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Educational Impact on Apixaban Adherence in Atrial Fibrillation (the AEGEAN STUDY): A Randomized Clinical Trial.
Montalescot, G, Brotons, C, Cosyns, B, Crijns, HJ, D'Angelo, A, Drouet, L, Eberli, F, Lane, DA, Besse, B, Chan, A, et al
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(1):61-71
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Abstract
INTRODUCTION Adherence to non-vitamin-K oral anticoagulants (NOACs) may be lower than to vitamin K antagonists because NOACs do not require routine monitoring. OBJECTIVE We assessed the impact of an educational program on adherence and persistence with apixaban in patients with non-valvular atrial fibrillation (NVAF). METHODS Patients with NVAF eligible for NOACs with one or more stroke risk factor (prior stroke/transient ischemic attack, age ≥ 75 years, hypertension, diabetes, or symptomatic heart failure) were randomized (1:1) to standard of care (SOC) or SOC with additional educational (information booklet, reminder tools, virtual clinic access). The primary outcome was adherence to apixaban (2.5 or 5 mg twice daily) at 24 weeks. Patients receiving the educational program were re-randomized (1:1) to continue the program for 24 further weeks or to switch to secondary SOC. Implementation adherence and persistence were reassessed at 48 weeks. RESULTS In total, 1162 patients were randomized (SOC, 583; educational program, 579). Mean implementation adherence ± standard deviation (SD) at 24 weeks was 91.6% ± 17.1 for SOC and 91.9% ± 16.1 for the educational program arm; results did not differ significantly between groups at any time-point. At 48 weeks, implementation adherence was 90.4% ± 18.0, 90.1% ± 18.6, and 89.3% ± 18.1 for continued educational program, SOC, and secondary SOC, respectively; and corresponding persistence was 86.1% (95% confidence interval [CI] 81.3-89.7), 85.2% (95% CI 81.5-88.2), and 87.8% (95% CI 83.4-91.1). Serious adverse events were similar across groups. CONCLUSION High implementation adherence and persistence with apixaban were observed in patients with NVAF receiving apixaban. The educational program did not show additional benefits. CLINICAL TRIAL REGISTRATION This study is registered at ClinicalTrials.gov [NCT01884350].
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Susceptibility to HIV-1 integrase strand transfer inhibitors (INSTIs) in highly treatment-experienced patients who failed an INSTI-based regimen.
Santoro, MM, Fornabaio, C, Malena, M, Galli, L, Poli, A, Menozzi, M, Zazzi, M, White, KL, Castagna, A, ,
International journal of antimicrobial agents. 2020;(1):106027
Abstract
The aim of this study was to characterize the genotypic and phenotypic resistance profile to the integrase strand transfer inhibitor (INSTI) bictegravir (BIC) and other INSTIs in patients who previously failed twice-daily raltegravir (RAL)-based or twice-daily dolutegravir (DTG)-based regimens. Twenty-two samples were collected after failure on an INSTI-based regimen in 17 highly treatment-experienced patients with HIV-1 with multi-drug-resistant virus, recorded in the Italian PRESTIGIO registry. Genotypic resistance mutations and phenotypic susceptibility to INSTIs were detected by GeneSeqIN and PhenoSenseIN assays, respectively (Monogram Biosciences, San Francisco, CA, USA). The primary INSTI resistance substitutions E138A/K, G140S, Y143C/H/R, Q148H and N155H were detected in 14 of 22 samples and were associated with resistance to one or more INSTIs, with G140S+Q148H present in 11 of 22 samples. Of these 14 samples, all showed high levels of resistance to elvitegravir (EVG) and RAL. Two isolates contained L74M, E138K, G140S and Q148H, or L74M, T97A, S119T, E138K, G140S, Y143R and Q148H, and had high-level resistance to all INSTIs, including BIC and DTG. Intermediate resistance was reported for eight of 14 isolates for BIC and nine of 14 isolates for DTG. Overall, for the 14 INSTI-resistant isolates, the median fold-change values in phenotypic susceptibility were: BIC 3.2 [interquartile range (IQR) 0.6-66], DTG 6.3 (IQR 0.8->186), EVG >164 (IQR 2.6->164) and RAL >188 (IQR 2.7->197). In conclusion, the study findings supported the in-vitro activity of BIC and DTG against most isolates derived from highly treatment-experienced patients who failed INSTI regimens.
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Duration of fever and symptoms in children after treatment with baloxavir marboxil and oseltamivir during the 2018-2019 season and detection of variant influenza a viruses with polymerase acidic subunit substitutions.
