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Roger Dmochowski, MD, FACS* and David R. Staskin, MD *Vanderbilt Continence Center, Vanderbilt University Medical Center, There is an emerging recognition that Q-T interval prolon- A-1302 Medical Center North, Nashville, TN 37232-2765, USA.
gation induced by pharmacologic agents can produce potential adverse outcomes, including cardiac syncope and Current Urology Reports 2005,
sudden death. This phenomenon was first identified in the Current Science Inc. ISSN 1527-2737Copyright 2005 by Current Science Inc.
middle of the twentieth century and was thought to beexemplified best by the syndrome of torsades de pointes(TDP). This particular dysrhythmia, TDP, is seen in associa- Antimuscarinic drugs form the mainstay of pharmaco- tion with congenital prolonged Q-T syndromes, but also therapy for the treatment of overactive bladder. The may be associated with drug effect in certain specific primary sites of activity of the agents for the desired thera- peutic effect are the M3 and M2 receptors of the bladder. In the antimuscarinic class of drugs used for the treat- Drug interaction with other non-vesical muscarinic recep- ment of OAB, this syndrome was noted first with the com- tors produces a range of undesired adverse events. In gen- pound terodiline [2,3,4•,5,6]. According to recent reviews, eral, certain adverse effects associated with antimuscarinic there are other contributing factors that may put certain agents such as dry mouth (salivary) and constipation individuals at risk for malignant dysrhythmias, such as (colon) may be considered only bothersome, and somno- TDP. One of these risk factors is female gender, which lence and confusion (central nervous system) may be apparently places patients at risk for congenital and considered more serious in nature. However, effects on the acquired prolonged Q-T syndromes. It is undetermined myocardium are considered to be more significant safety whether this predilection in the female population is issues and increased awareness and understanding of the related to gene-expression variability or other factors such effect of drugs on the myocardium, including the additional as metabolic or otherwise undetermined variables. Not all effects of drug-drug interaction, has increased a need for individuals with prolonged Q-T syndromes will develop the evaluation of new drugs for cardiac safety. The role of potentially fatal dysrhythmias. There is some evidence that genetics (and the identification of populations at risk) in the cardiac repolarization abnormalities (conduction patholo- causation of congenital dysrhythmias has received specific gies) may contribute to the risk variability associated with attention in this area. New drugs now must undergo more this phenomenon. Other factors, including hypokalemia intense scrutiny and cardiac testing to evaluate their effects and decreased cardiac rate, also may contribute to the vari- on cardiac rate and rhythm, especially the QT interval. The ability of risk associated with the development of TDP in recently approved agents (trospium, solifenacin, darifena- those individuals with prolonged Q-T intervals [1••].
cin) used for the treatment of overactive bladder have been Data are now being accrued that elucidate possible con- rigorously evaluated for these effects.
tributory molecular mechanisms that result in modificationof cardiac action potential and Q-T interval in healthy sub-jects and in those patients with congenital prolonged Q-T syndrome. There apparently are at least six genes that when It is apparent that cardiac-associated arrhythmias are an mutated, can contribute or cause congenital prolonged Q-T increasing concern with many pharmacologic agents.
syndrome. One of these genes controls potassium channel Throughout the past decade, more than 40 compounds proteins, which effect cardiac repolarization (HERG). The have been identified and nine different compounds have role of HERG in cardiac repolarization is important as a been withdrawn from use because of prolongation of specific current (known as IKr) can potentiate long Q-T inter- cardiac electrophysiologic rhythms (the Q-T interval). The vals. However, the identification of this gene in an individual intent of this review is to examine the current approach for is not specific for the development of prolonged Q-T inter- evaluation of drug effects on cardiac rhythm and to review vals. There appears to be an incomplete penetrance pattern recent changes in regulatory consideration of new com- associated with congenital prolonged Q-T syndrome in pounds, especially anticholinergics used in the treatment certain individuals. This mixed genetic presentation implies of overactive bladder (OAB) syndrome.
that individuals who have near normal Q-T intervals, but who carry the mutation for genes that are associated with drug in any single patient or population is imprecise at prolonged Q-T syndrome, may be at risk for sudden death, as best. Several mechanisms can cause arrhythmias such as TDP, including rhythm transmission block after depolar- Approximately 5% to 10% of patients who develop the ization or prolongation of action potentials. A combina- malignant dysrhythmia TDP develop this pathology after tion of effects likely is necessary to induce a malignant exposure to drugs that affect the Q-T interval by prolonga- arrhythmia. TDP is estimated to occur in 1% of patients tion. Genetic polymorphisms may produce variability that who ingest those drugs known to cause Q-T prolongation is difficult to detect in gene presentation, which may be (eg, anti-arrhythmic drugs). This effect is due largely to a apparent only after exposure to stressors with or without blockage of the IKr channel, with a subsequent increase in drugs that affect the HERG-regulated potassium channel.
