Risk Of QTc Interval Prolongation Research Articles

Not‐in‐trial simulation I: Bridging cardiovascular risk from clinical trials to real‐life conditions

The assessment of heart rate-corrected QT (QTc) interval prolongation relies on the evidence of drug effects in healthy subjects. This study demonstrates the relevance of pharmacokinetic-pharmacodynamic (PKPD) relationships to characterize drug-induced QTc interval prolongation and explore the discrepancies between clinical trials and real-life conditions. d,l-Sotalol data from healthy subjects and from the Rotterdam Study cohort were used to assess treatment response in a phase I setting and in a real-life conditions, respectively. Using modelling and simulation, drug effects at therapeutic doses were predicted in both populations. Inclusion criteria were shown to restrict the representativeness of the trial population in comparison to real-life conditions. A significant part of the typical patient population was excluded from trials due to weight and baseline QTc interval criteria. Relative risk was significantly different between sotalol users with and without heart failure, hypertension, diabetes and myocardial infarction (P < 0.01). Although drug effects do cause an increase in the relative risk of QTc interval prolongation, the presence of diabetes represented an increase from 4.0 [95% confidence interval (CI) 2.7-5.8] to 6.5 (95% CI 1.6-27.1), whilst for myocardial infarction it increased from 3.4 (95% CI 2.3-5.13) to 15.5 (95% CI 4.9-49.3). Our findings show that drug effects on QTc interval do not explain the observed QTc values in the population. The prevalence of high QTc values in the real-life population can be assigned to co-morbidities and concomitant medications. These findings substantiate the need to account for these factors when evaluating the cardiovascular risk of medicinal products.

Escitalopram and QTc prolongation

One should not conclude from the discussion by Lam1 that escitalopram is free of cardiac risks. Citalopram and escitalopram differ marginally in terms of their risk of prolonging the QTc interval sufficient to link to torsade de pointes (TdP). Citalopram and escitalopram each demonstrate a dose-dependent QTc prolongation.1 Although the magnitude of QTc prolongation appears to be greater for citalopram than escitalopram, the dose–QTc correlation is similar for both drugs. While the U.S. Food and Drug Administration and Health Canada issued warnings only for citalopram, the Medicines and Healthcare Products Regulatory Agency in the United Kingdom issued safety warnings for both citalopram and escitalopram.2 The threshold for clinical significance of the QTc interval is an absolute duration of 500 ms or longer or a change from baseline of 60 ms or more.3 The warnings did not specify whether any participants enrolled in the thorough QTc studies exceeded these thresholds for either drug. About 500 escitalopram overdoses and nearly 600 citalopram overdoses have been described, without serious cardiac sequelae or deaths due to either drug.4 Less than one-third of patients with citalopram overdoses presented with QTc interval prolongation. In 1 study, 14% of patients with escitalopram overdoses presented with QTc interval prolongation. In another study, the proportion of prolonged QTc intervals associated with escitalopram overdoses (1.7%) was not significantly different from that associated with citalopram overdoses (3.7%). These studies preclude a definitive assessment of the relative cardiotoxicity of citalopram versus escitalopram, but they do not demonstrate clinically meaningful differences in cardiotoxic effects. The mechanisms underlying drug-associated QTc interval prolongation are not well understood. Drug dosage is only 1 of several factors that increase the risk of QTc interval prolongation. In this regard it is notable that fewer than one-third of overdoses with citalopram or escitalopram are associated with QTc prolongation. If dose were a major factor with these drugs, you might expect that most overdoses would be associated with QTc prolongation. In our review,5 QTc interval prolongation or TdP due to citalopram occurred in the setting of citalopram overdose and/or in the presence of well-established risk factors, including advanced age, existing cardiac illness, multiple medical illnesses, electrolyte disturbances (hypokalemia, hypomagnesaemia) and concomitant use of QTc-prolonging drugs. These and other risk factors (baseline prolonged QTc, metabolic inhibition from other drugs, and hepatic impairment) have been emphasized in the regulatory warnings and would be particularly important for drugs like citalopram and escitalopram that prolong QTc interval marginally. Physicians should be mindful of these risk factors when prescribing these medications.

