Author + information
- Received August 22, 2018
- Revision received September 5, 2018
- Accepted September 13, 2018
- Published online February 4, 2019.
- Hang Zhang, MDa,∗,
- Juan Zhang, MDa,∗,
- Mengxuan Chen, MDb,∗,
- Du-Jiang Xie, MDc,∗,
- Jing Kan, MBBSa,
- Wande Yu, MDc,
- Xiao-Bo Li, MDc,
- Tian Xu, MBBSc,
- Yue Gu, PhDa,
- Jianzeng Dong, MDd,
- Hong Gu, MDd,
- Yaling Han, MDe and
- Shao-Liang Chen, MDa,∗ ()
- aDivision of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- bMailman School of Health, Columbia University, New York, New York
- cDivision of Cardiology, Nanjing Cardiovascular Hospital, Nanjing, China
- dDivision of Pulmonology, Anzhen Hospital, Capital Medical University, Beijing, China
- eDivision of Cardiology, Shenyang Northern Hospital, Shenyang, China
- ↵∗Address for correspondence:
Dr. Shao-Liang Chen, Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
Objectives The authors sought to assess the benefits of pulmonary artery denervation (PADN) among combined pre- and post-capillary pulmonary hypertension (CpcPH) patients in a prospective, randomized, sham-controlled trial.
Background PADN has been shown to improve hemodynamics of pulmonary arterial hypertension in a series of patients. Additionally, benefits of targeted medical therapy for patients with CpcPH secondary to left-sided heart failure are unknown.
Methods Ninety-eight CpcPH patients, defined as mean pulmonary arterial pressure ≥25 mm Hg, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance (PVR) >3.0 Wood units (WU), were randomly assigned to PADN or sildenafil plus sham PADN. Standard medical therapy for heart failure was administered to all patients in both groups. The primary endpoint was the increase in the 6-min walk distance at the 6-month follow-up. The secondary endpoint was change in PVR. Clinical worsening was assessed in a post hoc analysis. The main safety endpoint was occurrence of pulmonary embolism.
Results At 6 months, the mean increases in the 6-min walk distance 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 to 98.8 m; p < 0.001). PADN treatment was associated with a significantly lower PVR than in the sildenafil group (4.2 ± 1.5 WU vs. 6.1 ± 2.9 WU; p = 0.001). Clinical worsening was less frequent in the PADN group compared with the sildenafil group (16.7% vs. 40%; p = 0.014). At the end of the study, there were 7 all-cause deaths and 2 cases of pulmonary embolism.
Conclusions PADN is associated with significant improvements in hemodynamic and clinical outcomes in patients with CpcPH. Further studies are warranted to define its precise role in the treatment of this patient population. (Pulmonary Arterial Denervation in Patients With Pulmonary Hypertension Associated With the Left Heart Failure [PADN-5]; NCT02220335)
In patients with heart failure (HF), the backward transmission of increased left ventricular filling pressure results in elevated pulmonary venous pressure, a status known as passive or isolated post-capillary (Ipc) pulmonary hypertension (PH), without an elevation of pulmonary vascular resistance (PVR) or diastolic pressure gradient (DPG) (1–4). Fayyaz et al. (5) reported that PH is associated with global pulmonary vascular remodeling, leading to reactive or combined pre-capillary and post-capillary PH (CpcPH), which is defined as a DPG of ≥7 mm Hg, a PVR of >3 Wood units (WU), or both (3,4). Although the presence of PH is a hallmark of poor clinical outcomes in patients with HF (1,6), controversy exists regarding the routine treatment of CpcPH with drugs targeting pulmonary arterial hypertension (PAH) (7,8).