Saito, R, Osada, H, Wagatsuma, K, Chon, I, Sato, I, Kawashima, T, Saito, T, Kodo, N, Ono, Y, Shimada, Y, et al
Antiviral research. 2020;:104951
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Abstract
We conducted a prospective, multicenter, non-randomized observational study to assess the duration of fever and symptoms of influenza A/H1N1pdm09 and A/H3N2 infected children < 19 years old treated with either baloxavir or oseltamivir. Additionally, these symptoms were investigated in association with pre- and post-baloxavir treatment-emergent polymerase acidic unit (PA) variants as compared to non-substituted viruses. Following receipt of informed consent, baloxavir was administered to 102 influenza A patients, and oseltamivir to 52 patients during the 2018-2019 influenza season in Japan. The average age was higher in the baloxavir treatment group compared to the oseltamivir treatment group (10.6 ± 2.7 versus 6.9 ± 2.9 years old, p < 0.01). The duration of fever and symptoms in baloxavir-treated A/H1N1pdm09 and A/H3N2-infected children did not differ from those in oseltamivir-treated groups (median 22.0, 11.8, 23.0, and 21.0 h, and median 114.5, 121.0, 123.0, and 122.0 h, respectively). One (1.2%) of 83 A/H3N2 patients possessed a PA/I38T substituted virus prior to treatment. The frequency of PA variants in post-treatment samples obtained 2-11 days after beginning of baloxavir was 12.5% (4/32) for A/H1N1pdm09 and 14.1% (9/64) for A/H3N2 when the total number of cases was used as the denominator, however, were 57.1% (4/7) and 33.3% (9/27) when PCR-positive cases at the time of second sampling was used as the denominator. The most frequent PA substitution was I38T (9), with E23K (1), I38K (1), I38M (1), and PA/I38S (1) also observed. The duration of fever and overall symptoms did not differ significantly following baloxavir treatment in individuals with PA variant viruses, non-substituted virus, or in those that were PCR negative at the second sampling (median 20, 24 and 11 h, and median 121, 115 and 121 h, respectively). Rebound of viral RNA load was observed in 13.5% (2/13) of PA variants but it was not associated with recurrence of fever and symptoms. Hence, prolonged fever or symptoms were not observed in children treated with baloxavir following emergence of PA variants, however, further studies are needed to evaluate the clinical impact of PA variants.
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Does the CHA2DS2-VASc scale sufficiently predict the risk of left atrial appendage thrombus in patients with diagnosed atrial fibrillation treated with non-vitamin K oral anticoagulants?
Michalska, A, Gorczyca, I, Chrapek, M, Kapłon-Cieślicka, A, Uziębło-Życzkowska, B, Starzyk, K, Jelonek, O, Budnik, M, Gawałko, M, Krzesiński, P, et al
Medicine. 2020;(25):e20570
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Abstract
The CHA2DS2-VASc scale does not include potential risk factors for left atrial appendage thrombus (LAAT) formation such as a form of atrial fibrillation (AF) and impaired kidney function. The real risk of thromboembolic complications in AF patients is still unclear as well as an optimal anticoagulant treatment in males with a CHA2DS2-VASc score of 1 and females with a CHA2DS2-VASc score of 2.The aim of this study was to compare the predictive value of the CHA2DS2-VASc scale and other scales to estimate the risk of LAAT formation in AF patients treated with non-vitamin K oral anticoagulants (NOACs) and to assess the prevalence of thrombi in patients at intermediate risk of stroke.The observational study included consecutive patients with a diagnosis of non-valvular AF treated with NOACs, admitted to 3 high-reference institutions between 2013 and 2018. All individuals underwent transoesophageal echocardiography before cardioversion or ablation.Out of 1163 enrolled AF patients (62.1% male, mean age 62 years) the LAAT had been detected in 50 individuals (4.3%). Among patients with LAAT, 1 patient (2.0%) was classified as a low-risk category, 9 (18.0%) were at intermediate-risk, and 40 (80.0%) were at high risk of thromboembolic complications according to CHA2DS2-VASc scale. All patients were treated with NOACs: 51.0% rivaroxaban, 47.1% dabigatran, and 1.9% apixaban.Patients at intermediate stroke-risk with detected LAAT had higher R2CHADS2 score (2.1 ± 1.2 vs 1.2 ± 0.8, P = .007), higher CHA2DS2-VASc-RAF score (6.4 ± 4.4 vs 3.7 ± 2.6, P = .027) and more often had an estimated glomerular filtration rate below 56 mL/min/1.73 m (44.4% vs 13.2%, P = .026) compared to patients without LAAT. The receiver operating characteristics revealed that the CHA2DS2-VASc-RAF scale had better predictive ability to distinguish between patients with and without LAAT in the study group than CHA2DS2-VASc (P = .0006), CHADS2 (P = .0006) and R2CHADS2 scale (P = .0140).The CHA2DS2-VASc scale should be supplemented with an assessment of renal function and form of AF to improve stroke risk estimation. The application of additional scales to estimate the risk of LAAT might be especially useful among males with a CHA2DS2-VASc score of 1 and females with a CHA2DS2-VASc score of 2.