action potentials and resultant prolongation of the Q-T There also appears to be ethnic and other effects on the interval. Interestingly, drugs such as terfenadine only pro- polymorphism expressed in these individuals [1••].
long the Q-T interval by 6 msec, except in the setting of The premise of testing the effects of drugs on the Q-T heart failure when the Q-T prolongation is longer. This par- interval has been that an increase (albeit small) in Q-T inter- ticular pharmacologic agent is a strong IKr inhibitor, but is val may predispose to the potential development of malig- metabolically metabolized by the cytochrome system in nant dysrhythmias. Currently, measurement of the Q-T the liver to its major metabolite, which is not cardio-active.
interval change is used as an estimate of risk for the develop- In patients who had hepatic dysfunction (eg, cirrhosis) or ment of TDP. The absolute length of prolongation of Q-T other metabolic abnormalities, the un-metabolized parent interval necessary to produce this dysrhythmia has not been compound enters into the systemic circulation to a greater determined. Certain cardiovascular drugs, used for arrhyth- degree (higher plasma levels than encountered in healthy mia control, can prolong the Q-T interval by 15 msec or more subjects), resulting in longer prolongations of the Q-T as the inherent mechanism of action; however, prolongation to that degree can produce TDP. Therefore, intensive cardiac Terfenadine is an example of the problematic nature of monitoring usually is conducted during the initiation of cardiac testing in regulatory trials [8]. Many millions of therapy with these drugs. Increases as low as 10 msec in Q-T dose exposures occurred with no causation of TDP and interval have led to drug non-approval or withdrawal from therefore the mean increase of 6 msec with this particular regulatory approval. However, this is at best an imprecise drug would be considered to be low risk.
method for identifying the risk of cardiac complications with With those particular compounds that are potent IKr drug ingestion. Currently, the absolute criterion for establish- blockers, which are eliminated only by one primary route ing increased risk for dysrhythmia is prolongation of Q-T of metabolism that can be affected by concomitant interval greater than 500 msec [7•]. A variety of other meth- diseases (eg, cirrhosis) or a concomitant administration of ods have been used to identify changes in Q-T interval pat- compounds that may interfere with metabolism (eg, keto- terns and magnitudes. These methods include Q-T interval conazole), the potential for serious adverse events rate correction and the actual appearance (morphology) of increases substantially. In those patients who have heart failure or who have non-clinically overt congenital pro- Identification of this level of prolongation prompts a longed Q-T syndrome, a small increase in the Q-T interval serious consideration of the therapeutic index for the spe- cific drug in light of the indicated use. During regulatory Many other compounds are known to invoke arrhyth- approval of drugs of any non-antiarrhythmic drug agent, a mias such as TDP, including some antimetabolite agents.
generally limited number of patients are exposed to the Although these agents are known to induce TDP, their agent and arrhythmias are not observed often in the groups therapeutic benefit outweighs the risk of generation of the of patients undergoing regulatory trials. Post-marketing arrhythmia. In contradistinction, a drug that causes a very surveillance to exclude the possibility of fatal arrhythmia is low risk of TDP, but is indicated for use in less serious con- required by the US Food and Drug Administration as part ditions, may not be defensible on the basis of arrhythmia of the drug approval process; however, the actual event of causation. Regulatory review of new agents is hampered malignant arrhythmias actually may be under-reported or because clinical experience with drugs usually is short- term. Many new agents may affect or antagonize the IKr The relationship between drug effect and resulting receptor and actually may produce Q-T prolongations in changes in cardiac physiology, including prolongation of patients. Therefore, the final decision becomes a risk/bene- action potential and subsequent linkage to dysrhythmias fit decision for particular drug therapeutic indications in such as TDP, is not well defined. Clearly, some drugs can contradistinction to existing therapies. Moxifloxacin repre- block the IKr channel and not cause TDP (eg, cardiac anti- sents an excellent example of the previously mentioned arrhythmics). Other agents, such as anti-histaminic agents concerns. This agent is known to produce blockade of the (eg, terfenadine, which is a potent IKr blocker), cause TDP IKr receptor and Q-T interval prolongation of 5 to 14 msec but do not prolong action potentials. Thus, the ability to in trials; however, in the case of this drug, its clinical advan- predict the causation of malignant arrhythmias by any tage was suggested over existing therapies.
