Secular trends of health care resource utilization and costs between Brugada syndrome and congenital long QT syndrome: A territory-wide study.

BACKGROUND: Health care resource utilization (HCRU) and costs are important metrics of health care burden, but they have rarely been explored in the setting of cardiac ion channelopathies. HYPOTHESIS: This study tested the hypothesis that attendance-related HCRUs and costs differed between patients with Brugada syndrome (BrS) and congenital long QT syndrome (LQTS). METHODS: This was a retrospective cohort study of consecutive BrS and LQTS patients at public hospitals or clinics in Hong Kong, China. HCRUs and costs (in USD) for Accident and Emergency (A&E), inpatient, general outpatient and specialist outpatient attendances were analyzed between 2001 and 2019 at the cohort level. Comparisons were made using incidence rate ratios (IRRs [95% confidence intervals]). RESULTS: Over the 19-year period, 516 BrS (median age of initial presentation: 51 [interquartile range: 38-61] years, 92% male) and 134 LQTS (median age of initial presentation: 21 [9-44] years, 32% male) patients were included. Compared to LQTS patients, BrS patients had lower total costs (2 008 126 [2 007 622-2 008 629] vs. 2 343 864 [2 342 828-2 344 900]; IRR: 0.857 [0.855-0.858]), higher costs for A&E attendances (83 113 [83 048-83 177] vs. 70 604 [70 487-70 721]; IRR: 1.177 [1.165-1.189]) and general outpatient services (2,176 [2,166-2,187] vs. 921 [908-935]; IRR: 2.363 [2.187-2.552]), but lower costs for inpatient stay (1 391 624 [1 391 359-1 391 889] vs. 1 713 742 [1 713 166-1 714 319]; IRR: 0.812 [0.810-0.814]) and lower costs for specialist outpatient services (531 213 [531 049-531 376] vs. 558 597 [558268-558926]; IRR: 0.951 [0.947-0.9550]). CONCLUSIONS: Overall, BrS patients consume 14% less health care resources compared to LQTS patients in terms of attendance costs. BrS patients require more A&E and general outpatient services, but less inpatient and specialist outpatient services than LQTS patients.

QTc-time-prolongating drugs and additional risk factors for long-QT-syndrome at hospital admission of surgical patients - risk assessment by pharmacists.

Drugs can cause long-QTc-syndrome (LQTS), thereby elevating the risk for palpitations, syncopes, and sudden cardiac death. Additional risk factors such as the intake of more than one QTc-prolongating drug (QTPD) and surgery (cardiac and non-cardiac) increase the risk considerably. Therefore, a good knowledge of patients perioperative risk is important. Data concerning this issue in surgical patients is, however, scarce. We aimed to determine the number of surgical patients taking QTPD at hospital admission and to assess the presence of additional risk factors for LQTS. In addition, we determined the LQTS-risk at hospital admission by calculating the Tisdale Risk Score, enabling early detection of patients at risk. In a retrospective study, the pre-hospital medication of a 4-month cohort of surgical patients admitted to a tertiary teaching hospital was evaluated for QTPD-intake. For these patients, additional risk factors for LQTS were assessed and the Tisdale Risk Score was calculated. Of 837 surgical patients, 419 (50%) took at least one QTPD. In total, 3,376 drugs were taken and 723 (21%) classified as QTPD with a median number of 2 (range 1-8) per patient. The median number of LQTS-risk factors for these patients at hospital admission was 2 (range 0-5). The Tisdale Risk Score classified 23 patients (5%) as high, 187 (45%) as moderate, and 209 (50%) as low risk. These findings indicate a high number of surgical patients with QTPD and additional risk factors. The Tisdale Risk Score can be used as a screening instrument for patients at risk for QTc-prolongation during medication reconciliation by pharmacists at hospital admission. Patients identified as high and moderate risk should be evaluated for adjustable risk factors and monitored adequately. Medical treatment needs to be chosen carefully in view of in-hospital patient safety.

Adverse drug event risk assessment by the virtual addition of COVID-19 repurposed drugs to Medicare and commercially insured patients' drug regimens: A drug safety simulation study.

