Influence of Zoledronic Acid on Atrial Electrophysiological Parameters and Electrocardiographic Measurements

INTRODUCTION: Our objective was to determine effects of zoledronic acid (ZA) on atrial electrophysiological parameters and electrocardiographic measurements. METHODS AND RESULTS: Ex vivo perfusion study: Isolated guinea pig hearts were perfused with modified Krebs-Henseleit (K-H) buffer with or without ZA 0.07 mg/kg/L (each n = 6). In ZA-perfused hearts, atrial action potential at 90% repolarization (APD90 ) decreased more from baseline than in controls (-23.2% ± -5.1% vs. -2.1% ± -8.1%, P < 0 .0001), as did APD30 (-28.8% ± -3.8% vs. -2.1% ± -2.1%, P < 0.0001). In vivo dose-response study: Guinea pigs underwent intraperitoneal injections every 2 weeks in 1 of 4 groups (each n = 8): ZA 0.007 mg/kg (low-dose), ZA 0.07 mg/kg (medium-dose), ZA 0.7 mg/kg (high-dose), or placebo. Hearts were excised at 8 weeks and perfused with modified K-H. Atrial effective refractory period (ERP) was lower with medium- and high-dose ZA versus placebo (P = 0.004). Atrial APD30 was lower with high-dose ZA versus placebo, low and medium doses (P < 0.001). Canine ECG study: Mature female beagles received intravenous ZA 0.067 mg/kg or saline (placebo; each n = 6) every 2 weeks for 12 weeks. P wave dispersion was greater in the ZA group (7.7 ± 3.7 vs. 3.4 ± 2.6 ms, P = 0.04). There were no significant differences in P wave index, maximum or minimum P wave duration, or PR interval. CONCLUSION: ZA shortens left atrial APD and ERP and increases P wave dispersion

Influence of Oral Progesterone Administration on Drug-Induced QT Interval Lengthening: A Randomized, Double-Blind, Placebo-Controlled Crossover Study

Objectives We tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening. Background Evidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. Methods In this prospective, double-blind, crossover study, 19 healthy female volunteers (21-40 years) were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 49 days). On day 7, ibutilide 0.003 mg/kg was infused over 10 minutes, after which QT intervals were recorded and blood samples collected for 12 hours. Prior to the treatment phases, subjects underwent ECG monitoring for 12 hours to calculate individualized heart rate-corrected QT intervals (QTcI). Results Fifteen subjects completed all study phases. Maximum serum ibutilide concentrations in the progesterone and placebo phases were similar (1247±770 vs 1172±709 pg/mL, p=0.43). Serum progesterone concentrations were higher during the progesterone phase (16.2±11.0 vs 1.2±1.0 ng/mL, p<0.0001), while serum estradiol concentrations in the two phases were similar (89.3±62.8 vs 71.8±31.7 pg/mL, p=0.36). Pre-ibutilide lead II QTcI was significantly lower in the progesterone phase (412±15 vs 419±14 ms, p=0.04). Maximum ibutilide-associated QTcI (443±17 vs 458±19 ms, p=0.003), maximum percent increase in QTcI from pretreatment value (7.5±2.4 vs 9.3±3.4%, p=0.02) and area under the effect (QTcI) curve during the first hour post-ibutilide (497±13 vs 510±16 ms-hr, p=0.002) were lower during the progesterone phase. Progesterone-associated adverse effects included fatigue/malaise and vertigo. Conclusions Oral progesterone administration attenuates drug-induced QTcI lengthening

Characterization of Actions Taken During the Delivery of Medication Therapy Management: A Time-and-Motion Approach

