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Angina Drug May Have Some Ventricular Antiarrhythmic Effects

— Trial failed overall but on-tx analysis indicates VT/VF prevention

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CHICAGO -- The angina drug ranolazine (Ranexa) did not help prevent ventricular arrhythmia events in high-risk implantable cardioverter-defibrillator (ICD) device patients in a randomized trial, but signals for benefit left some excited to use it anyway.

For the primary endpoint of ventricular tachyarrhythmia or fibrillation (VT/VF) or death, there were not significantly fewer events with ranolazine (34.1% versus 39.4% with placebo, HR 0.84, 95% CI 0.67-1.05), Wojciech Zareba, MD, PhD, director of Cardiology Clinical Research and the Heart Research Follow Up Program at the University of Rochester Medical Center in New York, reported here at the Heart Rhythm Society meeting.

But for certain secondary endpoints, the drug did appear to effectively reduce risk as follows:

  • VT requiring antitachycardia pacing (ATP, 18.0% vs 23.3%, HR 0.73, 95% CI 0.55-0.98)
  • Recurrent VT/VF requiring ATP or shock (HR 0.70, 95% CI 0.51-0.96)
  • Recurrent VT requiring ATP (HR 0.65, 95% CI 0.45-0.93)
  • Recurrent inappropriate ATP (HR 0.50, 95% CI 0.26-0.97)

Compliance was a problem, however: 40% of placebo patients and 50% of ranolazine patients stopped taking the study medication over the 28-month trial.

Accounting for that poor compliance in an on-treatment analysis, Zareba and colleagues found that the primary endpoint of VT/VF or death became statistically significant (21.6% versus 30.9%, HR 0.75, 95% CI 0.57-0.97) along with several secondary endpoints.

"Altogether we think we showed an antiarrhythmic effect," Zareba said at a press conference for the studies in the late-breaking clinical trial session.

"This is a population of patients where we are always looking for something else to treat them, and with a drug that has minimal bad effects and does seem to work in your analysis on-treatment, it's exciting," said the chair of the press conference, Andrea Russo, MD, director of the Electrophysiology and Arrhythmia Service of Cooper University Hospital in Camden, N.J.

Added the press conference's co-chair, Christine Albert, MD, PhD, director of the Center for Arrhythmia Prevention at Brigham and Women's Hospital in Boston: "It's true that the primary endpoint was not met, but I think this is very promising -- the fact that we have another drug that doesn't have a lot of toxicity like some of the other drugs we have. You have to put it in perspective of what was being tested.

"This isn't something where you are making a claim that it reduces mortality. It's in a patient population where we don't have a lot of options for suppressing arrhythmias. So having seen this data, I think we would as electrophysiologists possibly use ranolazine to suppress ventricular arrhythmias in patients having arrhythmias that can't be suppressed in some other way."

The drug had minor, expected side effects, Zareba reported, but no serious adverse events, and no impact on mortality or risk of cardiovascular or heart failure hospitalizations. The most common side effects with ranolazine were dizziness (8% versus 2% with placebo) and nausea (6% versus 1%).

"In prior trials, the drug reduced VT storm," added James Reiffel, MD, co-director of the Electrocardiography Lab at New York Presbyterian Hospital, Columbia University Medical Center, who has been involved in prior trials with ranolazine, but was not involved with this study. "It has been effective against atrial fibrillation. So this adds to the evidence suggesting ranolazine has antiarrhythmic effects and can be beneficial against selected arrhythmias in appropriately chosen patients free of toxicity. Ranolazine doesn't produce pro-arrhythmia. It doesn't produce organ toxicity. So it's an exciting drug to study."

Amiodarone (Cordarone, Nextarone, Pacerone) does have toxicity and has been shown to increase mortality, while ablation is not an option for all patients, Zareba noted.

His study included 1,020 ICD recipients (66% with primary prevention indication) randomized in a double-blind fashion to ranolazine, given at the 500-mg bid dose for 1 week and then increased to 1,000 mg bid) or placebo with 28 weeks of follow-up.

He added, though, that further randomized study is unlikely, because ranolazine goes off-patent in 2 years, which, while encouraging use clinically, makes the manufacturer less interested in developing further indications.

Disclosures

The trial was funded by the National Institutes of Health. Gilead provided the drug and placebo.

Reiffel disclosed relationships with Medtronic, Portola Pharmaceuticals, Boehringer Ingelheim, and Johnson & Johnson.

Primary Source

Heart Rhythm Society

Zareba W, et al "Ranolazine in high-risk ICD patients (RAID) trial" HRS 2017; Abstract C-LBCT02-01. Heart Rhythm 2017.