Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive chronic disease that is characterized by obstruction of the pulmonary arterial vasculature by organized thrombotic material, leading to fibrosis, thickening of the intima, vascular remodeling and plexiform lesions that cause increased resistance and pressure in the pulmonary circulation, severe pulmonary hypertension (PH), right heart overload, right ventricular failure and death.1–6 Prognosis is poor if only treated medically, with one-, three- and five-year survival of 90.2%, 78.4% and 64.5%, respectively.7 Surgical pulmonary endarterectomy (PEA) is the first-line treatment for patients with CTEPH and, when performed in experienced centers, is associated with in-hospital mortality of <5% and leads to hemodynamic and functional improvement, with good long-term survival.8,9 However, fewer than 60% of patients are considered eligible for surgery.10–12 Reasons for patients to be rejected for surgery include more distal location of the disease (technically inoperable) and patient-related factors (technically operable but with a poor risk/benefit ratio for surgery due to comorbidities).10 Furthermore, up to 50% of operated patients suffer residual or recurrent PH, worsening morbidity and mortality.12–14 Medical treatment with riociguat, a soluble guanylate cyclase stimulator, improves hemodynamics and exercise capacity in these patients but is not curative.15–17 In this context, balloon pulmonary angioplasty (BPA), an endovascular procedure for dilating stenotic or obstructed pulmonary arteries, has emerged as an alternative therapeutic option for CTEPH patients who are unsuitable for surgery or who have recurrent or persistent PH after PEA.12

After the first case report, published in 1988,18 the first case series on BPA as a treatment for CTEPH, by Feinstein et al., was published in 2001.19 The technique proved to be effective, lowering mean pulmonary artery pressure (mPAP) and improving functional class, but had a high rate of complications, particularly fatal reperfusion pulmonary injury and need for mechanical ventilation,19 and was abandoned for a decade.

The technique re-emerged in 2012 when centers in Japan20–22 published three series reporting greater safety as well as clinical and pulmonary hemodynamic improvements. These favorable results were confirmed in a multicenter Japanese registry23 that included 308 patients with CTEPH treated by BPA in a total of 1408 sessions in seven centers. Significant hemodynamic improvements were seen, with lower pulmonary vascular resistance (PVR) in over 50% of patients, and overall survival at 1–3 years comparable to surgery (96.8% and 94.5%, respectively).

In Europe, the number of centers starting BPA programs has grown considerably in recent years.24–28 The largest case series in a single French center was recently published, including 184 patients participating in a total of 1006 BPA sessions; it confirmed significant short-term improvements in symptoms, exercise capacity and hemodynamics, as well as the safety of the procedure and its long-term efficacy, with three-year survival of 95.1%.29

No published data are currently available on the Portuguese experience with BPA. The present study aims to present the results of the initial experience in our center and to assess the short-term symptomatic, functional and hemodynamic benefits, as well as the safety, of BPA in the treatment of CTEPH patients.

In the present study, we report our center’s initial experience as well as the first national data on treatment of CTEPH by BPA. Hospital Garcia de Orta became a Portuguese reference center for pulmonary hypertension in 2014, and began offering BPA in December 2017 under the technical and scientific guidance of experts from high-volume centers in France and Japan. In all cases, eligibility for BPA was decided by a multidisciplinary team, as recommended by the current guidelines.12

Our results confirm the efficacy of the technique in the treatment of CTEPH patients who are inoperable or who have residual or recurrent PH following surgery. Under optimal pulmonary vasodilator therapy, BPA provided additional improvements in functional class and exercise capacity that were significant in the short term. All patients were without limitations in physical activity at six-month follow-up, as shown by a mean increase of 42 m in 6MWT distance. Oxygen therapy and prostaglandin analogs were also discontinued in 100% of patients, resulting in improved quality of life and reductions in the costs of these therapies. Overall, there was a tendency toward improvements in hemodynamic parameters (mPAP and PVR). The reduction in mPAP in our study (25%) was similar to that recently reported in the French series29 (26%) and greater than in a German series28 (18%), but less than in the Japanese registry,23 in which the mean reduction was 44%. Regarding PVR, a reduction of 42% was seen in our study, comparable to that of the French registry29 (43%), greater than in the German registry28 and less than the 66% in the Japanese registry.23

There are several possible reasons for the differences between our results and those of the multicenter Japanese registry. The Japanese centers have considerably more experience and larger sample sizes, with 308 patients treated in their multicenter registry23 (unlike the French series,29 in which, although the sample was larger than ours, with 154 patients, the hemodynamic results were similar). There were differences in study populations, such as a greater incidence of symptomatic acute venous thromboembolism in our study (73% in our series and the French series29 compared to 35% in the Japanese registry23). There may be a more inflammatory thrombotic phenotype in European CTEPH patients than in Japan, which could lead to different responses to treatment.34 In addition, selection procedures for BPA could differ, since Japanese centers have less surgical experience and thus many patients undergoing BPA in Japan would be considered operable in European centers,35 unlike the majority of patients in our series who were inoperable or post-surgical. There was also a longer interval between CTEPH diagnosis and the first BPA session (median 55 months in our study), which meant that some patients could have developed peripheral pulmonary arterial disease, affecting the hemodynamic results of the BPA sessions. Furthermore, a larger proportion of our patients (82%) were under pulmonary vasodilator therapy at the beginning of the BPA program than in the Japanese series (72%)23 and in the French series (62%),29 and so the statistically significant improvements in hemodynamic variables between diagnosis and beginning the program due to vasodilator therapy may have reduced the absolute benefit observed with BPA.

