Atrial fibrillation (AF) is the most common arrhythmia requiring medical care, with a prevalence of almost 1% in the unselected adult population. It has been estimated that the prevalence of AF will increase to at least 2% in the general population and in a far higher proportion of elderly patients (up to 10%) by the year 2050. The clinical presentation of AF is variable, and this variety requires a spectrum of therapeutic responses. Sudden-onset, symptomatic AF usually is treated with pharmacological agents or electrical cardioversion; recurrent AF demands preventive antiarrhythmic treatment; and permanent AF that is accepted by the patient and the physician is treated with rate control and anticoagulation.
Some forms of AF are considered for interventional therapy, notably for catheter ablation. Recent guidelines [1,2] have upgraded catheter-based pulmonary vein isolation to the second choice after one antiarrhythmic drug has failed. This applies particularly to younger patients with highly symptomatic paroxysmal AF in the absence of significant structural heart disease. The eventual impact of pulmonary vein isolation on long-term outcomes is not yet known. Prospective randomized clinical trials are currently underway to examine the long-term efficacy and safety of catheter ablation of AF. Nevertheless, there are already several reports from experienced ablation centers suggesting that ablation also may be beneficial in patients with more advanced heart disease, for example, congestive heart failure [3,4]. Such a benefit is particularly likely in patients in whom AF-induced tachy myopathy is suspected as the underlying cause of heart failure.
Despite the attractive prospect of “curative” therapy of AF by means of catheter ablation, in a large number of patients there remains a genuine choice between antiarrhythmic drug therapy to suppress the arrhythmia and improve outcome and rate control. The present review aims at providing contemporary insight into the development of new antiarrhythmic drugs that have novel mechanisms of action or new combinations of established antiarrhythmic activities. The review focuses on those innovative substances on which data from clinical studies have already been reported.
CURRENT OPTIONS FOR ANTIARRHYTHMIC DRUG THERAPY IN AF
Antiarrhythmic drugs have been defined as membrane-active agents modulating the opening and closing of ion channels responsible for the cardiac action potential (AP) or as substances that change the function of membrane pumps or activate or block membrane receptors. This may result in changes in automaticity, conduction velocity, and refractoriness of cardiac cells. However, although the effects of membrane-active antiarrhythmic drugs are somewhat predictable in healthy tissue, this is far less the case in diseased myocardium. As a result, all currently available antiarrhythmic drugs have limitations owing to only modest efficacy, tolerability issues, or the potential for serious ventricular proarrhythmic and organ toxicity.
From a theoretical point of view, an ideal antiarrhythmic drug for AF would be safe (ie, not provoking ventricular proarrhythmia) and efficacious in terminating AF and preventing its recurrence, in patients with and without structural heart disease. The drug should control the ventricular rate in case of recurrent AF, and it should not interfere with anticoagulation therapy applied to prevent thromboembolism. Unfortunately, none of the drugs available today satisfy these criteria. At present, amiodarone is probably the single most efficacious antiarrhythmic drug used for prevention of recurrent AF and for ventricular rate control, and it has a neutral effect on mortality [5]. In the recent SAFE-T trial (Sotalol, Amiodarone Atrial Fibrillation Efficacy Trial), amiodarone was superior to placebo and to sotalol in maintaining sinus rhythm (SR) [6]. The median times to recurrent AF were 487 days in amiodarone-treated patients, 74 days in the sotalol group, and 6 days in the placebo group. However, the use of amiodarone is hampered by a multitude of extracardiac side effects necessitating drug discontinuation in 13 to 18% of patients after 1 year [7]. Flecainide, propafenone, and ibutilide are popular for cardioversion of recent-onset AF, but none of these drugs are highly effective outside the setting of recent-onset AF, and only patients with no or minimal structural heart disease can receive these drugs. Beta blockers, finally, are often used for rate control in permanent AF, but they have limited efficacy in maintaining SR after cardioversion [8].
