MODERATO II: Pacemaker-based Therapy Tamps Down Hypertension

Patrice Wendling

October 01, 2019

SAN FRANCISCO — Pilot data look promising for a pacemaker-mediated cardiac neuromodulation therapy (CNT) in patients requiring a pacemaker with persistent hypertension, despite an average of three antihypertensive drugs.

The MODERATO II study met its primary end point, reducing 24-hour ambulatory systolic pressure by an average of 8.1 mm Hg at 6 months with BackBeat CNT (Orchestra BioMed) plus medical therapy, compared with standard pacing-alone plus medical therapy (= .01).

Karl-Heinz Kuck (Credit: Fredy Perojo/Medscape)

In presenting the late-breaking results at Transcatheter Cardiovascular Therapeutics 2019, study author Karl-Heinz Kuck, MD, PhD, Asklepios Klinik St. Georg, Hamburg, Germany, observed that more than 70% of patients with a pacemaker have hypertension and 60% of these have uncontrolled hypertension despite medical treatment.

BackBeat CNT is delivered via Moderato, an implantable pulse generator that provides standard pacing and recently received CE mark approval. The therapy reduces BP by targeting preload with an ultrashort atrioventricular (AV) delay and using neuromodulation to maintain the effect by afterload reduction, he said.

In the single-arm MODERATO I study, BackBeat CNT reduced 24-hour ambulatory systolic by 10.1 mm Hg among 27 patients, with the effect maintained for up to 2 years, observed Kuck.

Double-Blind Data

The present study enrolled 68 patients who required a dual-chamber pacemaker and had an average daytime ambulatory systolic pressure of at least 130 mm Hg and an office systolic pressure of at least 140 mm Hg while being treated with at least one antihypertensive (mean, 3.3). Exclusion criteria included atrial fibrillation, left ventricular ejection fraction less than 50%, and symptoms of class 2 or higher heart failure.

A total of 47 patients implanted with the Moderator were randomly assigned to double-blind activation of CMT or continued medical therapy alone if they had an ambulatory daytime systolic pressure of at least 125 mm Hg at week 3 of a 30-day run-in phase, during which the BackBeat algorithm remained off to reduce a placebo effect. One patient died before 6-month follow-up, leaving 26 patients in the BackBeat CNT group and 20 control subjects.

The population was elderly (mean age, about 74 years) and roughly half had coronary artery disease or diabetes. Isolated systolic hypertension was present in 88.5% of BackBeat patients and 71.4% of control subjects; 24-hour ambulatory diastolic pressure was normal at 74.0 mm Hg and 72.6 mm Hg, respectively.

From week 3 of the run-in to 6 months after randomization, the primary end point of ambulatory systolic pressure dropped 11.1 mm Hg in the BackBeat group (from 136.3 to 125.2 mm Hg; P <.001) and by 3.1 mm Hg in the control group (from 136.3 to 132.0 mm Hg; P = .17). As noted above, the between-group difference was significant.

The primary safety end point of major adverse cardiac events through 6 months was also met (0 vs 2 events).

On day 1 after randomization, there was an "instantaneous reduction" in blood pressure of 15.6 mm Hg with BackBeat CNT that was maintained through 6 months (–11.1 mm Hg), Kuck said.

Office systolic pressure also showed a significant difference between the two groups from week 4 of the run-in through 6 months, favoring BackBeat CNT (–12.3 mm Hg; P = .02). The results will be used to inform the pivotal trial, he said.

A "Sophisticated Pacing Mode"

"Those of us who have been doing renal denervation have excluded those sorts of patients because of a feeling that perhaps older people with isolated systolic hypertension don't have much sympathetic drive," discussant Michael Weber, MD, State University of New York Downstate College of Medicine, Brooklyn, said. "I think that's a mistake and we are going to remedy that. What I've learned from you today is encouraging."

Weber went on to question whether the device reduced peripheral resistance and sympathetic activity.

"The pacing mode is very sophisticated," Kuck replied. "The initial reduction in filling is caused by the ultrashort AV delay, which is ranging between 20 and 60 ms. This leads to an instantaneous drop of blood pressure. This, of course, activates the baroreflex and it would immediately let the blood pressure return by activation of the sympathetic nervous system and increase of the peripheral resistance."

"So we trick the baroreflex by the fact that after a sequence of eight to 10 beats with a short AV interval, we allow longer three to four beats with a longer PR interval or even normal conduction," he added. "As we know, the baroreflex has an asymmetrical response to the blood pressure lowering and decrease. If the blood pressure is lowered, you have a slow response of the baroreflex, but if the blood pressure increases, you have a rapid response of the baroreflex. And that rapid response lets the baroreflex believe the blood pressure is normal for those three beats and it doesn't activate the baroreflex."

A Growing Niche

Speaking to theheart.org | Medscape Cardiology, Weber said the study numbers were small and that a lot of patients were taking only one or two drugs and probably could have had their hypertension better treated.

"What they were benefiting from the pacemaker was nice, but not really something they necessarily needed," he remarked. "But that said, there are plenty of older people who need a pacemaker who've got isolated systolic hypertension where it's quite difficult to get control of their blood pressure. So what we've seen with this new device is actually very, very interesting because it may be the best way to get their blood pressure down to a safe level."

Study author Daniel Burkhoff, MD, PhD, Cardiovascular Research Foundation, Orangeburg, New York, agreed the study was small but also pointed out that despite physicians being advised not to change antihypertensive therapy, 23.8% of control subjects and 7.7% of BackBeat patients had their medications increased during the study.

"I think what you see in the first 24 hours is really the true magnitude of the effect because there's no interference from medications because you saw in the control group, over that period of time, there were many more times when the physicians increased their medications, compared to in the treatment group," he told theheart.org | Medscape Cardiology.

Because patients already had a pacemaker indication, Burkhoff said there are no added costs, either financial or in terms of safety, whereas using renal denervation to further reduce hypertension would require an additional procedure.

"The charm of the BackBeat is that if you have a situation where a patient happens to need a pacemaker and you're going to have to do it anyway, there's no reason to have to do renal denervation and you're going to get a very nice 10 to 12 mm Hg reduction from the BackBeat," he said. "I think that's where it's going to fit in very well."

The study was sponsored by BackBeat Medical/Orchestra BioMed. Kuck reported having no relevant industry relationships.

Transcatheter Cardiovascular Therapeutics (TCT) 2019. Presented September 28, 2019.

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, join us on Twitter and Facebook.

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