QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience

Background: Evidence has accrued that several non-cardiac drugs may prolong cardiac repolarisation (hence, the QT interval of the surface electrocardiogram) to such a degree that potentially life-threatening ventricular arrhythmias (e.g. torsades de pointes) may occur, especially in case of overdosage or pharmacokinetic interactions. Discussion: This has fostered discussion on the molecular mechanisms underlying the class-III anti-arrhythmic effect shared by apparently disparate classes of drugs, on the clinical relevance of this side effect and on possible guidelines to be followed by drug companies, ethics committees and regulatory agencies in the risk–benefit assessment of new and licensed drugs. This review provides an update on the different classes of non-cardiac drugs reported to prolong the QT interval (e.g. histamine H₁-receptor antagonists, antipsychotics, antidepressants and macrolides), on the possible underlying molecular mechanisms and on the clinical relevance of the QT prolonging effect. Identification and widespread knowledge of risk factors that may precipitate prolongation of the QT interval into life-threatening arrhythmias becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia), impaired hepatic/renal function and concomitant treatment with other drugs with known potential for pharmacokinetic/pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class-I or -III anti-arrhythmic agents). Future perspectives for drug research and development are also briefly outlined. Received: 4 October 1999 / Accepted in revised form: 13 January 2000     

QT interval measurement in the dog: chest leads versus limb leads

Introduction: An accurate measurement of the QT interval is dependent on the accurate identification of the end of the T wave. Although chest leads have been recommended in dog toxicology studies, their use has not been widely put into practice, as shown by a recent survey on methodology for ECG collection in the pharmaceutical industry. Therefore, there is little published data on dog QT measurement from chest leads. Methods: Electrocardiograms (ECGs) were taken from 100 beagle dogs (50 males, 50 females), with the dogs restrained in a sling. On the day of recording, measurements were performed at time zero and 1 h later. Recordings were repeated 7 to 10 days later. QT interval measurements were taken simultaneously from Lead II and the chest Lead CV5RL. Heart rate was taken from Lead II. Statistical analyses included the calculation of a QT correction formula, comparison of the mean values and variability of QT and QTc measurements from Leads II and CV5RL, the comparison of T-wave polarity from both leads, and a power analysis for QT and QTc. Results: The T wave was positive in almost all dogs (99/100) in the Lead CV5RL at all measurement periods, while it was either positive or negative in Lead II (64–75/100), and the incidence of positive T wave varied between measurement periods. The QT interval was significantly shorter (194±11 to 197±12 vs. 197±13 to 200±12 ms) when measured from the CV5RL lead at all recording periods and in both sexes. In addition, the standard deviation for QT measurement within each individual ECG record demonstrates less intra-animal variation when QT is measured from Lead CV5RL compared with Lead II (3.8 vs. 13.2 ms). The linear regression between QT and heart rate was improved when QT measurements were taken from CV5RL, as shown by the percentage of variability R². Discussion: Estimates of the sample sizes showed that fewer animals would be required to detect a change at both the high and the mid-doses when using the chest Lead CV5RL. Using Lead II, we are able to detect within-animal changes of 10% in either QT or QTc; with Lead CV5RL, we are able to detect 10% change in QT and 5% change in QTc.     

QT prolongation in guinea pigs for preliminary screening of torsadogenicity of drugs and drug-candidates. II

Experimental approaches on anaesthetised guinea pigs have been shown recently to be satisfactorily predictive of the torsadogenic risk of drugs. This work aimed at obtaining additional data, for a further understanding of the reliability and/or the limits of this model. Clonidine (non-torsadogenic in humans) induced a lengthening of the ECG parameter of RR in anaesthetised guinea pigs, without any corresponding increase of QT (corrected by the algorithms of Bazett and Fridericia). Thus, 'QT correct' prolonging effects produced by drugs torsadogenic in humans, on the guinea pig model are primarily due to inhibition of cardiac repolarisation. The corresponding RR prolongation is a consequence (not the cause) of this primary effect. Astemizole, haloperidol and terfenadine, torsadogenic in humans, produced in Langendorff perfused guinea pig hearts a prolongation of the QT interval. Chlorprotixene (non-torsadogenic) did not produce any significant effect on QT. These results are fully consistent with previous observations in anaesthetised guinea pigs. In Langendorff perfused hearts, pentobarbital does not affect cardiac repolarisation and does not potentiate the QT-prolonging effect of astemizole. Together with the findings reported by many authors, these data suggest that ECG recording in anaesthetised guinea pigs is a reliable model for cardiac safety studies evaluating the influence of drugs on the repolarisation process.     

