Functional Class Improvement and 3-Year Survival Outcomes in Patients With Pulmonary Arterial Hypertension in the REVEAL Registry

CHEST Original Research PULMONARY VASCULAR DISEASE Functional Class Improvement and 3-Year Survival Outcomes in Patients With Pulmonary Arterial Hypertension in the REVEAL Registry Robyn J. Barst, MD ; Lorinda Chung, MD ; Roham T. Zamanian, MD ; Michelle Turner, MS ; and Michael D. McGoon, MD Objective: New York Heart Association/World Health Organization functional class (FC) is associated with outcomes in pulmonary arterial hypertension (PAH). We assessed whether patients with PAH who improve from FC III to FC I/II have improved survival vs patients who remain at FC III or worsen to FC IV. Methods: Patients aged 19 years with FC III PAH from the Registry to Evaluate Early and Long- Term PAH Disease Management (REVEAL Registry) (N 5 982) were categorized as improved, unchanged, or worsened according to their change in FC from enrollment to first follow-up assessment within 1 year of enrollment. Kaplan-Meier estimates of 3-year survival from first follow-up and changes in 6-min walk distance (6MWD) from enrollment to first follow-up were determined. Subgroup analyses were conducted by cause (ie, idiopathic/familial, connective tissue disease [CTD], congenital heart disease) and time of diagnosis (ie, newly or previously diagnosed [diagnostic rightsided heart catheterization within or 3 months of enrollment, respectively]). Results: Overall, 27% of patients improved FC. Survival was better in patients whose FC improved (84% 2%, n 5 263) vs those who remained unchanged (66% 2%, n 5 645) or worsened (29% 6%, n 5 74) (all P,.001). Survival was also better in patient subgroups whose FC improved vs those who remained unchanged (idiopathic/familial [ P,.001], CTD-associated PAH [ P 5.009], whether newly [ P 5.004] or previously diagnosed [ P,.001]). 6MWD improvements were greater in patients whose FC improved vs those who remained unchanged in the overall ( P,.001) and CTD ( P 5.028) cohorts. Conclusion: Patients with PAH who improve from FC III to I/II, whether newly or previously diagnosed and regardless of PAH cause, have better survival vs patients who remain FC III. Trial registry: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov CHEST 2013; 144(1):160 168 Abbreviations: 6MWD 5 6-min walk distance; APAH 5 associated with pulmonary arterial hypertension; CHD 5 congenital heart disease; CTD 5 connective tissue disease; FC 5 functional class; FPAH 5 familial pulmonary arterial hypertension; IPAH 5 idiopathic pulmonary arterial hypertension; mpap 5 mean pulmonary artery pressure; PAH 5 pulmonary arterial hypertension; PCWP 5 pulmonary capillary wedge pressure; PH 5 pulmonary hypertension; PVR 5 pulmonary vascular resistance; REVEAL Registry 5 Registry to Evaluate Early and Long-term PAH Disease Management; RHC 5 right-sided heart catheterization; WHO 5 World Health Organization Functional class (FC) is a strong predictor of survival in pulmonary arterial hypertension (PAH). 1-5 Developed initially for heart failure by the New York Heart Association and adapted for pulmonary hypertension (PH) by the World Health Organization (WHO), patients fall into one of four classes according to limits on physical activity imposed by the disease. 6,7 Despite the subjectivity and sizeable interobserver variation in FC assessment, 8 studies consistently demonstrate 160 that patients assigned to WHO FC I or II have a better prognosis than those assigned to FC III or IV. 3,9-11 In addition, FC is a key variable in most predictive models of PAH, and regulatory approval and labeling of PAH therapies reflect the importance of FC on treatment strategy. The course of PAH is variable some patients die within a few months of diagnosis, whereas others live for decades. 3,9,10 Prognosis is highly dependent on Original Research

disease severity, rate of deterioration, and underlying cause. 3,9,12,13 For example, patients with PAH associated with congenital heart disease (CHD-APAH) live longer than those with connective tissue diseaseassociated PAH (CTD-APAH). 9,12 In particular, patients with systemic sclerosis-associated PAH have poorer outcomes than patients with idiopathic PAH (IPAH) or other subtypes of CTD-APAH. 14 Because PAH is a variable disease, it is important to periodically and regularly assess the trajectory of disease and the change in risk. Recently, in a single-center prospective study of 109 patients with IPAH, Nickel et al 15 demonstrated that improvements or deteriorations in FC over time were significant predictors of survival. In this analysis of the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), we assessed whether change in FC over time affects survival outcomes by comparing patients whose FC improved within the first year of follow-up after enrollment in the REVEAL Registry with those whose FC remained the same or worsened. We also conducted subgroup analyses to assess whether FC change and its impact on survival were affected by cause (ie, IPAH or familial PAH [FPAH], CHD-APAH, or CTD-APAH) or time from diagnosis. Patients Materials and Methods The REVEAL Registry includes patients with newly and previously diagnosed disease (diagnosis confirmed by right-sided heart catheterization [RHC] within or 3 months prior to enrollment, respectively) with group 1 PAH at the time of enrollment. Hemodynamic parameters confirming PAH (according to the Venice 2003 definition 16 at the time the REVEAL Registry was started) included mean pulmonary artery pressure (mpap) 25 mm Hg at rest or mpap. 30 mm Hg with exercise contemporaneous with pulmonary capillary wedge pressure (PWCP) or left ventricular enddiastolic pressure 18 mm Hg, and pulmonary vascular resistance (PVR) 240 dynes/s/cm 5. 17 Among the 3,515 patients enrolled in the REVEAL Registry, patients included in this analysis were 19 years of age at enrollment with a PCWP 15 mm Hg and Manuscript received October 1, 2012; revision accepted January 2, 2013. Affiliations: From the Columbia University College of Physicians and Surgeons (Dr Barst), New York, NY; the Vera Moulton Wall Center for Pulmonary Vascular Disease (Dr Zamanian), the Stanford University School of Medicine (Drs Chung and Zamanian), Stanford, CA; the Palo Alto VA Health Care System (Dr Chung), Palo Alto, CA; ICON Late Phase & Outcomes Research (Ms Turner), San Francisco, CA; and the Mayo Clinic (Dr McGoon), Rochester, MN. Died April 2013. Funding/Support: Funding and support for the REVEAL Registry were provided by CoTherix, Inc, and its affiliate, Actelion Pharmaceuticals US, Inc. Correspondence to: Michael McGoon, MD, Mayo Clinic, Department of Cardiovascular Diseases, 200 1st St SW, Rochester, MN 55902; e-mail: mmcgoon@mayo.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.12-2417 FC III at enrollment (based on the most recent preenrollment evaluation) who had one or more follow-up FC assessments within the first year after enrollment. Study Design Demographics, disease characteristics, and hemodynamic data were collected at enrollment. FC and 6-min walk distance (6MWD) were assessed at the first follow-up visit after enrollment, and 3-year survival from the time of the first follow-up visit was analyzed. Patients were classified as improved (if FC I/II), unchanged (if remained in FC III), or worsened (if deteriorated to FC IV). Subgroup analyses were conducted according to disease cause and time from diagnosis (date of confirmatory diagnostic RHC). Patients were classified as having IPAH or FPAH; PAH associated with CHD-APAH (repaired or, if unrepaired, with/without Eisenmenger syndrome), or CTD-APAH (without significant interstitial lung disease as defined by moderate or severe fibrosis on chest imaging and/or total lung capacity, 60% predicted). The 2003 (Venice) PH classification scheme was used because the REVEAL Registry began prior to the institution of the 2009 Dana Point scheme, and, thus, we use the term FPAH rather than heritable PAH. In addition, analysis of the overall population was assessed based on the time of diagnosis. Patients with newly or previously diagnosed disease were defined by the time of the diagnostic RHC as within or 3 months prior to enrollment, respectively. Three-year survival was also examined according to age at enrollment (, 65 years vs 65 years), sex, cause at enrollment, 6MWD (, 380 m vs 380 m), and the REVEAL risk score at enrollment (, 10 vs 10). Statistical Analysis Kaplan-Meier curves were estimated for 3-year survival from the time of the first follow-up visit with FC assessment, and differences between FC groups were assessed by the log-rank test. Changes in exercise capacity (as assessed by 6MWD) between enrollment and the first follow-up FC assessment (completed within 1 year after the first FC assessment) were compared between the groups with analysis of variance method. P values for continuous and categorical variables were calculated using the Student t test or one-sample t test and x 2 test, respectively. Sensitivity analyses were conducted stratifying each subgroup according to the time from diagnosis (ie, newly vs previously diagnosed). Results A total of 982 patients were classified as FC III at enrollment in the REVEAL Registry and met the inclusion criteria for the primary analysis. Of those patients, 496 had IPAH/FPAH, 278 had CTD-APAH, and 91 had CHD-APAH. Demographics and clinical characteristics of each analysis cohort according to FC (improved, unchanged, or worsened) are shown in Table 1. Among the overall analysis cohort, 27% of patients improved FC, 66% remained in FC III, and 8% worsened to FC IV from the time of enrollment in the REVEAL Registry to the first follow-up FC assessment. A similar distribution among FC categories was observed in the IPAH/FPAH and CTD cohorts. In comparison, a higher percentage of patients improved FC and a lower percentage remained unchanged in the CHD cohort. The majority of patients in the CTD subgroup had systemic sclerosis (n 5 188, 68%); of those, 69% remained in FC III. Of the 91 patients journal.publications.chestnet.org CHEST / 144 / 1 / JULY 2013 161

Table 1 Demographics and Characteristics of Patients With FC III PAH at Enrollment in the REVEAL Registry Characteristic Improved FC III I/II Unchanged FC III Worsened FC III IV P Value Improved vs Unchanged Full study cohort (N 5982) 263 (27) 645 (66) 74 (8) Group 1 PAH subgroup at enrollment.64 a IPAH/FPAH 128 (49) 330 (51) 38 (51) APAH 134 (51) 312 (48) 35 (47) CTD 68 (26) 197 (31) 21 (28).16 b CHD 31 (12) 53 (8) 7 (10).092 c Portal hypertension 12 (9) 28 (9) 1 (3) Drugs and toxins 18 (13) 26 (8) 6 (17) HIV 4 (3) 3 (1) 0 (0) Other d 1 (0.7) 5 (1.6) 0 (0.0) PVOD 1 (0.4) 3 (0.5) 1 (1.4) Age at enrollment, y 51 15 55 14 57 14,.001 6MWD, m 374 99 321 105 236 93,.001 Female 211 (80) 527 (82) 62 (84).60 Newly diagnosed 94 (36) 184 (29) 17 (23).032 Time from enrollment to first follow-up FC 5 3 4 3 5 3,.001 assessment, mo IPAH/FPAH (n 5496) 128 (26) 330 (67) 38 (8) IPAH 118 (92) 313 (95) 36 (95).28 FPAH 10 (8) 17 (5) 2 (5) Age at enrollment, y 50 16 55 15 57 16.005 6MWD, m 377 95 324 117 222 79.002 Female 101 (79) 267 (81) 32 (84).63 Newly diagnosed 46 (36) 90 (27) 9 (24).069 Time from enrollment to first follow-up FC 5 3 4 3 4 3.008 assessment, mo CTD (n 5278) 68 (25) 190 (68) 20 (7).55 Systemic scleroderma 42 (63) 130 (69) 16 (80) Systemic lupus erythematosus 17 (25) 28 (15) 0 (0) Mixed CTD 5 (8) 14 (7) 1 (5) Rheumatoid arthritis 2 (3) 6 (3) 0 (0) Sjögren syndrome 1 (1.5) 3 (1.6) 0 (0.0) Dermatomyositis/polymyositis 0 (0) 2 (1) 2 (10) Undifferentiated CTD 0 (0.0) 3 (1.6) 0 (0.0) Overlap syndrome 0 (0) 2 (1) 1 (5) Age at enrollment, mean SD, y 56 13 59 14 62 11.25 6MWD, mean SD, m 339 106 299 94 247 116.037 Female 63 (93) 170 (90) 17 (85).45 Newly diagnosed 24 (35) 66 (35) 4 (20).93 Time from enrollment to first follow-up FC 5 4 4 3 5 3.027 assessment, mo CHD (n 591) 31 (34) 53 (58) 7 (8) CHD repair status Repaired 11 (36) 12 (23) 1 (14).20 Unrepaired/partially repaired 20 (65) 41 (77) 6 (86) Eisenmenger syndrome 9 (45) 20 (49) 4 (67) Age at enrollment, y 41 13 49 13 49 10.019 6MWD, m 411 110 348 76 231 108.021 Female 22 (71) 39 (74) 7 (100).80 Newly diagnosed 6 (19) 7 (13) 2 (29).45 Time from enrollment to first follow-up FC assessment, mo 5 3 4 3 4 3.63 Data are given as No. (%) or mean SD. 6MWD 5 6-min walk distance; CHD 5 congenital heart disease; CTD 5 connective tissue disease; FC 5 functional class; FPAH 5 familial pulmonary arterial hypertension; IPAH 5 idiopathic pulmonary arterial hypertension; PAH 5 pulmonary arterial hypertension; PVOD 5 pulmonary venoocclusive disorder; REVEAL Registry 5 Registry to Evaluate Early and Long-term PAH Disease Management. a P value calculation for IPAH vs FPAH vs APAH vs PVOD. b P value calculation for CTD vs not CTD. c P value calculation for CHD vs not CHD. d Additional patients with APAH included hereditary hemorrhagic telangiectasia, hemoglobinopathy (n 52), thrombocythemia and myelofibrosis associated with obstructive sleep apnea and sarcoidosis, chronic myeloproliferative disorder. 162 Original Research

with CHD who were in FC III, 33 patients (36%) were categorized as having Eisenmenger syndrome. The first follow-up FC assessment was performed at a mean SD of 4 3 months after enrollment in the overall group. In the overall cohort, IPAH/FPAH subgroup, and CHD subgroup, patients who improved in FC were younger than those who remained unchanged (all P.019). In addition, in the overall cohort, Table 2 Hemodynamic Parameters of Patients With FC III PAH at Enrollment in the REVEAL Registry Characteristic Improved FC III I/II Unchanged FC III Worsened FC III IV P Value Improved vs Unchanged Full study cohort, No. 263 645 74 mrap, No. 225 576 71 Mean SD, mm Hg 9 5 9 6 10 5.95 mpap, No. 243 619 73 Mean SD, mm Hg 51 15 49 12 50 12.13 PCWP or LVEDP, a No. 240 612 73 Mean SD, mm Hg 10 4 9 4 11 4.56 PVR index, No., Wood units 3 m2 194 499 56 Mean SD 20 12 19 11 19 8.16 Cardiac index, b No., L/min/m 2 198 503 56 Mean SD 2.4 1.0 2.4 0.8 2.3 0.7..99 Idiopathic/familial PAH, No. 128 330 38 mrap, No. 109 290 38 Mean SD, mm Hg 9 5 9 6 11 5.95 mpap, No. 117 313 38 Mean SD, mm Hg 52 15 50 11 51 11.068 PCWP or LVEDP, a No. 115 308 38 Mean SD, mm Hg 10 4 10 4 10 4.97 PVR index, No., Wood units 3 m2 94 260 27 Mean SD 22 12 20 9 19 7.015 Cardiac index, b No. L/min/m 2 95 263 27 Mean SD 2.2 0.8 2.3 0.7 2.3 0.6.26 Connective tissue disease, No. 68 190 20 mrap, No. 53 174 18 Mean SD, mm Hg 9 5 9 5 9 5.63 mpap, No. 59 186 19 Mean SD, mm Hg 44 12 46 11 45 11.16 PCWP or LVEDP, a No. 59 185 19 Mean SD, mm Hg 9 4 9 4 11 4.64 PVR index, No. Wood units 3 m2 48 152 17 Mean SD 15 9 17 8 18 10.22 Cardiac index, b No., L/min/m 2 48 153 17 Mean SD 2.6 0.9 2.4 0.8 2.3 0.9.34 Congenital heart disease, No. 31 53 7 mrap, No. 30 46 7 Mean SD, mm Hg 8 5 9 5 7 2.79 mpap, No. 31 50 7 Mean SD, mm Hg 56 15 56 17 57 17.88 PCWP or LVEDP, a No. 31 49 7 Mean SD, mm Hg 10 4 9 4 9 3.45 PVR index, No., Wood units 3 m2 20 30 4 Mean SD 22 15 27 26 21 10.52 Cardiac index, b No., L/min/m 2 8 10 1 Mean SD 2.5 1.0 2.6 1.0 1.6.81 Pulmonary blood flow for unrepaired and partially 4 15 1 repaired cohort, c No., L/min/m2 Mean SD 4.0 1.3 2.7 1.2 2.1.057 Systemic blood flow for unrepaired and partially 5 14 1 repaired cohort, c No., L/min/m2 Mean SD 2.8 0.4 2.1 0.9 2.4.094 FC 5 functional class; LVEDP 5 left ventricular end-diastolic pressure; mpap 5 mean pulmonary artery pressure; mrap 5 mean right atrial pressure; PAH 5 pulmonary arterial hypertension; PCWP 5 pulmonary capillary wedge pressure; PVR 5 pulmonary vascular resistance. a Minimum of PCWP and LVEDP. b Fick cardiac index. If the Fick cardiac index is missing, then the thermodilution cardiac index is used. c Pulmonary and systemic blood flow are calculated from the Fick equation for congenital heart disease in unrepaired and partially repaired shunt patients. journal.publications.chestnet.org CHEST / 144 / 1 / JULY 2013 163

IPAH/FPAH subgroup, and CTD subgroup, time from enrollment to first follow-up was longer in the improved FC group vs the unchanged group (all P.027). In the overall cohort, a higher proportion of patients with newly diagnosed disease were assigned to the improved FC vs unchanged ( P 5.032). Survival was also better in patient subgroups whose FC improved vs those who remained unchanged (IPAH/FPAH [ P,.001], CTDassociated PAH [ P 5.009], whether newly [ P 5.004] or previously diagnosed [ P,.001]). The hemodynamic parameters at enrollment of each analysis cohort are shown in Table 2. There were no significant differences in hemodynamic parameters between those who improved in FC and those who remained unchanged, with the exception of PVR index at enrollment in the IPAH/FPAH group that had a higher mean PVR index in the improved FC group vs the unchanged group ( P 5.015). Three-Year Survival In the overall cohort, 3-year survival estimates were better among patients whose FC status improved (84% 2%, n 5 263) compared with those whose status remained unchanged (66% 2%, n 5 645) or worsened (29% 6%, n 5 74) (all P,.001) ( Fig 1A ). Similar patterns in 3-year survival outcomes were observed in patients with previously diagnosed disease (n 5 687, all P,.001); however, in patients with newly diagnosed disease (n 5 295), a significant difference in survival was only observed in patients who improved in FC vs those who remained unchanged ( P 5.004) (Fig 2 ). Similar to the overall cohort, 3-year survival estimates among patients in the IPAH/FPAH cohort whose FC status had improved (88% 3%, n 5 128) was higher than those whose FC remained unchanged (72% 3%, n 5 330) ( Fig 1B ) or worsened (27% 8%, n 5 38 [data not shown]; all P,.001). Among patients in the CTD cohort, 3-year survival estimates were also higher in those whose FC status had improved (69% 6%, n 5 68) compared with those whose FC remained unchanged (57% 4%, n 5 190, P 5.009) ( Fig 1C ) or worsened (22% 11%, n 5 20 [data not shown], P,.001). In the CHD cohort, 3-year survival among patients whose FC status improved (97% 3%, n 5 31) was higher than those whose FC worsened (43% 19%, n 5 7 [data not shown], P 5.001), but no significant difference in survival was observed between patients whose FC improved and those whose FC remained unchanged (72% 6%, n 5 53, P 5.075) (Fig 1D ). Figure 1. A, Three-year survival estimates ( SE) from the first follow-up FC assessment in the overall cohort. B, Three-year survival estimates ( SE) from the first follow-up FC assessment in the idiopathic pulmonary arterial hypertension (PAH)/familial PAH cohort. C, Three-year survival estimates ( SE) from the first follow-up FC assessment in the connective tissue disease cohort. D, Three-year survival estimates ( SE) from the first follow-up FC assessment in the congenital heart disease cohort. a 5 P,.001 vs unchanged; b 5 P,.001 vs worsened; c 5 P 5.009 vs unchanged. FC 5 functional class. 164 Original Research

Table 3 Three-Year Survival From First Follow-up FC Assessment of Patients Who Were FC III at Enrollment Characteristic Improved FC III I/II Unchanged FC III P Value Improved vs Unchanged All patients 84 2 66 2,.001 Age at enrollment, 65 y 87 2 70 2,.001 65 y 68 8 56 4.089 Sex Male 82 6 52 5.004 Female 84 3 69 2,.001 Cause at enrollment IPAH 87 3 72 3,.001 FPAH 100 0 61 13.11 CTD 69 6 57 4.009 CHD 97 3 72 6.075 6MWD at enrollment, 380 m 80 4 64 3.001 380 m 94 3 79 4.022 REVEAL risk score at enrollment, 10 88 2 75 2,.001 10 66 7 40 4.002 Data are presented as mean SE in %. See Table 1 legend for expansion of abbreviations. Figure 2. A, Three-year survival estimates ( SE) from the first follow-up FC assessment in patients with newly diagnosed disease. B, Three-year survival estimates ( SE) from the first follow-up FC assessment in patients with previously diagnosed disease. a 5 P 5.004 vs unchanged; b 5 P,.001 vs unchanged. See Figure 1 legend for expansion of abbreviation. Three-year survival according to age, sex, cause, 6MWD, and REVEAL Registry risk score is shown in Table 3. With the exception of patients aged 65 years and those with FPAH, survival was significantly greater among those whose FC had improved compared with those whose FC remained unchanged. Six-Minute Walk Distance Differences between patients whose FC improved and those whose FC remained unchanged were observed in 6MWD at enrollment and at the first follow-up visit in the overall cohort ( P,.001), IPAH/FPAH cohort ( P.002), CTD cohort ( P.037), and CHD cohort ( P.021) ( Fig 3 ). In addition, changes in 6MWD from enrollment to the first follow-up visit showed greater improvements in patients who improved in FC vs those whose FC remained unchanged in the overall cohort ( P,.001) and in the CTD cohort ( P 5.028) ( Fig 3, Table 4 ). Discussion In this analysis of the REVEAL Registry, patients with PAH who improve from FC III to FC I/II within 1 year of enrollment have a significantly better estimated 3-year survival than patients who remain in FC III or worsen to FC IV. This suggests that, despite the limitation of being a fairly simple and crude clinical index, change in FC status is a meaningful clinical parameter. Moreover, these data show that FC improvement impacts survival outcomes regardless of cause and/or time of diagnosis. Among those who were FC III at enrollment, 27% improved FC. We consider this a meaningful improvement. Those who do not improve FC, despite treatment and in the absence of adverse events such as bronchitis, or those who deteriorate back to FC III after temporarily improving to FC II, need to be reevaluated for further escalation of treatment. These results confirm the use of New York Heart Association/WHO FC as a clinically relevant prognostic indicator. Although previous studies have shown that single time-point measurements of FC are predictive of survival outcomes, 3,9-12,18 these data examined the effect of the FC change on survival outcomes using a large population of patients (N 5 982) from a multicenter US observational registry. Our results are consistent with those of a recent prospective, single-center study of 109 patients with IPAH by Nickel et al, 15 which demonstrated that FC improvements or deteriorations were associated with more favorable or poorer survival outcomes, respectively. Subgroup analysis by cause confirmed that patients with CTD had lower survival rates and patients with journal.publications.chestnet.org CHEST / 144 / 1 / JULY 2013 165

Figure 3. 6MWD at enrollment and at the first follow-up FC assessment after enrollment in the overall cohort. 6MWD 5 6-min walk distance. See Figure 1 legend for expansion of other abbreviation. CHD had higher survival rates after 3 years compared with the overall cohort and vs those with IPAH/FPAH. These results are consistent with previous studies demonstrating that patients with CTD are at higher risk for poorer outcomes, 3,12-14 and patients with CHD have a better prognosis. 12,13 In each cause subgroup, patients who improved in FC had significantly higher estimated 3-year survival compared with those whose FC was unchanged or worsened, except in the CHD cohort, in which a difference in 3-year survival was only significant when comparing patients whose FC status improved to those whose FC worsened; however, the small number of patients in the CHD group with worsened FC precludes drawing strong conclusions from this observation. When examining 3-year survival from diagnosis, patients with previously diagnosed disease who improved in FC had significantly longer 3-year survival compared with those whose FC remained unchanged or worsened; however, patients with newly diagnosed disease who improved had significantly longer 3-year survival compared with only those whose FC remained unchanged. Although this analysis did not formally compare patients with previously vs newly diagnosed disease, previous studies have shown conflicting results on whether time of diagnosis negatively or positively impacts survival. 12,13 Our results indicate that, regardless of whether PAH is newly or previously diagnosed, improvement in FC results in improved survival outcomes compared with an unchanged FC. At enrollment and first follow-up, 6MWD was significantly higher in patients whose FC improved compared with those whose FC remained unchanged in the overall cohort and for each cause subgroup. However, the changes in 6MWD between these two visits were only significantly greater between patients who improved in FC vs those whose FC remained unchanged in the overall cohort or in the CTD cohort. Our results reinforce current PH consensus guideline recommendations to assess FC and 6MWD at each office visit and recommend treatment goals that include achieving or maintaining FC I/II. 1,4,5 In fact, patients who achieve FC I/II have been shown to have a better long-term prognosis than those who remain at FC III or deteriorate to FC IV during therapy. 2,19 Thus, the clinical value of determining indicators of risk in patients with PAH is to adjust treatment when necessary. Although many risk predictors are based on a single point in time using static measurements of risk, 20 this analysis demonstrates the importance of serial risk reassessment at follow-up evaluations. These data show that reassessment and changes in FC within 1 year (median 4 months) was predictive of outcome. Furthermore, our results, along with those of Nickel et al, 15 suggest that incorporating changes in FC may improve the predictive capability of risk models. Our findings confirm the importance of FC change and reestablishing PAH disease outlook based on FC (and likely other parameters) during treatment. Given the importance of the disease trajectory in PAH, conscientious follow-up and periodic risk reassessment is necessary with escalation of therapies if warranted. Despite multiple factors contributing to assessment, particularly in the CTD population, wherein FC can be strongly affected by multiple comorbidities (eg, anemia, musculoskeletal conditions, serositis), FC change should be monitored on a routine basis. Although FC assessment is largely subjective and is only based upon a four-point scale, it is remarkably consistent from study to study and serves as a simple yet powerfully effective clinical tool that should continue to be used in clinical trials and clinical practice. Table 4 6MWD at Enrollment and at the First Follow-up FC Assessment After Enrollment in the Overall Cohort Time of 6MWD Assessment Overall Improved FC III I/II Unchanged FC III Worsened FC III IV P Value Improved vs Unchanged No. 475 138 310 27 Enrollment 331 108 374 99 321 105 236 93,.001 First follow-up 336 114 399 96 320 107 195 89,.001 Change from enrollment to first follow-up 4 70 25 71 0.78 67 42 74,.001 Data are given as mean SD unless otherwise indicated. See Table 1 legend for expansion of abbreviations. 166 Original Research

There may be room for improvement of the current structure and methods of FC assessment in the clinical setting. Refinement and standardization of FC definitions and assessments across disciplines (ie, pulmonology, cardiology, and rheumatology) and subspecialties should enhance the efficacy of this prognostic tool to account for the multidisciplinary care of patients with PAH such as those with CTD. In addition to the intrinsic limitations of an uncontrolled, observational registry analysis, the following limitations regarding FC assessment need to be considered. Patients were categorized by FC at enrollment defined as the most recent FC assessment prior to enrollment; however, the time between that FC assessment date and enrollment date varied significantly among patients. In addition, the frequency of office visits and FC assessments reflects clinical practice and was not protocol driven, and, thus, a selection bias may exist among the subset of patients who had the serial assessment within 1 year necessary to qualify for this analysis. Moreover, FC assessment is subjective and may have varied among the REVEAL Registry investigators among and within sites. In fact, concordance rates for FC assessment among clinicians have been reported to be as low as 54% to 60%. However, intraobserver variation is much greater. 8,21,22 In addition, with respect to the association between FC and 6MWD, selection bias may exist among patients who worsened from FC III to IV because of severe illness impeding the ability to perform a 6MWD test or if, in the opinion of the investigator, it was not needed to diagnose disease progression. Nevertheless, despite the subjective nature of assessing FC, it has remained a tried and true parameter as demonstrated in the PAH clinical trials in which it was assessed. In addition, our analysis was limited to patients who were assessed as FC III at enrollment and did not examine the effect of a change from FC IV to FC I/II or change from FC IV to FC III. Finally, a survival bias may exist for patients whose disease was previously diagnosed at the time of enrollment, which may be considered a potential limitation that is not present in patients with newly diagnosed disease. It is important to remember that FC assessment also includes the side effects of the treatment, as some side effects can significantly impact overall quality of life and therefore functional capacity. In conclusion, these data demonstrate that patients with PAH who improve from FC III to FC I/II, whether with newly or previously diagnosed disease and regardless of PAH cause, have better survival compared with patients who remain at FC III or worsen to FC IV. These data reinforce goal-oriented therapy guidelines that is, improving as many patients as possible to FC I/II to significantly improve overall quality of life and outcomes. Acknowledgments Author contributions: Dr Barst 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 Barst: contributed to the study design; collection, analysis, and interpretation of data; and drafting and critical review of the manuscript and has seen and approved the final version. Dr Chung: contributed to the study design; collection, analysis, and interpretation of data; and drafting and critical review of the manuscript and has seen and approved the final version. Dr Zamanian: contributed to the study design; collection, analysis, and interpretation of data; and drafting and critical review of the manuscript and has seen and approved the final version. Ms Turner: contributed to the study design; collection, analysis, and interpretation of data; and drafting and critical review of the manuscript and has seen and approved the final version. Dr McGoon: contributed to the study design; collection, analysis, and interpretation of data; and drafting and critical review of the manuscript and has seen and approved the final version. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Barst serves as a consultant for and has received honoraria from Actelion Pharmaceuticals US, Inc; Bayer AG; Eli Lilly and Company; Gilead; GlaxoSmithKline; Ikaria, Inc; the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI); Novartis AG; Pfizer, Inc; and VentriPoint, Inc. Dr Barst has provided expert testimony on diet pill litigation for the plaintiffs. Dr Barst has received honoraria for her service on the REVEAL Steering Committee, which is supported by Actelion Pharmaceuticals US, Inc, on behalf of CoTherix, Inc. Dr Chung has received research support funding from Gilead; Pfizer, Inc; and United Therapeutics Corporation and has received honoraria from Actelion Pharmaceuticals US, Inc and served as a consultant to Gilead (, $10,000 per year). Dr Zamanian has received research funding support through the NIH (NHLBI and National Institute of Allergy and Infectious Diseases), the Vera Moulton Wall Center for Pulmonary Vascular Disease, and ENTELLIGENCE-Actelion career development research grant ($75,000). He has served as a consultant to United Therapeutics Corporation; Ikaria, Inc; Bayer AG; and Gilead. Ms Turner 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 McGoon serves as a consultant for Actelion Pharmaceuticals US, Inc, Gilead, Lung Rx, and Medtronic, Inc and has received grants from Gilead and Medtronic, Inc. Dr McGoon has received honoraria for his service on the REVEAL Steering Committee, which is supported by Actelion Pharmaceuticals US, Inc on behalf of CoTherix, Inc. Role of sponsors : Assistance in manuscript development was provided by Kathryn Leonard, BS, CMPP, and Lisa M. Klumpp Callan, PhD, CMPP, of inscience Communications, Springer Healthcare. ICON Late Phase & Outcomes Research provided statistical programming support. This support was funded by Actelion Pharmaceuticals US, Inc. Other contributions: The authors are saddened to report the passing of Robyn J. Barst, MD, in April 2013. She was an esteemed physician, investigator, and colleague. Her research focused extensively on pulmonary hypertension and she was a distinguished leader in the field of pediatric pulmonary hypertension. Dr Barst s contributions to the field are invaluable. We thank the Principal Investigators and their Study Coordinators for their participation in the REVEAL Registry (e-appendix 1). Additional information: The e-appendix can be found in the Supplemental Materials area of the online article. References 1. 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