BackgroundRegulators and clinical experts increasingly recognize the importance of incorporating patient-reported outcomes (PROs) in clinical studies of therapies for pulmonary arterial hypertension (PAH). No PAH-specific instruments have been developed to date in accordance with the 2009 FDA guidance for the development of PROs as endpoints in clinical trials. A qualitative research study was conducted to develop a new instrument assessing PAH symptoms and their impacts following the FDA PRO guidance.MethodsA cross-sectional study was conducted at 5 centers in the US in symptomatic PAH patients aged 18–80 years. Concept elicitation was based on 5 focus group discussions, after which saturation of emergent concepts was reached. A PRO instrument for PAH symptoms and their impacts was drafted. To assess the appropriateness of items, instructions, response options, and recall periods, 2 rounds of one-on-one cognitive interviews were conducted, with instrument revisions following each round. Additional interviews tested the usability of an electronic version (ePRO). PRO development considered input from an international Steering Committee, and translatability and lexibility assessments.ResultsFocus groups comprised 25 patients (5 per group); 20 additional patients participated in cognitive interviews (10 per round); and 10 participated in usability interviews. Participants had a mean ± SD age of 53.1 ± 15.8 years, were predominantly female (93 %), and were diverse in race/ethnicity, WHO functional class (FC I/II: 56 %, III/IV: 44 %), and PAH etiology (idiopathic: 56 %, familial: 2 %, associated: 42 %). The draft PRO instrument (PAH-SYMPACT®) was found to be clear, comprehensive, and relevant to PAH patients in cognitive interviews. Items were organized in a draft conceptual framework with 16 symptom items in 4 domains (respiratory symptoms, tiredness, cardiovascular symptoms, other symptoms) and 25 impact items in 5 domains (physical activities, daily activities, social impact, cognition, emotional impact). The recall period is the past 24 h for symptoms, and the past 7 days for impacts.ConclusionsThe PAH-SYMPACT® was shown to capture symptoms and their impacts relevant to PAH patients, demonstrating content saturation, concept validity, and ePRO usability. Final content and psychometric validation of the instrument will be based on the results of an ongoing Phase IIIb clinical trial in PAH patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0388-6) contains supplementary material, which is available to authorized users.

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531T he serotonin hypothesis of pulmonary arterial hypertension (PAH) emerged . 40 years ago and was reemphasized in the 1990s following the association of pulmonary hypertension (PH) 1 with anorexic agents such as aminorex fumarate and fenfl uramine. [2][3][4][5] Serotonin promotes pulmonary arterial smooth muscle cell and fi broblast proliferation, pulmonary arterial vasoconstriction, and local microthrombosis-all key pathogenic features in PAH. These effects of serotonin are mediated by interactions between serotonin and its transporter and receptors. [6][7][8][9][10] In particular, the serotonin transporter (SERT) plays a key role in the pathogenesis of experimental PH; in animal models, SERT overexpression predisposes to the development of PH, whereas pharmacologic blockade of SERT is protective. 1,[11][12][13][14] In humans, a functional polymorphism in the SERT gene correlates with more severe PH associated with COPD. 15 Selective serotonin reuptake inhibitors (SSRIs) act via blockade of SERT, resulting in an extracellular accumulation of serotonin and increased activation of serotonin receptors. 16 SSRIs have been associated with both protection against and regression of PH in animal models, suggesting a possible role in the treatment of PAH in humans. 1,14,17 Early observational studies have suggested therapeutic effi cacy of SSRIs in patients with Background: Selective serotonin reuptake inhibitors (SSRIs) have been suggested to offer therapeutic benefi t in patients with pulmonary arterial hypertension (PAH). We conducted two analyses to explore the association between SSRI use and PAH outcomes using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry). Methods: First, new users (SSRI-naive patients who initiated treatment after enrollment, incident use analysis, n 5 220) were matched (1:2) with non-SSRI users (nonusers, n 5 440) by enrollment center, sex, date of most recent visit, age, and 6-min walk distance. Second, a cross-sectional design was used to compare nonusers (n 5 2,463), high-affi nity SSRI users (n 5 430), and non-high-affi nity SSRI users (n 5 125) at enrollment. Mortality and a composite end point defi ned by events indicative of clinical worsening were evaluated. Results: New users had a higher risk of death (unadjusted hazard ratio [HR], 1.74; 95% CI, 1.19-2.54; P 5 .004) and were less likely to be free from the composite end point 2 years after enrollment vs nonusers (25.7% vs 43.2%, respectively; P , .001). Similarly, among prevalent SSRI users (patients with a history of SSRI use at enrollment), high-affi nity SSRI users were less likely to be free from the composite end point vs nonusers (unadjusted HR, 1.20; 95% CI, 1.07-1.36; P 5 .003). In both analyses, differences in outcome were maintained after adjustment for clinical variables previously associated with PAH outcomes. Conclusions:In a large population of patients with PAH, incident SSRI use was associated with increased mortality and a greater risk of clinical worsening, although we could ...

