Percutaneous transluminal pulmonary angioplasty for ...

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Mar 27, 2015 - NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, UK.
International Journal of Cardiology 187 (2015) 401–403

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Editorial

Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension: Challenges and future directions Konstantinos Dimopoulos ⁎,1, Aleksander Kempny 1, Rafael Alonso-Gonzalez, Stephen J. Wort Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, UK NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, UK National Heart and Lung Institute, Imperial College School of Medicine, London, UK

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Article history: Received 21 March 2015 Accepted 24 March 2015 Available online 27 March 2015 Keywords: Chronic thromboembolic pulmonary hypertension Percutaneous transluminal pulmonary angioplasty Pulmonary balloon angioplasty Pulmonary endarterectomy Pulmonary hypertension Pulmonary embolism

a b s t r a c t Chronic thromboembolic pulmonary hypertension (CTEPH) is a common type of pulmonary hypertension, resulting from fibrotic transformation of pulmonary artery clots causing chronic obstruction of major pulmonary arteries and associated vascular remodeling in more distal vessels. The mainstay of CTEPH treatment is pulmonary endarterectomy (PEA), which has the potential to be curative but is possible in less than two thirds of cases. In inoperable patients and those with residual or recurrent CTEPH, medical therapy has been shown to be beneficial, albeit not curative. Balloon pulmonary angioplasty (BPA) is a percutaneous technique for the relief of chronic thromboembolic lesions, first reported over two decades ago. More recent case series have demonstrated that, as the technique is refined, results are improving. The potential indications for BPA are now expanding beyond inoperable CTEPH patients, with Shimura et al. demonstrating the aggressive nature of residual or recurrent CTEPH, treated successfully by BPA years after PEA. Major challenges lie ahead of BPA before it can take its place alongside PEA and medication in the treatment of CTEPH. © 2015 Elsevier Ireland Ltd. All rights reserved.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a common type of pulmonary hypertension, with an incidence which is rising likely due to an aging population, increased awareness and improved diagnostics [1]. CTEPH differs significantly from other types of pulmonary hypertension in terms of physiopathology and management. The rise in pulmonary vascular resistance occurs not only due to mechanical obstruction from organized clots in larger pulmonary arteries, but also due to vascular remodeling in both occluded and unobstructed, more distal vessels, sharing some histological similarities to idiopathic and other types of pulmonary arterial hypertension [2]. In terms of management, CTEPH is an exception within the spectrum of pulmonary hypertension, as it is the only condition in which outcome can be improved dramatically by intervention, i.e. pulmonary endarterectomy (PEA) [3]. Therefore, meticulous screening for CTEPH in all patients with unexplained pulmonary hypertension remains mandatory and referral to PEA is essential as it can be curative in the majority of patients. PEA can lead to significant functional and quality of life

⁎ Corresponding author at: Adult Congenital Heart Centre, Royal Brompton and Harefield NHS Foundation Trust, Sydney Street, SW3 6NP London, UK. E-mail address: [email protected] (K. Dimopoulos). 1 Authors contributed equally.

http://dx.doi.org/10.1016/j.ijcard.2015.03.361 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

improvement, with a low peri-operative morbidity when performed in experienced, high through-put centers. Unfortunately, a great proportion of CTEPH patients are deemed inoperable due to the presence of significant co-morbidity or distal disease, not amenable to surgery. Registry data suggest that over one third of CTEPH patients (37%) are currently deemed inoperable [4]. Moreover, up to 15% of patients undergoing PEA have clinically significant residual pulmonary hypertension requiring further treatment. Patients with residual pulmonary vascular disease (pulmonary vascular resistance N500–600 dyn s cm−5), have significantly worse survival compared to patients with lower resistance after PEA [5]. In total, about 40–50% of CTEPH patients require alternative/additional management, beyond or above PEA. PAH-targeted therapies are nowadays widely used in CTEPH, despite only 2 relatively large RCTs in this cohort of patients. The BENEFiT study using bosentan demonstrated a reduction in PVR but no improvement in 6MWT distance [6]; the CHEST-1 study, using riociguat, a new oral soluble guanylate cyclase stimulator, demonstrated a significant improvement in 6MWT distance of 46 m in patients deemed inoperable or having residual pulmonary hypertension post PEA [7]. Despite this, medical therapy with pulmonary vasodilators will not address obstructive lesions, either never operated on or residual to surgery. In this sense, balloon pulmonary angioplasty (BPA) is an appealing therapeutic option.

