Smoking history and pulmonary arterial hypertension: Demographics, onset, and outcomes.

BACKGROUND: Smoking prevalence and its association with pulmonary arterial hypertension (PAH) outcomes have not been described in patients in the United States. METHODS: Using the US-based Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), the prevalence, demographics, and outcomes in ever- versus never-smokers with PAH were determined. RESULTS: Ever-smoking status was more prevalent in males (61.7%) than in females (42.9%) enrolled in REVEAL. Ever-smokers were older than never-smokers at the time of PAH diagnosis and REVEAL enrollment. The time to first hospitalization, transplant-free survival, and survival did not differ between ever- and never-smokers overall; however, in newly diagnosed males, ever-smoking was associated with earlier death (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.1-3.0; p = 0.0199), the composite of transplant or death (HR 2.2, 95% CI 1.4-3.6; p = 0.0008), and first hospitalization (HR 1.8, 95% CI 1.2-2.7; p = 0.0063), though smoking exposure (pack-years) did not differ between newly and previously diagnosed males. CONCLUSIONS: REVEAL PAH data demonstrate that smoking prevalence in male PAH patients is disproportionate. The prevalence of cigarette smoking was significantly higher in males than females enrolled in REVEAL. Ever-smoking status was associated with increased age at PAH diagnosis and, in newly diagnosed male PAH patients, earlier time to hospitalization and shorter survival after PAH diagnosis.

An AI-driven clinical care pathway to reduce 30-day readmission for chronic obstructive pulmonary disease (COPD) patients.

Healthcare regulatory agencies have mandated a reduction in 30-day hospital readmission rates and have targeted COPD as a major contributor to 30-day readmissions. We aimed to develop and validate a simple tool deploying an artificial neural network (ANN) for early identification of COPD patients with high readmission risk. Using COPD patient data from eight hospitals within a large urban hospital system, four variables were identified, weighted and validated. These included the number of in-patient admissions in the previous 6 months, the number of medications administered on the first day, insurance status, and the Rothman Index on hospital day one. An ANN model was trained to provide a predictive algorithm and validated on an additional dataset from a separate time period. The model was implemented in a smartphone app (Re-Admit) incorporating four input risk factors, and a clinical care plan focused on high-risk readmission candidates was then implemented. Subsequent readmission data was analyzed to assess impact. The areas under the curve of receiver operating characteristics predicting readmission with ANN is 0.77, with sensitivity 0.75 and specificity 0.67 on the separate validation data. Readmission rates in the COPD high-risk subgroup after app and clinical intervention implementation saw a significant 48% decline. Our studies show the efficacy of ANN model on predicting readmission risks for COPD patients. The AI enabled Re-Admit smartphone app predicts readmission risk on day one of the patient's admission, allowing for early implementation of medical, hospital, and community resources to optimize and improve clinical care pathways.

The echocardiographic course of pretransplant pulmonary hypertension following kidney transplantation and associated outcomes.

The post 3 kidney transplant course of pretransplant echocardiographically-defined pulmonary hypertension (PH) was reviewed in 115 patients. Of these 61 patients (the largest cohort reported to date), underwent 160 "for indication" echocardiograms posttransplant (mean echocardiograms per patient: 2.6 ± 2.3). Patients undergoing posttransplant echocardiograms demonstrated greater risks for worse outcomes than those without posttransplant echocardiograms; however, there was no difference in mortality, death-censored graft failure or the composite of death or graft failure between these two groups. Of patients tested, 36 (59%) showed resolution of PH at a median of 37.5 months. Six patients (16.7%) in whom PH resolved (at a median of 29 months), experienced recurrence of PH after an interval of 48 months. No pretransplant demographic or echocardiographic characteristics distinguished those in whom PH persisted versus resolved. Though there was no difference in the risk for mortality or death-censored graft loss between the two groups at 3 and 5 years, there was a higher risk for the composite of mortality or graft loss at three but not at five years in the group with persistent PH. In conclusion, echocardiographically defined PH resolved in 59% of patients following kidney transplantation; but irrespective of resolution there was no clear association with worse outcome.

