Stroke In Non-valvular Atrial Fibrillation Research Articles

Epidemiology, prognosis, and challenges in the management of hyperthyroidism-related atrial fibrillation.

Atrial fibrillation (AF) is a common condition with a global estimated prevalence of 60 million cases, and the most common cardiac complication of hyperthyroidism, occurring in 5-15% of overtly hyperthyroid patients. Additionally, subclinical hyperthyroidism and high-normal free T4 have been associated with an increased risk in the development of AF. Hyperthyroidism-related AF is a reversible cause of AF, and the majority of patients spontaneously revert to sinus rhythm in 4-6 months during or after restoration of euthyroidism. Therefore, restoring thyroid function is an indispensable element in hyperthyroidism-related AF management. Rate control with beta-blockers consists another first-line therapy, reserving rhythm control in cases of persistent hyperthyroidism-related AF. It is still controversial whether hyperthyroidism is an independent risk factor of stroke in nonvalvular AF. As a result, initiating anticoagulation should be guided by the clinical thromboembolic risk score CHA2DS2-VASc score in the same way it is applied in patients with non-hyperthyroidism-related AF. Treatment with the novel direct oral anticoagulants appears to be as beneficial and may be safer than warfarin in patients with hyperthyroidism-related AF. In this review, we address the epidemiology, prognosis, and diagnosis of hyperthyroidism-related AF, and we discuss the management strategies and controversies in patients with hyperthyroidism-related AF.

Direct-Acting Oral Anticoagulants in patients at extremes of body weight: a review of pharmacological considerations and clinical implications.

Patients at extremes of body weight are underrepresented in randomized controlled trials of direct-acting oral anticoagulants (DOACs). Therefore, their optimal anticoagulant treatment remains a topic of debate. The aim of this narrative review is to summarize the evidence on the pharmacokinetic and pharmacodynamic profile of DOACs for treating patients at extremes of body weight in venous thromboembolism (VTE) and in the prevention of cardioembolic stroke in nonvalvular atrial fibrillation (NVAF). A literature search was conducted in the main bibliographic databases, and the most relevant reviews and original articles on the topic were selected. Although data in these patient groups are limited, apixaban and rivaroxaban show a favorable pharmacokinetic and pharmacodynamic profile in obese VTE treatment and NVAF patients and, in the case of apixaban, also in underweight patients. In particular, these drugs demonstrated comparable efficacy and safety to standard therapy. Very few data were available for dabigatran and edoxaban; the latter drug was safer at a lower dose, mainly in underweight patients. Our findings are in line with the last International Society of Haemostasis and Thrombosis position paper and European Heart Rhythm Association 2021 practical guide, suggesting the use of apixaban and rivaroxaban in morbidly obese patients (>120 kg or body mass index ≥40 kg/m 2 ) and the reduced dosage of edoxaban in low-weight patients. Future studies should focus on large populations of patients at extremes of body weights to acquire more clinical and pharmacokinetic evidence on all available DOACs, especially those currently less investigated.

DOAC Dosing Discordance Using Different Estimates of Kidney Function and Outcomes.

Direct oral anticoagulants (DOACs) are indicated for the prevention of stroke in non-valvular atrial fibrillation (NVAF). Although FDA labeling for DOACs utilizes estimated creatinine clearance (CrCL) according to the Cockcroft-Gault (C-G) equation, estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is often reported. The objectives of this study were to evaluate DOAC dosing discordance and to determine whether discordance based on various estimates of kidney function is associated with bleeding or thromboembolism. The study was an IRB-approved retrospective analysis of patients at UPMC Presbyterian Hospital from 01/01/2010-12/31/2016. Data were obtained through electronic medical records. Adults who received a medication charge for rivaroxaban or dabigatran, had a diagnosis code for atrial fibrillation, and a serum creatinine (SCr) within 3 days of DOAC initiation were included. Doses were considered discordant if the calculated dose based on CKD-EPI did not match the patient's dose during index admission, if dosed correctly utilizing C-G. Association of discordance with dabigatran, rivaroxaban, and clinical outcomes was determined using odds ratios and 95% confidence intervals. Rivaroxaban discordance was present among 49 of the 644 (8%) patients that were dosed correctly with C-G. Dabigatran discordance was present among 17 of the 590 (3%) patients that were dosed correctly. Discordance with rivaroxaban was found to increase the risk of thromboembolism when utilizing CKD-EPI (OR = 2.83; 95% CI, 1.02to7.79, p = 0.045) versus C-G. Our findings emphasize the need to dose DOACs, specifically rivaroxaban, appropriately in patients with NVAF. This article is protected by copyright. All rights reserved.

