Pulmonary Artery Denervation Significantly Increases 6-Minute Walk Distance for Patients with Pulmonary Hypertension Associated with Left-Side Heart Failure: A Prospective, Randomized, and Sham-Controlled PADN-5 Study

Abstract

Background: Heart failure (HF) is associated with sympathetic overactivation. Combined pre-capillary and post-capillary pulmonary hypertension (CpcPH) bears the same pathology as pulmonary arterial hypertension (PAH). Benefits of targeted-PAH medications for CpcPH patients are unknown. Pulmonary artery denervation (PADN), which showed benefit for both PAH and PH patients in a previous consecutive registry study, has not been studied in CpcPH patients using a randomized design. We therefore sought to assess the benefits of PADN for CpcPH patients. Methods: Of 865 patients with HF who were stable for ≥ 3 months and were admitted due to recent worsening of symptoms were enrolled, 387 patients after at least 3 days of treatment had a systolic pulmonary arterial pressure (PAP) ≥ 45 mmHg measured by echocardiography. Among them, 98 CpcPH patients (mean PAP≥25 mmHg, pulmonary capillary wedge pressure >15 mmHg, and pulmonary vascular resistance [PVR] > 3·0 Wood units) were randomly assigned to receive sildenafil plus anti-HF medication and sham PADN or PADN plus anti-HF medication without sildenafil. The primary endpoint was an increase in the 6-minute walk distance (6MWD) at the 6-month followup. PVR and clinical worsening were secondary endpoints. Pulmonary embolism was a safety endpoint. Findings: At the 6-month follow-up, the mean increases in the 6MWD were 83 m in the PADN group and 15 m in the sildenafil group ((least square mean difference 66 m, 95% confidence interval= 38·2-98·8; p<0·001). A 1-SD decrease in the 6MWD was strongly correlated with clinical worsening (corresponding hazard ratio [95% confidence interval] =3·02[ 1·05-8·74]; p=0·04). PADN treatment was associated with significant reduction (29·8%) in PVR and lower rate (16·7%) of clinical worsening, compared with 3·4% (hazard ratio [95% confidence interval] =4·73 [2·05-10·89]; p<0·001) and 40% (hazard ratio [95% confidence interval] =3·33 [1·29-8·59]; p=0·014) in the sildenafil group. At the end of the study, there were 7 all-cause deaths (5 in the sildenafil and 2 in the PADN group) and 2 embolisms (1 in each group). Interpretation: PADN is associated with significant improvements in hemodynamic parameters, cardiac function, and clinical outcomes, when compared with those after 6-month sildenafil treatment. Further studies are warranted to confirm the reduction of CpcPH-related events by PADN. Clinical Trial Number: Registration at clinicaltrials.com; identifier: NCT02220335 Funding Statement: National Science Foundation of China (NSFC 91639303 and NSFC 81770441). Declaration of Interests: CSL is the inventor of PADN patent, but not the owner. The remaining authors have nothing to disclosure. Ethics Approval Statement: The PADN-5 trial is a 4-center, randomized, and sham-controlled clinical trial, which was approved by the ethics committee at each participating center. All patients provided written informed consent. Sponsors had no access to the trial data and no role in the design, conduct, or reporting of the results. Clinical events were adjudicated by an independent committee.