14th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 2000

Jan. 29 - Feb. 5, 2000
Marilleva, Trento, Italy

RT-150

Acquired long QT syndrome

Yee Guan Yap, A. John Camm.
British Heart Foundation Research Fellow in Cardiology, Department of Cardiological Sciences, St. George’s Hospital Medical School, London, UK

Drug-induced acquired LQTS

The mechanism behind drug-induced LQTS is the result of the blockade of the slow rectifier transient outward IKr potassium current, resulting in slowing and prolongation of the action potential repolarisation. Blockade of the IKr current manifests clinically as a prolonged QT interval and the emergence of other T or U wave abnormalities on the surface ECG (Fig. 1). The prolongation of repolarisation may result in subsequent activation of an inward depolarization current, which promotes triggered activity at the end of repolarisation, known as an early after-depolarisation, especially in the Purkinje fibres and the mid-myocardial cells, so-called M cell. This may then provoke TdP, which is probably sustained by re-entry or spiral wave activity.

Generally, QT prolongation is considered when the QTc interval is greater than 440 ms (men) and 460 ms (women), although arrhythmias are most often associated with values of 550 ms or more. There is a characteristic initiating sequence prior to the onset of TdP, particularly in acquired TdP. The first ventricular complex of the sequence is usually of a ventricular ectopic beat or the last beat of a salvo of ventricular premature beats (Fig. 2). This is then followed by a pause terminated by a sinus beat. The sinus beat frequently has a very prolonged QT interval and an exaggerated U wave. A premature ventricular beat then falls on the exaggerated U wave of the sinus beat and precipitates the onset of TdP.

Fig. 1: ECG of a patient with drug-induced long QT syndrome. Note the prolonged T wave offset resulting in a prolonged QTc interval of 592 ms.

Fig. 2: Rhythm strip in a patient with drug-induced TdP. Note the typical short-long-short initiating ventricular cycle before the onset of TdP and the classical "twisting of a point" of the cardiac axis during TdP.

The severity of proarrhythmia at a given QT interval varies from drug to drug and from patient to patient. Unfortunately, the extent of QT prolongation and risk of TdP with a given drug may not be linearly related to the dose or plasma level of the drug because patient and metabolic factors are also important (e.g. gender, electrolytes level, etc.). Furthermore, there is no linear relationship either between the degree of drug induced QT prolongation and the likelihood of the development of TdP. Indeed, TdP can sometimes occur without any prolongation of the QT interval, although this is unusual.

Cardiac drugs

Many of the drugs that were initially known to prolong the QT interval were mostly antiarrhythmics, with quinidine being the most commonly implicated agent in reported cases. Quinidine has long been reported to produce serious ventricular arrhythmias, especially in intravenous administration. However, it was not until many years later that what was initially termed “quinidine syncope” was actually a result of TdP. The early landmark report by Selzer and Wray observed that quinidine use was associated with syncope and ventricular fibrillation or flutter¹. In their report, the risk of TdP with quinidine was not necessarily a consequence of excessive doses of the drug. Other workers confirmed that TdP with class Ia drugs could occur at low therapeutic or subtherapeutic concentration². Indeed, most of the class Ia drugs including quinidine, disopyramide and procainamide are strongly concordant in their production of TdP³.

The risk of TdP among antiarrhythmics is not confined to class Ia drugs. Class III also share the propensity to induce TdP, with the slight exception of amiodarone. The incidence of TdP with amiodarone has been reported to be low at approximately 0.7%⁴. The evidence from a recent meta-analysis of amiodarone trials showed that amiodarone actually reduced the risk of arrhythmic death and resuscitated cardiac arrest in patients after myocardial infarction or with heart failure⁵. In contrast, sotalol has an incidence rate of TdP between 0.3 to 3.8% for a daily dose of between 80 mg and 680 mg³. Furthermore, sotalol may also be particularly prone to TdP because of its reverse use dependency, such that the QT interval is more prolonged in the presence of bradycardia.

Other pure class III antiarrhythmics such as dofetilide and ibutilide do not fare any better in their pro-arrhythmic risk. The recently published data of dofetilide in congestive heart failure patients showed that the incidence of TdP was 3.3% compared with 0% in the placebo group⁶. Other new class III intravenous antiarrhythmic such as ibutilide, appears to be more toxic in inducing TdP. In the Ibutilide Repeat Dose Study, 8.3% of the patients developed TdP during or soon after the start of two 10-minute infusions, separated by 10 minutes of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg)⁷.

Early reports of TdP associated with cardiac drugs incriminated not only antiarrhythmics, but antianginal agents such as bepridil and prenylamine, both of which have been well documented to cause TdP^8,9. These antianginal agents have now been withdrawn from the market in most regulatory jurisdictions.