NOVEL ANTIARRHYTHMIC DRUGS: DEVELOPMENT STRATEGIES
The development of new antiarrhythmic drugs takes into consideration novel pathophysiological insights into the mechanism of AF gained over recent years. Many innovative drug-development strategies that target various aspects of AF development and maintenance are currently being explored. Data as compiled in an excellent review by Savelieva and Camm [9], indicate that there are agents targeting atrial repolarization (atrial repolarization delaying agents [ARDA]) as well as new antiarrhythmic drugs with more conventional antiarrhythmic mechanisms, predominantly newer multiple-channel blocking agents with better safety and tolerability profiles. There are also drugs with unconventional modes of action, including stretch receptor antagonists, blockers of the sodium-calcium exchanger, and gap junction modifiers. None of the latter agents, however, have clinical development data to demonstrate at present.
Atrial repolarization delaying agents
ARDA is an attractive principle of new antiarrhythmic efficacy for AF. These are drugs with highly selective affinity to ion channels specifically involved in atrial tissue repolarization. By acting exclusively (or at least predominantly) on atrial channels, these substances should not alter ventricular repolarization, thus avoiding QT prolongation and ventricular proarrhythmia (Figure 1). For example, the following targets for ARDA have been identified and explored [10]:
- The ultra-rapid delayed rectifier current (IKur) is called ultrarapid because it activates two orders of magnitude faster than IKr. IKur, is carried by Kv1.5 α-subunits, and is present in human atrial but not ventricular cells. The effects of IKur inhibition on atrial repolarization depend strongly on AP morphology, with the brief, triangular APs during AF being particularly susceptible to prolongation by IKur inhibition [11].
- The inwardly rectifying, acetylcholine-regulated current (IKACh) mediates vagal influences on heart rate and atrial repolarization. Pore-forming Kir3 α-subunits are prominently expressed in sinus node and atrioventricular nodes and atrial myocardium but are largely absent in ventricles. IKACh activation shortens action potential duration (APD) and causes hyperpolarization. Kir3.1 mRNA is downregulated, and the response to acetylcholine is blunted in AF [12]. In contrast, increases in the constitutively active (ie, active in the absence of agonist) form of this current contribute to AF-related electrical remodeling [13-15]. Because of this upregulation of constitutive IKACh, IKACh inhibition causes substantial APD prolongation and atrial tachyarrhythmia termination in the presence of atrial remodelling [15].
- Finally, the sodium current (INa) should be mentioned. The atrial INa block terminates AF by destabilizing AF-maintaining re-entrant rotors. Although atrial and ventricular Na+ channels have the same principal Na+- channel α-subunit (Nav1.5), differences in β-subunits could convey drug selectivity. State-dependent INa block could produce blocking selectivity for rapid rates like those of AF or for atrial APs [16].
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Figure 1. Atrial-selective (A) versus multiple-channel blocking (B) antiarrhythmic drugs. |
Atrially expressed connexin Cx43 is expressed throughout the heart, but Cx40 expression is restricted to atria and the conducting system. Cx40-knockout mice exhibit prolonged P waves and susceptibility to atrial arrhythmias. Cardiac-specific mutations in GJA5 (encoding Cx40) lead to idiopathic AF [17]. Connexins are remodelled in AF, but different studies have provided widely discrepant results [18]. At present, several potential antiarrhythmic drugs with the ARDA mode of action are in clinical development. Many of these substances act on more than one channel.
Vernakalant
Vernakalant (RSD 1235, Cardiome, Vancouver, B.C., Canada, and Astellas, Deerfield, IL, USA) is far advanced in its clinical development, and its intravenous formulation recently has been recommended for approval for pharmacological conversion of AF. This new compound blocks IKur, Ito, HERG, and the late sodium current (INa,late) [19]. Its sodium channel blocking property is characterized by fast offset kinetics, which is why vernakalant is not likely to cause conduction disturbances and proarrhythmia at low heart rates. The drug has little effect on Purkinje fiber repolarization under control conditions but was shown to reverse the AP prolonging effect of class III agents [20]. Despite vernakalant’s large pharmacological spectrum of activity, experimental data suggest that its AF-selective actions may be predominantly based on state-dependent INa blockade. Therefore, vernakalant has disease-specific action implying predominant efficacy at high heart rates (ie, in AF).
