CHEST

Original Research
PULMONARY VASCULAR DISEASE

Evaluation of the Predictive Value of a Clinical Worsening Denition Using 2-Year Outcomes in Patients With Pulmonary Arterial Hypertension
A REVEAL Registry Analysis
Adaani E. Frost, MD, FCCP; David B. Badesch, MD, FCCP; Dave P. Miller, MS; Raymond L. Benza, MD; Leslie A. Meltzer, PhD; and Michael D. McGoon, MD, FCCP

Background: Time to clinical worsening has been proposed as a primary end point in clinical trials of pulmonary arterial hypertension (PAH); however, neither standardized nor validated denitions of clinical worsening across PAH trials exist. This study aims to evaluate a proposed denition of clinical worsening within a large prospective, observational registry of patients with PAH with respect to its value as a predictor of proximate (within 1 year) risk for subsequent major events (ie, death, transplantation, or atrial septostomy). Methods: We assessed overall 2-year survival and survival free from major events to determine the relationship between clinical worsening and major events among adults with hemodynamically dened PAH (N 5 3,001). Freedom from clinical worsening was dened as freedom from worsening functional class (FC), a 15% reduction in 6-min walk distance (6MWD), all-cause hospitalization, or the introduction of parenteral prostacyclin analog therapy. Results: In the 2 years of follow-up, 583 patients died. Four hundred twenty-six died after a documented clinical worsening event, including FC worsening (n 5 128), a 15% reduction in 6MWD (n 5 118), all-cause hospitalization (n 5 370), or introduction of a prostacyclin analog (n 5 91). Patients who experienced clinical worsening had signicantly poorer subsequent 1-year survival postworsening than patients who did not worsen (P , .001). Conclusions: Clinical worsening was highly predictive of subsequent proximate mortality in this analysis from an observational study. These results validate the use of clinical worsening as a meaningful prognostic tool in clinical practice and as a primary end point in clinical trial design. Trial registry: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov CHEST 2013; 144(5):15211529
Abbreviations: 6MWD 5 6-minute walk distance; APAH-CTD 5 connective tissue disease-associated pulmonary arterial hypertension; FC 5 functional class; HR 5 hazard ratio; PAH 5 pulmonary arterial hypertension; PCWP 5 pulmonary capillary wedge pressure; REVEAL Registry 5 Registry to Evaluate Early and Long-term PAH Disease Management; RHC 5 right-sided heart catheterization; TTCW 5 time to clinical worsening

arterial hypertension (PAH) is a rare, Pulmonary chronic, progressive disorder of the pulmonary

arterial circulation characterized by increased pulmonary artery pressure associated with increased pulmonary vascular resistance, which can result in right ventricular dysfunction and ultimately right-sided heart failure and death.1-3 Time to clinical worsening (TTCW) is an end point in PAH trials that is increasingly considered relevant to patients and physicians.4,5 Nonmortal components of TTCW are used to assess disease

