Atrial Fibrillation
Conditions
Keywords
ablation
Brief summary
Propafenone is a currently used medicine to treat atrial fibrillation and is a mixture of two compounds, (R)-propafenone and (S)-propafenone. In this study, the investigators will randomize participants to (R)-propafenone, (S)-propafenone, or placebo.
Detailed description
Atrial fibrillation is a common cardiac arrhythmia that needs development of more effective medications. Propafenone is a medicine currently used to treat atrial fibrillation and is a mixture of two compounds, (R)-propafenone and (S)-propafenone. The investigators have discovered that purified (R)-propafenone may be more effective than (S)-propafenone for treatment of atrial fibrillation, and that (S)-propafenone reduces the efficacy of (R)-propafenone when administered as a mixture. This study will compare the ability of (R)-propafenone, (S)-propafenone, and placebo to suppress the induction of atrial fibrillation in participants undergoing an atrial fibrillation ablation procedure.
Interventions
DRUGPlacebo
DRUG(R)-propafenone
DRUG(S)-Propafenone
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion: 1. History of atrial fibrillation 2. Greater than or equal to 18 years of age 3. Scheduled to undergo an atrial fibrillation ablation procedure 4. Able to provide written informed consent Exclusion: 1. Long-standing persistent atrial fibrillation at the time of ablation (greater than 1 year of a continuous atrial fibrillation episode) 2. Is in atrial fibrillation or atrial flutter the morning of the ablation procedure 3. The presence of any of the following in a patient without a permanent pacemaker for implantable cardiac defibrillator 1. sick sinus syndrome indicated by the inability to previously tolerate an antiarrhythmic drug due to bradycardia 2. sinus bradycardia with a heart rate less than 50 beats per minute at the time of study drug administration 3. right bundle branch block, left bundle branch block, or bifascicular block 4. PR-interval \> 280ms, or history of 2nd or 3rd degree atrioventricular block 4. Concomitant use of CYP3A4 and CYP2D6 inhibitors 5. Previous surgical or catheter ablation for atrial fibrillation or Cox-Maze procedure 6. Amiodarone use within 3 months prior to enrollment 7. Antiarrhythmic drug (other than amiodarone) within 5 half-lives prior to atrial fibrillation ablation 8. Expected life span \< 1 year 9. Creatinine clearance \<30 mL/min 10. Reversible cause of atrial fibrillation (ie. thyrotoxicosis) 11. Unrevascularized coronary artery disease 12. Canadian class IV angina 13. Left ventricular ejection fraction \<40% 14. New York Heart Association Class III or IV symptoms 15. Previous heart transplantation 16. Planned heart transplantation or ventricular assist device 17. Cardiac/thoracic surgery \<6 months prior to enrollment 18. Severe asthma or chronic obstructive pulmonary disease 19. Breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter | Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes) | A rapid atrial pacing protocol was used to attempt to induce atrial fibrillation/atrial flutter. Twenty minutes after start of the study drug, participants underwent placement of a decapolar coronary sinus catheter. Pacing was performed from the proximal electrode at 20 milliamps and a pulse width of 2 ms. Bursts from the CS proximal electrode were induced to attempt atrial fibrillation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes) | Inducibility of atrial fibrillation (AF) or atrial flutter (AFL) expressed as an ordinal variable based on stage of the induction protocol. * Stage 1 measured the AV block (Wenckebach) cycle length (AVBCL), AV node effective refractory period (AVN ERP) and atrial ERP (AERP). AVN ERP and AERP were measured at drive trains (S1) of 600 ms and 450 ms. Extrastimuli (S2) were introduced starting at a coupling interval of 500ms and decremented by 10ms with each pacing train. * Stage 2 consisted of 15-beat bursts from the CS proximal electrode. The starting cycle length was 250ms, which was decremented by 10ms with each burst. A 10-second rest period was used between bursts. Step 2 was complete when 1:1 atrial capture was lost or a minimum cycle length of 180ms was reached. Stage 3 consisted of 15-second bursts. The cycle length used for the bursts was the fastest cycle length achieved during Step 2 that maintained 1:1 atrial conduction. |
| Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter | Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes) | A rapid atrial pacing protocol was used to attempt to induce atrial flutter. Twenty minutes after start of the study drug, participants underwent placement of a decapolar coronary sinus catheter. Pacing was performed from the proximal electrode at 20 milliamps and a pulse width of 2 ms. Bursts from the CS proximal electrode were induced to attempt atrial flutter. |
Countries
United States
Participant flow
Pre-assignment details
193 participants were enrolled. 1 participant withdrew consent prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| (R)-Propafenone Single intravenous dose of (R)-propafenone (1mg/kg) infused over 10 minutes
(R)-propafenone | 85 |
| (S)-Propafenone Single intravenous dose of (S)-propafenone (1mg/kg) infused over 10 minutes
(S)-Propafenone | 86 |
| Placebo Placebo (normal saline) is infused over 10 minutes
Placebo | 21 |
| Total | 192 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | arrived in afib/aflutter | 10 | 8 | 2 |
| Overall Study | Institutional delays (including COVID) | 2 | 2 | 0 |
| Overall Study | Physician Decision | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | (R)-Propafenone | Total | Placebo | (S)-Propafenone |
|---|---|---|---|---|
| Age, Continuous | 62 years | 63 years | 59 years | 64 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 85 Participants | 192 Participants | 21 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 84 Participants | 187 Participants | 20 Participants | 83 Participants |
| Region of Enrollment United States | 85 participants | 192 participants | 21 participants | 86 participants |
| Sex: Female, Male Female | 38 Participants | 81 Participants | 8 Participants | 35 Participants |
| Sex: Female, Male Male | 47 Participants | 111 Participants | 13 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 71 | 0 / 75 | 0 / 19 |
| other Total, other adverse events | 0 / 71 | 0 / 75 | 0 / 19 |
| serious Total, serious adverse events | 0 / 71 | 0 / 75 | 0 / 19 |
Outcome results
Primary
Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter
A rapid atrial pacing protocol was used to attempt to induce atrial fibrillation/atrial flutter. Twenty minutes after start of the study drug, participants underwent placement of a decapolar coronary sinus catheter. Pacing was performed from the proximal electrode at 20 milliamps and a pulse width of 2 ms. Bursts from the CS proximal electrode were induced to attempt atrial fibrillation.