Abstract 14037: Nonspecific Tools Performed Better in Discriminating Major Bleeding From Direct Oral Anticoagulants Than Specific Tools in a Real-World Population With Atrial Fibrillation

Background. Direct oral anticoagulants (DOACs) are the first-line guideline-recommended therapy for preventing stroke in non-valvular atrial fibrillation (AF) patients. DOACs are increasingly being prescribed in the US compared to warfarin because of lower bleeding risk overall, but the proportion of Emergency Department visits involving DOACs-related bleeding increased from 2.3% in 2011 to 37.9% in 2017. Therefore, tools that accurately predict bleeding risk from DOACs are needed. Aim. This study compared the performance of six tools for predicting major bleeding risk in non-valvular AF patients on DOACs. Methods. A retrospective cohort study was carried out with 2,364 Caucasians diagnosed with non-valvular AF and treated with rivaroxaban or apixaban at the University of Michigan Health System. Bleeding risk was calculated using six existing tools: CHA 2 DS 2 -VASc, Anticoagulation-specific Bleeding Score (ABS), HAS-BLED, ATRIA, HEMORR2HAGES, and ORBIT. Major bleeding events were retrieved from medical records and classified according to International Society of Thrombosis and Haemostasis criteria. Discrimination was estimated using the c-statistic, and the areas under the curves (AUC) were compared using the Hanley-McNeil test. RGui was used for all statistical analyses and p-values <0.05 were considered statistically significant. Results. A total of 97 (4.1%) patients experienced major bleeding on DOACs over 2.27 ± 2.03 years of follow-up. HAS-BLED and ABS are tools for specifically predicting major bleeding risk, but both had significantly lower performance than ATRIA, HEMORR2HAGES, and ORBIT ( Figure 1 ). There was no significant difference in the discriminative performance between HAS-BLED and ABS, as well as between ATRIA, HEMORR2HAGES, and ORBIT. Conclusion. ATRIA, HEMORR2HAGES, and ORBIT were the tools that performed better in discriminating major bleeding in AF patients if compared to HAS-BLED and ABS.

N-terminal pro-B-type natriuretic peptide and D-dimer combined with left atrial diameter to predict the risk of ischemic stroke in nonvalvular atrial fibrillation.

We aimed to explore the potential role of N-terminal pro-B-type natriuretic peptide (NT-proBNP), d-dimer, and the echocardiographic parameter left atrial diameter (LAD) in identifying and predicting the occurrence of ischemic stroke (IS) in patients with nonvalvular atrial fibrillation (NVAF). We conducted a retrospective study of 445 patients with NVAF in the First Affiliated Hospital of Nanchang University. They were divided into the NVAF (309 cases) and NVAF with stroke (136 cases) groups according to whether acute ischemic stroke (AIS) occurred at admission. Multivariate logistic regression was used to analyze the odds ratio (OR) of NT-proBNP, d-dimer, and LAD for IS. The predictive value of NT-proBNP, d-dimer, and LAD in identifying the occurrence of IS in NVAF was determined by plotting the receiver operating characteristic (ROC) curves. NT-proBNP, d-dimer, and LAD levels were significantly higher in the NVAF with stroke group than in the NVAF group (p < .05). NT-ProBNP, d-dimer, and LAD were independently associated with IS in NVAF patients (odds ratio [OR] = 1.12, 95% confidence interval [CI]: 1.08-1.16; OR = 1.87, 95% CI: 1.37-2.55; OR = 1.21, 95% CI: 1.13-1.28, p < .01). The optimal cutoff points for NT-ProBNP, d-dimer, and LAD levels to distinguish the NVAF group from the NVAF with stroke group were 715.0 pg/ml, 0.515 ng/ml, and 38.5 mm, respectively, with the area under the curve (AUC) being [0.801 (95% CI: 0.76-0.84); 0.770 (95% CI: 0.72-0.85); 0.752 (95% CI: 0.71-0.80), p < .01]. The combined score of NT-proBNP, d-dimer, and LAD improved the predictive efficacy of the single index, with an AUC of 0.846 (95% CI: 0.81-0.88, p < .01), sensitivity of 77.2%, and specificity of 76.4%. NT-proBNP, d-dimer, and the echocardiographic parameter LAD have outstanding value in predicting the risk of IS in patients with NVAF.

