Comparison of Balloon Pulmonary Angioplasty and Pulmonary Vasodilators for Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review and Meta-Analysis

Treatment options for chronic thromboembolic pulmonary hypertension (CTEPH) that is not amenable to thromboendarterectomy or is recurrent/persistent after thromboendarterectomy (inoperable CTEPH) include pulmonary vasodilators or balloon pulmonary angioplasty (BPA). We compared efficacy and safety outcomes of BPA with or without pulmonary vasodilators to pulmonary vasodilator therapy alone in patients with inoperable CTEPH. Observational and randomized trial data reporting outcomes for >5 patients with inoperable CTEPH were sought. Single-arm random effects meta-analyses were performed. The primary outcome was change in six-minute walk distance (6MWD). Secondary outcomes included safety; World Health Organization functional class (WHO FC); and change in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index. Thirty-four studies with 1604 patients were eligible for analyses. Both treatments resulted in significant improvement in 6MWD (71.0 meters, 95% CI: 47.4–94.5 meters with BPA versus 47.8 meters, 95% CI: 34.5–61.2 meters with pulmonary vasodilators), PVR [−3.1 Wood Units (WU), 95% CI: −4.9 to −1.4 WU versus −1.6 WU, 95% CI: −2.4 to −0.8 WU] and mPAP (−14.8 mmHg, 95% CI: −18.2 to −11.5 mmHg versus −4.9 mmHg, 95% CI: −6.9 to −2.8 mmHg). Cardiac index was similar and most patients were WHO FC II and III after their respective interventions. More complications occurred in the BPA arm. In conclusion, BPA and pulmonary vasodilators both improve 6MWD and hemodynamics in patients with inoperable CTEPH. While BPA may offer greater functional and hemodynamic improvements, this technique carries the accompanying risks of an invasive procedure.

outcome measures. The primary outcome was change in six-minute walk distance (6MWD). The secondary outcomes included World Health Organization (WHO)/New York Heart Association functional status, change in mean pulmonary arterial pressure (mPAP), change in pulmonary vascular resistance (PVR), change in cardiac index, and safety outcomes. The safety outcomes were divided into reperfusion pulmonary edema, wire injuries, and all-cause mortality during follow-up for the BPA arm. For the medical arm, the safety outcomes were divided into serious adverse events and all-cause mortality during follow-up. Adverse events were defined as serious if they necessitated admission to the hospital or prolonged existing hospitalization, led to an unplanned procedure, led to discontinuation of therapy, or were described as being life-threatening or causing severe disability. Any other events that the study authors defined as serious were also classified as serious adverse events. The outcome definitions are also outlined in Supplemental Appendix 3.

Data extraction.
A single investigator performed data extraction (R.K.) with random and blinded verification for consistency in data extraction by two other authors (K.P. and T.T.). Study quality was assessed via the Newcastle-Ottawa scale for observational studies 14 and the Cochrane Risk of Bias Tool for randomized controlled trials 15 . All disagreements in study design and data extraction were resolved via mutual consensus.
Data synthesis and statistical analyses. Categorical variables were represented as counts with proportions. Continuous variables were represented as means and 95% confidence intervals (95% CI). If authors reported medians and interquartile ranges, means and standard deviations were calculated. Standard deviations were estimated without knowledge of the correlation between pre-and post-treatment values where authors did not provide standard deviations. These estimates likely constituted an over-estimate of the standard deviation and produced more conservative results. Estimates of variance were digitally extracted where they were not reported in text by study authors 16 . The methods used to transform study-level data to a consistent form are outlined in full in Supplemental Appendix 4. Meta-analysis of proportions was used to summarize categorical baseline characteristics and outcomes. Where a proportion of 0 or 1 was noted, a continuity correction of 0.5 was applied. Meta-analysis of continuous variables was done with means and standard errors. Random effects models with inverse variance weighting were used to provide the most conservative effect estimates and 95% confidence intervals, as we expected a priori to see considerable variability between studies. I 2 values were used to assess for heterogeneity 17 . Two-tailed p-values were used for hypothesis testing and the significance level was set at 0.05. Publication bias was assessed using Egger's regression 18
The procedural protocol for BPA varied amongst the included studies. The mean number of procedures was 4.9 (95% CI: 3.1-6.7 procedures) and the patients underwent a mean 7.1 vessel angioplasties per procedure (95% CI: 0.8-13.3 vessels).

