Drug Evaluation
Vernakalant hydrochloride to treat atrial fibrillation
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Richard A Brown, Yee Cheng Lau & Gregory YH Lip† 1.
Introduction
2.
Basic mechanisms of AF
3.
Rhythm control
4.
Pharmacology
5.
Efficacy and safety
6.
Regulatory issues
7.
Conclusion
8.
Expert opinion
University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Cardiovascular Medicine, Birmingham, UK
Introduction: Intravenous vernakalant (Brinavess) has been developed and approved in Europe as a safe and efficacious drug to rapidly convert recent onset atrial fibrillation to sinus rhythm in patients with no minimal or structural heart disease. Areas covered: The pharmacology of vernakalant and the pivotal Phase II and III clinical trials undertaken during its development are discussed with regard to safety and efficacy. An extensive PubMed search was used to identify suitable papers. Expert opinion: As yet, there is no evidence of benefit over and above intravenous flecainide or propafenone for patients in whom vernakalant has a class 1a recommendation. As such, it is likely to be most useful in centres where only amiodarone is available. Keywords: antiarrhythmic drugs, atrial fibrillation, cardioversion, rhythm control, vernakalant Expert Opin. Pharmacother. (2014) 15(6):865-872
1.
Introduction
Atrial fibrillation (AF) is the most common arrhythmia in the developed world with an estimated prevalence of 1.5 -- 2% amongst the general population. This prevalence increases with age and affects almost 10% of the population over 80. Hospitalisation due to symptoms of palpitations and tachyarrhythmia is also very common. Thus, AF is a major cardiovascular challenge in modern society, and its medical, social and economic impact is likely to worsen over the coming decades as the population ages [1]. A number of treatments have been developed in recent years -- mainly focusing on the rhythmic and thrombogenic aspects of the condition -- which offer some possible solutions to the problems related to AF. One such antiarrhythmic drug (AAD), vernakalant, is discussed in the present review (Box 1). Only the intravenous (i.v.) preparation is discussed as the oral preparation is no longer being developed. 2.
Basic mechanisms of AF
The two main mechanisms contributing to AF are triggered activity (ectopics) and reentry [2]. Triggered activity -- a disorder of impulse formation [3] -- is caused by early or delayed after depolarisations (EADs or DADs), which occur during or after repolarisation of the atrial action potential (AP). EADs occur predominantly at slower heart rates in the setting of prolonged AP duration due to increased L type calcium (ICaL) or late sodium (INaLate) influx or decreased outward potassium currents. This excessive prolongation allows ICaL to recover from inactivation immediately following a depolarisation allowing calcium to enter and depolarise the cell to excitation threshold [4]. Late sodium influx via the sodium/calcium exchange channel (INCX) occurs prolonging the AP further. DADs are caused by spontaneous (i.e., not caused by an AP) calcium release from the sarcoplasmic reticulum of atrial myocyctes during diastole usually due to calcium overload. This increases the
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Vernakalant EU: Launched UK: Licensed but not launched Pharmacological conversion of recent onset atrial fibrillation Mixed potassium and sodium channel blocker predominantly acting on atrial myocytes Intravenous OH
N
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O
O
O
[47]
Pivotal trial(s)
Controlled Randomised Atrial Fibrillation Trial Atrial Arrhythmia Conversion Trials I, II, III, IV. AVRO SCENE 2
AVRO: A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation.
cytoplasmic concentration of calcium. This additional calcium is exchanged for extracellular sodium in a 1:3 ratio leading to a net inward movement of positive ions. When the threshold for depolarisation is reached (delayed), AP’s arise. Reentry -- a disorder of impulse propagation -- occurs when an impulse travels around an abnormal circuit (or multiple circuits) repetitively, reactivating areas that have already recovered, thereby providing a perpetuation of electrical activity [2,3]. Reentry that does not involve a fixed anatomical obstacle is called functional reentry of which two main models exist, the ‘leading circle’ model and the ‘spiral wave’ model [5]. Both refer to the proposed shape of the reentrant circuit as it propagates through excitable tissue. The leading circle model, perhaps the most well known of the two, refers to the smallest circuit required for reentry maintenance, given by the distance (‘wavelength’) the impulse travels in one effective refractory period (ERP). As Wavelength = conduction velocity ERP a decrease in action potential duration (leading to a decrease in ERP) will cause a decrease in wavelength leading to smaller and more numerous circuits within the same area, which means that AF becomes more stable and likely to persist [2,6]. 3.
Rhythm control
Many episodes of AF terminate spontaneously within the first hours or days. Where spontaneous termination does not occur, conversion from AF to sinus rhythm (SR) can be achieved using synchronised direct current electrical shock (‘electrical cardioversion’) or ‘pharmacological cardioversion’ using AADs [7]. Several trials performed have shown no appreciable difference between a rate control or a rhythm control strategy for AF in terms of mortality or morbidity [8-10]; current 866
management has become patient-centred and symptom directed. Indeed, current guidelines recommend rhythm control only in the presence of on-going symptoms (European Heart Rhythm Association [EHRA] score > 2) despite adequate heart rate control except where a clearly defined trigger exists that has been corrected [7]. Whilst the clinical data on the benefits of early rhythm control in AF are limited, it is likely that a window of opportunity to restore and maintain SR exists early in the course of the condition [7]. Furthermore, the restoration of SR may result in a reduction of tachyarrhythmia symptoms and an improvement in quality of life [11]. Previously, the only available pharmacological options for the rhythm control of AF were propafenone and flecainide (sodium channel blockers); sotalol and dofetilide (IKr potassium channel blockers) and amiodarone and dronedarone (mixed ion channel blockers) [12]. The safety and efficacy of these drugs limits their use in clinical practice -- for example, propafenone and flecainide are proarrhythmogenic, particularly in patients who have structural heart disease; sotalol can cause marked QT interval prolongation as well as being contraindicated in asthmatic patients and amiodarone-related toxicity is well described (although less important in the acute setting there have still been anecdotal reports of adverse effect after just a few days [13]). More recently, dronaderone, a benzofuran derivative, structurally related to amiodarone, has been implicated in causing severe liver injury [14,15]. 4.
