Publications by authors named "James E Tisdale"

68 Publications

Review of menopausal palpitations measures.

Womens Midlife Health 2021 May 31;7(1). Epub 2021 May 31.

College of Pharmacy, Purdue University, West Lafayette, IN, 47907, USA.

Palpitations are reported commonly by women around the time of menopause as skipped, missed, irregular, and/or exaggerated heartbeats or heart pounding. However, much less is known about palpitations than other menopausal symptoms such as vasomotor symptoms. The objective of this review was to integrate evidence on menopausal palpitations measures. Keyword searching was done in PubMed, CINAHL, and PsycINFO for English-language, descriptive articles containing data on menopause and palpitations and meeting other pre-specified inclusion criteria. Of 670 articles, 110 met inclusion criteria and were included in the review. Results showed that 11 different measures were used across articles, with variability within and between measures. Inconsistencies in the wording of measurement items, recall periods, and response options were observed even when standardized measures were used. Most measures were limited to assessing symptom presence and severity. Findings suggest that efforts should be undertaken to (1) standardize conceptual and operational definitions of menopausal palpitations and (2) develop a patient-friendly, conceptually clear, psychometrically sound measure of menopausal palpitations.
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http://dx.doi.org/10.1186/s40695-021-00063-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167994PMC
May 2021

Accuracy of a single-lead mobile smartphone electrocardiogram for QT interval measurement in patients undergoing maintenance methadone therapy.

Pharmacotherapy 2021 Jun 19;41(6):494-500. Epub 2021 Apr 19.

College of Pharmacy, Purdue University, Indianapolis, Indiana, USA.

Study Objective: Methadone is associated with QT interval prolongation and torsades de pointes. Expert panel recommendations advocate a pre-methadone electrocardiogram (ECG) and another ECG at 30 days of therapy in patients with risk factors. Some guidelines recommend a pre-methadone ECG and routine ECG monitoring in all methadone patients, but this is controversial due to the resources required. Availability of a convenient, less resource-intensive method of ECG monitoring for patients taking methadone is desirable. The objective of this study was to assess the accuracy of a handheld smartphone ECG (iECG) for QT measurement in patients on maintenance methadone therapy in an urban opioid treatment program.

Design: Prospective study.

Setting: Urban opioid treatment program.

Patients: n = 115 patients in normal sinus rhythm who were on steady-state maintenance methadone therapy INTERVENTION: Patients (n = 115) underwent a simultaneous 12-lead ECG and a single-lead iECG.

Measurements And Main Results: The first three QT and RR intervals from lead II of the 12-lead ECG and simulated lead I from the iECG were compared using the Bland-Altman analysis of measurement agreement. Mean [± standard deviation) age was 34 ± 11 years; 71% were female, 75% were white. Compared to the 12-lead ECG, the iECG was associated with a QTc bias of - 0.14 ms (SD = 12 ms, 95% CI = -2.4 to 2.1 ms). The absolute mean difference in QTc between the two methods was 9.5 ± 7.1 ms. For identification of patients with methadone-associated QTc prolongation, the iECG performed moderately well [c-statistic 0.97 (95% CI 0.91-0.99); sensitivity and specificity 75% (95% CI 43-95%) and 99% (95% CI 94-99%), respectively]. The positive and negative likelihood ratios of the iECG for identifying patients with methadone-associated QTc prolongation were 77.25 (95% CI 10.69 to 558.18) and 0.25 (95% CI 0.09 to 0.67), respectively, while the positive and negative predictive values were 90% (95% CI 56-99%) and 97% (95% CI 92-99%), respectively. The accuracy of the iECG for identifying patients with QTc prolongation was 97% (95% CI 91-99%).

Conclusion: A handheld smartphone ECG is accurate for QT interval measurement in patients taking maintenance methadone therapy, and its performance is moderately good for identifying patients with methadone-associated QTc prolongation.
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http://dx.doi.org/10.1002/phar.2521DOI Listing
June 2021

Methadone-associated QT interval prolongation in patients undergoing maintenance therapy in an urban opioid treatment program.

Pharmacotherapy 2021 03 2;41(3):238-246. Epub 2021 Feb 2.

College of Pharmacy, Purdue University, Indianapolis, Indiana, USA.

Study Objective: Methadone is associated with QT interval prolongation and torsades de pointes. The objective of this study was to (a) determine the incidence of QT interval prolongation among patients on maintenance methadone therapy in an urban opioid treatment program (OTP), (b) compare characteristics of patients who developed methadone-associated QT prolongation with those who did not develop QT prolongation, and (c) investigate the relationship between QT interval prolongation and stereospecific serum methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)] concentrations.

Design: Prospective study.

Setting: Urban opioid treatment program (OTP).

Patients: n = 93 patients on maintenance methadone therapy in an urban OTP.

