Computerized clinical decision support to improve stroke prevention therapy in primary care management of atrial fibrillation: a cluster randomized trial.

BACKGROUND: Despite guidelines supporting antithrombotic therapy use in atrial fibrillation (AF), under-prescribing persists. We assessed whether computerized clinical decision support (CDS) would enable guideline-based antithrombotic therapy for AF patients in primary care. METHODS: This cluster randomized trial of CDS versus usual care (UC) recruited participants from primary care practices across Nova Scotia, following them for 12 months. The CDS tool calculated bleeding and stroke risk scores and provided recommendations for using oral anticoagulants (OAC) per Canadian guidelines. RESULTS: From June 14, 2014 to December 15, 2016, 203 primary care providers (99 UC, 104 CDS) with access to high-speed Internet were recruited, enrolling 1,145 eligible patients (543 UC, 590 CDS) assigned to the same treatment arm as their provider. Patient mean age was 72.3 years; most were male (350, 64.5% UC, 351, 59.5% CDS) and from a rural area (298, 54.9% UC, 315, 53.4% CDS). At baseline, a higher than anticipated proportion of patients were receiving guideline-based OAC therapy (373, 68.7% UC, 442, 74.9% CDS; relative risk [RR] 0.97 (95% confidence interval [CI], 0.87-1.07; P = .511)). At 12 months, prescription data were available for 538 usual care and 570 CDS patients, and significantly more CDS patients were managed according to guidelines (415, 77.1% UC, 479, 84.0% CDS; RR 1.08 (95% CI, 1.01-1.15; P = .024)). CONCLUSION: Notwithstanding high baseline rates, primary care provider access to the CDS over 12 months further optimized the prescribing of OAC therapy per national guidelines to AF patients potentially eligible to receive it. This suggests that CDS can be effective in improving clinical process of care. TRIAL REGISTRATION: Clinical Trials NCT01927367. https://clinicaltrials.gov/ct2/show/NCT01927367?term=NCT01927367&draw=2&rank=1.

Resource use and cost associated with computerized decision support system and usual care in managing patients with atrial fibrillation: analysis of IMPACT-AF randomized trial data.

BACKGROUND: IMPACT-AF is a prospective, randomized, cluster design trial comparing atrial fibrillation (AF) management with a computerized decision support system (CDS) to usual care (control) in the primary care setting of Nova Scotia, Canada. The objective of this analysis was to compare the resource use and costs between CDS and usual care groups. METHODS: Case costing data, 12-month self-administered questionnaires, and monthly diaries from IMPACT-AF were used in this analysis. Descriptive statistics were used to compare costs and resource use between groups. All costs are presented in 2021 Canadian dollars and cover the 12-month period of participation in the study. RESULTS: A total of 1,145 patients enrolled in the trial. Case costing data were available for 466 participants (41.1%), 12-month self-administered questionnaire data for 635 participants (56.0%) and monthly diary data for 223 participants (19.7%). Emergency department visits and hospitalizations comprised the most expensive component of AF care. Across all three datasets, there were no statistically significant differences in costs or resource use between CDS and usual care groups. CONCLUSIONS: Although there were no significant differences in resource use or costs among CDS and usual care groups in the IMPACT-AF trial, this study provides insight into the methodology and practical challenges of collecting economic data alongside a trial. REGISTRATION: Clinicaltrials.gov (registration number: NCT01927367, date of registration: 2013-08-20).

Rhythm Control Vs Rate Control in a Contemporary Ambulatory Atrial Fibrillation Cohort: Post Hoc Analysis of the IMPACT-AF Trial.