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Editorial

The first case of BPA was described in 1988 by Voorburg et al. [8]. Thirteen years later Feinstein et al. published a case series of 18 patients treated with BPA [9]. Twenty seven years after the initial description of the technique, several teams from seven countries have reported on the use of BPA, with only three (USA, Japan and Norway) publishing clinical studies. Japan has clearly been the leader in this recent resurgence of BPA (Fig. 1). There are several challenges that appear to have hampered the widespread deployment of BPA, beyond the lack of interest by Industry. The technique has had to evolve significantly, especially in terms of reducing the incidence of reperfusion pulmonary edema and hemoptysis. Improvements have included not only technical aspects of the procedure (e.g. selection of target lesions, type and size of balloons, pressure and time of inflation, staging of the procedure treating few lung segments at a time) but also in terms of identifying patients at higher risk of reperfusion edema and planning the procedure (e.g. using the Pulmonary Edema Predictive Scoring Index, PEPSI, Fig. 2) [10]. Reperfusion pulmonary edema is, nowadays, becoming less frequent and is often manageable with diuretics and high flow oxygen, although it may require mechanical ventilation and intensive care. Vessel damage and hemoptysis is also a feared complication in these, often fragile, patients. Recent Japanese studies report that, with the use of pressure wires and scoring techniques, the rate of pulmonary edema has dropped to less than 5% of cases. However, the procedure itself can be challenging and is certainly time and resource-consuming, with most patients requiring 3–5 BPA sessions, each lasting 1.5–2 h [11,12], with an obvious risk of developing contrast nephropathy. Mortality directly related to the procedure is relatively low and improving. As the technique is evolving, its expanding role in the management of CTEPH will inevitably become obvious. Previous studies on BPA were focused on patients not suitable for CTEPH. In this edition of the IJC, Shimura et al. present their experience of BPA in patients with previous PEA and residual or recurrent pulmonary hypertension [11]. Despite the small sample size, the results are promising and open the road for BPA towards a new indication, i.e. completing the job that PEA has failed to deliver. The data presented by Shimura et al. also provide an interesting insight into the natural history of residual/recurrent pulmonary hypertension after PEA, a known risk factor for adverse outcome. This is an aggressive disease, affecting a quarter of operated patients in their cohort, with progressive deterioration in hemodynamics, translating into a functional decline a few years after PEA. While recurrent embolic events

are a possibility, it seems that residual obstructive lesions play a role in the development of progressive disease, with detrimental functional and hemodynamic effects. Redo PEA is an option, but may not be possible in patients with more distal disease, comorbidities or due to patient preference or availability. The results achieved by Shimura et al. in this cohort in terms of hemodynamics and functional status are encouraging. There is obvious enthusiasm in the pulmonary hypertension community about the possibilities offered by BPA. Registries should bring about refinements in the technology and technique, with the ultimate goal of producing agreed standards and defining the learning curve for operators. While there is no clear reason why BPA and PEA should be collocated, BPA should be limited to pulmonary hypertension centers with expertise in the acute/perioperative management of pulmonary hypertension patients and ECMO availability, as well as expertise in interventional cardiology or radiology. Randomized controlled trials will be essential in establishing the benefit of BPA as a primary treatment for CTEPH in inoperable patients, or following PEA. Likely comparisons include BPA versus no BPA on a background of medical therapy, or BPA versus medical therapy, riociguat being the treatment with the strongest evidence to date in inoperable/residual CTEPH. Blinding will be extremely difficult and it is not clear how such trials should be funded, unless a strong case for greater cost-effectiveness against the standard treatment can be made, or Industry develops an interest. As the technique is fine-tuned, a time may come when BPA will need to be compared to PEA in operable patients, not only in terms of efficacy and periprocedural risk, but also patient preference, tolerability and cost. While the introduction of promising new techniques and technologies should be encouraged, their safety and efficacy should be carefully assessed and regulated. Issues of cost-effectiveness should also be addressed before there is a wider take-up of the technique. Conflict of interests None. Funding Dr Kempny has received unrestricted educational grant support from Actelion. The Adult Congenital Heart Centre and Centre for Pulmonary Hypertension have received support from the British Heart Foundation. Dr Dimopoulos has received educational grants from Actelion, GSK and Pfizer and has acted as a consultant for Actelion and GSK. Dr. Alonso-Gonzalez has acted as a consultant for Lilly Spain and Pfizer Spain. Dr Wort has received unrestricted education and research grants from Bayer UK, Pfizer UK, Actelion UK and GSK UK as well as the Pulmonary Hypertension Association (UK). This project was supported by the NIHR Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. References