Pharmacogenetics of cardiac K(+) channels

A number of commonly prescribed drugs belonging to various therapeutic classes (antiarrhythmic, antibiotic, antifungal, antihistamine, antipsychotic, prokinetic drugs…) possess, in common, the adverse property to prolong cardiac repolarization [prolonged QT interval duration on surface electrocardiogram (ECG)], exposing patients to a risk of torsade-de-pointes arrhythmias, syncope, and sudden death. Arrhythmias related to drug-induced QT prolongation do not occur in every patient treated with these drugs but most likely occur in a subset of susceptible patients. These patients have a high risk of recurrence of arrhythmias upon exposure to any of the other drugs that broaden the QT interval. It is currently suspected (though not yet proven) that susceptible individuals carry a silent mutation in one of the genes responsible for the congenital long QT syndrome. Indeed, it appears more and more clear that a large proportion of congenital long QT syndrome gene carriers, have a normal QT interval and a normal phenotype and therefore, remain undiagnosed. Therefore, a much larger than previously thought proportion of the general population may be affected by asymptomatic mutations in cardiac ion channel encoding genes. No routine technology is currently available in identifying these patients preventively.     

Assessment of the effect of a single oral dose of telithromycin on sotalol-induced qt interval prolongation in healthy women

AIMS: Telithromycin belongs to ketolides, a new class of macrolide antibiotics. Macrolides are known to have the potential to prolong QT interval duration. Previous studies have shown that telithromycin did not induce significant QT interval prolongation in healthy subjects compared with placebo. The main objective of this study was to demonstrate the absence of amplification of QT interval prolongation induced by sotalol, when telithromycin and sotalol were co-administered. The secondary objective was to correlate the QT interval changes induced by the study drugs to plasma concentrations during the elimination phase. METHODS: Twenty-four women received sotalol (160 mg) together with placebo or telithromycin (800 mg) in a two-period, double-blind, randomized study. Electrocardiograms were recorded at rest. Comparison of maximal corrected QT interval (QTc(max)) with sotalol in the presence or absence of telithromycin was performed. The relation between sotalol concentration and QTc was studied using linear regression. RESULTS: Mean difference (95% CI) between QTc(max) with sotalol-placebo and QTc(max) with sotalol-telithromycin was -15.5 ms (-27.7 to -3.2 ms). QTc(max) interval prolongation was lower (P < 0.05) with sotalol-telithromycin than with sotalol-placebo, in relation to decreased sotalol plasma concentrations. Regression analysis showed that the relationship between sotalol plasma concentration and QTc interval duration was not modified by telithromycin co-administration. CONCLUSION: Our results do not support a potential synergistic effect on QT interval prolongation between sotalol and telithromycin. The decrease of mean QTc interval in subjects taking telithromycin and sotalol may be explained by a decrease of sotalol concentration.     