Background: We examined the characteristics and outcomes in a contemporary ambulatory population of patients with atrial fibrillation (AF), comparing rate control with rhythm control. Methods: This is a post hoc analysis of a cluster-randomized trial (Integrated Management Program Advancing Community Treatment of Atrial Fibrillation [IMPACT-AF]) in ambulatory AF patients from 2016 to 2018, which compared use of a clinical decision support tool for general practitioners to usual care. This analysis compared patients managed with rate vs rhythm control, at entry into the study. Outcomes included AF-related emergency department (ED) visits, unplanned cardiovascular hospitalizations, and bleeding events at 12 months. Results: A total of 870 patients were included in this analysis, 99 (11.4%) in the rhythm-control group, and 40% women. In the rhythm-control group, the mean age was younger (70 ± 11.4 vs 72.7 ± 9.5 years, P = 0.03), a higher number were paroxysmal (80% vs 43%, P < 0.001), and CHADS2 scores were lower. The rate of AF-related ED visits was higher in the rhythm-control group (17.2 vs 7.3%, P = 0.003), and repeat visits (rate ratio 3.03, 95% confidence interval [1.99-4.52], P < 0.001). The number of repeat ED visits was independently associated with female sex and being in the rhythm-control group. Conclusions: Both rate- and rhythm-control patients have recurrent ED visits, with a higher rate in patients treated with rhythm control. These findings are observational, but taken in the context of current guidelines could help develop further therapies aimed at improving symptom burden in both rhythm- and rate-control patients to broadly improve healthcare utilization in the AF population.

Contexte: Nous avons examiné les caractéristiques et le devenir de patients ambulatoires contemporains atteints de fibrillation auriculaire (FA) dans le cadre d'une comparaison entre la maîtrise de la fréquence cardiaque et la maîtrise du rythme cardiaque. Méthodologie: Nous avons effectué une analyse a posteriori d'un essai à répartition aléatoire par grappes ( I ntegrated M anagement P rogram A dvancing C ommunity T reatment of A trial F ibrillation [IMPACT-AF]) mené de 2016 à 2018 chez des patients ambulatoires atteints de FA en vue de comparer un outil d'aide à la décision clinique destiné aux omnipraticiens avec les soins habituels. Notre analyse a permis d'établir une comparaison entre les patients pris en charge par une maîtrise de la fréquence cardiaque et ceux pris en charge par une maîtrise du rythme cardiaque lors de leur inscription à l'essai. Les paramètres d'évaluation comprenaient les consultations aux urgences liées à la FA, les hospitalisations imprévues ayant des causes cardiovasculaires et les épisodes hémorragiques à 12 mois. Résultats: Au total, 870 patients ont été inclus dans cette analyse; 99 (11,4 %) faisaient partie du groupe pris en charge par une maîtrise du rythme cardiaque, et 40 % étaient de femmes. Dans le groupe pris en charge par une maîtrise du rythme cardiaque, l'âge moyen était moindre (70 ± 11,4 ans vs 72,7 ± 9,5 ans, P = 0,03), un plus grand nombre de patients présentaient une FA paroxystique (80 % vs 43 %, P < 0,001) et les scores CHADS2 étaient moins élevés. Le taux de consultations aux urgences liées à la FA était plus élevé dans le groupe pris en charge par une maîtrise du rythme cardiaque (17,2 vs 7,3 %, P = 0,003) tout comme le taux de consultations répétées aux urgences (rapport des taux de 3,03, intervalle de confiance à 95 % de 1,99 à 4,52, P < 0,001). Le nombre de consultations répétées aux urgences était indépendamment associé au sexe féminin et à l'inclusion dans le groupe pris en charge par une maîtrise du rythme cardiaque. Conclusions: Des consultations répétées aux urgences ont été notées tant chez les patients pris en charge par une maîtrise de la fréquence cardiaque que chez ceux pris en charge par une maîtrise du rythme cardiaque quoique plus fréquemment chez ces derniers. Nos constats sont de type observationnel. Néanmoins, dans le contexte des lignes directrices actuelles, ils pourraient contribuer à la mise au point d'autres traitements visant à atténuer le fardeau des symptômes tant chez les patients pris en charge par une maîtrise du rythme cardiaque que chez ceux pris en charge par une maîtrise de la fréquence cardiaque et ainsi permettre globalement une meilleure utilisation des soins de santé chez les patients atteints de FA.

