PADN-5: Ablation Reduces Pulmonary Hypertension in HF

Neil Osterweil

September 24, 2018

SAN DIEGO — Patients with combined pre- and postcapillary pulmonary hypertension (CpcPH) secondary to left-sided heart failure (HF) who underwent a pulmonary artery denervation (PADN) procedure had significant improvements in hemodynamic and clinical outcomes at 6 months, compared with patients who underwent a sham procedure, in the PADN-5 trial.

Among 98 patients with CpcPH assigned to receive either pulmonary denervation or sildenafil plus a sham procedure, PADN was associated with significantly better 6-minute walk distance and significantly lower pulmonary vascular resistance at 6 months, reported Shao-Liang Chen, MD, Nanjing Medical University, China.

The benefits of PADN were seen in patients with both ejection-fraction preserved HF and ejection-fraction reduced HF, he said here at Transcatheter Cardiovascular Therapeutics 2018.

The study was published online September 23 in JACC: Cardiovascular Interventions to coincide with the presentation.

But one clinical trials specialist questioned whether the patients in the trial — especially men — could truly be unaware of their treatment assignment, considering that sham-operated controls received sildenafil, which is approved for the treatment of erectile dysfunction.

"What's the point of doing a sham control if you're then unblinding the patients by giving them sildenafil?" said Ori Ben-Yehuda, MD, Cardiovascular Research Foundation, New York City, who moderated a briefing during which Chen presented the data prior to a late-breaking oral abstract session.

"I don't know how many men were in that study, but I think that in that age group, they might know whether they were taking what is essentially Viagra," he said in an interview with | Medscape Cardiology.

The investigators hypothesized that pulmonary artery denervation targets overactivation of sympathetic nerves in patients with HF and pulmonary hypertension.

In PADN5, investigators randomly assigned 98 patients — 60 men and 38 women with a mean age of 63 years — with CpcPH to receive anti-HF therapies (including calcium-channel blockers, β-adrenergic receptor blockers, digoxin, diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers) plus either sildenafil and a sham procedure or PADN.

Patients in the sham group were given open-label sildenafil, but those in the PADN group did not receive a sildenafil placebo, Chen said.

The investigators decided to use sildenafil because results from a meta-analysis previously demonstrated the beneficial effects of the drug in patients with pulmonary artery hypertension. However, in international treatment guidelines, neither sildenafil nor other therapies for pulmonary artery hypertension are recommended for patients with CpcPH, he acknowledged.

CpcPH was defined as a mean pulmonary arterial pressure of at least 25 mm Hg, pulmonary capillary wedge pressure above 15 mm Hg, and pulmonary vascular resistance above 3.0 Wood units.

PADN was performed in the peri-conjunctional area between the distal main trunk and the ostial left branch, with ablation at each point performed at temperatures of at least 45°C and energy of 20 watts or less over 120 seconds. Hemodynamic parameters were continuously monitored and recorded throughout the procedure.

For the sham procedure, the ablation catheter was positioned at the target sites and connected to a generator but ablation was not performed.

"To simulate the true PADN procedure, discussions among the operator, technician, and nurses, as well as beep sounds from the generator, were recorded on a cell phone from a previous PADN procedure. This recording was played during the sham procedure, leading the patient to believe that a PADN procedure was being performed," the investigators write in the study publication.

At 6 months, 6-minute walk distance, the primary end point, increased by a mean of 83 meters in the PADN group, compared with 15 in the sham group (P < .001).

A total of 12 patients in the sham group and six in the PADN group had reduction in 6-minute walk distance at 6 months, including seven patients with a decline of more than 15% in walk distance in the sham group, compared with 3% in the PADN group (hazard ratio, 2.947; 95% confidence interval, 1.152 - 4.501).

Patients who underwent the actual PADN ablation had significantly lower 6-month pulmonary vascular resistance (4.2 ± 1.5 vs 6.1 ± 2.9 Wood units; P = .001), and had a lower rate of clinical worsening, defined as worsening of symptoms, rehospitalizations due to worsening HF that required IV drugs or mechanical support, referral for heart/lung transplantation, and all-cause death (16.7% vs 40%, = .014).

Adverse events at 6 months included two cases of fatal pulmonary embolism: one in the PADN group 72 days after randomization and the other in the sham group 36 days after randomization.

Seven patients died: two in the PADN group and five in the sham group.

Ben-Yehuda told | Medscape Cardiology that despite his criticism of the trial design, the PADN approach is worth exploring.

"I think the technique has a lot going for it. There is a pathophysiologic rationale; in fact, yesterday we had a full hour session on pulmonary denervation, including preclinical animal data, so there is a scientific basis for doing this," he said.

He added, however, that "there are significant issues with the trial design, and the data themselves don't quite make physiologic sense."

At the briefing, he pointed out that wedge pressure went down in the denervation group, whereas it would be expected to rise because of a reduction in precapillary vasoconstriction, an effect seen with prostacyclin and other drugs used to treat pulmonary hypertension.

He also noted that the there was an apparently paradoxical increase in left ventricular ejection fraction in the PADN group, from a mean of 43.2% at baseline to 47.9% at 6 months.

"What would be the mechanism for that when you're affecting pulmonary artery and actually increasing blood flow to the left atrium and left ventricle?" he asked.

Chen acknowledged that the investigators did not currently have an explanation for the phenomenon.

The PADN-5 study was funded by grants from the Nanjing Health Bureau and the National Science Foundation of China . Chen is the inventor of record for PADN patents but not the patent holder. All other authors reported no relevant disclosures. Ben-Yehuda reported having nothing to disclose.

Transcatheter Cardiovascular Therapeutics (TCT) 2018. Presented September 23, 2018.

JACC: Card Intervent. Published online September 23, 2018. Abstract


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