The Q-T Interval and Antimuscarinic Drugs • Dmochowski and Staskin found to be due to a drug concentration-dependent prolon- Table 1. Medications that may interfere with
gation of the Q-T interval. Unfortunately, the activity of the cytochrome-based hepatic metabolism
antimuscarinic agents at the disparate muscarinic receptors throughout the body, and especially those in the myocar- dium, therefore must enter into the evaluation of drugs in True epidemiologic analyses for other anticholinergic/ antimuscarinic agents and relatively rare phenomena such as cardiac adverse events are lacking. Limited data have suggested no effect on the Q-T interval with agents such as oxybutynin or tolterodine. However, the antimuscarinic effects of the tertiary and quaternary amines used for pharmacologic treatment of the OAB provide the potential for antimuscarinic activity, which could have potential negative cardiac effects. For example, oxybutynin over- dosage (100 mg) has been associated with ventricularbigeminy and ventricular ectopy [10].
(Adapted from Roden [1••]).
In a retrospective cohort analysis, 14,638 patients with urinary incontinence who were enrolled in a Medicare/ Given the multiple factors that contribute to the devel- Medicaid pharmacy program database were evaluated for opment of cardiac dysrhythmias, physician screening to the outcomes of new onset ventricular arrhythmia, the ini- avoid untoward cardiovascular events becomes critical in tiation of antiarrhythmic medication, or sudden death those patients beginning therapy with an agent in ques- (attributable to cardiac causation) [11••]. Other variables tion. Many drugs require cardiovascular screening with a including concomitant medication use, demographics, and baseline electrocardiogram test before inception of use of antihistaminics and cytochrome 3A4 competitive therapy. However, in practice, this may not occur as agents also were assessed (Table 1). The use of all available cautioned. In addition, concomitant administration of antimuscarinic agents (oxybutynin, flavoxate, and hyos- drugs that may effect hepatic metabolism such as ketocon- cyamine) was tracked in this population and in the popu- azole (and other imidazole antifungals), antidepressants, lation evaluated for the aforementioned outcomes. No antiretroviral agents, antiarrhythmics, and drugs such as association was identified between the use of urinary anti- erythromycin should be identified when beginning treat- spasmodics and ventricular dysrhythmias (adjusted risk ment with these medications. Patient education and aware- ratio, 1.23) or sudden death (adjusted risk ratio, 0.70).
ness should include instruction regarding any new However, the use of antihistamines in combination with symptoms, such as syncope or cardiac rhythm abnormali- cytochrome P450 3A4 inhibitors was associated with a sig- ties (palpitations). The addition of diuretics may produce nificant risk of ventricular dysrhythmias (RR, 5.47) and hypokalemia and therefore cause a salubrious environ- cardiac sudden death (RR, 21.5). The authors concluded ment for the development of malignant arrhythmias.
that older OAB agents were not associated with any sub- Consideration of the possible interactions of a pharma- stantive cardiac phenomenon in an at-risk population; ceutical entity in question with the HERG protein in the however, the effect of confounders and concomitant medi- case of a single route of drug metabolism may create a cation must be considered, especially in populations using potentially dangerous situation. This scenario may be exac- other agents with potential cardiac effects (antihistamines) erbated by concomitant disease, generic variations, and the or metabolic effects (agents that alter cytochrome activity, administration of competitive compounds (for metabolic resulting in increased serum levels of active compound).
sites). The use of surrogate markers such as the Q-T interval Data regarding oxybutynin- and tolterodine-related provides some basis for decision-making; however, the cardiac effects in vitro do exist. Tolterodine has not been direct relationship between these surrogate markers and reported to alter cardiac repolarization. In cardiac myo- onset and the advent of specified arrhythmias is not exact.
cytes, tolterodine has been found to have high affinity forHERG, but does not produce Q-T prolongation after thera-peutic dose administration. This may be due partly to the Electrophysiologic Data for Antimuscarinic relatively low plasma levels of the drug after administra- tion and also to the mixed ion channel effects that the The possible causative role of antimuscarinics in the develop- compound causes (little effect on sodium channels, with ment of cardiac arrhythmias has been considered since the relatively greater effect on calcium channels) [12].