Drugs that prolong QT interval as an unwanted effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias

Medicinal products that, as an unwanted effect, prolong the QT interval of the electrocardiogram (ECG) can trigger episodes of polymorphic ventricular dysrhythmias, called torsades de pointes, which occasionally culminate in sudden death. The accurate measurement of QT interval requires the adoption of appropriate criteria of recording, measurement and data processing. Traditionally, QT interval is standardised to a reference heart rate of 60 beats/min by using the Bazett algorithm. However, this correction method can bias observed QT intervals in either direction. The ECG reflects cardiac electrical currents generated by ions (Na⁺, K⁺ and Ca²⁺) entering and leaving the cytosol mainly via transmembrane channels. Na⁺ and Ca²⁺ carry inward depolarising currents (I_Na, I_Ca) whereas K⁺ carries outward repolarising currents (I_to, I_Kr, I_KS and I_K1). Sometimes, a prolonged QT interval is a desired drug effect but, more commonly it is not, and reflects abnormalities in cardiac repolarisation heralding torsades de pointes. Furthermore, the potential torsadogenic activity of drugs is favoured by concurrent cardiac risk factors (old age, female gender, bradycardia, electrolyte imbalances, cardiac diseases etc.) which reduce cardiac repolarisation reserve. The evaluation of the cardiac safety of drug candidates can be started by determining their potency as I_Kr blockers in cloned Human Ether-a-go-go Related Gene (HERG) channels expressed in mammalian cells. Compounds passing successfully this test (desirable cardiac safety index >> 30, calculated as ratio of IC₅₀ against I_Kr over ED₅₀ determined in an efficacy test) should be further investigated in other relevant human cardiac ion currents, in in vitro animal heart preparations and finally in in vivo pharmacodynamic models. The decision as to whether the potential benefit of a new drug outweighs the cardiac risk inherent in its therapeutic use should be made in the light of the condition that it is expected to treat and with reference to alternative drug therapies. If a drug represents a unique therapeutic advance, non-clinical and clinical signals of unsatisfactory cardiac safety may not constitute sufficient grounds to abandon its development. However, if the drug offers only marginal benefits over existing therapies, decisions concerning its possible development should be taken by corporate policy makers.     

丹红注射液对兔离体左心室心电图及致心律失常作用

目的 观察丹红注射液(抗凝中药)对兔心脏电活动除极和复极过程的影响.方法 选用冠状动脉灌注兔左心室楔形组织块标本,对标本施加刺激周长(BCL)1000 ms基础刺激,1 h后进行实验;实验组给予丹红注射液;同时,分别以卡托普利和司帕沙星作为阴性对照组和阳性对照组,观察对跨壁心电图QRs复合波时程、QT间期、T波峰值至终点的时程(Tp-e)的影响,以及是否引早期后除极(EAD)和尖端扭转型室速(TdP).结果 丹红注射液对QRS波宽度无明显影响;当给予20、60 mL·L~(-1)时,较阴性对照组QT间期轻度延长(P<0.05),并与相关浓度的卡托普利作用一致;但对Tp-e间期及Tp-e/QT比值均无明显影响(P>0.05),且未诱发EAD或Tdp.结论 丹红注射液在本实验浓度范围内,仍无明显诱发尖端扭转型室速和其他室性心律失常的危险性.     

Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers

1 Sparfloxacin, a new fluoroquinolone, slightly increases the duration of the QT interval. Reverse rate-dependence of QT interval prolongation has been shown for many agents that are known to prolong QT interval duration, and QT prolongation at slow heart rates may be a risk factor for torsades de pointes.
2 A double-blind, randomized, placebo controlled, crossover study was performed in 15 healthy volunteers to determine the effects of single oral doses of sparfloxacin (200 and 400  mg) on the QT interval at various heart rates.
3 12-lead ECGs were recorded at rest and during exercise tests 5  h after sparfloxacin or placebo administration. QT intervals were calculated at predetermined RR intervals (1000, 800, 700, 600, 500 and 400 ms) after individual QT-RR curve fitting.
4 Sparfloxacin at both doses induced prolongation of the QT interval which was around 4% greater than placebo. No significant reverse rate-dependence of QT interval prolongation was observed.
5 Oral administration of sparfloxacin appears unlikely to be associated with marked QT interval prolongation.     