progression and to identify patients for therapy augmentation. Broadly used as a secondary end point, clinical worsening has been inconsistently dened across clinical drug trials, and the value of clinical worsening as an outcome predictor has not been unequivocally demonstrated.6 In an effort to develop useful clinical indices of therapeutic success in PAH, the Task Force on End Points and Clinical Trial Design convened at the Fourth World Symposium on Pulmonary Hypertension to
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consider a range of assessments with potential value as end points. Measurements of clinical worsening were highly favored as a balanced means to assess risk. Thus, the use of TTCW with mandatory adjudication of events has been recommended as a primary end point in phase 3 or pivotal trials, with assessment of exercise ability demoted to a secondary end point. The task force proposed a denition of clinical worsening for use in clinical trials that emphasizes hard events, including all-cause mortality, nonelective hospitalization for PAH with predened criteria, and disease progression.5 This task force recommended that disease progression be dened as a reduction from baseline in the 6-minute walk by 15%plus worsening functional class (except for patients already in functional class IV).5 These latter recommendations were largely based on expert opinion. The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) is the largest US registry of patients with PAH assembled to date and offers the opportunity to look at a particular denition of TTCW. Because the study protocol preceded the task force proposal and the REVEAL Registry is strictly observational with no mandated tests, an approximate denition of clinical worsening outcome was developed for evaluation in the current study. The goal of this analysis was to validate the assumption that clinical worsening by any of the currently conceived parameters is predictive of worse proximate outcome (arbitrarily chosen as 1 year). Materials and Methods
Study Population The design and baseline characteristics of patients enrolled in the REVEAL Registry have been previously described.7,8 The REVEAL Registry is a large, multicenter, observational, US-based study that provides current information about demographics, disease progression, and management of patients with conrmed group 1 pulmonary hypertension (ie, PAH) and represents a cohort Manuscript received December 17, 2012; revision accepted June 25, 2013. Afliations: From the Baylor College of Medicine (Dr Frost), Houston, TX; University of Colorado Health Sciences Center (Dr Badesch), Denver, CO; ICON Late Phase & Outcomes Research (Mr Miller), San Francisco, CA; Allegheny General Hospital (Dr Benza), Pittsburgh, PA; Actelion Pharmaceuticals US, Inc (Dr Meltzer), South San Francisco, CA; and Mayo Clinic (Dr McGoon), Rochester, MN. Funding/Support: Preparation of this manuscript was supported by Actelion Pharmaceuticals US, Inc. Funding and support for the REVEAL Registry was provided by CoTherix, Inc, and its afliate Actelion Pharmaceuticals US, Inc. Correspondence to: Adaani E. Frost, MD, FCCP, Baylor College of Medicine, MS 621, 6620 Main St, Houston, TX 77030; e-mail: frost@bcm.tmc.edu 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-3023
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of patients similar to those seen in routine clinical practice. Patients are followed for a minimum of 5 years from the time of enrollment, allowing for the collection of longitudinal data on PAH outcomes, including functional class (FC) status, exercise capacity, pulmonary function test results, hemodynamic measurements, initiation of PAH-specic therapies, hospitalizations, and death. Patients in the REVEAL Registry include both newly diagnosed (diagnosis conrmed by right-sided heart catheterization [RHC] , 3 months before enrollment) and previously diagnosed (diagnostic RHC 3 months before enrollment) patients with PAH. Time of diagnosis was dened as the time of the rst RHC that conrmed the presence of PAH. The minimum age at diagnosis was 3 months. Eligible patients were required to meet the following hemodynamic criteria: mean pulmonary artery pressure . 25 mm Hg at rest or . 30 mm Hg with exercise contemporaneous with pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure 18 mm Hg, and pulmonary vascular resistance 240 dyn/s/cm5 ( 3 Wood units). With the exception of the less restrictive PCWP criterion of 18 mm Hg as more inclusive of patients seen in clinical practice, REVEAL Registry inclusion criteria correspond to accepted hemodynamic denitions of PAH.1,2 Patients were excluded if clinical presentation was inconsistent with a diagnosis of PAH or informed consent was not given. The present analysis, however, was restricted to data from adults aged . 18 years with a PCWP 15 mm Hg at the time of diagnosis. All patient data were analyzed from the time of enrollment in the REVEAL Registry. Study Design Overall survival, survival free from major events, and survival free from major events or clinical worsening were assessed 2 years following study enrollment. Major events were dened as death, transplantation, or atrial septostomy. Clinical worsening was dened as worsening New York Heart Association FC, a 15% reduction in 6-min walk distance (6MWD), all-cause hospitalization, or the introduction of a parenteral prostacyclin analog for any reason. For each of the four events dened as clinical worsening, some patients could not, by denition, experience the event. Patients who were FC IV at baseline could not experience nonfatal worsening with respect to FC. Patients who did not have a baseline 6MWD could not have a reduction in 6MWD. Patients who were already hospitalized at baseline and were never discharged could not have a new hospital admission, and patients who were receiving parenteral prostacyclins at enrollment could not have parenteral prostacyclins added. These patients were counted as having worsened as dened by the worsening composite outcome if they worsened according to at least one of the other three criteria; however, it should be noted that in the evaluation of individual worsening components, the populations at risk were not identical. Statistical Analysis Sensitivity of the clinical worsening composite end point and the individual components of the composite outcome were assessed by evaluating the proportion of deaths that were preceded by worsening events. Kaplan-Meier product limit estimates were used to evaluate 2-year survival, survival free from major events, and survival free from major events or clinical worsening. Patients who worsened in the rst year of follow-up or who had 1 year of clinical worsening-free follow-up were compared with respect to demographics and 1-year survival. For this survival comparison, the 1-year at-risk period began the day of clinical worsening or the rst day after 1 year of clinical worsening-free survival. These estimates may be interpreted as positive predictive value and negative predictive value, respectively. Kaplan-Meier curves were compared by log-rank test.
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The 1-year time frame for evaluating worsening was selected because follow-up in the REVEAL Registry is entirely observational and not directed by protocol. Although follow-up schedules vary in actual practice, it is rare for a patient with PAH to go 1 year without clinical follow-up. A sensitivity analysis was conducted to assess worsening through only the rst 6 months of follow-up, comparing patients who worsened during that period with those who were free of worsening through 6 months. Both time cutoffs have the disadvantage of excluding patients who died before worsening during the rst period. To address this concern, a Cox proportional hazards model with time-varying covariates was t,9 where worsening was included as an indicator variable that changed over time if the patient worsened. In addition, this method was extended to t a multivariable Cox model adjusting for baseline differences.