Intervention: Patients underwent a 12-lead electrocardiogram (ECG) prior to initiating methadone and again during steady-state maintenance methadone therapy. In a subset (n = 43), blood was obtained to determine serum (S)- and (R)-methadone and (S)- and (R)-EDDP concentrations, which were compared in patients who developed Bazett's-corrected QT (QTc) prolongation [≥470 ms (men) or ≥480 ms (women) and/or ≥60 ms lengthening from pretreatment value] with those who did not have QTc prolongation.

Measurements And Main Results: Mean [± standard deviation (SD)] age was 36 ± 12 years; 73% were female, and 74% were white. QTc prolongation occurred in 14 (15.1%) patients. Patients who developed QTc prolongation were older (41 ± 13 vs. 35 ± 9 years, p = 0.03) and had a longer pre-methadone QTc compared with those who did not have QTc prolongation (429 ± 11 vs. 420 ± 20 ms, respectively, p = 0.02). Serum (S)-methadone concentrations were higher in patients with QTc prolongation compared to patients without prolongation (199 ± 81 vs. 128 ± 68 ng/ml, respectively, p = 0.01), whereas the difference in serum (R)-methadone concentrations between the groups did not reach significance (189 ± 68 vs. 125 ± 60 ng/ml, respectively, p = 0.08). Serum (R)-methadone concentrations correlated with QTc intervals [R  = 0.15 (95% confidence interval (CI) 0.11-0.62, p = 0.0009)]. The correlation between serum (S)-methadone concentrations and QTc did not reach significance [R  = 0.08 (95% CI -0.01 to 0.54, p = 0.06)]. Serum (S)-and (R)-EDDP concentrations were not significantly different between the groups and did not significantly correlate with QTc intervals.

Conclusions: Approximately 15% of patients taking maintenance methadone therapy developed QT interval prolongation. Both serum (S)- and (R)-methadone concentrations, but not (S)- or (R)-EDDP, contribute to methadone-associated QT prolongation.
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http://dx.doi.org/10.1002/phar.2498DOI Listing
March 2021

A Menopause Strategies-Finding Lasting Answers for Symptoms and Health (MsFLASH) Investigation of Self-Reported Menopausal Palpitation Distress.

J Womens Health (Larchmt) 2021 04 20;30(4):533-538. Epub 2020 Nov 20.

Department of Family Medicine and Public Health, University of California, San Diego, California, USA.

Study to describe the degree of menopausal palpitation distress and its demographic, clinical, symptom, and quality-of-life (QOL) correlates. Analysis of existing, baseline, data from peri- and postmenopausal women, 42 to 62 years of age, who participated in the Menopause Strategies-Finding Lasting Answers for Symptoms and Health (MsFLASH) clinical trials testing interventions for vasomotor symptoms ( = 759). Up to 46.8% of menopausal women report having palpitations, yet the symptom is relatively understudied. Little is known about palpitation distress or its correlates. Degree of distress from "heart racing or pounding" was self-reported over the past two weeks as "not at all," "a little bit," "moderately," "quite a bit," or "extremely." Other measures included self-report forms, clinic-verified body mass index (BMI), vasomotor symptom diaries, and validated symptom and QOL tools. The percentage who reported palpitation distress was 19.6%, 25.2%, and 33.5% in the three trials or 25.0% overall. In multivariate analysis, the odds of reporting palpitation distress was lower in past smokers (odds ratio [OR] = 0.59 [95% confidence interval (CI) 0.38-0.90]) and current smokers (OR = 0.48 [0.27-0.87]) relative to never-smokers and lower with every 5 kg/m higher BMI (OR = 0.82 [0.69-0.98]).The odds of reporting palpitation distress was higher with every five point more severe insomnia (OR = 1.28 [1.05-1.54]), five point worse depressive symptoms (OR = 1.47 [1.11-1.95]), five point worse perceived stress (OR = 1.19 [1.01-1.39]), and one point worse menopausal QOL (OR = 1.29 [1.06-1.57]). Menopausal palpitation distress is common and associated with demographic, clinical, symptom, and QOL factors. Findings can be used for screening in clinical practice and to justify additional research on this understudied symptom.
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http://dx.doi.org/10.1089/jwh.2020.8586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064942PMC
April 2021

Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men.

Clin Pharmacol Ther 2021 Jun 15;109(6):1499-1504. Epub 2020 Nov 15.

College of Pharmacy, Purdue University, Indianapolis, Indiana, USA.