Fig. 1. Case reports and clinical studies on BPA for CTEPH listed on PubMed. Studies (not case reports) are marked with squares. Since the first description by Voorburg et al., in 1988, the use of BPA has been reported by teams from only seven countries (gray line), suggesting slow deployment of this technique. There was a sharp increase in clinical interest over the last 2–3 years. The cumulative number of papers (gray area, top), with information on the country of origin, and the number of papers published (histogram, bottom) against time are also shown. NLD = The Netherlands, GER = Germany, JAP = Japan, NOR = Norway, POL = Poland, FRA = France.

[1] R. Condliffe, D.G. Kiely, J.S.R. Gibbs, P.A. Corris, A.J. Peacock, D.P. Jenkins, et al., Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension, Am. J. Respir. Crit. Care Med. 177 (2008) 1122–1127, http://dx.doi.org/10.1164/rccm.200712-1841OC. [2] M. Maruoka, S. Sakao, M. Kantake, N. Tanabe, Y. Kasahara, K. Kurosu, et al., Characterization of myofibroblasts in chronic thromboembolic pulmonary hypertension, Int. J. Cardiol. 159 (2012) 119–127, http://dx.doi.org/10.1016/j.ijcard.2011.02.037. [3] D.P. Jenkins, M. Madani, E. Mayer, K. Kerr, N. Kim, W. Klepetko, et al., Surgical treatment of chronic thromboembolic pulmonary hypertension, Eur. Respir. J. 41 (2013) 735–742, http://dx.doi.org/10.1183/09031936.00058112. [4] J. Pepke-Zaba, M. Delcroix, I. Lang, E. Mayer, P. Jansa, D. Ambroz, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international

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Fig. 2. Inami et al. proposed the Pulmonary Edema Predictive Scoring Index (PEPSI) as a means of predicting risk of significant reperfusion edema (RPE, Ngrade 1) after BPA [10]. PEPSI is the product of pulmonary vascular resistance (PVR, Wood units) prior to BPA and the sum of the change in pulmonary flow grades (PFG) with BPA: n segments treated   X P FGpostBPA −P FGpreBPA  PVR: 1

PFG ranges from Grade 0 (no antegrade flow through the stenosis) to Grade 3 (complete perfusion of pulmonary arteries and veins in the segment examined) and is assessed before and after the procedure to assess change. Inami et al. report that both PVR and the sum change in PFG are strong univariate predictors of outcome, as is their product (PEPSI). On the multivariate model, the PEPSI is the strongest predictor of reperfusion edema, while PVR and sum change in PFG are not, likely due to strong colinearity with the PEPSI.Using the univariate logistic model provided by Inami et al. and estimating the intercept from available data from their paper, it is obvious that the risk of RPE exceeds 10% with a PEPSI of above 12 and certainly above the recommended PEPSI of 35.4 (panel A, estimate with 95% confidence intervals) [10]. Assuming an average PFG change of 2 post BPA, the maximum number of segments that can “safely” be treated per BPA procedure can be estimated pre-procedure based on baseline PVR, as shown in panel B. For example, the risk of reperfusion edema from treating one segment appears to exceed 10% in patients with a PVR N 6 Wood units. Based on the same data and assuming a target PEPSI of 35.4 carries acceptable risk, the maximum change in PFG can be estimated and used to limit the number of vessels treated (panel C, with 95% confidence intervals).While the work by Inami et al. has been ground-breaking, there are significant methodological limitations [10]. Validation of a model that can be used to guide BPA treatment is urgently needed, based on robust registry data and with the use of appropriate statistical methods, which should also account for the multilevel nature of the data (procedures clustered within patients, violating the basic principle of independence of observations).

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