Twice- or once-daily dosing of direct oral anticoagulants and gastrointestinal bleeding in patient with atrial fibrillation

AimsDirect oral anticoagulant (DOAC) is widely used for the prevention of embolic stroke in non-valvular atrial fibrillation (NVAF) patients. However, the gastrointestinal bleeding risk in several DOAC regimens was higher than warfarin, especially in once-daily regimens. Methods and resultsWe conducted a single-center prospective registry of patients with NVAF treated with DOACs: the DIRECT registry (N = 2216; follow-up duration 650 [IQR 103–1574] days, UMIN000033283). All patients were divided into 2 groups: the twice-daily (BID) regimen group (dabigatran and apixaban) versus the once-daily (QD) regimen group (rivaroxaban and edoxaban). Out of 2216 patients, we successfully matched 904 patients in the QD group and 904 patients in the BID group using propensity score. The primary endpoint was gastrointestinal bleeding defined as any bleeding in the gastrointestinal tract that was identified through medical records regardless of bleeding site or severity. The BID group showed a significantly lower gastrointestinal bleeding rate than the QD group (3.5/100 person-year vs. 6.2/100 person-year, log-rank P < 0.0001). The secondary endpoints were all death, stroke, major bleeding, and any bleeding. The rate of major bleeding was significantly lower in patients with BID regimen group (log-rank P = 0.040). In contrast, all death, stroke, and any bleeding did not differ between both groups (log-rank P = 0.280, 0.520 and 0.066, respectively). ConclusionsThe BID regimen as compared with the QD regimen was associated with reduced risk of gastrointestinal bleeding.

Tolerability and Efficacy of Rivaroxaban vs Warfarin for Non Valvular Atrial Fibrillation

Introduction: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is seen in 1–2% of the general population. Objectives: The main objective of the study is to find the tolerability and efficacy of rivaroxaban Vs warfarin for non valvular atrial fibrillation. Material and methods: This cross sectional comparative study was conducted in Pakistan Institute of Medical Sciences Islamabad during January 2021 to June 2021. After permission from hospital ethical committee, total 70 patients meeting the inclusion and exclusion criteria was enrolled in the study from OPDs of cardiology and allied Departments of hospital. Detailed history and physical examination was done to meet the inclusion and exclusion criteria. Informed consent was obtained. Results: Out of 70 patients enrolled in total, 15 were excluded because of the above-mentioned exclusion criteria; 6 patients of NOAC group denied to participate and left cohort; and 4 patients lost the follow-up. Out of 45 participants, 21 were treated with rivaroxaban, while 24 were treated with warfarin. Conclusion: It is concluded that oral anticoagulant drugs for prevention of stroke in non-valvular AF have been evolved and adding new options and advantages for patients and physicians such as fewer frequency of drug and food interactions, no need for monitoring, broad therapeutic index and tolerated better by patients.