Pharmacology
Introduction to compound and chemistry Vernakalant is an atrial selective mixed potassium (K+) and sodium (Na+) channel blocker used in the acute cardioversion 4.1
Expert Opin. Pharmacother. (2014) 15(6)
Vernakalant
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Table 1. Ionic targets of vernakalant. Target
Affinity
IKur IK,Ach Ito IKr INaLate
++ ++ + + + at physiological heart rates ++ at higher heart rates
+: Mildly inhibited; ++: Potently inhibited; IK,Ach: Acetylcholine-activated inward rectifier K+ current; IKr: Rapidly activating delayed rectifier K+ current; IKur: Ultra-rapidly activating delayed rectifier K+ current; Ito: Transient outward current; INaLate: Late sodium current.
of AF. Based on preclinical animal studies and subsequently confirmed by human electrophysiological study, vernakalant has been shown to selectively prolong atrial ERPs without significant effects on ventricular ERPs [16,17]. This gives vernakalant a unique feature of controlling atrial arrhythmia, whilst having minimal proarrhythmic effect on ventricular tissue [18]. This is achieved by targeting atrial-selective channels, specifically IKur and IK,Ach by having a high selectivity for rapid rhythms like AF and using a rate-dependent blocking strategy for its additional Na+ channel block [19]. Vernakalant blocks the K+ channels IKur (ultra-rapidly activating delayed rectifier K+ current), Ito (transient outward current) and IK,ACh (acetylcholine-activated inward rectifier K+ current). IKur is blocked in the open state with preserved efficacy even at higher frequencies [17]. The atrial selective IK,Ach current is potently inhibited Table 1, whereas the Kv4.3 and human erythroblast transformation-specific related gene (hERG) channels that make up the Ito and IKr (rapidly activating delayed rectifier) currents, respectively, are also blocked by vernakalant but with lower affinity than flecainide or propafenone. This is important because IKr is an integral repolarising current in ventricular cells and its inhibition is known to cause QT prolongation with the subsequent risk of torsades de pointes [19]. This partially explains the lower rates of torsade des pointes seen with vernakalant in the clinical trials [20-23] and the improved safety profile over other class 1C antiarrhythmics [17]. Vernakalant also inhibits Nav 1.5, part of the sodium channel expressed in cardiac myocytes and human embryonic kidney cells [24]. At normal heart rates, vernakalant’s effect on Nav 1.5 is minimal because of rapid unbinding kinetics from the channel. At fibrillatory rates, the inhibitory potency is significantly increased [17,19]. In addition, the effects of vernakalant on Na channels are voltage dependent. The resting membrane potential of normal atrial myocytes is 10 mV more depolarised than that of ventricular myocytes. During AF when atrial myocytes are less likely to repolarise fully the atrioventricular (AV) difference in resting membrane potential is accentuated and many atrial Na+ channels are inactivated. This reduces the Na+ channel reserve predominantly in the atria and allows vernakalant to inhibit preferentially atrial Na+ channels [17]. Such voltage and
rate dependency is also typical for flecainide and propafenone, but they do not show atrial selectively. Vernakalant has been shown in vitro and in vivo rabbits to produce greater inhibition of the late inward sodium current (INa,late) than the early inward sodium current (INaEarly) [24] and hence prevent (and even reverse) the EADs and AP prolongation seen with typical class 3 antiarrhythmics [25]. Blocking INa,late prevents reactivation during repolarisation giving it a significant safety advantage over other agents. Whilst shortening of the AP may help to prevent triggered activity, it may, in some circumstances, promote further reentry by shortening the ERP and hence the wavelength of functional reentrant circuits. This may partly explain why vernakalant was found to be less efficacious in long-duration AF in the clinical studies [21,22]. Pharmacokinetics and metabolism The pharmacokinetics of vernakalant has been explored in healthy volunteers and in AF patients [26-28]. Vernakalant exhibits linear pharmacokinetics over the dose range of 0.1 -- 5.0 mg/kg in healthy subjects, and generally showed dose proportionality in patients with AF who received one or two vernakalant infusions. Following rapid metabolism by CYP 2D6 vernakalant then circulates predominantly as an inactive glucuronide conjugate. Plasma vernakalant concentration--time data are best fit by a two compartment mammillary model, with rapid first-order clearance from the central compartment [29]. Based on the results from all the clinical trials, the main factor affecting clearance is CYP2D6 genotype, with age and creatinine levels to a much lesser degree. Despite this, plasma vernakalant concentration is only estimated to be 15% higher in CYP2D6-poor metabolisers as compared with extensive metaboliser suggesting that dose adjustments for individual patients may be unnecessary [29]. 4.2
5.
Efficacy and safety
Efficacy Several clinical trials have shown that vernakalant rapidly terminates AF with maintenance of SR for up to 24 h. An active comparator trial with amiodarone showed that the 90-min conversion rate with vernakalant was substantially higher [19]. The Controlled Randomised Atrial Fibrillation Trial (CRAFT) study was a Phase IIa, multi-centered, randomised, double-blinded, step-dose, placebo-controlled, parallel group study [20]. Fifty-six patients with AF of 3 -- 72 h duration were randomised to one of two vernakalant doses or to placebo. The two vernakalant dosing groups were 0.5 mg/kg followed by 1 mg/kg or 2 mg/kg followed by 3 mg/kg, by i. v. infusion over 10 min; a second dose was given only if AF was present. The primary end point was termination of AF during infusion or within 30 min after the last infusion. Secondary end points included the number of patients in SR at 0.5, 1 and 24 h post-last infusion and time to conversion to SR. Termination of AF was significantly greater in the high5.1
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Table 2. Atrial arrhythmia conversion trials of vernakalant. Trial
ACT ACT ACT ACT
I II III IV
Year of publication
AF duration
2008 2009 2010 2010
3 3 3 3
h -- 45 days -- 72 h h -- 45 days h -- 45 days
Total number of patients
Median time to conversion (min) (overall p value)
336 161 265 236
11 (< 0.001) 12 (< 0.001) 8 (< 0.0001) 14*
Percentage (%)
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*Safety study. ACT: Atrial arrhythmia conversion trials; AF: Atrial fibrillation.
52.9
51.7
51.2
50.9
51.7
44.9
Vernakalant Placebo Amiodarone 14.80
5.30
CRAFT‡
4.00
ACT I*
3.60
ACT III*
5.20
ACT II*
ACT IV
AVRO*
Figure 1. Conversion of atrial fibrillation to sinus rhythm by vernakalant in Phase II and III clinical trials. *p < 0.0001. z p = 0.0015. AVRO: A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation.
dose group occurring in 61.1% of patients as compared with 11.1% of the low-dose group and 5.3% of placebo patients (p = 0.0003, at 30 min between high-dose regimen and placebo). There were no serious adverse events related to vernakalant. This study defined the dose that was used in all of the subsequent Phase III trials. There have been three randomised placebo-controlled trials [21-23] and a fourth open-label trial [30] -- the Atrial Arrhythmia Conversion Trials (ACT) -- shown in Table 2. ACT I and III are prospective, double-blind, multi-centre trials. Patients with AF (or atrial flutter [AFl]) were administered vernakalant 3 mg/kg over 10 min followed by a further 2 mg/kg if still in AF after 15 min observation. The study group in both trials was further subdivided into long- (8 h -- 45 days) and short-duration AF (3 h -- 7 days). In ACT I, 220 patients had short-duration AF and 116 had long-duration AF. The highest success rates were seen in the short-duration AF subgroup (Figure 1) as opposed to the long-duration subgroup (7.9 vs 0%, p = 0.09). The overall p value was still < 0.001. ACT III 868
demonstrated similar results again with highest success in the short-duration AF subgroup (Figure 1). ACT II examined the efficacy of vernakalant in patients developing AF (150) or AFl (10) 24 h -- 7 days postcardiac surgery. It was successful in cardioverting 44.9% of patients in the study group (none of whom had AFl) as opposed to 14.8% in the placebo group. Vernakalant has subsequently been shown to be ineffective against AFl [31]. The strength of all these trials is the high completion rate. Limitations include the small numbers of patients enrolled and the lack of allocation concealment. A meta-analysis of five vernakalant trials (ACT I, ACT III, ACT IV, CRAFT and A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation [AVRO]) [32] evaluated data from 1153 patients. The relative risk of being converted from AF to SR with vernakalant was 11.56% (95% CI 7.12 -- 18.75; p < 0.00001). The trials included had a mean Jadad score of three [33]. ACT II was not included in the meta-analysis as it was not blinded throughout its duration due to an interim analysis [34].
