Drug-Induced QT Prolongation and Torsades de Pointes: An All-Exclusive Relationship or Time for an Amicable Separation?

QT prolongation was perceived as a major antiarrhythmic mechanism, but soon became a surrogate for torsades de pointes (TdP) instead. Drugs that prolong the QT interval range from having potent torsadogenic activity to no proarrhythmic action and even antiarrhythmic effects. Blockade of hERG channels is the primary cause of TdP, but blockade/activation of other channels can also be torsadogenic. TdP is primarily caused by disturbances of TRIaD, but disturbance of wavelength can also contribute to TdP (where TRIaD is triangulation, reverse use dependence, instability and dispersion, and wavelength equals conduction velocity times effective refractory period). The above proarrhythmic parameters do not only result in TdP, but can also lead to ventricular tachycardia (VT) and ventricular fibrillation (VF). Note that QT prolongation (not listed as a causal factor) yields many false positives (potentially depriving patients from much needed drugs) and false negatives (potentially exposing patients to lethal arrhythmias). Thus, drug-induced QT prolongation is a bad surrogate for TdP, VT or VF; it is high time to move away from an oversimplified and erroneous surrogate.

Should Domperidone be Used as a Galactagogue? Possible Safety Implications for Mother and Child.

Domperidone has been used as a galactagogue; however, solid evidence from an adequate sized randomized clinical trial is missing. Optimal dosage, start of treatment, length of treatment and scope of patients who can benefit also remain unknown. Although milk obtained after domperidone administration has not been shown to have untoward effects on newborns, no sufficiently large randomized clinical trial has been done to establish safety. Domperidone has repeatedly been shown to produce sudden cardiac death, starting at 30 mg/day. Because of this known cardiac effect, the use of domperidone to increase breast milk production may not be justified.

Disturbances of cardiac wavelength and repolarization precede Torsade de Pointes and ventricular fibrillation in Langendorff perfused rabbit hearts.

Drug-induced proarrhythmia is strongly focused on Torsade de Pointes (TdP), and QT prolongation is commonly used as a surrogate for TdP. This surrogate may be of limited value, as it produces false positives and false negatives. Cardiac electrophysiological parameters were obtained from monophasic action potentials recorded from Langendorff perfused female rabbit hearts. In 3939 experiments 179 VFs and 124 TdPs occurred during testing of various chemicals. TdP occurred with prolongation of action potential duration (APD), but also with shortening. Thus, APD/QT prolongation alone cannot predict TdP. Drug-induced abnormalities, associated with TdP or VF, were identified. The 11 most predictive abnormalities were combined in a proarrhythmic score, proportional to the incidence and amplitude of the abnormalities. This score significantly increases starting at concentrations ∼100-fold below that at which TdP/VF developed (P < 0.001) and preceded all TdP and ∼98% of VF. This derived proarrhythmic score was then tested in 451 additional experiments (not used to develop the score) and it was found to predict all 15 TdPs and 18 of the 19 VFs. In conclusion, the derived proarrhythmic score has fewer false positives and false negative than the widely used surrogate (QT-prolongation). As such, it may help in preclinical development of safer medications (better rejection of false negatives) and allowing development of safe beneficial medications with QT prolongation (less rejection of false positives). Recognition of disturbances of the score in the clinical ECG may yield safer use of some medications in vulnerable patients.

Domperidone: limited benefits with significant risk for sudden cardiac death.

