronic kidney disease (CKD) is an independent risk factor for atrial fibrillation (AF), which is more prevalent among CKD patients than the general population. AF... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic kidney disease (CKD) is an independent risk factor for atrial fibrillation (AF), which is more prevalent among CKD patients than the general population. AF causes stroke or systemic embolism, leading to increased mortality. The conventional antithrombotic prophylaxis agent warfarin is often prescribed for the prevention of stroke, but risk of bleeding necessitates regular therapeutic monitoring. Recently developed direct oral anticoagulants (DOAC) are expected to be useful as alternatives to warfarin.
OBJECTIVES
To assess the efficacy and safety of DOAC including apixaban, dabigatran, edoxaban, and rivaroxaban versus warfarin among AF patients with CKD.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Specialised Register (up to 1 August 2017) through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) which directly compared the efficacy and safety of direct oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) with dose-adjusted warfarin for preventing stroke and systemic embolic events in non-valvular AF patients with CKD, defined as creatinine clearance (CrCl) or eGFR between 15 and 60 mL/min (CKD stage G3 and G4).
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies, assessed quality, and extracted data. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for the association between anticoagulant therapy and all strokes and systemic embolic events as the primary efficacy outcome and major bleeding events as the primary safety outcome. Confidence in the evidence was assessing using GRADE.
MAIN RESULTS
Our review included 12,545 AF participants with CKD from five studies. All participants were randomised to either DOAC (apixaban, dabigatran, edoxaban, and rivaroxaban) or dose-adjusted warfarin. Four studies used a central, interactive, automated response system for allocation concealment while the other did not specify concealment methods. Four studies were blinded while the other was partially open-label. However, given that all studies involved blinded evaluation of outcome events, we considered the risk of bias to be low. We were unable to create funnel plots due to the small number of studies, thwarting assessment of publication bias. Study duration ranged from 1.8 to 2.8 years. The large majority of participants included in this study were CKD stage G3 (12,155), and a small number were stage G4 (390). Of 12,545 participants from five studies, a total of 321 cases (2.56%) of the primary efficacy outcome occurred per year. Further, of 12,521 participants from five studies, a total of 617 cases (4.93%) of the primary safety outcome occurred per year. DOAC appeared to probably reduce the incidence of stroke and systemic embolism events (5 studies, 12,545 participants: RR 0.81, 95% CI 0.65 to 1.00; moderate certainty evidence) and to slightly reduce the incidence of major bleeding events (5 studies, 12,521 participants: RR 0.79, 95% CI 0.59 to 1.04; low certainty evidence) in comparison with warfarin.
AUTHORS' CONCLUSIONS
Our findings indicate that DOAC are as likely as warfarin to prevent all strokes and systemic embolic events without increasing risk of major bleeding events among AF patients with kidney impairment. These findings should encourage physicians to prescribe DOAC in AF patients with CKD without fear of bleeding. The major limitation is that the results of this study chiefly reflect CKD stage G3. Application of the results to CKD stage G4 patients requires additional investigation. Furthermore, we could not assess CKD stage G5 patients. Future reviews should assess participants at more advanced CKD stages. Additionally, we could not conduct detailed analyses of subgroups and sensitivity analyses due to lack of data.
Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Embolism; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Rivaroxaban; Stroke; Thiazoles; Warfarin
PubMed: 29105079
DOI: 10.1002/14651858.CD011373.pub2