Time frame: Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes)
Population: 27 Participants not analyzed as follows: R GROUP: (1) prolonged pharmacy time compounding the study med; (8) arrived in atrial fib/flutter; (1) physician withdrew due to PAC's; (1) took antiarrhythmic prior to ablation; (1) difficult anatomy (1) ischemia on MRI; (1) Due to COVID the lab halted elective research. S GROUP: (7) arrived in afib; (1) clot on TEE; (1) elevated anxiety in patient; (1) procedure scheduled late in day; (1) cardiac cath work-up needed. PLACEBO GROUP: (2) arrived in afib
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| (R)-Propafenone | Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter | Sustained AF and/or AFL induced | 60 Participants |
| (R)-Propafenone | Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter | Non-sustained AF and/or AFL induced | 11 Participants |
| (S)-Propafenone | Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter | Non-sustained AF and/or AFL induced | 15 Participants |
| (S)-Propafenone | Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter | Sustained AF and/or AFL induced | 60 Participants |
| Placebo | Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter | Sustained AF and/or AFL induced | 12 Participants |
| Placebo | Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter | Non-sustained AF and/or AFL induced | 7 Participants |
Secondary
Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol
Inducibility of atrial fibrillation (AF) or atrial flutter (AFL) expressed as an ordinal variable based on stage of the induction protocol. * Stage 1 measured the AV block (Wenckebach) cycle length (AVBCL), AV node effective refractory period (AVN ERP) and atrial ERP (AERP). AVN ERP and AERP were measured at drive trains (S1) of 600 ms and 450 ms. Extrastimuli (S2) were introduced starting at a coupling interval of 500ms and decremented by 10ms with each pacing train. * Stage 2 consisted of 15-beat bursts from the CS proximal electrode. The starting cycle length was 250ms, which was decremented by 10ms with each burst. A 10-second rest period was used between bursts. Step 2 was complete when 1:1 atrial capture was lost or a minimum cycle length of 180ms was reached. Stage 3 consisted of 15-second bursts. The cycle length used for the bursts was the fastest cycle length achieved during Step 2 that maintained 1:1 atrial conduction.
Time frame: Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes)
Population: 27 Participants not analyzed as follows: R GROUP: (1) prolonged pharmacy time compounding the study med; (8) arrived in atrial fib/flutter; (1) physician withdrew due to PAC's; (1) took antiarrhythmic prior to ablation; (1) difficult anatomy (1) ischemia on MRI; (1) Due to COVID the lab halted elective research. S GROUP: (7) arrived in afib; (1) clot on TEE; (1) elevated anxiety in patient; (1) procedure scheduled late in day; (1) cardiac cath work-up needed. PLACEBO GROUP: (2) arrived in afib
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| (R)-Propafenone | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Stage 1 | 5 Participants |
| (R)-Propafenone | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Stage 2 | 28 Participants |
| (R)-Propafenone | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Stage 3 | 27 Participants |
| (R)-Propafenone | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Non-inducible AF/AFL | 11 Participants |
| (S)-Propafenone | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Non-inducible AF/AFL | 15 Participants |
| (S)-Propafenone | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Stage 1 | 5 Participants |
| (S)-Propafenone | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Stage 3 | 24 Participants |
| (S)-Propafenone | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Stage 2 | 31 Participants |
| Placebo | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Non-inducible AF/AFL | 7 Participants |
| Placebo | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Stage 2 | 3 Participants |
| Placebo | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Stage 3 | 8 Participants |
| Placebo | Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Stage 1 | 1 Participants |
Secondary
Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter
A rapid atrial pacing protocol was used to attempt to induce atrial flutter. Twenty minutes after start of the study drug, participants underwent placement of a decapolar coronary sinus catheter. Pacing was performed from the proximal electrode at 20 milliamps and a pulse width of 2 ms. Bursts from the CS proximal electrode were induced to attempt atrial flutter.
Time frame: Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes)
Population: 27 Participants not analyzed as follows: R GROUP: (1) prolonged pharmacy time compounding the study med; (8) arrived in atrial fib/flutter; (1) physician withdrew due to PAC's; (1) took antiarrhythmic prior to ablation; (1) difficult anatomy (1) ischemia on MRI; (1) Due to COVID the lab halted elective research. S GROUP: (7) arrived in afib; (1) clot on TEE; (1) elevated anxiety in patient; (1) procedure scheduled late in day; (1) cardiac cath work-up needed. PLACEBO GROUP: (2) arrived in afib
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| (R)-Propafenone | Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter | Sustained AFL | 23 Participants |
| (R)-Propafenone | Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter | Non-Sustained AFL | 48 Participants |
| (S)-Propafenone | Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter | Sustained AFL | 26 Participants |
| (S)-Propafenone | Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter | Non-Sustained AFL | 49 Participants |
| Placebo | Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter | Sustained AFL | 1 Participants |
| Placebo | Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter | Non-Sustained AFL | 18 Participants |