Pulmonary delivery of flecainide causes a rate-dependent predominant effect on atrial compared with ventricular depolarization duration revealed by intracardiac recordings in an intact porcine model.

BACKGROUND: Pulmonary delivery of flecainide results in the rapid conversion of atrial fibrillation (AF) to normal sinus rhythm in large-animal models and is safe and well-tolerated by normal human volunteers. OBJECTIVE: We investigated the effects of pulmonary delivery of flecainide on atrial and ventricular depolarization and repolarization duration. METHODS: Intratracheal instillation (1.5 mg/kg, rapid push) of flecainide or sterile water (placebo) was performed in 12 closed-chest, anesthetized Yorkshire pigs with a catheter positioned at the bifurcation of the main bronchi. High-resolution electrograms obtained from catheters fluoroscopically positioned in the right atrium and left ventricle circumvented measurement errors due to the fusion of P and T waves in surface leads when rapid heart rates shortened the TP interval. Pacing was achieved using electrical stimuli delivered via right atrial catheter electrodes. RESULTS: During sinus rhythm (98 ± 4.7 beats/min), intratracheal flecainide caused comparable (P = 0.56) increases in atrial depolarization (P a ) duration by 22% (39.8 ± 3.2 to 48.7 ± 3.3 milliseconds) and left ventricular (LV) QRS complex duration by 20% (47.9 ± 1.6 to 57.3 ± 1.8 milliseconds) at peak effect at 2 minutes post-dosing. During right atrial pacing at 180 beats/min, Pa duration increased by 55% (37.0 ± 2.0 to 57.2 ± 1.6 milliseconds; P < 0.0001). The atrial response was greater (p = 0.001) than the 30% increase in LV QRS complex duration (46.6 ± 1.7 to 60.6 ± 2.5 milliseconds; P = 0.005). Pa duration and QRS complex duration were unchanged by placebo independent of pacing (P ≥ 0.4 for both). Atrial repolarization duration (PTa ; P = 0.46) and QTc interval (P = 0.49) remained unchanged. CONCLUSION: Intratracheal flecainide exerts a rate-dependent, predominant effect on atrial compared with ventricular depolarization duration. Pulmonary delivery of flecainide could facilitate AF conversion to sinus rhythm with reduced ventricular proarrhythmia risk.

Comparative Pharmacokinetic and Electrocardiographic Effects of Intratracheal and Intravenous Administration of Flecainide in Anesthetized Pigs.

We compared the pharmacokinetic (PK) profile and electrocardiographic (ECG) changes in response to intratracheal instillation of flecainide acetate into the left atrium and ventricle with intravenous (IV) flecainide acetate administration. In 12 closed-chest anesthetized Yorkshire pigs, we monitored the QRS complex and PR, JTc, and QTc intervals during sinus rhythm and correlated changes with venous plasma drug concentrations before and at 2, 5, 10, 15, and 30 minutes after drug administration. Intratracheal instillation of flecainide (0.75 and 1.5 mg/kg, rapid bolus) caused dose/concentration-dependent increases in the QRS complex duration of 10% and 19%, respectively, at 2 minutes, coinciding with peak venous plasma levels (1688 ± 177 and 2808 ± 217 ng/mL, respectively). IV infusion of flecainide (2 mg/kg) over 2 or 10 minutes similarly prolonged QRS complexes and PR intervals (both, P < 0.001). Intratracheal flecainide instillation increased PR interval briefly at 5 minutes. Neither intratracheal nor IV flecainide affected JTc or QTc intervals. Thus, the PK pattern of intratracheal instillation of flecainide is comparable to IV administration, although the absolute plasma concentrations were higher with IV infusion. Both modes of delivery elicited ECG changes that were consistent with the expected pharmacological activity of flecainide.

Orally Inhaled Flecainide for Conversion of Atrial Fibrillation to Sinus Rhythm: INSTANT Phase 2 Trial.

BACKGROUND: INSTANT (INhalation of flecainide to convert recent-onset SympTomatic Atrial fibrillatioN to sinus rhyThm) was a multicenter, open-label, single-arm study of flecainide acetate oral inhalation solution (FlecIH) for acute conversion of recent-onset (≤48 hours) symptomatic atrial fibrillation (AF) to sinus rhythm. OBJECTIVES: This study investigated the efficacy and safety in 98 patients receiving a single dose of FlecIH delivered via oral inhalation. METHODS: Patients self-administered FlecIH over 8 minutes in a supervised medical setting using a breath-actuated nebulizer and were continuously monitored for 90 minutes using a 12-lead Holter. RESULTS: Mean age was 60.5 years, mean body mass index was 27.0 kg/m2, and 34.7% of the patients were women. All patients had ≥1 AF-related symptoms at baseline, and 87.8% had AF symptoms for ≤24 hours. The conversion rate was 42.6% (95% CI: 33.0%-52.6%) with a median time to conversion of 14.6 minutes. The conversion rate was 46.9% (95% CI: 36.4%-57.7%) in a subpopulation that excluded predose flecainide exposure for the current AF episode. Median time to discharge among patients who converted was 2.5 hours, and only 2 patients had experienced AF recurrence by day 5. In the conversion-no group, 44 (81.5%) patients underwent electrical cardioversion by day 5. The most common adverse events were related to oral inhalation of flecainide (eg, cough, oropharyngeal irritation/pain), which were mostly of mild intensity and limited duration. CONCLUSIONS: The risk-benefit of orally inhaled FlecIH for acute cardioversion of recent-onset AF appears favorable. FlecIH could provide a safe, effective, and convenient first-line therapeutic option. (INhalation of Flecainide to Convert Recent Onset SympTomatic Atrial Fibrillation to siNus rhyThm [INSTANT]; NCT03539302).