AWAREness of Diagnosis and Treatment of Chronic Kidney Disease in Adults With Type 2 Diabetes (AWARE-CKD in T2D).

OBJECTIVES: Diabetes remains the leading contributor to the development of chronic kidney disease (CKD) and end-stage kidney disease, emphasizing the urgency of identifying barriers to early diagnosis and intervention. The primary objective of this study was to describe the awareness, values and preferences of physicians and patients with respect to managing CKD among patients with type 2 diabetes (T2D). METHODS: A cross-sectional survey was conducted among physicians and adult patients with T2D and CKD based on estimated glomerular filtration rate and urine albumin-to-creatinine ratio (uACR) measured within 1 year. Physicians were recruited from email networks across Canada, excluding Alberta, and patients were recruited from LMC Diabetes and Endocrinology clinics in Ontario and Quebec. Two separate surveys were developed by a steering committee. Survey responses from 160 physicians (60 general practitioners, 50 endocrinologists and 50 nephrologists) and 169 patients were analyzed descriptively. RESULTS: Gaps in physician care included insufficient use of uACR screening, limited knowledge or use of Kidney Disease Improving Global Outcomes (KDIGO) and KidneyWise resources and lower than expected prescription of recommended therapies. The patient data showed 51.5% of patients were unaware of a CKD diagnosis, and 75.6% of patients who received a prior CKD diagnosis would have preferred an earlier diagnosis. CONCLUSIONS: The results highlight several opportunities for improving CKD in T2D management. More education and clarity are needed for physicians interpreting uACR levels that should prompt a referral to a nephrologist, and additional understanding of kidney risk progression is vital for patients.

Prevalence of Chronic Kidney Disease in Type 2 Diabetes: The Canadian REgistry of Chronic Kidney Disease in Diabetes Outcomes (CREDO) Study.

PURPOSE: Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is associated with an elevated risk of end-stage kidney disease, cardiovascular disease (CVD), and death. As the breadth of treatment options for CKD in patients with T2D (CKD in T2D) continues to expand, an analysis of the current use of therapies and cardiovascular and kidney outcomes is necessary. The objectives of the study were to assess the prevalence of CKD in T2D among a contemporary cohort of patients, to describe patient characteristics and treatment patterns, and to examine health care practitioner rationale for initiating therapies. METHODS: The study was a retrospective, observational study (module A) with a prospective component (module B). For module A, sociodemographic data, medical history, prescription information, and laboratory investigations for patients seen by an endocrinologist in 2019 were retrieved from the LMC Diabetes Registry. Module B included a subset of patients for health care practitioner surveys to understand rationale for administering angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), steroidal mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), and glucagon-like peptide 1 receptor agonists (GLP-1RAs). Descriptive analyses were conducted. FINDINGS: The study included 14,873 patients (59% male). Mean patient age was 67 years, mean body mass index was 31 kg/m2, and mean glycosylated hemoglobin was 7.6%. Mean diabetes duration was 16 years. The prevalence of CKD in patients with T2D was 47.9%. Common comorbidities were hypertension (76%), dyslipidemia (71%), and obesity (51%). CVD was reported in 22%. The proportion of kidney medications and emerging therapies varied, with 76% of patients using an ACEi or ARB, 48% using an SGLT2i, 30% using a GLP-1RA, and 3% using a steroidal MRA. In module B, physicians identified that ACEis/ARBs, SGLT2is, GLP-1RAs, or steroidal MRAs were administered to primarily treat CKD in 33%, 12%, 0%, and 4% of the patients (n = 500), respectively. IMPLICATIONS: These findings improved our understanding of the current landscape and treatment patterns of CKD inT2D and highlighted the importance of considering treatments that will provide a comprehensive strategy for cardiovascular and kidney risk protection. Despite the high prevalence of CKD and comorbidities reported in a large, Canadian T2D specialist population, ACEis/ARBs, SGLT2is, and GLP-1RAs were underused, especially considering recent clinical trial reports. The relative use of steroidal MRAs was expectedly low. With an immense burden of CKD progression and among patients with T2D, the use of treatments that provide a comprehensive strategy for kidney protection will transform the landscape of CKD in T2D. ClinicalTrials.gov identifier: NCT04445181.

