Shlobin, Oksana A.

Abstract Rationale Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. The extent of medication nonadherence in PAH is uncertain and may be linked to adverse outcomes. There has been a lack of multicenter, registry-based studies assessing medication nonadherence and patient-centered outcomes in PAH. Objectives To determine the prevalence of self-reported nonadherence in Pulmonary Hypertension Association Registry (PHAR) participants with PAH or chronic thromboembolic pulmonary hypertension and the relationship of nonadherence with several patient-centered outcomes (mortality, hospitalization rates, emergency department visits, and health-related quality of life). Methods Self-reported PAH medication nonadherence was captured at PHAR enrollment and during follow-up visits. Predictors of nonadherence were modeled using generalized estimating equations assuming a binary distribution. Outcomes associated with nonadherence were modeled using generalized estimating equations with a Poisson distribution. Results A total of 1,543 patients were included, of whom 1,092 (70.8%) were female and 1,340 (86.8%) had PAH. The overall rate of any self-reported nonadherence was 6.1% (95% confidence interval [CI], 5.3–6.9). Predictors of nonadherence included self-reported male sex at birth (odds ratio [OR], 1.4; 95% CI, 1.0–1.9; P = 0.02), poverty (OR, 1.6; 95% CI, 1.2–2.3; P = 0.01), not being married or partnered (OR, 1.5; 95% CI, 1.1–1.9; P = 0.01), having Medicaid or no health insurance (OR, 2.1; 95% CI, 1.5–2.9; P < 0.001), and having completed high school but not having a college degree (OR, 1.7; 95% CI, 1.1–2.9; P < 0.001). PHAR participants who reported any nonadherence had 50.0% more emergency department visits (P < 0.001), 13.3% more hospital admissions (P = 0.03), and 61.9% more days hospitalized (P = 0.01). No relationship was observed between nonadherence and the type or number of PAH therapies or all-cause mortality. Participants reporting nonadherence had worse mean Short Form-12 scores (P < 0.001) and worse emPHasis-10 scores (P = 0.02). Conclusions The rate of self-reported nonadherence in PHAR registrants was low but was associated with male sex and several social determinants of health. Although the complexity or type of PAH regimen did not appear to influence nonadherence, nonadherence was associated with numerous adverse patient-centered outcomes, including greater healthcare use and worse health-related quality of life. Because of limitations in the structure of the gathered data, relationships between exposure and outcomes were not temporally definitive; these observations warrant additional prospective studies.

AbstractPulmonary hypertension (PH) is a risk factor for mortality in patients with sarcoidosis. Severe PH in chronic lung disease has previously been defined as mean pulmonary arterial pressure (mPAP) ≥ 35 mmHg or mPAP 25 ≥ mmHg with cardiac index (CI) ≤ 2 L/min/m2. However, there is no clear definition denoting severity of sarcoidosis‐associated PH (SAPH). We aimed to determine pulmonary hemodynamic cut‐off values where transplant‐free survival was worse among patients with SAPH. This was a retrospective cohort analysis of the Registry of SAPH database focusing on pulmonary hemodynamic predictors of transplant‐free survival among patients with precapillary SAPH. Cox regression was performed to determine which pulmonary hemodynamic values predicted death or lung transplantation. Kaplan−Meier survival analysis was performed on statistically significant predictors to determine pulmonary hemodynamic cut‐off values where transplant‐free survival was decreased. Decreased transplant‐free survival occurred among SAPH patients with mPAP ≥ 40 mmHg and SAPH patients with pulmonary vascular resistance (PVR) ≥ 5 Woods units (WU). Transplant‐free survival was not decreased in patients who fulfilled prior criteria of severe PH in chronic lung disease. We identified new cut‐offs with decreased transplant‐free survival in the SAPH population. Neither cut‐off of mPAP ≥ 40 mmHg nor PVR ≥ 5 WU has previously been shown to be associated with decreased transplant‐free survival in SAPH. These values could suggest a new definition of severe SAPH. Our PVR findings are in line with the most recent European Society of Cardiology/European Respiratory Society guideline definition of severe PH in chronic lung disease.

AbstractRight heart (RH) structure and function are major determinants of symptoms and prognosis in pulmonary arterial hypertension (PAH). RH imaging provides detailed information, but evidence and guidelines on the use of RH imaging in treatment decisions are limited. We conducted a Delphi study to gather expert opinion on the role of RH imaging in decision‐making for treatment escalation in PAH. A panel of 17 physicians with expertise in PAH and RH imaging used three surveys in a modified Delphi process to reach consensus on the role of RH imaging in PAH. Survey 1 used open‐ended questions to gather information. Survey 2 contained Likert scale and other questions intended to identify consensus on topics identified in Survey 1. Survey 3 contained Likert scale questions derived from Survey 2 and summary information on the results of Survey 2. The Delphi panel reached consensus that RH imaging is likely to improve the current risk stratification algorithms and help differentiate risk levels in patients at intermediate risk. Tricuspid annular plane systolic excursion, right ventricular fractional area change, right atrial area, tricuspid regurgitation, inferior venae cavae diameter, and pericardial effusion should be part of routine echocardiography in PAH. Cardiac magnetic resonance imaging is valuable but limited by cost and access. A pattern of abnormal RH imaging results should prompt consideration of hemodynamic evaluation and possible treatment escalation. RH imaging is an important tool for decisions about treatment escalation in PAH, but systematically collected evidence is needed to clarify its role.