tion, the majority of patients (. 90%) in the REVEAL Registry were receiving an endothelin receptor antagonist, phosphodiesterase type 5 inhibitor, or prostacyclin, whereas 36% were receiving combination therapy. Patients who died in the rst year without a prior clinical worsening event are included in the total number of patients but are not included in either the worsening or the nonworsening cohort. Two-Year Estimates of Clinical Worsening and Major Events The overall survival estimate ( SE) for all patients was 89.2% 0.6% at 1 year and 80.2% 0.7% at 2 years (Fig 2). Similarly, the probability of survival free from major events was 88.3% 0.6% and 78.9% 0.8% at 1 and 2 years, respectively. In contrast, the probability of survival free from either major events or clinical worsening was 51.2% 0.9% at 1 year and 36.3% 0.9% at 2 years. In a stratied analysis, newly diagnosed patients (diagnostic RHC , 3 months before enrollment) had a 2-year survival, a major event-free survival, and a survival free from clinical worsening or major events estimate of 75.0% 1.5%, 73.7% 1.6%, and 36.2% 1.7%, respectively. Previously diagnosed patients (diagnostic RHC 3 months before enrollment) had a 2-year survival, a major event-free survival, and a survival free from clinical worsening or major events estimate of 82.2% 0.8%, 80.9% 0.9%, and 36.3% 1.0%, respectively. Relationship Between Clinical Worsening and Survival Of the patients who survived without transplantation or septostomy, those who clinically worsened in the rst year of follow-up had a poorer survival in the subsequent 1 year of follow-up than those who did not (77.7% 1.1% vs 94.1% 0.6%, respectively; P , .001) (Fig 3A). Similarly, for newly diagnosed patients, 1-year survival was 74.6% 2.3% for those who clinically worsened and 90.3% 1.5% for those who did not clinically worsen (P , .001) (Fig 3B). Previously diagnosed patients had a 1-year survival of 77.6% 1.3% and 95.1% 0.7% for those who clinically worsened and those who did not clinically worsen, respectively (P , .001) (Fig 3C). As a sensitivity analysis, we compared patients who worsened during the rst 6 months of the assessment with those who did not. For this analysis, the at-risk clock began at the time of worsening or at 6 months. We observed a survival difference of 76.6% vs 92.8% for 914 patients who worsened and 1,937 patients who did not worsen, respectively. Additionally, a Cox model with time-varying covariates was t to avoid selection of an arbitrary time point. With the timevarying covariate approach, all patients were at risk
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Results Patient Characteristics At the data collection end point on September 15, 2011, 3,001 REVEAL Registry patients met the analysis criteria of age . 18 years at the time of diagnosis and PCWP 15 mm Hg (Fig 1). Of those patients, 839 were newly diagnosed (diagnostic RHC , 3 months before enrollment). Patient characteristics at baseline and in the rst year of follow-up are summarized in Table 1. Age and sex were similar between patients who clinically worsened in the rst year of follow-up (n 5 1,340) and patients who were free from clinical worsening (n 5 1,511). Patients who clinically worsened were more likely to be FC IV (9.3%) and have a shorter 6MWD (341.0 128.5 m) than those who did not clinically worsen (3.7%; 6MWD, 380.6 121.5 m). More than one-fourth of the patients in both the worsening and the nonworsening cohorts were newly diagnosed, reecting the enrichment of the REVEAL Registry cohort with newly diagnosed patients. In addi-

Figure 1. Analysis cohort of adult patients with traditional PAH at diagnosis. aSeven patients had overlapping exclusion criteria for age and PCWP. Newly and previously diagnosed patients were dened as having conrmatory RHC within or 3 months before enrollment, respectively. PAH 5 pulmonary arterial hypertension; PCWP 5 pulmonary capillary wedge pressure; REVEAL 5 Registry to Evaluate Early and Long-term PAH Disease Management; RHC 5 right-sided heart catheterization.
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Table 1Patient Characteristics

