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Home , Amiodarone, Azimilide, Diltiazem, Disopyramide, Dofetilide, Dronedarone

Europace doi:10.1093/europace/eum169

Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of atrial Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021

Eduard Shantsila, Timothy Watson, and Gregory YH Lip*

University Department of Medicine, City Hospital, Birmingham B18 7QH, UK

KEYWORDS Despite the large number of available antiarrhythmic agents, significant QT-interval prolongation and ; risk of severe proarrhythmia, including torsade de pointes, limit pharmacological opportunities in the Antiarrhythmic drugs; management of atrial arrhythmias. The risk of proarrhythmia has been demonstrated in class I Atrial fibrillation and class III drugs, but significant variability has been observed between agents of the same class. Electrophysiological drug effects found to be important in the etiology of proarrhythmia include QT-

interval prolongation through selective blockade of the delayed rectifying current (IKr), early afterdepolarizations, transmural dispersion of repolarization, and a reverse rate dependence. Interestingly, less proarrhythmic potential is seen or anticipated with agents that are able to block multiple ion channels and those with atrial selectivity, despite moderate QT prolongation. This obser- vation has helped steer the development of newer drugs, with some promising preliminary results.

Introduction Unfortunately, recurrence of AF is common, often requiring long-term drug therapy to improve maintenance From the early twentieth century, drug therapy has played an of sinus rhythm. For most current antiarrhythmic agents, important role in the management of atrial arrhythmias. Qui- the relapse rate is at least 50% during the first year,2–5 nidine was the first antiarrhythmic used to successfully although slightly better figures are seen with dofetilide6 restore and maintain sinus rhythm in atrial fibrillation (AF). and .7,8 A number of studies have also demon- Subsequently, a large number of other drugs have become strated that flecainide and are effective available. Although the efficacy of many of these agents is drugs for preventing AF recurrence.9–11 The effectiveness of impressive, side effects are a frequent occurrence. Amongst flecainide is comparable to , but with fewer side the most worrying side effects are QT-interval prolongation effects.12 In contrast, propafenone is more effective for main- and risk of proarrhythmia, including torsade de pointes (TdP). tenance of sinus rhythm than quinidine and as effective as .13,14 Generally, however, class Ic drugs are preferred Pharmacological treatment for atrial to class Ia drugs in view of their better safety profile.12,13 fibrillation The success of electrical for AF has been Pharmacological cardioversion of AF can be achieved using a quoted as between 75 and 93%, although this depends on left atrial size and co-existing structural disease, and number of drugs with different pharmacological properties, 15–17 including , , quinidine (all class ultimately on the duration of AF. Where there is some Ia), flecainide, propafenone (both class Ic), , ibuti- concern about a successful restoration of sinus rhythm (for lide, sotalol, and amiodarone (all class III). Currently, the example, previous cardioversion failure or early recurrence most commonly used drugs for chemical cardioversion are of AF), concomitant amiodarone or sotalol can be used flecainide, sotalol, and amiodarone. Little difference is pre-cardioversion to improve the success of electrical cardioversion.18 Such an approach is advocated by the observed between the route of administration for cardio- 2 version rates, although intravenous administration results in ACC/AHA/ESC guidelines on AF management. The frequency faster conversion. Indeed, in patients with recent onset AF, of recurrence of AF after electrical cardioversion is high, and successful cardioversion is reported in up to 80% of cases maintenance therapy with antiarrhythmic drugs such as amiodarone or sometimes b-blockers is somewhat useful to with oral therapy, rising only to 90% with intravenous 1 administration.1 prevent AF relapses. b-blockers are very effective at controlling ventricular rate and also may reduce the risk of AF recurrence following suc- * Corresponding author. Tel: þ44 121 554 3801; fax: þ44 121 554 4083. E-mail address: [email protected] cessful cardioversion (whether spontaneous, pharmacological,

& The European Society of 2007. All rights reserved. For permissions, please e-mail: [email protected] iv38 E. Shantsila et al.