EFFECTIVENESS OF A CLINICAL DECISION SUPPORT SYSTEM INCORPORATING A VALIDATED QT INTERVAL PROLONGATION RISK SCORE FOR REDUCING THE RISK OF QT INTERVAL PROLONGATION IN HOSPITALIZED PATIENTS

The objective of this study was to evaluate the effectiveness of a clinical decision support system (CDSS) for reducing use of drugs known to cause drug-induced torsades de pointes (TdP) and decreasing the risk of QTc interval prolongation in hospitalized patients with known TdP risk factors. We

Incidence and Risk of QTc Interval Prolongation among Cancer Patients Treated with Vandetanib: A Systematic Review and Meta-analysis

BackgroundVandetanib is a multikinase inhibitor that is under assessment for the treatment of various cancers. QTc interval prolongation is one of the major adverse effects of this drug, but the reported incidence varies substantially among clinical trials. We performed a systematic review and meta-analysis to obtain a better understanding in the risk of QTc interval prolongation among cancer patients administered vandetanib.Methodology and Principal FindingsEligible studies were phase II and III prospective clinical trials that involved cancer patients who were prescribed vandetanib 300 mg/d and that included data on QTc interval prolongation. The overall incidence and risk of QTc interval prolongation were calculated using random-effects or fixed-effects models, depending on the heterogeneity of the included studies. Nine trials with 2,188 patients were included for the meta-analysis. The overall incidence of all-grade and high-grade QTc interval prolongation was 16.4% (95% CI, 8.1–30.4%) and 3.7% (8.1–30.4%), respectively, among non-thyroid cancer patients, and 18.0% (10.7–28.6%) and 12.0% (4.5–28.0%), respectively, among thyroid cancer patients. Patients with thyroid cancer who had longer treatment duration also had a higher incidence of high-grade events, with a relative risk of 3.24 (1.57–6.71), than patients who had non-thyroid cancer. Vandetanib was associated with a significantly increased risk of all-grade QTc interval prolongation with overall Peto odds ratios of 7.26 (4.36–12.09) and 5.70 (3.09–10.53) among patients with non-thyroid cancer and thyroid cancer, respectively, compared to the controls.Conclusions/SignificanceTreatment with vandetanib is associated with a significant increase in the overall incidence and risk of QTc interval prolongation. Different cancer types and treatment durations may affect the risk of developing high-grade QTc interval prolongation.

Critical appraisal of lurasidone in the management of schizophrenia

Lurasidone is a new atypical antipsychotic in the benzoisothiazoles class of chemicals. Like most second-generation antipsychotics it is a full antagonist at dopamine D2 and serotonin 5-HT2A receptors, and is a partial agonist at 5-HT1A receptors, a property shared by some but not all older agents. It has much greater affinity for 5-HT7 subtype receptors than other atypical antipsychotics. Pharmacokinetic studies showed that lurasidone is reasonably rapidly absorbed, with bioavailability appearing to be increased by food. Lurasidone undergoes extensive metabolism to a number of metabolites, some of which retain pharmacological activities. Metabolism is mainly by CYP3A4, resulting in steady-state concentrations that vary between individuals and are potentially affected by strong inducers and inhibitors of this enzyme. Short-term clinical trials have demonstrated the efficacy of lurasidone in acute schizophrenia, with doses of 40 and 80 mg/day giving significant improvements from baseline in the PANSS and BPRS scores. The most common adverse events are nausea, vomiting, akathisia, dizziness, and sedation, with minimal increases in the risk of developing metabolic syndrome. Lurasidone did not raise the risk of QTc interval prolongation, although additional studies are required. Long-term trials are also needed to assess the risk of new-onset diabetes. Ongoing trials in patients with bipolar disorder are being completed but, again, efficacy and safety have been investigated only in a few short-term clinical trials.

