With the recognition of CTEPH, the therapy strategies are updated gradually, including the preferred PEA, targeted medicine and emerging interventional treatment. According to the guidelines, riociguat is the first medication recommened for persistent/recurrent PH after PEA or inoperable CTEPH. In 2012, Janpanese investigators refined the BPA procedure to make it an alternative therapeutic approch for patients with inoperable CTEPH. However, it is not clear whether patients who receive long-term riociguat still benefit from BPA procedures. Our current study demonstrates the exercise tolerance and hemodynamics are further improved after long-term riociguat and sequential combination with BPA procdures for the inoperable CTEPH. The main findings of the present study are that(1)riociguat continues to improve exercise capacity and hemodynamics over the long term; (2)the combination of riociguat and sequential BPA procedures generates further improvement in CO,CI, PVR ,6WMD and NT-proBNP, in addition to decreasing the mPAP; (3)BPA can reverse RV remodeling and improve RV function. These fingdings suggest that BPA can further increase the beneficial effects on inoperable CTEPH patients who take long-term riociguat.
In the CHEST-1 study, there were significant improvements in the 6MWD by 39±79m, the NT-proBNP level by -291±1717 pg/ml and WHO function class by 33%, the CO by 0.8±1.1 L/min, as well as a mean reduction in PVR of 226 dyn·s·cm−5 . In a 1-year open-label extension trial (CHEST-2), improvements in 6MWD and WHO FC were maintained, with a survival rate of 97% and a rate of clinical worsening-free survival of 88% at 1 year. Nevertheless, long-term outcome more than one year wasn’t showed in the CHEST study. In our present cohort, exercise capacity and hemodynamics parameters have improved for up to eight years after riociguat treatment and further improvements after BPA. Based on the results of several previous studies, exercise capacity and hemodynamics were associated with prognosis and overall survival among patients with CTEPH[14, 15]. Hence, our findings clearly suggest the benefits of the sequential combinational treatment with riociguat and BPA.
However, right heart size and function assessed by echocardiography have no significant changes during long-term treatment with riociguat, and even tend to deteriorate. The present result contradicts previous data showing that patients under long-term treatment with riociguat demonstrated significantly reduced right heart size and improved RV function in PAH and CTEPH. In the previous long-term riociguat study, the duration of administration was just 12 months, while our present study lasts 8 years whereby the results were beneficial, attesting to the long-term efficacy of riociguat. However, the study also shows an increased in mPAP, over-sized right heart and clinical worsening in some patients. As we know, CTEPH is a progressive condition. The CHEST study has shown that riociguat is not a curable treatment. Therefore, it is not surprising that patients who are technically inoperable or postoperative persistent pulmonary hypertension or have an unacceptable risk/benefit ratio for PEA, treated with riociguat, whose pulmonary hemodynamic/RV size and function may deteriorate over time. These findings suggest that riociguat alone is insufficient for the treatment in this group. The riociguat therapy can only improve the CO of right heart, nevertheless, the structure of right heart and function still gradually deteriorate due to the persistent pulmonary hypertension.
Since Japanese investigators refining the BPA procedure in 2012, it has rapidly spread around the world due to its dramatically improved efficacy and safety. Published data from different countries have shown significant improvements in hemodynamics, exercise capacity and markers of heart failure such as BNP or NT-proBNP level[17–19]. Currently, BPA carries a class Ⅱb recommendation for the treatment of inoperable CTEPH in the European guidelines. PH-targeted medical therapy is common in CTEPH patients prior to treatment with BPA procedure, however, the further benefits of this approach remain unclear. In a small randomized controlled study by Sugimura et al., patients with inoperable CTEPH were treated with medical therapy prior to BPA for 1-3 months, which resulted in improved CO/CI, and PVR, but little change in mPAP and 6MWD, which demonstrated that BPA combined with conventional vasodilator treatment was quite effective in terms of improving the pulmonary hemodynamics and short-term prognosis in patients with distal-type CTEPH. In another study of 36 patients by Wiedenroth et al, patients with inoperable CTEPH were given riociguat before BPA for mean five months, which suggested that the combination of riociguat and BPA was an effective treatment for patients with inoperable CTEPH, leading to significant improvements in physical capacity and pulmonary hemodynamics. These findings illuminated that the short-term use of targeted-PH agents prior to BPA, which contributed to the improvements of right heart function and hemodynamics of the inoperable CTEPH patients, may guarantee the safety of BPA procedure by reducing the incidence of reperfusion pulmonary edema. Our present study showed that BPA generated further benefits for who take riociguat up to 8 years. Kaspar Broch et al. reported a significant improvement in RV functional parameters by echocardiography after BPA in 2015, which indicated credibility to this form of treatment in patients with CTEPH who undergo BPA. In our current study, the changes of right heart size and function by echocardiography after BPA procedure are in line with the previous data. Thus, our study also supports the viewpoint that BPA procedure can reverse the remodeling of right heart structure and function.
Our results demonstrated that long-term riociguat and sequential combination with BPA is an effective treatment for patients with inoperable CTEPH. However, riociguat regulates the NO-sGC-cGMP pathway to prevent the development of PH, the use of anticoagulants for inoperable CTEPH patients merely prevent new thrombosis and reduce pulmonary arteries block. Therefore, medical therapy has limited effect, even long-term medication cannot avoid the aggravation of the disease. BPA procedure improves CTEPH patients’ hemodynamics and exercise tolerance through several mechanisms. Firstly, an overall vessel expansion induced by the stretching of the arterial wall leads to lumen enlargement immediately after BPA. Secondly, the BPA relieves hemodynamic stress towards the non-BPA-side lung and subsequently decreases the non-BPA-side PVR in patients with CTEPH, which plays a significant role in suppression or possibly regression of small-vessel arteriopathy in these patients. The last but not least, BPA procedure improves total pulmonary artery compliance in proportion to a decrease in PVR. Therefore, the BPA procedure directly opens the mechanical obstruction vessels through the above mechanisms to reduce pulmonary vascular resistance and pulmonary artery pressure, thereby decreasing the right cardiac load, significantly reversing remodeling of the RV structure as well as the improvement of RV function, and further improving the prognosis of patients.
Some limitations to this study must be considered. First, this is a single-center observational study. In addition, the number of patients enrolled was small. Furthermore, we have no matched control group. However, our research has its advantages. Namely, we selected patients from the CHEST study in China and our results derived from clinical real observational data. Those patients enrolled in study have taken riociguat for almost eight years, but their mPAP, right heart size and function did not improve significantly, even some patients were clinically worse. Given this, we did sessions of BPA procedures for them, which leading to decreasing mPAP, further enhancement in CO/CI, PVR, especially in right heart size and function by echocardiography. We confirmed not only the long-term efficacy of riociguat in patients with inoperable CTEPH, but also further benefits from BPA procedure.