Expert Opin. Pharmacother. (2014) 15(6)
Vernakalant
Table 3. Serious adverse and adverse events in selected trials of patients treated with vernakalant.
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Proportion SAE/AE in vernakalant patients (%) SAE/AE (patients receiving vernakalant)
ACT I (n = 221)
ACT II (n = 107)
ACT III (n = 118)
ACT IV (n = 236)
AVRO (n = 116)
Cardiological Hypotension Bradycardia Sustained ventricular arrhythmia Cardiogenic shock Cardiac arrest
6.3 0.5z 0 1 0
7.5 14 0 0 0
5 6 1 0 0
5.5 5.9 0 0 0
0 0 0
Noncardiological Dysgeusia Sneezing Parasthaesia Nausea Death* Discontinuation of study drug
29.9 16.3 10.9 9 0 4
0 -
21 23 8 5 1 6
18.6 16.1 7.6 0 10
0 0 0 3
*Attributed to vernakalant. z Only SAE mentioned. -: Not mentioned; ACT: Atrial arrhythmia conversion trial; AE: Adverse event; AVRO: A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation; SAE: Serious adverse event.
The active comparator study AVRO [35] was designed to show superiority of i.v. vernakalant over i.v. amiodarone in the acute conversion of AF. This Phase III, multinational, double-blind, double-dummy trial randomised 254 patients. One hundred and sixteen received a 10-min infusion of 3 mg/kg vernakalant followed by a 15 min observation period and an additional 10-min infusion of 2 mg/kg if still in AF. One hundred and sixteen received a 60-min infusion of 5 mg/kg amiodarone followed by a maintenance infusion of 50 mg over an additional hour. To maintain blinding sham infusions mimicking the timing of the other agent were infused at separate anatomical sites. Essentially, the results were overwhelmingly positive in favour of vernakalant with 51.7% of patients meeting the primary endpoint (number of patients in SR at 90-min post-first infusion) compared with 5.2% of patients treated with amiodarone (p < 0.0001). Patients taking vernakalant also reported greater symptom relief and perceived well-being. This study had a good completion rate with 89% of patients enrolled completing the trial limiting the potential for selection bias. However, the proportion of patients with structural heart disease (34.9%) including previous myocardial infarction (8.2%), heart failure (HF) (19.8%) or valve disease (6.9%) was low, which means that amiodarone would not necessarily have been first-line therapy in many of these patients. With a short follow-up time of 90 min and rapid binding kinetics of vernakalant, it is perhaps not surprising that it is able to convert AF more rapidly than i.v. amiodarone -- the onset of action of which is usually in the order of 2 -- 24 h not to mention the extensive pharmacokinetic variability between patients [36]. Nevertheless, rapid conversion, as demonstrated here, is a considerable advantage as it can result in less recurrence of AF and reduce hospital stay [35].
Safety and adverse events Clinical trials have consistently demonstrated that vernakalant is a well-tolerated and safe antiarrhythmic agent. Due to the short half-life (~ 2 h), safety evaluations have focused mainly on adverse events within the first 24 h of administration [19]. ACT IV was intended to be a safety and efficacy trial. Whilst its open-label design is a major limitation to the efficacy data they are in line with the other randomised double-blind trials [30]. The most common side effects selected from the larger trials are shown in Table 3. Noncardiac side effects are likely to be related to Na+ channel blockade in the CNS [19]. They have been considered minor and have not led to treatment discontinuation. All-cause mortality in the 889 patients treated with vernakalant was < 1%. Only one of the five reported deaths was attributed to vernakalant. Hypotension was a common adverse effect and was often transient and self-limiting; four cases (0.4%) required i.v. fluids and/or noradrenaline. 5.2
Electrophysiology and risk of ventricular arrhythmia
5.3
One of the major advantages of vernakalant seems to be the low overall risk of ventricular arrhythmias compared with other agents used for the same indication. One case of torsades de pointes has been recorded but that was in a patient who had received ibutilide as well [31]. There was one case of drug discontinuation due to QT prolongation [21] and the incidence of non-sustained ventricular tachycardia is comparable to placebo [19]. It is important to note that vernakalant was associated with QT prolongation (~ 20 -- 25 ms) in the Phase III trials (unlike in CRAFT) but that this effect had normally
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resolved within 50 min from the last infusion and was rarely associated with detrimental arrhythmias. Where ventricular arrhythmias did occur (including bigeminy, ventricular ectopics and salvos) they did so more commonly in patients with HF. Postmarketing data suggest cardioversion rates with vernakalant are 65 -- 70% but recommends caution in patients with HF [37]. While vernakalant is used for cardioverison of AF, and also for organisation of AF into AFl prior to termination of arrhythmia, there have been reported cases of administration of vernakalant for AF resulting in AFl with 1:1 AV conduction [38,39]. The exact electrophysiological mechanism(s) are yet to be fully elucidated, but possibly due to slowing of atrial conduction in fibrillation and facilitating macro-reentry flutter circuit, thus resulting in 1:1 AV conduction. 6.
Regulatory issues
The results of the above trials have brought about European Medicines Agency approval and recommendation in clinical guidelines for the pharmacological conversion of patients with recent onset (< 7 days) AF providing there is no or minimal structural heart disease (class 1a) [1]. For patients with moderate structural heart disease, New York Heart Association class III or IV HF, acute coronary syndrome in the last 30 days or severe aortic stenosis (AS) it receives a class 2b indication. The US FDA has yet to approve the drug for clinical use because of the suspension of ACT V due to a serious adverse event, and although licensed in the UK, vernakalant is yet to be marketed for use. 7.
Conclusion
Data from several clinical trials of vernakalant highlighting its efficacy and safety in the populations studied have been presented. Although relatively small in size and not all blinded, they all produce consistent and robust information. On clinical evidence alone vernakalant is appropriate for use alongside the other efficacious class 1C antiarrhythmics (i.v. flecainide or i.v. propafenone [40]). Without randomised evidence of efficacy over above other class 1C agents that are already in use its cost effectiveness remains uncertain. 8.
