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Balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension

Ogo, Takeshi

Current Opinion in Pulmonary Medicine: September 2015 - Volume 21 - Issue 5 - p 425–431
doi: 10.1097/MCP.0000000000000188
DISORDERS OF THE PULMONARY CIRCULATION: Edited by Richard N. Channick and Marc Humbert

Purpose of review: Chronic thromboembolic pulmonary hypertension (CTEPH), especially when severe in patients unsuited for pulmonary endarterectomy, has a poor prognosis. Balloon pulmonary angioplasty (BPA) is a new catheter-based alternative treatment option for patients with inoperable CTEPH. BPA has not been widely accepted, however, primarily because of possible fatal complications, although effects described in 2001 were encouraging. Recent studies about BPA from Japan and Norway are promising. However, this emerging catheter-based intervention is still considered to be experimental because of a number of concerns and unanswered questions. This review describes the recent progress in BPA at the dawn of a new CTEPH treatment era.

Recent findings: Recent studies about BPA show consistently beneficial effects in haemodynamics, symptoms, 6-minute walking distance, and biomarkers. Exercise capacity and right ventricular function are also improved by BPA. However, this new technique still has potentially fatal complications, including reperfusion oedema and pulmonary artery perforation, even in recent studies. There remain a number of concerns and unanswered questions about BPA, including indications, best procedural approach, and long-term outcomes.

Summary: Recent advances in BPA for inoperable CTEPH are promising. Further investigation by multidisciplinary CTEPH teams is mandatory before BPA's role in CTEPH treatment strategies is determined.

Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Centre, Osaka, Japan

Correspondence to Takeshi Ogo, MD, PhD, 5-7-1 Fujishirodai, Suita, Osaka 565-8565 Japan. Tel: +81 6 6833 5012; fax: +81 6 6833 5126; e-mail:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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Chronic thromboembolic pulmonary hypertension (CTEPH) is defined by pulmonary hypertension, persistent obstruction of the pulmonary artery with embolism, and no resolution of the embolism despite >3 months of anticoagulation therapy. CTEPH is a devastating disease with high pulmonary vascular resistance leading to right heart failure and death if untreated [1]. An unresolved organized thrombus or an in-situ organized pulmonary thrombosis could cause CTEPH, although the mechanism underlying this disease is not well understood. Pulmonary stenosis or obstruction because of chronic thromboembolism is considered to be one of the mechanisms underlying pulmonary hypertension. The current established gold standard curative therapy for CTEPH is pulmonary endarterectomy (PEA) [2]. However, one-third of CTEPH cases are judged to be inoperable according to the CTEPH international registry due to comorbidities and high-risk status predominantly because of distal lesions [3]. CTEPH cases diagnosed as inoperable have a poor prognosis. Alternative treatment options for inoperable CTEPH patients are anticipated. Recently long-term benefit of riociguat in CTEPH patients has been reported [4]. Medical treatment may be of interest in inoperable CTEPH patients [5].

Balloon pulmonary angioplasty (BPA) is a catheter-based invasive procedure to open stenoses or obstructed lesions in the pulmonary artery with a balloon catheter (Fig. 1). Balloon angioplasty for the pulmonary artery has been established as a treatment for congenital pulmonary stenosis [6,7]. BPA has been suggested as an alternative treatment for inoperable CTEPH and has been used in a small number of selected patients with inoperable CTEPH since 1988 [8]. The concept of BPA treatment in CTEPH is straightforward. Re-opening the occluded pulmonary artery is expected to improve pulmonary blood flow and reduce afterload for the right ventricle. Feinstein et al.[9] described a series of 18 CTEPH cases treated with BPA with promising haemodynamic effects in 2001. However, BPA has not been accepted widely as an alternative therapy for CTEPH primarily because of possible fatal complications, although the treatment effect was encouraging. Since then, Japanese and Norwegian groups have independently developed BPA procedures [10–13,14▪,15▪,16] (Table 1). Recent advances in BPA for inoperable CTEPH are promising in terms of effects and, importantly, safety (Table 2) [10–13,14▪,16]. Now, BPA is gradually being accepted as an alternative treatment option and is being investigated in some CTEPH centres [17,18] However, this emerging catheter-based treatment is still considered to be experimental, as there remain a number of concerns and unanswered questions, including long-term data. We continue to explore the possibility of BPA as a treatment option for inoperable CTEPH. This review summarizes the recent progress in BPA therapy, an emerging treatment option that may bring the dawn of new CTEPH treatment era.

