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Nonvitamin K Oral Anticoagulants in Patients With Atrial Fibrillation and Severe Renal Dysfunction.
Mahmood, M, Lip, GYH
Revista espanola de cardiologia (English ed.). 2018;(10):847-855
Abstract
Both atrial fibrillation (AF) and chronic kidney disease (CKD) are highly prevalent, especially with increasing age and associated comorbidities, such as hypertension, diabetes, heart failure, and vascular disease. The relationship between both AF and CKD seems to be bidirectional: CKD predisposes to AF while onset of AF seems to lead to progression of CKD. Stroke prevention is the cornerstone of AF management, and AF patients with CKD are at higher risk of stroke, mortality, cardiac events, and bleeding. Stroke prevention requires use of oral anticoagulants, which are either vitamin K antagonists (eg, warfarin), or the nonvitamin K antagonist oral anticoagulants (NOACs). While NOACs have been shown to be effective in mild-to-moderate renal dysfunction, there are a paucity of data regarding NOACs in severe and end-stage renal dysfunction. This review first discusses the evidence for NOACs in CKD. Second, we summarize the current knowledge regarding the efficacy and safety of NOACs to prevent AF-related stroke and systemic embolism in severe and end-stage renal disease.
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Dabigatran versus vitamin k antagonist: an observational across-cohort comparison in acute coronary syndrome patients with atrial fibrillation.
Gaubert, M, Resseguier, N, Laine, M, Bonello, L, Camoin-Jau, L, Paganelli, F
Journal of thrombosis and haemostasis : JTH. 2018;(3):465-473
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UNLABELLED Essentials Acute coronary syndrome (ACS) with atrial fibrillation (AF) is a therapeutic challenge. Dual and triple antithrombotic therapy showed a similar thrombotic risk in ACS patients with AF. The omission of aspirin during the first month did not increase the rate of ischemic events. Replacement of vitamin K antagonist by dabigatran leads to an increased thrombotic risk. SUMMARY Background Dual antithrombotic therapy comprising a vitamin K antagonist (VKA) plus clopidogrel reduces the incidence of major bleeding compared with triple therapy (VKA + clopidogrel + aspirin) in acute coronary syndrome (ACS) patients with atrial fibrillation (AF), with a similar thrombotic risk. The oral thrombin inhibitor dabigatran (150 mg twice a day) showed superiority over VKA in non-valvular AF, but data supporting its use in AF patients presenting with ACS are limited. Objective We sought to evaluate the efficacy of dabigatran vs. VKA in the management of AF patients undergoing percutaneous coronary intervention for an ACS. Methods In this open-label study, 133 consecutive patients received dabigatran plus clopidogrel. Another cohort of 133 patients treated with VKA plus clopidogrel was used as the control group. Results After propensity score adjustment, the cumulative incidence of major adverse cardiovascular events over 24 months was higher with dabigatran vs. VKA (adjusted hazard ratio, 2.28; 95% confidence interval, 1.46-3.56). Similar rates of major bleeding were found (adjusted hazard ratio, 1.17; 95% confidence interval, 0.46-2.96). Conclusions In AF patients presenting with ACS, replacement of VKA by dabigatran concurrently with clopidogrel is associated with an increased thrombotic risk, without a reduction in major bleeding.
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Management of thrombosis in children and neonates: practical use of anticoagulants in children.
Monagle, P, Newall, F
Hematology. American Society of Hematology. Education Program. 2018;(1):399-404
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Venous thrombosis (VTE) in children and neonates presents numerous management challenges. Although increasing in frequency, VTE in children and neonates is still uncommon compared with adults. The epidemiology of VTE is vastly different in neonates vs children vs adolescents vs adults. In reality, pediatric thrombosis should be viewed as a multitude of rare diseases (eg, renal vein thrombosis, spontaneous thrombosis, catheter-related thrombosis, cerebral sinovenous thrombosis), all requiring different approaches to diagnosis and with different short- and long-term consequences, but linked by the use of common therapeutic agents. Further, children have fundamentally different physiology in terms of blood flow, developmental hemostasis, and, likely, endothelial function. The American Society of Hematology 2017 Guidelines for Management of Venous Thromboembolism: Treatment of Pediatric VTE provides up-to-date evidence-based guidelines related to treatment. Therefore, this article will focus on the practical use of therapeutic agents in the management of pediatric VTE, especially unfractionated heparin, low-molecular-weight heparin, and oral vitamin K antagonists, as the most common anticoagulants used in children. Direct oral anticoagulants (DOACs) remain in clinical trials in children and should not be used outside of formal trials for the foreseeable future.
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Vitamin K Antagonists and Cognitive Decline in Older Adults: A 24-Month Follow-Up.