Vernakalant has been subjected to a careful clinical development program. In an initial, phase II, randomized, placebo-controlled, dose-finding study of patients with AF of 3 to 72 hours’ duration [21], vernakalant terminated AF in 61% of patients, compared to 5% in the placebo group. The median conversion time was only 14 minutes versus 162 minutes for patients assigned to placebo. There were no significant changes in the QRS and QTc duration associated with vernakalant, and no serious adverse effects, particularly no proarrhythmic effects, were observed. In a subsequent phase III trial (Atrial Arrhythmia Conversion Trial I or ACT I), 336 patients with AF of 3 hours’ to 45 days’ duration were randomized in a 2:1 fashion to receive vernakalant (3 mg/kg body weight for 10 minutes, followed by a second infusion of 2 mg/kg 15 minutes later if needed) or placebo [22]. The primary outcome measure was conversion of AF to SR within 90 minutes in the short-AF duration (3 hours to 7 days) patient group. In that group, 52% of patients assigned to receive vernakalant converted to SR, compared to only 4% of placebo patients (p <.001). Again, there was a median time of only 11 minutes to conversion, confirming results from the phase II study. In patients with a longer duration of AF, the drug was significantly less effective. Two additional medium-sized trials (ACT III and IV) have been completed, with AF lasting between 3 hours and 45 days, along with a study in patients after cardiovascular surgery (ACT II). Consistent results were observed in all studies, with AF conversion rates of about 50 to 55%, compared to less than 5% in the respective placebo groups. Of note was the short time to successful conversion, which averaged 11, 12, 8, and 14 minutes, respectively, in ACT I through IV. Across all studies, the highest efficacy rates were observed in AF lasting up to 72 hours. Conversely, the drug was relatively ineffective in patients with AF of more than 7 days’ duration as well as in patients with atrial flutter (Table 1).
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TABLE 1. Summary of clinical studies of vernakalant in atrial fibrillation |
In all studies, vernakalant was well tolerated and produced no significant QTc prolongation or torsade de pointes tachycardia. In three randomized studies, only 39 (5.3%) of 737 patients receiving the drug showed any ventricular arrhythmia within 2 hours after the infusion, and an additional 69 (9.4%) had a ventricular arrhythmia between 2 and 24 hours, compared to 20 (6.3%) and 41 (13%) in the placebo arm. Transient dysgeusia and sneezing were the most common side effects in vernakalant-treated patients. Currently, a prospective comparative study with intravenous amiodarone is being conducted.
The manufacturer of vernakalant is also pursuing an oral formulation of the compound. Two doses of the drug (300 and 600 mg twice daily) were compared to placebo in a small, phase IIa study lasting 28 days (because of limited toxicity data beyond this time interval). Both doses equally suppressed arrhythmia recurrences, although statistically significant results were obtained only for the 300 mg dose. However, determination of an ideal dose was not possible based on these results. Results of another phase IIb study in 446 patients treated for months were recently released. There were three different dosages (150, 300, and 500 mg twice daily), and patients receiving the highest dose were more likely to maintain SR, compared to patients receiving a placebo (52% vs 39%, p = .05). From both studies on the oral formulation of vernakalant, good tolerability data and no incidences of torsade de pointes were reported. Currently, phase III studies with the compound are in the planning stage.
