Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care.

Factor Xa-inhibitor apixaban is an oral anticoagulant prescribed in atrial fibrillation (AF) for stroke prevention. Its pharmacokinetic profile is known to be affected by cytochrome P450 (CYP)3A metabolism, while it is also a substrate of the efflux transporters ATP-binding cassette (ABC)B1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein, BCRP). In this study, we assessed the impact of interacting medication and pharmacogenetic variation to better explain apixaban concentration differences among 358 Caucasian AF patients. Genotyping (ABCG2, ABCB1, CYP3A4*22, CYP3A5*3) was performed by TaqMan assays, and apixaban quantified by mass spectrometry. The typical patient was on average 77.2 years old, 85.5 kg, and had a serum creatinine of 103.1 µmol/L. Concomitant amiodarone, an antiarrhythmic agent and moderate CYP3A/ABCB1 inhibitor, the impaired-function variant ABCG2 c.421C > A, and sex predicted higher apixaban concentrations when controlling for age, weight and serum creatinine (multivariate regression; R2 = 0.34). Our findings suggest that amiodarone and ABCG2 genotype contribute to interpatient apixaban variability beyond known clinical factors.

Pain management in adult patients with sickle cell disease in the emergency department: how does current practice compare with existing standards of care?

PURPOSE: Sickle cell disease (SCD) is an inherited blood disorder with a natural course punctuated by acute complications including painful vaso-occlusive episodes. The objectives were: (1) to determine what proportion of patients with SCD receive opioids within 30 min of triage as recommended by the current clinical recommendations and quality standard; and (2) to identify facilitators to timely opioid administration for patients with SCD. METHODS: This was a retrospective observational study. The primary outcome was the proportion of visits in which patients received opioid analgesia within 30 min of triage. Secondary outcomes were time in minutes from triage to any analgesic administration and time from triage to first opioid administration. Patient demographics and ED encounter characteristics were included as potential associated variables. RESULTS: There were 236 patient visits (by 103 patients) that met inclusion criteria. Patients received opioid analgesia within 30 min of triage in only 5.2% of visits. The median time from triage to opioid analgesia was 80 (IQR = 49.0, 125.5) minutes. Using an order set and receiving opioid analgesia prior to physician assessment were both associated with shorter times to opioid analgesia. CONCLUSION: Existing recommendations are that opioid analgesia be provided within 30 min of triage for patients with SCD and VOEs. Our data show this target is rarely met, even in a department in which SCD VOEs are a common presenting concern. The association of earlier opioid analgesia with order set use and administration prior to physician assessment highlights potential avenues for improving time to analgesia.

RéSUMé: OBJECTIF: La drépanocytose (ou l'anémie falciforme) est une maladie héréditaire du sang dont l'évolution naturelle est ponctuée de complications aiguës, notamment des épisodes vaso-occlusifs douloureux. Les objectifs étaient : (1) de déterminer quelle proportion de patients atteints de drépanocytose reçoivent des opioïdes dans les 30 minutes suivant le triage, comme le recommandent les recommandations cliniques et la norme de qualité actuelles ; et (2) d'identifier les facteurs facilitant l'administration rapide d'opioïdes aux patients atteints de drépanocytose. MéTHODES: Il s'agissait d'une étude observationnelle rétrospective. Le critère de jugement principal était la proportion de visites au cours desquelles les patients ont reçu une analgésie opioïde dans les 30 minutes suivant le triage. Les critères de jugement secondaires étaient le temps en minutes écoulé entre le triage et l'administration de tout analgésique et le temps écoulé entre le triage et la première administration d'opioïdes. Les caractéristiques démographiques des patients et les caractéristiques des rencontres aux urgences ont été incluses comme variables potentiellement associées. RéSULTATS: Il y a eu 236 visites de patients (par 103 patients) qui répondaient aux critères d'inclusion. Les patients ont reçu une analgésie opioïde dans les 30 minutes suivant le triage dans seulement 5,2 % des visites. Le temps médian écoulé entre le triage et l'analgésie opioïde était de 80 (IQR = 49,0, 125,5) minutes. L'utilisation d'un ensemble de commandes et la réception d'une analgésie opioïde avant l'évaluation du médecin étaient toutes deux associées à des temps plus courts d'analgésie opioïde. CONCLUSIONS: Les recommandations existantes sont que l'analgésie opioïde soit fournie dans les 30 minutes suivant le triage pour les patients atteints de drépanocytose et d'EVO. Nos données montrent que cet objectif est rarement atteint, même dans un service où les EVO de la drépanocytose sont une préoccupation courante. L'association d'une analgésie opioïde plus précoce avec l'utilisation d'un ensemble de commandes et l'administration avant l'évaluation du médecin met en évidence des pistes potentielles pour améliorer le temps d'analgésie.

