Pulmonary artery denervation (PADN) provides persistent and clinically significant hemodynamic improvements in patients with persistent chronic thromboembolic hypertension (CTEPH) after pulmonary endarterectomy (PEA), according to a randomized, sham-controlled trial.
“PADN in patients with CTEPH after PEA was safe and effective,” according to an investigating team led by Alexander Romanov, MD, PhD.
The mean reduction in pulmonary vascular resistance (PVR) was 258 dyn/sec per cm–5 for those randomized to PADN versus 149 dyn/sec per cm–5 (P = .001) for those randomized to the sham procedure, according to the newly published findings.
For the 6-minute walk test (6MWT), the mean distance was 470 m for the experimental group versus 399 m (P = .03) for the controls.
Several secondary endpoints measuring hemodynamics also favored PADN relative to the sham procedure at 12 months. This included the relative increase in tricuspid annular systolic excursion (P = .03) and the increase in the right ventricular fraction area (P < .001).
A total of 50 patients with residual CTEPH for at least 6 months after PEA despite medical therapy were enrolled and randomized. Entry criteria included a mean pulmonary artery pressure (PAP) of 25 mm Hg or greater or PVR greater than 400 dyn/sec per cm–5 on right heart catheterization. Patients with comorbidities associated with a life expectancy of less than 1 year were excluded.
Those randomized to the sham group were treated with riociguat over the course of follow-up. This therapy was not offered to patients in the PADN group, but all patients were blinded to the procedure and told that riociguat might or might not be administered.
Following the procedure, participating clinicians, who were also blinded to the procedure, were instructed to provide standard therapies for heart failure, such beta-blockers, diuretics, or digoxin, as needed. All patients were placed on an oral anticoagulant.
At 12 months the mean PAP (26 vs. 35 mm Hg; P < .001) and the mean systolic PAP (46 vs. 54 mm Hg; P = .01) were significantly lower in the PADN group versus those who underwent a sham procedure.
About 52% of the PADN group versus 12% of the sham group were classified as responders by the definition of a PVR reduction of at least 150 dyn/sec per cm–5 and 6MWT improvement of at least 20%, compared with baseline, reported Dr. Romanov, of the E. Meshalkin National Medical Research Center, ministry of health, Novosibirsk, Russia, and coinvestigators.
Of the three deaths caused by heart failure over the course of follow-up, two occurred in the sham group. Of the eight hospitalizations for heart failure, seven (29% of the sham group) occurred among controls versus one in those treated with PADN (4% of this group; P = .049).
There was one groin hematoma at the puncture site in each group. Both resolved without any consequences prior to hospital discharge. There were no other significant procedure-related complications in either group.
Larger multicenter trials are needed to confirm these findings, according to both the trial investigators and, who is charge of the pulmonary hypertension program at the Hannover (Germany) Medical School.
In an editorial that accompanied publication of these findings, Dr. Hoeper identified the small sample size of this study as one of its limitations, but he said the results are consistent with several other small studies associating pulmonary artery denervation with benefit in pulmonary hypertension.
“It appears as if we are currently witnessing the emergence of a new treatment option for various forms of pulmonary hypertension,” Dr. Hoeper wrote. In his critique of the study, he suggested that it would have been “more informative” if both groups were on background riociguat, but the data from this and other studies so far indicates that ablation to achieve denervation “is safe and feasible.”
The PADN technique used in this study might be relevant to the results. Dr. Hoeper noted that the investigators employed catheter tip–based electroanatomic mapping with a novel remote navigation system with three-dimensional imaging of the right ventricle and central pulmonary arteries.
“Apparently, this approach minimizes radiation exposure and provides precise location of ablation sites,” Dr. Hoeper observed. However, he called for direct comparisons of this tool to the guidance systems used in other studies.
In an interview, Dr. Hoeper acknowledged that it is not yet clear that a large-scale trial of pulmonary artery denervation for the indication evaluated in this study is coming. He noted several strategies in CTEPH are widely used without trials confirming a reduction in clinical events.
“Balloon pulmonary angioplasty for CTEPH has become an established treatment around the world without any randomized, controlled trial and without demonstration of improved outcomes. A couple of well-conducted observational trials might be sufficient to convince physicians to introduce PADN as well,” he said. If such studies associated PADN with “improvements in hemodynamics, exercise capacity, and patient-reported outcomes, it might be sufficient.”
Currently, Dr. Hoeper is most concerned about obtaining further evidence of safety, which he characterized as a “major issue.”
If a multicenter trial is conducted “the primary endpoint should be focused on clinical events,” according to Dr. Romanov, who was asked to comment on the next steps in validating PADN for the treatment of CTEPH-associated pulmonary hypertension persisting after endarterectomy.
“The mortality rate during 1-year long-term follow-up is not so high, but heart failure progression is a problem. So in my view, the primary endpoint should be a composite of death and heart failure hospitalization,” he said. He called for follow-up duration of 2-3 years.
Jonathan Steinberg, MD, director of cardiac clinical trials and education, Summit Medical Group, Montclair, N.J., also called a trial with hard endpoints, such as death, the ideal.
In the meantime, hemodynamic and functional measures “are still quite valuable and move the ball forward for this intervention,” he said in an interview. Senior author of this trial and principle investigator of the recent ERADICATE-AF trial, which evaluated renal denervation in preventing recurrence of atrial fibrillation (), Dr. Steinberg predicted, “I do indeed suspect we will see trials that are more accomplishable [than a large-scale, randomized, controlled trial] in the not too distant future.”
Dr. Romanov received funding from Biosense Webster. Dr. Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, Janssen, Merck Sharp & Dohme, and Pfizer.
SOURCE: Romanov A et al. .