Risk Of Torsade De Pointes Research Articles

The safety of modern anesthesia for children with long QT syndrome.

Patients with long QT syndrome (LQTS) may experience a clinical spectrum of symptoms, ranging from asymptomatic, through presyncope, syncope, and aborted cardiac arrest, to sudden cardiac death. Arrhythmias in LQTS are often precipitated by autonomic changes. This patient population is believed to be at high risk for perioperative arrhythmia, specifically torsades de pointes (TdP), although this perception is largely based on limited literature that predates current anesthetic drugs and standards of perioperative monitoring. We present the largest multicenter review to date of anesthetic management in children with LQTS. We conducted a multicentered retrospective chart review of perioperative management of children with clinically diagnosed LQTS, aged 18 years or younger, who received general anesthesia (GA) between January 2005 and January 2010. Data from 8 institutions were collated in an anonymized database. One hundred three patients with LQTS underwent a total of 158 episodes of GA. The median (interquartile range) age and weight of the patients at the time of GA was 9 (3-15) years and 30.3 (15.4-54) kg, respectively. Surgery was LQTS-related in 81 (51%) GA episodes (including pacemaker, implantable cardioverter-defibrillator, and loop recorder insertions and revisions and lead extractions) and incidental in 77 (49%). β-blocker therapy was administered to 76% of patients on the day of surgery and 47% received sedative premedication. Nineteen percent of patients received total IV anesthesia, 30% received total inhaled anesthesia, and the remaining 51% received a combination. No patient received droperidol. There were 5 perioperative episodes of TdP, all in neonates or infants, all in surgery that was LQTS-related, and none of which was overtly attributable to anesthetic regimen. Thus the incidence (95% confidence interval) of perioperative TdP in incidental versus LQTS-related surgery was 0/77 (0%; 0%-5%) vs 5/81 (6.2%; 2%-14%). With optimized perioperative management, modern anesthesia for incidental surgery in patients with LQTS is safer than anecdotal case report literature might suggest. Our series suggests that the risk of perioperative TdP is concentrated in neonates and infants requiring urgent interventions after failed first-line management of LQTS.

Current use of domperidone and co-prescribing of medications that increase its arrhythmogenic potential among older adults: a population-based cohort study in Ontario, Canada.

Domperidone is commonly used to treat nausea and gastrointestinal disorders. Recent data suggests that it may increase the risk of sudden cardiac death, particularly in older people. Little is known about how it is used in contemporary practice. This study sought to characterize the population of older adults newly dispensed domperidone, describe dosages of domperidone used, and determine the frequency of co-prescribing domperidone with medications that may increase the arrhythmogenic potential of domperidone. This is a retrospective cohort study using administrative health database information from Ontario, Canada. Prescription medication records were obtained from the Ontario Drug Benefit Claims Database. Diagnostic codes were obtained from the Ontario Health Insurance Plan Database, the Canadian Institute for Health Information Discharge Abstract Database, and the same-day surgery database. Patients who received a new prescription for domperidone between April 1, 2003 and March 31, 2010 were included. A total of 122,233 patients met inclusion criteria; 85 % were between 66 and 84 years old and 63 % were female. The mean estimated daily domperidone dose was 35 mg, and the estimated daily dose was <40 mg for 62 % of users. Strong or moderately strong cytochrome P-450 (CYP) 3A4 inhibitors were co-prescribed for 4.3 and 10.7 % of users, while medications with a known risk or possible risk for torsades de pointes (TdP) were co-prescribed to 18.3 and 18.8 % of users. Older domperidone users were commonly co-prescribed drugs with the potential to increase the risk for TdP. These combinations should be avoided, as iatrogenic QT prolongation is a modifiable risk factor for TdP.

Prescribers' practice of assessing arrhythmia risk with QT-prolonging medications.

