Identifying “super responders” in pulmonary arterial hypertension

Abstract

Pharmacotherapeutic options for pulmonary arterial hypertension (PAH) have increased dramatically in the last two decades and along with this have been substantial improvements in survival. Despite these advances, however, PAH remains a progressive and ultimately fatal disease for most patients and only epoprostenol has been shown to improve survival in a randomized control trial. Clinical observations of the heterogeneity of treatment response to different classes of medications across the phenotypically diverse PAH population has led to the identification of patients who derive significantly more benefit from certain medications than the population mean, the so-called “super responders.” This was first recognized among PAH patients with acute vasodilator response during invasive hemodynamic testing, a subset of whom have dramatically improved survival when treated with calcium channel blocker (CCB) therapy. Retrospective studies have now suggested a sex discrepancy in response to endothelin receptor antagonists (ERA) and phosphodiesterase inhibitors, and more recently a few studies have found genomic associations with response to CCBs and ERAs. With increasing availability of “omics” technologies, recognition of these “super responders,” combined with careful clinical and molecular phenotyping, will lead to advances in pharmacogenomics, precision medicine, and continued improvements in survival among PAH patients.

Apoptosis signal‐regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension

“…While the pre-clinical models recapitulate many of the features of PAH pathogenesis, they do not truly replicate the complexity of the disease in the patient population; rodent and cellular studies represent a homogenous study population, whereas it is known that PAH patients display differing genetic backgrounds, co-morbidities and are often currently on vasodilator therapies which may influence their ability to respond to novel treatments. [61][62][63] It is also well recognised that inter-individual differences mean that patients can respond differently to the same PAH treatment, 64 a point highlighted by the large standard deviation observed within each group in the ARROW study. 65 In the ARROW study, patients were eligible with idiopathic or heritable PAH; drug-and toxin-induced PAH or PAH associated with connective tissue disease, HIV infection or congenital heart defects; of these idiopathic and heritable PAH represented 56% and 15% of study participants, respectively.…”

Clinical and Hemodynamic Characterization Super Responders to IV Prostacyclin

“…We chose survival as a concrete endpoint that is clearly highly desirable to practitioners and patients but recognize that we may lose some patients from our analysis who are presently alive but without adequate exposure to prostacyclin to be defined as a super responder. We also recognize that there are other important outcomes that we did not include such as quality of life, six-minute walk distance, and freedom from adverse events of PAHdirected therapy that may alternatively define a super responder (Halliday & Hemnes, 2017). It is also important to recognize that using the definition we have, it is not known why the super responders had such prolonged survival, as it may be a particularly robust RV response to therapy, and not regression of pulmonary vascular disease, as suggested by a case report by Rich et al (Rich et al, 2010).…”

“…These patients are initially treated with long-term calcium channel blockers and have been shown to have longer survival as compared to non-acute responders. (Halliday & Hemnes, 2017;McLaughlin et al, 2002;Sitbon et al, 2002) Additionally, acute responders have also been shown to have improved response to long-term parental prostacyclin therapy. (McLaughlin, Genthner, Panella, & Rich, 1998) Unfortunately, acute responders only represent <10% of IPAH patients in most published registries.…”

“…1,20-22,(Galie et al, 2019) Though we know from randomized trials and observational data that overall survival is better with parenteral prostacyclins 15,18,23,24 , it is still largely unknown if there are phenotypes of PAH or specific demographic characteristics that predict who will respond better or worse to parenteral prostaglandin therapies outside of acute responders to vasodilators. There is no consensus definition of good, or even "super response" to IV prostaglandin therapy as yet (Halliday & Hemnes, 2017), however, the definition of acute responders in other classes of PAH therapies (Sitbon et al, 2005) has yielded peripheral blood signatures that may be useful in predicting drug responses and understanding underlying pathology (Benza et al, 2015;Hemnes et al, 2015;Hemnes et al, 2016). Thus, there is a potential significant benefit to understanding super responders to all classes of PAH therapies.…”

Clinical and genetic associations with prostacyclin response in pulmonary arterial hypertension

“…Heterogeneity of response is seen clinically, with some patients living well beyond what would be expected by current risk prediction models, while others rapidly deteriorate despite appropriate treatment. 5 …”