Previous studies (9,10) have indicated that a superimposed pulmonary arterial vasoconstrictor component is one of the major mechanisms that leads to the development of CpcPH, suggesting the potential of pulmonary artery denervation (PADN) to target the overactivation of the sympathetic nerves in patients with HF and PH. Our preliminary registry study showed the safety and feasibility of PADN for either PAH or PH secondary to left-sided HF (11). However, PADN has not been tested in a randomized comparison with a medical treatment. Accordingly, the present study (PADN-5 [Pulmonary Arterial Denervation in Patients With Pulmonary Hypertension Associated With the Left Heart Failure]) was designed as a prospective, randomized, sham-controlled trial to investigate the efficacy of PADN in patients with pre- and post-capillary PH associated with left HF.
The PADN-5 trial is a 4-center, randomized, sham-controlled clinical trial. The study organization, participating sites, and investigators appear in the Online Appendix. The protocol was designed by the steering committee and was approved by the ethics committee at each participating center. All patients provided written informed consent. The risks of undergoing a PADN or sham PADN procedure were described in detail to all patients. Patients were informed that they had the right to withdraw their consent at any time. 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. The authors attest to the accuracy and completeness of the data and analysis.
Patients who were admitted to the hospital with the diagnosis of HF (recent onset of dyspnea and physical activity limitation) were eligible for enrollment. A diagnosis of HF was independently adjudicated by 2 general cardiologists on the basis of the current guidelines (5). All patients were screened via a preliminary echocardiographic examination after they were stable for at least 3 days since the initial treatment on admission. Patients who had a systolic pulmonary arterial pressure (PAP) ≥45 mm Hg (Online Figure 1) were referred for right heart catheterization (RHC) 12 to 24 h after ultrasound measurements.
Inclusion and exclusion criteria
Eligible patients were randomly assigned in a 1:1 ratio to PADN or sildenafil plus sham PADN groups using a central interactive web-based computerized system. Patients were included if they were older than 18 years, had a mean PAP (mPAP) ≥25 mm Hg, a pulmonary capillary wedge pressure (PCWP) >15 mm Hg, and a PVR >3.0 WU; volunteered for all follow-up assessments; and had not received any medications targeting PAH in the 3 months before admission. By contrast, patients were excluded if they had World Health Organization–defined PAH groups I, III, IV, and V; severe renal dysfunction (creatinine clearance <30 ml/min); a blood platelet count <100,000/l; an expected life span <12 months based on the DEALE method (12); systematic inflammation; malignancy, tricuspid, or pulmonary valvular stenosis; or were allergic to any of the studied drugs or various metals. Women who were pregnant were also excluded.
Standard anti-HF medicines, including calcium channel blockers, β-adrenergic receptor blockers, digoxin, diuretics, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers, were administered. The dosage of anti-HF medications could be titrated if patients showed deterioration in any HF symptoms (1–6). A combination of diuretics (primarily chlorthalidone 25 to 50 mg/day with spironolactone 40 to 80 mg/day or furosemide 40 mg/day) was prescribed at the referring cardiologist’s discretion. A nurse who was unaware of the study design recorded the dosage of each drug every day.
Sildenafil, initially given at 20 mg 3 times daily, was the only primarily prescribed target drug in the sildenafil group. Patients were titrated to 40 mg 3 times daily after 1 week. A dose reduction was allowed if patients were intolerable to titration. The selection and dosage of other target drugs were left at the discretion of the referring physician. This part of the study was not blinded (i.e., patients in the sham PADN group were given open-label sildenafil).
Transthoracic echocardiography (Vivid 7, General Electric Co., Easton Turnpike, Connecticut) was performed by 2 registered cardiac sonographers based on a standard protocol (9,11) and read/measured by an expert echocardiographer from the Core Lab (Dr. Jing Ping Sun from the Chinese University of Hong Kong) who was unaware of the study design and treatment allocation. The following parameters were measured: right ventricular systolic pressure, systolic PAP, right atrial pressure, the tricuspid excursion index, wall thickness, chamber dimension, the left ventricular ejection fraction (LVEF), mitral inflow velocity, septal annulus relaxation velocity (E′), the E/E′ ratio, and tricuspid annular plane systolic excursion.