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Perampanel tolerability in children and adolescents with focal epilepsy: Effects on behavior and executive functions.
Operto, FF, Pastorino, GMG, Mazza, R, Di Bonaventura, C, Matricardi, S, Verrotti, A, Carotenuto, M, Viggiano, A, Coppola, G, Elia, M
Epilepsy & behavior : E&B. 2020;(Pt A):106879
Abstract
OBJECTIVES Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist recently approved for focal and generalized epilepsies as an add-on therapy. It is well tolerated and effective as treatment of various pediatric epilepsy syndromes; PER does not seem to negatively affect the cognitive profile of children and adolescents, but its influence on executive functions is still to be assessed. METHODS Our sample included 37 children aged 12-18 years, with focal pharmacoresistant epilepsy already in therapy with 2 or 3 antiepileptic drug (AED); PER was added with 1 mg/week increments up to a dose of 2-4 mg/day. Changes in executive functions were assessed by the EpiTrack Junior test. Emotional and behavioral aspects were evaluated through the interview for parents Child Behavior Checklist (CBCL). Both tests were performed before taking PER and after 6 and 12 months of treatment. RESULTS After 12 months of PER in 22/30 patients, global score of the EpiTrack Junior test remained almost unchanged; in 7/30 patients, this score improved. The CBCL did not show significant changes in emotional or behavioral problems. CONCLUSIONS Adjunctive treatment with PER did not negatively affect executive functions that could also be improved. No emotional/behavioral negative effects have been reported, and this suggests a good tolerability in the middle/long term.
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A Study to Evaluate Doravirine Pharmacokinetics When Coadministered With Acid-Reducing Agents.
Khalilieh, SG, Yee, KL, Sanchez, RI, Fan, L, Vaynshteyn, K, Deschamps, K, Martell, M, Jordan, HR, Iwamoto, M
Journal of clinical pharmacology. 2019;(8):1093-1098
Abstract
Doravirine is a novel non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus type 1 infection. Because of potential concomitant administration with acid-reducing agents, a drug-interaction trial was conducted to evaluate the potential impact of these types of medications on doravirine pharmacokinetics. In an open-label, 3-period, fixed-sequence trial, healthy adult participants received the following: period 1, a single dose of doravirine 100 mg; period 2, coadministration of a single dose of doravirine 100 mg and an antacid (1600 mg aluminum hydroxide, 1600 mg magnesium hydroxide, and 160 mg simethicone); period 3, 40 mg pantoprazole once daily on days 1-5 coadministered with a single dose of doravirine 100 mg on day 5. There was a minimum 10-day washout between periods. Plasma samples for pharmacokinetic evaluation were collected, and safety was assessed. Fourteen participants (8 male, 6 female) were enrolled, and 13 completed the trial. Geometric mean ratios (90% confidence intervals) for doravirine AUC0-inf , Cmax , and C24 for doravirine + antacid/doravirine were 1.01 (0.92-1.11), 0.86 (0.74-1.01), and 1.03 (0.94-1.12), respectively, and for doravirine + pantoprazole/doravirine were 0.83 (0.76-0.91), 0.88 (0.76-1.01), and 0.84 (0.77-0.92), respectively. Doravirine was generally well tolerated administered alone or with either of the acid-reducing agents. Coadministration of an aluminum/magnesium-containing antacid or pantoprazole did not have a clinically meaningful effect on doravirine pharmacokinetics, supporting the use of acid-reducing agents with doravirine.
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Apixaban enhances endogenous fibrinolysis in patients with atrial fibrillation.
