Tian, David MD*; Frishman, William H. MD†
Vernakalant (RSD1235) is a new antiarrhythmic drug that has been shown to act selectively on the atrium by only delaying atrial repolarization. It does this by selectively acting on K+ channels that exist primarily in the atrium (Kv1.5), thus resulting in atrial specific prolongation of the effective refractory period. This makes drugs such as vernakalant extremely valuable in treating atrial arrhythmias, since they appear not to cause ventricular arrhythmias (QT prolongation, torsades de pointes, etc.). Vernakalant is currently undergoing clinical trials, using the intravenous (IV) formulation, for the acute termination of atrial fibrillation and is also being evaluated in oral form for maintaining sinus rhythm in patients with recurrent atrial fibrillation.
MECHANISM OF ACTION
Vernakalant (Kynapid) is a newly discovered aminocyclohexyl ether (3-pyrrolidinol, 1-[(1R, 2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-B hydrochloride (3R)-) that acts selectively on atrial tissue (Fig. 1). 1,2 Vernakalant is able to selectively affect the atrium because it targets 2 channels that are mainly found in the atria and not in the ventricles. The first is the Kv1.5 channel, which carries the ultra rapid delayed rectifier potassium current (IK(ur)).3 The second is the Kir3.1/3.4 channel, which carries the acetylcholine dependent potassium current (IK(Ach)).3 Apart from its actions on the above channels, vernakalant can also work to block other ion currents as well, including Ito, late Ina, with minor blockade of IKr currents.4 The blockade of late Ina current is rate-dependent with fast offset kinetics, which means that blockage of the current is most significant at higher frequencies.4 This, in turn, can selectively slow conduction velocity in the atrium for those with atrial tachyarrhythmias, but not the ventricles.5 The blockade of the Ito current is through Kv4.3 channels, and is similar to late Ina, due to the fact that it too is rate-dependent and works to selectively prolong repolarization in the atrium for those patients with atrial tachyarrhythmias.6
IV vernakalant was found to have first-order elimination as well as linear kinetics following a 10-minute injection period.7 In that study, the plasma half-life in men was 3.1 hours and 2.9 hours in women, whereas the maximum plasma concentration was 3.29 μg/mL in men and 4.57 μg/mL in women.2 A study evaluating the bioavailability of oral vernakalant was performed using healthy subjects.8 One group of subjects was given 5 mg/kg by mouth while fasting, and the drug was shown to have a bioavailability of 71%, a Cmax of 1.8 μg/mL, and a plasma concentration of 4.9 uM. Another group was given 5 mg/kg by mouth while not fasting, and the drug was shown to have a bioavailability of 69%, a Cmax of 1.3 μg/mL, and a plasma concentration of 4 uM. The last group was given 7.5 mg/kg by mouth while fasting, and the drug was shown to have a bioavailability of 58%, with a Cmax of 1.9 μg/mL and a plasma concentration of 5 uM.8
Vernakalant is metabolized predominantly via hepatic metabolism by CYP2D6.7 Studies did not show age, race, sex, hepatic function, renal function, and heart failure as having any significant effect on pharmacokinetic properties of vernakalant.7,9 Drug interaction studies involving vernakalant are limited, however, specific studies did show that beta-blockers and CYP2D6 inhibitors did not affect pharmacokinetic properties of vernakalant.2
Pharmacodynamic studies have been performed on both humans and animals. The animal studies (goats and dogs) demonstrated that vernakalant was able to prolong the absolute atrial refractory period, without affecting ventricular repolarization, to terminate atrial fibrillation.8 The studies also showed that in conscious dogs who had normal heart rhythm on telemeters, the heart rate, mean arterial blood pressure, and EKG parameters (PR, RR, QT, QRS) were unaffected by any doses of vernakalant, including those that were 4 times the normal therapeutic concentration of the drug in humans. In addition, animal studies (rabbit) also showed that vernakalant can also have antiarrhythmic effects.8 In rabbits who had drug-induced QT prolongation and torsades de pointes, vernakalant significantly decreased the prevalence of drug-induced ventricular arrhythmias.8
In one human study, vernakalant was shown to prolong absolute atrial refractory periods.10 There were no observations of torsades de pointes or QT prolongation in the study participants. Other studies have looked at effects of vernakalant in subjects with normal heart rhythms, and in one study, at 5 mg/kg, there was a very mild dose dependent increases in heart rate from 61 to 70 beats/min, PR interval from 169 to 184 milliseconds, QRS interval from 88 to 100 milliseconds, and QT interval from 384 to 419 milliseconds.8 In another study, no significant changes were observed in vital signs or EKG intervals.8
Vernakalant use is currently divided into 2 clinical domains. The first is using IV vernakalant to terminate atrial fibrillation. The second is using oral vernakalant to maintain sinus rhythm after a recent conversion from atrial fibrillation to sinus rhythm.