Cost-Utility Analysis of Dabigatran and Warfarin for Stroke Prevention Among Patients With Nonvalvular Atrial Fibrillation in India

ObjectivesDabigatran has a better safety profile and requires less monitoring, but is costlier than warfarin. This study evaluated the cost-utility of dabigatran relative to warfarin for preventing stroke in nonvalvular atrial fibrillation (NVAF) in India. MethodsA Markov decision analysis model was developed to compare dabigatran (110 or 150 mg twice a day) to warfarin titrated to target prothrombin time in patients with NVAF at high risk of stroke. Model utilities and transition probabilities were based on literature and costs on market prices. Data on out-of-pocket expenses and income lost were taken from a nationally representative survey. We adopted a societal perspective and discounted both costs and outcomes at 3%. Ischemic stroke, intracranial bleed, other major bleeds, and death were outcomes of NVAF. The model projected the costs, life-years, and quality-adjusted life-years (QALYs) for each intervention over a lifetime. We used gross domestic product per capita of India (US dollars [US$]1889) as the cost-effectiveness threshold. Sensitivity analyses were conducted. ResultsTreatment with either dose of dabigatran was associated with gain in life-years and QALYs compared with warfarin. The discounted incremental cost-effectiveness ratios/QALYs for both doses of dabigatran (110 mg US$7519; 150 mg US$6634) were above the cost-effectiveness threshold, and the probability of being cost-effective at this threshold was low. Cost of dabigatran was an important factor in determining incremental cost-effectiveness ratio. Price reduction of 150 mg dose by 49% will make it cost-effective. ConclusionsDabigatran is not cost-effective in the Indian societal context. Reducing the price of dabigatran 150 mg by half will make it cost-effective.

Accuracy and reliability of left atrial appendage morphology assessment by new 3D transesophageal echocardiographic rendering modalities: a comparative study with computed tomography

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction. Left atrial appendage (LAA) morphology assessed by contrast-enhanced computed tomography (CT) has been associated to the risk of cardioembolic stroke in non-valvular atrial fibrillation. Subsequent studies with the traditional LAA classification system (CS) into 4 morphologies (Chicken wing, Cauliflower, Cactus and Windsock) yielded mixed results in terms of reliability and stroke risk association. Recently, a simple LAA morphology CS (new-LAAcs) based on the LAA bend angle measurement has been suggested. Three-dimensional transesophageal echocardiography (3D TOE) quality imaging has been improved and new volume rendering modalities developed. Purpose. Aim of this study was to evaluate the accuracy and reliability of 2D and new 3D TOE rendering modalities compared to CT in assessing LAA morphology. We used and validated a new simple LAA morphology classification system (new-LAAcs) based on the LAA bend angle in contrast to the traditional CS. Methods. 50 consecutive patients who underwent both cardiac CT and TOE were enrolled. LAA morphology was assessed by three different TEE modalities: (1) 2D TOE inspective evaluation (2D TOE), (2) 3D TOE multiplanar reconstruction (3D TOE MPR) and (3) 3D TOE Philips TrueVue Glass rendering (3D TOE GLASS). We assessed TOE accuracy compared to CT by sensitivity, specificity, accuracy, and Cohen’s kappa. Two trained readers independently adjudicated LAA morphologies in the new-LAAcs and the inter-rater reliability was obtained by percentage agreement and Cohen’s kappa. The reliability of the new- vs. traditional-LAAcs was assessed by CT in terms of reliability rates and influence on LAA morphology prevalence. Results. CT and TOE imaging analyses were feasible in all patients. 2D TOE was fairly accurate in identifying LAA morphology (κ 0.38, p = 0.022) and had only moderate inter-rater (κ 0.46, p = 0.027) and substantial intra-rater (κ 0.62, p = 0.003) reliability rates. 3D TOE showed high validity: 3D TOE MPR had an almost perfect accuracy (κ 0.84, p &amp;lt; 0.001) and substantial (κ 0.77, p &amp;lt; 0.001) inter-rater reliability; 3D TOE GLASS substantial accuracy (κ 0.67, p &amp;lt; 0.001) and almost perfect (κ 0.82, p &amp;lt; 0.001) inter-rater reliability. Intra-rater agreement was almost perfect for both 3D TOE modalities (κ 0.84, p &amp;lt; 0.001). In the comparison among CS the traditional-LAAcs inter-rater reliability was moderate (κ 0.47, p &amp;lt; 0.001) and the intra-rater reliability substantial (κ 0.68, p &amp;lt; 0.001) while the new-LAAcs yielded an almost perfect reliability level (inter-rater κ 0.84, p &amp;lt; 0.001 and intra-rater κ 0.93, p &amp;lt; 0.001). With the traditional-LAAcs, the prevalence of CW LAA was 30 (60%), while with the new-LAAcs the prevalence of low-risk-LAA was 13 (26%), leading to classify 17 (57%) CW morphologies as high-risk-LAA. Conclusions. 3D TOE is an accurate, reliable, and feasible alternative to CT in assessing LAA morphology with the new-LAAcs. The new-LAAcs shows higher reliability rates than the traditional one. Abstract Figure. Abstract Figure.