Characteristic Age at enrollment, y Female sex NYHA functional class I II III IV 6-min walk distance, m Newly diagnosed Overall (N 5 3,001)a 53.2 14.2 2,369 (78.9) 184 (6.8) 925 (34.3) 1,399 (51.8) 191 (7.1) 358.1 127.9 (n 5 2,324) 839 (28.0) Worsenedb (n 5 1,340) 53.4 14.4 1,049 (78.3) 89 (7.2) 401 (32.6) 625 (50.9) 114 (9.3) 341.0 128.5 (n 5 1,097) 370 (27.6) Not Worsenedb (n 5 1,511) 52.8 14.1 1,209 (80.0) 90 (6.7) 497 (37.2) 698 (52.3) 50 (3.7) 380.6 121.5 (n 5 1,130) 407 (26.9)

Data are presented as mean SD or No. (%). NYHA 5 New York Heart Association; REVEAL Registry 5 Registry to Evaluate Early and Longterm Pulmonary Arterial Hypertension Disease Management. aIncludes patients who died (n 5 105) or had a major event (n 5 14) without a precipitating worsening event or who were lost to follow-up while free of worsening in the rst year of follow-up (n 5 31). bIn the rst year of REVEAL Registry follow-up, excluding patients who died or had a major event in the rst year without a precipitating worsening event.

for events from the time they entered the study. In addition, they had an additional hazard beginning on whatever day they worsened from that point forward. With this methodology, the estimated hazard ratio (HR) associated with worsening was 6.00 (95% CI, 4.92-7.31; P , .001). After adjusting for baseline FC and 6MWD, the HR was 5.32 (95% CI, 4.37-6.48; P , .001). Adjusting for the baseline REVEAL Registry risk score,10 the HR was 4.48 (95% CI, 3.68-5.46; P , .001). In addition to the results for the composite worsening end point, each individual component of the composite was associated with poor survival 1 year after worsening compared with worsening free for 1 year (1 year following 15% reduction in 6MWD, 79.7% 2.1%; 1 year following worsening FC, 76.6% 2.1%; 1 year following hospitalization, 71.4% 1.5%; 1 year following addition of a prostacyclin or prostacyclin analog, 71.8% 3.0%). The analysis of individual components was repeated for the subgroup of newly diagnosed patients and for the subgroup of patients with connective tissue disease-associated PAH (APAHCTD). As in the overall cohort, patients in these subgroups who experienced any of the four individual worsening components were clearly distinct from patients who did not worsen. Among newly diagnosed

patients, the survival following all types of worsening was similarly poor regardless of the type of worsening (eg, 69.3% 5.0% following 6MWD worsening and 70.9% 2.9% following hospitalization). Among patients with APAH-CTD, survival was poor regardless of the type of worsening, but there was a wider range of estimates depending on the type of worsening (eg, 75.4% 3.8% following 6MWD worsening and 59.5% 3.2% following hospitalization). Clinical worsening was a strong marker for death in both previously diagnosed and newly diagnosed patients. In the rst 2 years of follow-up, there were 583 deaths (Table 2). Among the patients who died, 426 (73.1%) experienced clinical worsening in the previous year. FC worsening occurred in 128 patients (22.0%), 6MWD reduction in 118 (20.2%), all-cause hospitalization in 370 (63.5%), and the addition of a prostacyclin analog in 91 (15.6%). Patients who died after clinically worsening in the rst 2 years of follow-up had a mean SD of 7.2 6.0 months between the event of clinical worsening and death. Clinical worsening also was a strong marker for death in newly diagnosed patients (n 5 133; 65.5% clinically worsened before death). FC worsening, 6MWD reduction, allcause hospitalization, or the addition of a prostacyclin analog occurred in 15.3%, 17.2%, 52.7%, and 22.2% of newly diagnosed patients, respectively. Comparable results were found in previously diagnosed patients. Discussion Several registries and open-label, long-term extension studies of prior placebo-controlled randomized clinical trials have assessed both survival and predictors of survival. These published data demonstrate that overall survival in the contemporary treatment era is improved compared with survival data from the original National Institutes of Health registry.11
Original Research

Figure 2. Two-year survival and event-free survival.

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Figure 3. Subsequent 1-y survival in patients with and without prior clinical worsening. A, All patients. B, Newly diagnosed patients. C, Previously diagnosed patients.