Simple-to-use, reference criteria for revealing drug-induced QT interval prolongation in conscious dogs

Electrocardiogram (ECG) QT interval prolongation produced by drugs in certain animal models is currently believed to be predictive of cardiac proarrhythmic effects in humans. For this reason, nonclinical assessment of the effects of novel drugs on cardiac repolarization is a regulatory prerequisite for progressing such agents to clinical evaluation. The present investigation was carried out to develop reliable, simple-to-use reference criteria for identifying individual animals as responders to drugs that prolong the QT interval. ECG were recorded for 30 s at 0 (8 am), 2, 4, 6 and 24 h in 6 trained, conscious, beagle dogs during 5 control experimental sessions. QT intervals were measured and corrected for heart rate by applying the Van de Water algorithm (QTc). The maximal (QTc(max)) and minimal (QTc(min)) values of QTc observed in each of the five control recording sessions were noted. Two reference (R) criteria were used to designate an individual animal as a responder to drug treatment: 1) QTc(maxR) which was obtained by adding 10 ms to the largest value of QTc(max) observed during the five control recording sessions and 2) (QTc(max)-QTc(min))(maxR) which was obtained by increasing by 50% the largest of the (QTc(max)-QTc(min)) values [(QTc(max)-QTc(min))(max)] observed in the 5 control recording sessions. The sensitivity and reliability of these criteria were tested by determining QTc intervals before and 2, 4, 6 and 24 h after placebo or quinidine (200, 400 and 800 mg p.o. per animal). The reference values of QTc(maxR) and (QTc(max)-QTc(min))(maxR) for the various dogs ranged from 246 to 270 ms and from 15 to 19.5 ms, respectively. The number of dogs responding to treatment (T: quinidine at 200, 400 and 800 mg, p.o. per animal) with a QTc(maxT) and/or a (QTc(max)-QTc(min))(maxT) equal to or greater than the respective reference values was, respectively, 1/6, 3/6 and 5/6 dogs. Additionally, the number of responders correlated well with the concentration of free quinidine in the plasma. In conclusion, this investigation succeeded in establishing reliable, reference criteria for individual dogs despite the intrinsic daily variation of QTc interval. The application of these criteria allowed identifying individual animals responding to quinidine with delayed cardiac repolarization.     

QT prolongation in anaesthetized guinea-pigs: an experimental approach for preliminary screening of torsadogenicity of drugs and drug candidates

Many non-cardiovascular drugs can prolong the QT interval of the electrocardiogram (ECG); this is an accessory property not necessary for their pharmacological action and generally linked to the block of the potassium HERG channels and delayed cardiac repolarization. The QT prolongation can lead to a dangerous tachyarrhythmia, called torsade de pointes, and potentially to fatal ventricular fibrillation. The experimental approaches, aimed at an early identification of this undesidered property, often require sophisticated and expensive equipment or the use of superior animal species (dog, primates) that cannot be employed easily for ethical and/or economic reasons.This work aimed to study drug-induced QT prolongation in anaesthetized guinea-pigs and to evaluate the reliability of such an experimental approach to obtain a satisfying predictive parameter of the torsadogenicity of drugs in humans. Seven drugs that were torsadogenic in humans (astemizole, cisapride, haloperidol, quinidine, sotalol, terfenadine and thioridazine) and two that were non-torsadogenic (chlorprotixene and diazepam) were administered i.v. to guinea-pigs under pentobarbital anaesthesia. The ECGs were recorded by four electrodes inserted in the subcutaneous layer of the limbs. Both RR and QT intervals were measured in Leads II and III and then the correct QT values were calculated by Bazett and Fridericia algorithms (QTcB and QTcF, respectively). All the drugs, with the exception of chlorprotixene and diazepam, produced a dose-dependent prolongation of the QT and RR intervals and a significant increase of QTcB and QTcF values. It can be concluded that this method represents a rapid and low-cost procedure to evaluate the cardiac safety pro fi le in the preliminary screening of a high number of drugs or drug candidates.     