Expert opinion
The efficacy of vernakalant against placebo is undoubted. The main reasons for selecting amiodarone as a comparator were because it is the most widely used drug worldwide for the cardioversion of recent onset AF and hence the most available and it is suitable for a broader range of patients [35]. Both these points are extremely valid, however, comparing these two distinct pharmacological agents is akin to comparing apples with pears. The usefulness of amiodarone lies in its versatility and ability to be applied where all other agents are contraindicated such as severe AS or normotensive pulmonary oedema -- the 870
very patients that were excluded in the ACT and AVRO trials. For many patients in the AVRO study amiodarone would not have been first-line therapy. Hence vernakalant was, in many cases, compared with second-line therapy so it is uncertain if we can say that it is more efficacious than amiodarone, only that it is more efficacious than amiodarone in patients without significant structural heart disease. Vernakalant (i.v.) has been compared to both oral flecainide and oral propafenone where vernakalant was found, perhaps not surprisingly, to have significantly shorter conversion times to SR [41,42]. The importance of this finding lies in the reduction in hospital stay as more patients would be eligible for same day discharge leading to cost savings. Also, the speed with which vernakalant exerts its effects makes it suitable for administration in an emergency department setting thereby potentially reducing admission rates leading to further cost savings particularly where hospitals are penalised for readmissions. As there is no oral equivalent of vernakalant the situation where a patient who is taking a different AAD as maintenance therapy for paroxysmal AF requires conversion acutely is likely to arise quite frequently. Further clinical experience, preferably supported by data from clinical studies, is required to assess the safety of i.v. vernakalant in these patients. Nevertheless, the development of vernakalant is an important addition to current class 1C antiarrhythmic agents for cardioversion of new-onset AF, especially with its novel atrial selective ability and lower tendency for ventricular arrhythmia. In addition to rapid conversion of AF, a study is currently underway to determine if vernakalant leads to increased atrial contractility postconversion compared with flecainide [43]. This could potentially reduce adverse atrial remodelling leading to less AF recurrence and reduced stroke risk; however, more studies are required to investigate this possibility. Further research is required to define the role, if any, for vernakalant in patients presenting with New York Heart Association class IV HF as they were excluded from the current trials. A study by Van Middendorp et al. examined the electrophysiological and haemodynamic effects of both vernakalant and flecainide in canines with induced left bundle branch block (frequently present in HF) [44]. Although vernakalant was found to cause less QRS prolongation than flecainide they both produced similar negatively inotropic effects. Patients with HF who develop uncontrolled AF often require admission for stabilisation because of the resulting fluid retention brought about by their decompensating so the advantage of rapid conversion in terms of early discharge is less. Also, symptom control in this subset of patients (from rate or rhythm control) is often difficult as b-blockers and calcium channel blockers are contraindicated, and digoxin and amiodarone can be slow to act (although more recently ranolazine has been shown to enhance the efficacy of amiodarone for conversion of recent onset AF in patients with an enlarged left atrium [45]). The European Society of Cardiology (ESC) gives a class 1a indication for vernakalant in the same bracket as flecainide, propafenone and ibutilide and a class 2b recommendation for all other indications where amiodarone is also indicated [1].
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Vernakalant
Without further studies or an oral preparation, this perhaps leaves vernakalant with a relatively small niche in the current market -- such as those patients with recent onset AF who have had isolated coronary angioplasty in the past or have risk factors for coronary artery disease but have never had anatomical or functional assessment of ischaemia. This is evidenced by a recent European survey suggesting that the majority (63.1%) of centres in Europe are still using propafenone or flecainide with 35% using vernakalant [46].
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Roy D, Pratt CM, Torp-Pedersen C, et al. Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebocontrolled trial. Circulation 2008;117:1518-25 This trial (ACT 1) was the first of the Phase III trials demonstrating efficacy over placebo, particularly for shortduration AF. Pratt CM, Roy D, Torp-Pedersen C, et al. Usefulness of vernakalant hydrochloride injection for rapid conversion of atrial fibrillation. Am J Cardiol 2010;106:1277-83 The ACT 3 trial confirmed findings of ACT 1.
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23.
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.
Kowey PR, Dorian P, Mitchell LB, et al. Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery: a randomized, doubleblind, placebo-controlled trial. Circ Arrhythm Electrophysiol 2009;2:652-9 This trial showed efficacy and safety of vernakalant postcardiac surgery and also showed vernakalant to be ineffective in atrial flutter.
31.
.
Camm AJ, Toft E, Torp-Pedersen C, et al. Efficacy and safety of vernakalant in patients with atrial flutter: a randomized, double-blind, placebocontrolled trial. Europace 2012;14:804-9 This trial confirmed vernakalant to be ineffective in atrial flutter.
32.
He Y, Thi Thi A, Zhong G, et al. Meta-analysis of effect of vernakalant on conversion of atrial fibrillation. BMC Res Notes 2013;6:94
24.
Orth PMR, Hesketh JC, Mak CKH, et al. RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents. Cardiovasc Res 2006;70:486-96
33.
Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12
25.
Varkevisser R, Van der Heyden MA, Tieland RG, et al. Vernakalant is devoid of proarrhythmic effects in the complete AV block dog model. Eur J Pharmacol 2013;720:49-54
34.
European Medicines Agency (EMA) Assessment Report for Brinavess. EMA 2010. Available from: http://www.ema. europa.eu/docs/en_GB/document_library/ EPAR_-_Public_assessment_report/ human/001215/WC500097150.pdf [Last accessed 6 March 2014]
26.
.
27.
28.
29.
30.
.
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Mao ZL, Wheeler JJ, Clohs L, et al. Pharmacokinetics of novel atrial-selective antiarrhythmic agent vernakalant hydrochloride injection (RSD1235): influence of CYP2D6 expression and other factors. J Clin Pharmacol 2009;49:17-29 One of several important preclinical studies. This study showed that dose alteration of vernakalant is unnecessary. Mao Z, Wheeler JJ, Townsend R, et al. Population pharmacokineticpharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter. J Pharmacokinet Pharmacodyn 2011;38:541-62 Mao ZL, Alak A, Wheeler JJ, Keirns J. Disposition and mass balance of [14C] vernakalant after single intravenous and oral doses in healthy volunteers. Drug Metab Lett 2011;5:114-25 Mao ZL, Townsend RW, Gao Y, et al. Population pharmacokinetics of vernakalant hydrochloride injection (RSD1235) in patients with atrial fibrillation or atrial flutter. J Clin Pharmacol 2012;52:1042-53 Stiell IG, Roos JS, Kavanagh KM, Dickinson G. A multicenter, open-label study of vernakalant for the conversion of atrial fibrillation to sinus rhythm. Am Heart J 2010;159:1095-101 This trial provides further data supporting a favourable safety profile of vernakalant.
35.
..
36.
37.
38.
