Etripamil Nasal Spray Shows Promise for AF Patients With Rapid Ventricular Rate

A phase II study shows a rapid reduction in ventricular rate with few serious adverse events, paving the way for future studies.

Etripamil Nasal Spray Shows Promise for AF Patients With Rapid Ventricular Rate

PHILADELPHIA, PA—Etripamil nasal spray (Milestone Pharmaceuticals) appears to provide quick relief for patients with atrial fibrillation (AF) accompanied by a rapid ventricular rate, according to results from the phase II ReVeRA-201 study.

The mean maximum reduction in ventricular rate was greater with etripamil than with placebo (34.97 vs 5.06 bpm; P < 0.0001), Marco Alings, MD (Amphia Hospital, Breda, the Netherlands), reported here at the recent American Heart Association 2023 Scientific Sessions. Moreover, the median time to get to that point with active treatment was just 13 minutes.

That was accompanied by significant improvements in patient-reported symptom relief and satisfaction, he said. The most common adverse events were related to the site of drug administration, with a low rate of serious adverse events.

The results, published simultaneously online in Circulation: Arrhythmia and Electrophysiology, “indicate a potential role of etripamil in reducing ventricular rate in patients with atrial fibrillation with a high ventricular rate,” Alings said. Future investigation is warranted with at-home, self-administered etripamil.

The ReVeRA-201 Study

Etripamil is an L-type calcium channel blocker that has been formulated as a nasal spray for both rapid onset of action and a short-lasting plasma exposure, Alings said. It has been studied as a self-administered therapy for patients with paroxysmal supraventricular tachycardia, demonstrating rapid termination of the arrhythmia, reduced visits to the emergency department, and possibly fewer medical interventions.

In ReVeRA-201, conducted at 23 sites in Canada and the Netherlands, investigators tested the nasal spray’s effects in patients presenting to the emergency department with any type of AF accompanied by a rapid ventricular rate (≥ 110 bpm). Patients were randomized to etripamil or placebo, with the nasal sprays administered by medical staff.

The modified intention-to-treat cohort included 56 patients (mean age 64.6 years; 37.9% women) who received treatment and were included in the safety analyses. Efficacy analyses focused on 49 patients who remained in AF for at least 60 minutes after drug administration.

The primary endpoint was the mean maximum reduction in ventricular rate over the first 60 minutes after the spray was administered, and this was, on average, 29.91 bpm greater in the etripamil arm. The mean time from drug administration to the nadir ventricular rate was 12.1 minutes shorter with active treatment versus placebo.

Etripamil also resulted in greater proportions of patients who achieved a ventricular rate < 100 bpm (58.3% vs 4.0%), at least a 10% reduction in the rate (95.8% vs 20.0%), and at least a 20% reduction in the rate (66.7% vs 0; P < 0.0001 for all). The median time needed to get below 100 bpm was just 7 minutes.

The investigators also measured patient-reported outcomes using the Treatment Satisfaction Questionnaire for Medication-9, with etripamil-treated participants providing higher ratings of effectiveness (P < 0.0001) and global satisfaction (P = 0.0161) compared with those who received placebo. Ratings of convenience were not significantly different between groups (P = 0.1100).

On the individual question of symptom relief, patients treated with etripamil reported a higher rating (mean 4.63 vs 3.08 out of 7; P = 0.0002). A difference of 1 point is considered significant on this scale, Alings said.

As for safety, the most common treatment-emergent adverse events involved the site of drug administration and included higher rates of nasal discomfort (59.3% vs 37.9%) and rhinorrhea (33.3% vs 3.4%) in the etripamil group. There were two cases of bradyarrhythmia in the etripamil group and two cases of intracardiac thrombus in the placebo group.

There was one treatment-emergency serious adverse event in the etripamil group—transient severe bradycardia and syncope related to hypervagotonia in a patient with a history of vagal events, with no lasting consequences.

‘Addresses an Important Gap’

Sana Al-Khatib, MD (Duke University, Durham, NC), the discussant following Alings’ presentation, noted that AF can have a major impact on patients—including increased morbidity, worsened patient-reported outcomes, and greater healthcare utilization—particularly in the presence of a rapid ventricular response. Studies have shown that emergency department visits for AF increased over a recent 7-year period, a trend that has likely continued and carries economic implications, Al-Khatib added.

Thus, the current study “certainly addresses an important gap in care for our patients with atrial fibrillation and RVR [rapid ventricular rate],” she said. “It’s amazing to be able to self-administer a drug if you have A-fib with RVR and be able to avoid the need to go to the emergency room.”

The study has a strong design, with good representation of women, a solid effect size, and detailed information on safety, Al-Khatib said. But there are also some limitations, including a small sample size and the use of surrogate endpoints. Thus, there is a need to look at harder clinical endpoints, including healthcare utilization, she said. “We certainly need more data on larger cohorts, and hopefully future clinical studies can do that.”

In particular, Al-Khatib indicated that she’d like to know more about healthcare use associated with the side effects of treatment, questioning “whether we might be trading one reason for healthcare utilization for another if these side effects indeed led to a lot of clinic visits and ED visits.”

Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • The study was funded by Milestone Pharmaceuticals.
  • Alings reports honoraria and speaking/consulting fees from Sanofi and Milestone Pharmaceuticals.
  • Al-Khatib reports no relevant conflicts of interest.