Antidysrhythmic drugs

Comparative studies

There is some doubt about whether conversion to sinus rhythm produces a better long-term outcome than rate control. Five randomized controlled comparisons of rhythm control versus rate control, mostly in patients with persistent atrial fibrillation (n = 5175 in all), have all suggested that there are no major differences in beneficial outcomes between the two strategies [ , ], although there were fewer adverse drug reactions in patients randomized to rate control in three of the studies and in all the studies rate control was associated with fewer hospital admissions. Furthermore, in an analysis of cost-effectiveness, rate control plus warfarin was much cheaper than rhythm control in preventing thromboembolism, largely because of the use of expensive modern antidysrhythmic drugs for the latter [ ]. Although these results suggest that rate control might be preferable to rhythm control, they do not give any information about patients in whom sinus rhythm is established permanently after pharmacological or physical conversion, since many of the patients in whom rhythm control is used as a strategy will actually have paroxysmal atrial fibrillation.

In a substudy of the AFFIRM study [ ] different antidysrhythmic drugs were compared, by randomly assigning the first drug treatment to amiodarone, sotalol, or a class I drug [ ]. At one year, in 222 patients randomized between amiodarone and class I agents, 62% were successfully treated with amiodarone, compared with 23% taking class I agents. In 256 patients randomized between amiodarone and sotalol, 60% versus 38% were successfully treated. In 183 patients randomized between sotalol and class I agents, 34% versus 23% were successfully treated, although this portion of the substudy was stopped early when amiodarone was shown to be better than class I agents. Sinus rhythm was achieved in nearly 80% of patients at 1 year. There was only one case of torsade de pointes in this substudy (in a patient who had taken quinidine for more than 1 year). There were no cases of agranulocytosis or lupus syndrome induced by procainamide. However, adverse effects that caused discontinuation of the antidysrhythmic drugs during the first year were frequent ( Table 4 ), and occurred in 12% of patients taking amiodarone, 11% of those taking sotalol, and 28% of those taking class I agents. Among those who were randomized to amiodarone, pulmonary toxicity was diagnosed in two by 1 year, three by 2 years, and no additional patients by 3 years. Gastrointestinal adverse events were a common reason for stopping class I drugs.

Comparative studies with other treatments

The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT) was a multicenter randomized trial of atrioventricular junction ablation and pacing compared with pharmacological ventricular rate control in 99 patients, mean age 68 years, with mildly to moderately symptomatic permanent atrial fibrillation [ ]. At 12 months follow-up there was no significant difference in left ventricular ejection fraction or exercise duration on treadmill testing; however, the peak ventricular rate was lower in the ablation group during exercise (112 versus 153) as was a score of activities of daily life. The CAST quality-of-life questionnaire showed that patients who had ablation had fewer symptoms at 6 and 12 months, with a relative risk reduction in symptoms at 12 months of 18%. Global subjective semiquantitative measurement of quality of life using the “ladder of life” showed that ablation produced a 6% better quality of life at 6 months. There were no differences in adverse events between the two treatments.

Cardiac dysrhythmias

Antidysrhythmic drugs can themselves cause cardiac dysrhythmias, their major adverse effect. The risk of antidysrhythmic-induced cardiac dysrhythmias (prodysrhythmic effects) has been estimated at about 11–13% in non-invasive studies [ , ] and at up to 20% in invasive electrophysiological studies. However, the risk varies from drug to drug and is particularly low with class III drugs. In one study the quoted risks of dysrhythmias were: flecainide 30%, quinidine 18%, propafenone 7%, sotalol 6%, and amiodarone 0% [ ]. However, amiodarone does cause dysrhythmias, especially when the QT _c interval is over 600 ms.

The prodysrhythmic effects of antidysrhythmic drugs have been extensively reviewed [ ], as have drugs that prolong the QT interval [ ].

Dysrhythmias secondary to antidysrhythmic drugs are arbitrarily defined as either early (within 30 days of starting treatment) or late [ , ]. A lack of early dysrhythmias in response to antidysrhythmic drugs does not predict the risk of late dysrhythmias [ ].

Ventricular dysrhythmias due to drugs may be either monomorphic or polymorphic. The class Ia drugs are particularly likely to cause polymorphic dysrhythmias, as is amiodarone (although to a lesser extent). In contrast, the class Ic drugs are more likely to cause monomorphic dysrhythmias [ ].

Class Ic antidysrhythmic drugs have been reported to cause the characteristic electrocardiographic changes of Brugada syndrome, which consists of right bundle branch block, persistent ST segment elevation, and sudden cardiac death, in two patients [ ]. Class Ia drugs did not cause the same effect.

The prodysrhythmic effects of antidysrhythmic drugs have been reviewed in discussions of the pharmacological conversion of atrial fibrillation [ ] and the relative benefits of rate control in atrial fibrillation or maintaining sinus rhythm after cardioversion [ ].