Camm AJ, Capucci A, Hohnloser SH, et al. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recentonset atrial fibrillation. J Am Coll Cardiol 2011;57:313-21 This is the main active-comparator trial of vernakalant showing efficacy over amiodarone in patients with low rates of structural heart disease. Chow MS. Intravenous amiodarone: pharmacology, pharmacokinetics, and clinical use. Ann Pharmacother 1996;30:637-43 Savelieva I, Graydon R, Camm AJ. Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC Guidelines. Europace 2014;16(2):162-73 de Riva-Silva M, Montero-Cabezas JM, Salgado-Aranda R, et al. 1:1 atrial flutter after vernakalant administration for atrial fibrillation cardioversion. Rev Esp Cardiol (Engl Ed) 2012;65:1062-4
39.
Franzini C, Muller-Burri SA, Shah DC. Atrial flutter with 1 : 1 atrioventricular conduction after administration of vernakalant for atrial fibrillation. Europace 2014;16:3
40.
Bash LD, Buono JL, Davies GM, et al. Systematic review and meta-analysis of the efficacy of cardioversion by vernakalant and comparators in patients with atrial fibrillation. Cardiovasc Drugs Ther 2012;26:167-79 Expert Opin. Pharmacother. (2014) 15(6)
41.
Conde D, Costabel JP, Caro M, et al. Flecainide versus vernakalant for conversion of recent-onset atrial fibrillation. Int J Cardiol 2013;168:2423-5
42.
Conde D, Costabel JP, Aragon M, et al. Propafenone versus vernakalant for conversion of recent-onset atrial fibrillation. Cardiovasc Ther 2013;31:377-80
43.
Crijns HJ. Effects of Vernakalant and Flecainide on Atrial Contractility in Patients With Atrial Fibrillation. Maastricht University Medical Center 2012. Available from: http://clinicaltrials. gov/ct2/show/NCT01646281 [Last accessed 6 March 2014]
44.
van Middendorp LB, Strik M, Houthuizen P, et al. Electrophysiological and haemodynamic effects of vernakalant and flecainide in dyssynchronous canine hearts. Europace 2014. [Epub ahead of print]
45.
Koskinas KC, Fragakis N, Katritsis D, et al. Ranolazine enhances the efficacy of amiodarone for conversion of recentonset atrial fibrillation. Europace 2014. [Epub ahead of print]
46.
Hernandez-Madrid A, Svendsen JH, Lip GY, et al. Cardioversion for atrial fibrillation in current European practice: results of the European Heart Rhythm Association survey. Europace 2013;15:915-18 This survey provides an up-to-date insight of current clinical practice regards acute conversion of AF across Europe.
.
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Dobrev D, Hamad B, Kirkpatrick P. Vernakalant. Nat Rev Drug Discov 2010;9:915-16
Affiliation Richard A Brown1 MRCP, Yee Cheng Lau1 MRCP & Gregory YH Lip†2 MD † Author for correspondence 1 Clinical Research Fellow, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Cardiovascular Medicine, Birmingham, UK 2 Professor of Cardiovascular Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK Tel: +44 121 507 5080; Fax: +44 121 554 4083; E-mail: [email protected]
Vernakalant hydrochloride to treat atrial fibrillation
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Richard A Brown, Yee Cheng Lau & Gregory YH Lip† 1.
Introduction
2.
Basic mechanisms of AF
3.
Rhythm control
4.
Pharmacology
5.
Efficacy and safety
6.
Regulatory issues
7.
Conclusion
8.
Expert opinion
University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Cardiovascular Medicine, Birmingham, UK
Introduction: Intravenous vernakalant (Brinavess) has been developed and approved in Europe as a safe and efficacious drug to rapidly convert recent onset atrial fibrillation to sinus rhythm in patients with no minimal or structural heart disease. Areas covered: The pharmacology of vernakalant and the pivotal Phase II and III clinical trials undertaken during its development are discussed with regard to safety and efficacy. An extensive PubMed search was used to identify suitable papers. Expert opinion: As yet, there is no evidence of benefit over and above intravenous flecainide or propafenone for patients in whom vernakalant has a class 1a recommendation. As such, it is likely to be most useful in centres where only amiodarone is available. Keywords: antiarrhythmic drugs, atrial fibrillation, cardioversion, rhythm control, vernakalant Expert Opin. Pharmacother. (2014) 15(6):865-872
1.
Introduction
Atrial fibrillation (AF) is the most common arrhythmia in the developed world with an estimated prevalence of 1.5 -- 2% amongst the general population. This prevalence increases with age and affects almost 10% of the population over 80. Hospitalisation due to symptoms of palpitations and tachyarrhythmia is also very common. Thus, AF is a major cardiovascular challenge in modern society, and its medical, social and economic impact is likely to worsen over the coming decades as the population ages [1]. A number of treatments have been developed in recent years -- mainly focusing on the rhythmic and thrombogenic aspects of the condition -- which offer some possible solutions to the problems related to AF. One such antiarrhythmic drug (AAD), vernakalant, is discussed in the present review (Box 1). Only the intravenous (i.v.) preparation is discussed as the oral preparation is no longer being developed. 2.
Basic mechanisms of AF
The two main mechanisms contributing to AF are triggered activity (ectopics) and reentry [2]. Triggered activity -- a disorder of impulse formation [3] -- is caused by early or delayed after depolarisations (EADs or DADs), which occur during or after repolarisation of the atrial action potential (AP). EADs occur predominantly at slower heart rates in the setting of prolonged AP duration due to increased L type calcium (ICaL) or late sodium (INaLate) influx or decreased outward potassium currents. This excessive prolongation allows ICaL to recover from inactivation immediately following a depolarisation allowing calcium to enter and depolarise the cell to excitation threshold [4]. Late sodium influx via the sodium/calcium exchange channel (INCX) occurs prolonging the AP further. DADs are caused by spontaneous (i.e., not caused by an AP) calcium release from the sarcoplasmic reticulum of atrial myocyctes during diastole usually due to calcium overload. This increases the
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Vernakalant EU: Launched UK: Licensed but not launched Pharmacological conversion of recent onset atrial fibrillation Mixed potassium and sodium channel blocker predominantly acting on atrial myocytes Intravenous OH
N
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O
O
O
[47]
Pivotal trial(s)
Controlled Randomised Atrial Fibrillation Trial Atrial Arrhythmia Conversion Trials I, II, III, IV. AVRO SCENE 2
AVRO: A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation.
cytoplasmic concentration of calcium. This additional calcium is exchanged for extracellular sodium in a 1:3 ratio leading to a net inward movement of positive ions. When the threshold for depolarisation is reached (delayed), AP’s arise. Reentry -- a disorder of impulse propagation -- occurs when an impulse travels around an abnormal circuit (or multiple circuits) repetitively, reactivating areas that have already recovered, thereby providing a perpetuation of electrical activity [2,3]. Reentry that does not involve a fixed anatomical obstacle is called functional reentry of which two main models exist, the ‘leading circle’ model and the ‘spiral wave’ model [5]. Both refer to the proposed shape of the reentrant circuit as it propagates through excitable tissue. The leading circle model, perhaps the most well known of the two, refers to the smallest circuit required for reentry maintenance, given by the distance (‘wavelength’) the impulse travels in one effective refractory period (ERP). As Wavelength = conduction velocity ERP a decrease in action potential duration (leading to a decrease in ERP) will cause a decrease in wavelength leading to smaller and more numerous circuits within the same area, which means that AF becomes more stable and likely to persist [2,6]. 3.