AVE0118
AVE0118 (Sanofi-Aventis, Paris, France) is a biphenyl agent primarily targeting Ito/IKur, with additional IKAch blocking properties. AVE0118 binds to amino acids within the Kv1.5 pore region that are highly conserved between voltage-gated potassium channels (including Kv4.3) and aligns with the inner S6 α-helical domain in a manner blocking the putative activation gate. Studies in native cells showed that porcine atrial Kv1.5-based current—potentially representing a homolog of human IKur—is half-maximally inhibited by 1.25 μM AVE0118 [23]. Studies of human atrial APs recorded from right atrial trabeculae demonstrated that AVE0118 application leads to AP alterations in response to the cellular remodelling process induced by AF. APs recorded from AF trabeculae were prolonged by 6 μM AVE0118, whereas APs from SR trabeculae were shortened. This unusual behavior is explained by an increase in the AP plateau due to slowing of early phase-1 repolarization by IKur block with subsequently greater activation of ICa,L. Porcine left atrial vulnerability as an index of AF inducibility was reduced by 1 mg/kg of AVE0118 [23]. Similarly, AF reinducibility in goats with AF persistent for 48 hours was decreased by intravenous application of 5 mg/kg of AVE0118 [24]. The drug selectively prolonged atrial APD in both models, prolonged the atrial effective refractory period, and converted AF, whereas the atrial effective refractory period prolonging efficacy of dofetilide was reduced at high rates, in line with inferior conversion efficacy [24]. The clinical development of AVE0118 has been withheld for reasons that were not disclosed.
AZD7009
AZD7009 (AstraZeneca, Södertälje, Sweden) was first described as an ARDA, but it is a multiple-channel blocker inhibiting IKur, Ito, IKr, and IKs currents as well as the late sodium depolarizing current. Because of the blockade of IKr in particular, the drug has the potential to increase the ventricular refractory period and QTc, with the associated potential of ventricular proarrhythmia. Carlsson et al [25] showed that the effects of AZD7009 were more pronounced in the atria than in the ventricle. Animal studies have demonstrated that the compound increases atrial refractoriness, suppresses AF inducibility, and rapidly converts AF [26].
Crijns et al [27] performed a dose-finding study in 122 patients with AF or atrial flutter. AZD7009 cardioverted the arrhythmia in 45 to 58% of patients within 1 hour of starting administration, whereas SR was restored in none of the placebo patients. Conversion rates were highest in patients with short durations (<1 week) of AF, and pretreatment with the drug increased the success rate of electrical cardioversion. However, a bradycardia-related increase in QTc of >550 milliseconds was seen in 4 patients after 1 hour and in 7 patients after 3 hours of infusion. Accordingly, further development of this compound has been stopped, mainly due to its potential for ventricular proarrhythmia.
New class III antiarrhythmic drugs
A plethora of drugs that predominantly prolong repolarization (class III) has been developed, and many of them have been abandoned, for the most part because of their risk of torsade de pointes as a result of prolonged ventricular repolarization. Examples include almokalant, ersentilide, and ambasilide, to name a few.
Tedisamil
Tedisamil (Solvay, The Netherlands) is a novel, class III antiarrhythmic agent that blocks multiple potassium channels. It prolongs both atrial and ventricular AP duration by blocking the transient outward Ito, the adenosine-triphosphate–dependent IK-ATP, and the delayed rectifier potassium currents IKr, IKs, and IKur. Unlike other selective potassium-channel blocking drugs, tedisamil does not exhibit reverse rate-dependent effects on atrial and ventricular refractoriness. The drug has been abandoned as a compound for long-term use because of diarrhea due to potassium blockade in the intestinum and consequent hypokalemia and torsade de pointes. To establish an effective dose for AF cardioversion, a two-stage study [28] enrolled 201 patients with symptomatic AF of 3 to 48 hours’ duration. During stage 1, patients were randomized to receive intravenous tedisamil at 0.4 mg/kg body weight or matching placebo; during stage 2, patients were randomized to receive tedisamil at 0.6 mg/kg body weight or matching placebo. Treatments were given as a single intravenous infusion administered over 30 minutes. Of the 175 patients representing the intention-to-treat sample, conversion to SR was observed in 41% of the tedisamil 0.4 mg/kg group, 51% of the tedisamil 0.6 mg/kg group, and 7% of the placebo group (p <.001 for both tedisamil groups vs placebo). The average time to conversion was 35 minutes in patients receiving tedisamil. However, there were two instances of self-terminating ventricular tachycardia: one episode of torsade de pointes and one of monomorphic ventricular tachycardia, both observed in patients receiving 0.6 mg/kg tedisamil. The combination of relatively modest efficacy and a relatively high risk of torsade de pointes makes it very unlikely that tedisamil will be granted approval from the authorities.