A phase II, double blind, placebo-controlled, randomized study testing the efficacy and safety of IV vernakalant for terminating recent onset atrial fibrillation11 (Table 1) was conducted in 56 patients with atrial fibrillation from 3 to 72 hours of duration, and patients were either given placebo (n = 20), low dose vernakalant (n = 18), or high dose vernakalant (n = 18). The low dose group was given 0.5 mg/kg IV initially. If atrial fibrillation did not resolve, 1 mg/kg IV was also given. The high dose group was given 3.0 mg/kg IV initially. If atrial fibrillation did not resolve, 2 mg/kg IV was also given. The results showed that while placebo and low dose IV vernakalant did not convert atrial fibrillation to sinus rhythm, the high dose was able to convert atrial fibrillation to sinus rhythm. The high dose group compared with the placebo group had a 61% versus 5% conversion, respectively. At 30 minutes after dosing, the high dose group compared with the placebo group demonstrated 56% versus 5% of patients who retained sinus rhythm. At 60 minutes after dosing, the high dose group compared with the placebo group demonstrated 53% versus 5% of patients who retained sinus rhythm. The average time it took for atrial fibrillation termination in the high dose group compared with the placebo group was 14 versus 162 minutes.1 There were no QT prolongation, torsades de pointe, or other ventricular arrhythmias observed in the study, either in the low dose or high dose vernakalant groups.
IV vernakalant was also evaluated in 4 studies, consisting of Atrial Arrhythmia Conversion Trial (ACT) I, II, III, and IV. The objectives for ACT I was to test the efficacy and safety of IV vernakalant for terminating recent onset atrial fibrillation and atrial flutter.12,13 Vernakalant was determined to be efficacious if sinus rhythm was achieved within 90 minutes of dosing and the effect lasted for at least 1 minute.7 It was conducted on 336 patients with atrial fibrillation and atrial flutter from 3 hours to 45 days of duration, and patients were either given placebo or IV vernakalant. The vernakalant dosing group was given 3 mg/kg IV initially. If atrial fibrillation did not resolve, an additional 2 mg/kg IV was given.12,13 Exclusions included an ECG QT interval of >440 seconds, symptomatic bradycardia, or a heart rate <50 bpm, an ECG QRS duration of >140 milliseconds, previous failure of cardioversion, or having received class I or class III antiarrhythmic drugs, or IV amiodarone within the previous 24 hours. For the patients whose duration of atrial fibrillation was between 3 hours and 7 days (n = 220), 51% of the vernakalant group achieved sinus rhythm versus 4.0% of the placebo group (P < 0.0001), with a median conversion time of 11 minutes.7,13 For the patients whose duration of atrial fibrillation was between 7 days and 45 days, the conversion difference between the 2 groups was not statistically significant (P = 0.30).7,12 ACT I also evaluated atrial flutter conversion to sinus rhythm. Of 39 patients with atrial flutter, only 1 patient converted to sinus rhythm with IV vernakalant, compared with 0 of 15 for placebo patients.12 There were also no torsades de pointes reported in the study.
The ACT III study was a phase III trial that was very similar to ACT I in purpose and study design. It also involved testing the efficacy of IV vernakalant on both atrial fibrillation and atrial flutter, with efficacy of vernakalant shown to be the same as in ACT I.12,14 It was conducted in 276 patients with atrial fibrillation and atrial flutter from 3 hours to 45 days of duration, and patients were either given placebo or IV vernakalant. For the patients whose duration of atrial fibrillation was between 3 hours and 7 days (n = 170), 51.2% of the vernakalant group achieved sinus rhythm versus 3.6% of the placebo group (P < 0.0001), with a median conversion time of 8 minutes.7,12,14 For the patients whose duration of atrial fibrillation was between 7 days and 45 days, the efficacy difference between the 2 groups was not statistically significant (P = 0.33).7,14 In ACT III, 7% of patients with atrial flutter converted to sinus rhythm with IV vernakalant versus 0% for placebo patients.12 Torsades de pointes was not reported in the study.