Drug safety is generally established from clinical trials, by pharmacovigilance programs and during observational phase IV safety studies according to drug intended or approved indications. The objective of this study was to estimate the risk of potential adverse drug events (ADEs) associated with drugs repurposed for coronavirus disease 2019 (COVID-19) treatment in a large-scale population. Drug claims were used to calculate a baseline medication risk score (MRS) indicative of ADE risk level. Fictitious claims of repurposed drugs were added, one at a time, to patients' drug regimens to calculate a new MRS and compute a level of risk. Drug claims data from enrollees with Regence health insurance were used and sub-payer analyses were performed with Medicare and commercial insured groups. Simulated interventions were conducted with hydroxychloroquine and chloroquine, alone or combined with azithromycin, and lopinavir/ritonavir, along with terfenadine and fexofenadine as positive and negative controls for drug-induced Long QT Syndrome (LQTS). There were 527,471 subjects (56.6% women; mean [SD] age, 47 years [21]) were studied. The simulated addition of each repurposed drug caused an increased risk of ADEs (median MRS increased by two-to-seven points, p < 0.001). The increase in ADE risk was mainly driven by an increase in CYP450 drug interaction risk score and by drug-induced LQTS risk score. The Medicare group presented a greater risk overall compared to the commercial group. All repurposed drugs were associated with an increased risk of ADEs. Our simulation strategy could be used as a blueprint to preemptively assess safety associated with future repurposed or new drugs.

Prevalence and Outcome of High-Risk QT Prolongation Recorded in the Emergency Department from an Institution-Wide QT Alert System.

BACKGROUND: QT prolongation is an independent risk factor for sudden death, stroke, and all-cause mortality. However, additional studies have shown that in certain settings, QT prolongation may be transient and a result of external factors. OBJECTIVE: In this study, we evaluated the clinical characteristics and outcomes of patients seen in the emergency department (ED) with QT prolongation. METHODS: Between November 2010 and June 2011, 7522 patients had an electrocardiogram (ECG) obtained during their evaluation in the ED. Clinical, laboratory, and therapeutic information was collected for all patients with QT prolongation (i.e., ≥ 500 ms and QRS < 120 ms). Potential QT-inciting factors (drugs, electrolyte disturbances, and comorbidities) were synthesized into a pro-QT score. RESULTS: Among the 7522 patients with an ECG obtained in the ED, a QT alert was activated in 93 (1.2%; mean QTc 521 ± 34 ms). The majority of ED patients (64%) had more than one underlying condition associated with QT prolongation, with electrolyte disturbances in 51%, a QT prolonging condition in 56%, and QT-prolonging drugs in 77%. Thirty-day mortality was 13% for patients with QT prolongation noted in the ED. CONCLUSIONS: One percent of patients evaluated with an ECG in the ED activated our prolonged QTc warning system, with most demonstrating > 1 QT-prolonging condition. Thirty-day mortality was significant, but it requires further investigation to determine whether the QTc simply provided a non-invasive indicator of increased risk or heralded the presence of a vulnerable host at risk of a QT-mediated sudden dysrhythmic death.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review.

BACKGROUND: The cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio-oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life-threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario. METHODS AND RESULTS: In this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare. CONCLUSIONS: Our systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

Media attention regarding sudden cardiac death associated with domperidone use does not affect in hospital ECG recording.

PURPOSE: In March 2013, regulatory warnings concerning the potential risks of domperidone caused considerable media attention in the Netherlands. The aim of the study was to assess the effect of regulatory warnings and the resulting media hype on the frequency of electrocardiogram (ECG) monitoring of inpatients using domperidone. We also studied the effect on the frequency of prescribing domperidone by physicians. METHODS: A 2-centre, observational, retrospective cohort study was performed. Inpatients using domperidone in 2 hospitals in the Netherlands during a period of 384 days before and after the media hype were included. The main outcomes were (1) the proportion of domperidone users with ECGs before and/or during domperidone treatment, (2) the proportion of patients with an ECG before and during treatment, and (3) the proportion of patients with an ECG during treatment. Secondary outcome was the proportion of domperidone prescriptions comparing the before- and after-period. RESULTS: Four hundred twenty-eight patients were included. The main outcomes [respectively (1) relative risk (RR) 1.02, 95% confidence interval (CI), 0.85-1.21; (2) RR 1.06, 95% CI, 0.60-1.85; and (3) RR 1.27, 95% CI, 0.80-2.01) were not different. After stratifying for hospital, no significant differences were found. A statistically significant decrease (RR 0.40, 95% CI, 0.35-0.45) in numbers of prescriptions was found for the university medical centre only. CONCLUSIONS: No effect of the media hype was found on the intensity of ECG monitoring in domperidone users. In the university medical centre, domperidone prescriptions were reduced.