Lessons learned from Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF): a pragmatic clinical trial of computerized decision support in primary care.

BACKGROUND: Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) was a pragmatic, cluster randomized trial assessing the effectiveness of a clinical decision support (CDS) tool in primary care, Nova Scotia, Canada. We evaluated if CDS software versus Usual Care could help primary care providers (PCPs) deliver individualized guideline-based AF patient care. METHODS: Key study challenges including CDS development and implementation, recruitment, and data integration documented over the trial duration are presented as lessons learned. RESULTS: Adequate resources must be allocated for software development, updates and feasibility testing. Development took longer than projected. End-user feedback suggested network access and broadband speeds impeded uptake; they felt further that the CDS was not sufficiently user-friendly or efficient in supporting AF care (i.e., repetitive alerts). Integration across e-platforms is crucial. Intellectual property and other issues prohibited CDS integration within electronic medical records and provincial e-health platforms. Double login and data entry were impediments to participation or reasons for provider withdrawal. Data integration challenges prevented easy and timely data access, analysis, and reporting. Primary care study recruitment is resource intensive. Altogether, 203 PCPs and 1145 of their patients participated, representing 25% of eligible providers and 12% of AF patients in Nova Scotia, respectively. The most effective provider recruitment strategy was in-office, small group lunch-and-learns. PCPs with past research experience or who led patient consent were top recruiters. The study office played a pivotal role in achieving patient recruitment targets. CONCLUSIONS: A rapid growth in healthcare data is leading to widespread development of CDS. Our experience found practical issues to address for such applications to succeed. Feasibility testing to assess the utility of any healthcare CDS prior to implementation is recommended. Adequate resources are necessary to support successful recruitment for future pragmatic trials. CDS tools that integrate multiple co-morbid guidelines across eHealth platforms should be pursued. TRIAL REGISTRATION: ClinicalTrials.gov NCT01927367. Registered on August 22, 2013.

Patient-Reported Outcomes and Patient-Reported Experience of Patients With Atrial Fibrillation in the IMPACT-AF Clinical Trial.

Background The IMPACT-AF (Integrated Management Program Advancing Community Treatment of Atrial Fibrillation) trial is a prospective, randomized, cluster design trial comparing atrial fibrillation management with a computerized clinical decision support system with usual care (control) in the primary care setting of Nova Scotia, Canada. The objective of this analysis was to assess and compare patient-reported health-related quality of life and patient-reported experience with atrial fibrillation care between clinical decision support and control groups. Methods and Results Health-related quality of life was measured using the EuroQol 5-dimensional 5-level scale, whereas patient-reported experience was assessed using a self-administered satisfaction questionnaire, both assessed at baseline and 12 months. Health utilities were calculated using the Canadian EuroQol 5-dimensional 5-level value set. Descriptive statistics and generalized estimating equations were used to compare between groups. Among 1145 patients enrolled in the trial, 717 had complete EuroQol 5-dimensional 5-level data at baseline. The mean age of patients was 73.53 years, and 61.87% were men. Mean utilities at baseline were 0.809 (SD, 0.157) and 0.814 (SD, 0.157) for clinical decision support and control groups, respectively. At baseline, most patients in both groups reported being "very satisfied" with the care received for their atrial fibrillation. There were no statistically significant differences in utility scores or patient satisfaction between groups at 12 months. Conclusions Health-related quality of life of patients remained stable over 12 months, and there was no significant difference in patient satisfaction or utility scores between clinical decision support and control groups. Registration information clinicaltrials.gov. Identifier: NCT01927367.

Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF): A cluster randomized trial of a computerized clinical decision support tool.