The results of ACT I and ACT III were also evaluated after the data were pooled from the 2 studies. For the patients whose duration of atrial fibrillation was between 3 hours and 7 days, 51.1% of the vernakalant group achieved sinus rhythm versus 3.8% of the placebo group (P < 0.0001), with a median conversion time of 10 minutes.7 For the patients whose duration of atrial fibrillation was between 7 days and 45 days, the efficacy difference between the 2 treatment groups was not statistically significant (P = 0.142).7 The rate of conversion to sinus rhythm of patients who had only the first dose of vernakalant was 39.8%, whereas in those remaining who received the second dose, the conversion rate to sinus rhythm was only 19.7%.7 Also, 97.2% of patients who converted to sinus rhythm due to IV vernakalant were retained in sinus rhythm after 24 hours.7
New onset atrial fibrillation is common in postoperative patients. ACT II evaluated the efficacy of IV vernakalant in 161 patients who developed atrial fibrillation or atrial flutter following valve replacement surgery, coronary artery bypass graft surgery, or both.14 The efficacy determination of ACT II was similar to ACT I and III in that within 90 minutes of vernakalant injection, patients converted to sinus rhythm that lasted for at least 1 minute. Similar to ACT I and III, patients were divided into groups to receive either placebo or IV vernakalant. The vernakalant dosing group was given 3 mg/kg IV initially. If atrial fibrillation did not resolve within 15 minutes, an additional 2 mg/kg IV was given.14 In this study, 47.0% of the vernakalant group achieved sinus rhythm versus 14.0% of the placebo group (P < 0.001), with a median time of conversion of 12 minutes.14 For the patients who developed atrial flutter, vernakalant did not appear to be effective in converting patients to sinus rhythm. There were also no torsades de pointes, sustained ventricular tachycardia, or ventricular fibrillation reported in the study.
ACT IV was an open-label study used mainly to give additional safety data for IV vernakalant in the termination of atrial fibrillation.7 It was conducted in 236 patients with atrial fibrillation from 3 hours to 45 days. The vernakalant dosing and determination of efficacy end point was the same as in ACT I, II, and III. For the patients whose duration of atrial fibrillation was between 3 hours and 7 days, 50.9% of patients who received IV vernakalant converted to sinus rhythm, with a median time of conversion of 14 minutes.7
Recently the results of the Active Controlled, Multicenter Study of Vernakalant Injection Versus Amiodarone in Subjects with Recent Onset Atrial Fibrillation (AVRO) were reported on where vernakalant was shown to be significantly faster than intravenous amiodarone in converting atrial fibrillation patients to sinus rhythm.15 Vernakalant was studied in 116 patients with symptomatic atrial fibrillation (of 3 to 48 hours duration) versus 116 patients on amiodarone. The amiodarone infusion was given over 2 hours (1 hour loading dose of 5 mg/kg, followed by a 1 hour maintenance infusion of 50 mg). Patients treated with vernakalant infusion received 3 mg/kg for 10 minutes followed by a 10 minute infusion of 2 mg/kg. The primary endpoint of the study was to assess the conversion rate from atrial fibrillation to normal sinus rhythm with a minimum duration of 1 minute within 90 minutes of the first exposure of the study drug. In this study vernakalant converted 51.7% of patients to sinus rhythm at 90 minutes versus 5.2% of patients on amiodarone. Adverse effects or events leading to the discontinuation of study drugs were uncommon, and there were no reported cases of torsades de pointes, ventricular fibrillation or sustained ventricular tachycardia. Currently, a phase IIIb study is in progress evaluating the safety and efficacy of vernakalant versus placebo in 470 patients with recent onset symptomatic atrial fibrillation (ACT V).
Recently intravenous vernakalant was granted marketing approval (BrinavessTM) in the European Union for the rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults; for non-surgery patients with atrial fibrillation of 7 days or less; and for post-cardiac surgery patients with atrial fibrillation of 3 days or less. In 2007, the FDA Cardiovascular and Renal Advisory Committee recommended the approval of IV vernakalant, but the drug is not yet available for clinical use in the United States until more safety and efficacy data are accumulated.
Oral vernakalant has been evaluated for the maintenance of normal sinus rhythm in post-cardioversion patients having had atrial fibrillation. One phase 2a study of oral vernakalant looked at the safety, dosing, and efficacy of oral vernakalant in 59 patients who were at risk for recurrent atrial fibrillation.16 The study included patients with atrial fibrillation, the majority of whom had an atrial fibrillation duration between 30 and 180 days. The patients were split into 3 treatment groups: placebo twice daily, oral vernakalant 300 mg/kg twice daily, or 600 mg/kg twice daily. After 3 days of treatment, patients who remained in atrial fibrillation rhythm were subsequently cardioverted and continued with their treatment for 25 days, for a total treatment time of 28 days. The results showed that 61.0% of patients in both the 300 and 600 mg/kg groups maintained normal sinus rhythm at the end of 28 days versus 43.0% of the placebo group. When pooling the 300 and 600 mg/kg groups together versus placebo, the result was statistically significant (P < 0.028).16 There were no episodes of torsades de pointes seen in the study.