BACKGROUND: Domperidone (antinausea/vomiting agent) was recently shown by several groups to increase sudden cardiac death (SCD). Drug-induced disturbances of cardiac repolarization may be a major mechanism. METHODS AND RESULTS: Experiments were executed in isolated female rabbit hearts perfused for 150 minutes with domperidone 30, 60, or 100 nM. Domperidone significantly prolonged the action potential duration: +9% at 30 nM, +32% at 60 nM, and +48% at 100 nM. Domperidone induced significant disturbances of repolarization in 83% of hearts at 60 nM and in 100% at 100 nM, including early afterdepolarizations and polymorphic ventricular tachycardia. Maximum therapeutic free drug plasma concentration of domperidone (19 nM) yields a safety index of only ∼2.5, that is, 12-fold below the accepted minimum. Gastrointestinal benefits and risks for SCD were derived from the literature. The defined daily dose of domperidone (30 mg/day) fails to show unequivocal gastrointestinal benefits beyond a placebo effect. In contrast, 5 of 5 population-based studies show that oral domperidone significantly increases the odds ratio for SCD to 2.8 (1.53-6.21) and it increases sharply above 30 mg/day. CONCLUSIONS: Because domperidone has placebo-like benefits but is associated with increased SCD and a narrow safety margin, it should not be used in medicine.

Low safety index of domperidone: mechanism for increased odds ratio for sudden cardiac death.

OBJECTIVE: Domperidone is a dopamine antagonist with anti-nausea and anti-emetic activity. There have been several reports of sudden cardiac death (SCD) associated with the compound. Recently it was estimated to increase SCD nearly fourfold. I therefore tested domperidone for liability of cardiac repolarization disturbances (triangulation, reverse use dependence, instability and dispersion or TRIaD) and induction of arrhythmias. METHODS AND RESULTS: In Langendorff perfused rabbit hearts, domperidone significantly prolonged the action potential duration starting at 30 nM. It induced proarrhythmic TRIaD from 100 nM on. Since therapeutic free drug concentrations extend to 19 nM, the safety ratio for domperidone equals 100/19 = 5.25, i.e., far below the minimum safety ratio of 30. Hence, widespread use of domperidone cannot be without danger; especially since it is frequently used as an over the counter medication. CONCLUSION: In light of these new preclinical and of recent clinical warnings, domperidone should best be restricted to patients in whom its benefit is proven to justify the risks. Availability without prescription and advertising as an 'innocent' relief is incorrect and unsafe, and needs to be reconsidered.

Drug-induced QTC prolongation dangerously underestimates proarrhythmic potential: lessons from terfenadine.

BACKGROUND: Terfenadine's proarrhythmia prompted market withdrawal; therapeutic antihistaminic concentration is less than 1 nM, whereas IC50 of IKr and INa exceed 200 nM. METHODS AND RESULTS: Rabbit hearts were perfused with terfenadine (1-10,000 nM; 10-450 minutes). A dosage of 1 nM tended to shorten action potential duration (APD60) (-30 ± 30.5 ms; n = 6); 10 nM (450 minutes) significantly prolonged APD60 (46 ± 11 ms; n = 6), but after 1 hour washout, APD60 further prolonged. Above 30 nM, APD60 shortening was followed by prolongation; net effect depended on exposure time (n = 33). In the µM range, cardiac wavelength (λ) shortened (APD60 shortened, conduction slowed; P < 0.05). Terfenadine induced triangulation, reverse use dependence, instability and dispersion of repolarization (TRIaD) at 1 to 1000 nM, increasing with concentration (450 minutes: 1 nM yielded 50% of hearts, 10 nM 100%) and exposure (100 nM: 10 minutes yielded 16%, 30 minutes 33%, 150 minutes 66%, 450 minutes 100%). TRIaD with APD prolongation preceded two Torsade de Pointes, with shortening seven ventricular tachycardia and five ventricular fibrillation. Terfenadine causes normally little QTc prolongation in patients and Food and Drug Administration records suggest that incidence of ventricular tachycardia/ventricular fibrillation exceeds Torsade de Pointes. CONCLUSION: For terfenadine, TRIaD predicts drug-induced proarrhythmia: with λ prolongation, Torsade de Pointes is preferred, otherwise ventricular tachycardia/ventricular fibrillation. APD/QTc alone is clearly inadequate for proarrhythmia evaluation.

QTc prolongation as a surrogate for drug-induced arrhythmias: fact or fallacy?