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Indications and procedures for balloon pulmonary angioplasty

Current indications for BPA in our institute are as follows: inoperable CTEPH, as diagnosed by a multidisciplinary CTEPH team including an experienced PEA surgeon; 2) symptomatic (WHO-FC ≥II); no contraindications for catheter intervention (severe renal failure, iodine allergy, and so on); and informed consent. BPA should be considered in patients diagnosed as inoperable because PEA is the only established curative treatment. Recent studies in BPA centres indicate that the reasons for inoperability are predominantly distal lesions, comorbidity, age, residual pulmonary hypertension after PEA, and patient rejection of PEA [11,12,14▪]. Indications and the process for determining operability are important issues. Multidisciplinary CTEPH teams, including PEA surgeons, should determine operability, as operability assessment is complex [19]. Catheter treatment may be attractive for interventionists. However, pro-catheter treatment policy without proper operability discussion may overlook patients who would receive maximum benefit from the established curative PEA. Moreover, this catheter-based approach has not been firmly established and holds potential fatal risks, as described later. Therefore, multidisciplinary CTEPH teams, including PEA surgeons, should also be involved in the process of determining BPA indications. Initially, we used to recruit only severe CTEPH patients (WHO-FC ≥III) for BPA because benefit and risk of this procedure were not well understood. We started to include WHO-FC II patients as safety and efficacy are being confirmed by studies from experienced BPA centres including us.

Residual or recurrent pulmonary hypertension after PEA is also considered to be a possible indication for BPA [20]. Successful emergency rescue BPA cases in critical CTEPH patients have been reported [21,22]. A hybrid PEA and BPA therapy may be considered as a future CTEPH treatment strategy, and there may be additional possibilities for BPA in the treatment of CTEPH. Thus, CTEPH/PEA centres may be in a better position to promote BPA investigations and establish BPA as an alternative therapy.

The evaluation of target lesions for BPA is also an important issue. BPA is based on the simple concept of opening a stenosis or occluded distal pulmonary artery with an angioplasty balloon. The main target vessel is usually a segmental or subsegmental pulmonary artery accessible with a minimum 1.5–2.0 mm balloon. Pulmonary angiography and selective pulmonary angiography are considered to be standard modalities for evaluating target lesions for BPA. However, a clear picture of detailed distal CTEPH lesion morphology is not well understood. Thus, we evaluated distal CTEPH lesions by cone-beam computed tomography (CT) (Fig. 2) and classified them into four patterns (Fig. 3) [23▪]. The majority of the obstructed lesions in distal CTEPH are a mixture of webs and slits according to cone-beam CT findings, which will be easily missed by even selective pulmonary artery angiogram as these webs are not always clearly visualized [23▪] like coronary atherosclerotic lesions. These lesions can be recognized as weak contrast enhancement, delayed blood flow, or limited/delayed venous blood flow return. Webs lesions may be confirmed by intravascular ultrasound [12]. Main target lesions for BPA are considered to be webs and slits lesions. Lesions with severe narrowing or complete obstruction by webs could also be treatable as long as distal run-off is confirmed. However, pulmonary artery angiography or even selective pulmonary artery angiography sometimes underestimate distal antegrade pulmonary artery flow over the severe narrowing and mislead us to think that it is not distal run-off [23▪]. Wedged angiography or advanced imaging modalities (cone-beam CT among others) are helpful to detect unrecognized antegrade distal pulmonary artery flow over the severe narrowing or pseudo-complete obstruction. Pouching defects lesions without distal run-off or proper collateral flow are considered to be poor indication for BPA because of a pulmonary perforation risk. BPA for pouching defects lesions with distal run-off (antegrade flow or collateral) is challenging and no data have supported. We have to assess a balance between risks and benefits when we consider approaching these lesions in BPA, although it can be technically possible to penetrate it. Lesion type BPA assessment should be further investigated for efficient BPA procedure.

