RESUMEN
Warfarin is primarily metabolized by cytochrome 2C9, encoded by gene CYP2C9. Here, we investigated whether variants in nuclear receptor genes which regulate the expression of CYP2C9 are associated with warfarin response. We used data from 906 warfarin users from the Quebec Warfarin Cohort (QWC) and tested the association of warfarin dose requirement at 3 months following the initiation of therapy in nine nuclear receptor genes: NR1I3, NR1I2, NR3C1, ESR1, GATA4, RXRA, VDR, CEBPA, and HNF4A. Three correlated SNPs in the VDR gene (rs4760658, rs11168292, and rs11168293) were associated with dose requirements of warfarin (P = 2.68 × 10-5, P = 5.81 × 10-4, and P = 5.94 × 10-4, respectively). Required doses of warfarin were the highest for homozygotes of the minor allele at the VDR variants (P < 0.0026). Variants in the VDR gene were associated with the variability in response to warfarin, emphasizing the possible clinical relevance of nuclear receptor gene variants on the inter-individual variability in drug metabolism.
Asunto(s)
Coagulación Sanguínea/genética , Estudio de Asociación del Genoma Completo , Receptores de Calcitriol/genética , Warfarina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Receptor de Androstano Constitutivo , Citocromo P-450 CYP2C9/genética , Relación Dosis-Respuesta a Droga , Receptor alfa de Estrógeno/genética , Femenino , Factor de Transcripción GATA4/genética , Genotipo , Factor Nuclear 4 del Hepatocito/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Receptor X de Pregnano/genética , Quebec/epidemiología , Receptores de Calcitriol/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Glucocorticoides/genética , Receptor alfa X Retinoide/genética , Vitamina K/genética , Vitamina K/metabolismo , Warfarina/administración & dosificación , Warfarina/efectos adversosRESUMEN
Warfarin is an oral anticoagulant agent with a narrow therapeutic index. There is a marked inter- and intra-patient variability in warfarin dose requirement. All factors influencing warfarin response are not known and this study aims to evaluate if regular physical activity (RPA) is a determining factor. RPA level was collected with the Stanford Brief Activity Survey in 1064 incident warfarin users, as part of the Quebec Warfarin Cohort (QWC), and with the Global Physical Activity Questionnaire in 618 patients from the Montreal Heart Institute (MHI) Biobank. Linear regression was performed to model relationship of warfarin dose after 3 months of therapy in the QWC with RPA, while controlling for height, weight, age, CYP2C9 (*2 and *3 alleles) and VKORC1 (*2 allele) genotype. Warfarin dose of prevalent users was modeled in the MHI Biobank for replication. A higher level of physical activity was associated with higher doses of warfarin in both cohorts. In the QWC, physical activity could explain 5.4 % (P < 0.001) and 0.9 % (P = 3.23 × 10(-5)) of variance in dose, in univariate and multivariable models, respectively. Similarly, RPA was found to be associated with 1.7 % (P = 0.0012) and 0.5 % (P = 0.0391) of inter-individual variability in warfarin dose requirement before and after adjustment for other covariables, respectively. RPA is associated with higher warfarin dose requirement. The relevance of clinical recommendations on RPA to maintain a steady response to warfarin should be assessed in further studies.
Asunto(s)
Modelos Biológicos , Actividad Motora , Encuestas y Cuestionarios , Warfarina/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Citocromo P-450 CYP2C9/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vitamina K Epóxido Reductasas/genéticaRESUMEN
PURPOSE: Inconsistencies in the definition and the collection of warfarin dosing data could lead to bias in observational, clinical, and pharmacogenetic studies. The present study aims to assess the concordance between patient-reported and prescribed warfarin doses among new warfarin users in the Quebec Warfarin Cohort (QWC) study. METHODS: Demographic, clinical, and lifestyle data were collected at cohort entry and each three months during a 1-year follow-up period among a subgroup of 219 patients from the prospective QWC study. We evaluated the differences between reported and prescribed warfarin doses overall and at each follow-up period. Concordance was tested in a multivariate generalized linear mixed model and allowed to vary from 95% to 105% of the prescribed dose. RESULTS: Overall, there was no significant difference between reported and prescribed warfarin doses (p>0.05, Pearson coefficient=0.969, power=100%). There was also no significant difference across each of four timepoints tested (p>0.05). We found that 84.0% of the reported warfarin doses were concordant with the prescribed doses. Having a history of myocardial infarction was significantly associated with a low concordance (OR=0.494; CI 95%: 0.286-0.852). CONCLUSION: In our population, we found that patient-reported warfarin dose and prescribed warfarin dose were comparable for the conduct of observational and clinical studies as well as for the validation and implementation of warfarin dosing algorithms. Moreover, the effect was similar whether measured in new-onset users of warfarin and after up to 12 months of use.