Application of the REVEAL risk score calculator 2.0 in the CHEST study.

BACKGROUND: Currently there are no risk assessment recommendations for chronic thromboembolic pulmonary hypertension (CTEPH). The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score (RRS), developed for risk assessment in patients with pulmonary arterial hypertension, has previously predicted outcomes in CTEPH. RRS 2.0 was developed to refine the RRS. METHODS: This post hoc analysis of the CHEST study (n = 237), which assessed riociguat in patients with inoperable and persistent/recurrent CTEPH, evaluated RRS 2.0 and its relationship with survival and clinical worsening-free survival (CWFS). RESULTS: At CHEST-1 Week 16, RRS 2.0 significantly improved and more patients moved into the low-risk stratum with riociguat versus placebo; these improvements were maintained at CHEST-2 Week 12. RRS 2.0 at CHEST-1 baseline and Week 16, and change in RRS 2.0 from CHEST-1 baseline to Week 16 were significant predictors of survival and CWFS in CHEST-2. CONCLUSIONS: Our data suggest that RRS 2.0 may have utility in predicting outcomes and monitoring treatment response in patients with inoperable or persistent/recurrent CTEPH.

Change in REVEAL Lite 2 risk score predicts outcomes in patients with pulmonary arterial hypertension in the PATENT study.

BACKGROUND: Risk assessment is essential in pulmonary arterial hypertension (PAH) management. We investigated the effect of riociguat on REVEAL Lite 2 score, an abridged version of the REVEAL risk score, and its association with long-term outcomes in PATENT. METHODS: PATENT-1 was a randomized, double-blind study of riociguat vs placebo in patients with PAH. In the PATENT-2 open-label extension, all patients received riociguat up to 2.5 mg three times daily (n = 396). REVEAL Lite 2 scores were calculated at baseline, PATENT-1 Week 12, and PATENT-2 Week 12, with patients stratified as low- (1-5), intermediate- (6-7), or high-risk (≥8). Kaplan-Meier and Cox proportional hazards analyses assessed association of riociguat with survival and clinical worsening-free survival (CWFS). RESULTS: REVEAL Lite 2 score improved with riociguat 2.5 mg at PATENT-1 Week 12 (least-squares mean difference vs placebo: -0.8; p = 0.0004). More patients receiving riociguat 2.5 mg stabilized or improved risk stratum at PATENT-1 Week 12 vs placebo (p = 0.0005) and achieved low-risk status. REVEAL Lite 2 score at baseline and PATENT-1 Week 12 were associated with survival and CWFS (all p < 0.0001), as was change in score from baseline to Week 12 (p = 0.0002 and p < 0.0001, respectively). Survival and CWFS differed between risk strata at baseline (p < 0.0001) and PATENT-1 Week 12 (p < 0.0001). CONCLUSIONS: This analysis confirms the risk-reduction benefits of riociguat in patients with PAH and further contributes to the validation of REVEAL Lite 2 in facilitating PAH risk assessment.

Defining Vasoplegia Following Durable, Continuous Flow Left Ventricular Assist Device Implantation.

This study aimed to develop a definition of vasoplegia that reliably predicts clinical outcomes. Vasoplegia was evaluated using data from the electronic health record for each 15-minute interval for 72 hours following cardiopulmonary bypass. Standardized definitions considered clinical features (systemic vascular resistance [SVR], mean arterial pressure [MAP], cardiac index [CI], norepinephrine equivalents [NEE]), threshold strategy (criteria occurring in any versus all measurements in an interval), and duration (criteria occurring over multiple consecutive versus separated intervals). Minor vasoplegia was MAP < 60 mm Hg or SVR < 800 dynes⋅sec⋅cm-5 with CI > 2.2 L/min/m2 and NEE ≥ 0.1 µg/kg/min. Major vasoplegia was MAP < 60 mm Hg or SVR < 700 dynes⋅sec⋅cm-5 with CI > 2.5 L/min/m2 and NEE ≥ 0.2 µg/kg/min. The primary outcome was incidence of vasoplegia for eight definitions developed utilizing combinations of these criteria. Secondary outcomes were associations between vasoplegia definitions and three clinical outcomes: time to extubation, time to intensive care unit discharge, and nonfavorable discharge. Minor vasoplegia detected anytime within a 15-minute period (MINOR_ANY_15) predicted the highest incidence of vasoplegia (61%) and was associated with two of three clinical outcomes: 1 day delay to first extubation (95% CI: 0.2 to 2) and 7 day delay to first intensive care unit discharge (95% CI: 1 to 13). The MINOR_ANY_15 definition should be externally validated as an optimal definition of vasoplegia.