OBJECTIVES: To characterize actions performed by pharmacists and support staff during provision of medication therapy management (MTM) and to compare actions performed according to practice characteristics. METHODS: A purposeful sample of 7 MTM practices (2 call centers and 5 community practices) was identified and visited by investigators. Pharmacists and support staff were observed during their routine provision of MTM. Investigators characterized "major" (e.g., preparation for a comprehensive medication review) and "minor" (i.e., specific steps in overarching major action) actions with the use of a time-and-motion approach. RESULTS: A total of 32 major and 469 minor actions were observed. Practices were characterized as Later Maturity Level or Early Maturity Level on the basis of their self-reported MTM appointment volume, self-assessment of the extent of integration of chronic care model principles, and payer mix. Later Maturity Level practices were more likely to deliver follow-up medication therapy reviews and comprehensive medication reviews (CMRs) as opposed to targeted medication reviews (TMRs) and to receive physician referrals for MTM. Later Maturity Level practices were also more likely to use paid interns than pharmacy rotation students. CMR activities observed at Later Maturity Level practices lasted a median of 30.8 minutes versus 20.3 minutes for CMR activities at Early Maturity Level practices. Similarly, TMR activities observed at Later Maturity Level practices were longer: a median of 31.0 minutes versus 12.3 minutes. At Later Maturity Level practices, pharmacists spent a greater proportion of time providing patient education, while support staff spent a greater proportion of time on tasks such as capturing demographics and introducing or explaining MTM. CONCLUSION: MTM activities were longer at Later Maturity Level practices, and these practices were more likely to use paid pharmacy interns and to receive physician referrals for MTM. This work provides a foundation for future research

Effectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patients

BACKGROUND: We evaluated the effectiveness of a computer clinical decision support system (CDSS) for reducing the risk of QT interval prolongation in hospitalized patients. METHODS AND RESULTS: We evaluated 2400 patients admitted to cardiac care units at an urban academic medical center. A CDSS incorporating a validated risk score for QTc prolongation was developed and implemented using information extracted from patients' electronic medical records. When a drug associated with torsades de pointes was prescribed to a patient at moderate or high risk for QTc interval prolongation, a computer alert appeared on the screen to the pharmacist entering the order, who could then consult the prescriber on alternative therapies and implement more intensive monitoring. QTc interval prolongation was defined as QTc interval >500 ms or increase in QTc of ≥60 ms from baseline; for patients who presented with QTc >500 ms, QTc prolongation was defined solely as increase in QTc ≥60 ms from baseline. End points were assessed before (n=1200) and after (n=1200) implementation of the CDSS. CDSS implementation was independently associated with a reduced risk of QTc prolongation (adjusted odds ratio, 0.65; 95% confidence interval, 0.56-0.89; P<0.0001). Furthermore, CDSS implementation reduced the prescribing of noncardiac medications known to cause torsades de pointes, including fluoroquinolones and intravenous haloperidol (adjusted odds ratio, 0.79; 95% confidence interval, 0.63-0.91; P=0.03). CONCLUSIONS: A computer CDSS incorporating a validated risk score for QTc prolongation influences the prescribing of QT-prolonging drugs and reduces the risk of QTc interval prolongation in hospitalized patients with torsades de pointes risk factors

Distressed family caregivers of lung cancer patients: an examination of psychosocial and practical challenges

Purpose: Lung cancer and its treatment impose many demands on family caregivers, which may increase their risk for distress. However, little research has documented aspects of the caregiving experience that are especially challenging for distressed caregivers of lung cancer patients. This study aimed to explore caregivers' key challenges in coping with their family member's lung cancer. Methods: Single, semi-structured qualitative interviews were conducted with 21 distressed family caregivers of lung cancer patients. Results: Caregivers described three key challenges in coping with their family member's lung cancer. The most common challenge, identified by 38 % of caregivers, was a profound sense of uncertainty regarding the future as they attempted to understand the patient's prognosis and potential for functional decline. Another key challenge, identified by 33 % of caregivers, involved time-consuming efforts to manage the patient's emotional reactions to the illness. Other caregivers (14 %) characterized practical tasks, such as coordinating the patient's medical care, as their greatest challenge. Conclusions: Results suggest that clinical efforts are needed to assist distressed caregivers in providing practical and emotional support to the patient and attending to their own emotional needs

Hypertension treatment intensification among stroke survivors with uncontrolled blood pressure