莫西沙星在全面QT研究中的应用及特点

莫西沙星作为一种新型广谱氟喹诺酮类抗菌药在临床上主要用于治疗成人呼吸道感染。该药具有明确的可导致心电图QT间期延长的作用,同时对心率影响不大,相对于其他导致QT间期延长的药物来说,其导致的心律失常及其他的不良反应较为轻微,是目前全面QT研究中最常用的阳性对照药物。本文对莫西沙星在该项研究中的应用及其QT作用的特点进行了阐述。     

抗新型冠状病毒药物致QT间期延长的文献复习及药学监护

本文对新型冠状病毒肺炎患者临床用药方案涉及的抗病毒药物致QT间期延长的文献报道情况进行复习。根据目前文献复习结果可知,洛匹那韦/利托那韦和磷酸氯喹存在引起QT间期延长进而引发尖端扭转型室速的潜在风险。在新型冠状病毒肺炎患者中使用此类药物需关注由此带来的用药风险,熟悉临床上常用的可引起QT间期延长的药物,提高识别患者QT间期延长的易感因素和药物相互作用的能力,重视心电图、电解质管理来预防临床潜在的药物致急性心律失常事件,以降低新型冠状病毒肺炎患者的药物不良反应,避免药源性损害。     

Circadian changes in the QT variability index in the beagle dog

1. QT variability is a non-invasive marker of cardiac repolarization lability and a higher QT variability is associated with sudden death. No data exist as to the circadian fluctuations in QT variability and the QT variability index (QTvi) in the canine. The purpose of the present investigation was to explore QT interval variability over 24 h in the healthy dog. 2. Continuous lead II electrocardiogram and blood pressure data were collected for 24 h from three beagles instrumented with radiotelemetry devices. The mean heart rate (HR), detrended HR variance, mean QT interval and detrended QT variance were calculated from the instantaneous HR and QT time series of 1024 points (256 s), as described previously, and a normalized QTvi was derived. 3. The dog has a diurnal pattern of QTvi similar to healthy humans. Both dogs and humans exhibit a significantly higher QTvi during active waking hours, with more negative values during deep sleep. 4. These findings suggest QTvi may serve as an additional non-invasive tool to assess ventricular repolarization lability in dogs in relation to any conditions or drugs that are known to be associated with increased cardiac mortality.     

临床药师在莫西沙星致QT间期延长不良事件中的实践

1例59岁女性患者,入院诊断考虑肺部感染,给予莫西沙星联合头孢曲松抗感染治疗,当日心电图检查发现患者QT间期出现延长,考虑莫西沙星所致。临床药师查阅相关文献,明确了QT间期延长的标准,并根据药物致QT间期延长的高危因素评分表,对患者进行评估后,与医生充分沟通,提出停用莫西沙星的建议,医生予以采纳。停用莫西沙星第2天,复查心电图提示患者QTc值恢复正常,治疗19 d后患者病情好转出院。     

老年人短QT间期综合征与恶性心律失常的关系

目的：探讨老年人短QT间期综合征（SQTS）与恶性室性心律失常的关系。方法：随机测量72例老年人常规12导联心电图（ECG）QTfc和QTnc间期,根据R-R间期（R-R）和心率（HR）计算校正QT间期（QTfc、QTnc）值。QTfc、QTnc间期值≤300ms为短QT间期,观察短QTfc、QTnc间期与恶性室性心律失常的关系。应用利多卡因、奎尼丁、氟卡尼和除颤器（ICD）治疗,观察预后。结果：QTfc≤300ms的1年内总恶性室性心律失常发生率为72.22%,死亡率为38.89%;QTnc≤300ms总恶性室性心律失常发生率为72.22%%,死亡率为38.89%;利多卡因转律83.33%;奎尼丁、氟卡尼可使6例QTfc、6例QTnc间期值平均延长20ms,减少了恶性室性心律失常发生,P〈0.05;除颤器治疗6例SQTS患者在观察的1年中无恶性室性心律失常和死亡发生。结论：短QT间期与恶性室性心律失常有关;利多卡因可转律;奎尼丁、氟卡尼能延长QT间期,可减少恶性室性心律失常发生;ICD能有效防止恶性室性心律失常和死亡的发生。     