BACKGROUND: Clinical decision support (CDS) tools designed to digest, filter, organize, and present health data are becoming essential in providing clinical and cost-effective care. Many are not rigorously evaluated for benefit before implementation. We assessed whether computerized CDS for primary care providers would improve atrial fibrillation (AF) management and outcomes as compared to usual care. METHODS: Overall, 203 primary care providers were recruited, randomized, and then cluster stratified by location (urban, rural) to usual care (n = 99) or CDS (n = 104). Providers recruited 1,145 adult patients with AF to participate. The intervention was access to an evidenced-based, point-of-care computerized CDS designed to support guideline-based AF management. The primary efficacy outcome was a composite of unplanned cardiovascular hospitalizations and AF-related emergency department visits; the primary safety outcome was major bleeding, both over 1 year. Patients were the units of intention-to-treat analysis. RESULTS: No significant effects on the primary efficacy (130 control, 118 CDS, hazard ratio: 0.98 [95% CI 0.71-1.37], P = .926) or safety (n = 7 usual care, n = 8 CDS, 1.3% total, P = .939) outcomes were observed at 12-months. CONCLUSIONS: IMPACT-AF rigorously assessed a CDS tool in a highly representative sample of primary care providers and their patients; however, no impact on outcomes was observed. Considering the proliferating use of CDS applications, this study highlights the need for efficacy assessments prior to adoption and clinical implementation.

Optimizing primary care management of atrial fibrillation: The rationale and methods of the Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) study.

The Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) is an investigator designed, prospective, randomized, un-blinded, cluster design clinical trial, conducted in the primary care setting of Nova Scotia, Canada. Its aim is to evaluate whether an electronic Clinical Decision Support System (CDSS) designed to assist both practitioners and patients with evidence-based management strategies for Atrial Fibrillation (AF) can improve process of care and outcomes in a cost-efficient manner as compared to usual AF care. At least 200 primary care providers are being recruited and randomized at the level of the practice to control (usual care) or intervention (eligible to access to CDSS) cohorts. Over 1,000 patients of participating providers with confirmed AF will be managed per their provider's respective assignment. The targeted primary clinical outcome is a reduction in the composite of unplanned cardiovascular (CV) or major bleeding hospitalizations and AF-related emergency department visits. Secondary clinical outcomes, process of care, patient and provider satisfaction as well as economic costs at the system and patient levels are being examined. The trial is anticipated to report in 2018.

Nonvitamin K antagonist oral anticoagulant use in patients with renal impairment.

The nonvitamin K antagonist oral anticoagulants (NOACs), also referred to as direct oral anticoagulants (DOACs), dabigatran, apixaban, edoxaban, and rivaroxaban, have emerged as effective alternatives to vitamin K antagonists (VKAs) across several indications, including the prevention of stroke and systemic embolism (SSE) in patients with atrial fibrillation (AF) and the treatment of venous thromboembolism (VTE). Their use in patients with renal impairment is of particular importance, given the prevalence of renal dysfunction in the indicated populations and the impact of renal function on the metabolism of the NOACs. This publication reviews the pharmacokinetic/pharmacodynamic properties of the NOACs and clinical trial results for patients with renal impairment within the AF and VTE indications. Pharmacokinetic/pharmacodynamic data show the NOACs are dependent on renal clearance to varying extents. Relative to VKAs, the efficacy and safety of the NOACs is preserved in patients with moderate renal impairment. The dosing recommendations for patients with renal impairment differ depending on the NOAC, whereby some of the NOACs require dose reductions based solely on renal function, while others require consideration of additional criteria. However, despite these specific dosing recommendations, emerging real-world evidence suggests patients are not being dosed appropriately, indicating a possible knowledge gap. Adherence to recommended dosing algorithms has implications on the optimal efficacy and safety of the NOACs. To this end, renal function should be assessed in patients on a NOAC, as worsening of renal function may warrant change in the dose of a NOAC or change in oral anticoagulant.

Strategies and policies to address the opioid epidemic: A case study of Ohio.

