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Background: Long-term anticoagulation is recommended in idiopathic pulmonary arterial hypertension (IPAH). In contrast, limited data support anticoagulation in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-PAH). We assessed the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH., Methods and Results: Patients who initiated warfarin on study (n=187) were matched 1:1 with patients never on warfarin, by enrollment site, etiology, and diagnosis status. Descriptive analyses were conducted to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH). Two-thirds of patients initiating warfarin discontinued treatment before the last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) in comparison with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (hazard ratio, 1.57; P=0.031) or any time postbaseline (hazard ratio, 1.49; P=0.046) had increased mortality in comparison with warfarin-naïve patients., Conclusions: No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than in patients not receiving warfarin, even after adjusting for confounders., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214., (© 2015 The Authors.)

Background: Pulmonary arterial hypertension (PAH) is a rare, severe disease characterized by worsening right-sided heart failure, decreasing functional status, and poor survival. The present study characterizes the 5-year survival in the United States of a new and previous diagnosis of PAH in patients stratified by baseline functional class (FC). The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) is a 55-center observational US registry of the demographics, disease course, and management of patients with World Health Organization (WHO) group 1 PAH., Methods: The REVEAL Registry enrolled newly and previously diagnosed patients aged ≥ 3 months with WHO group 1 PAH consecutively from March 2006 to December 2009. Demographics, disease characteristics, and hemodynamic data were collected at enrollment. Survival analysis was conducted by FC and other subgroups in patients aged ≥ 18 years., Results: Survival differences between previously diagnosed and newly diagnosed patients at 1 year (90.4% vs 86.3%) were maintained to 5 years; 5-year survival for previously diagnosed patients was 65.4% compared with 61.2% for newly diagnosed patients. Previously diagnosed patients in FC I, II, III, and IV had an estimated 5-year survival rate of 88.0%, 75.6%, 57.0%, and 27.2%, respectively, compared with 72.2%, 71.7%, 60.0%, and 43.8% for newly diagnosed patients in FC I, II, III, and IV, respectively., Conclusions: Patient survival of advanced PAH remains poor at 5 years despite treatment advances. New York Heart Association FC remains one of the most important predictors of future survival. These observations reinforce the importance of continuous monitoring of FC in patients with PAH., Trial Registry: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Background: Clinical studies of pulmonary arterial hypertension have used the change in the 6-minute walk distance (6MWD) as a clinical end point; however, its association with survival outcomes has not been well established. In this analysis, we examined the prognostic value of the baseline 6MWD, absolute thresholds of the 6MWD, and change in the 6MWD., Methods: Patients in the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) with 6MWD at enrollment, with or without a follow-up assessment within the first year of observation, were included. Kaplan-Meier survival estimates were computed for sub-sets with baseline 6MWD results that were above or below all possible thresholds and for sub-sets with a change in the 6MWD that was 10 percentage points above or below all possible thresholds, including improvement thresholds and worsening thresholds. Multivariable Cox regression models assessed the effect of improvement and worsening in the 6MWD on 1-year survival, adjusted for baseline factors., Results: One-year survival estimates were higher for patients with a baseline 6MWD above vs below a threshold, although no specific threshold was more prognostic than another. In a model adjusted for the baseline 6MWD and risk score, worsening of the 6MWD over time significantly predicted decreased survival, but improvement in the 6MWD did not affect survival., Conclusions: No 6MWD improvement threshold carries particular prognostic value. Improvement in the 6MWD was not associated with survival, but worsening of the 6MWD was strongly and significantly associated with poor prognosis., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Data from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) were used previously to develop a risk score calculator to predict 1-year survival. We evaluated prognostic implications of changes in the risk score and individual risk-score parameters over 12 months., Methods: Patients were grouped by decreased, unchanged, or increased risk score from enrollment to 12 months. Kaplan-Meier estimates of subsequent 1-year survival were made based on change in the risk score during the initial 12 months of follow-up. Cox regression was used for multivariable analysis., Results: Of 2,529 patients in the analysis cohort, the risk score was decreased in 800, unchanged in 959, and increased in 770 at 12 months post-enrollment. Six parameters (functional class, systolic blood pressure, heart rate, 6-minute walk distance, brain natriuretic peptide levels, and pericardial effusion) each changed sufficiently over time to improve or worsen risk scores in ≥5% of patients. One-year survival estimates in the subsequent year were 93.7%, 90.3%, and 84.6% in patients with a decreased, unchanged, and increased risk score at 12 months, respectively. Change in risk score significantly predicted future survival, adjusting for risk at enrollment. Considering follow-up risk concurrently with risk at enrollment, follow-up risk was a much stronger predictor, although risk at enrollment maintained a significant effect on future survival., Conclusions: Changes in REVEAL risk scores occur in most patients with pulmonary arterial hypertension over a 12-month period and are predictive of survival. Thus, serial risk score assessments can identify changes in disease trajectory that may warrant treatment modifications., (Copyright © 2015 International Society for Heart and Lung Transplantation. All rights reserved.)

Background: Hospitalization is an important outcome in pulmonary arterial hypertension (PAH), shown previously to correlate with survival. Using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), we sought to characterize first-time hospitalizations and their effect on subsequent hospitalization and survival in patients with newly diagnosed disease., Methods: Patients with newly diagnosed PAH (n = 862, World Health Organization group 1) were evaluated for first-time hospitalization. The hospitalizations were categorized as PAH related or PAH unrelated based on the case report form. Categories for PAH-related and PAH-unrelated hospitalization were defined before independent review. Patient demographics and disease characteristics are described as well as freedom from hospitalization and survival., Results: Of 862 patients, 490 (56.8%) had one or more hospitalizations postenrollment: 257 (52.4%) PAH related, 214 (43.7%) PAH unrelated, and 19 (3.9%) of undetermined causes. The most common causes of PAH-related hospitalization were congestive heart failure and placement/removal of a central venous catheter. Patients with PAH-related hospitalizations were more likely to receive parenteral therapy, be in functional class III/IV, and have higher risk scores before hospitalization at enrollment. Following discharge, 25.4% ± 3.2% and 31.0% ± 4.0% of patients with PAH-related and PAH-unrelated first hospitalization, respectively, remained hospitalization-free for 3 years (P = .11). Survival estimates at 3 years postdischarge were 56.8% ± 3.5% and 67.8% ± 3.6% (P = .037) for patients with PAH-related and PAH-unrelated hospitalization, respectively., Conclusions: In the REVEAL Registry, PAH-related hospitalization was associated with relatively more rehospitalizations and worse survival at 3 years., Trial Registry: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.