Pulmonary artery denervation (PADN) plus a phosphodiesterase-5 inhibitor improved exercise capacity, cardiac function, and some clinical outcomes in patients with pulmonary arterial hypertension (PAH) in a sham-controlled trial.
The primary outcome of change from baseline in 6-minute walk distance increased in both groups at 30 days, with a median change at 6 months of 61 meters with denervation and 18 meters with sham treatment (P = .04).
The adjusted between-group mean difference was 33.8 meters favoring PADN (95% CI, 16.7 – 50.9; P < .001).
Walk distances did not improve in patients at low risk based on REVEAL scores, whereas intermediate- to high-risk patients had “an extremely high increase” of 81.4 meters vs 32.5 meters with sham treatment (P = .007), principal investigator Shao-Liang Chen, MD, reported in a late-breaking session at Transcatheter Cardiovascular Therapeutics (TCT) 2022.
There were no procedural complications in either group. Chest pain was more common in the PADN group but was mild and did not require analgesia.
“Treatment with PADN plus a PDE-5 inhibitor is very safe and significantly improves exercise capacity at 6 months compared with a sham treatment,” said Chen, of Nanjing First Hospital, Nanjing Medical University, China.
Previous observational studies, including TROPHY 1, have shown that denervation of the pulmonary artery improves hemodynamic and exercise capacity in patients with PAH, but its efficacy and safety have not been studied in a randomized trial, he noted.
The present trial, known as PADN-CFDA, was conducted at 11 centers in China between January 2018 and June 2021. Researchers enrolled 128 patients (mean age, 40.8 years) with World Health Organization group 1 PAH not taking any PAH-specific drugs for at least 30 days before randomization and assigned them to receive PADN or a sham procedure, plus either postprocedure sildenafil, 25 mg thrice daily, or tadalafil, 20 to 40 mg daily.
Denervation was performed at three sites at the conjunctional area between the distal main trunk and the ostial left branch for 120 seconds at 45 to 50 °C and 15 W or less. Chen invented the PADN catheter (Pulnovo Medical) but is not the patent holder.
At baseline, the mean 6-minute walk distance was 401 meters, mean pulmonary arterial pressure was 53.9 mm Hg, mean pulmonary vascular resistance was 10.9 Wood units, and mean N-terminal pro-brain natriuretic peptide (NT-proBNP) level was 2345 pg/mL.
As reported simultaneously in JACC: Clinical Interventions, PADN led to greater reductions at 6 months in NT-proBNP levels (–58.5% vs –25.2%; P = .018) and pulmonary vascular resistance (PVR) (–27% vs –14.8%; P = .003).
Cardiac function improved to a greater degree in the PADN than in the sham group, including right atrial pressure (–1.7 mm Hg vs 0.4 mm Hg) and right ventricular fractional area change (10.4% vs –0.6%) but, particularly, tricuspid annular plane systolic excursion (4.3 mm vs –0.1 mm) and right ventricular global longitudinal strain (–2.9% vs –0.1%,), Chen observed.
Mean pulmonary arterial pressure at 6 months was –7.8 mm Hg vs –3.5 mm Hg, respectively.
During follow-up, clinical worsening — defined as worsening pulmonary arterial hypertension, arterial septostomy, listing for lung transplantation, or all-cause death — occurred in one PADN patient and nine controls (hazard ratio, 0.11; 95% CI, 0.01 – 0.87).
Invited discussant, Ori Ben-Yuhuda, MD, Cardiovascular Research Foundation, New York City, asked how patients were blinded, particularly because the procedure was associated with some pain, and whether longer-term follow-up is planned.
“In the TROPHY study, we did see some decrease in efficacy using an ultrasound-based catheter after 6 months. So, this is an important long-term issue,” he said.
Chen reported that a blinding questionnaire showed 96.8% of PADN-treated and 95.4% of sham-treated patients believed they received active treatment, and said 12-month follow-up is very important, as are larger trials with clinical outcomes as the primary endpoint.
Asked during an earlier press conference why they chose not to enroll patients already receiving PAH medication, Chen said PAH is managed differently in China than in western countries and that conducting the trial during the COVID pandemic created challenges.
Commenting on the results, Riyaz Bashir, MD, director of vascular and endovascular medicine, Temple Heart & Vascular Institute, Philadelphia, Pennsylvania, told theheart.org | Medscape Cardiology the study is small but important because all patients started with a clean slate, off medication, and they saw a 33-meter difference in 6-minute walk distance.
“There are lots of challenges with walk tests,” he acknowledged. “Future trials should use, as the primary endpoint, an objective hemodynamic endpoint, which they had — PVR — and then combine that with clinical endpoints.”
Nevertheless, the study “helps us move the path forward because it is data we can trust, as opposed to registry data,” Bashir said. “What it’s telling us is that there’s a signal of benefit for the principle of denervation, but we need to develop better devices, use better devices, and use better endpoints.”
Pulnovo Medical announced in July that it is seeking U.S. Food and Drug Administration approval to begin the PADN Global Clinical Trial, similar to the present study in design and with current coauthor Gregg Stone, MD, as chair of the steering committee.
Also commenting for theheart.org | Medscape Cardiology, Dipti Itchhaporia, MD, immediate past president of the American College of Cardiology and an interventional cardiologist with Hoag Heart & Vascular Institute, Newport Beach, California, said, “It’s a provocative study, well-done, sham controlled, small, but larger trials are needed” for these often very sick patients.
“They only did one drug, and these sick patients sometimes benefit from multiple therapies, so the question is, What’s the best population?” she said.
Itchhaporia also pointed out that multiple drugs can be costly, difficult to obtain in some countries, and often hard to adhere to long-term. “All of those things are issues and that’s where a therapy like this may seem like a good alternative, particularly because sometimes people don’t feel good with those drugs.”
The study received grants from the National Scientific Foundation of China and was funded by the Nanjing First Hospital. Pulnovo provided all PADN catheters. Chen has received speaker honoraria from Microport, Pulnovo, Boston International Scientific, Medtronic, Sanofi, and BioMed and grants from the National Scientific Foundation of China. Coauthor Gregg Stone, MD, has multiple relationships with industry. Itchhaporia reports having no relevant disclosures.
JACC Cardiovasc Interv. Published online September 18, 2022. Abstract