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1.
Derivation and Application of a Tool to Estimate Benefits From Multiple Therapies That Reduce Recurrent Stroke Risk.
Richards, A, Jackson, NJ, Cheng, EM, Bryg, RJ, Brown, A, Towfighi, A, Sanossian, N, Barry, F, Li, N, Vickrey, BG
Stroke. 2020;(5):1563-1569
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Abstract
Background and Purpose- Lowering blood pressure and cholesterol, antiplatelet/antithrombotic use, and smoking cessation reduce risk of recurrent stroke. However, gaps in risk factor control among stroke survivors warrant development and evaluation of alternative care delivery models that aim to simultaneously improve multiple risk factors. Randomized trials of care delivery models are rarely of sufficient duration or size to be powered for low-frequency outcomes such as observed recurrent stroke. This creates a need for tools to estimate how changes across multiple stroke risk factors reduce risk of recurrent stroke. Methods- We reviewed existing evidence of the efficacy of interventions addressing blood pressure reduction, cholesterol lowering, antiplatelet/antithrombotic use, and smoking cessation and extracted relative risks for each intervention. From this, we developed a tool to estimate reductions in recurrent stroke risk, using bootstrapping and simulation methods. We also calculated a modified Global Outcome Score representing the proportion of potential benefit (relative risk reduction) achieved if all 4 individual risk factors were optimally controlled. We applied the tool to estimate stroke risk reduction among 275 participants with complete 12-month follow-up data from a recently published randomized trial of a healthcare delivery model that targeted multiple stroke risk factors. Results- The recurrent stroke risk tool was feasible to apply, yielding an estimated reduction in the relative risk of ischemic stroke of 0.36 in both the experimental and usual care trial arms. Global Outcome Score results suggest that participants in both arms likely averted, on average, 45% of recurrent stroke events that could possibly have been prevented through maximal implementation of interventions for all 4 individual risk factors. Conclusions- A stroke risk reduction tool facilitates estimation of the combined impact on vascular risk of improvements in multiple stroke risk factors and provides a summary outcome for studies testing alternative care models to prevent recurrent stroke. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT00861081.
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Stroke Prevention in Older Adults: Recent Advances.
Spence, JD, Azarpazhooh, MR, Larsson, SC, Bogiatzi, C, Hankey, GJ
Stroke. 2020;(12):3770-3777
Abstract
The risks of stroke and dementia increase steeply with age, and both are preventable. At present, the best way to preserve cognitive function is to prevent stroke. Therapeutic nihilism based on age is common and unwarranted. We address recent advances in stroke prevention that could contribute greatly to prevention of stroke and dementia at a time when the aging of the population threatens to markedly increase the incidence of both. Issues discussed: (1) old patients benefit even more from lipid-lowering therapy than do younger patients; (2) patients with stiff arteries are at risk from a target systolic blood pressure <120 mm Hg; (3) the interaction of the intestinal microbiome, age, and renal function has important dietary implications for older adults; (4) anticoagulation with direct-acting oral anticoagulants should be prescribed more to old patients with atrial fibrillation; (5) B vitamins to lower homocysteine prevent stroke; and (6) most old patients in whom intervention is warranted for carotid stenosis would benefit more from endarterectomy than from stenting. An 80-year-old person has much to lose from a stroke and should not have effective therapy withheld on account of age. Lipid-lowering therapy, a more plant-based diet, appropriate anticoagulation or antiplatelet therapy, appropriate blood pressure control, B vitamins to lower homocysteine, and judicious intervention for carotid stenosis could do much to reduce the growing burden of stroke and dementia.
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Clot Lysis Time Predicts Stroke During Anticoagulant Therapy in Patients with Atrial Fibrillation.