One-year survival in patients with PAH (idiopathic PAH and associated PAH) varies from as high as 96%12 to 79%.13 Contemporary 1-year survival restricted to patients with idiopathic PAH, familial PAH, and anorexigen-associated PAH is similarly much improved (92%).14 Data from these and other studies have been explored to determine whether predictors of mortality can be derived. A multivariate analysis of the REVEAL Registry has already determined that a 6MWD of , 165 or 440 m is correlated with worse and better survival, respectively.15 The concept of clinical worsening as a clinically relevant end point for studies dates from the large BREATHE-1 (Bosentan Randomized Trial of Endothelin Receptor Antagonist Therapy) study of bosentan,16 and most subsequent denitions in randomized clinical trials of clinical worsening incorporated factors that either were generally accepted as highly predictive of worse outcome or represented a worse outcome in themselves (ie, death, transplantation, atrial septostomy, hospitalization for worsening pulmonary hypertension, or study withdrawal because of adjudicated clinical worsening). The rst study that included nonvalidated markers of clinical worsening (ie, the combination of worsening FC and a 15% decline in 6MWD from baseline) was STRIDE-2 (Sitaxsentan To Relieve Impaired Exercise-2), a study of sitaxsentan in PAH.17 This end point was chosen somewhat arbitrarily, largely on the basis of expert opinion. Since then, many current and ongoing studies have chosen clinical worsening as a primary end point and have included a 15% decrease in walk distance and FC deterioration as indices of clinical worsening (eg, GRIPHON [Selexipag (ACT-293987) in Pulmonary Arterial Hypertension], SERAPHIN [Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hyperjournal.publications.chestnet.org

tension to Improve Clinical Outcome], AMBITION [A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension], studies of selexipag, macitentan, and primary combination therapy with tadalal and ambrisentan vs monotherapy, respectively). This is in spite of the fact that no published data have ever validated the association between a decrease in walk distance or worsening FC and mortality. There are substantial data correlating absolute values, but not a deterioration in 6MWD with either survival or mortality (, 165, , 380, , 320, . 440, , 305, , 307 m).15,18-21 Some population-based evidence also supports a relationship between longer or shorter walk distances and survival. The only data published to date on change in walk distance are from an original observation that an improvement in walk distance, even if large, was not predictive of improved survival22 unless a certain goal level was achieved. The appropriateness of what is now a frequently used study end point as an indicator of worse outcome (ie, percent deterioration in walk distance) has never been validated. Similarly, the need for hospitalization or augmented therapy for PAH with an IV prostacyclin, although intuitively associated with worsening disease, has never been validated as predictive of worse survival, and in fact, both interventions might substantially benet outcome. Hence, there is a need for validation of these indices. In this subanalysis of the REVEAL Registry, we proposed a composite denition of TTCW (ie, deterioration in 6MWD or FC, all-cause hospitalization, or the initiation of a prostacyclin analog) and attempted to validate the presumption inherent in most studies that any or all of these factors predict an adverse outcome (eg, death or transplantation). In doing so, we
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Table 2Worsening Before Death in the First 2 y of Follow-up

All Patients (N 5 3,001) Event Total deaths Major events (excluding death) Transplantation Atrial septostomy Worsening FC worsening 6MWD reduction All-cause hospitalization Addition of prostacyclina No. (%) 583 13 (2.2) 12 (2.1) 1 (0.2) 426 (73.1) 128 (22.0) 118 (20.2) 370 (63.5) 91 (15.6) Mean Time Between Event and Death, mo ( SD) NA 5.9 6.2 5.6 6.4 8.8 NA 7.2 6.0 5.5 5.0 7.3 5.2 6.4 6.0 6.7 6.0 Newly Diagnosed Patients (n 5 839) No. (%) 203 2 (1.0) 2 (1.0) 0 (0.0) 133 (65.5) 31 (15.3) 35 (17.2) 107 (52.7) 45 (22.2) Mean Time Between Event and Death, mo ( SD) NA 1.4 1.9 1.4 1.9 NA 6.7 5.8 4.5 4.3 6.7 4.6 5.8 5.9 7.1 6.2

6MWD 5 6-min walk distance; FC 5 functional class; NA 5 not applicable. aPatients who were introduced to a prostacyclin analog on or after enrollment.