or electrical) and are currently used as first-line prophylactic potential. However, IKr is often more susceptible to agents in paroxysmal AF. b-blockers have also been shown to drug effects that may manifest clinically as a prolonged reduce the frequency of post-operative AF, although sotalol QT interval and the emergence of other T- or U-wave (which also has class III effects) appears to be the most abnormalities on the surface electrocardiogram (ECG). effective in this setting. As AF commonly coexists with hyper- Moreover, pharmacological inhibition of the current IKr tension or congestive , b-blockers may also be appears to be responsible for the proarrhythmic effect of part of conventional therapy in such patients. antiarrhythmic, as well as non-antiarrhythmic, drugs. Rate-limiting, non-dihydropyridine Wang et al.22 showed that an early ultra rapid component blockers (, ) are frequently used to of the delayed rectifier (IKur) contributes significantly to optimize rate control where b-blockers are contraindicated repolarization of the human atrial . As IKur or ineffective. An intravenous b-blocker (for example, is present in atrial (but not in ventricular) myocytes in or ) or rate-limiting calcium antagonists man, it is a potential target for the development of drugs Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021 (diltiazem, verapamil) are indicated where urgent pharma- that prevent atrial re-entrant arrhythmias without a risk of cological rate control is required. Intravenous amiodarone ventricular proarrhythmia.23 is a useful alternative in situations where the administration of b-blockers or calcium antagonists is not feasible, such as Early afterdepolarization in the presence of heart failure. The prolongation of repolarization may promote action All current class Ia, Ic, and III antiarrhythmic drugs have potential instability with increased beat-to-beat variability significant side effects. This includes non-cardiovascular of duration. Subsequently, this may result in activation of effects (e.g. pulmonary fibrosis and dysfunction premature inward depolarization currents, known as an with amiodarone), and of particular importance, the risk early afterdepolarization (EAD).24 EADs are generally of life-threatening ventricular proarrhythmia including TdP considered to result from reactivation of the voltage- in up to 5% of patients.19,20 Most of these antiarrhythmic dependent Ca2þ current with secondary depolarization of drugs prevent or terminate AF by altering the function the cell.25 However, other mechanisms such as increased of potassium or channels within the atrial cells. late sodium current and potassium blockade have also Blockade of potassium channels may prolong ventricular been proposed.26,27 Regardless of underlying mechanism, repolarization — and hence, the refractory period — result- when EADs have sufficient amplitude, they may trigger ing in QT-interval prolongation. Given the risk of severe pro- another action potential and promote triggered activity. As , the safety profile of many current antiarrhythmic a result EADs, especially when accompanied by the presence drugs is far from ideal. of a notably increased dispersion of repolarization (see below), may induce re-entry and may be responsible for Mechanisms of antiarrhythmic drug-induced initiation of a . QT prolongation and proarrhythmia Dispersion of repolarization Blockade of ionic currents Repolarization of ventricular cardiomyocytes is further The QT interval represents the cellular ventricular action complicated by temporal and spatial inhomogeneity of the potential and is the net result of co-ordinated function of action potential. Significant regional heterogeneity of the various ionic currents. Naþ and Ca2þ inward currents are action potential profile and duration across the left ventricu- primarily responsible for the action potential upstroke and lar wall can be demonstrated, reflecting different functional depolarization, whereas outward Kþ currents in combination expression of ion channels of cells in different transmural with a reduction in depolarizing currents are predominantly regions of the left ventricular wall.28 For example, EADs are responsible for the myocyte repolarization. Furthermore, easily induced in a subset of myocardial cells from the the same outward Kþ currents lead to restoration of mid-ventricular myocardium, known as M cells, and in the 29 negative myocardial intracellular polarity at rest. His-Purkinje network. In response to IKr blockade, M cells Very high membrane resistance and low current flow demonstrate more pronounced action potential prolongation characterize the plateau phase of the action potential. compared with subendocardial or subepicardial cells.29 Thus, abnormalities of the depolarizing and repolarizing Consequently, this leads to differential recovery of activated currents can dramatically change the duration of the cells and areas of functional refractoriness in the mid- plateau and, therefore, the duration of the action potential. myocardial layer, which may provoke re-entrant arrhythmia Drug-induced increases in depolarizing currents and/or and TdP. It is possible that EADs may be responsible for decreases in repolarizing currents will prolong the ventricu- initiation of a tachycardia, whereas dispersion of repolariza- lar action potential duration and thus the QT interval.21 tion may be responsible for its perpetuation. However, the repolarization phase of the action potential Separation of the epicardial action potentials from that of is especially important in QT-interval prolongation, resulting M cells during the plateau phase has been suggested to be predominantly from attenuated outward movement of represented on the ECG by the beginning of the upright potassium ions. T wave.30 Under normal conditions, this separation is A variety of different Kþ channel subtypes are found in the gradual such that the precise start of the T wave is difficult heart, some of which are presented exclusively in atria. The to determine. Final epicardial repolarization is proposed to two main subtypes responsible for ventricular repolarization correspond with the peak of the T wave, whereas final are the so-called ‘rapid’ (IKr) and ‘slow’ (IKs) potassium repolarization of the M cells is consistent with the end of currents. Blockade of either of these delayed rectifier Kþ the T wave. Therefore, the descending limb of the T wave currents is associated with lengthening of the action represents transmural dispersion of repolarization (TDR), QT prolongation and proarrhythmic risk in treatment of AF iv39 although it has recently been suggested to be a marker of Such trends do not occur with the class Ic agent flecainide, total dispersion of repolarization time.31 This phenomenon where the incidence of TdP appears to be dose dependent.39 may in part explain why the descending limb of the T wave One possible explanation for this discrepancy is that the is so vulnerable. For example, a premature electrical blockade of sodium channels by class Ia drugs seems to impulse might potentially provoke functional transmural have less QT-prolonging effect at higher drug concen- re-entry leading to the development of TdP. trations. Although class Ic drugs have a less dramatic The time interval between the peak and the end of the effect on repolarization and appear to be safer than class T wave has been demonstrated to be a clinically useful Ia agents in terms of life-threatening proarrhythmia, individ- index of TDR in assessing arrhythmic risk.32–34 Furthermore, ual cases of TdP have also been reported for propafenone, the heterogeneous effect of a blocker or activator of an ion flecainide, and .39,43–45 channel may exaggerate the differences in action potential It is important to remember that quinidine-like class Ic shape and duration favouring development of re-entry drugs can enhance conduction with Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021 arrhythmias. increasing ventricular response in patients with AF or Structural heart disease can reduce the repolarization flutter, predominantly due to inherent vagolytic properties. reserve and thus alter impulse conduction. This is often In some patients, particularly in the presence of renal associated with impaired function of Kþ and Ca2þ channels impairment, these drugs can induce atrial flutter with 1:1 and altered intracellular handling of ions, which may atrioventricular-nodal conduction and haemodynamic represent electrical remodelling, particularly characteristic instability. Thus, the concomitant use of atrioventricular- of heart failure. The next result, once more, is evolving nodal blocking agents, such as b-blockers or rate-reducing action potential prolongation.35 In fact, the presence of calcium antagonists, is recommended. structural heart disease is well established as a potent risk factor for the development of drug-induced polymorphic ventricular tachyarrhythmia and TdP. Class III antiarrhythmic agents