Currently, our group is utilizing advanced CT imaging [23▪] in addition to angiography as part of a pre-BPA strategy assessment process that includes analyzing lesion location, type, and vessel sizing for efficient treatment in each patient. Current advancements in imaging will change our understanding of CTEPH lesions and enable sophisticated BPA treatment. New imaging techniques, including advanced CT, magnetic resonance angiography, and positron emission tomography may be useful for pre-BPA assessment including anatomical assessment, risk and benefits in lesion types, distal run-off, and collateral information. New intravascular modalities such as optical coherence tomography [24] may also be useful during the procedure to evaluate vessel size and lesion anatomy. Further investigations for distal CTEPH lesion are mandatory.

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Effect of balloon pulmonary angioplasty

All recent BPA studies show consistently favourable haemodynamic effects. Pulmonary vascular resistance decreased by 33–65% [10,12,13,14▪,16]. This haemodynamic improvement is achieved on average by 2–5 staged sessions. Haemodynamic improvement is considered to some extent in proportion to the number of treated vessels. The more the pulmonary artery is opened, the better the haemodynamic improvement for the patient. Interestingly, haemodynamic improvement is not often observed immediately after each BPA [11]. It may take some hours for haemodynamic improvement whose process and mechanisms are not still clear. WHO functional class and 6-minute walking distance clearly improved in most of the recent studies. Exercise capacity and ventilatory efficiency as measured by cardiopulmonary exercise tests also improved [13,25]. Our results showed that exercise capacity and ventilatory inefficiency improved early after the final BPA procedure [25]. BPA is often performed in a stage-by-stage manner. Interestingly, exercise capacity improvement is associated more with the number of procedures than is haemodynamic change. It may be speculated that exercise capacity improves stepwise along with haemodynamics, amelioration of heart failure symptoms, increased activity, and subsequent peripheral adaptation acquired during the interval between sessions.

Right heart function is one of the most important factors for predicting the prognosis of pulmonary hypertension. Right ventricular (RV) reverse remodelling with BPA as assessed by cardiac MRI [14▪] and three-dimensional/speckle-tracking echocardiography [26] are observed along with haemodynamic improvement. BPA improved RV volumes, RV systolic function, interventricular septal bowing, and RV dyssynchrony [14▪,26]. Improved RV function will support the usefulness of BPA for CTEPH. The evaluation of RV function by noninvasive modalities in BPA could provide significant information in terms of efficacy, treatment goals, and outcomes.

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Complications and prognosis with balloon pulmonary angioplasty

Complications remain one of the current important problems with BPA. Reperfusion oedema could lead to critical conditions. Over-blood flow, high pressure, sheer stress, and possibly cytokines after dilatation of target vessel could lead to acute over-reperfusion insults. Reperfusion oedema is still a relatively common complication after BPA, with a reported incidence of 53–60% [11,12]. Severe reperfusion oedema was recognized in 0–7% of cases in recent studies, although it is sometimes difficult to distinguish between reperfusion oedema and haemorrhage without haemoptysis. High pulmonary artery pressure [9], first BPA session, and severe haemodynamics (low cardiac output and high brain natriuretic peptide levels) [11] are reported to be the risk factors for pulmonary oedema.

Prevention and management of complications are important for well tolerated BPA procedures. Inami et al. proposed the PEPSI [27] (predicting score: Blood flow × haemodynamics) score as a predictor for pulmonary oedema. They also reported that a combined approach using pressure wire guidance and the PEPSI score might reduce reperfusion oedema [28]. Further evaluation of this approach to forecast and prevent reperfusion oedema is necessary. Nasal continuous positive airway pressure or nasal high-flow [29] are used to treat mild-to-moderate low oxygenation in reperfusion oedema instead of artificial respirators. Preventive effect of nasal continuous airway pressure for reperfusion oedema is not clear. What is the key to avoid serious reperfusion? A stepwise approach is suggested to reduce the chance to have reperfusion oedema. Although there are no solid data for the benefit of a stepwise BPA approach, it sounds reasonable, considering first BPA session, high blood flow, and severe haemodynamics may contribute to the reperfusion oedema [9,11]. Limiting blood flow improvement by under vessel size pulmonary artery dilatation will reduce the re-perfused vascular insults at initial sessions with severe haemodynamic status. And we then dilate the vessels with proper size balloon at subsequent sessions when haemodynamics is not severe. There are no solid data on pre-BPA medical treatments, such as steroids, to prevent reperfusion oedema. We previously reported that continuous intravenous prostacyclin therapy before PEA might be beneficial [30]. Benefits of medical treatment before BPA could be an issue to be studied. Further investigation is needed to determine the mechanisms and prevention for reperfusion oedema.