Spinthakis, N, Gue, Y, Farag, M, Srinivasan, M, Wellsted, D, Arachchillage, DRJ, Lip, GYH, Gorog, DA
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2019;(9):1297-1306
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AIMS: Approximately 20% of ischaemic stroke patients exhibit spontaneous arterial recanalization, attributable to endogenous fibrinolysis, which strongly relates to improved functional outcome. The impact of oral anticoagulants on endogenous fibrinolysis is unknown. Our aim was to test the hypothesis that apixaban enhances endogenous fibrinolysis in non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS In a prospective cross-sectional analysis, we compared endogenous fibrinolysis in NVAF patients (n = 180) taking aspirin, warfarin, or apixaban. In a prospective longitudinal study, patients were tested before and after apixaban (n = 80). Endogenous fibrinolysis was assessed using the Global Thrombosis Test (GTT) and thromboelastography (TEG). Endogenous fibrinolysis [measured by GTT lysis time (LT)] was shorter on apixaban compared with warfarin or aspirin [median 1850 (IQR 1591-2300) vs. 2758 (2014-3502) vs. 2135 (1752-2463) s, P < 0.0001]. Among TEG indices, a small but significant difference in clot lysis time (CLT) was observed [apixaban 60.0 (45.0-61.0) vs. warfarin 61.0 (57.0-62.0) vs. aspirin 61.0 (59.0-61.0) min, P = 0.036]. Apixaban improved endogenous fibrinolysis measured using the GTT [LT pre-treatment 2204 (1779-2738) vs. on-treatment 1882 (1607-2374) s, P = 0.0003], but not by using TEG. Change in LT (ΔLT) with apixaban correlated with baseline LT (r = 0.77, P < 0.0001). There was weak correlation between ΔLT and ΔCLT in response to apixaban (r = 0.28, P = 0.02) and between on-apixaban LT and CLT (r = 0.25, P = 0.022). CONCLUSION Apixaban enhances endogenous fibrinolysis, with maximal effect in those with impaired fibrinolysis pre-treatment. Apixaban-treated patients exhibit more favourable fibrinolysis profiles than those taking warfarin or aspirin. Whether apixaban may confer additional thrombotic risk reduction in NVAF patients with impaired fibrinolysis, compared to warfarin, merits further study.
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Patient characteristics and stroke and bleeding events in nonvalvular atrial fibrillation patients treated with apixaban and vitamin K antagonists: a Spanish real-world study.
Ramagopalan, SV, Sicras-Mainar, A, Polanco-Sanchez, C, Carroll, R, de Bobadilla, JF
Journal of comparative effectiveness research. 2019;(14):1201-1212
Abstract
Aim: To compare the risk of stroke, systemic thromboembolism and bleeding, in patients initiating apixaban or acenocoumarol for the treatment of nonvalvular atrial fibrillation. Methods: An observational, retrospective study was performed using medical records of patients who initiated apixaban or acenocoumarol between 2015 and 2017. Propensity score matching was used to match patients; stroke, systemic thromboembolism, major and minor bleeding events were compared between the matched patients. Results: Patients who were prescribed apixaban had a lower rate of systemic embolism/stroke (hazard ratio [HR] = 0.54; 95% CI: 0.38-0.78; p = 0.001), minor bleeding (HR = 0.64; 95% CI: 0.52-0.79; p < 0.001) and major bleeding (HR = 0.51; 95% CI: 0.37-0.72; p < 0.001). Conclusion: Patients prescribed apixaban for the treatment of nonvalvular atrial fibrillation had lower rates of thromboembolic events and minor/major bleeding than patients on acenocoumarol.
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Apixaban versus warfarin in evaluation of progression of atherosclerotic and calcified plaques (prospective randomized trial).
Win, TT, Nakanishi, R, Osawa, K, Li, D, Susaria, SS, Jayawardena, E, Hamal, S, Kim, M, Broersen, A, Kitslaar, PH, et al
American heart journal. 2019;:129-133
Abstract
Warfarin has been showed to increase vascular calcification. Apixaban, a direct factor Xa inhibitor, has no interaction with vitamin K and its effect on coronary plaques is unknown. We randomized and compared warfarin and apixaban on progression of coronary atherosclerotic plaques measured by coronary computed tomographic angiography in 66 subjects with non-valvular atrial fibrillation over the period of one-year follow up. There was significant higher total, calcified and low attenuation plaque volume in the group randomized to warfarin as compared to apixaban (all P < .05). Greater volume of total (β2 = 28.54; P = .03), low attenuation plaque (β2 = 3.58; P = .02) and calcified (β2 = 14.10; P = .005) plaque progression was observed in the VKA_group.
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Hospitalization Among Patients With Atrial Fibrillation and a Recent Acute Coronary Syndrome or Percutaneous Coronary Intervention Treated With Apixaban or Aspirin: Insights From the AUGUSTUS Trial.
Vora, AN, Alexander, JH, Wojdyla, DM, Aronson, R, Granger, CB, Darius, H, Windecker, S, Mehran, R, Averkov, O, Budaj, A, et al
Circulation. 2019;(23):1960-1963