Potent blockade of IKr occurs with class III drugs (sotalol, amiodarone, and dofetilide), and with a number of other Antiarrhythmic agents and QT prolongation 46 agents, and results in QT prolongation. Selective IKr The risk of proarrhythmia has been predominantly potassium-blocking antiarrhythmic drugs (Table 1), such as demonstrated with class Ia, class Ic, and class III agents. sotalol, prolong QT interval and induce TdP in a dose- However, incidences strongly depend on the presence of dependent manner up to a plateau resulting from complete predisposing conditions, in particular, high drug dosage and potassium current blockade.44,45,47 The incidence of concomitant use of other medicines, which can prolong sotalol-induced TdP is 0.3% for a daily dose of 80 mg, ~1% QT interval. for patients taking between 160 and 240 mg/day, and up to 5–7% for a daily dose of 480–640 mg.45,48 The risk is Class I antiarrhythmic agents much higher in women and those with renal or congestive 36 heart failure, sustained , and with Selzer and Wray first described a ‘specific toxic effect of concomitant use of diuretics and hypokalaemia.49 Of note, quinidine’ and introduced the term ‘quinidine syncope’. drugs that prolong ventricular repolarization by blocking Later, it was demonstrated that such syncope was most outward potassium currents generally demonstrate a frequently caused by quinidine-induced ventricular tachy- 36 reverse rate dependence, showing greater effects at cardia (often TdP) with an incidence of 0.5–4.4%. slower rather than higher stimulation rates. Meta-analysis of randomized trials evaluating the role of While all class Ia drugs demonstrate comparable risk of TdP, quinidine in the maintenance of sinus rhythm after cardio- there is a marked discrepancy in the frequency of serious version from AF demonstrated that this drug was associated proarrhythmia within class III antiarrhythmic agents. For with a significant increase in mortality (2.9% in the quinidine example, despite similar effects on QT prolongation with group vs. 0.8% in the control group), possibly as the result of quinidine-induced proarrythmia.37 Class Ia drugs are known to induce pro-arrhythmogenic effects including both ventricular tachycardia and TdP. The Table 1 Vaughn–Williams classification risk of proarrhythmia appears to be lower with disopyramide than with quinidine.38 The frequency of flecainide (class Ic) Class IA associated ventricular proarrhythmia is low in the treatment Quinidine, disopyramide, procainamide of AF and only a few cases of serious proarrhythmia have blockers been reported in patients who have no or minimal structural Class II heart disease.39 However, in patients treated with flecainide b-blockers Propranalol, metoprolol, , or after myocardial , the mortality rate , sotalol 40 was higher than observed in the control group. Therefore, Class III given the relatively high risk of proarrhythmia in patients ‘Pure’ potassium channel blockers: with coronary disease or left ventricular dysfunction, blockers Sotalol, dofetilide, class Ic drugs should not be used in this situation. Multiple channel blockers: Amiodarone, Interestingly, TdP can occur at low therapeutic or , , subtherapeutic doses of class Ia drugs.41 This phenomenon Class IV is reported for most of the available class Ia agents, Calcium antagonists Verapamil, diltiazem including quinidine, disopyramide, and procainamide.42 iv40 E. Shantsila et al.