Risk Factors for Ischemic Stroke in Non-Valvular Atrial Fibrillation: A Systematic Review and Meta-Analysis

Risk Factors for Ischemic Stroke in Non-Valvular Atrial Fibrillation: A Systematic Review and Meta-Analysis

47 DOSING OF DIRECT ORAL ANTICOAGULANTS IN OLDER ADULTS

Abstract Background Direct oral anticoagulants (DOACs) are approved for a variety of uses including prevention of stroke in non-valvular atrial fibrillation and treatment and prevention of deep vein thrombosis and pulmonary embolism. Adjustment to DOAC dosing may be required for age, weight and renal impairment. Incorrect lower dosing puts patients at risk of thromboembolic events whereas inappropriate higher dosing increases the risk of bleeding. We compared current DOAC dosing for patients admitted to our hospital and compare this against HSE best practice to determine if patients were receiving the correct dose [1]. Methods A prospective single-centre study. Patients admitted to our hospital following a fracture and reviewed by the Orthogeriatric team between August–October 2020 were eligible for inclusion. We recorded admission DOAC dose, age, weight and renal function. We also obtained data including sex and Clinical Frailty Scale (CFS). Results Thirty-one patients were included. Mean age was 86 years [range 66–99] and 21(68%) were female. Apixaban was the most commonly used DOAC; 25(81%). Stroke prevention in non-valvular atrial fibrillation was the most common DOAC indication; 29(93%). Twelve patients (39%) had an inappropriate DOAC dose prescribed. Eight patients (67%) had an inappropriately low dose and 4 patients (33%) had an inappropriately high dose. The mean CFS was 5 [Range 2–7] classifying our cohort as mildly frail. Conclusion Our study has shown that over one-third of our patients were on an inappropriate DOAC dose on admission with the majority (67%) due to under-dosing. Many factors may have influenced dosing choices by clinicians but our findings highlight the challenges in dosing, monitoring and the overall management of DOAC therapy in older people. Further studies and research are required to establish the most accurate and effective dosing strategies for DOACs in older adults. Reference 1. Health Service Executive [Internet]. Ireland ‘Anticoagulation Prescribing Tips’ https://www.hse.ie/eng/services/publications/clinical-strategy-and-programmes/noac-prescribing-tips-for-noacs.pdf.

Abstract 8996: Efficacy and Safety of Direct Oral Anticoagulants in Those Identifying as Black or African-American: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Introduction: Direct oral anticoagulants (DOACs) are indicated for prevention of stroke in non-valvular atrial fibrillation (AF) and for both treatment and prevention of recurrence of venous thromboembolism (VTE). Very little is known about efficacy and safety of these agents in patients identifying as Black or African-American (AA), as landmark trials demonstrating their non-inferiority to vitamin K antagonists (VKAs) are notable for discrepancies in enrollment by patient’s race. As the primary efficacy and safety outcomes for both AF and VTE are similar, we hypothesized that the cumulative efficacy and safety of DOACs in AA patients would be similar to that of the general population. Methods: A systematic review was conducted of clinical trials that investigated the comparison between DOACs and VKAs in patients for both AF and VTE. The Mantel-Haenszel Method was used to estimate pooled risk ratios (RRs) and corresponding confidence intervals (CIs) for the efficacy and safety of DOACs in AAs compared to the general population. Primary efficacy outcome was defined as stroke or systolic embolism in AF or symptomatic, recurrent VTE. Primary safety outcome was defined as major bleeding in both AF and VTE. Results: Nine studies were used for meta-analysis, with 26 eliminated due to lack of randomization or subgroup data for AAs. A total of 80,688 of patients were analyzed with 1.67% being AA. Regarding efficacy, the RR for AAs using DOACs compared to VKAs was 0.98 (95% CI 0.62,1.55; I 2 =0%; p=0.94), while the RR for the entire population was 0.90 (CI 0.78,1.04; I 2 =41%; p=0.1). Regarding safety, the RR for AAs using DOACs compared to VKAs was 0.83 (CI 0.56,1.25; I 2 =0%; p=0.92), while the RR for the entire population was 0.78 (CI 0.65,0.93; I 2 =76%; p&lt;0.01). Conclusions: The use of DOACs versus VKAs in AF and VTE for AAs results in similar efficacy to the general population. DOACs are non-inferior to VKAs with respect to safety outcomes in AF and VTE for AAs. It is uncertain why superiority of safety outcomes seen in the general population are not seen in the AA population, and will require further studies.