Hemodynamic measurements via RHC
Hemodynamic measurements were performed before and immediately after the PADN procedure using a 7.5-F flow-directed Swan-Ganz catheter (774P75, Edwards Lifesciences, Irvine, California). These measurements were repeated at 6 months, with patients in a fasting state and in the supine position just 12 to 24 h after the measurement of the 6-min walk distance (6MWD). A continuous cardiac output (CO) and mixed venous oxygen saturation were simultaneously recorded (Vigilance II, Edwards Lifesciences) (13). Five criteria, in order to evaluate whether a PCWP measurement was valid, have been described elsewhere (11). If the PCWP measurement was unreliable, then the left ventricular end-diastolic pressure was measured and used. Additional derived parameters included PVR (PVR = [mPAP − PCWP]/CO), transpulmonary pressure gradient (TPG = mPAP − PCWP), DPG (DPG = pulmonary arterial diastolic pressure − diastolic PCWP), and pulmonary arterial compliance (PAC) (PAC = stroke volume/pulse pressure), where pulse pressure = systolic PAP − diastolic PAP.
Assessment of N-terminal pro–B-type natriuretic peptide levels
Blood samples (taken in the supine position) were obtained in the morning to measure the levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP) before and 6 months after randomization.
The details of the device and the PADN procedure have been previously described (11). Briefly, PADN was performed only in the periconjunctional area between the distal main trunk and the ostial left branch. The following ablation parameters were programmed at each point: temperature ≥45°C, energy ≤20 W, and time 120 s. The hemodynamic parameters were monitored and recorded continuously throughout the procedure. After the procedure, oral warfarin was prescribed for 1 month and adjusted to an international normalized ratio of 1.5 to 2.5 for patients with atrial fibrillation. Aspirin (100 mg per day) and clopidogrel (75 mg per day) were prescribed for 1 month for patients with sinus rhythms or for patients with atrial fibrillation with contraindications for warfarin. For a sham PADN procedure in the sildenafil group: the PADN catheter was positioned at the target sites and connected to a generator (as in the actual PADN procedure), 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.
Assessment of functional capacity
Functional capacity was determined before, 1 week, 1 month, 3 months, and 6 months after treatment using the standard 6MWD test according to the guidelines of the American Thoracic Society protocol. Patients avoided heavy meals 2 h before testing and were also instructed to avoid caffeine, alcohol, tea, and intense physical exercise within the previous 24 h. Before each test, patients walked as far as possible for 6 min without speaking; rests were allowed, but the patients were told to resume walking as soon as they were able. During the test, patients were given feedback at the end of every minute with encouragement. Dyspnea was assessed using the Borg scale at peak exercise during 6MWD test. The 6MWD measurement and the World Health Organization classification of dyspnea were recorded by a physician who was unaware of the treatment allocation.
Patients were contacted every month by telephone after hospital discharge during the 6-month follow-up period. An office visit at a participating center was scheduled for any patient who was suspected of having worsening symptoms. A repeat 6MWD measurement (within 2 weeks) was required for any patient who showed a reduction of >15% on the 6MWD.
Endpoints and definitions
The primary endpoint was the change in the 6MWD at 6-month follow-up evaluation. The secondary endpoint was the change in PVR (measured using pulmonary hemodynamics during RHC) The safety endpoint was the occurrence of pulmonary embolism (PE), defined as: 1) suspected PE (including a new intraluminal filling defect on computed tomography, magnetic resonance imaging, or a pulmonary angiogram; a new perfusion defect of at least 75% on a V/Q lung scan; or an inconclusive spiral computed tomography/pulmonary angiogram/lung scan with the demonstration of deep vein thrombosis in the lower extremities via venography); or 2) fatal PE (including PE based on objective diagnostic testing, autopsy, or death not attributed to a documented cause for which deep vein thrombosis/PE could not be ruled out) (14,15). Clinical worsening was defined as any occurrence of the following: 1) worsening of symptoms defined as either failure to improve (persistent symptoms and signs of acute HF during treatment) or recurrent symptoms and signs of acute HF, pulmonary edema, or cardiogenic shock after initial stabilization since randomization, either of which requiring increased use of diuretics (as outpatient or inpatient), addition of a new intravenous therapy (diuretics, inotrope, or vasodilator) or mechanical support; 2) rehospitalization due to worsening HF requiring intravenous pharmacological agents (inotrope or vasodilator), mechanical ventilation, mechanical support or ultrafiltration, hemofiltration, or dialysis; 3) referral for heart/lung transplantation (rapidly progressive disease despite maximal medical therapy); and 4) all-cause death. Worsening of HF status was documented by monitoring nurses, clinicians and coordinators on a standardized case report form. Clinical events were blindly assessed by a clinical event committee.