QTc prolongation is commonly used as a surrogate for drug-induced torsade de pointes (TdP) because it is frequently associated with TdP. However, TdP can also occur in the absence of QTc prolongation or even when QTc is shortened. In the absence of disturbances of lambda-TRIaD (lambda: cardiac wavelength, Triangulation, Reverse use dependence, Instability and Dispersion; TRIaD) QTc prolongation can be antiarrhythmic. In the presence of disturbances of lambda-TRIaD, QTc prolongation still reduces proarrhythmia but frequently cannot overcome the proarrhythmic effect induced by lambda-TRIaD disturbances. Safety evaluation focused upon QTc prolongation (antiarrhythmic parameter) instead of disturbances of lambda-TRIaD (proarrhythmic parameters), is scientifically incorrect. Such evaluation can impede the development of highly valuable drugs, while not recognizing agents that disturb lambda-TRIaD and hereby endanger patient safety. It must be concluded that the century old proposal by Lewis that prolongation of action potential duration and refractory period can be antiarrhythmic is still correct, provided it is not contaminated by disturbances of lambda-TRIaD.

QT prolongation is an unreliable predictor of ventricular arrhythmia.

Not all drugs that prolong the QT interval are proarrhythmic, and absence of QT prolongation is no guarantee for lack of proarrhythmia. Thus, QT prolongation is an unreliable predictor of ventricular arrhythmia. Development of drugs based on the absence of QT prolongation may stop development of some of the safest agents (with respect to arrhythmias). Conversely, drug-induced shortening of the QT interval may facilitate reentry, which might have lethal consequences in vulnerable patients. If QT prolongation and QT shortening must be avoided, then the pharmaceutical industry faces a mission impossible. Cardiac safety is better evaluated in terms of lambda, TRIaD (Triangulation, Reverse use dependence, Instability, and Dispersion), and disturbances of automaticity.

QT and TdP. QT: an unreliable predictor of proarrhythmia.

When triangulation, reverse use dependence, instability and dispersion (TRIaD) of the action potential are associated with drug-induced prolongation of the QT interval, then proarrhythmia in the form of torsade de pointes is most likely. However, as the QT interval is shortened, TRIaD increasingly leads to ventricular fibrillation (VF). Thus, use of QT prolongation by itself may not recognize drug-induced VF (false negatives) and in the absence of TRIaD may erroneously incriminate valuable and safe agents (false positives). In patients,TRIaD equivalents in the ECG may likewise be more important than QT interval.

Use and abuse of QT and TRIaD in cardiac safety research: importance of study design and conduct.

Triangulation, reverse use dependence, instability and dispersion of ventricular repolarization (TRIaD), together with the cardiac wavelength (lambda), are powerful proarrhythmic predictors. QT interval prolongation as such is not, as it provides false positives as well as false negatives. This has been established in various preclinical experiments on isolated tissues, perfused hearts and experimental animals, as well as in the clinic. Numerous risk factors including female gender, low serum potassium and magnesium, bradycardia and genetic predisposition, further promote arrhythmogenesis. Reliable quantitative preclinical cardiac safety studies using any experimental approach always require (1) rigorous adherence to Good Laboratory Practices (GLP), (2) collection of data only after complete drug equilibration has been established, (3) adequate resolution, (4) analysis based upon suitably powered statistical tests, (5) a sufficient number of experiments and (6) validated experimental protocols. Genesis of data not in accord with such standards and reported in an incorrect fashion confounds the significance of preclinical results for eventual clinical studies and elicits confusion regarding important drug effects. In this context, establishing a preclinical research consortium is suggested. This to assure: (1) the use of standardized experimental protocols and animal models; (2) data analysis with appropriately powered statistical tests; (3) correct testing and reporting and (4) elimination of some of the errors and abuses outlined in this paper.

Short patent lives jeopardize drug and patient safety.

