Early Results of Sotatercept Treatment in Patients With Severe Pulmonary Hypertension and a Potts Shunt

ABSTRACT

Twelve patients with severe pulmonary hypertension (PH) who had a pulmonary artery‐to‐descending aorta (Potts) shunt were treated with the novel PH drug sotatercept for an average of 12 months. Overall, the group showed significant improvement in a number of clinical parameters with no serious complications. Thus, a trial of sotatercept could be considered prior to an invasive intervention in patients with severe PH. Similarly, it may also be useful in patients with Eisenmenger‐like physiology.

1. Introduction

Thirty years ago with the advent of prostacyclin analogues, and the subsequent addition of endothelin receptor antagonists (ERA) and PDE5 inhibitors (PDE5i), the survival of patients afflicted with pulmonary hypertension (PH) has improved dramatically [1]. Despite these successes, patients still die from their disease. For younger patients, especially children, with medically refractory PH, two options are available: bilateral lung transplantation or a pulmonary artery‐to‐descending aorta shunt, generically referred to as a Potts shunt. A study of 110 children with severe PH who underwent a shunt procedure demonstrated that a shunt can provide significant clinical improvement, with 5‐year survival comparable to that seen with lung transplantation [2]. While providing real benefit to children with severe PH, shunts are obviously not a cure and the underlying disease process can still progress beyond the ability of the shunt to provide relief. With this concern in mind, we were interested in whether the novel PH medication sotatercept could provide additional benefit to these heretofore “medically refractory” patients. Sotatercept is a fusion protein that helps to restore the balance within the pulmonary vasculature between growth‐promoting and growth‐inhibiting signals [3]. Adult studies have shown it to improve hemodynamics, exercise capacity and World Health Organization functional class (WHO‐FC), while reducing time to clinical worsening. Adverse events were relatively minimal with concerns centered around bleeding (especially epistaxis), thrombocytopenia, and polycythemia.

2. Case Descriptions

We initiated sotatercept therapy in 12 patients who had previously undergone a shunt procedure. Consent was obtained for data usage. Eleven of the patients were classified as having WHO type 1 PH, that is, pulmonary arterial hypertension. One had both WHO type 1 and type 3 disease (PH secondary to lung disease) due to having had a congenital diaphragmatic hernia. Average age at the time of their shunt was 12.4 years (range 6–21.3 years). Seven had shunts consisting of valved conduits placed via a median sternotomy, two had shunts placed using a catheter‐based intervention, one had stenting of a residual patent ductus arteriosus and two had shunts placed via a left thoracotomy. At the time of sotatercept initiation, all 12 patients were on a PDE5i and a prostacyclin analogue, while 11/12 were on an ERA. Seven of the 12 were on prostacyclin infusion therapy. Average age at the time of sotatercept initiation was 15 years (range 11–22 years) with an average time of 2.8 years (range 3 months–7.6 years) between their shunt procedure and sotatercept initiation. Duration of time on sotatercept when final data were collected was a mean of 12.1 months (range of 4.5–18 months). At the end of data collection, 9 of the 12 patients were on the recommended maximum dose of sotatercept at 0.7 mg/kg/dose administered every 21 days. Three had their dose reduced to 0.3 mg/kg/dose as detailed below. Clinical and laboratory factors were assessed prior to the initiation of sotatercept (pre) and at the last time of data collection after sotatercept initiation (post). Factors assessed included WHO‐FC, 6 min walk distance (6MWD), NT‐proBNP levels, upper extremity/lower extremity oxygenation saturation (Sa02) differences (the pulmonary‐to‐systemic shunts typically send deoxygenated blood to the descending aorta, resulting in a lower Sa02 in the lower extremities compared to the upper extremities). Also compared were hemoglobin (Hgb) levels and platelet counts. Statistics were done using the Wilcoxon signed‐rank test for FC, paired t‐test for other variables. A p‐value < 0.05 was considered significant.