We hypothesized that at 6 months, the increase of 6MWD would be higher among patients in the PADN group than among patients in the sildenafil group. We anticipated a mean value and SD of the difference for the 6MWD increase at 85 m and 60 m according to our previous results (9). We estimated that a sample size of 41 patients in each group would provide 80% power with a 2-tailed alpha of 0.025. To account for a possible 20% of patients lost to follow-up, 100 patients (50 in each group) were planned for enrollment. All analyses were performed on an intention-to-treat basis. Data on patients who were lost to follow-up were censored at the date of the last contact with the patient. The categorical variables were reported as counts and percentage and compared using the chi-square test or Fisher exact test. The continuous variables were expressed as mean ± SD or median (interquartile range) and compared using Student’s t-test or the Wilcoxon rank sum score (for example, for comparison of 6MWD between groups or between baseline and 6-month follow-up) where appropriate. The change of the 6MWD in individual patients was illustrated using a scatterplot. The corresponding hazard ratio (HR) and 95% confidence interval (CI) for a decrease of 1 SD in the 6MWD for the prediction of clinical worsening and all-cause death were calculated using a Cox proportional hazard model. Time-to-first event curves were generated by Kaplan-Meier analysis and compared using the log-rank test. The Cox proportional hazard model was also used to calculate the difference in the occurrence of time-to-clinical event between 2 planned groups, with reports of HR and 95% CI. Additional post hoc analyses included the receiver operating characteristic curve and the correlation between PVR and PAC or between the absolute increment of the 6MWD and PAC using a regression variable plot and curve estimation (inverse model). Pre-specified subgroup analyses included: difference in 6MWD between EF-preserved HF (HFpEF) (defined as LVEF ≥50%) versus EF-reduced HF (HFrEF) (defined as LVEF <50%), time-to-event stratified by cutoff values of the 6MWD at baseline or at 6-month follow-up. Two-tailed p values of <0.05 were considered to indicate statistical significance. All analyses were performed using SPSS version 24.0 (SPSS Institute Inc., Chicago, Illinois).
Among 865 screened patients, 387 patients with HF had a systolic PAP ≥45 mm Hg measured by echocardiography. Among them, 112 patients (28.9%) met all the inclusion and exclusion criteria; however, 2 died soon after echocardiographic screening, and 10 did not consent to participate. Of the remaining 100 patients, 98 were then randomly assigned to the PADN group (n = 48) or the sildenafil (plus sham PADN) group (n = 50) (Online Figure 1). Two patients were excluded because of erroneous repeat randomization by the study nurses.
Baseline clinical, echocardiographic, and hemodynamic characteristics were similar between the 2 groups (Tables 1, 2, and 3⇓⇓⇓). In general, 38.8% of patients were classified with HFpEF and 61.2% with HFrEF; 52% of patients had atrial fibrillation. The time interval from HF to PH varied from 0.3 years to 9.8 years. Of the 98 patients, 3 patients were defined as IpcPH according solely to PVR criterion (2 in the PADN group and 1 in the sildenafil group) (Table 1). In total, 35 (73.0%; p = 0.068) in the PADN group and 29 patients (58.0%) in the sildenafil group had a transpulmonary pressure gradient of >12 mm Hg (Table 2).