Sensitivity analyses.
There was significant heterogeneity in the change in 6MWD in the BPA arm (I 2 = 70.5%). In order to evaluate heterogeneity, meta-regression was performed to evaluate the effect of procedural volume on change in 6MWD after BPA. The number of procedures reported by the authors was used as a study-level covariate. There were no differences in change in 6MWD by procedural volume (p = 0.32, Fig. 4).     www.nature.com/scientificreports www.nature.com/scientificreports/ There was also significant heterogeneity in change in 6MWD in the pulmonary vasodilators arm (I 2 = 94.4%). Meta-regression analyses were performed to evaluate whether the type of pulmonary vasodilator affected change in 6MWD. There were no differences in change in 6MWD by the type of pulmonary vasodilator (p = 0.94, Fig. 5).
Given that riociguat is currently the only approved drug with a label to treat inoperable CTEPH in the United States, we also analyzed the subset of pulmonary vasodilator studies that evaluated riociguat usage 10

Discussion
Here, we show that BPA and pulmonary vasodilators improve mean 6MWD, PVR, and mPAP in patients with inoperable or recurrent CTEPH after thromboendarterectomy. There are multiple potential explanations for our results. First, CTEPH occurs from the combination of large and moderate-sized vascular obstruction with a microvascular arteriopathy that emerges over time 1,52 . We hypothesize that the improvements in 6MWD, mPAP, and PVR in the BPA arm are related to the relief of the macrovascular obstruction. Relief of macrovascular obstruction is thought to mitigate disease progression and improve prognosis across the spectrum of pulmonary thromboembolic disease. This is evident in patients undergoing thromboendarterectomy for operable CTEPH 53 , but also in patients undergoing catheter-based intervention and surgical pulmonary embolectomy in the setting of acute pulmonary embolism 54,55 . This may partly explain why pulmonary thromboendarterectomy improves survival in CTEPH whereas pulmonary vasodilators do not 56 . However, pulmonary vasodilators improve functional and hemodynamic measures likely by targeting the microvascular arteriopathy in patients with inoperable CTEPH. The relative differences in the functional and hemodynamic changes between pulmonary vasodilators and BPA were of great interest to us. The smaller improvements observed with pulmonary vasodilators in comparison to BPA suggest that the large-and www.nature.com/scientificreports www.nature.com/scientificreports/ moderate-obstruction predominates in the pathology of CTEPH rather than the microvascular arteriopathy, which is consistent with the prior understanding of this disease 1,6,7 . Regardless, all of these explanations (particularly relating to the location and type of obstruction) are highly speculative and further translational research is required to elucidate these mechanisms.
Our work adds to the existing literature base pertaining to treatment strategies for inoperable CTEPH. Our investigation reports outcomes for the breadth of techniques used for BPA and the full gamut of pulmonary vasodilators that have been trialed for the treatment of inoperable CTEPH. Phan et al. compared hemodynamic and functional outcomes in patients with inoperable CTEPH in their meta-analysis. They found that BPA has a greater functional and hemodynamic improvement than with pulmonary vasodilators 57 . This is consistent with our results. However, Phan et al. 's investigation did not include several key studies pertaining to BPA 8,22-29 and pulmonary vasodilators 12,33,34,39,43,46 . Wang et al. also compared riociguat to BPA in patients with inoperable CTEPH 58 . The results in this investigation matched those in our overall investigation and our sensitivity analysis. We believe that our investigation, through its inclusion of multiple pulmonary vasodilator therapies, is more reflective of real world patterns as a large European registry of expert centers 56 , an international physician survey 59 , and the recent French cohort of BPA patients 30 suggest that CTEPH patients are routinely treated with  www.nature.com/scientificreports www.nature.com/scientificreports/ different pulmonary vasodilators (riociguat, phosphodiesterase-5 inhibitors, endothelin antagonists, and prostacyclins) and many patients are on combination therapy. Additionally, the Wang investigation did not evaluate safety outcomes for pulmonary vasodilator therapies. Khan et al. 60 and Zoppellaro et al. 61 evaluated the benefit of BPA in patients with inoperable CTEPH through single-arm meta-analyses of the available BPA data. Both investigations demonstrated improvements in mean 6MWD, mPAP and PVR with effect estimates that were similar to ours. However, neither investigation had a comparison with pulmonary vasodilator therapy, thus limiting the generalizability of their study results. Moreover, there was significant duplication of outcome reporting in their investigation from the individual cohorts that were pooled and reported in the Ogawa et al. investigation 8 . Nonetheless, our results along with the previously published results show that both BPA and pulmonary vasodilators provide beneficial effects in inoperable CTEPH.