We have previously reported that transdermal testosterone attenuates drug-induced QT interval lengthening in older men. However, it is unknown whether this is due to modulation of early ventricular repolarization, late repolarization, or both. In a secondary analysis of a prospective, randomized, double-blind, placebo-controlled three-way crossover study, we determined if transdermal testosterone and oral progesterone attenuate drug-induced lengthening of early and late ventricular repolarization, represented by the electrocardiographic measurements J-T c and T -T , respectively, as well as T -T /QT, a measure of transmural dispersion of repolarization. Male volunteers ≥ 65 years of age (n = 14) were randomized to receive transdermal testosterone 100 mg, oral progesterone 400 mg, or matching transdermal/oral placebo daily for 7 days. On the morning following the seventh day, subjects received intravenous ibutilide 0.003 mg/kg, after which electrocardiograms were performed serially. One subject was excluded due to difficulty in T-wave interpretation. Pre-ibutilide J-T c was lower during the testosterone phase than during progesterone and placebo (216 ± 23 vs. 227 ± 28 vs. 227 ± 21 ms, P = 0.002). Maximum post-ibutilide J-T c was also lower during the testosterone phase (233 ± 22 vs. 246 ± 29 vs. 248 ± 23 ms, P < 0.0001). Pre-ibutilide T -T was not significantly different during the three phases, but maximum post-ibutilide T -T was lower during the testosterone phase (80 ± 12 vs. 89 ± 18 vs. 86 ± 15 ms, P = 0.002). Maximum T -T /QT was also lower during the testosterone phase (0.199 ± 0.023 vs. 0.216 ± 0.035 vs. 0.209 ± 0.031, P = 0.005). Progesterone exerted minimal effect on drug-induced lengthening of J-T c, and no effect on T -T or T -T /QT. Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men.
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http://dx.doi.org/10.1002/cpt.2072DOI Listing
June 2021

Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association.

Circulation 2020 Oct 15;142(15):e214-e233. Epub 2020 Sep 15.

Many widely used medications may cause or exacerbate a variety of arrhythmias. Numerous antiarrhythmic agents, antimicrobial drugs, psychotropic medications, and methadone, as well as a growing list of drugs from other therapeutic classes (neurological drugs, anticancer agents, and many others), can prolong the QT interval and provoke torsades de pointes. Perhaps less familiar to clinicians is the fact that drugs can also trigger other arrhythmias, including bradyarrhythmias, atrial fibrillation/atrial flutter, atrial tachycardia, atrioventricular nodal reentrant tachycardia, monomorphic ventricular tachycardia, and Brugada syndrome. Some drug-induced arrhythmias (bradyarrhythmias, atrial tachycardia, atrioventricular node reentrant tachycardia) are significant predominantly because of their symptoms; others (monomorphic ventricular tachycardia, Brugada syndrome, torsades de pointes) may result in serious consequences, including sudden cardiac death. Mechanisms of arrhythmias are well known for some medications but, in other instances, remain poorly understood. For some drug-induced arrhythmias, particularly torsades de pointes, risk factors are well defined. Modification of risk factors, when possible, is important for prevention and risk reduction. In patients with nonmodifiable risk factors who require a potentially arrhythmia-inducing drug, enhanced electrocardiographic and other monitoring strategies may be beneficial for early detection and treatment. Management of drug-induced arrhythmias includes discontinuation of the offending medication and following treatment guidelines for the specific arrhythmia. In overdose situations, targeted detoxification strategies may be needed. Awareness of drugs that may cause arrhythmias and knowledge of distinct arrhythmias that may be drug-induced are essential for clinicians. Consideration of the possibility that a patient's arrythmia could be drug-induced is important.
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http://dx.doi.org/10.1161/CIR.0000000000000905DOI Listing
October 2020

Enhanced Response to Drug-Induced QT Interval Lengthening in Patients with Heart Failure with Preserved Ejection Fraction.

J Card Fail 2020 Sep 24;26(9):781-785. Epub 2020 Jun 24.

Krannert Institute of Cardiology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana.

Background: Patients with heart failure (HF) with reduced ejection fraction demonstrate enhanced response to drug-induced QT interval lengthening and are at increased risk for torsades de pointes. The influence of HF with preserved ejection fraction (HFpEF) on response to drug-induced QT lengthening is unknown.

Methods And Results: We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched control subjects without HF. Serial 12-lead electrocardiograms were obtained for determination of QT intervals. Demographics, maximum serum ibutilide concentrations, area under the serum ibutilide concentration vs time curves, and baseline Fridericia-corrected QT (QT) (417 ± 14 vs 413 ± 15 ms, P = .54) were similar in the HFpEF and control groups. Area under the effect (QTvs time) curve (AUEC) from 0 to 1.17 hours during and following the ibutilide infusion was greater in the HFpEF group (519 ± 19 vs 497 ± 18 ms·h, P= .04), as was AUEC from 0 to 8.17 hours (3576 ± 125 vs 3428 ± 161 ms·h, P = .03) indicating greater QT interval exposure. Maximum QT (454 ± 15 vs 443 ± 22 ms, P = .18) and maximum percent increase in QT from baseline (8.2 ± 2.1 vs 6.7 ± 1.9%, P = .10) in the 2 groups were not significantly different.