This study aimed to assess prescribers' monitoring for arrhythmic risk with QT-prolonging medications (LQT drugs). Over a 6-month period, all inpatients under the care of Cardiologists (Cohort A) and General Physicians (Cohort B) at Aberdeen Royal Infirmary who were prescribed drugs with known risk of Torsades de Pointes (TdP) were identified. Admission and repeat electrocardiograms (ECG) after 48h of commencing a LQT drug were examined. Actions taken if QTc was prolonged and drug-drug interactions were examined. A risk estimate on the UK hospital population was calculated. Of the 4133 patients admitted during the study period, 234 (6%) patients were prescribed a LQT drug. There were 100 (43%) patients in Cohort A and 134 (57%) patients in Cohort B. Of those admitted with a pre-existing LQT drug prescription, an ECG was performed in 167 (96%) of patients and QTc prolongation was identified in 59 (34%). Of those who received a new prescription of LQT drug, 23 (38%) had QTc prolongation and more patients in Cohort A than Cohort B had a repeat ECG within 48h (84% vs. 11%, P<0.0001). QTc prolongation was only recognized in 6 (14%) and 2 (5%) patients in cohorts A and B, respectively. Only one patient at risk of drug interaction had QTc prolongation. None of our patients had documented TdP in hospital. Extrapolating these findings to the UK hospital population, at least 204 and <17-175 patients on cardiac and noncardiac LQT drugs, respectively, might be expected to have TdP each year. Recognition of acquired QTc prolongation is poor. Clinician education and an electronic prescribing system may improve this situation.

Pattern of antimalaria treatment and risk factors for torsades de pointes in admitted heart failure patients in Lagos-Nigeria

Background: In a malaria-holoendemic region, concurrent malaria complicating heart failure (HF) occurs; with higher morbidity and increased adverse drug-drug interactions. Aim: To characterise malaria treatment and risk factors of cardio-toxicity among HF patients. Objectives: To characterise the use of anti-malaria agents (AMA), compare risk factors of torsades de pointes (TdP) amongst AMA-users and non-users, and to assess length of hospital stay. Methods: Admitted HF patients were retrospectively studied, and grouped on the basis of malaria treatment. TdP risk factors- advanced age, bradycardia, hypokalemia, and QTc prolongation were compared in the two groups. Results: The 160 HF patients (mean ejection fraction 39.6% ± 12.6%, mean age 54.9 ± 14.6 years) included 82 males (51.3%), with predominant non-ischemic HF. Malaria treatment occurred in 32.5% (52), though diagnosis was presumptive in 48 (92.3%). All (100%) malaria prescriptions were artemisinin-based, but monotherapeutic in 6 (11.4%). Partner-drugs included sulphadoxine-pyrimethamine (SP) 26 (50%), and lumefantrine 7 (13.5%). TdP risk-factors of age 65 years, prolonged QTc, hypokalemia, and bradycardia occurred in 43 (26.9%), 63 (39.4%), 48 (30%), and 8 (5.0%) respectively. Group 1 (AMA treated) and group 2 patients were comparable on all mean values of risk factors. Nevertheless, affected proportions were significantly different for hypokalemia (X2 = 6.1), QTc prolongation (48.1% versus 35.2%, p &lt; .05), and older age (38.5% versus, 21.3%, p &lt; .05%). Conclusion: Though all HF patients similarly demonstrated risks of TdP, univariate analysis indicates a significantly higher proportion in malaria-treated patients; supporting further therapeutic caution in this patient subset.

Determinants of torsades de pointes in older patients with drug-associated long QT syndrome: a case-control study.

Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS. In this retrospective, case-control study, documented reports of drug-associated LQTS plus TdP (n=125) and LQTS without TdP (n=81) in patients ≥65years of age were retrieved from the French Pharmacovigilance Database over a 10-year period. Available clinical, biological, and drug therapy data were compared in the two groups and logistic regression was performed to identify significant predictors of TdP. The uncorrected QT interval was significantly longer in patients with TdP than in patients without TdP (577±79 vs. 519±68 ms; p=0.0001). The number of drugs with a known risk of TdP administered to each patient was not a predictor of arrhythmia, nor was female gender. Logistic regression analysis identified the uncorrected QT interval as the only significant predictor of TdP. The receiver operating characteristic curve analysis was characterized by an area under the curve of 0.77 (95% confidence interval 0.64-0.88) and a QT cutoff of 550ms. The uncorrected QT interval was significantly associated with the probability of TdP in elderly patients with acquired, drug-associated LQTS.

