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A Mechanistic Clinical Trial Using (R)- Versus (S)-Propafenone to Test RyR2 (Ryanodine Receptor) Inhibition for the
M Benjamin Shoemaker1, Zachary T Yoneda1, Diane M Crawford1
1Division of Cardiology (M.B.S., Z.T.Y., D.M.C., T.R., J.A.M., P.S., J.C.E., A.K., S.T.S., G. F. M., G.C., C.R.E.), Department of Medicine, Vanderbilt University Medical Center.
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.
Insights
This study found no difference in atrial fibrillation (AF) induction between (R)-propafenone and (S)-propafenone. Both enantiomers, along with placebo, showed similar AF inducibility, with atrial flutter rates higher than placebo due to sodium-channel blockade.
Area of Science:
- Cardiology
- Electrophysiology
- Pharmacology
Background:
- Ryanodine receptor (RyR)-mediated calcium leak is a proposed mechanism for atrial fibrillation (AF).
- Propafenone has two enantiomers: (R)-propafenone inhibits RyRs, while (S)-propafenone does not.
- Human evidence linking RyR inhibition to AF prevention is limited.
Purpose of the Study:
- To test if (R)-propafenone, an RyR inhibitor, prevents AF induction compared to (S)-propafenone or placebo.
- To investigate the role of RyR inhibition in AF pathogenesis in humans undergoing ablation.
Main Methods:
- A randomized trial involving 193 patients undergoing AF ablation.
- Participants received a single intravenous dose of (R)-propafenone, (S)-propafenone, or placebo.
- AF and/or atrial flutter induction was assessed using rapid atrial pacing before ablation.
Main Results:
- Sustained AF/atrial flutter was induced in 84.5% of (R)-propafenone, 80.0% of (S)-propafenone, and 63.2% of placebo recipients.
- Atrial flutter occurred significantly more often in both propafenone groups compared to placebo (32.4% and 34.7% vs 5.3%).
- No significant difference in AF/atrial flutter induction was observed between (R)-propafenone and (S)-propafenone.
Conclusions:
- Clinically relevant concentrations of (R)-propafenone and (S)-propafenone did not differ in their effect on AF inducibility.
- High rates of atrial flutter induction in both groups suggest confounding by sodium-channel blockade.
- The study did not support a role for RyR inhibition in preventing AF induction in this context.
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