Optimization of Acute Kidney Injury (AKI) Time Definitions Using the Electronic Health Record: A First Step in Automating In-Hospital AKI Detection.

Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney injury (AKI) definitions were evaluated for cases detected and their respective outcomes using expanded time windows to 168 h. AKI incidence and outcomes with expanded time intervals were identified in the electronic health records (EHRs) from 126,367 unique adult hospital admissions (2012-2014) and evaluated using multivariable logistic regression with bootstrap sampling. The incidence of AKI detected was 7.4% (n = 9357) using a 24-h time window for both serum creatinine (SCr) criterion 1a (≥0.30 mg/dL) and 1b (≥50%) increases from index SCr, with additional cases of AKI identified: 6963 from 24-48 h.; 2509 for criterion 1b from 48 h to 7 days; 3004 cases (expansion of criterion 1a and 1b from 48 to 168 h). Compared to patients without AKI, adjusted hospital days increased if AKI (criterion 1a and 1b) was observed using a 24-h observation window (5.5 days), 48-h expansion (3.4 days), 48-h to 7-day expansion (6.5 days), and 168-h expansion (3.9 days); all are p < 0.001. Similarly, the adjusted risk of in-hospital death increased if AKI was detected using a 24-h observation window (odds ratio (OR) = 16.9), 48-h expansion (OR = 5.5), 48-h to 7-day expansion (OR = 4.2), and 168-h expansion (OR = 1.6); all are p ≤ 0.01. Expanding the time windows for both AKI SCr criteria 1a and 1b standardizes and facilitates EHR AKI detection, while identifying additional clinically relevant cases of in-hospital AKI.

Application of the REVEAL risk score calculator 2.0 in the PATENT study.

BACKGROUND: Regular risk assessment is recommended in pulmonary arterial hypertension (PAH) management to improve patient outcomes. The REVEAL risk score (RRS) predicts survival in patients with PAH, including those from the PATENT study, which assessed riociguat, a soluble guanylate cyclase stimulator approved for PAH treatment. An updated version, RRS 2.0, has been developed to further refine risk prediction. METHODS: This post hoc analysis of PATENT-1 and its open-label extension PATENT-2 (n = 396) assessed RRS 2.0 score and risk stratum and their association with survival and clinical worsening-free survival (CWFS). RESULTS: At PATENT-1 Week 12, riociguat improved RRS 2.0 versus placebo (least-squares mean difference versus placebo: -1.0 [95% confidence interval - 1.4 to -0.6; p < 0.0001]) and more patients improved risk stratum with riociguat (57%) versus placebo (42%). These improvements were maintained at PATENT-2 Week 12. RRS 2.0 score and risk strata at PATENT-1 baseline and Week 12 were significantly associated with survival and CWFS in PATENT-2 (p < 0.0001); change in RRS 2.0 score from PATENT-1 baseline to Week 12 was also significantly associated with outcomes. CONCLUSIONS: These data suggest that RRS 2.0 has clinical utility in predicting long-term outcomes and monitoring treatment response in patients with PAH.

United States Pulmonary Hypertension Scientific Registry: Baseline Characteristics.