OBJECTIVE: To describe the strategies and policies implemented in Ohio to improve opioid safety and to discuss the role that pharmacists can play in implementing, promoting, and enhancing the effectiveness of these policies. SETTING: Ohio has the fifth highest rate of drug overdose deaths (24.6 deaths per 100,000) in the United States. Unintentional drug overdose has become the leading cause of injury-related death in Ohio. In 2015, there were 3050 overdose deaths in Ohio, and in 2014 there were an estimated 12,847 overdose events reversed by emergency medical services with naloxone. PRACTICE DESCRIPTION: Not applicable. PRACTICE POLICY INNOVATION: In 2011, the Governor's Cabinet Opiate Action Team was created to implement a multifaceted strategy, in part (1) to promote the responsible use of opioids, (2) to reduce the supply of opioids, and (3) to support overdose prevention and expand access to naloxone. Innovations to assist these goals include the development of Ohio guidelines on the responsible use of opioids, mandatory use of Ohio's prescription drug monitoring program, closing pill mills, promotion of drug take-back programs and increased access to naloxone and public health campaigns. EVALUATION: Not applicable. RESULTS: Since the development of the Governor's Cabinet Opiate Action Team, there were 81 million fewer doses of opioids dispensed to Ohio patients in 2015 compared with 782 million doses dispensed in 2011. As such, the proportion of unintentional drug overdose deaths involving prescription opioids has reduced from 45% in 2011 to 22% in 2015. CONCLUSION: Strong political support was crucial in Ohio to facilitate the rapid implementation opioid overdose prevention programs and the promotion of public awareness campaigns. However, the misuse and abuse of prescription opioids are complex problems requiring a comprehensive and multifaceted approach. Pharmacists are identified as a crucial component of the state strategy to addressing opioid abuse by promoting responsible prescribing and adopting prevention practices.

Values and Preferences of Physicians and Patients With Nonvalvular Atrial Fibrillation Who Receive Oral Anticoagulation Therapy for Stroke Prevention.

BACKGROUND: Real-world data on patients' and physicians' values related to the use of oral anticoagulant (OAC) therapy for stroke prevention in patients with nonvalvular atrial fibrillation are currently lacking. We sought to assess the values, preferences, and experience of patients who receive OAC therapy, and of physicians who prescribe OAC therapy. METHODS: A national survey of randomly selected patients (n = 266) and physicians (n = 178) was conducted between May and September 2014. Each was asked to evaluate the importance of individual OAC attributes and identify which of 2 medication profiles they would prefer (individual attributes were progressively modified to determine which were the most valued and/or influenced treatment choice). Medication adherence and prescription practice was also assessed. RESULTS: The preferences of patients and physicians regarding OAC therapy differed but largely focused on characteristics related to safety and, to a lesser extent, efficacy. When based solely on the basis of the attribute profile (blinded to the specific agent), physicians were more likely to select apixaban (61%), whereas patients showed no significant preference among apixaban, rivaroxaban, and warfarin. Despite this, 49% of physicians spontaneously stated rivaroxaban as their preferred agent (vs 25% apixaban). Patients prescribed and taking once daily medications (rivaroxaban or warfarin) showed better compliance with their OAC therapy (approximately 30% of twice daily medications being taken once daily, with significantly more missed doses compared with once daily medications). CONCLUSIONS: Real-world prescriptions do not reflect reported values, which suggests that other factors influence patient-physician decision-making around OAC therapy. Data on self-reported adherence to OAC therapy and discordance in the use of OACs from prescribed regimens are concerning and warrant further investigation.

Trends in Prescribing Oral Anticoagulants in Canada, 2008-2014.