One of the most critical complications in BPA is pulmonary artery perforation, which may lead to severe lung haemorrhage and death. Pulmonary perforation is recognized in 0–7% of cases [11–13,14▪]. One patient (1.5%) was reported to have died from perforation [12]. Proper wire positioning and knuckle wire techniques may be helpful to reduce pulmonary perforation. Disproportionate balloon size to the vessel could be the risk of pulmonary artery rupture. I summarized some points to avoid reperfusion oedema and pulmonary artery perforation/rupture (Table 3). Periprocedural mortality was reported to be 0–10% [11–13,14▪,15▪,16] in recent studies. As a catheter-based procedure, BPA largely relies on operator techniques and proficiency. Therefore, BPA may have a steep learning curve. In my opinion, an operator must perform at least 50 cases to perform stable procedures. Therefore, it may be suitable to centralize BPA procedures to high-volume CTEPH centres to reduce procedure-related complications. Improved devices and innovative techniques for safer BPA may prevent procedural complications.

At present, no obvious re-stenosis or recurrence after BPA has been reported. Stent implantation to prevent re-stenosis in BPA for CTEPH will not be necessary, assuming at least short-term good patency. Retrospective study data showed that the BPA group had better survival compared with the group receiving medical treatment, and the prognosis for BPA patients was comparable with that for PEA patients [15▪,16]. However, it is too soon to advocate that BPA is superior to medical treatment and similar to PEA. Long-term patency and prognosis are mandatory for this new procedure. Further evaluation of BPA is necessary to determine its role in CTEPH treatment [31▪▪]. In the future, standardization of the BPA procedure, new devices, and better strategies to maximize effects and minimize complications need continuous investigation. Treatment goal, combination with medical therapy, hybrid therapy with PEA, micro-vessel pulmonary arteriopathy involvement, poor-responder, residual pulmonary hypertension after BPA, late haemodynamic improvement mechanism, BPA education, radiation exposure, and cost-effectiveness [31▪▪] are also issues remaining to be clarified.

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CTEPH is a life-threatening disease, especially for patients with severe, inoperable disease. Balloon pulmonary angioplasty, a new alternative treatment option for selected patients with inoperable CTEPH, has been promising in terms of clinical effectiveness in recent studies, although it still holds potential life-threatening complications. However, it is too soon to advocate rapid widespread application to CTEPH patients because there are still a number of concerns and unanswered questions related to this procedure. Multidisciplinary CTEPH teams should be involved in the process of investigating and establishing BPA's position in CTEPH treatment. Further investigations of BPA, including long-term data, are mandatory before the role of BPA can be determined in the new CTEPH treatment era [15▪,31▪▪].

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I would like to thank Dr Jin Ueda, Dr Sigefumi Fukui, Dr Akihiro Tsuji, Dr Yoshiaki Morita, Dr Yoshihiro Sanda, Dr Tetsuya Fukuda, and Dr Norifumi Nakanishi for their contribution to BPA.

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Financial support and sponsorship

This work was supported by the Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Centre, Japan.

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Conflicts of interest

T.O. has received lecture fees from GlaxoSmithKline K.K., Actelion Pharmaceuticals Japan Ltd., Nippon Shinyaku Co., Pfizer Japan Inc., and Bayer Yakuhin Ltd., and research grant from Pfizer Japan Inc., Mochida pharmaceutical Co., Lts., Fujimoto pharmaceutical Co.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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Right ventricular function, one of the most important prognostic factors in pulmonary hypertension, is improved by BPA using cardiac MRI, which is the most trustable modality to evaluate right ventricular function. These data support the effectiveness of this intervention in CTEPH.

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This retrospective study describes the effectiveness of BPA comparing pulmonary endarterectomy. It indicates the current changing new CTEPH strategy including BPA.

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This study describes detailed morphology of organized thrombus in distal pulmonary artery.

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This is the latest CTEPH treatment review including new treatment such as BPA and medical treatment.


balloon pulmonary angioplasty; catheter intervention; chronic thromboembolic pulmonary hypertension

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