The baseline 6MWD was comparable between the 2 groups (Figure 1). In the PADN group, the mean increment of the 6MWD at the 6-month follow-up was 83 m (21.4% increase, least square mean difference 66 m, 95% CI: 38.2 to 98.8; p < 0.001), significantly higher than 15 m (a 4.9% increase in median value) in the sildenafil group (Figure 1). Eighteen patients showed a reduction in the 6MWD at the end of the follow-up period, including 6 (12.5%) in the PADN group (3 [6.3%] having a reduction of >15% in the 6MWD, HR: 2.947, 95% CI: 1.152 to 4.501; p < 0.001) (Figure 1) and 12 (26.7%) in the sildenafil group (7 [14%] having a reduction of >15% in 6MWD). Of the 91 surviving patients, the mean increase, percentage increase, and the absolute mean value of the 6MWD in the PADN group were 85.1 m, 50.2%, and 442.4 m, respectively. The corresponding values in the sildenafil group were 20.1 m, 6.8%, and 373.5 m, respectively. All comparisons were statistically significantly higher in the PADN group (p < 0.001 for all). However, the change of the 6MWD in both HFpEF and HFrEF subgroups in either the PADN or sildenafil group was comparable (Online Figure 2). By Cox regression analysis, a decrease of 1 SD in the 6MWD significantly predicted the occurrence of clinical worsening (corresponding HR: 3.023, 95% CI: 1.052 to 8.742; p = 0.040), but not the prediction of all-cause death, worsening of HF, and rehospitalization (Table 4).
At 6 months, PADN treatment was associated with a significantly lower PVR than in the sildenafil group (4.2 ± 1.5 WU vs. 6.1 ± 2.9 WU; p = 0.001). The average reduction of PVR from baseline to 6-month RHC was 29.8% in the PADN group and 3.4% in the sildenafil group (HR: 4.73, 95% CI: 2.05 to 10.89; p < 0.001) (Table 2), which was consistent with the increase of CO and PAC.
Post hoc analysis
At the 6-month follow-up, clinical worsening was reported in 28 patients (Table 3, Figure 2): 20 (40.0%) in the sildenafil group and 8 (16.7%) in the PADN group (HR: 2.690, 95% CI: 1.184 to 6.113; p = 0.018) (Figure 2), primarily driven by the protocol defined worsening of HF (36.0% vs. 14.6%, HR: 2.743, 95% CI: 1.145 to 6.571; p = 0.024) (Figure 2). The PADN procedure was associated with significant improvements in all hemodynamic parameters (Table 2), except for right atrial pressure which tended to be lower, but there was no significant difference. PAC was significantly improved at 6 months after PADN, in parallel with the absolute increase in the 6MWD (Online Figure 3). However, PVR was unchanged after 6 months in the sildenafil group (Online Figure 3). These results were in line with the lower requirement for diuretic titration, the reduction of NT-proBNP, Borg index, and improvement of cardiac function (Table 3). Of the 48 patients in the PADN group, 4 (8.3%) were nonresponders, defined as a reduction of mPAP or systolic PAP <10% post-PADN (9), and 3 patients showed a post-PADN PCWP higher than the baseline value (but no worsening of symptoms). For these 3 patients, repeat RHC was performed 1 week after PADN, and the temporary increment of PCWP decreased thereafter. At 6 months, 6MWD measurement was a statistically significant predictor of clinical worsening or all-cause death (Online Figure 4).
At the 6-month follow-up, 2 fatal pulmonary embolisms were reported, with one at 72 days after randomization in the PADN group and the other at 36 days in the sildenafil group. There were 7 deaths: 2 in the PADN group (one died of pump failure at 6 days, the other died suddenly at 29 days) and 5 in the sildenafil group (1 died suddenly at 17 days, and the remaining 4 died of pump failure at 17, 93, 100, and 154 days).
The present randomized sham-controlled study is the first to our knowledge to report the safety and efficacy of PADN for patients with CpcPH. We found that after a 6-month follow-up, PADN resulted in a significant increase in the 6MWD, consistent with the significant improvements in PVR, other hemodynamic parameters, and cardiac function. Post hoc analysis demonstrated significantly less frequent clinical worsening with PADN compared with sildenafil therapy. A decrease of 1 SD in the 6MWD strongly predicted the occurrence of clinical worsening.