Risk management of QTc-prolongation in patients receiving haloperidol: an epidemiological study in a University hospital in Belgium.

BACKGROUND: Many drugs, including haloperidol, are linked with a risk of QTc-prolongation, which can lead to Torsade de Pointes and sudden cardiac death. OBJECTIVE: To investigate the prevalence of concomitant risk factors for QTc-prolongation in patients treated with haloperidol, and the use of safety measures to minimize this risk. SETTING: University Hospitals of Leuven, Belgium. Methods A retrospective epidemiological study was performed. On 15 consecutive Mondays, all patients with a prescription for haloperidol were included. A risk score for QTc-prolongation, inspired by the pro-QTc score of Haugaa et al., was calculated based on gender, comorbidities, lab results and concomitant QTc-prolonging drugs (each factor counting for one point). Available electrocardiograms before and during the treatment of haloperidol were registered. MAIN OUTCOME MEASURE: Management of the risk of QTc-prolongation. RESULTS: Two hundred twenty-two patients were included (59.0 % men, median age 77 years) of whom 26.6 % had a risk score of ≥4 (known to significantly increase the mortality). Overall, 24.3 % received haloperidol in combination with other drugs with a known risk of Torsade de Pointes. Half of the patients had an electrocardiogram in the week before the start of haloperidol; only in one-third a follow-up electrocardiogram during haloperidol treatment was performed. Of the patients with a moderately (n = 41) or severely (n = 14) prolonged QTc-interval before haloperidol, 48.8 % and 42.9 % respectively had a follow-up electrocardiogram. In patients with a risk score ≥4, significantly more electrocardiograms were taken before starting haloperidol (p = 0.020). CONCLUSIONS: Although many patients had risk factors for QTc-prolongation (including the use of other QTc-prolonging drugs) or had a prolonged QTc on a baseline electrocardiogram, follow-up safety measures were limited. Persistent efforts should be taken to develop decision support systems to manage this risk.

Are ECG monitoring recommendations before prescription of QT-prolonging drugs applied in daily practice? The example of haloperidol.

PURPOSE: Monitoring of the QT duration by electrocardiography (ECG) prior to treatment is frequently recommended in the label of QT-prolonging drugs. It is, however, unknown how often general practitioners in daily clinical practice are adhering to these risk-minimization measures. We assessed the frequency of ECG measurements in patients where haloperidol was initiated in primary care. METHODS: Patients (≥18 years) with a first prescription of haloperidol in the UK Clinical Practice Research Datalink (2009-2013) were included. The proportion of ECGs made was determined in two blocks of 4 weeks: during the exposure period when haloperidol was initiated, and during the control period, 1 year before. Conditional logistic regression analysis was applied to calculate the relative risk of having an ECG in the exposure period compared with the control period. Subgroup analyses were performed to assess the proportion of ECG measurements in patients with one or more additional risk factors for QT prolongation. RESULTS: In total, 3420 patients were prescribed haloperidol during the exposure period, and 1.8% of them had an ECG at treatment initiation, compared with 0.8% during the control period (relative risk [RR] 2.4 [1.5-3.8]). Of the patients with additional risk factors for QT prolongation, 1.9% of the patients had an ECG at initiation of the prescription, compared with 1.0% during the control period (RR 2.1 [1.2-3.5]). CONCLUSIONS: Compliance with recommendations to perform an electrocardiogram when starting a new QT-prolonging drug is extremely low, when haloperidol is taken as an example.

A detailed description and assessment of outcomes of patients with hospital recorded QTc prolongation.

