Denervation Shows Potential in Heart Failure-Related Pulmonary Hypertension

Adding pulmonary-artery denervation to guideline-directed medical therapy (GDMT) reduced clinical worsening in patients with pulmonary hypertension associated with left heart disease and heart failure, results of a Chinese randomized trial showed.

The estimated 2-year incidence of clinical worsening — a composite of death, heart or lung transplantation, hospitalization for heart failure, outpatient worsening of heart failure requiring intravenous diuresis, or a decline in the 6-minute walk distance — was just 25.7% for those randomized to denervation plus GDMT as compared with 51.5% for the group receiving GDMT only (HR 0.49, 95% CI 0.30-0.82, P=0.006).

Similar results were seen in a secondary analysis that excluded the 6-minute walk test component of the composite endpoint, Shao-Liang Chen, MD, from Nanjing Medical University in China, reported at the European Society of Cardiology Congress (ESC) in Munich. Results were published simultaneously in the New England Journal of Medicine.

Chen did point to several limitations of the so-called PADN-HF-PH trial, including that it was open-label, had a relatively short follow-up of about a year, and was conducted only in one country.

“However, the generalizability and the impact of blinding are being assessed in the ongoing international sham-controlled PULSE-LHD trial,” Chen said.

Pulmonary hypertension caused by left heart disease and associated with heart failure may be driven by sympathetic overactivation leading to increased pulmonary vascular resistance, right ventricular dysfunction, and poor outcomes, the investigators noted in their paper. Pulmonary-artery denervation interrupts the sympathetic nerves innervating the pulmonary artery, reducing sympathetic activity, which may in turn improve outcomes.

ESC discussant Felix Mahfoud, MD, from University Hospital Basel in Switzerland, called the PADN-HF-PH results “quite promising” but flagged the open-label design.

“We have a compelling efficacy signal with concordant physiological and patient-centered signals, although no hard change of morbidity and mortality,” he noted, and none of the individual endpoints in the overall composite were statistically significantly different between groups. However, the main limitation in his view was the lack of a sham control for the procedure.

“The physicians and patients were aware of treatment allocation, and what we have learned from other trials is that invasive placebos can be quite powerful,” said Mahfoud. “They may change behavior and can also influence uptitration of medication, for instance, or adherence to medication, and thereby symptoms, and 6-minute walking distance.”

Before a final conclusion can be drawn on pulmonary denervation, said Mahfoud, further confirmation is needed with larger, sham-controlled international trials that include hard endpoints and have longer follow-up and careful phenotype selection.

PADN-HF-PH was a multicenter, open-label, randomized trial conducted in China. A total of 264 patients with pulmonary hypertension associated with left heart disease and heart failure were randomly assigned 1:1 to receive pulmonary-artery denervation plus GDMT or GDMT alone. Median follow-up for the primary analysis was 338 days.

The procedure was successful in all 134 patients. Patients had no or minimal discomfort, and only 1.5% received additional analgesia, Chen said. At 10 minutes after pulmonary-artery denervation, the mean pulmonary-artery pressure was reduced by at least 1% in 88% of the patients and by at least 10% in 53%.

“Acute reductions also occurred in pulmonary vascular resistance and pulmonary-artery wedge pressure, and cardiac output increased,” the investigators wrote in their paper.

Access-site hematomas occurred in two patients in the denervation arm and one patient in the control arm. Adverse events occurred with similar frequency between groups.