Cardiovascular risk assessment of atypical antipsychotic drugs in a zebrafish model

The zebrafish model has been developed and evaluated for its ability to predict the toxicity of chemicals. Zebrafish additionally serve as an excellent model for assessing drug-induced cardiotoxicity, although zebrafish and mammalian hearts differ in structure. Recently, regulatory authorities have expressed concerns about a possible relationship between antipsychotics and risk of QTc interval prolongation, serious arrhythmia and sudden cardiac death. In the current study, we performed a cardiovascular risk assessment of six atypical antipsychotic drugs in zebrafish, specifically, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone. Visual endpoints, such as lethality, edema (the presence of heart and trunk edema), hemorrhage (clustering of a pool of blood in an area outside the normal circulation), abnormal body shape (including bent or misshapen caudal region of the larvae) and motility, were evaluated as general toxicity endpoints, and the heart beat rate calculated as the cardiovascular toxicity endpoint. The zebrafish model facilitates determination of the heart beat rate, and may thus be an attractive screening tool for cardiovascular risk assessment of atypical antipsychotic drugs to understand the variations in response to QT-prolonging drugs.

5 HT 3-receptor antagonists and cardiac repolarization time in patients expressing a novel genetic target associated with baseline QTc interval abnormalities

Study Objective To investigate whether a common single nucleotide polymorphism (SNP), rs10494366, is associated with significant prolongation of the QTc interval following administration of 5-HT 3 -receptor antagonists in the perioperative setting. Design Post-hoc analysis of deoxyribonucleic acid (DNA) samples and electrocardiographic (ECG) data from an established perioperative genomics database. Setting University teaching hospital. Measurements DNA samples of 132 ASA physical status 1, 2, and 3 patients were obtained from an established genomic database of surgical patients who had received either granisetron or dolasetron as part of their general anesthesia plan. ECG recordings were collected on all subjects before administration of antiemetic medication, then 10 minutes after drug injection. DNA analysis was performed using TaqMan real-time PCR genotyping assay. Results from the TaqMan real-time PCR assay were used to calculate relative frequencies of the T (major) and G (minor) alleles, in addition to calculating the genotype frequencies. QTc intervals were calculated according to Bazett's formula. Results Relative frequencies for T and G alleles were 0.63 and 0.37, respectively. The relative frequencies of the pertinent genotypes were TT 39.4%, TG 46.9%, and GG 13.7%. No significant difference was noted in QTc interval pre-antiemetic or post-antiemetic drug administration for the homozygous carriers of the minor allele GG ( P = 0.059), but a significant difference was seen in the pre-drug and post-drug QTc intervals in the heterozygous and homozygou s carriers of the major allele TG and TT ( P = 0.003 and P = 0.017, respectively). Compared with homozygous carriers of the minor allele, absolute risk increase for QTc interval prolongation after antiemetic administration was 0.08 and 0.15 in heterozygous and homozygous carriers of the major allele, respectively. Conclusion Homozygous and heterozygous carrier status for the major SNP, rs10494366 allele ( T), in intron 1 of the human NOSA1P gene may be associated with an increased risk of QTc interval prolongation following administration of 5-HT 3 -receptor antagonists in the perioperative setting, when compared with homozygotes for the minor ( G) allele.