PURPOSE: The non-vitamin K antagonist oral anticoagulants (NOACs), dabigatran, rivaroxaban, and apixaban, provide several advantages over vitamin K antagonists, such as warfarin. Little is known about the trends of prescribing OACs in Canada. In this study we analyzed changes in prescription volumes for OAC drugs since the introduction of the NOACs in Canada overall, by province and by physician specialty. METHODS: Canadian prescription volumes for warfarin, dabigatran, rivaroxaban, and apixaban from January 2008 to June 2014 were obtained from the Canadian Compuscript Audit of IMS Health Canada Inc and were analyzed by physician specialty at the national and provincial levels. Total prescriptions by indication were calculated based on data from the Canadian Disease and Therapeutic Index for all OAC indications and for each commonly prescribed dose of dabigatran (75, 110, and 150 mg), rivaroxaban (10, 15, and 20 mg), and apixaban (2.5 and 5 mg). FINDINGS: The overall number of OAC prescriptions in Canada has increased annually since 2008. With the availability of the NOACs, the proportion of total OAC prescriptions attributable to warfarin has steadily decreased, from 99% in 2010 to 67% by June 2014, and the absolute number of warfarin prescriptions has been decreasing since February 2011. The greatest decline in proportionate warfarin prescriptions was in Ontario. In general, the increase of NOAC prescriptions coincided with the introduction of provinces' reimbursement of NOAC prescription costs. The proportion of total OAC prescriptions represented by the NOACs varied by specialty, with the greatest proportionate prescribing found among orthopedic surgeons, cardiologists, and neurologists. IMPLICATIONS: Since their approval, the NOACs have represented a growing share of total OAC prescriptions in Canada. This trend is expected to continue because the NOACs are given preference over warfarin in guidelines on stroke prevention in patients with atrial fibrillation, because of growing physician experience, and due to the emergence of potential new indications. An understanding of the current prescribing patterns will help to encourage knowledge translation and possibly influence policy/reimbursement strategies.

Modeling of human hepatic CYP3A4 enzyme kinetics, protein, and mRNA indicates deviation from log-normal distribution in CYP3A4 gene expression.

AIMS: To determine whether the variability in cytochrome P(450) (CYP)3A4 metabolic function is exhibited at both transcription and translation levels and to examine the population distribution of CYP3A4 enzyme kinetics, protein, and mRNA. METHODS: Enzyme kinetics of testosterone 6beta-hydroxylation, immunoblot CYP3A4 protein, and CYP3A4 mRNA were determined in a microsomal bank of human livers. The distribution of these determinations was analyzed using cumulative distribution (probit) plots and normality test variable (NTV) to detect deviation from normality. RESULTS: Mean hepatic CYP3A4 protein and relative CYP3A4 mRNA were 35+/-23 pmol/mg and 79+/-59 (CYP3A4/beta-actin), respectively. Kinetic parameter estimates of testosterone 6beta-hydroxylation were 611+/-684 pmol/mg/min for maximum rate of the reaction (V(max)) and 206+/-48 micro M for the Michaelis constant (K(m)). The CYP3A4 gene expression and its activity exhibited a relatively high degree of interindividual variability. Furthermore, significant correlation between CYP3A4 protein and V(max) of testosterone 6beta-hydroxylation (r=0.82, P<0.001) as well as CYP3A4 protein and its mRNA (r=0.52, P<0.01) was observed. Cumulative distribution plots and histograms for the CYP3A4 protein, its mRNA, and maximum testosterone 6beta-hydroxylation exhibited evidences of deviation from log-normal distribution. The minimum NTV value for the distribution of CYP3A4 protein corresponding to the inflection point in the probit occurred at approximately 10% cumulative frequency. The percentage of low CYP3A4 protein phenotype was consistent for CYP3A4 activity and its mRNA. In contrast, the distribution of K(m) of testosterone 6beta-hydroxylation does not show evidence of bimodality. CONCLUSIONS: The distribution of CYP3A4 metabolic function, protein, and mRNA is non-normal and may represent a regulatory polymorphism in hepatic CYP3A4 gene expression. In contrast, assessment of the possibility of a structural variant of CYP3A4 through evaluation of the standard deviation relative to the mean kinetic constant value suggests that structural mutation of CYP3A4 may not be a major factor affecting interindividual variation in CYP3A4 metabolic function.

De la fundación por Uno a la práctica entre varios

Trabajo presentado durante las III Jornadas del RI3, Red Internacional de Instituciones Infantiles, Bruselas, 1 y 2 de febrero de 1997 y publicado en Préliminaire nro. 9-10