Ranolazine, Dronedarone Combo Calms Paroxysmal AF in HARMONY

May 12, 2014

SAN FRANCISCO, CA — Researchers presenting new findings on a potential fixed-dose drug combination for a common arrhythmia allowed themselves a good measure of optimism, perhaps an indulgence given the study's limited size and phase 2 nature. But in the small placebo-controlled study called HARMONY , nascent enough to still be exploring optimal dosage levels, the combination of ranolazine (Ranexa, Gilead Sciences) and dronedarone (Multaq, Sanofi) appeared to lower the burden of atrial fibrillation (AF) by >70% over three months in 45% to 60% of patients with the paroxysmal form of the arrhythmia[1]. The apparent benefit was precisely documented in the trial; all of its 134 mostly low-risk patients had dual-chamber pacemakers with electrogram storage capability.

"I think that HARMONY achieved its goal of demonstrating a clear efficacy [of ranolazine/dronedarone] superior to placebo or to either component of the combination when used alone," said Dr Peter R Kowey (Lankenau Medical Center and Institute for Medical Research, Wynnewood, PA), concluding his presentation of the trial here at the Heart Rhythm Society (HRS) 2014 Scientific Sessions . "So it's with a good deal of pleasure that I'm able to stand up here today and finally deliver some good news about the efficacy and safety of antiarrhythmic therapy in patients with atrial fibrillation."

Dr Charles Antzelevitch (Masonic Medical Research Laboratory, Utica, NY) summed up the root of the excitement: "Of the drugs that we have available today [for AF], those that are safe are not very effective, and those that are effective are not very safe." Antzelevitch, a specialist in electrophysiologic pharmacology, is credited with conceiving the idea to combine ranolazine and dronedarone based on indications that they may have complementary effects on some arrhythmia mechanisms, although he didn't have direct involvement in HARMONY. "So this will be the first time that we'll have safe and effective drugs for the management of atrial fibrillation, if it's all borne out," he said to heartwire .

Currently ranolazine is approved for chronic angina but is recently appreciated to have some antiarrhythmic effects; dronedarone is approved for arrhythmias. Both are blockers of multiple ion channels.

But, Kowey observed, "It has been our impression that neither of these drugs as monotherapy have been terribly effective for the [arrhythmia] indication. I think no one in this audience would disagree that we have been somewhat disappointed with the overall efficacy of dronedarone in real clinical practice. And in addition, there have been a number of safety concerns raised with regard to the use of dronedarone." Those issues may be related to its calcium-channel–blocking action and negative inotropic effects at conventional antiarrhythmic dosages.

The trick in avoiding those effects in HARMONY, Antzelevitch said, was to use a dronedarone dosage lower than the threshold required to block the calcium channel. That may allow another of its effects, inhibition of the sodium channel in its inactivated state, to safely complement ranolazine's blockage of the activated-state sodium channel. The hypothesis was that "hitting the sodium channel at both ends would provide a synergistic effect on the sodium-dependent parameters in the atria." The study's results, he said, are consistent with mechanism working as predicted.

HARMONY's 134 patients with paroxysmal AF (burden from 2% to 70% during a four-week run-in period) and no other antiarrhythmic use were randomized in the US, Israel, and four European countries to one of five arms that included twice-daily treatment with one of two ranolazine/dronedarone combinations, either drug by itself, or placebo.

Over 12 weeks, the AF burden fell by 45% (p=0.072) for the 26 patients on the ranolazine 750 mg/dronedarone 150 mg regimen, compared with the 26 patients on placebo; 27% of the group achieved an AF-burden reduction of at least 70%.

The AF burden went down 59% (p=0.008) for the 27 patients who took ranolazine 750/dronedarone 225 mg; 45% of them achieved reductions of at least 70%.

Neither ranolazine 750 mg alone (n=26) nor dronedarone 225 mg alone (n=26) were associated with significant reductions in AF burden: only 17% and 9%, respectively, compared with placebo.

Adverse-Event Rates by Regimen in HARMONY (No Significant Differences Between Groups by End Point)

End points Placebo (%) Ranolazine 750 twice daily (%) Dronedarone 225 mg twice daily (%) Ranolazine 750/Dronedarone 150 twice daily (%) Ranolazine 750/ Dronedarone 225 twice daily (%)
Adverse events 58 65 69 61 74
Adverse events* leading to treatment discontinuation 11 19 15 19 18
*Most common adverse events leading to discontinuation: atrial fibrillation, vertigo and dizziness, dyspnea and pruritus, and hypotension

In the ATHENA and PALLAS trials, both of which highlighted safety issues with dronedarone, it was given at 400 mg twice daily.

Kowey pointed out that not only do the HARMONY results reflect efficacy in suppressing AF for the drug combination, with neither drug alone performing as well, they show a dose-response effect for dronedarone.

"Our plans are to embark on a phase 3 trial experience that will consist of two large trials, one using time to [AF] recurrence and the other an outcomes trial using CV hospitalization or CV death as primary end points," Kowey said, adding the trials will include patients "at substantially higher cardiovascular risk."

Kowey discloses being a paid consultant to Gilead "on an ad hoc basis for several years for this and other projects," that he has no "retainer agreement" with Gilead, and that he does not own stock in Gilead or any other pharmaceutical company. Antzelevitch has previously disclosed consulting for and receiving research support from Gilead Sciences and AstraZeneca and to receiving research support from Cardiome and Merck.

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