The major drugs that have been implicated in prolonging the QT interval in one way or another, including cardiac and non-cardiac drugs, are listed in Table 6 .

Mechanisms

There are four major mechanisms whereby antidysrhythmic drugs cause dysrhythmias [ ]:

• 1.

  Worsening of a pre-existing dysrhythmia. For example, ventricular extra beats can be converted to ventricular tachycardia or the ventricular rate in atrial flutter can be accelerated when slowing of the atrial rate results in the conduction of an increased number of atrial impulses through the AV node.

• 2.

  The induction of heart block or suppression of an escape mechanism. For example, slowing of conduction through the AV node can impair a mechanism that allows the conducting system to escape a re-entry mechanism.

• 3.

  The uncovering of a hidden mechanism of dysrhythmia. For example, antidysrhythmic drugs can cause early or delayed after-depolarizations, which can result in dysrhythmias.

• 4.

  The induction of a new mechanism of dysrhythmia. For example, a patient in whom myocardial ischemia has predisposed to dysrhythmias may be more at risk when an antidysrhythmic drug alters conduction.

Combinations of these different mechanisms are also possible.

The prodysrhythmic effects of antidysrhythmic drugs have been reviewed, with regard to mechanisms at the cellular level [ ] and molecular level [ ]. As far as the cellular mechanisms are concerned, the antidysrhythmic drugs have been divided into three classes (which do not overlap with the classes specified in the electrophysiological classification).

• 1.

  Group 1 drugs have fast-onset kinetics and the block saturates at rapid rates (about 300 beats/minute).

• 2.

  Group 2 drugs have slow-onset kinetics and the block saturates at rapid rates.

• 3.

  Group 3 drugs have slow-onset kinetics and there is saturation of frequency-dependent block at slow heart rates (about 100 beats/minute).

The fast-onset kinetics of the Group 1 drugs makes them the least likely to cause dysrhythmias. Group 2 drugs, which include encainide, flecainide, procainamide, and quinidine, are the most likely to cause dysrhythmias, because of their slow-onset kinetics. Although this also applies to the Group 3 drugs, which include propafenone and disopyramide, block is less likely to occur during faster heart rates and serious dysrhythmias are therefore less likely during exercise.

The most common mechanism of dysrhythmias at the molecular level is by inhibition of the potassium channels known as IK _r , which are encoded by the human ether-a-go-go-related gene (HERG). The antidysrhythmic drugs that affect these channels include almokalant, amiodarone, azimilide, bretylium, dofetilide, ibutilide, sematilide, d -sotalol, and tedisamil (all drugs with Class III actions) and bepridil, disopyramide, prenylamine, procainamide, propafenone, quinidine, and terodiline (all drugs with Class I actions). Other drugs that affect these channels but are not used to treat cardiac dysrhythmias include astemizole and terfenadine (antihistamines), cisapride, erythromycin, haloperidol, sertindole, and thioridazine.

Prolongation of the QT interval, resulting from inhibition of the human ether-a-go-go related gene (HERG) potassium channels by antidysrhythmic drugs, can cause serious ventricular dysrhythmias and sudden death. In 284 426 patients with suspected adverse reactions to drugs that are known to inhibit HERG channels reported to the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, 5591 cases (cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia) were compared with 278 835 non-cases [ ]. HERG inhibitory activity was defined as the effective therapeutic unbound plasma concentration divided by the HERG IC50 value of the suspected drug. There was a significant association between HERG inhibitory activity and the risk of serious ventricular dysrhythmias and sudden death ( Table 7 ). The antidysrhythmic drugs that least followed the predicted pattern were amiodarone, bepridil, flecainide, ibutilide, and sotalol, for which the odds were higher than expected, and aprindine, for which the odds were lower than expected.

The mechanism of action of class I antidysrhythmic drugs has been studied in 14 patients with accessory pathways and orthodromic atrioventricular re-entrant tachycardia [ ]. The drugs were cibenzoline (n = 7), pilsicainide (n = 2), disopyramide (n = 2), and procainamide (n = 3). In four of six patients with a manifest accessory pathway, class I drugs induced unidirectional conduction block of the accessory pathway (anterograde conduction block associated with preserved retrograde conduction) and enhanced the induction of atrioventricular re-entrant tachycardia with atrial extrastimulation. In eight patients with a concealed accessory pathway, there was outward or inward expansion of the tachycardia induction zone in patients who had greater prolongation of the conduction time than the refractory period of the retrograde accessory pathway after class I drugs. During ventricular extrastimulation, induction of bundle branch re-entry after class I drugs initiated atrioventricular re-entrant tachycardia in all the patients. The authors concluded that the adverse effects of all class I drugs in patients with accessory pathways are mainly due to induction of unidirectional retrograde conduction in manifest accessory pathways and greater prolongation of retrograde conduction time in concealed accessory pathways than the refractory period, regardless of the subtype of drug.