Rhythm control
Many episodes of AF terminate spontaneously within the first hours or days. Where spontaneous termination does not occur, conversion from AF to sinus rhythm (SR) can be achieved using synchronised direct current electrical shock (‘electrical cardioversion’) or ‘pharmacological cardioversion’ using AADs [7]. Several trials performed have shown no appreciable difference between a rate control or a rhythm control strategy for AF in terms of mortality or morbidity [8-10]; current 866
management has become patient-centred and symptom directed. Indeed, current guidelines recommend rhythm control only in the presence of on-going symptoms (European Heart Rhythm Association [EHRA] score > 2) despite adequate heart rate control except where a clearly defined trigger exists that has been corrected [7]. Whilst the clinical data on the benefits of early rhythm control in AF are limited, it is likely that a window of opportunity to restore and maintain SR exists early in the course of the condition [7]. Furthermore, the restoration of SR may result in a reduction of tachyarrhythmia symptoms and an improvement in quality of life [11]. Previously, the only available pharmacological options for the rhythm control of AF were propafenone and flecainide (sodium channel blockers); sotalol and dofetilide (IKr potassium channel blockers) and amiodarone and dronedarone (mixed ion channel blockers) [12]. The safety and efficacy of these drugs limits their use in clinical practice -- for example, propafenone and flecainide are proarrhythmogenic, particularly in patients who have structural heart disease; sotalol can cause marked QT interval prolongation as well as being contraindicated in asthmatic patients and amiodarone-related toxicity is well described (although less important in the acute setting there have still been anecdotal reports of adverse effect after just a few days [13]). More recently, dronaderone, a benzofuran derivative, structurally related to amiodarone, has been implicated in causing severe liver injury [14,15]. 4.
Pharmacology
Introduction to compound and chemistry Vernakalant is an atrial selective mixed potassium (K+) and sodium (Na+) channel blocker used in the acute cardioversion 4.1
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Vernakalant
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Table 1. Ionic targets of vernakalant. Target
Affinity
IKur IK,Ach Ito IKr INaLate
++ ++ + + + at physiological heart rates ++ at higher heart rates
+: Mildly inhibited; ++: Potently inhibited; IK,Ach: Acetylcholine-activated inward rectifier K+ current; IKr: Rapidly activating delayed rectifier K+ current; IKur: Ultra-rapidly activating delayed rectifier K+ current; Ito: Transient outward current; INaLate: Late sodium current.
of AF. Based on preclinical animal studies and subsequently confirmed by human electrophysiological study, vernakalant has been shown to selectively prolong atrial ERPs without significant effects on ventricular ERPs [16,17]. This gives vernakalant a unique feature of controlling atrial arrhythmia, whilst having minimal proarrhythmic effect on ventricular tissue [18]. This is achieved by targeting atrial-selective channels, specifically IKur and IK,Ach by having a high selectivity for rapid rhythms like AF and using a rate-dependent blocking strategy for its additional Na+ channel block [19]. Vernakalant blocks the K+ channels IKur (ultra-rapidly activating delayed rectifier K+ current), Ito (transient outward current) and IK,ACh (acetylcholine-activated inward rectifier K+ current). IKur is blocked in the open state with preserved efficacy even at higher frequencies [17]. The atrial selective IK,Ach current is potently inhibited Table 1, whereas the Kv4.3 and human erythroblast transformation-specific related gene (hERG) channels that make up the Ito and IKr (rapidly activating delayed rectifier) currents, respectively, are also blocked by vernakalant but with lower affinity than flecainide or propafenone. This is important because IKr is an integral repolarising current in ventricular cells and its inhibition is known to cause QT prolongation with the subsequent risk of torsades de pointes [19]. This partially explains the lower rates of torsade des pointes seen with vernakalant in the clinical trials [20-23] and the improved safety profile over other class 1C antiarrhythmics [17]. Vernakalant also inhibits Nav 1.5, part of the sodium channel expressed in cardiac myocytes and human embryonic kidney cells [24]. At normal heart rates, vernakalant’s effect on Nav 1.5 is minimal because of rapid unbinding kinetics from the channel. At fibrillatory rates, the inhibitory potency is significantly increased [17,19]. In addition, the effects of vernakalant on Na channels are voltage dependent. The resting membrane potential of normal atrial myocytes is 10 mV more depolarised than that of ventricular myocytes. During AF when atrial myocytes are less likely to repolarise fully the atrioventricular (AV) difference in resting membrane potential is accentuated and many atrial Na+ channels are inactivated. This reduces the Na+ channel reserve predominantly in the atria and allows vernakalant to inhibit preferentially atrial Na+ channels [17]. Such voltage and
rate dependency is also typical for flecainide and propafenone, but they do not show atrial selectively. Vernakalant has been shown in vitro and in vivo rabbits to produce greater inhibition of the late inward sodium current (INa,late) than the early inward sodium current (INaEarly) [24] and hence prevent (and even reverse) the EADs and AP prolongation seen with typical class 3 antiarrhythmics [25]. Blocking INa,late prevents reactivation during repolarisation giving it a significant safety advantage over other agents. Whilst shortening of the AP may help to prevent triggered activity, it may, in some circumstances, promote further reentry by shortening the ERP and hence the wavelength of functional reentrant circuits. This may partly explain why vernakalant was found to be less efficacious in long-duration AF in the clinical studies [21,22]. Pharmacokinetics and metabolism The pharmacokinetics of vernakalant has been explored in healthy volunteers and in AF patients [26-28]. Vernakalant exhibits linear pharmacokinetics over the dose range of 0.1 -- 5.0 mg/kg in healthy subjects, and generally showed dose proportionality in patients with AF who received one or two vernakalant infusions. Following rapid metabolism by CYP 2D6 vernakalant then circulates predominantly as an inactive glucuronide conjugate. Plasma vernakalant concentration--time data are best fit by a two compartment mammillary model, with rapid first-order clearance from the central compartment [29]. Based on the results from all the clinical trials, the main factor affecting clearance is CYP2D6 genotype, with age and creatinine levels to a much lesser degree. Despite this, plasma vernakalant concentration is only estimated to be 15% higher in CYP2D6-poor metabolisers as compared with extensive metaboliser suggesting that dose adjustments for individual patients may be unnecessary [29]. 4.2
5.