Drabik, L, Konieczyńska, M, Undas, A
The Canadian journal of cardiology. 2020;(1):119-126
Abstract
BACKGROUND Formation of dense fibrin clots has been reported in both atrial fibrillation (AF) and ischemic stroke. We have previously demonstrated that such clot properties can predict thromboembolism and major bleeding in AF patients treated with vitamin K antagonists (VKAs). In this longitudinal cohort study, we evaluated whether impaired fibrinolysis is associated with clinical outcomes in AF. METHODS In 236 patients with AF receiving VKAs, we measured ex vivo plasma clot lysis time (CLT), a measure of global fibrinolysis along, with von Willebrand factor antigen (vWF), plasminogen activator inhibitor 1 antigen (PAI-1), and other fibrinolysis modulators. The primary outcome were ischemic cerebrovascular events. Secondary end points were death and major bleeding. RESULTS During a median follow-up time of 4.3 (interquartile range 3.7-4.8) years, annual rates of death, ischemic cerebrovascular events, and major bleeding were 1.48%, 2.96%, and 3.45%, respectively. Patients with CLT in the fourth quartile (> 115 min) had 8-fold higher stroke or transient ischemic attack (TIA) rates compared with the other patients (8.67% vs 1.1%; P < 0.0001). CLT correlated with PAI-1 and vWF (r = 0.59; P < 0.0001 for both). In the multivariate Cox regression analysis adjusted for potential confounders, the independent predictors of stroke or TIA were CLT > 115 minutes (hazard ratio [HR] 7.67, 95% confidence interval [CI] 2.78-21.17; P < 0.0001), PAI-1 (HR 1.16, 95% 1.05-1.28; P = 0.003), and CHA2DS2-VASc score ≥3 (HR 5.18, 95% 1.76-15.29; P = 0.003). CLT was not associated with death or major and minor bleeding events. CONCLUSIONS Impaired fibrinolysis may predict thromboembolic events in AF patients receiving VKA.
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Non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation: evidences from the real-world data.
Xue, Z, Zhou, Y, Wu, C, Lin, J, Liu, X, Zhu, W
Heart failure reviews. 2020;(6):957-964
Abstract
The role of non-vitamin K antagonist oral anticoagulants (NOACs) in stroke prevention remains unclear in Asian patients with atrial fibrillation (AF). Therefore, we performed a meta-analysis to compare the efficacy and safety outcomes of NOACs in Asian patients with AF from the real-world settings. The PubMed and Embase databases were systematically searched to identify eligible observational studies until June 2019. The odds ratios (OR) and 95% confidence intervals (CIs) were calculated and then pooled by a random-effects model. A total of 18 observational studies were included. Compared with warfarin, dabigatran (OR, 0.56, 95% CI 0.43-0.73), rivaroxaban (OR, 0.54, 95% CI 0.44-0.67), apixaban (OR, 0.41, 95% CI 0.35-0.48), and edoxaban (OR, 0.19, 95% CI 0.14- 0.25) reduced the risk of major bleeding, while dabigatran (OR, 0.78, 95% CI 0.71-0.85), rivaroxaban (OR, 0.74, 95% CI 0.68-0.82), and edoxaban (OR, 0.29, 95% CI 0.22-0.39) were associated with reduced risks of stroke or systemic embolism. In addition, dabigatran versus apixaban was associated with increased risks of ischemic stroke and gastrointestinal bleeding, while rivaroxaban versus apixaban was associated with elevated risks of stroke or systemic embolism, ischemic stroke, intracranial hemorrhage, and gastrointestinal bleeding. In Asian patients with AF, NOACs are non-inferior to warfarin for stroke prevention, and apixaban may be a better choice compared with dabigatran or rivaroxaban.
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Profile of Patients Diagnosed With Acute Venous Thromboembolism in Routine Clinical Practice: The RE-COVERY DVT/PE™ Study.
Goldhaber, SZ, Ageno, W, Casella, IB, Chee, KH, Schellong, S, Singer, DE, Desch, M, Reilly, PA, Donado, E, Tang, W, et al
The American journal of medicine. 2020;(8):936-945
Abstract
BACKGROUND The safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) have been established in randomized controlled trials, but limited data are available on their use in clinical practice across geographical regions. METHODS In the international RE-COVERY DVT/PE observational study (enrollment January 2016 to May 2017), we sought to characterize the patient population and describe the prescribed anticoagulant. Patient characteristics and anticoagulants administered after objective diagnosis of VTE were recorded at the baseline visit and again at hospital discharge or at 14 days after the diagnosis, whichever was later. RESULTS A total of 6095 patients were included, 50.2% were male, and the mean age was 61.5 years. The most common comorbidities were hypertension (35%), diabetes mellitus (11%), cancer (11%), prior VTE(11%), and trauma/surgery (7%). Overall, 77% of patients received oral anticoagulants, with 54% on NOACs and 23% on vitamin K antagonists (VKAs); 20% received parenteral anticoagulation only. NOACs comprised about 60% of anticoagulant treatment in Europe and Asia but substantially less in Latin America (29%) and the Middle East (21%). For NOAC therapies, the distribution (as a percentage of the total cohort) was rivaroxaban 25.6%, dabigatran 15.5%, apixaban 11.3%, and edoxaban 1.7%. Treatment with NOACs was less frequent in patients who had cancer, chronic renal disease, heart failure, or stroke. CONCLUSIONS These findings enhance our understanding of baseline characteristics and the initial management of patients with VTE in routine practice.