BACKGROUND: The treatment, genotyping, and phenotyping of patients with World Health Organization Group 1 pulmonary arterial hypertension (PAH) have evolved dramatically in the last decade. RESEARCH QUESTION: The United States Pulmonary Hypertension Scientific Registry was established as the first US PAH patient registry to investigate genetic information, reproductive histories, and environmental exposure data in a contemporary patient population. STUDY DESIGN AND METHODS: Investigators at 15 US centers enrolled consecutively screened adults diagnosed with Group 1 PAH who had enrolled in the National Biological Sample and Data Repository for PAH (PAH Biobank) within 5 years of a cardiac catheterization demonstrating qualifying hemodynamic criteria. Exposure and reproductive histories were collected by using a structured interview and questionnaire. The biobank provided genetic data. RESULTS: Between 2015 and 2018, a total of 499 of 979 eligible patients with clinical diagnoses of idiopathic PAH (IPAH) or familial PAH (n = 240 [48%]), associated PAH (APAH; n = 256 [51%]), or pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis (n = 3 [1%]) enrolled. The mean age was 55.8 years, average BMI was 29.2 kg/m2, and 79% were women. Mean duration between symptom onset and diagnostic catheterization was 1.9 years. Sixty-six percent of patients were treated with more than one PAH medication at enrollment. Past use of prescription weight loss drugs (16%), recreational drugs (27%), and oral contraceptive pills (77%) was common. Women often reported miscarriage (37%), although PAH was rarely diagnosed within 6 months of pregnancy (1.9%). Results of genetic testing identified pathogenic or suspected pathogenic variants in 13% of patients, reclassifying 18% of IPAH patients and 5% of APAH patients to heritable PAH. INTERPRETATION: Patients with Group 1 PAH remain predominately middle-aged women diagnosed with IPAH or APAH. Delays in diagnosis of PAH persist. Treatment with combinations of PAH-targeted medications is more common than in the past. Women often report pregnancy complications, as well as exposure to anorexigens, oral contraceptives, and/or recreational drugs. Results of genetic tests frequently identify unsuspected heritable PAH.

The Association of Pretransplant Pulmonary Hypertension With Patient and Graft Survival After Kidney Transplantation: A Retrospective Cohort Study.

BACKGROUND: Pulmonary hypertension (PH) has been well characterized in end-stage kidney disease and carries a grave prognosis. Its relationship to kidney transplantation outcomes is uncertain. The purpose of the present study was to characterize PH in kidney transplant candidates and to evaluate the relationship of PH to post-transplantation outcomes. METHODS: A retrospective review of medical records and echocardiographic findings in all patients listed and transplanted at a large urban academic medical center from 2010 to 2015 was undertaken. PH (defined as echocardiographic evidence of pulmonary artery systolic pressure ≥ 35 mm Hg) was assessed along with demographics, and comorbidities for its relationship to patient, and graft survival by univariable and multivariable analysis. RESULTS: Of 733 patients, 15.6% (115) had PH. PH in this population was primarily due to left ventricular (LV) diastolic dysfunction. Patient survival (78.3% vs 89.6%, P = .02) and the composite of patient and graft survival (70.7% vs 85.0%, P = .04) was reduced at 5 years in patients with PH as compared to patients with No PH, respectively. However, multivariable analysis suggested that age at presentation, race, and left ventricular systolic function but not PH were significantly associated with patient mortality or graft loss. CONCLUSION: Reduced patient and graft survival seen in patients with pulmonary hypertension appears to be related to risk factors other than the pulmonary hypertension itself; therefore, pretransplant PH should not be considered as a barrier to kidney transplantation.

A novel BMPR2 mutation with widely disparate heritable pulmonary arterial hypertension clinical phenotype.

Mutations in the gene encoding bone morphogenetic protein receptor type II (BMPR2) have been associated with heritable pulmonary arterial hypertension (HPAH), whereas mutations in the gene encoding eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) are associated with heritable pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (HPVOD/PCH). We describe two unrelated patients found to carry the same hitherto unreported pathogenic BMPR2 mutation; one of whom presented with typical pulmonary arterial hypertension, whereas the second patient presented with aggressive disease and characteristic clinical features of PVOD/PCH. These two clinically divergent cases representative of the same novel pathogenic mutation exemplify the variable phenotype of HPAH and the variable involvement of venules and capillaries in the pathology of the pulmonary vascular bed in pulmonary arterial hypertension.

Spironolactone in pulmonary arterial hypertension: results of a cross-over study.