Variability of QT Interval Measurements in Opioid-Dependent Patients on Methadone

Background: Methadone can prolong the QT interval, a precursor to ventricular dysrhythmias. Measurement of the QT interval can vary with intrinsic and extrinsic factors. Our objective was to assess the agreement and repeatability between different QT interval measurements. Methods: We recorded ECGs daily for five consecutive days from adults receiving a stable, single daily dose of methadone for opioid dependence. We compared manually measured QT intervals and the calculated QTc intervals to automated measurements. Results: We obtained 123 ECGs from 26 patients receiving a mean methadone dose of 71 mg/day (range 5 to 240 mg). The manually measured QT intervals from leads II and V5 were similar and consistent (95% limits of agreement -46 to 59 ms), as were the corresponding manual QTc. However, the automated QT reported by the ECG was less consistent (95% limits of agreement -85 to 65 ms), especially at higher QT intervals and at methadone doses over 100 mg/day. Only one of the two subjects at greatest risk for torsades de pointes was identified based on the automated QT reading, while six other patients had at least one automated QTc over 480 ms that could not be confirmed on manual measurement. Conclusions: Accurate identification of QT prolongation in methadone patients is difficult because of intrinsic patient variability in QT length and accuracy of automated measurements. When contemplating ECG screening for this population, these challenges are best overcome with manual and serial QT measurements, especially at doses exceeding 100 mg/day, and interpretation using a QT nomogram to determine risk of ventricular dysrhythmia.

QTc Prolongation with Antipsychotics

Whether or not QTc interval should be routinely monitored in patients receiving antipsychotics is a controversial issue, given logistic and fiscal dilemmas. There is a link between antipsychotic medications and prolongation of QTc interval, which is associated with an increased risk of torsade de pointes (TdP). Our goal is to provide clinically practical guidelines for monitoring QTc intervals in patients being treated with antipsychotics. We provide an overview of the pathophysiology of the QT interval, its relationship to TdP, and a discussion of the QT prolonging effects of antipsychotics. A literature search for articles relevant to the QTc prolonging effects of antipsychotics and TdP was conducted utilizing the databases PubMed and Embase with various combinations of search words. The overall risk of TdP and sudden death associated with antipsychotics has been observed to be low. Medications, genetics, gender, cardiovascular status, pathological conditions, and electrolyte disturbances have been found to be related to prolongation of the QTc interval. We conclude that, while electrocardiogram (ECG) monitoring is useful when administering antipsychotic medications in the presence of co-existing risk factors, it is not mandatory to perform ECG monitoring as a prerequisite in the absence of cardiac risk factors. An ECG should be performed if the initial evaluation suggests increased cardiac risk or if the antipsychotic to be prescribed has been established to have an increased risk of TdP and sudden death.

Chemotherapy and QT Prolongation: Overview With Clinical Perspective.

Cardiotoxic adverse events are of concern to physicians treating cancer patients; they are encountered with a variety of agents. Cardiac events may delay the approval of new drugs or impose burdensome monitoring requirements as either part of the pre-approval process or in the daily use of these agents. Among the cardiac issues are the development of QT prolongation and the fear of torsades de pointes (TdP), an unusual yet potentially fatal form of ventricular tachycardia associated with QT prolongation. Several risk factors, including electrolyte imbalance and polypharmacy with concomitant QT prolonging agents use can increase the risk of TdP in cancer patients; separating the individual contributions of the various triggers for TdP remains problematic. Understanding the individual risk of QT prolongation associated with particular chemotherapies can better differentiate between those shown to have higher risk vs. those with lower risk potential. Cardiac monitoring and electrocardiogram analysis require recognition of the common challenges with regard to the precise measurement of the QT interval such as the presence of U waves, intraventricular conduction delays, and heart rate correction. Rapid identification and treatment of QT prolongation and TdP is critical in mitigating the risk of sudden cardiac death in cancer patients. A multidisciplinary treatment approach among cardiologists and oncologists should be employed to help facilitate an appropriate balance between oncologic efficacy and adverse cardiac events.