Conclusions: HFpEF is associated with enhanced response to drug-induced QT interval lengthening.
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http://dx.doi.org/10.1016/j.cardfail.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529874PMC
September 2020

Chloroquine and Hydroxychloroquine in the Era of SARS - CoV2: Caution on Their Cardiac Toxicity.

Pharmacotherapy 2020 05 13;40(5):387-388. Epub 2020 Apr 13.

Purdue University College of Pharmacy and Indiana University School of Medicine, Indianapolis, Indiana.

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http://dx.doi.org/10.1002/phar.2387DOI Listing
May 2020

Progesterone Metabolites Inhibit the Human Ether-a-go-go-Related Gene and Predict QT Interval Length.

J Clin Pharmacol 2019 Dec 12. Epub 2019 Dec 12.

Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.

A decrease in the human ether-a-go-go-related gene (hERG/KCNH2)-related channel has been linked to intrauterine fetal death. The formation of cytochrome P450 (CYP) 3A-mediated progesterone metabolites, 6-beta-hydroxy-progesterone (6β-OHP) and 16α-hydroxy-progesterone (16α-OHP), is variable among adults and differs from fetal metabolism. The primary objective of this study was to assess the potential for progesterone metabolites to inhibit hERG-related current and predict QTc intervals. Whole-cell voltage-clamp electrophysiology was performed on human embryonic kidney 293 cells stably expressing hERG exposed to progesterone or metabolites. Both 6β-OHP and 16α-OHP positively shifted the voltage dependence of activation relative to vehicle from -4.0 ± 0.8 to -0.3 ± 0.8 mV, P < .01; and 1.0 ± 0.6 mV, P < .01, respectively. In addition, 6β-OHP decreased maximal outward tail currents from 49.4 ± 4.9 to 32.5 ± 4.1 pA/pF, P < 0.01, and reduced the expression of fully glycosylated hERG by 42%. Healthy female subjects were administered progesterone 400 mg orally for 7 days, ibutilide 0.003 mg/kg was infused, and serial electrocardiograms and blood samples collected. Relationships between rate-corrected QT intervals (QTcI) with circulating hormones and metabolites were assessed. The 6β-OHP and 16α-OHP metabolites were independent predictors of QTcI intervals prior to and following ibutilide administration. In conclusion, the progesterone metabolites formed via CYP3A cause inhibitory effects on hERG channels and predict QTcI intervals in healthy women pretreated with progesterone. Further study into maternal and fetal exposure to these metabolites and potential to prolong cardiac repolarization is warranted.
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http://dx.doi.org/10.1002/jcph.1563DOI Listing
December 2019

Premature ventricular complexes: diagnostic and therapeutic considerations in clinical practice : A state-of-the-art review by the American College of Cardiology Electrophysiology Council.

J Interv Card Electrophysiol 2020 Jan 11;57(1):5-26. Epub 2019 Dec 11.

Kansas City Heart Rhythm Institute & Research Foundation, Overland Park, KS, 66221, USA.

Premature ventricular complexes (PVCs) are common arrhythmias in the clinical setting. PVCs in the structurally normal heart are usually benign, but in the presence of structural heart disease (SHD), they may indicate increased risk of sudden death. High PVC burden may induce cardiomyopathy and left ventricular (LV) dysfunction or worsen underlying cardiomyopathy. Sometimes PVCs may be a marker of underlying pathophysiologic process such as myocarditis. Identification of PVC burden is important, since cardiomyopathy and LV dysfunction can reverse after catheter ablation or pharmacological suppression. This state-of-the-art review discusses pathophysiology, clinical manifestations, how to differentiate benign and malignant PVCs, PVCs in the structurally normal heart, underlying SHD, diagnostic procedures (physical examination, electrocardiogram, ambulatory monitoring, exercise testing, echocardiography, cardiac magnetic resonance imaging, coronary angiography, electrophysiology study), and treatment (lifestyle modification, electrolyte imbalance, medical, and catheter ablation).
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http://dx.doi.org/10.1007/s10840-019-00655-3DOI Listing
January 2020

Editorial commentary: Amiodarone-induced thyroid diseases: Additional unintended consequences.

Authors:
James E Tisdale

Trends Cardiovasc Med 2019 07 13;29(5):296-297. Epub 2018 Oct 13.

The Department of Pharmacy Practice, College of Pharmacy, Purdue University, Indianapolis, IN, United States; The Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, United States. Electronic address:

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http://dx.doi.org/10.1016/j.tcm.2018.10.003DOI Listing
July 2019

Proarrhythmic food for thought.