Dronedarone
Dronedarone (Sanofi-Aventis) is a derivative of the amiodarone molecule, which was modified to eliminate the toxicity problems of this effective antiarrhythmic agent [29]. The most important modifications were the removal of iodine, with the goal of eliminating iodine-related organ toxicity, and the addition of a methane sulfonyl group to decrease lipophilicity and thereby prevent tissue accumulation of the drug. Accordingly, the elimination half-life of dronedarone in humans is approximately 24 to 30 hours. Dronedarone functions as a multiple-channel blocker, exhibits noncompetitive antiadrenergic activity, and has calcium antagonist properties. In terms of electrophysiology, dronedarone blocks a series of potassium-mediated outward currents as well as inward currents mediated by sodium and calcium, resulting in prolongation of refractory periods. Taken together, the electrophysiological and pharmacokinetic features of the molecule suggest beneficial effects on SR and ventricular rate, but a low propensity to cause proarrhythmia or organ toxicity.
Table 2 provides an overview of the dronedarone development program. The first clinical study was a dose-finding study in 270 patients with persistent AF who were randomized to receive dronedarone 400, 600, or 800 mg twice daily or placebo [30]. Of the 3 dosing regimens, only the lowest (400 mg twice daily) was associated with a statistically significant prolongation of the time to recurrence in comparison with placebo: the median time to first AF recurrence was 60 days, compared with 5.3 days for the placebo group (relative risk reduction 55%, 95% CI 72-28%, p = .001). At 6 months, 35% of patients in the dronedarone 400 mg group and 10% of those in the placebo group were still in SR. Accordingly, the 400 mg dose was selected for the subsequent phase III trials.
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TABLE 2. Summary of clinical studies of dronedarone in atrial fibrillation |
Two pivotal efficacy studies of dronedarone have been completed, the EURIDIS (European Trial in Atrial Fibrillation of Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm) and ADONIS (American-Australian-African Trial With Dronedarone in Atrial Fibrillation/Flutter Patients for the Maintenance of Sinus Rhythm) trials [31]. These identically designed trials enrolled 612 and 625 outpatients with paroxysmal or persistent AF or atrial flutter. Patients were randomized 2:1 to receive either dronedarone 400 mg twice daily (n = 828, pooling data from the two studies) or placebo (n = 409) for 12 months. The primary endpoint was the time to first recurrence of AF, though the study also assessed the effect of dronedarone on symptoms, hospitalization, and ventricular rate. Dronedarone substantially increased the median time to first recurrence of AF. Combining data for the two trials, the median time to the first episode of AF was 53 days in the placebo group, compared with 116 days in the dronedarone group (hazard ratio [HR] 0.75, CI 0.65-0.87, p <.0001). Similar results were obtained when the data for the two trials were analyzed separately, with reductions in the risk of AF recurrence over 1 year by 29% (p = .0059) and 26% (p = .0244) in EURIDIS and ADONIS, respectively. Dronedarone was found to be superior to placebo in the prophylaxis of AF in a variety of patient subgroups in EURIDIS/ADONIS, including patients with structural heart disease, hypertension, heart failure criteria, and previous amiodarone intake. The drug also significantly reduced the ventricular rate during the first recurrence of AF/flutter. Mean heart rate was 102.3 beats per minute (bpm) and 104.6 bpm in the dronedarone treatment arms, compared to 117.5 bpm (p <.0001) and 116.6 bpm (p <.0009) in the placebo arms.