Association of Sex With Stroke and Bleeding Risk of Apixaban and Rivaroxaban in Elderly Atrial Fibrillation Patients Using Propensity Score Weights.

BACKGROUND: Evidence from clinical trials suggests a differential effect of sex on the effectiveness and safety of direct oral anticoagulants (DOACs) for stroke prophylaxis in atrial fibrillation (AF). METHODS: This population-based cohort study examined the independent effect of sex on hemorrhage and ischemic stroke in 23,884 patients (55% females; age ≥ 66 years) with AF starting apixaban or rivaroxaban treatment in Ontario, Canada. Patients were followed for 90 days after their DOAC prescription. Using female sex as the exposure of interest, differences in baseline characteristics were balanced between sexes using inverse probability weights based on propensity scores. Applying weighted modified Poisson regression, risk ratios (RRs) were estimated for major hemorrhage, ischemic stroke/systemic embolism/transient ischemic attack (hereafter stroke), myocardial infarction, and all-cause mortality, with males as a reference. RESULTS: Females were older, had higher predicted stroke risk (based on CHADS2 score), and had fewer comorbidities than did males. Males had a higher prevalence of coronary artery disease, diabetes, and cancer, and similar predicted bleeding risk (based on HAS-BLED score). After weighting, baseline characteristics were well balanced. The 90-day risks for hemorrhage (RR 0.96; 95% confidence interval [CI] 0.80-1.15; P = 0.69) and stroke (RR 1.01; 95% CI 0.86-1.19; P = 0.94) were similar between sexes, which remained true when assessing each DOAC separately by dosing regimen. Compared to males, females had a lower risk for myocardial infarction (RR 0.66; 95% CI 0.52-0.84; P = 0.0008), and for all-cause mortality (RR 0.76; 95% CI 0.67-0.87; P < 0.0001). CONCLUSIONS: Our findings do not suggest an association of sex with the 90-day risk of hemorrhage or ischemic stroke in older AF patients prescribed apixaban or rivaroxaban.

CONTEXTE: Les données probantes issues des essais cliniques donnent à penser que l'efficacité et l'innocuité des anticoagulants oraux directs (AOD) utilisés pour la prophylaxie des accidents vasculaires cérébraux (AVC) dans un contexte de fibrillation auriculaire (FA) varient selon le sexe du patient. MÉTHODOLOGIE: Cette étude de cohorte populationnelle a examiné l'effet indépendant du sexe sur l'hémorragie et l'AVC ischémique chez 23 884 patients (55 % de femmes; âge ≥ 66 ans) atteints de FA ayant amorcé un traitement par l'apixaban ou le rivaroxaban en Ontario (Canada). Les patients ont été suivis pendant 90 jours après avoir reçu une ordonnance d'AOD. Le sexe féminin constituant l'exposition d'intérêt, les différences quant aux caractéristiques initiales ont été réparties de façon équilibrée entre les sexes au moyen d'une pondération par probabilité inverse reposant sur le score de propension. La régression de Poisson modifiée avec pondération a servi à estimer les rapports de risques (RR) d'hémorragie majeure, d'AVC ischémique/d'embolie systémique/d'accident ischémique transitoire (ci-après AVC), d'infarctus du myocarde et de mortalité toutes causes confondues, les hommes formant la population de référence. RÉSULTATS: Les femmes étaient plus âgées, présentaient un risque prévu d'AVC plus élevé (d'après le score CHADS2) et présentaient moins de maladies concomitantes que les hommes. Les hommes présentaient une prévalence plus élevée de coronaropathie, de diabète et de cancer, et un risque prévu d'hémorragie similaire (compte tenu du score HAS-BLED). Après la pondération, la répartition des caractéristiques initiales des patients était bien équilibrée. Le risque d'hémorragie (RR : 0,96; intervalle de confiance [IC] à 95 % : 0,80-1,15; P = 0,69) et d'AVC (RR : 1,01; IC à 95 % : 0,86-1,19; P = 0,94) sur 90 jours était similaire pour les deux sexes, et il en était de même lorsque chaque AOD a été évalué séparément en fonction du schéma posologique. Par rapport aux hommes, les femmes présentaient un risque plus faible d'infarctus du myocarde (RR : 0,66; IC à 95 % : 0,52-0,84; P = 0,0008) et de mortalité toutes causes confondues (RR : 0,76; IC à 95 % : 0,67-0,87; P < 0,0001). CONCLUSIONS: Nos résultats ne laissent présumer aucune association entre le sexe et le risque d'hémorragie ou d'AVC ischémique sur une période de 90 jours chez les patients âgés atteints de FA à qui l'apixaban ou le rivaroxaban sont prescrits.