Authors:
James E Tisdale

Heart Rhythm 2019 08 15;16(8):1149-1150. Epub 2019 May 15.

Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, Indiana; Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2019.05.010DOI Listing
August 2019

Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts.

J Cardiovasc Electrophysiol 2019 06 21;30(6):941-949. Epub 2019 Apr 21.

Department of Medicine, Krannert Institute of Cardiology, School of Medicine, Indiana University, Indianapolis, Indiana.

Introduction: Higher progesterone concentrations are protective against drug-induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug-induced torsades de pointes (TdP).

Methods And Results: Female New Zealand white rabbits (2.5-3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21-day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15-minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QT intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo-treated rabbits (3.8 [range, 2.8-5.1] vs 0.7 [0.4-1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22-72] vs 53 [34-62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone-treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone-treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT interval and short-term beat-to-beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone-treated rabbits.

Conclusions: Pretreatment with progesterone reduces the incidence of drug-induced TdP, bigeminy, and trigeminy in isolated perfused AV node-ablated rabbit hearts.
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http://dx.doi.org/10.1111/jce.13942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591050PMC
June 2019

Amiodarone for prevention of atrial fibrillation following esophagectomy.

J Thorac Cardiovasc Surg 2019 07 5;158(1):301-310.e1. Epub 2019 Feb 5.

Department of Surgery, School of Medicine, Indiana University, Indianapolis, Ind.

Objectives: Atrial fibrillation (AF) is a common complication after esophagectomy and is associated with symptoms, hemodynamic instability, prolonged hospital stay, and an increased incidence of mortality. Our objective was to determine the efficacy and safety of intravenous amiodarone for prophylaxis of postesophagectomy AF.

Methods: In this retrospective cohort study, 309 patients who underwent esophagectomy formed the initial cohort. Following propensity score-matching, 110 patients who received prophylactic amiodarone 43.75 mg/hour via continuous intravenous infusion over 96 hours (total dose, 4200 mg) were matched to a control group of patients who did not undergo amiodarone prophylaxis (n = 110). The propensity score was obtained using a multivariate logistic regression model with amiodarone as the variable and the following covariates: age, sex, surgical approach, history of neoadjuvant chemotherapy and/or radiation, chronic obstructive pulmonary disease, heart failure, cardiovascular disease, alcohol use (>7 drinks/week), preadmission β-blockers discontinued during hospitalization, preoperative use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, preoperative use of corticosteroids, postoperative use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, postoperative use of corticosteroids, postoperative use of statins, and preoperative Charlson comorbidity index.

Results: The incidence of AF requiring treatment due to rapid ventricular rate and symptoms was lower in the amiodarone group (17 out of 110 [15.5%] vs 32 out of 110 [29.1%]; odds ratio, 0.45; 95% confidence interval, 0.23-0.86; P = .015). There were no significant differences between the groups in median postoperative length of hospital stay, incidence of pulmonary complications, or mortality. The incidences of hypotension requiring treatment (42.7% vs 21.8%; P = .001), bradycardia (8.2% vs 0.0%; P = .002), and corrected QT interval prolongation (10.9% vs 0.0%; P ≤ .0001) were significantly higher in the amiodarone group.

Conclusions: Prophylactic intravenous amiodarone is associated with a reduction in the incidence of AF following esophagectomy, but is not associated with shorter postoperative length of hospital stay. Intravenous amiodarone for prophylaxis of postesophagectomy AF is associated with hypotension, bradycardia, and corrected QT interval prolongation.
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http://dx.doi.org/10.1016/j.jtcvs.2019.01.095DOI Listing
July 2019

Navigating the Minefield of QTc Interval-Prolonging Therapy in Nursing Facility Residents.

J Am Geriatr Soc 2019 07 12;67(7):1508-1515. Epub 2019 Feb 12.

College of Pharmacy, Purdue University, School of Medicine, Indiana University, Indianapolis, Indiana.

Background: The exponential increase in the number of medications associated with clinically important prolongation of the heart rate-corrected QT interval (QTc) places older adults at increased risk of arrhythmias including life-threatening torsade de pointes (TdP) and sudden death. Risk factors, other than age older than 65 years and female sex, include multiple concurrent drugs that prolong QTc and a variety of underlying predisposing conditions. Although electronic medical records and pharmacy dispensing systems can alert clinicians to the risk of QTc-prolonging therapy, more than 95% of safety alerts are overridden, and many systems have deactivated QTc drug interaction alerts. The clinical consequences, magnitude of the effect, mitigation strategies, and recommended monitoring are not well defined for nursing facility (NF) residents.

Design: Narrative review.

Setting: NFs in the United States.

Participants: NF residents.