Factors associated with primary nonadherence to newly initiated direct oral anticoagulants in patients with nonvalvular atrial fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) are widely used for the prevention of stroke in nonvalvular atrial fibrillation (NVAF); however, real-world primary nonadherence (failing to collect the first prescription) has been measured in very few studies. OBJECTIVE: To report primary nonadherence in NVAF patients who are newly prescribed DOACs and identify associated factors. METHODS: This observational retrospective cohort study used a large primary care database in Catalonia. Patients with NVAF who were newly prescribed a DOAC between January 2009 and December 2015 were identified, and primary nonadherence was measured by comparing prescribing records to pharmacy claims data. Multivariable logistic regression was used to determine associated factors. RESULTS: A total of 12,257 patients met the inclusion and exclusion criteria; of these, 1,276 (10.4%) were primary nonadherent. Primary nonadherence was found to be 12.8% for apixaban, 8.6% for dabigatran, and 10.8% for rivaroxaban. Multivariable logistic regression indicated higher odds of primary nonadherence with apixaban and rivaroxaban compared to dabigatran (apixaban: OR = 1.61, 95% CI = 1.39-1.87; rivaroxaban: OR = 1.28, 95% CI = 1.11-1.47). Patients aged at least 80 years showed lower odds of primary nonadherence compared to those aged less than 65 years (OR = 0.78, 95% CI = 0.66-0.93). A diagnosis of chronic kidney disease was associated with primary nonadherence (OR = 1.27, 95% CI = 1.08-1.50). Whereas, diabetes (OR = 0.85, 95% CI = 0.74-0.97), hypertension (OR = 0.79, 95% CI = 0.70-0.91), and stroke/transient ischemic attack (OR = 0.70, 95% C I =0.59-0.82) were inversely associated with primary nonadherence. CONCLUSIONS: Overall, 10.4% of patients prescribed DOACs were primary nonadherent, failing to collect the first prescription. The percentage could have serious implications for patient outcomes and the real-world cost-effectiveness of prescribing DOACs in NVAF. Rates of primary nonadherence and associated factors may provide useful information for the design and evaluation of adherence interventions. DISCLOSURES: No outside funding was received for this study. The data for this study came from the European Medicines Agency PE-PV project (Grant/Award Number EMA/2015/27/PH). The authors have nothing to disclose. A preliminary version of this work was presented at the European Drug Utilisation Research Group (EuroDURG) Conference, Szeged, Hungary, March 5, 2020.

Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Reversal of Factor Xa-Associated Intracranial Hemorrhage.

[Figure: see text].

Rivaroxaban: Expanded Role in Cardiovascular Disease Management—A Literature Review

Direct oral anticoagulants (DOACs) are widely used for the prevention of stroke in nonvalvular atrial fibrillation, treatment of deep venous thrombosis and pulmonary embolism, and as prophylaxis after hip and knee surgery after approval by the Food and Drug Administration. In the last decade, DOACs were studied for various indications; this review is focused on rivaroxaban, a factor Xa inhibitor, which is used in an expanded evidence-based fashion for coronary artery disease, peripheral artery disease, heart failure, malignancy, and prophylaxis of deep venous thrombosis in acute medical illnesses.

Critical Analysis of Apixaban Dose Adjustment Criteria.