Cardiotoxicity Induced by Antifungal Drugs

This review addresses the potential of antifungal drugs to cause cardiac toxicity. Many antifungal drugs, especially antifungal azoles, rarely cause torsades de pointes (TdP) and carry the risk of sudden death. Interventions to avoid TdP should include cautious use of azoles in combination with other drugs that cause QTc prolongation, and elimination of risk factors for TdP whenever possible. These risk factors include: hypokalemia, hypomagnesemia, severe bradycardia, and preexisting long QT syndrome. ECG monitoring should be considered when the use of multiple QT-prolonging drugs is unavoidable and TdP risk factors cannot be resolved. Itraconazole exhibits negative inotropic activity which may present as worsening heart failure in patients with preexisting heart failure. A few cases of severe bradycardia have also been described with voriconazole. Most cases of cardiac toxicity associated with amphotericin B are due to severe electrolyte abnormalities, rapid administration or overdose. Although cardiac toxicity is not common with the use of antifungal drugs, recognition of the potential to cause serious cardiac-related outcomes, evaluation of risk factors, and monitoring is warranted.

SAFETY OF ORAL DOFETILIDE LOADING FOR RHYTHM CONTROL OF ATRIAL ARRHYTHMIAS

Although dofetilide is widely used in the United States for rhythm control in patients with symptomatic atrial fibrillation (AF), there is minimal safety data in the AF population despite its known risk of Torsade de pointes (TdP). We conducted a retrospective chart review of a cohort of 1,404

Antibiotic‐induced Cardiac Arrhythmias

This review aims to clarify the underlying risk of arrhythmia associated with the use of macrolides and fluoroquinolones antibiotics. Torsades de pointes (TdP) is a rare potential side effect of fluoroquinolones and macrolide antibiotics. However, the widespread use of these antibiotics compounds the problem. These antibiotics prolong the phase 3 of the action potential and cause early after depolarization and dispersion of repolarization that precipitate TdP. The potency of these drugs, as potassium channel blockers, is very low, and differences between them are minimal. Underlying impaired cardiac repolarization is a prerequisite for arrhythmia induction. Impaired cardiac repolarization can be congenital in the young or acquired in adults. The most important risk factors are a prolonged baseline QTc interval or a combination with class III antiarrhythmic drugs. Modifiable risk factors, including hypokalemia, hypomagnesemia, drug interactions, and bradycardia, should be corrected. In the absence of a major risk factor, the incidence of TdP is very low. The use of these drugs in the appropriate settings of infection should not be altered because of the rare risk of TdP, except among cases with high-risk factors.

The electromechanical window is no better than QT prolongation to assess risk of Torsade de Pointes in the complete atrioventricular block model in dogs

The electromechanical window (EMW), the interval between the end of the T-wave and the end of the left ventricular pressure (LVP) curve, has recently been proposed as a predictor of risk of Torsade de Pointes (TdP) in healthy animals, whereby a negative EMW (mechanical relaxation earlier than repolarization) after drug administration indicates an increased TdP risk. The aims of this study were to assess (i) the effect of the ventricular remodelling in the canine chronic, complete atrioventricular block (CAVB) model on EMW; (ii) the effect of the I(Kr) -blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility. Our 11 year database of experiments of CAVB in dogs under general anaesthesia was reviewed and experiments included if ECG and LVP were recorded simultaneously at spontaneous rhythm. In total, 89 experiments in 44 dogs were appropriate and were analysed. During normally conducted sinus rhythm or acute atrioventricular block, EMW was positive. During CAVB, EMW was decreased to negative values. Dofetilide further reduced EMW before inducing repetitive TdP in 82% of the experiments. However, subclassification into inducible and non-inducible dogs revealed no difference in EMW. Analysis of the components of EMW revealed that the observed changes in EMW were solely caused by QT prolongation. In the canine CAVB model, ventricular remodelling and I(Kr) block by dofetilide are associated with negative EMW values, but this reflects QT prolongation, and implies that the EMW lacks specificity to predict dofetilide-induced TdP.