The rate-controlling efficacy during AF was subsequently evaluated in the ERATO trial (efficacy and safety of dronedarone for the control of ventricular rate) in 174 patients with permanent AF and resting heart rates >80 bpm despite standard therapy with beta blockers, digoxin, and calcium antagonists [32]. Therapy with dronedarone was associated with a significant reduction in the 24-hour mean heart rate when compared to the control group.
Importantly, tolerability of the drug was excellent in all of these studies. In particular, there was no evidence of thyroid, pulmonary, or skin toxicity. No instance of torsade de pointes arrhythmia was observed.
Although these AF studies demonstrated that dronedarone has an excellent safety profile, a trial in patients with unstable heart failure (without AF as an enrollment criterion) was prematurely stopped because of increased mortality with dronedarone [33]. The ANDROMEDA study (Antiarrhythmic Trial With Dronedarone in Moderate to Severe CHF evaluating morbidity decrease) investigated the use of dronedarone in patients with symptomatic, recently decompensated heart failure requiring diuretic treatment, a left ventricular ejection fraction of <0.35, and at least one New York Heart Association class III-IV episode in the month prior to randomization. Patients were assigned to dronedarone 400 mg twice daily or placebo. The primary efficacy evaluation was the incidence of all-cause mortality and hospitalization. After the inclusion of 627 patients (310 in the dronedarone group and 317 in the placebo group) and a median treatment duration of approximately 2 months, the trial was stopped. Twenty-five patients (8.0%) in the dronedarone group and 12 patients (3.8%) in the placebo group had died (HR 2.13, 95% CI 1.07- 4.25; p = .027). The deaths were predominantly a result of worsening heart failure, and there was no evidence of proarrhythmia or an increased incidence of sudden death in the dronedarone group. Importantly, deaths during the double-blind phase were found to be associated with lack of treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Because dronedarone causes a reversible increase in the serum creatinine level that might be mistaken for ACE or ARB toxicity, it is suspected that inappropriate withdrawal of ACE inhibitors or ARBs in the dronedarone group may have contributed to the increased mortality rate.
The results of this trial prompted a large outcomes trial with dronedarone, the ATHENA study (A Placebo Controlled Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of CV Hospitalisations or Death From Any Cause in Patients With Atrial Fibrillation/ Atrial Flutter), which, to date, is the largest antiarrhythmic drug trial regarding AF [34,35]. This multinational study recruited 4628 patients and randomized patients with paroxysmal or persistent AF or atrial flutter in a 1:1 ratio to treatment with dronedarone 400 mg twice daily or placebo. The primary endpoint was a composite of cardiovascular hospitalization and death. The mean follow-up was 21 ± 5 months. Among 2301 patients randomized to dronedarone, primary outcome events occurred in 734 (31.9%). Among 2327 patients randomized to placebo, primary outcome events occurred in 917 (39.4%). The HR for the primary endpoint was 0.76 (95% CI 0.69-0.84; p <.0001). There were 116 deaths (5.0%) in the dronedarone group and 139 (6.0%) in the placebo group (HR 0.84; 95% CI 0.66-1.08; p = .18). Among the deaths, 63 (2.7%) in the dronedarone group and 90 (3.9%) in the placebo group (HR 0.71; 95% CI 0.51-0.98; p = .03) were of cardiovascular origin, which was largely due to a reduction in arrhythmic death with dronedarone. Figure 2 shows cumulative Kaplan-Meier event curves for the primary and for important prespecified secondary study outcomes. Overall, dronedarone was well tolerated, although the dronedarone group had higher rates of bradycardia, nausea, diarrhea, and increases in serum creatinine levels than did the placebo group. Rates of thyroid and pulmonary adverse events were not different between the two groups. Only one case of torsade de pointes was reported in the dronedarone group.