sotalol and amiodarone, the incidence of TdP is much lower Azimilide blocks both the rapid (IKr) and slow (IKs) with amiodarone compared with sotalol. A literature review components of the delayed rectifier potassium current, of the incidence of TdP with amiodarone found only 0.7% in distinguishing it from other potassium channel blockers such 17 uncontrolled studies (2878 patients), and no proarrhythmia as sotalol, dofetilide, and ibutilide. Several randomized, was reported in a further 7 studies (1464 patients).50 In the placebo-controlled clinical trials have demonstrated the Canadian Amiodarone Arrhythmia Trial efficacy of azimilide in prolonging symptom-free interval in (CAMIAT) and in the European Myocardial Infarction patients with AF or atrial flutter.61,62 The preliminary results Amiodarone Trial (EMIAT), amiodarone treatment was associ- from the ALIVE (Azimilide Post-infarction Survival Evaluation) ated with a proarrhythmia rate of ,1% — less than observed study have demonstrated that 100 mg of azimilide has a in the control groups and probably as a result of its low incidence of TdP even in high-risk post-myocardial infarc- multi-channel inhibitory effects.51,52 Indeed, a recent tion patients with left ventricular systolic dysfunction.63,64 meta-analysis of amiodarone trials proved that amiodarone Azimilide also reduced the risk of symptomatic AF recurrence Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021 significantly reduced the risk of arrhythmic death and resusci- by 40% compared with placebo,61 although in other studies tated in patients with heart failure or after such efficacy was not demonstrated. This agent prolongs the myocardial infarction.53 The risk of TdP with amiodarone QT interval by 4–42% at doses up to 200 mg/day.65 Infrequent, predominantly occurs in patients with other concomitant but serious adverse events, including severe neutropenia risk factors, such as hypokalaemia or . and TdP, were reported. These complications occurred in The relatively new class III antiarrhythmic drugs, dofeti- up to 1 and 1.5% of patients, respectively — predominantly lide and ibutilide, also possess the risk of excess QT in patients with bradycardia, pauses, or hypokalaemia. A prolongation and developing TdP. For example, in one ran- recent analysis of cumulative evidence from 19 clinical domized, double-blinded trial, infusion of ibutilide resulted studies in the azimilide database demonstrates that the risk in polymorphic ventricular tachycardia in 8.3% of treated of TdP with azimilide is low (1%) and less than that observed patients, whereas all 86 placebo-treated patients were with selective IKr potassium channel blockers such as dofeti- free of this complication.54,55 Similar to sotalol, dofetilide lide and ibutilide.66 has a dose-dependent effect on QT prolongation and TdP.56 Dronedarone is structurally similar to amiodarone but The incidence of TdP in the summary basis of approval was lacking the moiety — a feature of amiodarone that 0–10.5% depending on dose.56 As a rule, severe has been linked to many non-cardiac side effects (including proarrhythmia occurred during the first 3 days of dofetilide , ocular effects, , and treatment initiation. hepatic dysfunction). The Dronedarone Study After Electrical Cardioversion (DAFNE) trial demon- strated the efficacy and safety of dronedarone in preventing New antiarrhythmics under development 67 AF recurrence after cardioversion in 199 patients. In the As the life-threatening complications of available anti- EURIDIS (European trial in atrial fibrillation or flutter arrhythmic drugs are predominantly related to effects on patients receiving dronedarone for the maintenance of ventricular electrophysiological modalities, the search for sinus rhythm) and ADONIS (American–Australian–African safer approaches has focused on identifying agents that trial with dronedarone in atrial fibrillation or flutter patients specifically target the atria. Such targets include the ultra for the maintenance of sinus rhythm) trials, dronedarone rapid delayed rectifying potassium current (IKur), which is was effective in preventing AF recurrence and was shown partly blocked by drugs such as AZD700957 and AVE0118.58 to reduce the ventricular response during AF relapse. In pre-clinical studies, these drugs caused minimal ventricu- There was no evidence of proarrhythmia (including TdP), lar proarrhythmias and were effective for restoring sinus heart failure exacerbation, or thyroid, pulmonary, or other rhythm. However, all of these antagonize other channels organ toxicity. The mortality rate was low (1.0%) and not and are therefore best described as ‘mixed ion-channel significantly different from placebo (0.7%) during the blockers’. Preliminary results have been encouraging, 12-month follow-up.68 However, the Antiarrhythmic Trial with a recent clinical study demonstrating the efficacy of with Dronedarone in Moderate-to-Severe Congestive Heart intravenous AZD7009. Here up to 70% of patients converted Failure Evaluating Morbidity Decrease (ANDROMEDA) was to sinus rhythm from persistent AF.59 Although some patients stopped prematurely because of a trend towards increased exhibited QT prolongation, particularly at higher dosages, risk of death in the dronedarone group, but this numerical only one patient exhibited (asymptomatic) non-sustained increase in mortality was not statistically significant. In ventricular tachycardia. Despite these promising results, 2006, the Food and Drug Administration AZD7009 development has been discontinued based on non- issued a non-approvable letter based on safety concerns. cardiovascular safety findings in clinical studies. Consequently, the drug manufacturer withdrew an Given that the class III antiarrhythmic, amiodarone, was application for licensing to the European Agency for the found to be effective and relatively safe in AF, a group of Evaluation of Medicinal Products. drugs each with some properties similar to amiodarone Tedisamil was originally developed as an anti-anginal has been developed (e.g. dronedarone, azimilide, and tedi- agent and Phase III studies in patients with coronary artery samil). These agents block outward potassium currents and disease have demonstrated its efficacy in this setting. consequently delay atrial and ventricular repolarization. Additionally, tedisamil has been shown to have significant Importantly, it was hoped that by blocking various other class III antiarrhythmic properties with multiple ion-channel ion channels, these novel agents would retain the efficacy effects. Its efficacy and safety in cardioverting AF was and safety (in terms of proarrhythmia) of amiodarone, but recently proved in a multicentre, double-blinded, random- without the associated toxicity. There is some evidence, ized, placebo-controlled study.69 In this trial, 41 and 51% however, that this may not be the case with dronedarone.60 of patients receiving the lower and higher doses, QT prolongation and proarrhythmic risk in treatment of AF iv41 respectively, cardioverted to sinus rhythm, with two cases (1.8%) of possible proarrhythmia (one TdP and one mono- Table 2 Some predisposing factors for developing torsade de pointes morphic