Corrected QT (QTc) interval prolongation has been shown to be an independent predictor of mortality in many clinical settings and is a common finding in hospitalized patients. The causes and outcomes of patients with extreme QTc interval prolongation during a hospital admission are poorly described. The aim of this study was to prospectively identify patients with automated readings of QTc intervals >550 ms at 1 academic tertiary hospital. One hundred seventy-two patients with dramatic QTc interval prolongation (574 ± 53 ms) were identified (mean age 67.6 ± 15.1 years, 48% women). Most patients had underlying heart disease (60%), predominantly ischemic cardiomyopathy (43%). At lease 1 credible and presumed reversible cause associated with QTc interval prolongation was identified in 98% of patients. The most common culprits were QTc interval-prolonging medications, which were deemed most responsible in 48% of patients, with 25% of these patients taking ≥2 offending drugs. Two patients were diagnosed with congenital long-QT syndrome. Patients with electrocardiograms available before and after hospital admission demonstrated significantly lower preadmission and postdischarge QTc intervals compared with the QTc intervals recorded in the hospital. In conclusion, in-hospital mortality was high in the study population (29%), with only 4% of patients experiencing arrhythmic deaths, all of which were attributed to secondary causes.

Congenital long QT syndromes: prevalence, pathophysiology and management.

Long QT syndrome is a genetic disorder associated with life threatening ventricular arrhythmias and sudden death. This inherited arrhythmic disorder exhibits genetic heterogeneity, incomplete penetrance, and variable expressivity. During the past two decades there have been major advancements in understanding the genotype-phenotype correlations in LQTS. This genotype-phenotype relationship can lead to improved management of LQTS. However, development of genotype-specific or mutation-specific management strategies is very challenging. This review describes the pathophysiology of LQTS, genotype-phenotype correlations, and focuses on the management of LQTS. In general, the treatment of LQTS consists of lifestyle modifications, medical therapy with beta-blockers, device and surgical therapy. We further summarize current data on the efficacy of pharmacological treatment options for the three most prevalent LQTS variants including beta-blockers in LQT1, LQT2 and LQT3, sodium channel blockers and ranolazine for LQT3, potassium supplementation and spironolactone for LQT2, and possibly sex hormone-based therapy for LQT2.

Comparison of droperidol and haloperidol for use by paramedics: assessment of safety and effectiveness.

BACKGROUND: Since the 2001 "black box" warning on droperidol, its use in the prehospital setting has decreased substantially in favor of haloperidol. There are no studies comparing the prehospital use of either drug. The goal of this study was to compare QTc prolongation, adverse events, and effectiveness of droperidol and haloperidol among a cohort of agitated patients in the prehospital setting. METHODS: In this institutional review board-approved before and after study, we collected data on 532 patients receiving haloperidol (n = 314) or droperidol (n = 218) between 2007 and 2010. We reviewed emergency department (ED) electrocardiograms when available (haloperidol, n = 78, 25%; droperidol, n = 178, 76%) for QTc length (in milliseconds), medical records for clinically relevant adverse events (defined a priori as systolic blood pressure (SBP) <90 mmHg, seizure, administration of anti-dysrhythmic medications, cardioversion or defibrillation, bag-valve-mask ventilation, intubation, cardiopulmonary arrest, and prehospital or in-hospital death). We also compared effectiveness of the medications, using administration of additional sedating medications within 30 minutes of ED arrival as a proxy for effectiveness. RESULTS: The mean haloperidol dose was 7.9 mg (median 10 mg, range 4-20 mg). The mean droperidol dose was 2.9 mg (median 2.5 mg, range 1.25-10 mg.) Haloperidol was given i.m. in 289 cases (92%), and droperidol was given i.m. in 132 cases (61%); in all other cases, the medication was given i.v.. There was no statistically significant difference in median QTc after medication administration (haloperidol 447 ms, 95% CI: 440-454 ms; droperidol 454 ms, 95% CI: 450-457). There were no statistically significant differences in adverse events in the droperidol group as compared to the haloperidol group. One patient in the droperidol group with a history of congenital heart disease suffered a cardiopulmonary arrest and was resuscitated with neurologically intact survival. There was no significant difference in the use of additional sedating medications within 30 minutes of ED arrival after receiving droperidol (2.9%, 95% CI: -2.5-8.4%). CONCLUSIONS: In this cohort of agitated patients treated with haloperidol or droperidol in the prehospital setting, there was no significant difference found in QTc prolongation, adverse events, or need for repeat sedation between haloperidol and droperidol.

Assessment of drug-induced torsade de pointes risk for hospitalized high-risk patients receiving QT-prolonging agents.