assessed the power of a composite denition of clinical worsening in predicting a subsequent major event. This analysis demonstrates that currently used end points, such as FC and 6MWD deterioration, that were included in our denition of clinical worsening are both likely to occur in a clinical trial and are highly predictive of a signicant decrease in survival. We also included an analysis of the impact of these worsening components on survival by comparing newly diagnosed patients (ie, those with a diagnostic RHC within 3 months of enrollment) and previously diagnosed patients (ie, those with RHC . 3 months before enrollment). This was done because of data indicating that newly diagnosed patients have worse survival from enrollment (the time of initiating prospective follow-up) than those with more long-standing disease23the so-called survivor bias. Although data indicate that time since diagnosis is not as predictive of outcome as the presence or absence of other validated risk factors (FC IV, 6MWD , 165 m, men aged . 60 years, APAH-CTD, etc), it seemed relevant to see whether our proposed components of clinical worsening would maintain their reliable prediction of mortality irrespective of whether the patients were newly or previously diagnosed. The percentage of patients who were newly diagnosed in those with and without clinical worsening was similar, and the impact of the components of clinical worsening on outcome was similarly predictive of reduced survival in those who were newly or previously diagnosed. Clinical worsening evaluated over a 1-year time frame strongly distinguishes patients with poor prognosis regarding subsequent major events compared with patients without clinical worsening through the subsequent year of follow-up. The survival curve is steepest in the 4 to 6 months after clinical worsening is identied, underscoring the need for clinical vigilance and therapy modication in patients experiencing clinical worsening.
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Our denition of clinical worsening deviates from that of the Fourth World Symposium on Pulmonary Hypertension task force in two ways. First, all-cause hospitalization was used rather than nonelective hospitalization because hospitalizations were not adjudicated in the REVEAL Registry. Second, worsening FC and 6MWD were not required to be concurrent; thus, worsening FC or worsening 6MWD rather than worsening FC and worsening 6MWD was used in our denition. In contrast to clinical trials that assessed improvement in 6MWD,24-26 the present analysis of REVEAL Registry data looked at worsening in 6MWD as a component of TTCW. Clinical trials and guidelines have used differing denitions of TTCW, and not all may be feasible in day-to-day clinical practice. Several limitations to this analysis should be considered. First, the REVEAL Registry is an observational study in which FC and 6MWD assessment are not required. Lack of worsening in FC or 6MWD could be a result of (1) FC and 6MWD tests being conducted and patients showing no signs of worsening or (2) FC and 6MWD tests not being conducted for patients who would have shown worsening. Second, assessments of FC and 6MWD are not required at regular intervals in standard clinical practice (unlike some clinical trials), so dening clinical worsening in clinical practice may require an either/or criterion (as has been validated in this study) rather than a both/and criterion (as used in clinical trials). Third, because FC IV is the most severe category, it is not possible for patients already classied as FC IV to have a worsening event by FC criteria, further supporting the rationale for an either/or denition for clinical worsening. Finally, our denition of clinical worsening uses all-cause hospitalization rather than hospitalization due to worsening PAH, which could result in inated numbers of patients who experienced worsening. However, it should be noted that the
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clinical worsening end point from this observational study was nonetheless strongly predictive, despite the end point not matching the denition of clinical worsening set forth by the task force guidelines. These analyses support the importance of assessing clinical worsening as an outcome and early warning for therapy augmentation. This composite denition of clinical worsening, which includes any component of worsening FC, worsening 6MWD, all-cause hospitalization, and/or introduction of a parenteral prostacyclin analog, represents simple and now-validated predictors of mortality that can no longer be considered laden with supposition. Acknowledgments
