Stéphanie Dumas

Adherence to antihypertensive agents after ischemic stroke and risk of cardiovascular outcomes

ABSTRACT 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.

Higher vitamin K intake is associated with better INR control and a decreased need for INR tests in long-term warfarin therapy

Warfarin is an oral anticoagulant that still remainswidely prescribed for the prevention of thromboembolic conditions, despite the introduction of new anticoagulant agents. It acts by inhibiting the vitamin K epoxyde reductase, decreasing the activation of vitamin K-dependent clotting factors. Physicians monitor the consequent anticoagulant effect using the International Normalized Ratio (INR), aimingwithin a narrow target range (e.g. 2.0-3.0). However, despite close monitoring, INRs are in the therapeutic range only ≈ 55% (95%CI: 51-58%) of the time [1]. Such poor INR control is associated with an increased risk of bleeding, especially in older adults, and of thromboembolic events [2]. Variations in vitamin K intake are known to influence INR control [3]. However, better INR control has been reported among patients with high vitamin K intakes, regardless of its variations [4–6]. While interesting, these observations were not based on validated indicators of INR control, which limits their interpretation in terms of clinical significance. Rosendaal et al. [7] validated an indicator of INR control where percentage of time in therapeutic range (%TTR) is assessed using linear interpolation between consecutive INRs. In the present study, we investigated the association between usual vitamin K intakes and %TTR in warfarin-treated older adults. We also examined whether high vitamin K intakes were associated with a decreased need for INR tests. From May 2010 through June 2011, 313 patients from the anticoagulation clinic of the Hôpital du Sacré-Coeur de Montréal (HSCM) were invited to participate. Eligibility required age ≥65 years, warfarin therapy for ≥1 year, a target INR range of 2.0-3.0, and ≤3 months between consecutive INR tests in the previous year. Twenty-four percent of eligible patients declined participation, 20% were inapt to participate (e.g. hospitalization, did not speak English or French), and 7% were unreachable. Verbal informed consent was provided by 153 patients. Ethical approval was obtained from the HSCM Ethics Committee. The primary outcome was %TTR over 1 year and the secondary outcome, the annual number of INR tests as ordered by physicians. A semiquantitative food frequency questionnaire (FFQ) specifically designed to assess usual vitamin K intake (μg/d) during the previous yearwas administered by a registered dietitian through a telephone interview. This 50-item FFQ has been proved valid for ranking individuals according to their usual vitamin K intake [8]. Outcomes and vitamin K intake were measured over the same 12-month period. Demographic and clinical data, including duration of warfarin therapy (years), INRs and shortterm warfarin interruptions (e.g. one-day surgery), were obtained from medical charts. Annual mean warfarin dose (mg) was calculated from prescriptions. Patients self-reported their weight (kg), height

Avoidance of Vitamin K−Rich Foods Is Common among Warfarin Users and Translates into Lower Usual Vitamin K Intakes

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.

Pillbox Use and INR Stability in a Prospective Cohort of New Warfarin Users.

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 warfarins 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.

Validation of patient-reported warfarin dose in a prospective incident cohort study.

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.

Rationale, design, and preliminary results of the Quebec Warfarin Cohort Study

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.

Nuclear receptor gene polymorphisms and warfarin dose requirements in the Quebec Warfarin Cohort

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.