Results: Medications known to prolong QTc include selected anti-infectives, antidepressants, urinary anticholinergics, antipsychotics, and cholinesterase inhibitors (eg, donepezil), used commonly in NFs. Drug-drug interactions are a risk when adding a medication that exaggerates the effect or inhibits the metabolism of a QTc-prolonging medication. The vast majority of patients in whom TdP is induced by noncardiac drugs have risk factors that are easily identifiable.

Conclusions: Recommendations are provided to improve standardization and use of drug interaction alerts, evaluate the risk of QTc-prolonging drugs in older adults receiving generally lower doses, validate a QTc risk score addressing complex multimorbidity, garner evidence to guide clinical decision making, avail NFs of access to electrocardiograms and interpretive recommendations, and develop standards of practice for hosting risk discussions with residents and their families. J Am Geriatr Soc, 1-8, 2019.
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http://dx.doi.org/10.1111/jgs.15810DOI Listing
July 2019

Predictive Analytics for Identification of Patients at Risk for QT Interval Prolongation: A Systematic Review.

Pharmacotherapy 2018 08 18;38(8):813-821. Epub 2018 Jul 18.

Department of Pharmacy Practice, College of Pharmacy, Purdue University, Indianapolis, Indiana.

Prolongation of the heart rate-corrected QT (QTc) interval increases the risk for torsade de pointes (TdP), a potentially fatal arrhythmia. The likelihood of TdP is higher in patients with risk factors that include female sex, older age, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, concomitant administration of two or more QTc interval-prolonging medications, among others. Assessment and quantification of risk factors may facilitate prediction of patients at highest risk for developing QTc interval prolongation and TdP. Investigators have utilized the field of predictive analytics, which generates predictions using techniques including data mining, modeling, machine learning, and others, to develop methods of risk quantification and prediction of QTc interval prolongation. Predictive analytics have also been incorporated into clinical decision support (CDS) tools to alert clinicians regarding patients at increased risk of developing QTc interval prolongation. The objectives of this article are to assess the effectiveness of predictive analytics for identification of patients at risk of drug-induced QTc interval prolongation and to discuss the efficacy of incorporation of predictive analytics into CDS tools in clinical practice. A systematic review of English-language articles (human subjects only) was performed, yielding 57 articles, with an additional 4 articles identified from other sources; a total of 10 articles were included in this review. Risk scores for QTc interval prolongation have been developed in various patient populations including those in cardiac intensive care units (ICUs) and in broader populations of hospitalized or health system patients. One group developed a risk score that includes information regarding genetic polymorphisms; this score significantly predicted TdP. Development of QTc interval prolongation risk prediction models and incorporation of these models into CDS tools reduce the risk of QTc interval prolongation in cardiac ICUs and identify health system patients at increased risk for mortality. The impact of these QTc interval prolongation predictive analytics on overall patient safety outcomes, such as TdP and sudden cardiac death relative to the cost of development and implementation, requires further study.
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http://dx.doi.org/10.1002/phar.2146DOI Listing
August 2018

La recherche réalisée par les pharmaciens d’hôpitaux : une composante indispensable de la pratique quotidienne ou une attente irréaliste?

Authors:
James E Tisdale

Can J Hosp Pharm 2018 Mar-Apr;71(2):97-98. Epub 2018 Apr 30.

, B. Sc. Pharm., Pharm. D, est professeur titulaire au Département de pratique pharmaceutique de la Faculté de pharmacie de l'Université Purdue et professeur associé de l'École de médecine de l'Université d'Indiana, à Indianapolis, en Indiana, aux États-Unis. Il est également rédacteur adjoint au Journal canadien de la pharmacie hospitalière.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931081PMC
April 2018

Research Conducted by Hospital Pharmacists: Integral Component of Daily Practice or Unrealistic Expectation?

Authors:
James E Tisdale

Can J Hosp Pharm 2018 Mar-Apr;71(2):95-96. Epub 2018 Apr 30.

, BScPharm, PharmD, is Professor in the Department of Pharmacy Practice, College of Pharmacy, Purdue University, and Adjunct Professor in the School of Medicine, Indiana University, Indianapolis, Indiana. He is also an Associate Editor with the Canadian Journal of Hospital Pharmacy.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931080PMC
April 2018

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca-activated K channels.

Am J Physiol Heart Circ Physiol 2018 08 20;315(2):H375-H388. Epub 2018 Apr 20.

Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine , Indianapolis, Indiana.

Apamin-sensitive small-conductance Ca-activated K (SK) current ( I) is encoded by Ca-activated K channel subfamily N ( KCNN) genes. I importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that I inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT receptor antagonist ondansetron blocks I. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca sensitivity, increasing I density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced I inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca sensitivity and I density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent I blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT receptor antagonist, blocks small-conductance Ca-activated K (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of drug-induced long QT syndrome.
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http://dx.doi.org/10.1152/ajpheart.00479.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139629PMC
August 2018

Editorial Commentary: Optimization of dose selection for nonvitamin K antagonist oral anticoagulants.