The renin-angiotensin-aldosterone system is implicated in the pathophysiology of pulmonary arterial hypertension. We undertook this study to determine the effects of spironolactone, a mineralocorticoid receptor blocker, on collagen metabolism in pulmonary arterial hypertension patients. After obtaining institutional review board approval and informed consent, 42 pulmonary arterial hypertension patients were prospectively enrolled and 35 patients completed the 16-week randomized double-blinded crossover clinical trial. Subjects received 50 mg spironolactone or placebo and at the end of week 8, treatment arm was switched. Circulating levels of collagen biomarkers, brain natriuretic peptide, and aldosterone levels were measured, and six-minute walk distance, liver function tests, and echocardiogram data were collected at weeks 0, 8, and 16. Mean age was 45 ± 15 years and 87% were females. At baseline, brain natriuretic peptide and aldosterone levels were 74 ± 95 pg/ml and 7 ± 8 pg/ml, respectively. There was no change in the levels of amino-terminal propeptide of procollagen type III (PIIINP), MMP-9, TIMP-1, and MMP-9/TIMP-1 ratio at weeks 8 and 16 compared to baseline values in placebo arm and treatment arm. The baseline six-min walk distance was 436 ± 115 meters at baseline and no change in walk distance was noted at weeks 8 and 16 (P = 0.372). None of the patients developed hyperkalemia or liver function test abnormalities at weeks 8 and 16 requiring discontinuation of study drug. Our study showed no change in collagen metabolite levels in pulmonary arterial hypertension patients treated with spironolactone. Spironolactone was safe and well tolerated by pulmonary arterial hypertension patients with no increased hyperkalemia or liver function test abnormalities.

Impact of race on survival in pulmonary arterial hypertension: Results from the REVEAL registry.

BACKGROUND: Prior research has suggested that the prevalence and outcomes of pulmonary arterial hypertension (PAH) may vary by race or ethnicity. However, these studies have been limited by small sample size or methodological techniques relying on epidemiologic data. The purpose of this study is to evaluate the relationship between race/ethnicity and survival in a large U.S.-based prospective multicenter registry. METHODS: Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by race/ethnicity. Baseline hemodynamic characteristics, clinical characteristics, and medication use was described. The relationship between race/ethnicity and outcome was evaluated by Kaplan-Meier and Cox proportional hazards modeling techniques. Left-truncation analysis, which adjusted for time from diagnosis to study enrollment, was used to minimize the effect of survivor bias. RESULTS: This analysis included 3,046 patients; 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. Unadjusted Kaplan-Meier survival analysis indicated that white patients had the lowest survival rates. After adjusting for variables of prognostic impact, race/ethnicity was no longer significantly associated with survival. Other results showed that black patients were more likely to have connective tissue disease-associated PAH, Hispanic patients were more likely to have portopulmonary hypertension, and Asian patients were more likely to have congenital heart disease-associated PAH. CONCLUSIONS: Analysis of the REVEAL registry did not find race/ethnicity to be a significant predictor of mortality. This is the largest analysis to date evaluating the role of race/ethnicity on outcomes in PAH.

Outcomes of kidney transplantation using deceased donors with history of diabetes.

Deceased diabetic kidneys are increasingly utilized in transplantation. The relationship of donor's history of diabetes to clinical and histological outcomes was examined. Forty-nine diabetic deceased donor kidneys (D-DM) were transplanted into 26 normal (R-N/D-DM) and 23 diabetic recipients (R-DM/D-DM) and compared to 211 diabetic recipients of normal kidneys(R-DM/D-N) and 466 normal recipients of normal kidneys (R-N/D-N). Patient survival at 5 years was 89.7% in R-N/D-N, 96.2% in R-N/D-DM, 80.1% in R-DM/D-N, and a 71.6% in R-DM/D-DM (P = .008). Death-censored graft survival at 5 years was 86.3% in R-N/D-N, 87.4% in R-N/D-DM, 93.5% in R-DM/D-N, and 87.5% in R-DM/D-DM (P = .24). Multivariable regression analysis showed that compared to non-diabetic recipients, diabetic recipients had a 2- to 3-fold increased risk of mortality. In this cohort, there was no impact on death-censored graft survival of diabetic donor status. Only 6 of 26 post-perfusion biopsies showed evidence of diabetic nephropathy (

Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension With Oral Prostacyclin Pathway Agents.

