By Jamie L.W. Kennedy, MD, FACC

Associate Professor, Division of Cardiology, Advanced Heart Failure & Transplant Cardiology, University of California, San Francisco

Dr. Kennedy reports no financial relationships relevant to this field of study.

SYNOPSIS: A trial of patients with residual chronic thromboembolic pulmonary hypertension following pulmonary endarterectomy showed pulmonary artery denervation is superior to medical management with riociguat.

SOURCE: Romanov A, Cherniavskiy A, Novikova N, et al. Pulmonary artery denervation for patients with residual pulmonary hypertension after pulmonary endarterectomy. J Am Coll Cardiol 2020;76:916-926.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon but severe complication of pulmonary embolism, leading to exercise intolerance, right heart failure, and death. Pulmonary endarterectomy (PEA) is the treatment of choice for appropriate surgical candidates and can be curative, although it is only available at a few centers. Many patients do not undergo surgery for a variety of reasons. Some are not referred for surgery, some decline surgical evaluation or intervention, some are not surgical candidates because of comorbid conditions, and some lesions are not amenable to PEA. In addition, a few patients experience residual pulmonary hypertension after surgery. Clinical trials have revealed modest benefit from pulmonary vasodilators (riociguat, macitentan, bosentan, sildenafil, and prostacyclins) for inoperable or residual CTEPH. Balloon pulmonary angioplasty also has been explored as an option for inoperable or residual disease, often requiring multiple sessions over weeks or months and offered at a few centers.

Pulmonary artery denervation (PADN) has been studied in small trials over the last few years as an intervention for pulmonary hypertension of various etiologies. It is based on the theory that the autonomic nervous system plays a role in pulmonary vasoconstriction. In animal PH models, PADN results in an immediate decrease in pulmonary artery pressure. TROPHY 1, a pilot study in the United States and Europe, showed the addition of intravascular ultrasound PADN to medical management in PAH patients resulted in mean reduction in pulmonary vascular resistance (PVR) of 94 ± 151 dyn-s-cm-5 after four to six months.

Romanov et al screened 278 patients with CTEPH who had undergone PEA for residual pulmonary hypertension by echo, followed by right heart catheterization for confirmation. They identified 50 patients with mean pulmonary artery pressure > 25 mmHg and PVR > 400 dyn-s-cm-5. The average age was 48 years, half were men, and average six-minute walk distance was 380 m. Half of patients had NYHA class II symptoms (one-quarter each were class I and III). On average, patients had CTEPH for four years before PEA and were diagnosed with residual CTEPH 29 months after PEA. Twenty-five patients were randomized to PADN and placebo medication, and 25 patients were randomized to sham procedure and medical management with riociguat.

PADN was performed by radiofrequency ablation lesion sets in the main pulmonary artery 2-3 mm proximal of the bifurcation, and in both the left and right pulmonary arteries 2-3 mm distal from the bifurcation. The procedure was guided by a combination of fluoroscopy and remote magnetic navigation. The most significant complications were transient bradycardia, chest pain, cough, and access site hematoma.

The primary endpoint was pulmonary vascular resistance at 12 months. The PADN group demonstrated a mean reduction of 258 ± 135 dyn-s-cm-5 vs. 149 ± 73 dyn-s-cm-5 in the medical management group (P = 0.001). Several secondary endpoints also were reported. Mean pulmonary artery pressure improved in the PADN group, from 35 ± 9 mmHg at baseline to 26 ± 7 mmHg at 12 months. In the medical management group, there was minimal change, from 36 ± 9 mmHg to 34 ± 6 mmHg (P < 0.001). Echo showed both tricuspid annular plane systolic excursion (TAPSE) and right ventricular (RV) fractional area change improved significantly in the PADN group, but did not change in the medical management group. The six-minute walk distance improved substantially (470 ± 84 m), while the medical management group improved marginally (399 ± 116 m; P = 0.03).

In the PADN arm, one patient was hospitalized, and one died of worsening heart failure. In the medical management arm, seven patients were hospitalized, and two died of worsening heart failure. NT-pro-BNP improved an average of 632 pg/mL in the PADN arm and 176 pg/mL in the medical management arm (P = 0.04). The authors concluded PADN is a promising new intervention for residual pulmonary hypertension after PEA.

COMMENTARY

To date, trials of PADN have been heterogeneous in terms of patient populations, concomitant medical management, and PADN technique, making comparisons difficult. The Romanov et al study is an advance in that it was a randomized, sham-controlled, placebo-controlled trial focused on a single patient population. The PADN technique demonstrated significant benefit compared to standard of care medical management. Future studies of the CTEPH population also may include patients deemed inoperable. The primary role of PEA in the treatment of CTEPH remains unchanged, as does the importance of evaluating every PH patient for CTEPH and every CTEPH patient for PEA. The relative roles of medical management, balloon angioplasty, and PADN for residual and inoperable CTEPH remain to be clarified. Other patient populations may benefit from PADN, particularly those with PH caused by left heart disease, in which trials to date have struggled to demonstrate benefit from treatments directed at the pulmonary vasculature.