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Anticoagulantes/administración & dosificación , Cooperación del Paciente , Autoinforme/normas , Warfarina/administración & dosificación , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Estudios de Seguimiento , Humanos , Incidencia , Estudios ProspectivosRESUMEN
Over- and undercoagulation with warfarin are associated with hemorrhagic and thromboembolic events, respectively. Genetic and clinical factors affect warfarin response, and the causes of this variability remain unclear. We present descriptive statistics and test for predictors of poor anticoagulation control. The Quebec Warfarin Cohort (QWC) comprises 1059 new warfarin users, with prospective follow-up using telephone questionnaires every 3 months for 1 year, and using healthcare administrative databases (RAMQ and Med-Echo) for 5 years prior to cohort entry and up to 10 years following active patient participation. Genetic material was collected, and genotyping of CYP2C9 and VKORC1 genes was conducted. Measured outcomes included the percentage of time patients spent within therapeutic range, anticoagulation control, warfarin dose, bleeding, and thromboembolic events. We report baseline characteristics and outcomes after 1 year of follow-up. Poor anticoagulation control was defined as time in therapeutic range <60% in the 3- to 12-month interval. Participants had a mean age of 71 years, and 62% were men. The most common indication for warfarin was atrial fibrillation (87%). Mean time in therapeutic range was 56% (±25%) in the 3 months following warfarin initiation, and 70% (±21%) in the 3- to 12-month interval. During follow-up, the rate of stroke or systemic embolism was 1.8 events per 100 person-years; for major bleeding events, 3.3 events per 100 person-years. Independent predictors of poor anticoagulation control were chronic kidney disease, heart failure, dyslipidemia, and age. The QWC represents a good research cohort to investigate clinical and genetic factors in a warfarin-anticoagulated population.
Asunto(s)
Anticoagulantes/administración & dosificación , Coagulación Sanguínea/efectos de los fármacos , Tromboembolia/prevención & control , Warfarina/administración & dosificación , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Protocolos Clínicos , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Bases de Datos Factuales , Femenino , Encuestas de Atención de la Salud , Hemorragia/inducido químicamente , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Farmacogenética , Variantes Farmacogenómicas , Datos Preliminares , Estudios Prospectivos , Quebec , Proyectos de Investigación , Factores de Riesgo , Tromboembolia/sangre , Tromboembolia/etiología , Factores de Tiempo , Resultado del Tratamiento , Vitamina K Epóxido Reductasas/genética , Vitamina K Epóxido Reductasas/metabolismo , Warfarina/efectos adversosRESUMEN
Biologic extracellular matrix (ECM)-based wound dressings offer promise in the treatment of chronic wounds. A variety of animal and human tissue derived dressings are currently available. These products are processed and/or sterilized by a range of chemical and mechanical processes, which will impact the final quality of the matrices--ultimately affecting the overall wound healing process. A novel method is described to prepare a sterile and biocompatible biological wound dressing. The advantages and the clinical implications of this wound dressing preparation are also discussed.
RESUMEN
BACKGROUND: Warfarin users should aim for stable daily vitamin K intakes. However, some studies report that patients are often advised to avoid eating green vegetables. Whether this advice impacts vitamin K intakes is unknown. OBJECTIVE: Our aim was to describe the nature and sources of vitamin K-related dietary recommendations that patients received at the initiation of warfarin therapy, assess their adherence to these recommendations, and examine whether usual vitamin K intakes vary according to these recommendations. DESIGN: We conducted a retrospective cohort study with patients enrolled in the Québec Warfarin Cohort Study. Patients were asked to report dietary recommendations they had received at warfarin initiation and their adherence to these recommendations. Usual vitamin K intakes were assessed using a validated semi-quantitative food frequency questionnaire. PARTICIPANTS/SETTING: Three hundred seventeen patients aged 36 to 97 years who initiated warfarin between 2011 and 2012 and were treated for 12 months or longer with a target international normalized ratio range of 2.0 to 3.0 or 2.5 to 3.5. STATISTICAL ANALYSES PERFORMED: Patients were classified according to vitamin K-related recommendations reported: limit or avoid vitamin K-rich foods; aim for stable consumption of vitamin K-rich foods; or no vitamin K-related advice. A one-way analysis of covariance was used to compare mean usual vitamin K intakes between patients after adjustment for covariates. RESULTS: Most patients (68%) reported being advised to limit or avoid vitamin K-rich foods, particularly green vegetables, 10% reported being advised to aim for stable consumption of vitamin K-rich foods, and 22% did not recall receiving any vitamin K-related recommendation. Mean usual vitamin K intakes of patients adhering to the recommendation to limit or avoid vitamin K-rich foods was 35% to 46% lower than those of other patients (P<0.001), a difference resulting almost entirely (82%) from a lower consumption of green vegetables. CONCLUSIONS: In contrast with current dietary recommendation, most warfarin users reported avoiding vitamin K-rich foods, which translated into lower usual vitamin K intakes.