Author contributions: Dr Frost had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Frost: contributed to the study design; data collection, analysis, and interpretation; and drafting, critical review, and nal approval of the manuscript. Dr Badesch: contributed to the study design; data collection, analysis, and interpretation; and drafting, critical review, and nal approval of the manuscript. Mr Miller: contributed to the study design; data collection, analysis, and interpretation; and drafting, critical review, and final approval of the manuscript. Dr Benza: contributed to the study design; data collection, analysis, and interpretation; and drafting, critical review, and final approval of the manuscript. Dr Meltzer: contributed to the study design; data collection, analysis, and interpretation; and drafting, critical review, and nal approval of the manuscript. Dr McGoon: contributed to the study design; data collection, analysis, and interpretation; and drafting, critical review, and nal approval of the manuscript. Financial/nonnancial disclosures: The authors have reported to CHEST the following conicts of interest: Dr Frost serves as a consultant for Actelion Pharmaceuticals US, Inc, and Gilead. She has received honoraria from Actelion Pharmaceuticals US, Inc; Gilead; and Pzer Inc and has provided expert testimony on diet pill litigation. She also has received (through Baylor College of Medicine) funds for institutional review board-approved research from Gilead; Actelion Pharmaceuticals US, Inc; United Therapeutics Corporation; Eli Lilly and Company; Pzer, Inc; Novartis Corporation; and Bayer AG. Dr Frost has received honoraria for her service on the REVEAL Registry Steering Committee, which is supported by Actelion Pharmaceuticals US, Inc, on behalf of CoTherix, Inc. Dr Badesch has received honoraria for service on steering committees and/or advisory boards for Actelion Pharmaceuticals US, Inc; Arena Pharmaceuticals, Inc; Bayer AG; Ikaria, Inc; Gilead; Encysive Pharmaceuticals; Pzer, Inc; GlaxoSmithKline; Lung Rx, Inc; United Therapeutics Corporation; Eli Lilly and Company; Biogen Idec; and mondoBIOTECH. He has received grants from Actelion Pharmaceuticals US, Inc; Gilead; Encysive Pharmaceuticals; Pzer, Inc; United Therapeutics Corporation; Lung Rx, Inc; Eli Lilly and Company; Novartis Corporation; Ikaria, Inc; and the National Institutes of Health, National Heart, Lung, and Blood Institute. Dr Badesch has previously been deposed in appetite suppressant litigation, serving as both a treating physician and an expert witness. He has received honoraria for his service on the REVEAL Registry Steering Committee, which is supported by Actelion Pharmaceuticals US, Inc, on behalf of CoTherix, Inc. Dr Badesch has been consulted in a legal matter by Actelion Pharmaceuticals US, Inc. Mr Miller is employed by ICON Late Phase & Outcomes Research, a company that receives research support from Actelion Pharmaceuticals US, Inc, on behalf of CoTherix, Inc, and other pharmaceutical companies. Dr Benza
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has received honoraria from Actelion Pharmaceuticals US, Inc; Gilead; and United Therapeutics Corporation and has received or is pending receipt of grants from Actelion Pharmaceuticals US, Inc; the American Heart Association; Bayer AG; National Institutes of Health, National Heart, Lung, and Blood Institute; Novartis Corporation; Pzer, Inc; and United Therapeutics Corporation. He has received honoraria for his service on the REVEAL Registry Steering Committee, which is supported by Actelion Pharmaceuticals US, Inc, on behalf of CoTherix, Inc. Dr Meltzer is a former employee of Actelion Pharmaceuticals US, Inc. Dr McGoon serves as a consultant for Actelion Pharmaceuticals US, Inc; Gilead; Lung Rx Inc; and Medtronic, Inc. He has received grants from Gilead and Medtronic, Inc. Dr McGoon has received honoraria for his service on the REVEAL Registry Steering Committee, which is supported by Actelion Pharmaceuticals US, Inc, on behalf of CoTherix, Inc. Role of sponsors: The REVEAL Registry is sponsored by Actelion Pharmaceuticals US, Inc. Medical writing support was provided by Latoya M. Mitchell, PhD, and Kathryn Leonard of inScience Communications, Springer Healthcare. SAS programming support was provided by Ginny Lai of ICON Late Phase & Outcomes Research. Editorial and programming support was funded by Actelion Pharmaceuticals US, Inc. Other contributions: This work was performed at 55 participating sites across the United States. The authors thank the principal investigators and their study coordinators for their participation in REVEAL Registry: David Badesch, MD, FCCP, University of Colorado Health Sciences Center, Aurora, CO, and Deb McCollister, RN; Erika Berman-Rosenzweig, MD, Columbia University, New York, NY, and Daniela Brady, RN; Charles Burger, MD, Mayo Clinic, Jacksonville, FL, and Pamela Long, RN, CCRP; Sif Hansdottir, MD, University of Iowa Hospitals & Clinics, Iowa City, IA, and Page Scovel, RN, BSN; Murali