ventricular tachycardia) observed. Age Pauses associated with the conversion of atrial fibrillation to sinus rhythm Is antiarrhythmic drug-induced QT-interval Female gender Malignant ventricular arrhythmia prolongation a strong predictor of proarrhythmic potential? Electrolyte imbalance Previous history of proarrhythmia (hypokalaemia, The incidence of TdP is not proportional to the extent of QT hypomagnesaemia) prolongation. The highest rates of TdP are observed with use Congestive heart failure Use of diuretics Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021 of selective IKr blockers, such as sotalol and dofetilide. These drugs preferentially prolong subendocardial and Prolonged QT interval Use of endocardial repolarization, leading to dose-dependent QT Bradycardia or renal failure prolongation, together with a markedly pronounced increase in TDR.70,71 Clinical use of these drugs is therefore associated with very high incidence of TdP.72,73 How do we minimize the risk As already noted, blockade of sodium channels at higher of proarrhythmia of antiarrhythmic concentrations of class Ia agents may attenuate repolari- drugs currently in use? zation delay and risk of TdP, implying a favourable effect from modulation of multiple ion channels. The effects of Hypokalaemia, hypomagnesaemia, congenitally prolonged drugs that affect several ion channels on the development QT intervals, bradycardia, congestive heart failure, female of TdP are complex. For example, amiodarone is a potent sex, and pauses associated with the conversion of AF to antiarrhythmic drug that can significantly prolong the QT sinus rhythm are known risk factors for development of interval, however, the risk of proarrhythmia is very low for TdP (Table 2). The risk of QT prolongation and TdP may be amiodarone and it rarely induces TdP, even in those who increased further by concomitant use of a wide range of have previously developed TdP as a complication of other , especially those which interfere with the QT-prolonging agents.74 The safety of amiodarone may be hepatic metabolism of antiarrhythmic drugs.83 It is attributed to its multi-channel inhibitory effects, which therefore advisable that these drugs are not prescribed to include sodium, potassium, and calcium currents in the patients taking other substances known to promote QT heart. Long-term use of amiodarone reduces TDR by producing prolongation (such as ) and that a 12-lead a greater prolongation of action potentials in the epicar- ECG be requested after initiating treatment. dium.75 In addition, its ability to inhibit inward currents may There are reports of ‘cross-reactivity’ when TdP devel- prevent the occurrence of EAD.76 Still, there is some debate oped in the same patient following administration of about a possible protective role of certain opposing inward different antiarrhythmic agents. ‘Cross-reactivity’ was currents such as late INa and ICa, which may not be inhibited described with different class Ia and class III drugs. until much higher amiodarone concentrations than those However, amiodarone has been used safely in patients with 74 required to block IKr. a history of drug-induced TdP. In summary, the development of TdP under QT-interval pro- Some electrocardiographic findings can also indicate longation is mainly dependent on two prerequisites: the higher probability of TdP development. For example, genesis of EAD that functions as a trigger and enhanced TDR QT-interval dispersion represents the difference between that facilitates EAD propagation and serves as a functional the maximum and the minimum measured QT interval re-entrant substrate to maintain TdP and is not directly on the same 12-lead ECG — whereas normal QT-interval related to the degree of QT-interval prolongation. Develop- dispersion is 50 + 15 ms; in patients with TdP, the average ment of a drug with multiple points of action may prevent QT dispersion is 100 + 40 ms.84 QT dispersion is independent potentially dangerous disturbance of the electrophysiological of length of QT interval and may serve as an independent myocardial balance, and thereby reduce undesirable risk predictor of drug-induced TdP. Of note, QT dispersion proarrhythmic effects, even despite QT prolongation. For was demonstrated to be significantly less for amiodarone example, , a novel anti-anginal drug with anti- than sotalol and class Ia drugs, even despite similar absolute arrhythmic properties, has pharmacological effects attribu- QT-interval prolongation.85 table to the preferential blocking of the late sodium current Initiation of TdP is typical when a pause (long RR interval) (INaL) relative to peak sodium current (INa). Ranolazine demon- is noted on the ECG and then followed by premature strates some action potential prolonging effects,77,78 and ventricular contraction with markedly prolonged repolariza- studies have reported a small degree of QT prolongation in tion. This situation may predispose to EADs and triggered both experimental models77 and human subjects.79,80 Multi activity. ‘TU- or U-wave alternans’ is another risk factor ion-channel blockade, particularly the ability to block INaL, for TdP, which is characterized by a significant beat-to-beat has been suggested as the underlying mechanism whereby change in the TU axis. this drug prolongs the QT interval without any apparent Given the data with sotalol treatment, where TdP usually increase in TdP.77 It is important to note that ranolazine, occurs within 5 days of initiation,86 it is probably safer to even at high doses does not induce EADs,81 and no TdP has initiate sotalol in hospital where facilities for continuous been observed either in experimental models77,82or clinical ECG monitoring and cardiac exist. The risk of studies.79,80 TdP can be reduced by dose adjustment relative to iv42 E. Shantsila et al. clearance and by monitoring the ECG for excessive increases 12. Naccarelli GV, Dorian P, Hohnloser SH, Coumel P. Prospective comparison in the QT interval. Sotalol is contraindicated in patients with of flecainide versus quinidine for the treatment of paroxysmal atrial a QT interval .450 ms or creatinine clearance ,40 mL/min. fibrillation/flutter. The Multicenter Atrial Fibrillation Study Group. Am J Cardiol 1996;77:53A–9A. 13. Lee SH, Chen SA, Chiang CE, Tai CT, Wen ZC, Wang SP et al. Comparisons of oral propafenone and quinidine as an initial treatment option in Future directions patients with symptomatic paroxysmal atrial fibrillation: a double-blind, In conclusion, despite the large number of antiarrhythmic randomized trial. J Intern Med 1996;239:253–60. 14. Reimold SC, Cantillon CO, Friedman PL, Antman EM. Propafenone versus agents that are currently available, modern cardiology is sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J still waiting for the introduction of new efficient and safe Cardiol 1993;71:558–63. drugs for the treatment of atrial arrhythmias. The ideal anti- 15. Gallagher MM, Guo XH, Poloniecki JD, Guan YY, Ward D, Camm AJ. Initial arrhythmic agent must efficiently cardiovert AF patients and energy setting, outcome and efficiency in direct current cardioversion of atrial fibrillation and flutter. J Am Coll Cardiol 2001;38:1498–504.

