Mixed Results With Rheos System, But Development Continues

April 08, 2011

April 8, 2011 (New Orleans, Louisiana) — Mixed results from a so-called "pivotal" trial of a new pacemakerlike device for the treatment of highly resistant hypertension, the Rheos system (CVRx, Minneapolis, MN), were reported at the American College of Cardiology (ACC) 2011 Scientific Sessions earlier this week. The study met three out of five end points, Dr John D Bisognano (University of Rochester, NY) told a featured clinical research session, explaining that more research will be needed but development of the product is continuing.

Dr John D Bisognano

"The data are very encouraging; this is a modality that will work, but I would anticipate further studies--which are ongoing in Europe and continuing in the US--to define which group of patients this benefits greatest," he said.

Last year, the future of the Rheos system appeared to be hanging in the balance when CVRx CEO Nadim Yared told heartwire the company was in discussion with the FDA regarding what the requirements would be for approval of such a device. This followed the withdrawal of a planned presentation at the ASH meeting last year on the first 55 patients from this pivotal trial.

At the ACC meeting, Bisognano stressed that the trial has not been changed in any way since last year: he explained that the first of the five end points--short-term acute response--was not significantly different in the active group from the control group, and it was this that prompted the withdrawal of the ASH presentation. "We just felt it was best to do our homework and look at the data before presenting it in a late-breaking trial."

How Does the Rheos System Compare With Renal Artery Denervation?

The Rheos system is "about the size of an iPod" and requires surgical implantation, with leads that electrically stimulate the carotid baroreceptors in the carotid sinus. It is implanted just below the clavicle and delivers four to six volts to the carotid arteries, mimicking the carotid baroreflex, which prompts a fall in blood pressure. The device is designed for use only in patients with resistant hypertension who continue to struggle to control their blood pressure despite being on maximal medical therapy of up to five antihypertensive drugs, Bisognano explained.

He was congratulated by panel members at ACC for completing what they said was a "complex" trial, whereby all of the patients were implanted with the device, but a third of them served as controls and did not have the system switched on for the first seven months.

When asked how the Rheos system compares with another new approach for the treatment of resistant hypertension, renal artery denervation therapy, a procedure for which exciting results were reported just six months ago at the AHA meeting, Bisognano observed: "It is great that the disease state of resistant hypertension is being viewed as the severe disease that it is." He agreed that the data "are certainly good on catheter-based renal artery denervation," but he pointed to the irreversible nature of that approach, contrasting it with the fact that the Rheos system "is a titratable device."

One panelist also applauded the inclusion of the control arm in the Rheos trial, noting that the renal artery denervation trial "did not have a sham procedure" as a control.

Pivotal Data; Response in Control Group Was Greater Than Expected

The Rheos system pivotal trial was prospective, randomized, and double-blind, with 265 patients who were randomized on a 2:1 basis from 49 sites. All patients had to have systolic BP of >160 mm Hg and/or diastolic BP >80 mm Hg, with 24-hour ambulatory BP monitoring (ABPM) readings of >135 mm HG and at least one month of maximally tolerated therapy with at least three appropriate antihypertensive medications, including a diuretic. The patients had a mean body-mass index (BMI) of 32 to 33, and they were taking an average of 5.2 antihypertensive therapies.

All patients were surgically implanted with the device, with group A, consisting of 181 patients, having the device turned on after one month. The remainder (n=84), group B, had the device implanted, but it was turned off for the first seven months. There were five co–primary end points: the short-term acute response six months after the device was turned on; the long-term sustained response; short-term procedural adverse events; short-term hypertension-therapy adverse events; and long-term device adverse events.

The first end point, short-term acute response, failed to reach significance in the on-treatment group, with 65% of patients in that group achieving the goal, a 10-mm-Hg reduction in systolic BP at six months, compared with 45% in the off-treatment group.