Apixaban is indicated for the prevention of ischemic stroke in non-valvular atrial fibrillation (NVAF), as well as for the prevention and treatment of venous thromboembolism (VTE). Dose adjustment is based on age, weight, and serum creatinine in NVAF, while there are no recommended adjustment criteria for VTE. Such adjustment is unconventional compared to other commonly used medications. The objective of this manuscript is to critically analyze each apixaban dosing adjustment criterion and its associated outcomes. PubMed articles from March 2013 to March 2020 were selected with search terms “apixaban,” and “dose adjustment,” “adjustment,” or “adjustment criteria.” Pharmacokinetic studies demonstrated increased apixaban exposure in patients >65 years of age, those with extreme body weights, and those with advanced renal impairment, though post-hemodialysis dosing may off-set the elevated apixaban exposure. However, clinical data show that among patients >75 years, <60 kg, and with estimated glomerular filtration rate <50 mL/min, including those on dialysis, there is no reduction in apixaban safety or efficacy. Published literature describes variable dosing strategies utilized in clinical practice. Overall, apixaban dose adjustment criteria may need to be re-evaluated.

Infarct volumes of patients with acute ischemic stroke receiving direct oral anticoagulants due to non-valvular atrial fibrillation

Direct oral anticoagulants (DOACs) have been shown to decrease the risk of ischemic stroke in non-valvular atrial fibrillation (NVAF). This study aims to investigate whether DOACs result in a significant change in lesion volume and the severity of the subsequent disability in patients who have experienced a stroke.Methods:The study included a total of 137 patients with NVAF and acute stroke. The cohort included 76 patients using DOACs, 21 patients using acetylsalicylic acid (ASA), and 40 patients with newly diagnosed atrial fibrillation (NDAF) who did not use antiaggregants or anticoagulants. Diffusion-weighted MRI was performed 6–12 hours after the first stroke symptoms and infarct volumes were measured by two independent observers. Baseline National Institutes of Health Stroke Scale (NIHSS) score, modified Rankin Scale (mRS) score at discharge and period of hospitalization were calculated.Results:When patients using DOACs due to NVAF and patients with NDAF were compared, the volumes of patients using DOACs (median 7.8 vs 23.1 cm3; P ≤ 0.01) were statistically significantly smaller. However, there was no difference in volume between ASA users (median 16.9 cm3; P = 0.16) and patients with NDAF. The DOACs group was significantly different compared to the NDAF group in terms of NIHSS scores (median 4.4 vs 8.3; P ≤ 0.01) and mRS scores at discharge (median 1.7 vs 2.7; P ≤ 0.01), and period of hospitalization (median 6.4 vs 10.4 days; P ≤ 0.01).Conclusion:We observe, while using DOACs, the infarct volumes of patients who experience stroke are smaller than those with NDAF and using ASA, as well as mRS scores at discharge are low and length of hospital stay is short.

PCV91 CAN Disparities between Health Technology Appraisal (HTA) Decisions Result in Inequitable Access to Treatment? the Case of NOVEL ORAL Anticoagulants (NOACS) in the Prevention of Stroke in NON-Valvular Atrial Fibrillation (NVAF)

PCV91 CAN Disparities between Health Technology Appraisal (HTA) Decisions Result in Inequitable Access to Treatment? the Case of NOVEL ORAL Anticoagulants (NOACS) in the Prevention of Stroke in NON-Valvular Atrial Fibrillation (NVAF)