Brangier, A, Ferland, G, Rolland, Y, Gautier, J, Féart, C, Annweiler, C
Nutrients. 2018;(6)
Abstract
Vitamin K participates in brain physiology. This study aimed to determine whether using vitamin K antagonists (VKAs), which interfere with the vitamin K cycle, were (i) cross-sectionally associated with altered cognitive performance, and (ii) independent predictors of cognitive changes in older adults over 24 months. Information was collected on the use of VKAs (i.e., warfarin, acenocoumarol, and fluindione) among 378 geriatric outpatients (mean, 82.3 ± 5.6 years; 60.1% female). Global cognitive performance and executive functions were assessed with Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores, respectively, at baseline and after 12 and 24 months of follow-up. Age, gender, body mass index, mean arterial pressure, disability, gait speed, comorbidities, atrial fibrillation, stroke, carotid artery stenosis, leukoaraiosis grade on computed tomography (CT) scan, psychoactive drugs, antidementia drugs, blood-thinning drugs (i.e., anticoagulants other than VKAs, antiplatelet medications), serum creatinine levels, and vitamin B12 concentrations were considered as potential confounders. Using VKAs was associated with lower (i.e., worse) FAB score at baseline (adjusted β = -2.1, p = 0.026), and with a decrease in FAB score after 24 months (adjusted β = -203.6%, p = 0.010), but not after 12 months (p = 0.659). Using VKAs was not associated with any change in MMSE score at baseline (p = 0.655), after 12 months (p = 0.603), or after 24 months (p = 0.201). In conclusion, we found more severe executive dysfunction at baseline and incident executive decline over 24 months among geriatric patients using VKAs, when compared with their counterparts.
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Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants.
Pastori, D, Lip, GYH, Farcomeni, A, Del Sole, F, Sciacqua, A, Perticone, F, Marcucci, R, Grifoni, E, Pignatelli, P, Violi, F, et al
International journal of cardiology. 2018;:58-63
Abstract
OBJECTIVES To investigate the incidence of bleeding events in atrial fibrillation (AF) patients treated with vitamin K (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) screened for the presence of liver fibrosis (LF). BACKGROUND Previous studies provided conflicting results on bleeding risk in AF patients with liver disease on VKAs, and no data on NOACs in this setting are available. METHODS Post-hoc analysis of a prospective, observational multicentre study including 2330 AF outpatients treated with VKAs (n = 1297) or NOACs (n = 1033). Liver damage was quantified by the FIB-4 score (>3.25), a validated marker of LF. The primary endpoint was the incidence of any bleeding, according to ISTH classification. RESULTS A high FIB-4 was present in 129 (5.5%) patients: 77 (5.9%) on VKA and 52 (5.0%) on NOACs (p = 0.344). During follow-up, 357 (15.3%) patients experienced a bleeding: 261 (80 major and 180 minor) with VKAs (7.2%/year), and 96 (40 major and 56 minor) with NOACs (6.4%/year). In VKA-treated patients, but not in those on NOACs, FIB-4 >3.25 was associated with higher major bleeding (14.3% vs. 5.6%, log-rank test p < 0.001). Multivariable Cox regression model showed that FIB-4 was associated with major bleeding only in VKA-treated patients (HR: 3.075, 95% CI 1.626-5.818, p = 0.001). On multivariable analysis, FIB-4 was not significantly associated with CVEs neither in VKA or NOAC-treated patients. CONCLUSION We found a significant association between LF and major bleedings in AF patients treated with VKA, which was not evident in patients on NOACs.
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Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation.
