Updates on anti-arrhythmic agents

The INSTANT study showed that oral inhalation of flecainide restored sinus rhythm in patients with recent-onset atrial fibrillation. In the NODE-301 trial, etripamil nasal spray showed to significantly improve paroxysmal supraventricular tachycardia-related symptoms. Small-conductance calcium-activated potassium channel inhibitors showed to delay the cardiac action potential and seem to be atrial selective. Sulcardine reduced the J-Tp interval, a feature only seen for this agent. The GENETIC-AF trial showed a preventive effect of bucindolol on new-onset atrial fibrillation (AF), and, finally, botulinum toxin A delayed postoperative AF after injection.

Prof. John Camm (St George’s University of London, UK) discussed the latest evidence concerning the development of novel anti-arrhythmic drugs (AAD) and corresponding administration methods [1].

Inhaled flecainide for AF is currently being tested in the phase 2 INSTANT study (NCT03539302) [2]. Although preliminary results showed only approximately 50% AF conversion in 90 minutes for patients with the highest plasma concentration, a large variation in inhaled drugs between participants was observed. Adding saccharin to the inhaled product appeared to be more successful and may increase the success rate of inhaled flecainide.

Another agent with an alternative administration method is etripamil currently undergoing testing in the NODE-301 trial (NCT03464019). This is a novel, short-acting, calcium channel antagonist, which has demonstrated to reach a maximum plasma concentration in 5 minutes through intranasal administration and showed corresponding PR interval prolongation. An analysis of the NODE-301 results showed that after 30 minutes, 54% of the patients on etripamil achieved conversion compared with 35% of the patients on placebo (HR 1.87; P<0.02) [3].

Small-conductance calcium-activated potassium channels are an interesting group of novel agents as well. These agents were able to delay cardiac action potentials up to 75 ms at top dosage. They appear to be highly atrial selective, since animal studies have shown that the atrial effective refractory period is significantly prolonged with this agent, whereas QT intervals are not prolonged [4]. Clinical studies need to be conducted to assess these agents in human participants.

The next discussed agent was sulcardine, a multiple ion-channel inhibitor. It acts on late-sodium and late-calcium channels, thereby inducing a reduction of J-Tp, the interval between the QRS complex and the peak of the T-wave. This feature has not been observed in other agents. Moreover, almost all intervals were significantly prolonged on the top dosage. Two phase 1 trials have been completed successfully, and a phase 2 trial (NCT01235156) assessing this agent is underway [5,6].

A preventive effect of bucindolol on new-onset AF has been observed in the GENETIC-AF trial [7,8]. This effect was largely confined to the genotype of the β1 adrenergic receptor with 389 Arginine/arginine homozygous genotype. The effect was not observed in the corresponding heterozygous genotype. Furthermore, bucindolol was significantly favoured over metoprolol regarding AF burden in patients with the aforementioned homozygous genotype.

Finally, the Task1 inhibitor doxapram is currently being investigated for AF in the DOCTOS trial (EudraCT 2018-002979-17), and botulinum toxin A is being assessed in the large phase 2 NOVA trial (NCT03779841) for the prevention of postoperative AF. This agent has demonstrated to delay postoperative AF after injection in a previous phase 2 study [9].

1. Camm J. New antiarrhythmic drugs - news on the horizon? What is in the pipeline for us: new innovations, EHRA 2022, 3–5 April, Copenhagen, Denmark.
2. Crijns HJGM, et al. Circ AE. 2022;15(3).
3. Stambler B, et al. Session 403-13, ACC 2021, 15‒17 May.
4. Burashnikov A, et al. J Cardiovasc Pharmacol. 2020;76(2):164‒172.
5. Mason JW, et al. Circulation. 2019;140:A11495.
6. Wang W, et al. Eur J Drug Metab Pharmacokinet. 2017;42(4):593‒599.
7. Piccini JP, et al. JACC Heart Failure. 2019;7(7):586‒598.
8. Piccini JP, et al. Circulation: AE. 2021;14:e009591.
9. Romanov A, et al Heart Rhythm. 2019;16:172‒177.

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Posted on 1 June 202218 March 2024