Chakinala, MD, FCCP, Washington University, St Louis, MO, and Ellen Lovato, RN, BSN; Monica Colvin-Adams, MD, University of Minnesota Medical Center, Fairview, Minneapolis, MN, and Nonyelum Harcourt; Maria Rosa Costanzo, MD, Midwest Heart Foundation, Naperville, IL, and Debbie Heidenreich, RN, BSN; Curt Daniels, MD, Childrens Research Institute at Ohio State, Columbus, OH, and Julianne Williamson-Mueller, RN, BSN; Curt Daniels, MD, Ohio State University, Columbus, OH, and Jami Maccombs; Raed Dweik, MD, Cleveland Clinic Foundation, Cleveland, OH, and Jennie Newman; Greg Elliott, MD, Intermountain Medical Center and the University of Utah, Salt Lake City, UT, and Natalie Kitterman, RN, BSN, CCRP; Harrison Farber, MD, Boston University School of Medicine, Boston, MA, and Kim Tobin Finch; Robert Frantz, MD, Mayo Clinic College of Medicine, Rochester, MN, and Louise Durst, RN; Adaani Frost, MD, FCCP, Baylor College of Medicine, Houston, TX, and Helena Purl, RN, BSN; Mardi Gomberg, MD, University of Chicago Hospitals, Chicago, IL, and Sandra Coslet, RN, MSN, MBA; James Gossage, MD, Medical College of Georgia, Augusta, GA, and Melissa James, RN; Dan Grinnan, MD, Virginia Commonwealth University, Richmond, VA, and Amy Frayser; Paul Hassoun, MD, Johns Hopkins Medical Center, Baltimore, MD, and Jude Aidam, MB ChB, MPH, CM, CCRP; Kristin Highland, MD, Medical University of South Carolina, Charleston, SC, and Laura Bailey; Nicholas Hill, MD, Tufts-New England Medical Center, Boston, MA, and Karen Visnaw, RN; Dunbar Ivy, MD, Childrens Hospital Department of Cardiology, Aurora, CO, and Kathleen Miller-Reed, RN; James Klinger, MD, Rhode Island Hospital, Providence, RI, and Barbara Smithson, RN, BSN; Steve Knoper, MD, University of Arizona, Tucson, AZ; Deborah Jo Levine, MD, University of Texas Health Science Center, San Antonio, TX, and Regina Whitener, RN, BSN; George Mallory, MD, Texas Childrens Hospital, Houston, TX, and Ann Bogran, RN, BSN; Catherine Markin, MD, Legacy Clinic Northwest, Portland, OR, and Lisa Roessel, RN, FNP, ARNP-BC; Michael Mathier, MD, University of Pittsburgh School of Medicine, Pittsburgh, PA, and Mary Pollera, RN; Wesley McConnell, MD, Kentuckiana Pulmonary Associates, Louisville, KY, and Kim Hobbs, MSN, ARNP; Dana McGlothlin, MD, UCSF Medical Center, San Francisco, CA, and Erin Kobashigawa, BA; Donald Moore, MD, Childrens Hospital at Vanderbilt, Nashville, TN, and Mary Beth Boyd, RN, BSN; Hassan Alnuaimat, MD, University of Florida, Gainesville, FL, and
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Christina Eagan; Srinivas Murali, MD, Allegheny General Hospital, Pittsburgh, PA, and Pranav Ravi, MBBS; Steven Nathan, MD, Inova Heart and Vascular Institute, Falls Church, VA, and Lori Schlegel, RN, BSN; Ronald Oudiz, MD, LA Biomedical Research Institute at Harbor-UCLA, Torrance, CA, and Joy Beckmann, RN, MSN; Myung Park, MD, University of Maryland School of Medicine, Baltimore, MD, and Faith E. Paahana-Janowick, RN, BSN; Ivan Robbins, MD, Vanderbilt University Medical Center, Nashville, TN, and Tracy Oyler, RN; David Ross, MD, UCLA Medical Center, Los Angeles, CA, and Michaela Dyke; Ghulam Saydain, MD, FCCP, Wayne State University, Detroit, MI, and Muhammad Usman, MD; Robert Schilz, DO, PhD, University Hospital of Cleveland, Cleveland, OH, and Dave Haney, RRT; Shelley Shapiro, MD, PhD, VA Greater Los Angeles Health System, Los Angeles, CA, and Wendy Hill, RN, NP, MSN; Roxana Sulica, MD, Beth Israel Medical Center, New York, NY, and Rebecca Fenton, RN; John Swisher, MD, Suncoast Lung Center, Sarasota, FL, and Laura Karasick; Darren Taichman, MD, PhD, University of Pennsylvania Medical Center, Philadelphia, PA, and Mamta J. Patel, RN, BSN; Jose Tallaj, MD, University of Alabama at Birmingham, Birmingham, AL, and Terri Tahmaseb, RN; Arunabh Talwar, MD, North Shore University-LIJ Medical Center, New Hyde Park, NY, and Rebecca Miller; Victor Tapson, MD, Duke University Medical Center, Durham, NC, and Sandy McNeilly; Victor Test, MD, UCSD Medical Center, La Jolla, CA, and Melissa Thrasher, CCRC; Ramagopal Tumuluri, MD, St Lukes Medical Center-Aurora, Milwaukee, WI, and Susan Oxborough, RN, CVN; Hector Ventura, MD, Ochsner Clinic Foundation, New Orleans, LA, and Bobbett Harris; Aaron Waxman, MD, PhD, Brigham and Womens Hospital, Boston, MA, and Laurie Lawler, RN; Sheila Weaver, MD, Temple Lung Center, Philadelphia, PA, and Ellen Bedenko, RN; James White, MD, PhD, University of Rochester Medical Center, Rochester, NY, and Karen Frutiger, RN, BSN; Jeffrey Wilt, MD, Spectrum Health Hospitals, Grand Rapids, MI, and Beth VanOver, RN, BSN; Delphine Yung, MD, Seattle Childrens, Seattle, WA, and Anne Davis, RN; and Roham Zamanian, MD, Stanford University Medical Center, Palo Alto, CA, and Val Scott, RN.

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