Efficacy and safety
Efficacy Several clinical trials have shown that vernakalant rapidly terminates AF with maintenance of SR for up to 24 h. An active comparator trial with amiodarone showed that the 90-min conversion rate with vernakalant was substantially higher [19]. The Controlled Randomised Atrial Fibrillation Trial (CRAFT) study was a Phase IIa, multi-centered, randomised, double-blinded, step-dose, placebo-controlled, parallel group study [20]. Fifty-six patients with AF of 3 -- 72 h duration were randomised to one of two vernakalant doses or to placebo. The two vernakalant dosing groups were 0.5 mg/kg followed by 1 mg/kg or 2 mg/kg followed by 3 mg/kg, by i. v. infusion over 10 min; a second dose was given only if AF was present. The primary end point was termination of AF during infusion or within 30 min after the last infusion. Secondary end points included the number of patients in SR at 0.5, 1 and 24 h post-last infusion and time to conversion to SR. Termination of AF was significantly greater in the high5.1
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Table 2. Atrial arrhythmia conversion trials of vernakalant. Trial
ACT ACT ACT ACT
I II III IV
Year of publication
AF duration
2008 2009 2010 2010
3 3 3 3
h -- 45 days -- 72 h h -- 45 days h -- 45 days
Total number of patients
Median time to conversion (min) (overall p value)
336 161 265 236
11 (< 0.001) 12 (< 0.001) 8 (< 0.0001) 14*
Percentage (%)
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*Safety study. ACT: Atrial arrhythmia conversion trials; AF: Atrial fibrillation.
52.9
51.7
51.2
50.9
51.7
44.9
Vernakalant Placebo Amiodarone 14.80
5.30
CRAFT‡
4.00
ACT I*
3.60
ACT III*
5.20
ACT II*
ACT IV
AVRO*
Figure 1. Conversion of atrial fibrillation to sinus rhythm by vernakalant in Phase II and III clinical trials. *p < 0.0001. z p = 0.0015. AVRO: A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation.
dose group occurring in 61.1% of patients as compared with 11.1% of the low-dose group and 5.3% of placebo patients (p = 0.0003, at 30 min between high-dose regimen and placebo). There were no serious adverse events related to vernakalant. This study defined the dose that was used in all of the subsequent Phase III trials. There have been three randomised placebo-controlled trials [21-23] and a fourth open-label trial [30] -- the Atrial Arrhythmia Conversion Trials (ACT) -- shown in Table 2. ACT I and III are prospective, double-blind, multi-centre trials. Patients with AF (or atrial flutter [AFl]) were administered vernakalant 3 mg/kg over 10 min followed by a further 2 mg/kg if still in AF after 15 min observation. The study group in both trials was further subdivided into long- (8 h -- 45 days) and short-duration AF (3 h -- 7 days). In ACT I, 220 patients had short-duration AF and 116 had long-duration AF. The highest success rates were seen in the short-duration AF subgroup (Figure 1) as opposed to the long-duration subgroup (7.9 vs 0%, p = 0.09). The overall p value was still < 0.001. ACT III 868
demonstrated similar results again with highest success in the short-duration AF subgroup (Figure 1). ACT II examined the efficacy of vernakalant in patients developing AF (150) or AFl (10) 24 h -- 7 days postcardiac surgery. It was successful in cardioverting 44.9% of patients in the study group (none of whom had AFl) as opposed to 14.8% in the placebo group. Vernakalant has subsequently been shown to be ineffective against AFl [31]. The strength of all these trials is the high completion rate. Limitations include the small numbers of patients enrolled and the lack of allocation concealment. A meta-analysis of five vernakalant trials (ACT I, ACT III, ACT IV, CRAFT and A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation [AVRO]) [32] evaluated data from 1153 patients. The relative risk of being converted from AF to SR with vernakalant was 11.56% (95% CI 7.12 -- 18.75; p < 0.00001). The trials included had a mean Jadad score of three [33]. ACT II was not included in the meta-analysis as it was not blinded throughout its duration due to an interim analysis [34].
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Vernakalant
Table 3. Serious adverse and adverse events in selected trials of patients treated with vernakalant.
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Proportion SAE/AE in vernakalant patients (%) SAE/AE (patients receiving vernakalant)
ACT I (n = 221)
ACT II (n = 107)
ACT III (n = 118)
ACT IV (n = 236)
AVRO (n = 116)
Cardiological Hypotension Bradycardia Sustained ventricular arrhythmia Cardiogenic shock Cardiac arrest
6.3 0.5z 0 1 0
7.5 14 0 0 0
5 6 1 0 0
5.5 5.9 0 0 0
0 0 0
Noncardiological Dysgeusia Sneezing Parasthaesia Nausea Death* Discontinuation of study drug
29.9 16.3 10.9 9 0 4
0 -
21 23 8 5 1 6
18.6 16.1 7.6 0 10
0 0 0 3
*Attributed to vernakalant. z Only SAE mentioned. -: Not mentioned; ACT: Atrial arrhythmia conversion trial; AE: Adverse event; AVRO: A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation; SAE: Serious adverse event.
The active comparator study AVRO [35] was designed to show superiority of i.v. vernakalant over i.v. amiodarone in the acute conversion of AF. This Phase III, multinational, double-blind, double-dummy trial randomised 254 patients. One hundred and sixteen received a 10-min infusion of 3 mg/kg vernakalant followed by a 15 min observation period and an additional 10-min infusion of 2 mg/kg if still in AF. One hundred and sixteen received a 60-min infusion of 5 mg/kg amiodarone followed by a maintenance infusion of 50 mg over an additional hour. To maintain blinding sham infusions mimicking the timing of the other agent were infused at separate anatomical sites. Essentially, the results were overwhelmingly positive in favour of vernakalant with 51.7% of patients meeting the primary endpoint (number of patients in SR at 90-min post-first infusion) compared with 5.2% of patients treated with amiodarone (p < 0.0001). Patients taking vernakalant also reported greater symptom relief and perceived well-being. This study had a good completion rate with 89% of patients enrolled completing the trial limiting the potential for selection bias. However, the proportion of patients with structural heart disease (34.9%) including previous myocardial infarction (8.2%), heart failure (HF) (19.8%) or valve disease (6.9%) was low, which means that amiodarone would not necessarily have been first-line therapy in many of these patients. With a short follow-up time of 90 min and rapid binding kinetics of vernakalant, it is perhaps not surprising that it is able to convert AF more rapidly than i.v. amiodarone -- the onset of action of which is usually in the order of 2 -- 24 h not to mention the extensive pharmacokinetic variability between patients [36]. Nevertheless, rapid conversion, as demonstrated here, is a considerable advantage as it can result in less recurrence of AF and reduce hospital stay [35].