prevent relapses without proarrhythmic potential. To Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021 16. Lundstrom T, Ryden L. Chronic atrial fibrillation. Long-term results of achieve this, it seems that such drugs should be atrial selec- direct current conversion. Acta Med Scand 1988;223:53–9. tive, should have multi ion-channel effects, should not 17. Dittrich HC, Erickson JS, Schneiderman T, Blacky AR, Savides T, Nicod PH. increase TDR, should not produce EADs, and should not Echocardiographic and clinical predictors for outcome of elective exhibit reverse use-dependency. cardioversion of atrial fibrillation. Am J Cardiol 1989;63:193–7. 18. Singh SN, Singh BN, Reda DJ, Fye CL, Ezekowitz MD, Fletcher RD et al. Comparison of sotalol versus amiodarone in maintaining stability of Conflict of interest: G.Y.H.L. has received funding for research, sinus rhythm in patients with atrial fibrillation (Sotalol-Amiodarone Fibrillation Efficacy Trial [Safe-T]). Am J Cardiol 2003;92:468–72. educational symposia, consultancy, and lecturing from different 19. Friedman PL, Stevenson WG. Proarrhythmia. Am J Cardiol 1998;82: manufacturers of drugs used for the treatment of atrial fibrillation. 50N–8N. He was Clinical Advisor to the Guideline Development Group that 20. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed wrote the United Kingdom National Institute for Health and Clinical rectifier Kþ current. Differential sensitivity to block by class III anti- Excellence (NICE) Guidelines on atrial fibrillation management arrhythmic agents. J Gen Physiol 1990;96:195–215. (www.nice.org.uk). E.S. is a European Society of Cardiology 21. Tomaselli GF, Beuckelmann DJ, Calkins HG, Berger RD, Kessler PD, research fellow. Lawrence JH et al. Sudden cardiac death in heart failure. The role of abnormal repolarization. Circulation 1994;90:2534–9. 22. Wang Z, Fermini B, Nattel S. Sustained depolarization-induced outward References current in human atrial myocytes. Evidence for a novel delayed rectifier Kþ current similar to Kv1.5 cloned channel currents. Circ Res 1993;73: 1. Hersi A, Wyse DG. Management of atrial fibrillation. Curr Probl Cardiol 1061–76. 2005;30:175–233. 23. Li GR, Feng J, Yue L, Carrier M, Nattel S. Evidence for two components of 2. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA et al. delayed rectifier Kþ current in human ventricular myocytes. Circ Res ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial 1996;78:689–96. Fibrillation: a report of the American College of Cardiology/American 24. Aronson RS. Afterpotentials and triggered activity in hypertrophied Heart Association Task Force on Practice Guidelines and the European myocardium from rats with renal . Circ Res 1981;48:720–7. Society of Cardiology Committee for Practice Guidelines (Writing 25. Marban E, Robinson SW, Wier WG. Mechanisms of arrhythmogenic delayed Committee to Revise the 2001 Guidelines for the Management of Patients and early afterdepolarizations in ferret ventricular muscle. J Clin Invest With Atrial Fibrillation): developed in collaboration with the European 1986;78:1185–92. Heart Rhythm Association and the Heart Rhythm Society. Circulation 26. Gibb WJ, Wagner MB, Lesh MD. Effects of simulated potassium blockade 2006;114:e257–e354. on the dynamics of triggered cardiac activity. J Theor Biol 1994;168: 3. Markides V, Schilling RJ. Atrial fibrillation: classification, pathophysiol- 245–57. ogy, mechanisms and drug treatment. Heart 2003;89:939–43. 27. Noble D, Noble PJ. Late sodium current in the pathophysiology of cardio- 4. Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M et al. vascular disease: consequences of sodium-calcium overload. Heart 2006; Amiodarone to prevent recurrence of atrial fibrillation. Canadian trial 92:iv1–iv5. of atrial fibrillation investigators. N Engl J Med 2000;342:913–20. 28. Antzelevitch C, Sicouri S, Litovsky SH, Lukas A, Krishnan SC, Di Diego JM 5. Waldo AL. Management of atrial fibrillation: the need for AFFIRMative et al. Heterogeneity within the ventricular wall. Electrophysiology and action. AFFIRM investigators. Atrial fibrillation follow-up investigation pharmacology of epicardial, endocardial, and M cells. Circ Res 1991; of rhythm management. Am J Cardiol 1999;84:698–700. 69:1427–49. 6. Pedersen OD, Bagger H, Keller N, Marchant B, Kober L, Torp-Pedersen C. 29. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in generated by afterdepolarizations. Role of M cells in the generation of patients with reduced left ventricular function: a Danish investigations U waves, triggered activity and torsade de pointes. J Am Coll Cardiol of arrhythmia and mortality on dofetilide (diamond) substudy. 1994;23:259–77. Circulation 2001;104:292–6. 30. Yan GX, Antzelevitch C. Cellular basis for the normal T wave and the 7. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of electrocardiographic manifestations of the long-QT syndrome. Circulation sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003;42:20–9. 1998;98:1928–36. 8. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB 31. Opthof T, Coronel R, Wilms-Schopman FJ, Plotnikov AN, Shlapakova IN, et al. A comparison of rate control and rhythm control in patients with Danilo P Jr et al. Dispersion of repolarization in canine atrial fibrillation. N Engl J Med 2002;347:1825–33. and the electrocardiographic T wave: Tp-e interval does not reflect 9. Anderson JL, Gilbert EM, Alpert BL, Henthorn RW, Waldo AL, Bhandari AK transmural dispersion. Heart Rhythm 2007;4:341–8. et al. Prevention of symptomatic recurrences of paroxysmal atrial fibril- 32. Lubinski A, Kornacewicz-Jach Z, Wnuk-Wojnar AM, Adamus J, Kempa M, lation in patients initially tolerating antiarrhythmic therapy. A multicen- Krolak T et al. The terminal portion of the T wave: a new electrocardio- ter, double-blind, crossover study of flecainide and placebo with graphic marker of risk of ventricular arrhythmias. Pacing Clin Electro- transtelephonic monitoring. Flecainide Supraventricular Tachycardia physiol 2003;23:1957–9. Study Group. Circulation 1989;80:1557–70. 33. Takenaka K, Ai T, Shimizu W, Kobori A, Ninomiya T, Otani H et al. Exercise 10. Pietersen AH, Hellemann H. Usefulness of flecainide for prevention of stress test amplifies genotype-phenotype correlation in the LQT1 and paroxysmal atrial fibrillation and flutter. Danish–Norwegian Flecainide LQT2 forms of the long-QT syndrome. Circulation 2003;107:838–44. Multicenter Study Group. Am J Cardiol 1991;67:713–7. 34. Aiba T, Shimizu W, Inagaki M, Satomi K, Taguchi A, Kurita T et al. 11. A randomized, placebo-controlled trial of propafenone in the prophylaxis Excessive increase in QT-interval and dispersion of repolarization of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrilla- predict recurrent ventricular tachyarrhythmia after amiodarone. Pacing tion. UK Propafenone PSVT Study Group. Circulation 1995;92:2550–7. Clin Electrophysiol 2004;27:901–9. QT prolongation and proarrhythmic risk in treatment of AF iv43