Inverstigating Stereoselectivity of Pharmacological Inhibition of Herg Channels

The potential for stereoselectivity of hERG K+ channel inhibition by drugs that exist as racemic mixtures is recognised; stereoselectivity has been established for some compounds (reviewed in (1)). Both the class Ia antiarrhythmic drug disopyramide (DISO) and the serotonin-selective reuptake inhibitor citalopram exist as racemic mixtures. Both have been associated with cases of drug-induced QT prolongation, with its attendant risk of torsades de pointes (TdP). Prior work has established that both compounds inhibit hERG current (IhERG) significantly at low micromolar concentrations (eg 2,3). In this study, we have investigated the potential for stereoselective hERG current (IhERG) inhibition by these drugs.Whole-cell patch-clamp measurements of IhERG were made at 37°C from hERG-expressing HEK 293 cells. All observations reported here are from at least 5 replicates. For citalopram, action potential voltage-clamp experiments were performed on racemic citalopram and the S(+) enantiomer (escitalopram). Application of 3μM citalopram inhibited maximal IhERG during the repolarisation phase of the AP by 69.6±3.6%, whilst escitalopram blocked the current by 63.4±7.1% (p>0.05, student t test). On the other hand, with a conventional screening protocol (S+) DISO was found to block IhERG ∼3 -fold more potently than did (R-) DISO (IC50 values of 3.9±0.6 μM and 12.9±1.4 μM respectively with normal (4mM) [K+]e). With high (94 mM) [K+]e, the IC50 values for (S+) and (R-) DISO were 16.9 ±3.0 μM and 61.1±7.4 μM respectively.Our data provide evidence that disopyramide exhibits stereoselective inhibition of IhERG. Our initial findings with citalopram are suggestive of a lack of notable stereoselectivity for that compound, though this needs further investigation.Funded by the British Heart Foundation(1) Grilo LS, et al, Front Pharmacol, 2010;1:137.(2) Ashok AP,et al, BBSRC, 2001, 280:1243-1250.(3) Witchel HJ, et al, FEBS Lett 2002;512:59-66.

Assessment of Drug-Induced Torsade de Pointes Risk for Hospitalized High-Risk Patients Receiving QT-Prolonging Agents

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. Describe the prevalence of risk for TdP in patients and associations between risk factors and QTc prolongation (QTcP) at a tertiary teaching hospital. 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. 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. 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.

Torsadogenic Risk of Antipsychotics: Combining Adverse Event Reports with Drug Utilization Data across Europe