Exposure of patients to new medications carries potential safety hazards during widespread clinical practice. These are often detected only after a substantial period of use. Thus, there is considerable need for measures reducing drug-related morbidity and mortality, such as adequate, active postmarketing drug-safety surveillance systems with obligatory follow-up studies of suspected safety problems, or even an additional "Phase IV" safety study before marketing. However, drug development processes erode substantially into the useful patent life of a new drug. Therefore, we suggest that the potential benefits of patent life prolongation should be considered, under certain conditions for the sake of patient safety.

Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T-wave, incriminates safe drugs, and misses profibrillatory drugs.

Drug-induced QT prolongation has such a strong correlation with torsade de pointes (TdP) that it comes to serve as a surrogate for TdP. As a result, drugs that prolong QT by as little as a few ms, even without any evidence of TdP, may get dropped from development or blocked from approval. However, measurement of QT with ms accuracy may be impossible to achieve. Worse, some drugs that lengthen the QT interval are not only not proarrhythmic, they may even be antiarrhythmic; while some that shorten the QT can be strongly proarrhythmic. Indeed, proarrhythmia related to repolarization disturbances is caused by triangulation, reverse use dependence, instability, and dispersion (TRIaD). When TRIaD is present with QT prolongation it commonly yields TdP, but when TRIaD is combined with QT shortening it preferentially leads to VF instead. While TdP is lethal in less than 20% of instances, VF is much more morbid. Worse, available evidence suggests that there is more death from drug-induced fibrillation than TdP. Thus, QT prolongation alone is not very useful. Instead, the T-wave should be used in alternate ways: extraction of TRIaD.

Refining detection of drug-induced proarrhythmia: QT interval and TRIaD.

QT interval prolongation is so frequently associated with torsades de pointes (TdP) that it has come to be recognized as a surrogate marker of this unique tachyarrhythmia. However, not only does TdP not always follow QT interval prolongation, but TdP can occur even in the absence of a prolonged QT interval. Worse still, even shortening of the QT interval may be associated with serious arrhythmias (particularly ventricular tachycardia [VT] and ventricular fibrillation [VF]). It appears increasingly probable that the distinction between various ventricular tachyarrhythmias may be arbitrary, and drug-induced TdP, polymorphic VT, VT, catecholaminergic polymorphic VT, and VF may represent discrete entities within a spectrum of drug-induced proarrhythmia. Although they are differentiated by the coupling interval and the duration of QT interval, they appear to share a common substrate: a set of disturbances of repolarization characterized by Triangulation, Reverse use dependency, electrical Instability of the action potential, and Dispersion (TRIaD). It is becoming increasingly evident that augmentation of TRIaD, rather than changes in the duration of QT interval, provides the proarrhythmic substrate. In contrast, when not associated with an increase of TRIaD, QT interval prolongation can be an antiarrhythmic property. Electrophysiologically, augmentation of TRIaD can be explained by inhibition of hERG (human ether-a-go-go related gene) channel. Because drug-induced disturbances in repolarization commonly result from inhibition of hERG channels or I(Kr), hERG blockade and the resulting prolongation of QT interval are important properties of a drug to be studied. However, these need only be a concern if associated with TRIaD. More significantly, TRIaD so often precedes prolongation of action potential duration or QT interval and ventricular tachyarrhythmias that it should be considered a marker of proarrhythmia until proven otherwise, even in the absence of QT interval prolongation. Detecting drug-induced augmentation of TRIaD may offer an additional, more sensitive, and accurate indicator of the broader proarrhythmic potential of a drug than may QT interval prolongation alone.

TRIad: foundation for proarrhythmia (triangulation, reverse use dependence and instability).

There exist both safe and dangerous prolongations of the QT interval. Proarrhythmia can be induced by triangulation of the cardiac action potential, reverse use dependence and instability, a set of three features termed TRIad. TRIad leads to dispersion (spatial, transmural and temporal), stalling of fast repolarization or even early after-depolarization (EAD). EAD can progress to Torsade de Pointes (TdP) especially in the presence of prolonged APD; as the QT interval shortens (e.g. by reverse use-dependence), the cardiac wavelength shortens and TdP can progress to ventricular fibrillation (VF). In the absence of TRIad and QT prolongation, chemicals exhibit on average neither pro- nor anti-arrhythmia. However, QT prolongation in the absence of TRIad becomes antiarrhythmic. Furthermore, this desirable effect increases as TRIad components are replaced by squaring of the action potential, use-dependent prolongation of APD and stabilization of the action potential. It is concluded that proarrhythmic characteristics of drugs can readily be recognized and that hope exists for an effective and safe class III antiarrhythmic agent after all.