Authors:
James E Tisdale

Trends Cardiovasc Med 2017 11 30;27(8):573-574. Epub 2017 Jun 30.

Department of Pharmacy Practice, College of Pharmacy, Purdue University, Indianapolis, IN; Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN. Electronic address:

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http://dx.doi.org/10.1016/j.tcm.2017.06.015DOI Listing
November 2017

Contribution of medications and risk factors to QTc interval lengthening in the atherosclerosis risk in communities (ARIC) study.

J Eval Clin Pract 2017 Dec 10;23(6):1274-1280. Epub 2017 Jul 10.

UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Rationale, Aims, And Objectives: Prolongation of the corrected QT (QTc) interval is associated with increased morbidity and mortality. The association between QTc interval-prolonging medications (QTPMs) and risk factors with magnitude of QTc interval lengthening is unknown. We examined the contribution of risk factors alone and in combination with QTPMs to QTc interval lengthening.

Method: The Atherosclerosis Risk in Communities study assessed 15 792 participants with a resting, standard 12-lead electrocardiogram and ≥1 measure of QTc interval over 4 examinations at 3-year intervals (1987-1998). From 54 638 person-visits, we excluded participants with QRS ≥ 120 milliseconds (n = 2333 person-visits). We corrected the QT interval using the Bazett and Framingham formulas. We examined QTc lengthening using linear regression for 36 602 person-visit observations for 14 160 cohort members controlling for age ≥ 65 years, female sex, left ventricular hypertrophy, QTc > 500 milliseconds at the prior visit, and CredibleMeds categorized QTPMs (Known, Possible, or Conditional risk). We corrected standard errors for repeat observations per person.

Results: Eighty percent of person-visits had at least one risk factor for QTc lengthening. Use of QTPMs increased over the 4 visits from 8% to 17%. Among persons not using QTPMs, history of prolonged QTc interval and female sex were associated with the greatest QTc lengthening, 39 and 12 milliseconds, respectively. In the absence of risk factors, Known QTPMs and ≥2 QTPMs were associated with modest but greater QTc lengthening than Possible or Conditional QTPMs. In the presence of risk factors, ≥2 QTPM further increased QTc lengthening. In combination with risk factors, the association of all QTPM categories with QTc lengthening was greater than QTPMs alone.

Conclusion: Risk factors, particularly female sex and history of prolonged QTc interval, have stronger associations with QTc interval lengthening than any QTPM category alone. All QTPM categories augmented QTc interval lengthening associated with risk factors.
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http://dx.doi.org/10.1111/jep.12776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741511PMC
December 2017

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

JACC Clin Electrophysiol 2016 Dec;2(7):765-774

Krannert Institute of Cardiology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana.

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 (QTI).

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 QTI was significantly lower in the progesterone phase (412±15 vs 419±14 ms, p=0.04). Maximum ibutilide-associated QTI (443±17 vs 458±19 ms, p=0.003), maximum percent increase in QTI from pretreatment value (7.5±2.4 vs 9.3±3.4%, p=0.02) and area under the effect (QTI) 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 QTI lengthening.
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http://dx.doi.org/10.1016/j.jacep.2016.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403156PMC
December 2016

Prevalence and significance of acquired QT interval prolongation in hospitalized patients.

Authors:
James E Tisdale

Heart Rhythm 2017 07 30;14(7):979-980. Epub 2017 Mar 30.

Department of Pharmacy Practice, College of Pharmacy, Purdue University, Indianapolis, Indiana, and Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2017.03.036DOI Listing
July 2017

Iterative Development and Evaluation of a Pharmacogenomic-Guided Clinical Decision Support System for Warfarin Dosing.

Appl Clin Inform 2016 11 23;7(4):1088-1106. Epub 2016 Nov 23.

Brian R. Overholser, PharmD, FCCP, Associate Professor, Purdue University College of Pharmacy, Research Institute 2: Room 402, 950 W. Walnut St., Indianapolis, IN 46202, Office (317) 278-4001, Fax: (317) 880-0568, Email:

Objective: Pharmacogenomic-guided dosing has the potential to improve patient outcomes but its implementation has been met with clinical challenges. Our objective was to develop and evaluate a clinical decision support system (CDSS) for pharmacogenomic-guided warfarin dosing designed for physicians and pharmacists.

Methods: Twelve physicians and pharmacists completed 6 prescribing tasks using simulated patient scenarios in two iterations (development and validation phases) of a newly developed pharmacogenomic-driven CDSS prototype. For each scenario, usability was measured via efficiency, recorded as time to task completion, and participants' perceived satisfaction which were compared using Kruskal-Wallis and Mann Whitney U tests, respectively. Debrief interviews were conducted and qualitatively analyzed. Usability findings from the first (i.e. development) iteration were incorporated into the CDSS design for the second (i.e. validation) iteration.

