vernakalant and Atrial-Flutter

Vernakalant is a novel, relatively atrial-selective antiarrhythmic agent for conversion of atrial fibrillation (AF) to sinus rhythm. This study examined the safety and efficacy of vernakalant in converting atrial flutter (AFL) to sinus rhythm.. This was a phase 2/3, randomized, double-blind, placebo-controlled trial. Adults with AFL received either a 10 min infusion of 3.0 mg/kg vernakalant (n = 39) or placebo (n = 15). If AFL or AF persisted at the end of a 15 min observation period, a second 10 min infusion of 2.0 mg/kg vernakalant or placebo was administered. The primary efficacy outcome was the proportion of patients who had treatment-induced conversion of AFL to sinus rhythm for a minimum duration of 1 min within 90 min after the start of the first infusion. No patient in the placebo group met the primary outcome. Only one patient receiving vernakalant (1 of 39, 3%) converted to sinus rhythm. A reduced mean absolute ventricular response rate occurred within 50 min in patients receiving vernakalant (mean change from baseline -8.2 b.p.m.) vs. patients receiving placebo (-0.2 b.p.m.) (P = 0.037). A post-hoc analysis revealed that vernakalant increased AFL cycle length by an average of 55 ms, whereas the AFL cycle length was unchanged in the placebo group (P < 0.001). There was no occurrence of 1 : 1 atrio-ventricular conduction. Dysgeusia and sneezing were the most common treatment-related adverse events, consistent with previous reports.. Vernakalant did not restore sinus rhythm in patients with AFL. Vernakalant modestly slowed AFL and ventricular response rates, and was well tolerated.

Topics: Aged; Aged, 80 and over; Anisoles; Anti-Arrhythmia Agents; Atrial Flutter; Double-Blind Method; Dysgeusia; Female; Heart Atria; Heart Conduction System; Humans; Male; Middle Aged; Placebos; Pyrrolidines; Sneezing; Treatment Outcome

Vernakalant hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were initially given a 10-min intravenous (IV) infusion of vernakalant 3 mg/kg or placebo. If SR was not evident after a 15-min observation, then a second 10-min IV infusion of vernakalant 2 mg/kg or placebo was given. Population pharmacokinetic/pharmacodynamic (PK/PD) models were constructed for QT interval prolongation corrected for heart rate by Fridericia's formula (QTcF) and for changes in systolic blood pressure (SBP). The exposure-response relationships for QTcF and SBP were best described by sigmoidal maximum-effect (E (max)) models. For QTcF, the model was characterized by a typical E (max) of 20.3 ms, and by a vernakalant median effective concentration dependent (EC₅₀) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by E (max) of 3.05 mmHg and EC₅₀ of 1,141 ng/ml. Risk of hypotension (SBP <90 mmHg) was primarily associated with low baseline SBP and to a smaller extent with a history of congestive heart failure (CHF); plasma vernakalant concentrations showed a small contribution to the risk of hypotension (relative risk = 1.4 at 4,000 ng/ml), which may be significant with a baseline SBP of <105 mmHg. These results show that vernakalant had a smaller effect on QTcF in patients who demonstrated conversion to SR than those remaining in AF or AFL, and it had a relatively small effect on SBP.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Blood Pressure; Computer Simulation; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Female; Heart Failure; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Pyrrolidines

The objective of the present study was to assess the safety and effectiveness of vernakalant hydrochloride injection (RSD1235), a novel antiarrhythmic drug, for the conversion of atrial fibrillation (AF) or atrial flutter to sinus rhythm (SR). Patients with either AF or atrial flutter were randomized in a 1:1 ratio to receive vernakalant (n = 138) or placebo (n = 138) and were stratified by an arrhythmia duration of >3 hours to ≤7 days (short duration) and 8 to ≤45 days (long duration). The first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if the arrhythmia had not terminated. A total of 265 patients were randomized and received treatment. The primary end point was conversion of AF to SR for ≥1 minute within 90 minutes of the start of the drug infusion in the short-duration AF group. Of the 86 patients receiving vernakalant in the short-duration AF group, 44 (51.2%) demonstrated conversion to SR compared to 3 (3.6%) of the 84 in the placebo group (p <0.0001). The median interval to conversion of short-duration AF to SR in the responders given vernakalant was 8 minutes. Of the entire AF population (short- and long-duration AF), 47 (39.8%) of the 118 vernakalant patients experienced conversion of AF to SR compared to 4 (3.3%) of the 121 placebo patients (p <0.0001). Transient dysgeusia and sneezing were the most common adverse events in the vernakalant patients. One vernakalant patient who had severe aortic stenosis experienced hypotension and ventricular fibrillation and died. In conclusion, vernakalant demonstrated a rapid and high rate of conversion for short-duration AF and was well tolerated.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Chi-Square Distribution; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Placebos; Prospective Studies; Pyrrolidines; Treatment Outcome

Postoperative atrial arrhythmias are common and are associated with considerable morbidity. This study was designed to evaluate the efficacy and safety of vernakalant for the conversion of atrial fibrillation (AF) or atrial flutter (AFL) after cardiac surgery.. This was a prospective, randomized, double-blind, placebo-controlled trial of vernakalant for the conversion of AF or AFL after coronary artery bypass graft, valvular surgery, or both. Patients were randomly assigned 2:1 to receive a 10-minute infusion of 3 mg/kg vernakalant or placebo. If AF or AFL was present after a 15-minute observation period, then a second 10-minute infusion of 2 mg/kg vernakalant or placebo was given. The primary end point was the conversion of postcardiac surgery AF or AFL to sinus rhythm within 90 minutes of dosing. In patients with AF, 47 of 100 (47%) who received vernakalant converted to SR compared with 7 of 50 (14%) patients who received placebo (P<0.001). The median time to conversion was 12 minutes. Vernakalant was not effective in converting postoperative AFL to sinus rhythm. Two serious adverse events occurred within 24 hours of vernakalant administration (hypotension and complete atrioventricular block). There were no cases of torsades de pointes, sustained ventricular tachycardia, or ventricular fibrillation. There were no deaths.. Vernakalant was safe and effective in the rapid conversion of AF to sinus rhythm in patients who had AF after cardiac surgery.. clinicaltrials.gov. Identifier: NCT00125320.

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Argentina; Atrial Fibrillation; Atrial Flutter; Coronary Artery Bypass; Double-Blind Method; Electrocardiography; Europe; Female; Heart Valve Prosthesis Implantation; Humans; India; Infusions, Intravenous; Male; Middle Aged; North America; Prospective Studies; Pyrrolidines; Time Factors; Treatment Outcome

Topics: Adult; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Female; Humans; Pyrrolidines; Treatment Outcome

Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.

Topics: Adult; Age Factors; Aged; Anisoles; Anti-Arrhythmia Agents; Area Under Curve; Atrial Fibrillation; Atrial Flutter; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Creatinine; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Female; Genotype; Humans; Injections, Intravenous; Male; Middle Aged; Models, Biological; Pyrrolidines; Randomized Controlled Trials as Topic; Time Factors; Young Adult

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Electric Countershock; Electrocardiography; Heart Conduction System; Humans; Male; Pyrrolidines; Sodium Channel Blockers