Key result
(R)-propafenone fails to reduce inducible atrial fibrillation or flutter compared to (S)-propafenone.
Why the study?
Experimental data suggest ryanodine receptor-mediated intracellular calcium leak is a mechanism for AF, but human evidence is still needed.
Does targeting RyR2 with (R)-propafenone prevent induction of atrial fibrillation compared to (S)-propafenone or placebo in patients undergoing AF ablation?
RCT (n=193)
Double-blind
4:4:1 permuted block randomization
No
Does targeting RyR2 with (R)-propafenone prevent induction of atrial fibrillation compared to (S)-propafenone or placebo in patients undergoing AF ablation?
Odds Ratio: 0.53 (95% CI 0.21–1.39)
Absolute Event Rate: 84.5% vs 80%
p-value: p=0.199
Pharmacological inhibition of the RyR2 channel with (R)-propafenone did not significantly reduce AF inducibility in humans compared to (S)-propafenone, although interpretation was limited by proarrhythmic sodium-channel effects.
R-propafenone shows no advantage over S-propafenone for preventing AF induction; challenges RyR2 inhibition as an antiarrhythmic strategy amid sodium-channel confounding.
Background: Experimental data suggest ryanodine receptor-mediated intracellular calcium leak is a mechanism for atrial fibrillation (AF), but evidence in humans is still needed. Propafenone is composed of two enantiomers that are equally potent sodium-channel blockers; however, (R )-propafenone is an ryanodine receptor inhibitor whereas (S )-propafenone is not. This study tested the hypothesis that ryanodine receptor inhibition with (R )-propafenone prevents induction of AF compared to (S )-propafenone or placebo in patients referred for AF ablation. Methods: Participants were randomized 4:4:1 to a one-time intravenous dose of (R )-propafenone, (S )-propafenone, or placebo. The study drug was given at the start of the procedure and an AF induction protocol using rapid atrial pacing was performed before ablation. The primary endpoint was 30 s of AF or atrial flutter. Results: A total of 193 participants were enrolled and 165 (85%) completed the study protocol (median age: 63 years, 58% male, 95% paroxysmal AF). Sustained AF and/or atrial flutter was induced in 60 participants (84.5%) receiving (R )-propafenone, 60 (80.0%) receiving (S )-propafenone group, and 12 (63.2%) receiving placebo. Atrial flutter occurred significantly more often in the (R )-propafenone (N=23, 32.4%) and (S )-propafenone (N=26, 34.7%) groups compared to placebo (N=1, 5.3%, P =0.029). There was no significant difference between (R )-propafenone and (S )-propafenone for the primary outcome of AF and/or atrial flutter induction in univariable ( P =0.522) or multivariable analysis ( P =0.199, adjusted for age and serum drug level). Conclusions: There is no difference in AF inducibility between (R )-propafenone and (S )-propafenone at clinically relevant concentrations. These results are confounded by a high rate of inducible atrial flutter due to sodium-channel blockade. Registration: https://clinicaltrials.gov ; Unique Identifier: NCT02710669.
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Shoemaker et al. (2022) conducted an RCT in Atrial Fibrillation (n=193). (R)-propafenone vs. (S)-propafenone or placebo was evaluated on Induction of 30 seconds of AF, atrial flutter (AFL), or atrial tachycardia (OR 0.53, 95% CI 0.21-1.39, p=0.199). (R)-propafenone did not significantly differ from (S)-propafenone in preventing the induction of atrial fibrillation or atrial flutter (OR 0.53, 95% CI 0.21-1.39, P=0.199).
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