Drug-induced proarrhythmia and use of QTc-prolonging agents: Clues for clinicians
Introduction
Drug-induced proarrhythmia is a growing challenge shared by the pharmaceutical industry, prescribing clinicians, and regulatory bodies charged with evaluating and monitoring drug safety. The greatest risk of drug-induced proarrhythmia with current agents is the risk of prolongation of the corrected QT interval (QTc) on the electrocardiogram (ECG), which can be associated with a potentially life-threatening form of polymorphic ventricular tachycardia termed torsades de pointes (TdP). Drugs with proven lengthening of the QTc interval or a definite association with TdP are common and are estimated to compose approximately 2% to 3% of all prescriptions written.1 Among the most common noncardiac drugs with QTc interaction seen in clinical practice are antibiotics and psychotropic drugs,2 which in the vast majority of cases are prescribed by noncardiologists. Although uncommon in routine clinical practice, TdP is extremely difficult to predict accurately despite known risk factors and mechanism. A large number of drugs in clinical use are associated with QTc prolongation based upon studies in humans, animals, and various experimental preparations (Figure 1).
Because of the risk of drug-induced arrhythmia associated with QTc prolongation, regulatory agencies now require detailed evaluation of the effects of new agents on cardiac repolarization prior to drug approval, as well as postmarketing surveillance of approved drugs with perceived risk. As a result of this scrutiny, a number of drugs have been denied approval for use in humans, have received approval with warnings related to QTc effects (either at the time of approval or relabeled after initial approval), or have been withdrawn from the market after previously unappreciated proarrhythmic effects were detected (Figure 2). The pharmaceutical industry and regulatory bodies are charged with safety monitoring at all stages of drug evaluation, both before and after approval for human use. Despite the industry and regulatory body monitoring, clinicians ultimately are responsible for the safety of the patients to whom they prescribe drugs. Many approved drugs have the potential—either demonstrated or theoretical—for QTc prolongation and TdP. As a result, prescription of all agents must be based upon informed evaluation of the risks and benefits of each drug compared with available alternatives.
A mechanistic understanding of drug-induced arrhythmia has been appreciated only recently. In the 1920s, quinidine (a new antiarrhythmic agent at that time) was associated with syncope. Advances in ECG monitoring in the ensuing decades identified pause-dependent polymorphic ventricular tachycardia, later termed TdP, as the responsible mechanism.3, 4 Similarly, cases of cardiac toxicity with antipsychotics and antihistamines were reported in the 1960s and 1970s, but the cases were poorly understood, and little regulatory oversight was in practice. In concert with growing appreciation of drug-induced arrhythmia, the first descriptions of heritable syndromes linking a long QTc interval with sudden cardiac death were reported.4, 5, 6 Knowledge of both drug-induced QTc lengthening and the heritable long QTc syndromes has proved complementary in elucidating the mechanisms responsible for the clinical features of TdP.
Section snippets
Terfenadine: a case study
Terfenadine is a nonsedating antihistamine that was widely used (>100 million prescriptions filled while an approved agent) prior to its withdrawal from the market in 1998. Use of terfenadine at therapeutic concentrations produces a measurable increase in the QTc interval, but the increase is relatively modest (6–8 ms average QTc increase across the dosing interval, 18 ms at peak drug levels).7 Furthermore, terfenadine appeared to be safe in large, postapproval monitoring of approximately
Mechanisms of drug-induced arrhythmia
In order to understand the molecular basis of QTc prolongation, an understanding of the molecular basis of the QT interval is critical (for review, see Fenichel et al.13). The QT interval represents a summation of the entire duration of the cardiac action potentials of ventricular cardiomyocytes, from the onset of depolarization until the completion of repolarization. The membrane voltage is governed by inward currents (primarily sodium and calcium), which lead to depolarization, and outward
Risk factors for proarrhythmia
In order to assess the risk of drug-induced TdP in an individual patient, the known effects of the drug and the dose in question on the QT and QTc interval must be considered. In addition, careful attention must be given to the susceptibility of the individual patient, including the presence of known risk factors for drug-induced TdP and the use of concomitant medications, which may exhibit pharmacodynamic or pharmacokinetic interactions with the drug in question. As demonstrated with
Strategies for clinicians
Drug-induced TdP is a rare but potentially lethal event; therefore, it must be considered by all clinicians who prescribe drugs. It would be possible for regulatory bodies to reduce but not eliminate entirely the risk of TdP by declining to approve any drug with the potential to prolong the QTc interval, even to a modest degree. Although intuitively appealing, this approach inevitably would harm the public interest by denying patients access to many therapeutic agents whose proven clinical
Computer-assisted approaches
As our understanding of drug-induced arrhythmia and the number of medications with potential proarrhythmic effects continues to grow, the burden on clinicians to be aware of and consider the proarrhythmic potential of prescribed drugs becomes ever greater. Most drugs with proarrhythmic potential are prescribed by noncardiologists, and it is unrealistic to expect physicians to stay current with advancing knowledge on the proarrhythmic potential of all drugs in clinical use. Lists of drugs with
Conclusion
An increasing number of drugs with the potential to prolong the QTc interval and cause TdP are being used in routine clinical practice. Research on the molecular and cellular bases of the cardiac action potential and of genetic long QT syndromes has shed considerable light on the mechanisms responsible for drug-induced QT prolongation. Despite the increased knowledge, TdP in the clinical setting remains difficult to predict and is related to multiple variables, including patient age, gender,
Acknowledgments
This work was funded in part by a Clinical Investigator Training Program award (Harvard/MIT Health Sciences and Technology-Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc. and Merck & Co.) to EKH.
References (37)
- et al.
QTc and psychotropic drugs
Lancet
(2000) - et al.
Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients
Am J Med
(2003) - et al.
Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval, and sudden death
Am Heart J
(1957) - et al.
Risk of developing life-threatening ventricular arrhythmia associated with terfenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine
Am J Cardiol
(1994) - et al.
Terfenadine-associated ventricular arrhythmias and QTc interval prolongation. A retrospective cohort comparison with other antihistamines among members of a health maintenance organization
Ann Epidemiol
(1995) Second-generation antihistaminesthe risk of ventricular arrhythmias
Clin Ther
(1999)- et al.
Molecular and cellular mechanisms of cardiac arrhythmias
Cell
(2001) - et al.
Assessing predictors of drug-induced torsade de pointes
Trends Pharmacol Sci
(2003) - et al.
Torsades de pointes associated with nonantiarrhythmic drugs and observations on gender and QTc
Am J Cardiol
(2002) - et al.
Quinidine syncope, paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias
Circulation
(1964)