correlation between the compound terodiline and cardiac Oxybutynin, in comparison with terodiline, had rela- dysrhythmias was established in the 1990s. The occurrence tively little effect in the S-isomeric form on cardiac ion of TDP in patients ingesting the tertiary amine terodiline was channels [13]. The non-specific effects of this isomer were thought to indicate a lack of significant effect on cardiac sequential periods using doses of 10, 20, and 30 mg of solif- repolarization. Other studies of otherwise healthy inconti- enacin; a second group of 25 subjects completed a sequence nent patients have shown that oxybutynin in doses of 2.5 of moxifloxacin and placebo. All of the subjects undergoing to 10 mg has little or no effect on resting heart rate or Q-T evaluation were female volunteers between the ages of 19 interval [14]. These effects were attributed to little drug and 79 years. The highest does of solifenacin (30 mg) was effect (at the stated plasma levels) at the M2 receptors in chosen based on an exposure amount (plasma level) similar the myocardium. Further data on the effect of oxybutynin to that observed with the coadministration of a 10-mg dose on rabbit and guinea pig papillary muscles have shown of a potent cytochrome P450 inhibitor (ketoconazole 400 that at therapeutic plasma concentrations (0.01–0.1 mg). During administration, the median difference from microM), adverse effects on cardiac function are unlikely baseline in heart rate associated with the 10- and 30-mg to occur. Only at supratherapeutic ranges of greater than 3 doses was -2 and 0 beats per minute, respectively. When the microM did effects on action potentials and muscle 10-mg dose was administered, there was a 2-msec change in the QTC interval (using the Fridericia method); with the use Recent changes in federal regulatory guidance docu- of 30 mg, this change was noted to increase to 8 msec. The ments for cardiac safety testing have produced specific effects of the positive control (moxifloxacin) in three differ- results for several new antimuscarinic agents used for the ent administration sessions were 11, 12, and 16 msec, respec- treatment of OAB. The development of tolterodine and tively. The prescribing information concludes that the Q-T oxybutynin in immediate- and extended-release formula- interval effect appeared to be greater with the 30-mg dose tions preceded the specified testing noted in the guidance compared with the 10-mg dose and that this effect did not documents; therefore, the prescribing information summa- appear as large as what was associated with the positive con- rized is for the three compounds that were new to the trol moxifloxacin, although the confidence intervals over- lapped. In clinical trials, no cardiac adverse event greater than1% occurred [18].
Enablex (darifenacin)
In animal models (rodent), only at supratherapeutic Enablex (Novartis, Switzerland [darifenacin]) was evalu- plasma levels was solifenacin noted to induce a cardiac effect ated for its effects on the Q-T/QTC interval in multiple- (bradycardia). This finding again stresses the importance of dose, randomized, placebo- and active-controlled studies plasma levels in contributing to cardiac toxicity [19].
(active control was moxifloxacin 400 mg). These studieswere performed with 179 healthy adults (44% male, 56% Trospium chloride
female) who were between the ages of 18 and 65 years.
Trospium chloride also has undergone electrophysiologic Dose exposures ranged from 15 to 75 mg (5 times the evaluation during registration studies. Electrophysiologic upper dose for prescription purposes). Q-T intervals were evaluation included the administration of trospium at 20 measured over 24-hour periods prior to drug administra- mg twice daily (up to 100 mg twice daily) and subsequent tion and also at a steady state. The 75-mg dose was selected effects on Q-T interval in single-blind, randomized, to achieve similar drug level exposure to that seen in placebo-controlled trials (using the active control moxi- patients known to demonstrate poor metabolism floxacin 400 mg/qd) in 170 healthy female and male vol- (CYP2D6 deficient) and in the circumstance of simulta- unteers between the ages of 18 and 45 years. The Q-T was neous administration of a potent CYP3A4 inhibitor. At measured during a 24-hour period at steady state. The 100- these doses, Enablex did not show prolongation of the Q- mg dose was chosen because this level achieved the maxi- T/QTC interval during steady state, whereas the active con- mum concentration associated with renal dysfunction.
trol moxifloxacin showed a QTC change of approximately Trospium was not associated with an increase in individual 7 msec when compared with placebo. The mean heart rate QTC or with the Fridericia correction of Q-T. Moxifloxacin change increases noted during administration were 3.1 was associated with a 6.4-msec overall increase and also (drug) and 1.3 (placebo) beats per minute; however, in with an increase in the Fridericia-corrected Q-T.
expanded clinical trials, no heart rate changes were noted Non-specific T-wave inversions were observed more compared with placebo. In clinical trials, no significant often in patients receiving the active compound than in cardiac adverse events were noted [17].
those receiving placebo or moxifloxacin. This was notnoted in two large-scale clinical trials, which led to drug Solifenacin succinate
approval. According to the prescribing information, the Electrophysiologic evaluation of solifenacin was performed significance of this inversion is unknown. Administration as part of the registration for this compound in the United of the active drug was associated with an increase in heart States. Two doses were tested (10 and 30 mg), with subse- rate, which appeared to be related to plasma concentra- quent evaluation of the Q-T interval in multidose, random- tions. At the 20-mg dose, trospium demonstrated a 9.1- ized, double-blind, placebo- and positive-controlled trials beat per minute increase compared with placebo. This (moxifloxacin 400 mg trials). Serial observations were per- increased to 18 beats per minute at the 100-mg dose formed in a subgroup of patients (51 patients) for three (standard dose is 20 mg twice daily). However, the overall The Q-T Interval and Antimuscarinic Drugs • Dmochowski and Staskin mean increase in heart rate compared with placebo was 4.• Thomas SHL, Higham PD, Hartigan-Go K, et al.: three beats per minute in the first large-scale phase-3 trial Concentration-dependent cardiotoxicity of terodiline in
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