Safety and adverse events Clinical trials have consistently demonstrated that vernakalant is a well-tolerated and safe antiarrhythmic agent. Due to the short half-life (~ 2 h), safety evaluations have focused mainly on adverse events within the first 24 h of administration [19]. ACT IV was intended to be a safety and efficacy trial. Whilst its open-label design is a major limitation to the efficacy data they are in line with the other randomised double-blind trials [30]. The most common side effects selected from the larger trials are shown in Table 3. Noncardiac side effects are likely to be related to Na+ channel blockade in the CNS [19]. They have been considered minor and have not led to treatment discontinuation. All-cause mortality in the 889 patients treated with vernakalant was < 1%. Only one of the five reported deaths was attributed to vernakalant. Hypotension was a common adverse effect and was often transient and self-limiting; four cases (0.4%) required i.v. fluids and/or noradrenaline. 5.2
Electrophysiology and risk of ventricular arrhythmia
5.3
One of the major advantages of vernakalant seems to be the low overall risk of ventricular arrhythmias compared with other agents used for the same indication. One case of torsades de pointes has been recorded but that was in a patient who had received ibutilide as well [31]. There was one case of drug discontinuation due to QT prolongation [21] and the incidence of non-sustained ventricular tachycardia is comparable to placebo [19]. It is important to note that vernakalant was associated with QT prolongation (~ 20 -- 25 ms) in the Phase III trials (unlike in CRAFT) but that this effect had normally
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resolved within 50 min from the last infusion and was rarely associated with detrimental arrhythmias. Where ventricular arrhythmias did occur (including bigeminy, ventricular ectopics and salvos) they did so more commonly in patients with HF. Postmarketing data suggest cardioversion rates with vernakalant are 65 -- 70% but recommends caution in patients with HF [37]. While vernakalant is used for cardioverison of AF, and also for organisation of AF into AFl prior to termination of arrhythmia, there have been reported cases of administration of vernakalant for AF resulting in AFl with 1:1 AV conduction [38,39]. The exact electrophysiological mechanism(s) are yet to be fully elucidated, but possibly due to slowing of atrial conduction in fibrillation and facilitating macro-reentry flutter circuit, thus resulting in 1:1 AV conduction. 6.
Regulatory issues
The results of the above trials have brought about European Medicines Agency approval and recommendation in clinical guidelines for the pharmacological conversion of patients with recent onset (< 7 days) AF providing there is no or minimal structural heart disease (class 1a) [1]. For patients with moderate structural heart disease, New York Heart Association class III or IV HF, acute coronary syndrome in the last 30 days or severe aortic stenosis (AS) it receives a class 2b indication. The US FDA has yet to approve the drug for clinical use because of the suspension of ACT V due to a serious adverse event, and although licensed in the UK, vernakalant is yet to be marketed for use. 7.
Conclusion
Data from several clinical trials of vernakalant highlighting its efficacy and safety in the populations studied have been presented. Although relatively small in size and not all blinded, they all produce consistent and robust information. On clinical evidence alone vernakalant is appropriate for use alongside the other efficacious class 1C antiarrhythmics (i.v. flecainide or i.v. propafenone [40]). Without randomised evidence of efficacy over above other class 1C agents that are already in use its cost effectiveness remains uncertain. 8.
Expert opinion
The efficacy of vernakalant against placebo is undoubted. The main reasons for selecting amiodarone as a comparator were because it is the most widely used drug worldwide for the cardioversion of recent onset AF and hence the most available and it is suitable for a broader range of patients [35]. Both these points are extremely valid, however, comparing these two distinct pharmacological agents is akin to comparing apples with pears. The usefulness of amiodarone lies in its versatility and ability to be applied where all other agents are contraindicated such as severe AS or normotensive pulmonary oedema -- the 870
very patients that were excluded in the ACT and AVRO trials. For many patients in the AVRO study amiodarone would not have been first-line therapy. Hence vernakalant was, in many cases, compared with second-line therapy so it is uncertain if we can say that it is more efficacious than amiodarone, only that it is more efficacious than amiodarone in patients without significant structural heart disease. Vernakalant (i.v.) has been compared to both oral flecainide and oral propafenone where vernakalant was found, perhaps not surprisingly, to have significantly shorter conversion times to SR [41,42]. The importance of this finding lies in the reduction in hospital stay as more patients would be eligible for same day discharge leading to cost savings. Also, the speed with which vernakalant exerts its effects makes it suitable for administration in an emergency department setting thereby potentially reducing admission rates leading to further cost savings particularly where hospitals are penalised for readmissions. As there is no oral equivalent of vernakalant the situation where a patient who is taking a different AAD as maintenance therapy for paroxysmal AF requires conversion acutely is likely to arise quite frequently. Further clinical experience, preferably supported by data from clinical studies, is required to assess the safety of i.v. vernakalant in these patients. Nevertheless, the development of vernakalant is an important addition to current class 1C antiarrhythmic agents for cardioversion of new-onset AF, especially with its novel atrial selective ability and lower tendency for ventricular arrhythmia. In addition to rapid conversion of AF, a study is currently underway to determine if vernakalant leads to increased atrial contractility postconversion compared with flecainide [43]. This could potentially reduce adverse atrial remodelling leading to less AF recurrence and reduced stroke risk; however, more studies are required to investigate this possibility. Further research is required to define the role, if any, for vernakalant in patients presenting with New York Heart Association class IV HF as they were excluded from the current trials. A study by Van Middendorp et al. examined the electrophysiological and haemodynamic effects of both vernakalant and flecainide in canines with induced left bundle branch block (frequently present in HF) [44]. Although vernakalant was found to cause less QRS prolongation than flecainide they both produced similar negatively inotropic effects. Patients with HF who develop uncontrolled AF often require admission for stabilisation because of the resulting fluid retention brought about by their decompensating so the advantage of rapid conversion in terms of early discharge is less. Also, symptom control in this subset of patients (from rate or rhythm control) is often difficult as b-blockers and calcium channel blockers are contraindicated, and digoxin and amiodarone can be slow to act (although more recently ranolazine has been shown to enhance the efficacy of amiodarone for conversion of recent onset AF in patients with an enlarged left atrium [45]). The European Society of Cardiology (ESC) gives a class 1a indication for vernakalant in the same bracket as flecainide, propafenone and ibutilide and a class 2b recommendation for all other indications where amiodarone is also indicated [1].
Expert Opin. Pharmacother. (2014) 15(6)
Vernakalant
Without further studies or an oral preparation, this perhaps leaves vernakalant with a relatively small niche in the current market -- such as those patients with recent onset AF who have had isolated coronary angioplasty in the past or have risk factors for coronary artery disease but have never had anatomical or functional assessment of ischaemia. This is evidenced by a recent European survey suggesting that the majority (63.1%) of centres in Europe are still using propafenone or flecainide with 35% using vernakalant [46].
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 10/12/14 For personal use only.
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Affiliation Richard A Brown1 MRCP, Yee Cheng Lau1 MRCP & Gregory YH Lip†2 MD † Author for correspondence 1 Clinical Research Fellow, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Cardiovascular Medicine, Birmingham, UK 2 Professor of Cardiovascular Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK Tel: +44 121 507 5080; Fax: +44 121 554 4083; E-mail: [email protected]