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Ischemic Stroke and Transient Ischemic Attack Risk Following Vitamin K Antagonist Cessation in Newly Diagnosed Atrial Fibrillation: A Cohort Study.
Martinez, C, Wallenhorst, C, Rietbrock, S, Freedman, B
Journal of the American Heart Association. 2020;(2):e014376
Abstract
Background In nonvalvular atrial fibrillation (AF), oral anticoagulants prevent ischemic strokes and transient ischemic attacks (TIAs), but nonpersistence with vitamin K antagonist (VKA) oral anticoagulant therapy (20-50% at 1 year) is problematic. The precise risk of stroke/TIA after VKA cessation and its time course during extended follow-up is unknown. Methods and Results The study cohort of incident AF in patients receiving initial VKA between 2001 and 2013 was identified from the UK Clinical Practice Research Datalink (linked hospitalizations and causes of death). Using a nested case-control analysis, patients with incident stroke/TIA were matched to patients without stroke/TIA (controls). Relative risk with time since VKA cessation compared with current VKA use was approximated from conditional logistic regression. We studied 16 696 patients with incident AF and initial VKA treatment. There were 489 stroke/TIA cases matched to 2137 controls (mean CHA2DS2-VASc score 4.3). Compared with current VKA use, the excess incidence rate of stroke/TIA following VKA cessation in the first year after AF diagnosis was 2.29 (95% CI, 0.98-3.90) per 100 person-years of VKA cessation or 1 additional stroke/TIA per 43 patients per year discontinuing VKA, compared with 1.43 (95% CI, 0.97-1.88) per 100 person-years corresponding to 1 additional stroke/TIA per 70 patients per year, when VKA was discontinued more than 1 year after AF diagnosis. Conclusions VKA cessation is associated with a continuous excess thromboembolic stroke/TIA risk. Increasing oral anticoagulant persistence, especially in the year after AF diagnosis, should be a therapeutic target to reduce stroke/TIA in AF.
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Community pharmacy-based study of adherence to non-vitamin K antagonist oral anticoagulants.
Capiau, A, Mehuys, E, Van Tongelen, I, Christiaens, T, De Sutter, A, Steurbaut, S, Moudallel, S, Rydant, S, Vrijens, B, de Backer, TLM, et al
Heart (British Cardiac Society). 2020;(22):1740-1746
Abstract
OBJECTIVE This study aimed to assess implementation adherence (how well the patient's actual intake matches the prescribed dosing regimen) to non-vitamin K antagonist oral anticoagulants (NOACs) and to explore experiences with and beliefs about NOACs in a real-world sample of long-term NOAC users. METHODS A cross-sectional observational study was conducted in home-dwelling adults who started taking a NOAC at least 1 year prior to inclusion. Pharmacy dispensing data were used to calculate the Medication Possession Ratio (MPR). Patients were recruited in 158 community pharmacies in Flanders, Belgium. They completed a questionnaire collecting basic characteristics and exploring self-reported adherence to NOACs (using the Medication Adherence Report Scale, MARS) and experiences with and beliefs about NOACs (using the Beliefs about Medicines Questionnaire, BMQ). RESULTS A total of 766 patients (mean age 76.2±8.8 years, median CHA2DS2-VASc score 4 (IQR=3-4)) were included. The majority (93.5%) used NOAC for stroke prevention in atrial fibrillation. The median MPR was 95.2% (IQR=87.8-99.7) which corresponds with half of the study population not taking their NOAC on at least 17 cumulative days per year. Almost 21% of participants reported non-adherence on the MARS (score <25), with unintentional non-adherence (forgetfulness) most frequently reported (15.4%). Although two-thirds of NOAC users indicated to experience adverse drug reactions, the BMQ demonstrated a positive attitude towards NOAC therapy, where necessity beliefs outweigh the concerns. CONCLUSIONS Our data indicate that long-term NOAC users have high implementation adherence and a positive attitude towards NOAC therapy. However, taking into account patients' thromboembolic risk and NOACs' short half-lives, further optimisation of NOAC use seems warranted in this population.