Exercise and pharmacologic stress-induced interlead T-wave heterogeneity analysis to detect clinically significant coronary artery stenosis.

BACKGROUND: Despite widespread use of ETT and vasodilator-stress with myocardial perfusion imaging (MPI) for noninvasive detection of flow-limiting coronary artery disease, there is continued need to improve diagnostic accuracy. We examined whether measurement of interlead T-wave heterogeneity (TWH) during exercise tolerance testing (ETT) or pharmacologic stress testing improves detection of stenoses in large epicardial coronary arteries. METHODS: All 137 patients at our institution who underwent diagnostic coronary angiography within 0 to 5 days after ETT (N = 81) or dipyridamole IV infusion (N = 58) in 2016 were studied, including 2 patients with both tests. Cases (N = 93) had angiographically significant stenosis (≥50% of left main or ≥ 70% of an epicardial coronary artery ≥2 mm in diameter); controls (N = 44) did not. TWH, i.e., interlead splay of T waves, was determined by second central moment analysis from precordial leads by an investigator blinded to angiographic results. RESULTS: At rest, TWH levels were similar for cases and controls. ETT and dipyridamole stress testing increased TWH by 69% (p < 0.0001) and 27% (p < 0.0001), respectively, in cases. In controls, TWH did not change. Areas under the ROC curves for TWH increase for any flow-limiting coronary artery stenosis were 0.737 (p < 0.0001) for ETT and 0.818 (p < 0.0001) for dipyridamole stress testing. By contrast, neither ST-segment changes during ETT (p = 0.12) nor MPI during dipyridamole stress testing (p = 0.60) discriminated cases from controls. CONCLUSIONS: TWH measurement is a novel method that improves detection of angiographically confirmed flow-limiting stenoses in large epicardial coronary arteries during both ETT and MPI during pharmacologic stress testing with dipyridamole.

Optimizing flecainide plasma concentration profile for atrial fibrillation conversion while minimizing adverse ventricular effects by rapid, low-dose intratracheal or intravenous administration.

BACKGROUND: We investigated whether rapid administration of a low dose of flecainide, either intratracheally or intravenously (IV), could accelerate conversion of atrial fibrillation (AF) while reducing adverse ventricular effects. METHODS: Flecainide was delivered via intratracheal administration at 1.5 mg/kg bolus and compared to IV infusion at 1.0 mg/kg over 2 min (lower-dose, rapid) and 2.0 mg/kg over 10 min (ESC guideline) in closed-chest, anesthetized Yorkshire pigs. Catheters were fluoroscopically positioned in right atrium to measure atrial depolarization (Pa) duration and left ventricle (LV) to measure QRS complex duration and contractility (LV dP/dt) during atrial pacing at 140 beats/min. Flecainide was delivered intratracheally via a catheter positioned at the bifurcation of the main bronchi. AF was induced by intrapericardial administration of acetylcholine followed by burst pacing. RESULTS: Flecainide reduced AF duration similarly by intratracheal and IV delivery. Peak plasma levels were comparable but Tmax differed and coincided with peaks in Pa prolongation. The area under the curve indicating sustained plasma levels was greater for higher-dose, slow IV flecainide than for either intratracheal instillation (by 32%) or lower-dose, rapid IV infusion (by 88%). As a result, higher-dose, slow IV flecainide caused 58% (p < 0.03) and 48% (p < 0.006) greater increases in QRS complex duration and 61% and 96% (both, p < 0.02) greater reductions in contractility compared to intratracheal and lower-dose, rapid IV flecainide, respectively. CONCLUSION: Lower-dose, rapid flecainide, delivered either intratracheally or IV, optimizes the plasma concentration profile for effective conversion of AF while minimizing adverse effects on QRS complex duration and LV contractility.

Accelerated conversion of atrial fibrillation to normal sinus rhythm by pulmonary delivery of flecainide acetate in a porcine model.

BACKGROUND: Pulmonary delivery of antiarrhythmic agents has the potential to increase rapidly targeted drug concentrations in pulmonary veins and left atrium to terminate atrial fibrillation (AF). OBJECTIVE: We evaluated the efficacy of flecainide administered via intratracheal instillation in terminating AF in a reliable preclinical model. METHODS: In 11 closed-chest anesthetized Yorkshire pigs, AF was induced by intrapericardial administration of acetylcholine (1 mL of 102.5 mM solution) followed by burst pacing and allowed to continue for 2 minutes before intratracheal flecainide (0.4 or 0.75 mg/kg) administration. RESULTS: Both the 0.4- and 0.75-mg/kg doses of intratracheal flecainide significantly reduced AF duration by 35% (P = .02) and 54% (P = .001), respectively, compared to no-drug baseline. There was a strong inverse correlation (r2 = 0.87; P = .03) between the duration of AF and the change in atrial depolarization duration in response to intratracheal flecainide. Induction of AF resulted in a marked increase in ventricular rate and corresponding reduction in mean arterial pressure, which returned to baseline levels within 5 minutes after conversion. CONCLUSION: Intratracheal flecainide instillation is effective in rapidly converting AF to normal sinus rhythm and restoring mean arterial pressure and heart rate to baseline values. The basis for this efficacy is likely rapid absorption of the drug through the lungs and delivery as a first-pass bolus to the left atrial and ventricular chambers and then to the coronary arterial circulation. The anti-AF effect of flecainide is inversely correlated with the drug's prolongation of atrial depolarization, implicating slowing of intra-atrial conduction as an important mechanism underlying conversion of AF to normal sinus rhythm.