Bruins Slot, KM, Berge, E
The Cochrane database of systematic reviews. 2018;(3):CD008980
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BACKGROUND Factor Xa inhibitors and vitamin K antagonists (VKAs) are now recommended in treatment guidelines for preventing stroke and systemic embolic events in people with atrial fibrillation (AF). This is an update of a Cochrane review previously published in 2013. OBJECTIVES To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for preventing cerebral or systemic embolic events in people with AF. SEARCH METHODS We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (August 2017), MEDLINE (1950 to April 2017), and Embase (1980 to April 2017). We also contacted pharmaceutical companies, authors and sponsors of relevant published trials. We used outcome data from marketing authorisation applications of apixaban, edoxaban and rivaroxaban that were submitted to regulatory authorities in Europe and the USA. SELECTION CRITERIA We included randomised controlled trials (RCTs) that directly compared the effects of long-term treatment (lasting more than four weeks) with factor Xa inhibitors versus VKAs for preventing cerebral and systemic embolism in people with AF. DATA COLLECTION AND ANALYSIS The primary efficacy outcome was the composite endpoint of all strokes and systemic embolic events. Two review authors independently extracted data, and assessed the quality of the trials and the risk of bias. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. In case of moderate or high heterogeneity of treatment effects, we used a random-effects model to compare the overall treatment effects. We also performed a pre-specified sensitivity analysis excluding any open-label studies. MAIN RESULTS We included data from 67,688 participants randomised into 13 RCTs. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux, idrabiotaparinux, or rivaroxaban. The majority of the included data (approximately 90%) was from apixaban, edoxaban, and rivaroxaban.The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic events was reported in all of the included studies. Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin in participants with AF (OR 0.89, 95% CI 0.82 to 0.97; 13 studies; 67,477 participants; high-quality evidence).Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.78, 95% CI 0.73 to 0.84; 13 studies; 67,396 participants; moderate-quality evidence). There was, however, statistically significant and high heterogeneity (I2 = 83%). When we repeated this analysis using a random-effects model, it did not show a statistically significant decrease in the number of major bleedings (OR 0.88, 95% CI 0.66 to 1.17). A pre-specified sensitivity analysis excluding all open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.75, 95% CI 0.69 to 0.81), but high heterogeneity was also observed in this analysis (I2 = 72%). The same sensitivity analysis using a random-effects model also showed a statistically significant decrease in the number of major bleedings in participants treated with factor Xa inhibitors (OR 0.76, 95% CI 0.60 to 0.96).Treatment with a factor Xa inhibitor significantly reduced the risk of intracranial haemorrhages (ICHs) compared with warfarin (OR 0.50, 95% CI 0.42 to 0.59; 12 studies; 66,259 participants; high-quality evidence). We observed moderate, but statistically significant heterogeneity (I2 = 55%). The pre-specified sensitivity analysis excluding open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.47, 95% CI 0.40 to 0.56), with low, non-statistically significant heterogeneity (I2 = 27%).Treatment with a factor Xa inhibitor also significantly reduced the number of all-cause deaths compared with warfarin (OR 0.89, 95% 0.83 to 0.95; 10 studies; 65,624 participants; moderate-quality evidence). AUTHORS' CONCLUSIONS Treatment with factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in people with AF. The absolute effect of factor Xa inhibitors compared with warfarin treatment was, however, rather small. Factor Xa inhibitors also reduced the number of ICHs, all-cause deaths and major bleedings compared with warfarin, although the evidence for a reduction in the latter is less robust.
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Antithrombotic therapy after mitral valve repair: VKA or aspirin?
van der Wall, SJ, Olsthoorn, JR, Heuts, S, Klautz, RJM, Tomsic, A, Jansen, EK, Vonk, ABA, Sardari Nia, P, Klok, FA, Huisman, MV
Journal of thrombosis and thrombolysis. 2018;(4):473-481
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The optimal antithrombotic therapy following mitral valve repair (MVr) is still a matter of debate. Therefore, we evaluated the rate of thromboembolic and bleeding complications of two antithrombotic prevention strategies: vitamin K antagonists (VKA) versus aspirin. Consecutive patients who underwent MVr between 2004 and 2016 at three Dutch hospitals were evaluated for thromboembolic and bleeding complications during three postoperative months. The primary endpoint was the combined incidence of thromboembolic and bleeding complications to determine the net clinical benefit of VKA strategy as compared with aspirin. Secondary objectives were to evaluate both thromboembolic and bleeding rates separately and to identify predictors for both complications. A total of 469 patients were analyzed, of whom 325 patients (69%) in the VKA group and 144 patients (31%) in the aspirin group. Three months postoperatively, the cumulative incidence of the combined end point of the study was 9.2% (95%CI 6.1-12) in the VKA group and 11% (95%CI 6.0-17) in the aspirin group [adjusted hazard ratio (HR) 1.6, 95%CI 0.83-3.1]. Moreover, no significant differences were observed in thromboembolic rates (adjusted HR 0.82, 95%CI 0.16-4.2) as well as in major bleeding rates (adjusted HR 1.89, 95%CI 0.90-3.9). VKA and aspirin therapy showed a similar event rate of 10% during 3 months after MVr in patients without prior history of AF. In both treatment groups thromboembolic event rate was low and major bleeding rates were comparable. Future prospective, randomized trials are warranted to corroborate our findings.
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Portuguese Observational Study of Ischaemic Stroke in Patients Medicated with Non-Vitamin K Antagonist Oral Anticoagulants.