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Non-Vitamin K Antagonist Oral Anticoagulant for Atrial Fibrillation in Obese Patients.
Wang, SY, Giugliano, RP
The American journal of cardiology. 2020;:176-183
Abstract
Four non-vitamin K antagonist oral anticoagulants (NOACs) are approved for use to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation (AF). However, data are limited regarding the use of NOACs in the obese population. This manuscript summarizes current concepts regarding obesity in patients with AF and reviews in depth the data on the efficacy and safety of NOACs in obese patients with AF. The Pubmed database was searched for relevant articles. When evaluating obese patients with AF, weight loss is important to reduce disease burden. Recent analyses of the four NOAC versus warfarin trials (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48) stratified by body mass index (BMI) demonstrate preserved efficacy with NOACs versus warfarin in obese patients, with similar risk of major bleeding. Although the data are limited in class III obese patients (body mass index ≥40kg/m2), the efficacy and safety of apixaban or edoxaban appears to be similar to warfarin in patients with BMI 40-50kg/m2. In conclusion, these new data should be considered in updated guidelines, which currently provide limited, and sometimes conflicting recommendations regarding the use of NOACs in obese patients, particularly in severely obese patients.
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CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis.
Takeuchi, M, Kobayashi, T, Biss, T, Kamali, F, Vear, SI, Ho, RH, Bajolle, F, Loriot, MA, Shaw, K, Carleton, BC, et al
The pharmacogenomics journal. 2020;(2):306-319
Abstract
Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.
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Efficacy and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonist (VKA) among patients with atrial fibrillation and hypertrophic cardiomyopathy: a systematic review and meta-analysis.
Rujirachun, P, Charoenngam, N, Wattanachayakul, P, Winijkul, A, Owattanapanich, W, Ungprasert, P
Acta cardiologica. 2020;(8):724-731
Abstract
Background/objectives: Long-term oral anticoagulant therapy is recommended for patients with hypertrophic cardiomyopathy (HCM) who develop atrial fibrillation (AF) to prevent cardioembolic complications. In patients with non-valvular AF, direct oral anticoagulants (DOACs) has been proved to be non-inferior to adjusted-dose vitamin K antagonist (VKA). However, the role of DOACs in patients with AF in the setting of HCM has not been fully established.Methods: A comprehensive literature review was conducted by searching for published articles indexed in MEDLINE and EMBASE databases from inception through 1 May 2019. Eligible studies must start with recruitment of patients with AF in the setting of HCM who received either DOACs or VKA. The studies must follow them for the occurrence of ischaemic stroke. Hazard ratio (HR) and confidence interval (CI) of developing ischaemic stroke between the two groups must be reported. Pooled HR was calculated using a random-effect, generic inverse variance method of DerSimonian and Laird.Results: A total of three retrospective cohort studies with 4,418 participants met the eligibility criteria and were included into the meta-analysis. A significantly lower risk of all-cause death was observed in the DOACs group than in the VKA group with the pooled HR of 0.43 (95% CI, 0.33-0.58, I2 = 0%). However, the risk of ischaemic stroke among patients with AF and HCM who received DOACs was not significantly different from those who received VKA with the pooled HR of 0.95 (95% CI, 0.73-1.22, I2 = 0%). Both major bleeding and intracranial bleeding were also not significantly different between those who received DOACs versus those who received VKA with the pooled HR of 0.94 (95% CI, 0.70-1.26, I2 = 0%) and 0.61 (95% CI, 0.27-1.37, I2 = 0%), respectively.Conclusions: The current study found that the risk of all-cause death was significantly reduced but the risk of ischaemic stroke, major bleeding and intracranial bleeding were not significantly different between patients with AF and HCM who had received DOACs and those who received VKA.