Non-cardiac drugs

Since 1990s, several non-cardiac drugs marketed in the United Kingdom, namely, terfenadine, astemizole, cisapride, terodiline, halofantrine, sertindole and pimozide, attracted regulatory attention because of their propensity to produce QT prolongation, TdP and/or sudden death. The lists of non-cardiac drugs that can cause QT prolongation with the potential risk of causing TdP continue to grow and presents with considerable public health problem. Some of these drugs have since been withdrawn from the market (prenylamine, terodiline, sertindole, ketanserin and in some countries, terfenadine, astemizole and grepafloxacin). Unfortunately, the pro-arrhythmic risk of many of these drugs was not realised until several years after they were marketed.

Like class III antiarrhythmics, the proarrhythmic effect of these non-cardiac drugs was a result of prolongation of the monophasic action potential and QT interval, which lead to the development of early after-depolarisation and TdP through inhibition of IKr channel. To date, there are as many as 50 commercially available or investigational non-cardiac drugs that have been implicated to cause QT prolongation, with or without reports of TdP (Tab. I). Broadly, the range of non-cardiac drugs that are capable of prolonging QT interval includes non-sedating antihistamines (e.g. terfenadine, astemizole, etc.), tricyclic antidepressants (e.g. imipramine, amitriptyline, etc.), antipsychotics (e.g. sertindole, pimozide, etc.), antimicrobials (e.g. erythromycin, grepafloxacin, ketoconazole, etc.), antimalarials (e.g. quinine, halofantrine, etc.), serotonin antagonists (e.g. cisapride), immunosuppressants (e.g. tacrolimus) and antidiuretics (e.g. vasopressin).

There are many conditions that may increase the risk QT prolongation and TdP associated with non-cardiac drugs that deserve some attention. For, instance, in the case of terfenadine, TdP occurred in overdoses of the drug, at normal doses, with concurrent use of drugs that inhibit hepatic cytochrome P450 CYP3A4 enzymes (imidazole, antifungals and macrolide antibiotics), in patients with impaired liver function or congenital LQTS¹⁰. As almost all of the non-sedating antihistamines were metabolised via the hepatic cytochrome P-450 CYP3A4 system, concomitant administration of drugs that inhibit the hepatic cytochrome P-450 CYP3A4 (imidazole antifungals, macrolide antibiotics) or compromised liver function may result in the accumulation of the parent drug and cardiotoxicity¹¹. Imidazole antifungals such as ketoconazole and macrolide antibiotics such as erythromycin can themselves also prolong QT interval when given alone by blocking the IKr channels¹⁰. In the case of antimalarials, cardiotoxicity of the drugs is increased in patients with acute renal failure especially after three days of therapy. Hypokalaemia, commonly a result of diuretic intake, can exacerbate the risk of QT prolongation and TdP. For instance, at both therapeutic and toxic doses, thioridazine can induce TdP but in the presence of hypokalaemia, TdP can develop even with a low dose (50 mg daily) of thioridazine^12,13. Last but not least, co-administration of non-sedating antihistamines with drugs that prolong the QT interval by the same or other mechanism (e.g. antiarrhythmics, antipsychotics, tricyclic antidepressants) also increases their adverse effect on the cardiac repolarisation¹¹.

Apart from antiarrhythmics, many drugs capable of inducing QT prolongation and/or TdP are non-cardiac and used for relatively benign conditions. Regulatory authorities in the EU are now concerned that the risk should be identified and if possible quantified during the pre-clinical and clinical development of a drug. Currently there are no guidelines from other regulatory authorities to address this issue. In 1997, the Committee for Proprietary Medicinal Products (CPMP) adopted a document entitled “Points to Consider: The Assessment of the Potential for QT Interval Prolongation by Non-cardiovascular Medicinal Products”¹⁴. The CPMP guideline document should be viewed as a strong signal from the public health authorities that the problem of QT prolongation, especially by non-cardiac drugs is now very significant. Careful scrutiny and research efforts are required for any compound undergoing future development. This document details the necessary pre-clinical and clinical stages required for testing the safety of new active substances.

In clinical practice, adverse effects of QT prolonging drugs can be prevented by not exceeding the recommended dose, avoiding their use in patients with pre-existing heart disease or risk factors as mentioned above, previous ventricular arrhythmias and/or electrolyte imbalance such as hypokalaemia. Concomitant administration of drugs that inhibit the cytochrome P450 (e.g. imidazole antifungals, macrolide antibiotics) or those that can prolong the QT interval or drug that cause hypokalaemia should be avoided. Serum potassium level should be checked regularly as a matter of routine care when the patient is on diuretics. If the patient develops TdP, the offending drug should be stopped and electrolyte abnormalities corrected. Any adverse event suggestive of cardiac arrhythmias should be urgently reported to drug safety authorities and/or drug manufacturers.

TABLE I – Drugs that can prolong QT interval and TdP (this list is not comprehensive)