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531T he serotonin hypothesis of pulmonary arterial hypertension (PAH) emerged . 40 years ago and was reemphasized in the 1990s following the association of pulmonary hypertension (PH) 1 with anorexic agents such as aminorex fumarate and fenfl uramine. [2][3][4][5] Serotonin promotes pulmonary arterial smooth muscle cell and fi broblast proliferation, pulmonary arterial vasoconstriction, and local microthrombosis-all key pathogenic features in PAH. These effects of serotonin are mediated by interactions between serotonin and its transporter and receptors. [6][7][8][9][10] In particular, the serotonin transporter (SERT) plays a key role in the pathogenesis of experimental PH; in animal models, SERT overexpression predisposes to the development of PH, whereas pharmacologic blockade of SERT is protective. 1,[11][12][13][14] In humans, a functional polymorphism in the SERT gene correlates with more severe PH associated with COPD. 15 Selective serotonin reuptake inhibitors (SSRIs) act via blockade of SERT, resulting in an extracellular accumulation of serotonin and increased activation of serotonin receptors. 16 SSRIs have been associated with both protection against and regression of PH in animal models, suggesting a possible role in the treatment of PAH in humans. 1,14,17 Early observational studies have suggested therapeutic effi cacy of SSRIs in patients with Background: Selective serotonin reuptake inhibitors (SSRIs) have been suggested to offer therapeutic benefi t in patients with pulmonary arterial hypertension (PAH). We conducted two analyses to explore the association between SSRI use and PAH outcomes using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry). Methods: First, new users (SSRI-naive patients who initiated treatment after enrollment, incident use analysis, n 5 220) were matched (1:2) with non-SSRI users (nonusers, n 5 440) by enrollment center, sex, date of most recent visit, age, and 6-min walk distance. Second, a cross-sectional design was used to compare nonusers (n 5 2,463), high-affi nity SSRI users (n 5 430), and non-high-affi nity SSRI users (n 5 125) at enrollment. Mortality and a composite end point defi ned by events indicative of clinical worsening were evaluated. Results: New users had a higher risk of death (unadjusted hazard ratio [HR], 1.74; 95% CI, 1.19-2.54; P 5 .004) and were less likely to be free from the composite end point 2 years after enrollment vs nonusers (25.7% vs 43.2%, respectively; P , .001). Similarly, among prevalent SSRI users (patients with a history of SSRI use at enrollment), high-affi nity SSRI users were less likely to be free from the composite end point vs nonusers (unadjusted HR, 1.20; 95% CI, 1.07-1.36; P 5 .003). In both analyses, differences in outcome were maintained after adjustment for clinical variables previously associated with PAH outcomes. Conclusions:In a large population of patients with PAH, incident SSRI use was associated with increased mortality and a greater risk of clinical worsening, although we could ...

The recent identification of depression as an important comorbidity in pulmonary arterial hypertension (PAH) 1,2 is leading to a broad array of efforts to further refine our understanding of this disorder, enhance patient and provider education about it, and encourage prompt recognition, appropriate diagnosis, and treatment of affected individuals. We will provide an update on the nature and extent of the problem, and describe ongoing and future efforts to address this very important determinant of quality of life and possible long-term outcome in patients with PAH.