35. Tomaselli GF, Marban E. Electrophysiological remodeling in hypertrophy 58. Blaauw Y, Gogelein H, Tieleman RG, van Hunnik A, Schotten U, and heart failure. Cardiovasc Res 1999;42:270–83. Allessie MA. ‘Early’ class III drugs for the treatment of atrial fibrillation: 36. Selzer A, Wray HW. Quinidine syncope, paroxysmal ventricular efficacy and atrial selectivity of AVE0118 in remodeled atria of the goat. fibrillations occurring during treatment of chronic atrial arrhythmias. Circulation 2004;110:1717–24. Circulation 1964;30:17–26. 59. Crijns HJ, Van Gelder IC, Walfridsson H, Kulakowski P, Ronaszeki A, 37. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and Dedek V et al. Safe and effective conversion of persistent atrial safety of quinidine therapy for maintenance of sinus rhythm after cardio- fibrillation to sinus rhythm by intravenous AZD7009. Heart Rhythm version. A meta-analysis of randomized control trials. Circulation 1990; 2006;3:1321–31. 82:1106–16. 60. Quaglino D, Ha HR, Duner E, Bruttomesso D, Bigler L, Follath F et al. 38. Podrid PJ, Schoeneberger A, Lown B. Congestive heart failure caused by Effects of metabolites and analogs of amiodarone on alveolar oral disopyramide. N Engl J Med 1980;302:614–7. macrophages: structure-activity relationship. Am J Physiol Cell 39. Falk RH. Flecainide-induced ventricular tachycardia and fibrillation in Mol Physiol 2004;287:L438–47. patients treated for atrial fibrillation. Ann Intern Med 1989;111:107–11. 61. Page RL, Connolly SJ, Wilkinson WE, Marcello SR, Schnell DJ, Pritchett EL. 40. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH Antiarrhythmic effects of azimilide in paroxysmal supraventricular et al. Mortality and morbidity in patients receiving encainide, flecainide, tachycardia: efficacy and dose–response. Am Heart J 2002;143:643–9. Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021 or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 62. Connolly SJ, Schnell DJ, Page RL, Wilkinson WE, Marcello SR, Pritchett EL. 324:781–8. Dose–response relations of azimilide in the management of symptomatic, 41. Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The recurrent, atrial fibrillation. Am J Cardiol 2001;88:974–9. long QT syndromes: a critical review, new clinical observations and a 63. Pratt CM, Singh SN, Al Khalidi HR, Brum JM, Holroyde MJ, Marcello SR unifying hypothesis. Prog Cardiovasc Dis 1988;31:115–72. et al. The efficacy of azimilide in the treatment of atrial fibrillation in 42. Lazzara R. Antiarrhythmic drugs and torsade de pointes. Eur Heart J the presence of left ventricular systolic dysfunction: results from the 1993;14:88–92. Azimilide Postinfarct Survival Evaluation (ALIVE) trial. JAmColl 43. Hii JT, Wyse DG, Gillis AM, Cohen JM, Mitchell LB. Propafenone-induced Cardiol 2004;43:1211–6. torsade de pointes: cross-reactivity with quinidine. Pacing Clin 64. Black SC, Butterfield JL, Lucchesi BR. Protection against programmed Electrophysiol 1991;14:1568–70. electrical stimulation-induced ventricular tachycardia and sudden 44. Kaul U, Mohan JC, Narula J, Nath CS, Bhatia ML. Ajmaline-induced cardiac death by NE-10064, a class III antiarrhythmic drug. J Cardiovasc torsade de pointes. Cardiology 1985;72:140–3. Pharmacol 1993;22:810–8. 45. Stanton MS, Prystowsky EN, Fineberg NS, Miles WM, Zipes DP, Heger JJ. 65. Corey A, Al Khalidi H, Brezovic C, Marcello S, Parekh N, Taylor K et al. Arrhythmogenic effects of antiarrhythmic drugs: a study of 506 patients Azimilide and upon multiple oral treated for ventricular tachycardia or fibrillation. J Am Coll Cardiol 1989; dosing. Biopharm Drug Dispos 1999;20:59–68. 14:209–15. 46. Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S 66. Pratt CM, Al Khalidi HR, Brum JM, Holroyde MJ, Schwartz PJ, Marcello SR et al. Relationships between preclinical cardiac electrophysiology, et al. Cumulative experience of azimilide-associated torsade de pointes clinical QT-interval prolongation and torsade de pointes for a broad ventricular tachycardia in the 19 clinical studies comprising the azimilide range of drugs: evidence for a provisional safety margin in drug develop- database. J Am Coll Cardiol 2006;48:471–7. ment. Cardiovasc Res 2003;58:32–45. 67. Touboul P, Brugada J, Capucci A, Crijns HJ, Edvardsson N, Hohnloser SH. 47. Kehoe RF, Zheutlin TA, Dunnington CS, Mattioni TA, Yu G, Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Spangenberg RB. Safety and efficacy of sotalol in patients with Eur Heart J 2003;24:1481–7. drug-refractory sustained ventricular tachyarrhythmias. Am J Cardiol 68. Hohnloser SH. EURIDIS and ADONIS: maintenance of sinus rhythm with 1990;65:58A–64A. dronedarone in patients with atrial fibrillation or flutter. Hot line II: 48. Falk RH. Proarrhythmia in patients treated for atrial fibrillation or flutter. Acute coronary syndromes/medical treatment II. Program of abstracts Ann Intern Med 1992;117:141–50. from the European Society of Cardiology Congress 2004. 49. McKibbin JK, Pocock WA, Barlow JB, Millar RN, Obel IW. Sotalol, hypo- 69. Hohnloser SH, Dorian P, Straub M, Beckmann K, Kowey P. Safety and kalaemia, syncope, and torsade de pointes. British Heart Journal 1984; efficacy of intravenously administered tedisamil for rapid conversion of 51:157–62. recent-onset atrial fibrillation or atrial flutter. J Am Coll Cardiol 2004; 50. Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proar- 44:99–104. rhythmic effects. A review with special reference to torsade de pointes 70. Yan GX, Wu Y, Liu T, Wang J, Marinchak RA, Kowey PR. Phase 2 early after- tachycardia. Ann Intern Med 1994;121:529–35. depolarization as a trigger of polymorphic ventricular tachycardia in 51. Crystal E, Kahn S, Roberts R, Thorpe K, Gent M, Cairns JA et al. Long-term acquired long-QT syndrome: direct evidence from intracellular recordings amiodarone therapy and the risk of complications after cardiac surgery: in the intact left ventricular wall. Circulation 2001;103:2851–6. results from the Canadian Amiodarone Myocardial Infarction Arrhythmia 71. Wu Y, Carlsson L, Liu T, Kowey PR, Yan GX. Assessment of the Trial (CAMIAT). J Thorac Cardiovasc Surg 2003;125:633–7. proarrhythmic potential of the novel AZD7009 52. Milliez P, Leenhardt A, Maisonblanche P, Vicaut E, Badilini F, Siliste C and dofetilide in experimental models of . et al. Usefulness of ventricular repolarization dynamicity in predicting J Cardiovasc Electrophysiol 2005;16:898–904. arrhythmic deaths in patients with ischemic cardiomyopathy (from the 72. Lehmann MH, Hardy S, Archibald D, quart B, MacNeil DJ. Sex difference in European Myocardial Infarct Amiodarone Trial). Am J Cardiol 2005;95: risk of torsade de pointes with d,l-sotalol. Circulation 1996;94:2535–41. 821–6. 73. Moller M, Torp-Pedersen CT, Kober L. Dofetilide in patients with 53. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic congestive heart failure and left ventricular dysfunction: safety aspects amiodarone on mortality after acute myocardial infarction and in and effect on atrial fibrillation. The Danish Investigators of Arrhythmia congestive heart failure: meta-analysis of individual data from 6500 and Mortality on Dofetilide (DIAMOND) Study Group. Congest Heart Fail patients in randomised trials. Lancet 1997;350:1417–24. 2001;7:146–50. 54. Ellenbogen KA, Stambler BS, Wood MA, Sager PT, Wesley RC Jr, 74. Mattioni TA, Zheutlin TA, Sarmiento JJ, Parker M, Lesch M, Kehoe RF. Meissner MC et al. Efficacy of intravenous ibutilide for rapid termination Amiodarone in patients with previous drug-mediated torsade de of atrial fibrillation and atrial flutter: a dose–response study. J Am Coll pointes. Long-term safety and efficacy. Ann Intern Med 1989;111: Cardiol 1996;28:130–6. 574–80. 55. Stambler BS, Wood MA, Ellenbogen KA, Perry KT, Wakefield LK, 75. Antzelevitch C. Arrhythmogenic mechanisms of QT prolonging drugs: is VanderLugt JT. Efficacy and safety of repeated intravenous doses of QT prolongation really the problem? J Electrocardiol 2004;37:15–24. ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide 76. van Opstal JM, Schoenmakers M, Verduyn SC, de Groot SH, Leunissen JD, Repeat Dose Study Investigators. Circulation 1996;94:1613–21. Der Hulst FF et al. Chronic amiodarone evokes no torsade de pointes 56. Cardiovascular drugs that prolong the QT-interval. http://www://www arrhythmias despite QT lengthening in an animal model of acquired fda gov/ohrms/dockets/ac/00/slides/3619s1_06_throckmorton/sld008 long-QT syndrome. Circulation 2001;104:2722–7. htm (14 March 2007). 77. Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, 57. Goldstein RN, Khrestian C, Carlsson L, Waldo AL. Azd7009: a new anti- Fish JM et al. Electrophysiological effects of ranolazine, a novel arrhythmic drug with predominant effects on the atria effectively termi- agent with antiarrhythmic properties. Circulation 2004; nates and prevents reinduction of atrial fibrillation and flutter in the 110:904–10. sterile pericarditis model. J Cardiovasc Electrophysiol 2004;15:1444–50. iv44 E. Shantsila et al.