The hemodynamic results in our study were better than in the German series, which may be explained by the number of vessels treated; although the median number of sessions per patient was similar, a mean of 3.9 vessels were treated in our center compared to 2.0 in the German series.28 As pointed out by Matsubara and Ogawa,36 to improve the efficacy of BPA, it is necessary to increase the number of vessels treated (by increasing the number of sessions per patient or the number of vessels treated per procedure). These authors also underline the importance of approaching difficult lesions, such as occlusions, despite the greater risk of complications, since the hemodynamic benefit from treating these obstructive lesions is potentially greater than from dilating less stenotic vessels. By avoiding treating highly complex lesions with a greater risk of complications (only 8.6% of treated lesions were total occlusions, whereas webs were dilated in most cases), the more conservative approach in the present series may also have contributed to the smaller hemodynamic improvement compared to the Japanese series.

Compared to the previously available therapies, the hemodynamic effects of BPA seen in our study were overall inferior to those reported for PEA surgery, which reduces mPAP by around 40% and PVR by around 60%.6,8,9,11 Nevertheless, in the subgroup of patients with severely impaired hemodynamics the hemodynamic benefits were similar to those of PEA, with reductions of 51% in mPAP and 67% in PVR, with final values within the normal range and thus with the potential to achieve hemodynamic normalization. These findings raise the question of the best way to measure the efficacy of BPA in patients with less severely impaired or even normal hemodynamics. In patients with less severely impaired hemodynamics, the efficacy of BPA should probably not be measured in terms of hemodynamics at rest, but rather by exercise parameters such as cardiopulmonary exercise testing or even exercise right heart catheterization.37

Regarding medical therapy, the profile of hemodynamic changes seen with BPA was different from that reported with pulmonary vasodilator therapy, since we observed improvements in mPAP and PVR but only very slight changes in cardiac index. Medical therapy, by contrast, tends mainly to improve cardiac output, with only modest effects on mPAP.15–17 The increase in cardiac output seen with pulmonary vasodilator therapy may be in part the result of systemic vasodilation.38 In the present series, cardiac index was normal (mean 2.7 l/min/m2) immediately before the beginning of the BPA program, so it would be hard to demonstrate any improvement in this parameter.

The procedure-related complication rate in our study was 25%, which is higher than reported in previous European series (9% in the German series28 and 11% in the French registry29), but lower than the 36% in the Japanese registry.23 However, these complications were mild, not requiring intensive care or leading to death. By contrast, the rate of fatal complications ranged from 2% to 4% in the three studies referred to above.23,28,29 Similarly to the German series, and in agreement with the literature,39–41 the most frequent complication was pulmonary vascular injury with or without pulmonary hemorrhage; the incidence of reperfusion pulmonary injury, the most common complication in the Japanese23 and French series,29 was low in our study.

There are several possible explanations for the high number of minor complications and low number of major complications, including reperfusion injury, in our study. These include the fact that all minor complications were recorded, and that the sessions were planned on the basis of thoracic computed tomography angiography studies that are known to provide more detailed information on the peripheral pulmonary arteries, enabling a more reliable assessment of vessel accessibility, morphology and diameter and lesion characteristics, and more accurate sizing of the angioplasty balloons.42,43 We did not use low molecular weight heparin bridging in patients taking direct oral anticoagulants, which is associated with a higher risk of bleeding.44 Furthermore, almost all of our patients were under optimal pulmonary vasodilator therapy before the first BPA session. The BPA procedure was guided by pressure wire in the first sessions in all patients with severely impaired hemodynamics, since higher mPAP and PVR are predictors of pulmonary injury.29 One of the main benefits of using a pressure wire is that pressures distal to the target lesions can be measured; another is that it helps to avoid overdilation of the target vessel. This may help to reduce angiographic complications, decreasing the risk of vascular injury during the procedure and of associated reperfusion pulmonary injury.45,46 Last but not least, we began our BPA program with improved techniques22 and based on the experience of experts in high-volume centers.29 As has been pointed out, there is a learning curve associated with the BPA technique, and its efficacy and safety improve with experience.29,35,36

Our study has some limitations. Firstly, it is a single-center study that includes a limited number of patients and BPA sessions. Secondly, a high proportion (82%) of our patients were under optimal therapy with at least one pulmonary vasodilator before the first BPA session, which could mean that medical therapy affected post-procedure results, as reported in previous studies.22,23,47 Finally, long-term follow-up results, required to assess the efficacy of the technique beyond six months post-procedure, are as yet unavailable.

The data presented here are of the first series of CTEPH patients treated by BPA in Portugal so far described in the literature. Before the implementation of the BPA program in our center, the only therapeutic alternatives for patients with inoperable CTEPH or residual or recurrent PH after surgery was medical therapy with pulmonary vasodilators. The implementation of our BPA program provided another therapeutic strategy for these patients. After the operationalization of this multidisciplinary program, its results need to be validated in terms of both efficacy and safety. The results described above confirm the significant benefits of the procedure in terms of pulmonary vascular hemodynamics, as well as of symptoms and functional capacity, which were sustained for at least six months of follow-up. These benefits were accompanied by a significant number of minor periprocedural complications, but there were no major procedure-related complications or deaths. Finally, the short- and long-term results of BPA need to be properly assessed in a prospective multicenter study.

The study has no funding to declare.

The authors have no conflicts of interest to declare.