A phase 2b study of oral vernakalant was also carried out in 605 subjects.15 The patients were randomized to receive placebo twice daily, oral vernakalant 150 mg/kg twice daily, 300 mg/kg twice daily, and 500 mg/kg twice daily. The total treatment time was 90 days. The results showed that 51.0% of the 500 mg/kg group maintained normal sinus rhythm at the end of 90 days versus 37.0% of the placebo group. The 150 and 300 mg/kg groups had sinus rhythm maintenance results that were statistically nonsignificant when compared with placebo. There were no episodes of torsades de pointes that were seen in the study.
SAFETY AND SIDE EFFECTS
In the clinical trials, adverse events from IV vernakalant were evaluated within the first 24 hours after drug infusion, because most, if not all, of vernakalant has gone from the body by then. The findings from the phase II and phase III trials of IV vernakalant versus placebo (ACT I, II, III, IV, CRAFT), demonstrated that the side effects mostly experienced by patients were dysgeusia (20.4% vs. 2.4%), sneezing (15% vs. 0.0%), paresthesias (8.8% vs. 1.5%), nausea (6.5% vs. 1.2%), and hypotension (5.8% vs. 3.6%).7 These effects were also all transient. For the most serious adverse events, IV vernakalant had higher incidences than placebo: complete atrioventricular block (0.3% vs. 0.0%), sinus arrest (0.3% vs. 0.0%), sinus bradycardia (0.3% vs. 0.0%), ventricular fibrillation (0.3% vs. 0.0%), torsades de pointes (0.1% vs. 0.0%), and hypotension (1.2% vs. 0.3%).7 Of the 2 patients with ventricular fibrillation, 1 of them (CRAFT trial) developed ventricular fibrillation only after unsynchronized cardioversion due to equipment malfunction following an unsuccessful infusion of 0.5 and 1.0 mg/kg to convert atrial fibrillation to sinus rhythm.7 The other patient had severe aortic stenosis with an acute coronary syndrome and received IV vernakalant: within the first 2 hours the patient developed ventricular fibrillation and died. There were actually 3 patients out of all the pooled participants who developed torsades de pointes in the vernakalant groups, but 2 of them developed torsades after 24 hours and these episodes were deemed not to be a result of vernakalant.7 An ECG QT prolongation of 10 milliseconds was observed, but the incidence of total ventricular arrhythmias between the placebo and vernakalant groups were similar (16.5% vs. 12.5%).7
The safety profile of the oral form is similar to that of IV vernakalant. In the oral treatment studies, there were no episodes of torsades de pointes noted and there were similar incidences of serious adverse events in both placebo and vernakalant groups.16 In the phase 2a trial, serious adverse events were present in 1% of the placebo group, 4% in the 300 mg/kg group, and 6% in the 500 mg/kg group. In the phase 2b trial, serious adverse events were observed in 0.5% of the placebo group, 1.1% in the 150 mg/kg group, 0.5% in the 300 mg/kg group, and 0.5% in the 500 mg/kg group.16
The results from all the studies (ACT I, II, III, IV, CRAFT) demonstrate that IV vernakalant is effective for terminating atrial fibrillation whose duration is <7 days. It does not appear to be effective for those patients whose duration of atrial fibrillation is >7 days or for termination of atrial flutter.17
It also appears that IV vernakalant is effective in terminating atrial fibrillation in patients who have undergone cardiac surgery, though it appears to be ineffective for patients who develop atrial flutter.
Oral vernakalant, according to the phase 2a and 2b trial results, appears to be effective in preventing recurrences of atrial fibrillation at a dose of 500 mg/kg twice daily. What the oral vernakalant studies did not show was how many patients were cardioverted compared with those that were not cardioverted who reverted to normal sinus rhythm. Thus, the role of oral vernakalant, in and of itself, to terminate atrial fibrillation, is not known.
One of the big issues involving current antiarrhythmic therapies is drug-induced ventricular arrhythmias. In the reported studies, vernakalant appears to have caused minimal drug-induced ventricular arrhythmias (ventricular fibrillation, torsades de pointes, etc.) and appears to be safe for clinical use. While the most common side effects do not appear to be harmful, hypotension caused by the drug is a concern, especially in patients with symptomatic left ventricular dysfunction. There is also no experience with the drug when used in patients with acute myocardial infarction and acute coronary syndrome.
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