Ondansetron for the Management of Atrial Fibrillation

Inhibition of Small Conductance Calcium-Activated Potassium Current: A New Therapeutic Approach for Atrial Fibrillation

"Afib" is a common irregular heartbeat. Afib can cause stroke, blood clots, dementia and death. Medicines used to treat Afib often do not work well and can cause serious side effects. Clinicians need medicines that work better for Afib. Medicines for Afib work by blocking a current in the heart called a potassium current. There is a newer potassium current called IKas that can contribute to Afib. A medicine called ondansetron is used to keep people with cancer from getting sick to their stomach and throwing up. The investigators have found that ondansetron blocks IKas, and the investigators think that this means that ondansetron may work well to treat Afib. So, in this study the investigators want to find out if ondansetron can: 1) Stop Afib, 2) Reduce the amount of time that people have Afib, and 3) Slow down the heart rate when people have Afib. The investigators will study 80 people who come to the hospital to have a small electric shock to stop their Afib. These patients will be assigned by chance (like flipping a coin) to one of two groups: ondansetron 8 mg by mouth twice daily or a sugar pill (placebo). The people in the study will not know whether they are receiving ondansetron or placebo. The ondansetron or placebo will be started 2 days before the electric shock. The investigators will find out if ondansetron stops the Afib in the 2 days before their electric shock is scheduled. If ondansetron stops the Afib, those people will not need the electric shock. The other people in the study will get the electric shock to stop their Afib, but this does not work in everyone, and the Afib can quickly come back. So, after the first 2 days, all people in the study will stay on ondansetron or placebo for 28 more days. The investigators will find out if ondansetron reduces the percentage of time that people are in Afib. Also, in the 2 days before the electric shock and in the 28 days after, the investigators will find out if ondansetron slows the heart rate while people are having Afib. The investigators will compare the people in the study who take ondansetron with the people in the study who take placebo. This research will help the investigators to find out if ondansetron can be used as a medicine for people who have Afib.

Atrial fibrillation (AF) is a common arrhythmia associated with symptoms, stroke, systemic embolism, heart failure, dementia, and mortality. Guideline-recommended strategies for conversion to and maintenance of sinus rhythm (SR) and ventricular rate (VR) control are of limited efficacy and/or are poorly tolerated. There is a critical need for safer, more effective alternatives for AF drug therapy. The apamin-sensitive small-conductance calcium-activated potassium (SK) ion current (IKas) is important for repolarization in the atria and pulmonary vein muscle sleeves. IKas also contributes to sinoatrial and AV node electrophysiology. Therefore, IKas may be a target for rhythm and rate control in AF. Evidence suggests: 1) IKas plays an important role in the mechanism of AF, 2) The antiemetic agent ondansetron at therapeutic concentrations is a potent IKas inhibitor, and 3) Ondansetron is a cardiac-selective IKas inhibitor. Thus, the investigators hypothesize that ondansetron is effective for rhythm and rate control in patients with AF. Specific Aim 1: Determine the efficacy and safety of ondansetron for conversion of AF to SR. This aim will be achieved via a prospective, randomized, double-blind placebo-controlled study in patients with AF (n=80). Patients with persistent AF scheduled to undergo elective direct current cardioversion (DCC) will be randomized to oral ondansetron 8 mg twice daily (n=40) or matching placebo (n=40) for 2 days. ECG recording will be performed using adhesive skin patch ECG monitors, which provide 14-days of continuous recording. The primary outcome measure will be proportion of patients who are in SR prior to scheduled DCC. Successful pharmacological cardioversion will be defined as maintenance of SR for a minimum of 24 hours. Specific Aim 2: Determine the efficacy and safety of ondansetron for reducing AF burden. Patients who did not convert to SR on ondansetron/placebo will undergo DCC. Patients will remain in their originally randomized group for 28 days. Continuous ECG monitoring will be performed using successive 14-day adhesive skin patch ECG monitors. The primary outcome measure will be AF burden (percentage of time in AF). Specific Aim 3: Determine the efficacy and safety of ondansetron for VR control in AF. The effect of ondansetron versus placebo on VR control will be assessed in both phases of the study. Primary outcome measures will be mean daily heart rates on the 2 days prior to and on days 7, 14, 21 and 28 days post-AF conversion.

Patients with atrial fibrillation scheduled for electrical conversion to sinus rhythm will receive treatment with ondansetron 8 mg orally twice daily for 31 days (n=40)

Patients with atrial fibrillation scheduled for electrical conversion to sinus rhythm will receive treatment with matching placebo orally twice daily for 31 days (n=40)

Proportion of patients who are in sinus rhythm prior to scheduled electrical cardioversion. Successful cardioversion will be defined as maintenance of sinus rhythm for a minimum of 24 hours

Inclusion Criteria: Men and women 18-100 years of age Persistent ECG-verified AF requiring elective conversion to SR Receiving guideline-recommended anticoagulation (if CHA2DS2-VASc score is 0 (men) or 1 (women), anticoagulation can be omitted) Exclusion Criteria: Women of childbearing potential Subject reported syncope of unknown origin within the previous 6 months Diagnosis of active thyrotoxicosis Diagnosis AF from reversible noncardiac causes Diagnosis of acutely decompensated heart failure Left ventricular ejection fraction less than or equal to 20% New York Heart Association class IV heart failure Diagnosis if severe liver disease (Child-Pugh score greater than or equal to 10) Cardiac surgery (preceding 2 months) Not receiving anticoagulation due to contraindications (as determined by treating physician and recorded in the medical record) Pretreatment QRS > 180 ms, QTc > 450 ms within two weeks of screening visit Heart rate < 50 beats per minute in SR Diagnosis of hypotension Diagnosis of Wolff-Parkinson-White syndrome Previous ondansetron hypersensitivity or serotonin syndrome Diagnosis of phenylketonuria Diagnosis of congenital long QT syndrome Concomitant therapy with both beta-blockers and a nondihydropyridine CCB History of drug-induced TdP or QTc prolongation Concomitant therapy with QTc-prolonging medications (www.crediblemeds.org) Concomitant therapy with serotonergic drugs (selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, mirtazapine, lithium, tramadol), apomorphine, phenytoin, carbamazepine, oxcarbazepine, rifampin. Patients with pre-existing allergies to adhesives Patients with neuromuscular stimulators

Data will become available upon publication of study results in clinical trials.gov. Data will be available indefinitely