BACKGROUND: Treatment of pulmonary arterial hypertension (PAH) has evolved substantially over the past two decades and varies according to etiology, functional class (FC), hemodynamic parameters, and other clinical factors. Current guidelines do not provide definitive recommendations regarding the use of oral prostacyclin pathway agents (PPAs) in PAH. To provide guidance on the use of these agents, an expert panel was convened to develop consensus statements for the initiation of oral PPAs in adults with PAH. METHODS: A systematic literature search was conducted using MEDLINE. The established RAND/University of California Los Angeles appropriateness method, which incorporates the Delphi method and the nominal group technique, was used to create consensus statements. Idiopathic, heritable, repaired congenital heart defect, and drug- or toxin-induced PAH (IPAH+) was considered as one etiologic grouping. The process was focused on the use of oral treprostinil or selexipag in patients with IPAH+ or connective tissue disease-associated PAH and FC II or III symptoms receiving background dual endothelin receptor antagonist/phosphodiesterase type 5 inhibitor therapy. RESULTS: The panel developed 14 consensus statements regarding the appropriate use of oral PPAs in the target population. The panel identified 13 clinical scenarios in which selexipag may be considered as a treatment option. CONCLUSIONS: The paucity of clinical evidence overall, and particularly from randomized trials in this setting, creates a gap in knowledge. These consensus statements are intended to aid physicians in navigating treatment options and using oral PPAs in the most appropriate manner in patients with PAH.

Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION trial.

BACKGROUND: The purpose of this study was to compare patients with pulmonary arterial hypertension enrolled in the AMBITION trial with (excluded from the primary analysis set [ex-primary analysis set]) and without (primary analysis set) multiple risk factors for left ventricular diastolic dysfunction. METHODS: Treatment-naive patients with pulmonary arterial hypertension were randomized to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary end point was time from randomization to first adjudicated clinical failure event. RESULTS: Primary analysis set patients (n = 500), compared with ex-primary analysis set patients (n = 105), were younger (mean, 54.4 vs 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 vs 330.5 meters) and fewer comorbidities (e.g., hypertension and diabetes). Treatment effects of initial combination therapy vs pooled monotherapy were directionally the same for both populations, albeit of a lower magnitude for ex-primary analysis set patients. Initial combination therapy reduced the risk of clinical failure compared with pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% confidence interval, 0.35-0.72), whereas the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% confidence interval, 0.35-1.37). Overall, primary analysis set patients had fewer clinical failure events (25% vs 33%), higher rates of satisfactory clinical response (34% vs 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% vs 31%) than ex-primary analysis set patients. CONCLUSIONS: Efficacy of initial combination therapy vs pooled monotherapy was directionally similar for primary analysis set and ex-primary analysis set patients. However, ex-primary analysis set patients (with multiple risk factors for left ventricular diastolic dysfunction) experienced higher rates of clinical failure events and the response to combination therapy vs monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients.

Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension.

BACKGROUND: Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants. METHODS: AMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to once-daily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline. RESULTS: This analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42% (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups. CONCLUSIONS: Treatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe. Funded by Gilead Sciences, Inc. and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.

United States Pulmonary Hypertension Scientific Registry (USPHSR): rationale, design, and clinical implications.

Diagnostic World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) and Diagnostic Group 1' pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) are progressive and fatal disorders. Past registries provided important insights into these disorders, but did not include hormonal exposures or genomic data. The United States Pulmonary Hypertension Scientific Registry (USPHSR) will provide demographic, physiologic, anorexigen and hormone exposure, genomic, and survival data in the current therapeutic era for 499 patients diagnosed with PAH, PVOD, or PCH. The USPHSR also will explore the relationship between pharmacologic, non-pharmacologic, and dietary hormonal exposures and the increased risk for women to develop idiopathic or heritable PAH.