The Role of Next-Generation Sequencing in Pharmacogenetics and Pharmacogenomics.

Inherited genetic variations in pharmacogenetic loci are widely acknowledged as important determinants of phenotypic differences in drug response, and may be actionable in the clinic. However, recent studies suggest that a considerable number of novel rare variants in pharmacogenes likely contribute to a still unexplained fraction of the observed interindividual variability. Next-generation sequencing (NGS) represents a rapid, relatively inexpensive, large-scale DNA sequencing technology with potential relevance as a comprehensive pharmacogenetic genotyping platform to identify genetic variation related to drug therapy. However, many obstacles remain before the clinical use of NGS-based test results, including technical challenges, functional interpretation, and strict requirements for diagnostic tests. Advanced computational analyses, high-throughput screening methodologies, and generation of shared resources with cell-based and clinical information will facilitate the integration of NGS data into candidate genotyping approaches, likely enhancing future drug phenotype predictions in patients.

Targeted next generation sequencing as a tool for precision medicine.

BACKGROUND: Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response. METHODS: A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms. RESULTS: Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy. CONCLUSIONS: PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.

Apixaban Concentrations with Lower than Recommended Dosing in Older Adults with Atrial Fibrillation.

OBJECTIVES: Lower than recommended doses of direct-acting oral anticoagulants are often prescribed to older adults with nonvalvular atrial fibrillation (NVAF). Our goal was to determine the consequences of lower than recommended dosing on plasma apixaban concentrations during the clinical care of older adults with NVAF. DESIGN: Convenience sample of patients receiving anticoagulation during 2017. SETTING: Academic medical center. PARTICIPANTS: Stable adults older than 65 years with NVAF receiving apixaban on a chronic basis. MEASUREMENTS: Patient age, weight, creatinine, co-medications, and apixaban concentrations. RESULTS: A total of 110 older adults with NVAF (mean age = 80.4 y; range = 66-100 y with 45% women) were studied. Overall, 48 patients received recommended dosing of 5 mg twice/day, and 42 received lower than recommended dosing. One patient in each category had concentrations below the expected 5% to 95% range at time of peak concentrations. Differences in proportion of apixaban concentrations within or outside expected ranges were not significant between patients receiving lower than recommended doses and those dosed as recommended at 5 mg twice/day (P = .35). However, in patients dosed as recommended with 5 mg twice/day, four had concentrations above the 5% to 95% range for peak levels expected at 3 to 4 hours after dosing; in two, this occurred around the midpoint of the dosing interval. Twenty patients received 2.5 mg twice/day as recommended. One-third had apixaban concentrations higher than expected peak concentrations compared with the clinical trials, and more than two-thirds had levels above the reported median for peak concentrations. CONCLUSIONS: Apixaban concentrations in older adults with NVAF seen clinically were higher than expected based on clinical trial data. The findings raise questions about the optimal dosing of apixaban in older adults with NVAF encountered outside of clinical trials and suggest a role for the monitoring of apixaban concentrations during care of patients that differ from those in randomized trials or when considering dosing outside of published guidelines. J Am Geriatr Soc 67:1902-1906, 2019.

Interpatient Variation in Rivaroxaban and Apixaban Plasma Concentrations in Routine Care.

BACKGROUND: Direct-acting oral anticoagulants (DOACs) are widely prescribed for stroke prevention in patients with atrial fibrillation (AF). An important advantage of DOACs is that routine monitoring of an anticoagulation response is not necessary. Nevertheless, because of their mechanism of action, a DOAC anticoagulation effect can be inferred based on the observed plasma concentration. However, there is a paucity of data relating to observed interpatient variation in DOAC plasma concentrations in the postmarket clinical setting. METHODS: We determined rivaroxaban and apixaban plasma concentrations in patients with AF during routine clinic visits. RESULTS: Among 243 patients (rivaroxaban, n = 94; apixaban, n = 149) enrolled in this study, a 60- and 50-fold interpatient variation in plasma concentration was observed for rivaroxaban and apixaban, respectively. Approximately 12% of patients receiving rivaroxaban and 13% of patients receiving apixaban exceeded the 95th percentile for predicted maximum plasma concentration observed in clinical trials. CONCLUSIONS: In this routine-care setting, rivaroxaban and apixaban plasma concentrations tended to be more variable than those observed in clinical trials. Identification of additional clinical and molecular determinants that more fully predict patients at risk for excessively high or low DOAC concentrations may enable a more precise DOAC dosing regimen for the individual patient.