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Figure 2. Important clinical outcomes in the ATHENA study, which randomized patients with nonpermanent atrial fibrillation to dronedarone 400 mg twice daily or placebo. Kaplan-Meier cumulative incidences of the primary study outcome (A) (composite of first cardiovascular hospitalization or death from any cause; hazard ratio [HR] 0.76, p <.001), all-cause mortality (B) (HR 0.84, p = .18), death from cardiovascular causes (C) (HR 0.71, p = .03), and first cardiovascular hospitalization (D) (HR 0.74, p <.001).
(Reproduced with permission from Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:668-678. Copyright © 2009 Massachusetts Medical Society. All rights reserved) |
How can one explain the differences in mortality observed in the ANDROMEDA and ATHENA studies? The most important difference between these two trials is the fact that ANDROMEDA included patients with congestive heart failure who had been hospitalized recently because of their unstable hemodynamic situations. AF was not a mandatory inclusion criterion. On the other hand, ATHENA specifically excluded hemodynamically unstable patients, and all had AF. Given the known grave prognosis of congestive heart failure patients with a recent hospitalization [36], this specific patient feature may have been responsible for the high mortality observed early in the ANDROMEDA study.
The last study completing the portfolio of dronedarone is the DIONYSOS trial (Randomized Double Blind Trial to Evaluate the Efficacy and Safety of Dronedarone Versus Amiodarone for at Least Six Months for the Maintenance of Sinus Rhythm in Patients With AF), which is a direct comparison of dronedarone 400 mg twice daily and amiodarone (200 mg/day). The primary endpoint of this study is recurrence of AF or premature drug discontinuation from the study. The HR for the primary endpoint was 1.59 (p <.001) for dronedarone compared to amiodarone because of a higher rate of SR maintenance in the amiodarone group. Drug tolerability, however, was better for dronedarone than for amiodarone. Full details of this important study are still awaited.
Dronedarone has in the meantime received approval by the US Food and Drug Administration for therapy of patients with nonpermanent AF, with the prospect of reducing cardiovascular hospitalizations in this population.
Budiodarone (ATI-2042)
There is intense research into the development of amiodarone derivates besides dronedarone, with modifications of the molecule resulting in more rapid action, shorter half-life, and a more favorable side effect profile. One of these developments is budiodarone (ATI-2042; ARYx, Fremont, CA, USA), an oral, rapidly metabolized amiodarone analogue with a short half-life of approximately 7 hours. Thus, less tissue accumulation is expected, with the prospect of less amiodarone-like organ toxicity. The electrophysiological profile of the compound resembles that of amiodarone. Like amiodarone, budiodarone causes a balanced increase in atrial refractoriness, which was associated with a significant reduction in left atrial vulnerability to AF [37]. In a small proof-of-concept study in 6 patients with implanted pacemakers and AF, the drug reduced the amount of time the patients were in AF in a dose-dependent manner by up to 87% [38]. A phase IIb efficacy and safety study in 72 AF patients with pacemakers has been completed in which the electrograms storages of the devices were used to record the time in AF. Patients were randomized to receive budiodarone at oral doses of 200, 400, and 600 mg twice daily or matched-dose placebo for 12 weeks. The primary efficacy analysis was the percent change in AF burden from baseline to the entire 12-week treatment period. For budiodarone at 400 and 600 mg doses, there was a significant reduction in AF burden from baseline by 54% and 75%, respectively. The overall dose-response effect was robust at a p value of .001. More detailed results are expected in the near future.
SUMMARY
There are several new antiarrhythmic drugs that are expected to be released shortly for treatment of AF. Although the ARDAs have the prospect of better safety by virtue of lack of ventricular proarrhythmia, new multiple-channel blocking drugs such as dronedarone may for the first time allow treatment of AF with the view toward not only reduction in symptoms but also improvement in morbidity and mortality. Finally, the more we learn about specific pathophysiological mechanisms of AF, the more specific targets for drug therapy may be defined, such as gap junction modulators, stretch receptor antagonists, or effective upstream anti-inflammatory and antifibrotic substances.
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