BackgroundAntipsychotics (APs) have been associated with risk of torsade de Pointes (TdP). This has important public health implications. Therefore, (a) we exploited the public FDA Adverse Event Reporting System (FAERS) to characterize their torsadogenic profile; (b) we collected drug utilization data from 12 European Countries to assess the population exposure over the 2005-2010 period.MethodsFAERS data (2004-2010) were analyzed based on the following criteria: (1) ≥4 cases of TdP/QT abnormalities; (2) Significant Reporting Odds Ratio, ROR [Lower Limit of the 95% confidence interval>1], for TdP/QT abnormalities, adjusted and stratified (Arizona CERT drugs as effect modifiers); (3) ≥4 cases of ventricular arrhythmia/sudden cardiac death (VA/SCD); (4) Significant ROR for VA/SCD; (5) Significant ROR, combined by aggregating TdP/QT abnormalities with VA and SCD. Torsadogenic signals were characterized in terms of signal strength: from Group A (very strong torsadogenic signal: all criteria fulfilled) to group E (unclear/uncertain signal: only 2/5 criteria). Consumption data were retrieved from 12 European Countries and expressed as defined daily doses per 1,000 inhabitants per day (DID).Results Thirty-five antipsychotics met at least one criterium: 9 agents were classified in Group A (amisulpride, chlorpromazine, clozapine, cyamemazine, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone). In 2010, the overall exposure to antipsychotics varied from 5.94 DID (Estonia) to 13.99 (France, 2009). Considerable increment of Group A agents was found in several Countries (+3.47 in France): the exposure to olanzapine increased across all Countries (+1.84 in France) and peaked 2.96 in Norway; cyamemazine was typically used only in France (2.81 in 2009). Among Group B drugs, levomepromazine peaked 3.78 (Serbia); fluphenazine 1.61 (Slovenia).ConclusionsThis parallel approach through spontaneous reporting and drug utilization analyses highlighted drug- and Country-specific scenarios requiring potential regulatory consideration: levomepromazine (Serbia), fluphenazine (Slovenia), olanzapine (across Europe), cyamemazine (France). This synergy should be encouraged to support future pharmacovigilance activities.

Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC Guidelines

Pharmacological rhythm control (often including electrical or pharmacological cardioversion) is an integral part of therapy for atrial fibrillation (AF) worldwide. Antiarrhythmic drug strategies would be preferred in many patients provided effective and safe antiarrhythmic agents are available. Also, pharmacological cardioversion could be the preferred option if the limitations of currently available drugs, such as restriction to patients without structural heart disease (flecainide and propafenone), risk of torsade de pointes (ibutilide), and slow onset of action (amiodarone), were overcome. The intravenous formulation of vernakalant (Brinavess, Cardiome) has been approved for pharmacological cardioversion of recent-onset AF (≤7 days) and early (≤3 days) post-operative AF in the European Union, Iceland, and Norway. Vernakalant has a high affinity to ion channels specifically involved in repolarization of atrial tissue and has minimal effects in the ventricles and thus, is thought to have a low proarrhythmic potential. Vernakalant is administered as a 10 min infusion of 3 mg/kg, and if AF persists after 15 min, an additional dose of 2 mg/kg can be given. The efficacy and safety of the drug has been extensively investigated in randomized controlled trials against placebo and an active comparator (amiodarone). The placebo-extracted efficacy of vernakalant is ∼47%. A significant advantage is a rapid effect, with the median to conversion ranging between 8 and 14 min, with the majority of patients (75-82%) converting after the first dose. Vernakalant retained its efficacy in subgroups of patients with associated cardiovascular disease such as hypertension and ischaemic heart disease, but its benefit may be lower and risk of adverse effects is higher in patients with heart failure. In the post-market reports, cardioversion rates with vernakalant are 65-70%. This review focuses on the role of vernakalant in pharmacological cardioversion for AF.

Selective serotonin reuptake inhibitors and torsade de pointes: new concepts and new directions derived from a systematic review of case reports.

In the light of the recent United States Food and Drug Administration (FDA) warning to clinicians on using previously approved doses of citalopram because of the purported higher risk of torsade de pointes (TdP), we pursued the broader question: are selective serotonin reuptake inhibitor (SSRI) antidepressant agents as a group unsafe because they might induce QTc interval prolongation and TdP? We reviewed the literature and found only 15 case reports (6 of fluoxetine, 1 of sertraline and 8 of citalopram) of SSRI-associated QTc interval prolongation linking to TdP. A total of 13 cases contained sufficient information for analysis. In the setting of TdP, QTc interval prolongation does not clearly relate to SSRI dose. Applying conventional statistics as the FDA does may not be the best tool to study this phenomenon because SSRI-associated TdP is a very rare event and hence best understood as an 'extreme outlier'. Despite the limitations inherent in case report material, case reports on drug-associated QTc interval prolongation and TdP provide valuable information that should be considered along with other sources of information for clinical guidance.