Abstract Background Post-hoc analyses of the FREEDOM-EV study demonstrated that addition of oral treprostinil (ORE) to background monotherapy improves risk in patients with pulmonary arterial hypertension (PAH). Evidence is needed to understand the incremental effect of ORE added to dual background therapy with an endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5)/soluble guanylate cyclase stimulator (sGC). Purpose To describe longitudinal changes in REVEAL Lite 2 and COMPERA 2.0 risk status in patients initiating ORE on dual background therapy. Methods A multisite, double-blind retrospective chart review of PAH patients was conducted by US PAH-treating physicians and included patients meeting prior diagnostic PAH criteria (mPAP ≥25 mmHg/PAWP ≤15 mmHg/PVR >3 WU), age ≥18 at diagnosis, began a PAH treatment 01/2014–03/2017, and had NT-proBNP/BNP, WHO functional class (FC), and 6-minute walk distance (6MWD) at baseline visit. Baseline was most recent assessment prior to ORE initiation. This analysis included a subset of patients on dual background therapy at time of ORE initiation without prior prostacyclin use. Follow-up was evaluated in 0–6 and 6–12 months after ORE initiation. Results 30 (61.2%) of 49 ORE patients were on dual background therapy at time of ORE start; 23 had baseline assessments while on dual background therapy and were included in this analysis. At baseline, mean (SD) 6MWD was 140.9 (49.8) m and 21 (91.3%) patients were FC III. Prior to ORE, median (IQR) time on ERA was 6.6 (5.5–7.6) months and PDE5/sGC was 3.7 (3.3–5.7) months. After ORE start, median (IQR) time to follow-up was 4.3 (3.4–5.6) months in 0–6 months and 10.9 (9.6–11.6) months in 6–12 months. Using REVEAL Lite 2, baseline mean (SD) REVEAL Lite 2 risk score was 7.9 (0.8); 1 (4.4%), 2 (8.7%), and 20 (87%) patients were in the low, intermediate, and high risk strata, respectively. In 0–6 months (n=22), 13 (59.1%) patients improved and 9 (40.9%) stabilized REVEAL Lite 2 risk strata from baseline. In 6–12 months (n=22), mean (SD) REVEAL Lite 2 risk score was 6.5 (1.1); 15 patients (68.2%) improved, 6 (27.3%) stabilized, and 1 (4.6%) worsened REVEAL Lite 2 risk strata from baseline. Using COMPERA 2.0, at baseline, 1 (4.4%) patient was in the intermediate-low and 22 (95.7%) patients were in the intermediate-high risk strata. In 0–6 months (n=15), 10 (66.7%) patients improved and 5 (33.3%) patients stabilized COMPERA 2.0 risk strata from baseline. In 6–12 months (n=17), 15 (88.2%) patients improved and 2 (11.8%) stabilized COMPERA 2.0 risk strata from baseline. Conclusion Of patients initiating oral treprostinil in this study, most were on dual background therapy and at high risk by REVEAL Lite 2 or intermediate-high risk by COMPERA 2.0. This analysis suggests adding ORE to dual background therapy can improve risk status in patients, with clinical benefit attained within 6 months and continued incremental improvement through first year of therapy. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): United Therapeutics Corporation

Abstract Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, morbid, potentially curable subtype of pulmonary hypertension that negatively impacts health‐related quality of life (HRQoL). Little is known about differences in HRQoL and hospitalization between CTEPH patients and idiopathic pulmonary arterial hypertension (IPAH) patients. Using multivariable linear regression and mixed effects models, we examined differences in HRQoL assessed by emPHasis‐10 (E10) and SF‐12 between CTEPH and IPAH patients in the Pulmonary Hypertension Association Registry, a prospective multicenter cohort of patients newly evaluated at a Pulmonary Hypertension Care Center. Multivariable negative binomial regression models were used to estimate incidence rate ratios (IRR) for hospitalization amongst the two groups. We included 461 IPAH patients and 169 CTEPH patients. Twenty‐one percent of CTEPH patients underwent pulmonary thromboendarterectomy (PTE) before the end of follow‐up. At baseline, patients with CTEPH had significantly worse HRQoL (higher E10 scores) (ß 2.83, SE 1.11, p = 0.01); however, differences did not persist over time. CTEPH patients had higher rates of hospitalization (excluding the hospitalization for PTE) compared to IPAH patients after adjusting for age, sex, body mass index, WHO functional class and six‐minute walk distance (IRR 1.66, 95%CI 1.04–2.65, p = 0.03). CTEPH patients who underwent PTE had improved HRQoL as compared to those who were medically managed, but patients who underwent PTE were younger, had higher cardiac outputs and greater six‐minute walk distances. In this large, prospective, multicenter cohort, CTEPH patients had significantly worse baseline HRQoL and higher rates of hospitalizations than those with IPAH. CTEPH patients who underwent PTE had significant improvements in HRQoL.

Abstract The diagnosis and management of pulmonary arterial hypertension (PAH) includes several advances, such as a broader recognition of extrapulmonary vascular organ system involvement, validated point-of-care clinical assessment tools, and focus on the early initiation of multiple pharmacotherapeutics in appropriate patients. Indeed, a principal goal in PAH today is an early diagnosis for prompt initiation of treatment to achieve a minimal symptom burden; optimize the patient’s biochemical, hemodynamic, and functional profile; and limit adverse events. To accomplish this end, clinicians must be familiar with novel risk factors and the revised hemodynamic definition for PAH. Fresh insights into the role of developmental biology (i.e., perinatal health) may also be useful for predicting incident PAH in early adulthood. Emergent or underused approaches to PAH management include a novel TGF-β ligand trap pharmacotherapy, remote pulmonary arterial pressure monitoring, next-generation imaging using inert gas–based magnetic resonance and other technologies, right atrial pacing, and pulmonary arterial denervation. These and other PAH state of the art advances are summarized here for the wider pulmonary medicine community.