Results: During the CDSS validation iteration, participants took more time to complete tasks with a median (IQR) of 183 (124-247) seconds versus 101 (73.5-197) seconds in the development iteration (p=0.01). This increase in time on task was due to the increase in time spent in the CDSS corresponding to several design changes. Efficiency differences that were observed between pharmacists and physicians in the development iteration were eliminated in the validation iteration. The increased use of the CDSS corresponded to a greater acceptance of CDSS recommended doses in the validation iteration (4% in the first iteration vs. 37.5% in the second iteration, p<0.001). Overall satisfaction did not change statistically between the iterations but the qualitative analysis revealed greater trust in the second prototype.

Conclusions: A pharmacogenomic-guided CDSS has been developed using warfarin as the test drug. The final CDSS prototype was trusted by prescribers and significantly increased the time using the tool and acceptance of the recommended doses. This study is an important step toward incorporating pharmacogenomics into CDSS design for clinical testing.
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http://dx.doi.org/10.4338/ACI-2016-05-RA-0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228145PMC
November 2016

[Not Available].

Authors:
James E Tisdale

Can J Hosp Pharm 2016 May-Jun;69(3):185-6. Epub 2016 Jun 30.

B. Sc. Pharm., Pharm. D, est professeur titulaire, Département de pratique pharmaceutique de la Faculté de pharmacie de l'Université Purdue et professeur associé de l'École de médecine de l'Université d'Indiana, à Indianapolis, en Indiana, aux États-Unis. Il est également rédacteur adjoint au Journal canadien de la pharmacie hospitalière.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924937PMC
July 2016

Drug-Induced QT Interval Prolongation in Children: Are the Kids Alright?

Authors:
James E Tisdale

Can J Hosp Pharm 2016 May-Jun;69(3):183-4. Epub 2016 Jun 30.

BScPharm, PharmD, is Professor, Department of Pharmacy Practice, College of Pharmacy, Purdue University, and Adjunct Professor, School of Medicine, Indiana University, Indianapolis, Indiana. He is also an Associate Editor for the Canadian Journal of Hospital Pharmacy.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924936PMC
http://dx.doi.org/10.4212/cjhp.v69i3.1552DOI Listing
July 2016

Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers.

J Cardiovasc Electrophysiol 2016 10 25;27(10):1206-1213. Epub 2016 Jul 25.

Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette.

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 ∆∆QTcF were observed at 6 hours (14 milliseconds; 95% CI [1; 27]), 12 hours (18 milliseconds; 95% CI [-4; 40]), and 18 hours (6 milliseconds; 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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065384PMC
http://dx.doi.org/10.1111/jce.13032DOI Listing
October 2016

Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management.

Authors:
James E Tisdale

Can Pharm J (Ott) 2016 May 8;149(3):139-52. Epub 2016 Apr 8.

College of Pharmacy, Purdue University, and the School of Medicine, Indiana University, Indianapolis, Indiana, USA.

Torsades de pointes (TdP) is a life-threatening arrhythmia associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram. More than 100 drugs available in Canada, including widely used antibiotics, antidepressants, cardiovascular drugs and many others, may cause QTc interval prolongation and TdP. Risk factors for TdP include QTc interval >500 ms, increase in QTc interval ≥60 ms from the pretreatment value, advanced age, female sex, acute myocardial infarction, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, treatment with diuretics and elevated plasma concentrations of QTc interval-prolonging drugs due to drug interactions, inadequate dose adjustment of renally eliminated drugs in patients with kidney disease and rapid intravenous administration. Pharmacokinetic drug interactions associated with the highest risk of TdP include antifungal agents, macrolide antibiotics (except azithromycin) and drugs to treat human immunodeficiency virus interacting with amiodarone, disopyramide, dofetilide or pimozide. Other important pharmacokinetic interactions include antidepressants (bupropion, duloxetine, fluoxetine, paroxetine) interacting with flecainide, quinidine or thioridazine. Pharmacists play an important role in minimizing the risk of drug-induced QTc interval prolongation and TdP through knowledge of drugs that are associated with a known or possible risk of TdP, individualized assessment of risk of drug-induced QTc interval prolongation, awareness of drug interactions most likely to result in TdP and attention to dose reduction of renally eliminated QTc interval-prolonging drugs in patients with kidney disease. Treatment of hemodynamically stable TdP consists of discontinuation of the offending drug(s), correction of electrolyte abnormalities and administration of intravenous magnesium sulfate 1 to 2 g.
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http://dx.doi.org/10.1177/1715163516641136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860751PMC
May 2016
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