Pharmacist Monitoring of QTc Interval–Prolonging Medications in Critically Ill Medical Patients: A Pilot Study

No data exist regarding the value of pharmacist monitoring of drugs associated with QTc interval prolongation. To assess the capability, clinical impact, and economic impact of pharmacists monitoring for drug-induced QTc interval prolongation in critically ill medical adult patients. In a prospective, parallel-group study, 149 consecutive medical intensive care unit (ICU) patients prescribed a QTc interval-prolonging drug at the Los Angeles County + University of Southern California Medical Center were assigned on alternating days to an intervention group (clinical pharmacist on physician team monitored drugs using a standardized algorithm) or a standard care group (team without pharmacist using an algorithm). The monitoring algorithm used daily assessments of electrocardiograms and laboratory data to generate pharmacotherapeutic recommendations. The primary endpoint was the frequency of QTc interval prolongation (>500 msec at any time or an increase > or =60 msec over baseline). Secondary endpoints included QTc interval greater than 470 msec in women or greater than 450 msec in men, mean increase in QTc interval at 48 hours, recommendation acceptance rate, and cost of care. QTc interval prolongation occurred less frequently in the intervention group compared with the standard care group (19% vs 39%, respectively; p = 0.006). Incidence of QTc interval greater than 500 msec (13% vs 33%, respectively; p = 0.003) was also lower in the intervention group. Incidence of QTc interval increase of 60 msec or more over baseline (12% vs 21%, respectively; p = 0.12) and increase in QTc interval at 48 hours over baseline (mean +/- SD; 6.4 +/- 40.8 vs 18.2 +/- 42.3 msec, respectively; p = 0.097) were not significantly different between the groups. Algorithm-generated recommendations were accepted 70% of the time by the intervention group physician team. Total cost and cost per day were not significantly different between groups. In this preliminary study, pharmacist monitoring of QTc interval-prolonging drugs using a simple algorithm was feasible and reduced the risk of QTc interval prolongation. Further studies that monitor other proarrhythmic medications are warranted.

Pediatric Case Report of Quetiapine Overdose and QTc Prolongation

Consideration of the risk of QTc interval prolongation associated with atypical antipsychotic administration is mounting, as this can lead to sudden cardiac death. This is a case report of a 14-year-old boy with a history of major depressive disorder with psychotic features, post-traumatic stress disorder, oppositional defiant disorder, and polysubstance abuse who ingested 1900 mg of quetiapine. One and one half hours after ingestion, the QTc interval lengthened from 453 msec to 618 msec on the printout (manual calculation was 444 msec to 500 msec, respectively). On the baseline EKG, the QTc interval was 411 msec (manual calculation of 416 msec). This report presents an association between higher doses of quetiapine, resulting in higher serum levels and QTc interval prolongation. Also, this report demonstrates the importance of manually calculating the QTc interval to ensure accuracy of the measurement. A review of the literature revealed two case reports and a study where quetiapine was associated with an increase in QTc interval. Further studies are necessary to understand the relationship between higher doses of quetiapine, resulting in higher serum levels, and the propensity for QTc interval prolongation to ensure safe clinical use of this medication.

No Significant QTc Interval Changes with High-Dose Ziprasidone: A Case Series

This study examined the effects of high-dose ziprasidone on the electrocardiograms (ECGs) of adult inpatients. This was done in an effort to assess the incremental risk of QTc interval prolongation when using ziprasidone in doses above the maximum dose of 160 mg/day approved by the Food and Drug Administration. We retrospectively examined pre- and post-treatment QTc intervals in 15 subjects at the James A. Haley Veterans Affairs Medical Center who had received high doses of ziprasidone, ranging from 240 to 320 mg/day, due to intractable psychotic symptoms. Pure baseline ECGs were not always attainable, since the majority of the subjects were taking concomitant medications at the time that ziprasidone was initiated. Analysis yielded an average increase of 3.4 msec from pre- to post-treatment, with a maximum post-treatment interval of 452 msec and no cases having a pre- to post- treatment QTc interval increase > 20 msec. These findings are statistically insignificant and do not approach the 500 msec threshold of concern. This study suggests that high-dose ziprasidone does not have a significant incremental effect on QTc interval prolongation in certain subsets of patients. However, it does not rule out the possibility that ziprasidone could have deleterious effects in higher risk populations or that ziprasidone could have rare, idiosyncratic cardiogenic effects. Limitations of the study are identified and recommendations for future research are presented.