The development of PH is a common complication related to left-sided HF (1–3,5). Previous clinical studies did not confirm the effectiveness of medications targeting PAH for patients with HF and PH (1,3,5), although meta-analysis studies reported an overall benefit of sildenafil for IpcPH patients (8,16). This controversy regarding the beneficial effect of sildenafil for CpcPH underscores the importance of fully understanding the neurohumoral mechanisms in these patients (17).
Neurohumoral overactivation in HF with PH is clinically demonstrated by increased circulating catecholamine levels and impaired heart rate variability (6,7,18), which may indicate the potential of using local denervation for patients with CpcPH. In an experimental study, we further found that both the localization of PA nerve trunk (at the left lateral wall of main PA) and a shorter distance between nerve trunk and PA intimal surface (19) anatomically favor the performance of PADN at this specific location. Furthermore, PADN was tested in a single-center registry of patients with idiopathic PAH and PH secondary to left-sided HF, demonstrating beneficial effects on hemodynamic parameters and exercise capacity (11,20). In the present randomized study, PADN treatment (plus standard anti-HF medications) was associated with a significant increase in 6MWD at the 6-month follow-up, which was in parallel to the improvement in pulmonary hemodynamics and cardiac functions, compared with the effects of sildenafil plus standard medications, which further confirmed our previous reports (11,20). We attempted to minimize or eliminate the placebo effect by performing a sham PADN procedure on patients in the sildenafil group. Blinding may not have been complete due to the open administration of sildenafil in only 1 of the randomized groups.
The 6MWD was selected as the primary endpoint in previous studies of patients with PAH, and a >15% reduction in the 6MWD is a criterion for a clinical event (6,10). An 83-m increase in 6MWD achieved by PADN treatment from the present study (Figures 1 and 3) was similar to the 90-m increase in our previous reports (11,20). Moreover, McCabe et al. (21) reported that the baseline 6MWD predicted the 30-day rehos-pitalization rate among patients with HF. Our findings demonstrated that both 6MWD at 6-month follow-up and 1-SD decrease in 6MWD strongly predicted clinical worsening and further enhanced the prognostic importance of 6MWD for CpcPH patients. Although the pathogenesis of HFpEF is different from that of HFrEF (22–24), PADN resulted in equally improved 6MWD in patients with either HFrEF or HFpEF. This treatment effect by PADN may be partially explained by the fact that both diastolic and systolic cardiac functions were significantly improved after PADN procedure. However, the underlying mechanisms linking PADN to improvements in left ventricular function require further basic and clinical studies.
We further found that a significant reduction of clinical worsening in the PADN group, mainly driven by the decrease in the rate of worsening of HF in the PADN group. This is different from the significant reduction of rehospitalization in previous studies (16,17), which may be explained by the differences in the definitions of worsening of HF and rehospitalization between studies. This unexpected clinical benefit from the PADN procedure is an indication for our next clinical trial. However, the mechanisms underlying the interplay between pulmonary arterial hemodynamics and exercise capacity in HF patients were complicated and not fully understood in CpcPH patients (2–5). In this study, the improvements in the PAC–PVR and PAC–6MWD relationships achieved by the PADN procedure suggested the sustained recovery of stiffer pulmonary arterial structure (25) rather than a change in remodeling status affecting small arterioles. Notably, the reduction in PCWP achieved by PADN dispelled our original concerns that PCWP would undergo a deleterious change because there is a large amount of blood return following mPAP reduction and CO increases (hyperkinetic status) (3–7) after PADN. In fact, the decrease in PCWP in this study may well explain the significant reduction in both left atrial and left ventricular diameters, which is consistent with the improvements in 6MWD, and left ventricular systolic and diastolic functions when compared with medication treatment, a finding that implied a potential role of PADN for left ventricular remodeling. This improvement in left ventricular function is unlikely to be due to the right–left interaction because right ventricular function was marginally altered. Interestingly, the improvements in the hemodynamic parameters and right ventricular function after the PADN procedure were not followed by a statistically significant education in right atrial dimension and RAP. This is not clearly understood. It could be explained by the fact that 6 months of follow-up was too short a time to record the improvement in right atrial dimension/pressure in such severe cases of patients with CpcPH and indicates the importance of long-term follow-up.