Beato-Coelho, J, Marto, JP, Alves, JN, Marques-Matos, C, Calado, S, Araújo, J, Cunha, L, Pinho, J, Azevedo, E, Viana-Baptista, M, et al
European neurology. 2018;(1-2):108-112
Abstract
INTRODUCTION Clinical trials and subsequent meta-analyses showed advantages of non-vitamin K antagonists oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation. The impact of preadmission anticoagulation in acute ischaemic stroke (AIS) has not been established. OBJECTIVE To compare functional outcome of patients with AIS with preadmission NOACs vs. VKAs. METHODS A retrospective analysis was conducted on consecutive AIS patients under oral anticoagulation (VKAs or NOACs) admitted in 4 Portuguese hospitals within a period of 30 months. Two primary outcomes were defined and compared between VKA and NOAC groups: symptomatic intracerebral hemorrhage transformation (sICH) and modified Rankin Scale (mRS) at 3 months. RESULTS Four hundred sixty-nine patients were included, of whom 332 (70.8%) were treated with VKA and 137 (29.2%) with NOAC. Patients' median age was 78.0 and 234 (49.9%) were male. NOAC-treated patients had a higher median CHA2DS2-VASc score than those under VKA (5.0 vs. 4.0, p = 0.023). The two primary outcomes showed no statistical differences between the VKAs' group and the NOACs' group (sICH: 5.4 vs. 5.4% [p = 0.911]; mRS at 3 months: 3.0 vs. 3.0 [p = 0.646], respectively). CONCLUSION Preadmission anticoagulation with NOACs in AIS has a functional impact similar to that of VKAs.
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Is use of vitamin K antagonists associated with the risk of prostate cancer?: A meta-analysis.
Luo, JD, Luo, J, Lai, C, Chen, J, Meng, HZ
Medicine. 2018;(49):e13489
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BACKGROUND Vitamin K antagonists (VKAs) may have potential antitumor effects in prostate cancer. However, the findings of observational studies are inconsistent. The purpose of the present study was to estimate the quantitative association between VKAs use and prostate cancer risk by combining the results of all eligible observational studies. METHODS PubMed and Web of Science database were searched from inception until May, 2018. A DerSimonian random-effects model was used to combine the studies. Study heterogeneity was measured using the chi-squared and I statistics. RESULTS Six eligible studies were eventually included in our meta-analysis. There was an inverse but not statistically significant association between ever use of VKAs and the risk of prostate cancer (relative risk [RR] 0.84, 95% confidence interval [CI] 0.70-1.01, P = .063) with large heterogeneity across studies (P < .001 for heterogeneity, I = 94.6%). When analysis restricted to long term of VKAs user (>3 years), the pooled risk estimate was 0.83 (0.77-0.90) without obvious heterogeneity (P = .597, I = 0.0%). CONCLUSION This meta-analysis indicates that VKAs use may be associated with a decreased risk of prostate cancer, especially in long-term users.
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Meta-Analysis of Genotype-Guided Versus Standard Dosing of Vitamin K Antagonists.
Kheiri, B, Abdalla, A, Haykal, T, Osman, M, Ahmed, S, Hassan, M, Bachuwa, G
The American journal of cardiology. 2018;(7):879-887
Abstract
Vitamin K antagonist (VKA) is a commonly prescribed anticoagulant with a narrow therapeutic window. Genetic polymorphisms account for high VKA dosage variability. Hence, we performed an updated meta-analysis of all randomized clinical trials (RCTs) comparing genotype-guided VKA versus standard dosing algorithms. We conducted a systematic search of electronic databases from inception to October 2017 for all RCTs. The primary outcome was the percentage of time in therapeutic range (TTR). Secondary outcomes were international normalized ratio >4, major and all bleeding events, thromboembolism, adverse and serious adverse events, and all-cause mortality. We calculated the weighted mean difference for the primary outcome and risk ratio (RR) for secondary outcomes using a random-effect model. We included 20 RCTs and analyzed a total of 5,980 adult patients. Our pooled analysis showed greater improvement in TTR for the genotype-guided group in comparison with the standard group (mean difference 3.41%, 95% confidence interval [CI] 0.71 to 6.10, p = 0.01). In addition, there were significant reductions in major and all bleeding events ((RR 0.35, 95% CI 0.20 to 0.63, p = 0.0004) and (RR 0.79, 95% CI 0.66 to 0.95, p = 0.01), respectively). However, there were no significant differences between the groups for international normalized ratio >4 (RR 0.89, 95% CI 0.80 to 1.00, p = 0.06), thromboembolism (RR 0.81, 95% CI 0.56 to 1.17, p = 0.25), serious adverse events (RR 0.79, 95% CI 0.61 to 1.03, p = 0.08), any adverse events (RR 0.94, 95% CI 0.88 to 1.01, p = 0.07), or all-cause mortality (RR 0.73, 95% CI 0.32 to 1.66, p = 0.46). In conclusion, genotype-guided VKA dosing can improve the TTR and reduce the risk for bleeding episodes, in comparison with standard dosing algorithms.