Pharmacokinetics and Pharmacogenetics of Apixaban

Apixaban is oral anticoagulant, it is widely used in prevention of stroke in non-valvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism. Its main mechanism of action is through reversible inhibition of factor Xa. It specifically binds and inhibits both free and bound factor Xa which ultimately results in reduction in the levels of thrombin formation. Apixaban is mainly metabolized by CYP3A4 with minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP2J2 isoenzymes. Some of the major metabolic pathways of apixaban include o-demethylation, hydroxylation, and sulfation, with o-demethylapixabansulphate being the major metabolite. The aim of this review is analysis of associated researches of single nucleotide variants (SNV) of CYP3A5 and SULT1A1 genes and search for new candidate genes reflecting effectiveness and safety of apixaban. The search for full-text publications in Russian and English languages containing key words “apixaban”, “pharmacokinetics”, “effectiveness”, “safety” was carried out amongst literature of the past twenty years with the use of eLibrary, PubMed, Web of Science, OMIM data bases. Pharmacokinetics and pharmacogenetics of apixaban are considered in this review. The hypothesis about CYP и SULT1A enzymes influence on apixaban metabolism was examined. To date, numerous SNVs of the CYP3A5 and SULT1A1 genes have been identified, but their potential influence on pharmacokinetics apixaban in clinical practice needs to be further studies. The role of SNVs of other genes encoding beta-oxidation enzymes of apixaban (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2J2) and transporter proteins (ABCB1, ABCG2) in its efficacy and safety are not well understood, and ABCB1 and ABCG2 genes may be potential candidate genes for studies of the drug safety.

Admission blood glucose level as an ischemic stroke risk modifier in patients with new-onset non-valvular atrial fibrillation

Abstract Background Several scores have been proposed to assess the stroke risk in patients with non-valvular atrial fibrillation (NVAF). However, type 2 diabetes mellitus (T2DM) is considered a major stroke risk factor regardless of glycemic control. Whether basal blood glucose level modifies the risk of stroke in NVAF is still unclear. Purpose To evaluate the risk of ischemic stroke according to the presence of T2DM and admission blood glucose (ABG) level in patients with new-onset NVAF starting direct oral anticoagulants (DOACs). Methods We analyzed all consecutive patients with NVAF at our outpatient clinic from January to December 2018. The study population was constituted by 1014 patients with new-onset NVAF starting DOACs. Baseline characteristics were evaluated in the overall cohort whereas outcomes were assessed for 915 patients. The median follow-up time was 19.6±12.9 months. Results Overall, 50.3% were male with a mean age of 73.9±12.5 years. Diabetic NVAF patients were more frequently male (p=0.04) with higher prevalence of dyslipidemia (p&amp;lt;0.001), hypertension (p&amp;lt;0.001), severe renal impairment (p=0.02), peripheral vasculopathy (p=0.007) and history of myocardial infarction (p&amp;lt;0.001) compared to non-diabetic NVAF. Conversely, no differences were observed between subgroups in terms of age (p=0.8). Baseline blood glucose level was significantly higher in the diabetic NVAF population (160±67 mg/dL vs 119±39 mg/dL; p&amp;lt;0.001). As expected, the mean CHA2DS2-VASc score was significantly higher in diabetic NVAF compared to non-diabetic group (4.7±1.4 vs 3.2±1.5; p&amp;lt;0.001). During a 2 year-follow up period, we collected 27 (3.0%) ischemic stroke. As expected, the rates of stroke were significantly higher in diabetic NVAF (7.6% vs 2.3%, p&amp;lt;0.001). Also, the ABG was significantly greater in NVAF who had an ischemic stroke compared to others (160±68 mg/dL vs 119±39 mg/dL, p=0.005). The incidence of stroke was almost five-time greater in NVAF with ABG level major than 150 mg/dl (9.8% vs 1.9%, p&amp;lt;0.001). At multivariate Cox-regression model adjusted for age, sex and presence of T2DM, blood glucose level at admission was the only independent predictor of ischemic stroke at follow up (HR 1.01, 95% CI 1.001–1.02; p=0.03). Finally, another multivariate Cox-regression model, adjusted for the mean CHA2DS2-VASc score, showed that the ABG level still remained a strong independent predictor of ischemic stroke at follow up (HR 1.012, 95% CI 1.003–1.02; p=0.01). Conclusions Diabetic NVAF had a worse baseline profile and higher stroke risk compared to non-diabetic NVAF. Baseline blood glucose level was an independent predictor of stroke regardless of the presence of T2DM or stroke risk profile. These findings underline the role of basal blood glucose level as a potential stroke risk modifier and therefore emphasize the importance of its routine determination to better stratify the stroke risk in NVAF starting DOACs. Funding Acknowledgement Type of funding source: None