Multiple Source Annotation of ECG T-Waves for Measuring QT in Drug Development

QT interval (adjusted for heart rate) of electrocardiogram (ECG) is the current measure for assessing cardiac safety of noncardiac drugs in drug development. It measures the length between the onset of the Q-wave and the offset of the T-wave. Many single-lead methods are developed to annotate the wave boundaries. While they agree quite closely on the onsets of the Q-waves, often times they differ by large margins on the offsets of the T-waves, since the T-waves are more variable. We propose three methods to combine the annotation results from multiple sources, which can either be annotations from different leads or annotations using different methods. The three methods are the meta-analysis methods for integrating independent and dependent sources and the Bayes-expectation-maximization (EM) algorithm method. The results from these information integrated methods are much better than those obtained from single-source methods, which is illustrated by a simulation study and real-data applications.     

运用回归分析法对心电图QT间期正常界限值快速估算的分析研究

传统的心电图ＱＴ间期正常界限值的计算方法较为繁琐，本文运用回归分析法推算出ＱＴ间期正常界限值：（３ｍ＋１８）／１００≤ＱＴ≤（ｎ＋２０）／１００（ｍ、ｎ分别为ＲＲ间期的中格数、小格数，ＱＴ间期单位为秒，适用范围为１２≤ｎ≤３０，ｍ＝ｎ／５），据此可进行快速估算，值得在临床心电图诊断中推广应用。     

西沙必利与其他药物的相互作用

目的 了解促胃肠动力药西沙必利与其他药物合用时的相互作用。方法 通过对近期文献的阅读、分析和归纳，加以综述。结果 西沙必利由细胞色素P—450(CYP)3A4代谢，有较强的首过效应，所以许多CYP3A4底物或(和)抑制剂都能抑制西沙必利的代谢，使其血药浓度升高，从而可能引起心脏QT间期延长、心律失常，甚至导致扭转型室速(TdP)。药效学研究表明，西沙必利与可以引起QT间期延长的药物合用后，也可能增加心脏的毒性反应。结论 西沙必利应避免与CYP3A4抑制刑、CYP3A4底物及易引起QT间期延长的药物合用。如果必需合用，应密切观察合用后的情况，并进行心电监护或血药浓度的监测，以保证临床用药的安全有效。     

EFFECTS OF THORACIC EPIDURAL ANAESTHESIA ON CARDIAC REPOLARIZATION

• 1 Prolongation of the QT interval is associated with a risk of life‐threatening cardiac arrhythmias. In the present study, we examined whether reversible blockade of preganglionic sympathetic fibres of the heart, achieved by thoracic epidural anaesthesia, affects cardiac repolarization and thus confers an anti‐arrhythmic effect.
• 2 Fifty‐two men, aged between 28 and 65 years, were included in the study: 28 were patients scheduled for thoracic epidural anaesthesia (Group T) and 24 were patients scheduled for lumbar epidural anaesthesia (Group L). Epidural blockade was achieved with 0.5% isobaric bupivacaine solution. Measurements were taken from electrocardiogram fragments obtained before epidural anaesthesia and after detection of blockade (T1 or T8 segment sensory block in Groups T and L, respectively). Correction of the QT interval was calculated using Bazett's formula (QT_cb), Fridericia's correction (QT_cf) and the Framingham formula (QT_cF). Transmural dispersion of repolarization (TDR) was determined using the T_peak – T_end time, where T_peak is the peak of the T wave and T_end is the end of the T wave.
• 3 Significant shortening of the QT_cb interval and TDR was detected after blockade in Group T. However, there were no changes in the ECG parameters in Group L.
• 4 In conclusion, reversible blockade of preganglionic sympathetic fibres to the heart, achieved by thoracic epidural anaesthesia, results in a reduction in QT_cb, as well as the TDR. These changes may explain the anti‐arrhythmic action seen with central blockade.