BACKGROUND: Although risk factors for torsade de pointes (TdP) are known, identifying hospitalized patients at greatest risk for QTcP who should receive cardiac monitoring is poorly defined. OBJECTIVES: Describe the prevalence of risk for TdP in patients and associations between risk factors and QTc prolongation (QTcP) at a tertiary teaching hospital. METHODS: This retrospective analysis assessed physiological and pharmacological risk factors for TdP of adult patients receiving ≥1 QTc-prolonging medications (QTcMed) during hospitalization. The QTcMeds were stratified by risk for causing TdP (probable, possible, and conditional). Baseline electrocardiograms (ECGs) were assessed for QTcP associated with risk for TdP. RESULTS: During a 6-month period, 12,401 (51%) hospitalizations received ≥1 QTcMed. A baseline ECG was obtained for 2381 (19%) patients. A total of 386 (16%) patients with a baseline ECG were found to have QTcP. Significant associations for QTcP were found with the following physiological risk factors: female (P = .021), left-ventricular ejection fraction <40% (P < .0001), cardiac arrest (P < .0001), and cardioversion (P = .007). Significantly more patients with QTcP (n = 209, 54%) received probable-risk QTcMeds than those without QTcP (n = 542, 27%; P < .0001). Probable-risk QTcMeds administered alone or concomitantly with other QTcMeds were more frequently associated with QTcP. No documented cases of TdP were identified. CONCLUSIONS: Of the population receiving QTcMeds, only a small portion had a baseline ECG, identifying a large population at risk of QTcP without appropriate monitoring. Patients with cardiac disease receiving probable-risk QTcMeds were associated with the highest risk of QTcP and should be monitored closely.

Stress proneness in molecularly defined long QT syndrome: a study using temperament assessment by behavioural inhibition system scale.

The long QT syndrome (LQTS) is an inherited cardiac disorder that predisposes the mutation carrier to ventricular arrhythmias that can lead to sudden death. The objective of the present study was to replicate the previous finding in terms of stress-related temperament trait, i.e. behavioural inhibition system (BIS). The study subjects included 583 LQTS mutation carriers (256 symptomatic and 327 asymptomatic) from the Finnish LQTS registry and 79 healthy subjects randomly derived from the population-based sample of the Young Finns Study. Symptomatic and asymptomatic LQTS mutation carriers did not differ from each other on BIS (3.27 versus 3.24, p > 0.05), whereas LQTS mutation carriers scored higher on BIS than the comparison group derived from the representative population-based sample (3.25 versus 2.99, p = 0.003, η² = 0.014). BIS was significantly higher in women than in men (3.32 versus 3.06, p < 0.001, η² = 0.017). The results confirm our previous finding of higher stress proneness of LQTS mutation carriers. Their innate stress proneness may have relevance because it increases our understanding on the role of stress in the manifestation of symptoms.

Facilitating assessment of QT interval duration during ventricular pacing.

AIMS: We aimed to facilitate the assessment of the QT interval duration during conventional right ventricular pacing (VP) by uncovering relationships with the underlying QT interval during intrinsic atrioventricular conduction (IC). METHODS AND RESULTS: The study patients (n = 122, age 68 ± 11 years) were dual-chamber device recipients with preserved IC and narrow QRS complexes. Patients were classified into either 'normal-QT' (n = 70) or 'prolonged-QT' (n = 52) group. Incremental atrial pacing rates were exercised to record serial QT/JT intervals over 5 min periods in IC mode and then in VP mode. Six different QT correction methods for heart rate were applied to assess the effect (i) of pacing mode (IC vs. VP) and (ii) of heart rate on the derived QT(c)/JT(c) intervals by mixed-effects linear models. Following VP, the uncorrected QT/JT intervals as well as the JTc intervals shortened (P < 0.001), whereas the QTc intervals prolonged (P < 0.001). In both patient groups, the Framingham and Nomogram methods demonstrated the optimal balance to assess QTc, with low heart rate dependence during VP and minimal interaction between pacing mode and heart rate. The Rautaharju formula provided excellent correction for the QT changes induced by VP, but the QTc interval responded differently to rate changes in IC vs. VP mode. Bazett's formula exaggerated QTc/JTc rate dependency during VP. CONCLUSION: The Framingham and Nomogram correction methods perform most reliably in assessing the underlying QT interval during IC from the ventricular paced QT interval.

Ventricular repolarization before and after treatment in patients with secondary hypertension due to renal-artery stenosis and primary aldosteronism.

