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RESTORE SR: Vanoxerine effective for AF, but harmful in certain patients
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A single oral dose of vanoxerine can restore normal sinus rhythm in patients with recent atrial fibrillation or atrial flutter, but it is associated with an increased risk for ventricular proarrhythmia in patients with structural heart disease, according to results from the RESTORE SR trial.
Jonathan P. Piccini, MD, MHS, FACC, FAHA, FHRS, and colleagues evaluated the efficacy and safety of a one-time oral dose of 400 mg vanoxerine (Laguna Pharmaceuticals) vs. placebo in converting patients after recent onset of AF or atrial flutter. Sixty-six percent of patients had underlying structural heart disease.
Jonathan P. Piccini
Piccini, from Duke Clinical Research Institute and Duke Heart Center, Duke University School of Medicine, and colleagues randomly assigned 41 patients 2:1 to vanoxerine (n = 26) or placebo (n = 15).
The primary efficacy outcome was the conversion from AF/atrial flutter to sinus rhythm or an atrial-paced rhythm within 24 hours of drug administration. The primary safety outcome was a composite of any of the following: death through day 8, ventricular fibrillation on ECG through 32 hours, ventricular tachycardia (VT) with heart rate greater than 120 bpm requiring intervention through 32 hours or torsades de pointes greater than 10 seconds on ECG through 32 hours.
Conversion to sinus rhythm occurred in 69% of the vanoxerine group and 20% of the placebo group (P = .0024). Patients in the placebo group did not experience any serious adverse events or polymorphic VT, but the trial was terminated after three patients with structural heart disease in the vanoxerine group experienced polymorphic VT events. Four patients in the vanoxerine group also experienced serious adverse events through day 8. There were no deaths at 30 days.
“The QT prolongation observed with vanoxerine led to a significant risk [for torsades de pointes]” and that risk “occurred despite the absence of proarrhythmia in both preclinical data and a phase 2 clinical trial,” the researchers wrote.
The possible reasons for an increased risk for proarrhythmia, according to Piccini and colleagues, are too high a dosage of vanoxerine, presence of additional risk factors and early afterdepolarizations.
“Another critical issue raised by this trial is how many early safety or proarrhythmic events are required to properly signal a problem with drug safety, particularly when events occur in patients who had either unrecognized contraindications to the protocol or additional risk factors that develop after randomization,” the researchers wrote. – by Tracey Romero
Disclosure: The study was funded by Laguna Pharmaceuticals. Piccini reports receiving grants from ARCA Biopharma, Boston Scientific, Gilead, Johnson & Johnson, ResMed, St. Jude Medical and Spectranetics; and consulting for Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Laguna Pharmaceuticals, Medtronic and Spectranetics. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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