Predicting Survival in Patients With Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and Comparison With ESC/ERS-Based Risk Assessment Strategies.

BACKGROUND: Pulmonary arterial hypertension is a progressive, fatal disease. Published treatment guidelines recommend treatment escalation on the basis of regular patient assessment with the goal of achieving or maintaining low-risk status. Various strategies are available to determine risk status. This analysis describes an update of the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk calculator (REVEAL 2.0) and compares it with recently published European Society of Cardiology/Respiratory Society guideline-derived risk assessment strategies. METHODS: A subpopulation from the US-based registry REVEAL that survived ≥ 1 year postenrollment (baseline for this cohort) was analyzed. For REVEAL 2.0, point values and cutpoints were reassessed, and new variables were evaluated. The Kaplan-Meier method was used to estimate survival at 12 months postbaseline; discrimination was quantified using the c-statistic. Mortality estimates and discrimination were compared between REVEAL 2.0 and Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and French Pulmonary Hypertension Registry (FPHR) risk assessment strategies. For this comparison, a three-category REVEAL 2.0 score was computed in which patients were classified as low-, intermediate-, or high-risk. RESULTS: REVEAL 2.0 demonstrated similar discrimination as the original calculator in this subpopulation (c-statistic = 0.76 vs 0.74), provided excellent separation of risk among the risk categories, and predicted clinical worsening as well as mortality in patients who were followed ≥ 1 year. The REVEAL 2.0 three-category score had greater discrimination (c-statistic = 0.73) than COMPERA (c-statistic = 0.62) or FPHR (c-statistic = 0.64). Compared with REVEAL 2.0, COMPERA and FPHR both underestimated and overestimated risk. CONCLUSIONS: REVEAL 2.0 demonstrates greater risk discrimination than the COMPERA and FPHR risk assessment strategies in patients enrolled in REVEAL. After external validation, the REVEAL 2.0 calculator can assist clinicians and patients in making informed treatment decisions on the basis of individual risk profiles. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00370214; URL: www.clinicaltrials.gov.

Safety and tolerability of transition from inhaled treprostinil to oral selexipag in pulmonary arterial hypertension: Results from the TRANSIT-1 study.

BACKGROUND: A long-term trial showed that the oral prostacyclin (PGl2) receptor (IP) agonist, selexipag, delayed disease progression in patients with pulmonary arterial hypertension (PAH). Transition to selexipag in patients treated with more burdensome inhaled therapies that target the prostacyclin pathway may be considered by patients and physicians. The Phase 3b, prospective, open-label TRANSIT-1 (Tolerability and Safety of the Transition From Inhaled Treprostinil to Oral Selexipag in Patients With Pulmonary Arterial Hypertension) study evaluated the safety and tolerability of transition from inhaled treprostinil to oral selexipag. METHODS: Patients receiving non-prostanoid oral PAH therapy and inhaled treprostinil at stable doses, in World Health Organization Functional Class II/III, with 6-minute walk distance ≥ 300 meters were enrolled. The 16-week main treatment period included downtitration of inhaled treprostinil over 8 weeks and parallel uptitration of selexipag over 12 weeks. Sustained treatment transition at Week 16 was defined as (1) receiving selexipag at Week 16; (2) no selexipag interruption(s) totaling ≥ 8 days; and (3) no inhaled treprostinil or other prostanoids after Week 8. Clinical parameters and patient-reported treatment satisfaction outcomes were assessed at Week 16. RESULTS: All 34 enrolled patients completed the study. At Week 16, 32 patients (94.1%) had stopped inhaled treprostinil and were receiving selexipag. Twenty-eight patients (82.4%) met all criteria for sustained treatment transition. During the study, 3 patients discontinued selexipag due to adverse events. Overall, most adverse events were typical of prostanoid therapies and started during the uptitration phase. In general, patients remained clinically stable throughout treatment and reported improved convenience. CONCLUSIONS: Transition to oral selexipag from inhaled treprostinil in PAH patients was successful and well tolerated in most patients, and associated with greater convenience. CLINICAL TRIAL NUMBER: NCT02471183.