A prolonged QT interval is a risk factor for ischemic heart disease in hypertensive subjects. Patients with renal-artery stenosis and primary aldosteronism (PA) are at increased risk of cardiovascular events. The objective of the present study was to evaluate the QT interval in patients with renovascular hypertension (RV) and PA before and after treatment. A total of 24 patients with RV and 38 with PA were studied; 89 patients with essential hypertension (EH) served as control group. Corrected QT intervals (QTcH) were measured from a 12-lead ECG. Basal QTcH was longer in RV (429±30 ms) and PA (423±23 ms) compared with EH controls (407±18 ms; P<0.001). The prevalence of QTcH >440 ms was higher in RV (29%) and PA patients (29%) compared with EH controls (4%; P<0.001). QTcH interval was evaluated after treatment in 19 RV and 15 PA patients. QTcH was reduced after renal-artery angioplasty in RV patients (419±14 ms; P=0.02), and after spironolactone or adrenalectomy in PA (403±12 ms; P=0.01). In conclusion, QT interval was prolonged in patients with RV and PA compared with controls with EH. After angioplasty of renal-artery stenosis in RV, and treatment with spironolactone or adrenalectomy in PA, the cardiovascular risk of such patients may be reduced by concomitant blood pressure lowering and QT duration shortening.

Mixed models for data from thorough QT studies: part 1. assessment of marginal QT prolongation.

We investigate mixed models for repeated measures data from cross-over studies in general, but in particular for data from thorough QT studies. We extend both the conventional random effects model and the saturated covariance model for univariate cross-over data to repeated measures cross-over (RMC) data; the resulting models we call the RMC model and Saturated model, respectively. Furthermore, we consider a random effects model for repeated measures cross-over data previously proposed in the literature. We assess the standard errors of point estimates and the coverage properties of confidence intervals for treatment contrasts under the various models. Our findings suggest: (i) Point estimates of treatment contrasts from all models considered are similar; (ii) Confidence intervals for treatment contrasts under the random effects model previously proposed in the literature do not have adequate coverage properties; the model therefore cannot be recommended for analysis of marginal QT prolongation; (iii) The RMC model and the Saturated model have similar precision and coverage properties; both models are suitable for assessment of marginal QT prolongation; and (iv) The Akaike Information Criterion (AIC) is not a reliable criterion for selecting a covariance model for RMC data in the following sense: the model with the smallest AIC is not necessarily associated with the highest precision for the treatment contrasts, even if the model with the smallest AIC value is also the most parsimonious model.

In-vitro experimental models for the risk assessment of antibiotic-induced QT prolongation.

The prolongation of the ventricular repolarization and proarrhythmic effects (Torsade de Pointes: TdP) of five reference antibiotics were compared in four in-vitro models. 1. Using the patch clamp technique on the human ether-a-gogo-related gene (HERG) current, the rank order for blockade of the HERG-current (IC(50)) was: sparfloxacin (44 microM)>telithromycin=moxifloxacin=erythromycin (+/-100 microM). 2. Assessing their effects on action potential duration (APD(90)) and incidence of early afterdepolarizations in isolated rabbit Purkinje fibers, the rank order was: sparfloxacin>moxifloxacin>telithromycin>erythromycin (prolongation of APD(90) at 100 microM: 83%, 48%, 33% and 17% from baseline compared to +5% with solvent, P<0.05, respectively). 3. Assessing the drug effects on the APD(60), triangulation, reverse use-dependency, and instability in isolated Langendorff-perfused rabbit hearts, the rank order was: moxifloxacin>erythromycin>sparfloxacin>telithromycin. 4. Assessing their torsadogenic potentials (scores of effects on QT-interval, peak of the T wave to end of T wave: T(p-e), T(p-e)/QT ratio, R wave on T wave (R on T) and TdP in isolated rabbit left ventricular wedge preparations, the rank order for their TdP risk score was: sparfloxacin>erythromycin>moxifloxacin>telithromycin. Additional experiments with grepafloxacin indicate that the rank order to detect grepafloxacin-induced long QT was the wedge preparation>the Purkinje fiber>HERG>the isolated heart, where the isolated heart was unable to detect grepafloxacin-induced APD prolongation. The present study demonstrates that the first three in-vitro models can be used to assess the ability of antibiotic compounds to delay ventricular repolarization. However, with respect to their known clinical effects on QT and TdP incidence, the wedge preparation appears to be more predictive and suitable for detecting torsadogenic action of antibiotics.