The emergence of pulmonary vasodilator and BPA therapies for inoperable CTEPH reiterates the need for a multi-disciplinary approach to optimize CTEPH treatment. An expert team should collaboratively determine the operability of CTEPH patients and when patients are deemed inoperable, the optimal treatment approach whether BPA, medical therapy, or a combination of both should be determined. In CTEPH centers, the established infrastructure of cardiac catheterization laboratories may facilitate carefully selected specialists to perform BPA to reduce the symptom burden in inoperable CTEPH. However, for patients with operable CTEPH, surgical thromboendarterectomy remains the preferred option and should not be replaced by BPA until head-to-head comparisons can be performed 9 . Additionally, the rise of the hybrid approaches such as combining BPA and medical therapy both pre and post-surgical thromboendarterectomy, may lead to further hemodynamic improvement and improve long-term survival in CTEPH 62 . Aoki et al. 63 and Wiedenroth et al. 64 have previously demonstrated that a combination approach of BPA and pulmonary vasodilators likely exhibits a treatment interaction to improve mPAP, PVR, and WHO FC more than just the isolated use of BPA or pulmonary vasodilators. Our findings also highlight the heterogeneity in the definition of inoperable CTEPH. This is evidenced by the wide variation in functional and hemodynamic status of patients who were deemed inoperable (Table 1). This is also in the context of changing criteria for pulmonary thromboendarterectomy candidacy from primarily anatomic criteria to greater integration of hemodynamics and functional status 7 .
We acknowledge that our investigation has several important limitations. The pooling of data in the form of meta-analyses has well-recognized limitations 65 . Additionally, there are inherent biases in the comparison of observational data for BPA to clinical trial data for medical therapy. We did pool all medical therapy together, but there is evidence in pulmonary arterial hypertension that prostacyclin has greater hemodynamic benefits than oral vasodilators 66 . Moreover, only riociguat is approved for treatment of CTEPH so other medical therapies are considered experimental 9 . However, our investigation was meant to provide a broad overview of the treatment approaches to identify major trends. The greatest limitation is the lack of head-to-head data comparing pulmonary vasodilators and BPA. Our hope is that two ongoing randomized trials, UMIN000019549 67 and NCT02634203 68 , will provide estimates of each approach's relative efficacy.
There are important considerations and limitations in our study regarding the effectiveness of BPA. First, there is regional variability in the definition of operable CTEPH. Many investigations in our meta-analyses did not outline the adjudication process for inoperability, and thus the treatment effect of BPA may be exaggerated. Another important consideration for BPA is the emerging experience and continued refinement of the procedure, which may lead to heterogeneity in BPA data. For instance, there is no clear standard on how many procedures of BPA should be done per patient, what the timing between procedures should be, what the optimal technical approach is, and which pulmonary artery segments should be intervened on first 6 . There has been a reduction in the incidence of reported complications since Feinstein first reported the use of BPA for inoperable CTEPH. This was noted in later published series and is likely attributed to improvement in procedural techniques, devices, and greater use of intravascular imaging. The lack of an accepted protocol or standard of when to perform BPA and/ or administer pulmonary vasodilator therapies may introduce bias. Furthermore, there may also be treatment interactions between the relief of macrovascular obstruction by BPA and concomitant/subsequent administration of pulmonary vasodilators that may overestimate the treatment benefit of BPA. This hybrid approach requires further investigation before widespread implementation as prior estimates of the costs of pulmonary vasodilator www.nature.com/scientificreports www.nature.com/scientificreports/ therapy in CTEPH have ranged from $12,000 to $98,000 American dollars per annum 69 . We were unable to fully identify the benefit of hybrid therapy via sensitivity analyses since we did not plan them a priori.
Finally, there were minimal changes in cardiac index in both arms. This was likely biased by limited reporting of cardiac index in the included studies.

conclusions
In summary, BPA and pulmonary vasodilators both improve functional and hemodynamic outcomes in patients with inoperable CTEPH. While BPA may offer greater functional and hemodynamic improvements, this technique carries the accompanying risks of an invasive procedure. More high-quality randomized data with long-term follow-up is needed to definitively examine the role of BPA and pulmonary vasodilators for the treatment of inoperable CTEPH.