Overall, there was a significant improvement in average WHO‐FC after sotatercept treatment, 2.5 pre vs. 1.8 post, p = 0.01 (Table 1). Consistent with this finding, average 6MWD also improved, from 423 m pre to 493 m post, p = 0.04. NT‐proBNP levels decreased substantially from 861 pg/ml pre to 125 pg/mL post, p = 0.02. Also notable, the average Sa02 differential decreased significantly from 8.8 pre to 1.9 post, p = 0.002, consistent with improved pulmonary vascular function and thus less shunt utilization. Platelet levels did not change significantly pre vs. post sotatercept use, p = 0.8. The lowest platelet levels recorded during sotatercept treatment ranged from 55 to 237 k/mm³. Consistent with their chronic desaturation, Hgb levels were relatively high pre‐sotatercept, average 15.3 g/dL, but did not increase significantly while on sotatercept, p = 0.6. Highest recorded Hgb levels noted during sotatercept treatment ranged from 15 to 20.5 g/dL. None of the patients exhibited symptoms of hyperviscosity. No patient had an escalation in PH‐specific therapy. Indeed, most notably, four of the seven patients on prostacyclin infusion therapy were weaned completely off the medication. None of the patients experienced life‐threatening complications. Three had their sotatercept dose decreased from 0.7 to 0.3 mg/kg/dose: one reduction was due to a Hgb level that rose > 20 g/dL, a second due to worsening hypoxia with activity, and the third due to epistaxis. One patient eventually discontinued sotatercept after 8 months due to persistent epistaxis per family's request.

Table 1.

Average changes in clinical parameters pre‐ and post‐sotatercept usage in 12 patients with pulmonary artery‐to‐descending aorta shunts.

	WHO‐FC	6MWD (m)	NT‐proBNP(pg/ml)	Sa02 Δ	Plts (k/mm3)	Hgb (g/dL)
Pre	2.5	421	861	8.8	170	15.3
Post	1.8	493	125	1.9	174	15.6
p value	0.01	0.04	0.02	0.002	0.8	0.6

Abbreviations: BNP = Brain natriuretic peptide, Hgb = Hemoglobin, Plts = Platelets, SaO₂ Δ = Saturation difference between upper and lower extremities, 6MWD (m) = 6 min walk distance in meters, WHO‐FC = World Health Organization functional class

3. Discussion

Creating a Potts shunt in someone with severe PH is generally reserved for those who have failed PH‐specific medical therapy [2]. Until now, that medical therapy did not include the novel agent sotatercept. In our series of 12 patients with shunts, we found marked clinical improvement after initiation of sotatercept. An improvement that was seen in a relatively short period of time (4.5–18 months) over a range of key PH metrics, including weaning off prostacyclin infusion therapy. Furthermore, these improvements were seen without serious adverse events. We acknowledge that long‐term benefits and side effects in PH patients, including children, treated with sotatercept, remain to be seen. Nonetheless, our initial findings suggest that a trial of sotatercept might be considered prior to shunt placement or even transplantation in those failing conventional PH‐specific medications.

One concern in adult trials is sotatercept's propensity to lower platelet levels while raising Hgb concentration [3]. In our study, platelet levels were relatively unchanged and in only one patient did levels ever fall below the 75 k/mm³ cutoff that would have resulted in dose modification in the adult studies. By its nature, a pulmonary artery‐to‐descending aorta shunt in a patient with severe PH typically results in relative hypoxia in the lower half of the body, essentially mimicking Eisenmenger syndrome physiology. Like many Eisenmenger patients, our cohort had elevated baseline Hgb levels. Indeed, in our series, the average Hgb level of 15.3 g/dL prior to sotatercept initiation would have excluded them from inclusion in the recent adult trials. We therefore elected to use dose modification criteria based on the treatment of Eisenmenger patients, choosing a Hgb > 20 g/dL, and/or symptoms of hyperviscosity, as an indication to alter dosing [4]. Despite these concerns, average Hgb levels post‐sotatercept treatment in our study did not rise significantly above pre‐treatment levels and no patient demonstrated hyperviscosity symptoms. Why our patients did not demonstrate a Hgb rise as seen in the adult trials is unclear. Perhaps the erythropoietic pathway stimulated by sotatercept is already “maximized” in our cohort due to their chronic desaturation from shunt flow. Regardless, our results suggest that sotatercept could also be beneficial in those with classic Eisenmenger syndrome.

Author Contributions

All authors contributed to data collection and manuscript preparation.

Ethics Statement

Written and/or verbal informed consent was obtained for data usage from patient or legally authorized representative.

Conflicts of Interest

The authors declare no conflicts of interest.

Guarantor

The authors have nothing to report.

Aggarwal M. A., Merrill K, Yung D, Mark Grady R, “Early Results of Sotatercept Treatment in Patients With Severe Pulmonary Hypertension and a Potts Shunt,” Pulmonary Circulation 0 (2026): e70296, 10.1002/pul2.70296.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.