麻豆传媒

CHICAGO -- The novel intranasal agent etripamil was safe and rapidly converted most patients with paroxysmal supraventricular tachycardia (PSVT) back into normal rhythm, the phase II NODE-1 trial showed.

The higher doses tested -- 70, 105, and 140 mg -- hit the primary endpoint of conversion of PSVT within 15 minutes in significantly more patients awaiting ablation than did placebo (87%, 75%, and 95% versus 35%, respectively, all P<0.05), with an average time to conversion around 3 minutes.

The drug, a calcium channel blocker, was well tolerated with an "acceptable safety profile," Bruce Stambler, MD, of the Piedmont Heart Institute in Atlanta, reported here at a late-breaking clinical trials session at the Heart Rhythm Society (HRS) meeting.

Adverse events in the 104-patient, randomized, dose-ranging trial typically related to the intranasal administration route, with up to 45% of patients reporting nasal congestion and up to 17% reporting cough with etripamil, which was severe in one patient (the only serious adverse event related to the drug). Stambler noted that these events became less common after patients were told to keep their chins down during administration.

Cardiac adverse events included AV block in one patient, which resolved 43 minutes after administration, and symptomatic hypotension (65/57 mm Hg) in one patient, which resolved 26 minutes after dosing.

Systolic blood pressure dipped transiently with the 105 mg dose of etripamil and less transiently with the highest, 140 mg dose.

Because of this, 70 mg appeared to be the "sweet spot" that would be studied further, Stambler said. The next step, he said, should be a "real world" trial of patient self-administration to terminate PSVT -- and just such a phase III trial is being finalized, with the plan being to allow patients to try vagal maneuvers to try to terminate the arrhythmia before use of the drug or placebo.

"Patients, when they have these episodes, can be anywhere -- they can be on an airplane, they can be at work, they can be asleep," Stambler noted. If vagal maneuvers don't work, the available options are highly effective, but "inconvenient," and they increase healthcare utilization. "This is a potential new therapy that patients could use at home on an as-needed basis or anywhere in their environment. They could potentially carry it with them."

Electrophysiologists at the conference described the proof-of-concept findings as exciting, because treatment has typically required an urgent care or emergency department visit for IV drugs or, as a permanent fix, ablation.

"It has been a long time since we're seeing any new medications come on board," the session's co-chair, Jeanne Poole, MD, of the University of Washington in Seattle, said at a press conference at which the study was discussed. "This could be useful for these patients, so I am excited about these results. I think it could be a game changer" if confirmed.

For patients with recurrent PSVT, "every patient is a little different in how ready they feel to have an ablation," commented Matthew Reynolds, MD, of Lahey Hospital and Medical Center in Burlington, Mass. "Some patients have SVT, it's infrequent, they don't want to have an invasive procedure, but they still could use some way to reliably abort the episodes once they get going. It beats coming to the emergency room."

While more data is clearly needed, and clinical availability would still be some time off, an agent like this might help prevent hospitalization for patients with infrequent spells or who decide against ablation, HRS Vice-President Thomas Deering, MD, said at the press conference. "I think it has a potentially very strong impact to change the way in which things are done."

"We think of this as a fixable problem," noted the session's co-chair, Andrew Krahn, MD, of the University of British Columbia in Vancouver. "Here's the disruptive way of thinking of this: Imagine SVT is like migraine. When you get a migraine, you take your shot. So instead of a fixable problem, it's a manageable problem with a home remedy ... There may be an element of this population, particularly if they get SVT later in life, who would rather use a medical approach to this once or twice a year than undergo an invasive procedure."

But, Poole noted, the two treatment approaches would not have to be mutually exclusive. "This could be something that was offered to patients while they are waiting for a definitive procedure."

Notably, patients with ventricular pre-excitation (Wolff-Parkinson-White pattern on the ECG) were excluded from the trial, and it would be important to rule out such patients before use of the drug, if it were eventually approved, Stambler said.

"We know, as this is an L-type calcium channel blocker, that there are reports of verapamil [another calcium channel blocker] given to patients with PSVT causing very serious rhythm disturbance -- i.e., ventricular fibrillation," he said at the session. "It will be important, in my judgment, to exclude those patients and make sure that patients have documented narrow complex tachycardia first, no pre-excitation. I think patients in the phase III trial will likely need some kind of event monitor so that we can further understand this compound outside the hospital environment."

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