Prolonged QT interval by methadone: Relevance for daily practice? A prospective study in patients with cancer and noncancer pain

Increased methadone use in patients with pain has raised concerns that the effect of methadone on the QT interval duration and the potential risk of torsades de pointes (TdP) has been underestimated. Most studies on prolonged QT intervals by methadone are performed in maintenance patients; however, doses of methadone in pain treatment are much lower. Hardly any studies have prospectively addressed QT interval prolongation by methadone in patients with pain, and this study aims to address this literature gap. In a period of 3 years, while 130 patients used methadone as pain treatment at a stable dose for at least 1 week, 12-lead electrocardiograms (ECGs) were performed. Corrected QT times, demographic features, methadone dose, duration of therapy, and relevant comedication were documented. The findings included 50 percent of 130 patients, with a mean methadone dose of 18.2 mg/d, were potentially at risk for TdP. Beyond this, 5 percent were at definite risk for TdP. No correlations were found between QTc and gender, age, serum potassium or magnesium levels, methadone dose, underlying disease, or comedication. The study found that in our patients with pain, with relatively low doses of methadone, 5 percent had QTc times ≥500 ms and were thus at serious at risk for TdP. ECGs have to be made in all patients with methadone therapy 1 week after introducing methadone (or after dosage increases).

MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes

Drug-induced block of the cardiac hERG (human Ether-à-go-go-Related Gene) potassium channel delays cardiac repolarization and increases the risk of Torsade de Pointes (TdP), a potentially lethal arrhythmia. A positive hERG assay has been embraced by regulators as a non-clinical predictor of TdP despite a discordance of about 30%. To test whether assaying concomitant block of multiple ion channels (Multiple Ion Channel Effects or MICE) improves predictivity we measured the concentration-responses of hERG, Nav1.5 and Cav1.2 currents for 32 torsadogenic and 23 non-torsadogenic drugs from multiple classes. We used automated gigaseal patch clamp instruments to provide higher throughput along with accuracy and reproducibility. Logistic regression models using the MICE assay showed a significant reduction in false positives (Type 1 errors) and false negatives (Type 2 errors) when compared to the hERG assay. The best MICE model only required a comparison of the blocking potencies between hERG and Cav1.2.

QT variability during initial exposure to sotalol: experience based on a large electronic medical record

A prolonged QT interval is associated with increased risk of Torsades de pointes (TdP) and may be fatal. We sought to investigate the extent to which clinical covariates affect the change in QT interval among 'real-world' patients treated with sotalol and followed in an electronic medical record (EMR) system. We used clinical alerts in our EMR system to identify all patients in whom a new prescription for sotalol was written (2001-11). Rate-corrected QT (QTc) was calculated by Bazett's formula. Correlates of sotalol-induced change in the QTc interval and sotalol discontinuation were examined using linear and logistic regression, respectively. Overall, 541 sotalol-exposed patients were identified (n = 200 women, 37%). The mean first sotalol dose was 86 ± 39 mg, age 64 ± 13 years, and BMI 30 ± 7 kg/m(2). Atrial fibrillation/flutter was the predominant indication (92.2%). After initial exposure, the change in the QTc interval from baseline was highly variable: ΔQTc after 2 h = 3 ± 42 ms (P = 0.17) and 11 ± 37 ms after ≥48 h (P < 0.001). Multivariable linear regression analysis identified female gender and age, reduced left ventricular ejection fraction, high sotalol dose, hypertrophic cardiomyopathy, and loop diuretic co-administration as correlates of increased ΔQTc at ≥48 h (P < 0.05 for all). Within 3 days of initiation, 12% discontinued sotalol of which 31% were because of exaggerated QTc prolongation. One percent developed TdP. In this EMR-based cohort, the increase in QTc with sotalol initiation was highly variable, and multiple clinical factors contributed. These data represent an important step in ongoing work to identify real-world patients likely to tolerate long-term therapy and reinforces the utility of EMR-based cohorts as research tools.