First, we selected to use sildenafil plus standard medical therapy and sham PADN in the control group, even though neither sildenafil nor other PAH therapies are recommended in patients with CpcPH according to international guidelines. We based this decision on a meta-analysis demonstrating beneficial effects of sildenafil in PAH patients, but it should be clear that our data did not provide support for the use of these agents in CpcPH. Second, the use of sildenafil without a comparable placebo in the PADN group may have affected the blinding of patients and treating physicians to the treatment allocation. Third, the 6MWD, but not the clinical endpoint, was the primary endpoint in this study. There is a well-known learning effect, and 6MWD measurements may be different from day to day (20,22). As result, the interpretation of our results should be made cautiously. Fourth, patients were screened only after being treated medically for only 3 days, and adequate diuresis was not objectively measured, which may not have been adequate to stabilize and optimally treat their HF. Fifth, international normalized ratio values below 2 in anticoagulated patients would be considered subtherapeutic. Sixth, we did not investigate the underlying mechanisms that contributed to the improvement of cardiac function by PADN. However, our results may imply there is a beneficial effect of PADN on pulmonary arterial compliance. Finally, both patients with HFrEF and those with HFpEF were included. It is therefore important to further study the mechanisms of PADN treatment focusing on HFpEF.
The PADN-5 trial is the first randomized sham-controlled trial to demonstrate the hemodynamic and functional benefits of PADN in patients with CpcPH. Additional randomized clinical trials are warranted to compare long-term improvements in clinical outcomes after treatment with PADN in this patient population.
WHAT IS KNOWN? HF is a leading cause of mortality. CpcPH in HF patients can be severe and is a marker of poor clinical outcomes. Optimal therapies in patients with CpcPH are not clear.
WHAT IS NEW? PADN not been studied for CpcPH in a randomized sham-controlled design.
WHAT IS NEXT? In this multicenter, randomized, sham-controlled study, PADN plus standard medical therapy led to a significant improvement in the 6-min walk distance and pulmonary vascular resistance. It was also associated with a significantly lower rate of clinical worsening, compared with patients treated with sildenafil and standard medical therapy.
The authors acknowledge Ms. Wen Teng, Ms. Ling Lin, and Ms. Hai-Mei Xu for the data monitoring and collection performed throughout the study. The authors appreciate Dr. Bao-Xiang Duan (Director of the Event Committee) for his valuable work in assessing the clinical events, and thank Dr. Ori-Ben Yehuda for hemodynamic measurement instruction before this study.
↵∗ The first 4 authors equally contributed to this work.
This study was funded by grants from Nanjing Healthy Bureau and the National Science Foundation of China (Funding numbers NSFC 91639303 and NSFC 81770441). Dr. S.-L. Chen is the inventor of patents for PADN but not the owner. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- 6-min walk distance
- confidence interval
- cardiac output
- combined pre- and post-capillary pulmonary hypertension
- diastolic pressure gradient
- heart failure
- heart failure with preserved ejection fraction
- heart failure with reduced ejection fraction
- hazard ratio
- isolated post-capillary pulmonary hypertension
- left ventricular ejection fraction
- mean pulmonary arterial pressure
- pulmonary artery
- pulmonary artery compliance
- pulmonary artery denervation
- pulmonary arterial hypertension
- pulmonary arterial pressure
- pulmonary capillary wedge pressure
- pulmonary embolism
- pulmonary hypertension
- pulmonary vascular resistance
- right heart catheterization
- Wood unit(s)
- Received August 22, 2018.
- Revision received September 5, 2018.
- Accepted September 13, 2018.
- 2019 American College of Cardiology Foundation
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