Detection of proarrhythmia in the female rabbit heart: blinded validation.

INTRODUCTION: Reliable detection of drug-induced proarrhythmia, especially the potential for polymorphic ventricular tachycardia, is of great importance in the development of new compounds that are safe for the heart and was evaluated in a blinded study. METHODS AND RESULTS: In 142 female rabbits, the monophasic action potential was used to determine intraventricular conduction, action potential duration (APD), triangulation (APD30 to APD90), reverse use-dependence, instability and presence of chaotic behavior, early afterdepolarizations, torsades de pointes (TdP), and ventricular fibrillation. In addition, 31 coded drugs were tested in a blinded fashion in another 150 hearts. Prototype cardiovascular agents [quinidine (IA), lidocaine (IB), flecainide (IC), propranolol (II), sotalol (IIIB), amiodarone (IIIAB) and verapamil (IV)] were correctly characterized in terms of their effects upon conduction and APD. Agents documented in clinical practice to have proarrhythmic potential (droperidol, sotalol, mibefradil, bepridil, lidoflazine, ketanserin, sertindole, terfenadine, haloperidol, astemizole, cisapride, ziprasidone, lubeluzole, dofetilide, quinidine, ibutilide) were identified as such. Pimozide is reported to rarely produce TdP and was also found to elicit Class III action with few adverse effects. Equally important, agents believed not to be proarrhythmic (two solvents, atenolol, propranolol, fenoximone, cetirizine, verapamil, sildenafil, lidocaine, diltiazem) were identified as having no proarrhythmic activity. CONCLUSION: The SCREENIT method properly characterized and quantified prototype cardiovascular drugs and correctly identified proarrhythmic noncardiovascular agents of various mechanisms, but it did not produce false-positive results.

Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs: importance of triangulation, reverse use dependence, and instability.

Drug-induced proarrhythmia is a rare but potentially lethal adverse drug reaction. To test whether the SCREENIT system (an automated computerized test apparatus), using an isolated perfused heart obtained from female rabbits, could correctly identify agents that lengthen the action potential duration (APD) and drugs known to induce proarrhythmia, 14 drugs (penicillin G, haloperidol, adriamycin, indapamide, verapamil, aspirin, lidocaine, clomipramine, propranolol, erythromycin, quinidine, terfenadine, amiodarone, and thioridazine) were coded and submitted for a blinded test. Of these drugs, eight are reported to induce QT prolongation in the clinic (adriamycin, clomipramine, quinidine, amiodarone, and thioridazine), while three do not lengthen and three shorten the QT. To test for reproducibility, four drugs were given in duplicate (haloperidol, aspirin, erythromycin, and terfenadine). The drug effects on monophasic APD, conduction, instability (index of variability of APD), triangulation (index of duration of fast repolarization), and reverse use dependence were measured at five drug concentrations (0.05, 0.15, 0.5, 1.5, and 5 mg/l). All 14 blinded drugs, in the concentrations used, were correctly identified as to their effects on APD and conduction. The drugs eliciting drug-induced proarrhythmia in patients were also identified as promoting instability, triangulation, and reverse use dependence in the rabbit heart. Importantly, none of the safe agents was labeled as proarrhythmic, and the results were very consistent between duplications. In conclusion, SCREENIT correctly identifies prolongation of APD, accurately separates safe agents form proarrhythmic drugs, and has highly reproducible results. Thus, the isolated perfused rabbit heart can be a valuable tool in a preclinical proarrhythmia test battery in drug development.