Asunto(s)
Dieta/métodos , Ingestión de Alimentos , Conducta Alimentaria , Vitamina K/análisis , Vitaminas/análisis , Warfarina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Registros de Dieta , Encuestas sobre Dietas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quebec , Ingesta Diaria Recomendada , Estudios Retrospectivos , Verduras/química , Vitamina K/administración & dosificación , Vitamina K/normas , Vitaminas/administración & dosificaciónRESUMEN
BACKGROUND: Warfarin, a frequently prescribed oral anticoagulant, is well known for its narrow therapeutic index. Adherence to warfarin may help to achieve a stable international normalized ratio (INR), but little data are available regarding the impact of using a pillbox as a potential adherence aid device. OBJECTIVE: To evaluate the association between pillbox use and time in therapeutic range (TTR) < 60% and INR instability pattern. METHODS: This study was based on a prospective cohort of 1,069 new warfarin users who initiated warfarin between May 2010 and July 2013 within 17 hospitals in Quebec, Canada. Demographic, lifestyle, and clinical data were collected for 3 months to a year after warfarin initiation, and genetic factors were assessed. Patients usingh self-prepared and pharmacist-prepared pillboxes were compared with nonusers for the 3- to 12-month follow-up period. The primary outcome was a TTR < 60%, which represents a low percentage of time in the INR therapeutic range or an unstable patient. The secondary outcome was the INR instability pattern (unstable below range; unstable over range; unstable with erratic pattern; and stable) to better describe patient INR profiles. A multivariate generalized linear mixed model was used for the primary outcome, along with a multivariate multinomial linear mixed model for the secondary outcome. RESULTS: The cohort included patients with a mean age of 70.4 ± 11.7 years; 61.8% of patients were men; 76.3% had atrial fibrillation as warfarin's primary indication; and 35.6% had a previous history of myocardial infarction or angina. Self-prepared and pharmacist-prepared pillbox use was not associated with TTR < 60% or a specific INR instability pattern. A sensitivity analysis showed that self-prepared pillbox users had a higher TTR than nonusers (3.55% ± 1.69%; P = 0.036). This effect was greater among patients aged < 70 years (5.48% ± 2.50%; P = 0.029) than among older patients (1.92% ± 2.31%; P =0.406). CONCLUSIONS: Pillbox use was not associated with TTR < 60% or a specific INR instability pattern. The impact of self-prepared pillbox use was greater among younger patients, but results were not clinically significant. Future studies adjusting for concomitant drug use are needed to clarify these results. DISCLOSURES: This study was funded by Canadian Institutes of Health Research (CIHR) and the Centre for Excellence in Personalised Medicine. Both funding sources were not involved in the design, conduct, and reporting of this study. The data used for this study came from the Quebec Warfarin Cohort Study (QWCS), which was supported by the CIHR and the Centre for Excellence in Personalised Medicine. Dumas received a doctoral training award from the CIHR. Perreault and Dubé received a salary award from the Fonds Québécois de Recherche en Santé. Study concept and design were contributed by Talajic, Tardif, Dubé, and Perreault. Dumas, Rouleau-Mailloux, Bouchama, and Lahcene collected the data, which was interpreted by Dumas, Dubé, and Perreault. The manuscript was written and revised by Dumas, Dubé, and Perreault.
Asunto(s)
Anticoagulantes/uso terapéutico , Almacenaje de Medicamentos , Relación Normalizada Internacional/normas , Cumplimiento de la Medicación , Warfarina/uso terapéutico , Anciano , Anciano de 80 o más Años , Anticoagulantes/sangre , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Quebec/epidemiología , Warfarina/sangreRESUMEN
OBJECTIVE: To evaluate the relationship between antihypertensive (AH) drug adherence and cardiovascular (CV) outcomes among patients with a recent ischemic stroke and assess the validity of our approach. METHODS: A cohort of 14,227 patients diagnosed with an ischemic stroke was assembled from individuals 65 years and older who were treated with AH agents from 1999 to 2007 in Quebec, Canada. A nested case-control design was used to evaluate the occurrence of nonfatal major CV outcomes and mortality. Each case was matched to 15 controls by age and cohort entry time. Medication possession ratio was used for AH agent adherence level. Adjusted conditional logistic regression models were used to estimate the rate ratio of CV events. The validity of the approach was assessed by evaluating the adherence level of CV-protective and non-CV-protective drugs. RESULTS: Mean age was 75 years, 54% were male, 38% had coronary artery disease, 23% had diabetes, 47% dyslipidemia, and 14% atrial fibrillation or flutter. High adherence to AH therapy was mirrored by similar adherence to statins and antiplatelet agents and was associated with a lower risk of nonfatal vascular events compared with lower adherence (rate ratio 0.77 [0.70-0.86]). We observed a paradoxic link between adherence to several drugs and all-cause mortality. CONCLUSION: Adherence to AH agents is associated with adherence to other secondary preventive therapies and a risk reduction for nonfatal vascular events after an ischemic stroke. Overestimation of all-cause mortality reduction may be related to frailty and comorbidities, which may confound the apparent benefit of different drugs.