78. Fredj S, Sampson KJ, Liu H, Kass RS. Molecular basis of ranolazine 82. Schram G, Zhang L, Derakhchan K, Ehrlich JR, Belardinelli L, Nattel S. block of LQT-3 mutant sodium channels: evidence for site of action. Ranolazine: ion-channel-blocking actions and in vivo electrophysiological Br J Pharmacol 2006;148:16–24. effects. Br J Pharmacol 2004;142:1300–8. 79. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J 83. Darpo B. Spectrum of drugs prolonging the QT-interval and the incidence et al. Effects of ranolazine with atenolol, , or diltiazem of torsades de pointes. Eur Heart J 2001;3:70–80. on exercise tolerance and frequency in patients with 84. Hii JT, Wyse DG, Gillis AM, Duff HJ, Solylo MA, Mitchell LB. Precordial QT severe chronic angina: a randomized controlled trial. JAMA 2004;291: interval dispersion as a marker of torsade de pointes. Disparate effects of 309–16. class Ia antiarrhythmic drugs and amiodarone. Circulation 1992;86: 80. Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J et al. 1376–82. Anti-ischemic effects and long-term survival during ranolazine 85. van de LA, Klingenheben T, Hohnloser SH. Amiodarone therapy after monotherapy in patients with chronic severe angina. J Am Coll Cardiol sotalol-induced torsade de pointes: prolonged QT interval and QT 2004;43:1375–82. dispersion in differentiation of pro-arrhythmic effects. Z Kardiol 1994; 81. Song Y, Shryock JC, Wu L, Belardinelli L. Antagonism by ranolazine of the 83:887–90. pro-arrhythmic effects of increasing late INa in guinea pig ventricular 86. Haverkamp W. Torsade de pointes induced by d,I-sotalol. Circulation

myocytes. J Cardiovasc Pharmacol 2004;44:192–9. 1993;88:1872. Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021