Bisognano said the "off" group had a much greater response than anticipated, as the trial design had assumed that only around 20% of these patients would achieve a 10-mm-Hg reduction. He noted that for the most part, primary-care doctors were continuing to titrate antihypertensive medications and that this could have played a role. It is also possible that there may have been some stimulation of the carotid baroreceptors during the surgery that could have contributed to the effect seen in the "off" group, he noted. The 24-hour ABPM readings are currently being analyzed, which might help provide a clearer picture of what happened, he said.

Short-Term Procedural Adverse Events Evident; Changes to Be Made

End point two, the long-term sustained response, did reach significance. However, only those in group A, the patients in whom the device was turned on a month after implantation, and not those in group B--in whom the device was turned on six months later--were assessed in this end point, Bisognano told heartwire .

He explained that this end point was calculated by starting with all those in group A who were responders, as defined by having a systolic BP that dropped at least 10 mm Hg from month 0. Then the systolic-BP change from month 0 to month 12 in these 97 subjects was examined to see whether they had maintained a systolic BP reduction that was at least 10 mm Hg and that the reduction at 12 months was at least 50% of the response observed at six months or the subject was at goal systolic BP (defined as <140 mm Hg or <130 mm Hg in subjects with diabetes or renal disease).  

"For example, if the reduction at six months was 30 mm Hg, then to be considered a sustained responder at 12 months the systolic-BP reduction would have to be at least 15 mm Hg or the patient had to be at goal pressure," he said. Of these 97 subjects, 88% met the criteria for long-term sustained response (p<0.001).

There were a number of adverse events relating to the surgical procedure to implant the Rheos system, and as a result, end-point three--short-term procedural adverse events--was not met. Overall, 75% of patients were free of procedural adverse events at 30 days, but the prespecified figure for this was 82%. In terms of adverse procedural events, 4.4% of patients had permanent nerve injury, 4.8% had transient nerve injury, 4.4% had general surgical complications, and 2.6% had respiratory complications. There were 76% of all adverse events fully resolved, Bisognano noted, with the explant rate with the device being "about the same as for pacemakers," he said. "There was no erosion of the arteries, and going into the study we were worried that we would injure the artery," he pointed out.

The other two end points--long-term device safety and short-term therapy safety--were met, and "the weight of overall evidence suggests the long-term efficacy of baroreflex activation therapy to reduce BP in resistant hypertension, and justifies further development," he said.

It may be helpful for such patients to be managed medically by a physician who frequently treats patients with resistant hypertension . . . before being considered for this therapy.

Asked by heartwire who would be the ideal recipient of this device, Bisognano said it would be patients with truly resistant hypertension who are not getting to their BP goal with standard drug therapy. "It may be helpful for such patients to be managed medically by a physician who frequently treats patients with resistant hypertension--cardiologist, nephrologist, hypertension expert--before being considered for this therapy," he added.  And "since there's evidence showing it decreases left ventricular hypertrophy, patients with LV hypertrophy may be good candidates as well."

Questions About Duration of Therapy and Spironolactone

Dr Prakash C Deedwania

Panel member Dr Prakash C Deedwania (University of California, Fresno) asked whether primary aldosteronism had been ruled out as a cause of resistant hypertension in the patients in the trial and about the use of spironolactone in the study and duration of therapy, because, he pointed, a number of antihypertensive therapies can take some time to exert their maximal effects.

Bisognano said that unfortunately spironolactone use was "lumped into the group on diuretics"--which made up over 90% of the study population--so it was difficult to be precise. "I think you make excellent points with regard to spironolactone and duration of therapy," Bisognano noted, while adding, "but given how new the device was, conceptually, in 2005, the patients really had a very good go at getting their resistant hypertension under control [before they enrolled in the trial]."

Moving forward, the size of the carotid sinus leads has been much reduced in a newer version of the device being implanted in trials in Europe, Bisognano noted, and the surgical technique, including duration of the procedure, "continues to improve." In addition, there will be tighter control of the number and type of antihypertensive drugs that are allowed to be taken concomitantly with the Rheos system, he said.

Bisognano has received consulting fees from CVRx.