Pulmonary Denervation Shows Promise for Resistant Pulmonary Hypertension

07.16.2013

July  16, 2013

Source: TCTMD

Key Points:Pilot study tests pulmonary artery denervation for idiopathic pulmonary hypertensionTreatment reduces pulmonary pressure, increases functional capacity at 3 monthsProcedure could open new avenue for patients with few options, outside experts say

By Yael L. Maxwell Tuesday, July 16, 2013

A novel pulmonary artery denervation approach is safe and effective for patients with idiopathic pulmonary artery hypertension not responding optimally to medical therapy, according to a proof-of-concept study published online July 10, 2013, ahead of print in the Journal of the American College of Cardiology.The study was initially presented in October 2012 at the annual Transcatheter Cardiovascular Therapeutics symposium in Miami Beach, FL.Researchers led by Shao-Liang Chen, MD, of Nanjing Medical University (Nanjing, China), studied 21 patients with idiopathic pulmonary hypertension who were treated with either pulmonary artery denervation alone (n = 13) or continued medical therapy (n = 8) from March to May 2012. Prior to enrollment, all patients received a diuretic (hydrochlorothiazide 12.5 mg to 25 mg once daily and/or spironolactone 20 mg to 40 mg once daily) and beraprost (120 mg, 4 times daily), with either sildenafil (20 mg, 3 times daily), bosentan (120 mg, twice daily), or digoxin (0.125 mg, once daily).Echocardiographic, Functional Gains SeenAfter 3 months, the control group reported no differences in echocardiographic measurements compared with baseline. However, denervation was associated with reductions in systolic pulmonary artery pressure and mean pulmonary artery pressure.

In addition, the treatment reduced pericardial effusion size and improved RV tricuspid excursion index (P < 0.001 for all comparisons; table 1).Table 1. Hemodynamic Measurements of the Study Group BaselinePost-DenervationImmediate3 MonthsSystolic Pulmonary Pressure, mm Hg86 ± 872 ± 571 ± 6Mean Pulmonary Pressure, mm Hg55 ± 539 ± 736 ± 5RV Tricuspid Excursion Index0.3 ± 0.04–0.5 ± 0.04Pericardial Effusion Thickness, mm3.5 ± 0.82.7 ± 0.50.7 ± 0.4 Following the decrease in pulmonary artery pressure, cardiac output increased from 2.0 ± 0.2 L/min/m2 to 2.8 ± 0.3 L/min/m2 (P < 0.001), which both reduced transpulmonary pressure gradient and pulmonary vessel resistance and increased venous oxygen saturation in the pulmonary artery.Functional capacity was improved in the study arm as shown by the 6-minute walk test (P = 0.004) and reduced NT-BNP levels (P = 0.003) at 3 months, while no improvements were seen in controls (table 2).Table 2. Functional Assessment of Study Group BaselinePost-Denervation1 Month3 Months6-Minute Walk Distance, m324 ± 21459 ± 42491 ± 38NT-BNP, pg/mL2,005 ± 442910 ± 205822 ± 201

Procedural success was 92.3%, with 1 patient experiencing intolerable chest pain induced by denervation. Rehospitalization was needed in more than half (62.5%) of controls and none of the denervation patients (P < 0.001). Two patients in the study arm died at 3 months; 1 from septic shock and the other from RV failure.Several Advantages over Medical TherapyDr. Chen and colleagues suggest that, based on the safety and efficacy shown in the study, pulmonary artery denervation may prove to be useful in patients who do not respond to medication, much like renal denervation for resistant hypertension. Currently available medications are limited by their high cost, severe side effects, complex intravenous or subcutaneous injection set-up, and unpredictable long-term effects, they add.All medications in the current study were discontinued safely apart from 1 patient who continued receiving a diuretic after denervation

“[T]his might imply the ‘pure’ effect of [denervation] itself on improvements in cardiac function, hemodynamic measurements, and functional capacity,” they say, adding that the toxicity of medications prescribed before denervation could not be ignored.While the procedure proved safe, aneurysm is a risk, the researchers note, acknowledging the existence of a learning curve and need for further study in randomized trials.Data Supports Larger Trials Pulmonary artery denervation is enough of a departure from renal artery denervation that it is hard to speculate if results would be similar, Ajay S. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview. But the data support a randomized trial, he said, noting,

“This would certainly open an avenue of opportunity for these patients who are very difficult to treat otherwise.”However, another consideration would be the circular catheter specifically designed for this indication. “We worry a little bit about causing what we call circumferential burn in the renal arteries because that could potentially lead to stenosis, and so it’s just something to think about with this,” he observed. “You just want to make sure there is no late formation of pulmonary stenosis, which would potentially decrease the pulmonary pressures, but would increase the strain on the RV.”The population studied by Dr. Chen and colleagues is a good place to start as they are the most likely to respond, Dr. Kirtane said. “But what’s unclear is if this can be used in lieu of the medications they are already on. Or is this only for the patient population that they are studying?” he asked.

“There’s a whole avenue of investigation they’ve opened up.”In addition, George Bakris, MD, of the University of Chicago Medical Center (Chicago, IL), told TCTMD in a telephone interview that the study offers preliminary evidence backing the treatment. Since idiopathic pulmonary hypertension “is a bit of an orphan disease with no pharmacological treatment showing a clear advantage primarily due to tolerability issues, . . .this procedure shows great promise as an alternative to treatments for this disease,” he said.

Patient Population Needs Definition

However, in an accompanying editorial, Nazzareno Galiè, MD, and Alessandra Manes, MD, PhD, both of Bologna University Hospital (Bologna, Italy), are a bit more skeptical.“The characteristics of the patient population . . . are unusual for a group [that carries] the diagnosis of idiopathic [pulmonary artery hypertension],” they write, noting that more than half of patients were male, all were on long-term oxygen therapy, and many were possibly long-term survivors. Moreover, it is “highly unusual” to see poor responders to medical therapy with normal right arterial pressure at rest, they add.Drs. Galiè and Manes also argue that denervation should have been performed “on top of the current medical treatment to match the medical treatment of the control group.”In response, Dr. Bakris emphasized the pilot nature of the study, adding that “what’s exciting for me is the possibility that [denervation] actually did something or has the potential for doing something.”Study DetailsAll patients presented with dyspnea and fatigue. Patients in the study group had more frequent chest pain compared with the control group (P = 0.033). Average time interval between the onset of symptom to diagnosis was 3.5 years. All patients did not respond optimally to current medical treatment after an average of 3.3 years of therapy using at least 2 drugs. Sources:1. Chen S-L, Zhang F-F, Xu J, et al. Pulmonary artery denervation to treat pulmonary arterial hypertension: A single-center, prospective, first-in-man PADN-1 study. J Am Coll Cardiol. 2013;Epub ahead of print.2. Galiè N, Manes A. New treatment strategies for pulmonary arterial hypertension: Hopes or hypes? J Am Coll Cardiol. 2013;Epub ahead of print. Disclosures:Drs. Chen and Kirtane report no relevant conflicts of interest.Dr. Galiè reports serving on an advisory board for Actelion, Bayer, GlaxoSmithKline, Lilly, and Pfizer and receiving lecture fees from Actelion, Bayer, and GlaxoSmithKline.Dr. Manes reports receiving lecture fees from Actelion, Bayer, and GlaxoSmithKline.Dr. Bakris reports serving as co-principal investigator of Symplicity HTN-3 and as a consultant to several pharmaceutical companies including Abbott, Boehringer Ingelheim, Daiichi-Sankyo, Janssen, and Takeda. 

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