Objective The study objective was to evaluate a pharmacist hypertension care management program within the patient-centered medical home. Methods This was a retrospective case-control study. Cases included all patients with hypertension who were referred to the care management program, and controls included patients with hypertension who were not referred to the program during the same 1-year period. Each case was matched to a maximum of 3 controls on the basis of primary care physician, age ±5 years, gender, diagnoses of diabetes and kidney disease, baseline systolic blood pressure ±10 mm Hg, and number of unique antihypertensive medications. Pharmacists provided a hypertension care management program under an approved scope of practice that allowed pharmacists to meet individually with patients, adjust medications, and provide patient education. Primary outcomes were systolic blood pressure and diastolic blood pressure at 6 and 12 months. Multivariate regression models compared each blood pressure end point between cases and controls adjusting for age, comorbidities, baseline blood pressure, and baseline number of blood pressure medications. Results A total of 573 patients were referred to the hypertension program; 86% (465/543) had at least 1 matched control and were included as cases in the analyses; 3:1 matching was achieved in 90% (418/465) of cases. At baseline, cases and controls did not differ with respect to age, gender, race, or comorbidity; baseline blood pressure was higher (139.9/80.0 mm Hg vs 136.7/78.2 mm Hg, P ≤ .0002) in the cases compared with controls. Multivariate regression modeling identified significantly lower systolic blood pressure for the cases compared with controls at both 6 and 12 months (6-month risk ratio [RR], 9.7; 95% confidence interval [CI], 2.7-35.3; 12-month RR, 20.3; 95% CI, 4.1-99.2; P < .01 for both comparisons). Diastolic blood pressure was significantly lower at 12 months (RR, 2.9; 95% CI, 1.2-7.1; P < .01) but not at 6 months (RR, 1.0; 95% CI, 0.31-3.4; P = .9) for the cases compared with controls. Conclusions Patients who were referred to the pharmacist hypertension care management program had a significant improvement in most blood pressure outcomes. This program may be an effective method of improving blood pressure control among patients in a medical home model of primary care

Factors associated with comprehensive medication review completion rates: A national survey of community pharmacists

Background Completion rates for medication therapy management (MTM) services have been lower than desired and the Centers for Medicare and Medicaid Services has added MTM comprehensive medication review (CMR) completion rates as a Part D plan star measure. Over half of plans utilize community pharmacists via contracts with MTM vendors. Objectives The primary objective of this survey study was to identify factors associated with the CMR completion rates of community pharmacies contracted with a national MTM vendor. Methodsl Representatives from 27,560 pharmacy locations contracted with a national MTM vendor were surveyed. The dependent variable of interest was the pharmacies' CMR completion rate. Independent variables included the pharmacy's progressiveness stratum and number of CMRs assigned by the MTM vendor during the time period, as well as self-reported data to characterize MTM facilitators, barriers, delivery strategies, staffing, selected items from a modified Assessment of Chronic Illness Care, and pharmacist/pharmacy demographics. Univariate negative binomial models were fit for each independent variable, and variables significant at p < 0.05 were entered into a multivariable model. Results Representatives from 3836 (13.9%) pharmacy locations responded; of these, 90.9% (n = 3486) responses were useable. The median CMR completion rate was 0.42. Variables remaining significant at p < 0.05 in the multivariable model included: progressiveness strata; pharmacy type; scores on the facilitators scale; responses to two potential barriers items; scores on the patient/caregiver delivery strategies sub-scale; providing MTM at multiple locations; reporting that the MTM vendor sending the survey link is the primary MTM vendor for which the respondent provides MTM; and the number of hours per week that the pharmacy is open. Conclusions Factors at the respondent (e.g., responses to facilitators scale) and pharmacy (e.g., pharmacy type) levels were associated with CMR completion rates. These findings could be used by MTM stakeholders to improve CMR completion rates

Preparing for the spread of patient-reported outcomes (PROs) data collection from primary care to community pharmacy: stakeholder insights

Medication non-adherence is a significant public health problem. Patient-reported outcomes (PROs) offer a rich data source to facilitate resolution of medication non-adherence. PatientToc™ is an electronic PRO data collection software originally implemented at primary care practices in California, United States (US). Currently, the use of standardized PRO data collection systems in US community pharmacies is limited. Thus, we are conducting a two-phase evaluation of the spread and scale of PatientToc™ to US Midwestern community pharmacies. This report focuses on the first phase of the evaluation. The objective of this phase was to prepare for implementation of PatientToc™ in community pharmacies by conducting a pre-implementation developmental formative evaluation to (1) identify potential barriers, facilitators, and actionable recommendations to PatientToc™ implementation and (2) create a draft implementation toolkit

Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers

Background Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. Objective The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. Methods EFV was administered to healthy volunteers (n=57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. Results EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ΔΔQTcF were observed at 6 hrs (14 ms; 95% CI [1; 27]), 12 hrs (18 ms; 95% CI [−4; 40] and 18 hrs (6 ms; 95% CI [−1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 µg/mL significantly inhibited outward hERG tail currents (P<0.05). Conclusions This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG