Prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary arterial hypertension Ploegstra, Mark-Jan

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1 University of Groningen Prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary arterial hypertension Ploegstra, Mark-Jan IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Ploegstra, M-J. (2017). Prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary arterial hypertension. [Groningen]: Rijksuniversiteit Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Chapter 9 Clinical worsening as composite study endpoint in pediatric pulmonary arterial hypertension Mark-Jan Ploegstra * Sanne Arjaans * Willemijn M.H. Zijlstra Johannes M. Douwes Theresia R. Vissia-Kazemier Marcus T.R. Roofthooft Hans L. Hillege Rolf M.F. Berger *Contributed equally Chest 2015: 148:

3 208 Chapter 9 Abstract Background Clinical worsening (CW), an increasingly used composite end point in adult pulmonary arterial hypertension (PAH), has not yet been evaluated in pediatric PAH. This study aims to evaluate the usefulness of CW in pediatric PAH by assessing the event incidence and prognostic value of each separate component of CW and of the composite CW end point. Methods Seventy pediatric patients with PAH from the Dutch National Network for Pediatric Pulmonary Hypertension, who started PAH-targeted therapy between January 2000 and January 2014, were included and underwent standardized follow-up. The following CW-components were prospectively registered: death, lung-transplantation (LTx), PAH-related hospitalizations, initiation of IV prostanoids and functional deterioration (World Health Organization functional-class deterioration, 15% decrease in 6-min walk distance, or both). The longitudinal event incidence and prognostic value were assessed for each separate component and their combination. Results The end-point components of death, LTx, hospitalizations, initiation of IV prostanoids, and functional deterioration occurred with a longitudinal event rate of 10.1, 2.5, 21.4, 9.4 and 48.1 events per 100 person-years, respectively. The composite CW end point occurred 91.5 times per 100 person-years. The occurrences of either hospitalization, initiation of IV prostanoids or functional deterioration were predictive of death or LTx (p<01 for each component). In this cohort, 1-, 3- and 5-year transplant-free survival was 76%, 64% and 56%, respectively. Freedom from CW at 1, 3 and 5 years was 43%, 22% and 17%, respectively. Conclusions CW occurred with a high event incidence and each of the soft end point components was predictive of death or LTx. This supports the usefulness of CW as a study end point in clinical trials in pediatric PAH.

4 Clinical worsening in pediatric PAH 209 Introduction Pediatric pulmonary arterial hypertension (PAH) is a severe, progressive disease of the pulmonary vasculature and has an unsatisfactory prognosis despite the introduction of PAH-targeted therapies. 1 3 Most drugs currently used in the treatment of PAH have not been evaluated in pediatric clinical trials. 4,5 This is largely explained by the rarity and heterogeneity of pediatric PAH, leading to small study cohorts, but is also due to the lack of appropriate outcome parameters to evaluate drug efficacy. 6 8 Time to death would seem the most robust trial end point, as improving survival is the first priority in treating pediatric PAH. 3 However, death as an end point would require long-duration clinical trials in a very vulnerable group of pediatric patients unable to give consent, thereby challenging study ethics and leading to high costs. 7,8 Short-duration clinical trials with lower number of patients required are preferable but need an alternative end point to obtain sufficient statistical power. Such an end point should be either a direct or surrogate measure of how a patient feels, functions or survives 9 and would ideally be able to be measured earlier and more frequently than the final end point of interest. 10 Such an end point would lead to increased statistical power, reduction of required study participants, shorter study periods, and lower costs. 11 The 6-min walk distance (6MWD) has been the most commonly used primary end point in the pivotal trials in adult PAH. 12,13 The absolute value of 6MWD is regarded as a clinically meaningful end point, measuring how a patient functions. Moreover, 6MWD has been demonstrated to be an independent predictor of mortality in adults and in children >7 years old. 14,15 However, in the current era with accumulating treatment modalities, more ambitious treatment effects such as improved morbidity and mortality are desired. Evidence suggests that changes in 6MWD are not accurate surrogates for disease progression or survival, neither in adults or children. 13,16,17 This challenges the usefulness of 6MWD as an end point and has led to a call for alternative, more clinically meaningful end points. Clinical worsening (CW) has been suggested as an alternative end point in PAH CW consists of a combination of hard unambiguous events such as death and lung-transplantation (LTx), and softer events, including hospitalizations, need for additional therapy and worsening of function. CW has been used for some time as primary or secondary end point in adult trials, and its validity has been evaluated in adults. 40 Using 2-year outcome data from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), it was shown that the soft CW end point components were highly predictive of subsequent mortality. As 6MWD is not reliable in young children, this end point is not feasible for the pediatric age group. Although not yet evaluated, CW might be an appealing clinical end point in pediatric PAH, since it provides a patient-centered composite end point that 9

5 210 Chapter 9 decreases the required study participants and it would be applicable in different age groups. Moreover, it would account for the risk of rapid clinical deterioration in children. 8 However, before CW can be used in clinical trials, essential evaluation steps are required that would include a description of how frequent the end point components of CW occur, how the soft end point components relate to mortality and what the timing of CW is compared with mortality. 10 Therefore, the primary aim of this study was to evaluate the usefulness of CW in pediatric PAH by assessing event incidence and prognostic value of each separate component end point and the composite CW end point. The secondary aim was to describe the timing of CW compared with death or LTx in pediatric PAH. Materials and methods Study design and population This study is a retrospective analysis of data from a prospective clinical registry. In the Netherlands, all children with PAH are referred to the University Medical Center Groningen, which serves as the national referral center of the Dutch National Network for Pediatric Pulmonary Hypertension. 41 Children are followed and registered prospectively according to a standardized protocol. Ethical approval for this ongoing registry was obtained from the institutional review board (medical ethics review board of the University Medical Center Groningen, approval number M ) and the subjects and/ or their guardians provided written informed consent at enrollment. All treatment-naive patients in whom PAH-targeted therapy was initiated between January 1, 2000, and January 1, 2014, were included in this study. End point definition and data collection The definition of CW included the following end point components: (1) death; (2) LTx; (3) nonelective PAH-related hospitalizations, including hospitalizations for atrial septostomies; (4) initiation of IV prostanoids; and (5) functional deterioration, defined as either worsening of World Health Organization functional class (WHO-FC), 15% decrease in 6MWD, or both. This CW definition is in-line with various CW end points used in adult PAH trials and as proposed in consensus statements. 42,43 As the change in 6MWD as an end point has been challenged, a sensitivity analysis was performed with defining functional deterioration as worsening of WHO-FC only. The CW components were longitudinally registered from initiation of PAH-targeted therapy until the last follow-up visit before January 1, 2014.

6 Clinical worsening in pediatric PAH 211 Data analysis Data are presented as mean±sd, median (interquartile range[iqr]) or frequencies (percentage). Statistical analysis was performed using IBM SPSS version 22.0 (IBM Corporation). All statistical tests were two-sided and P values <5 were considered statistically significant. For the first functional deterioration event, follow-up WHO-FC and 6MWD were compared to the best achieved WHO-FC or 6MWD in the first year after treatment initiation. For consecutive events, WHO-FC and 6MWD were compared to the preceding follow-up visit. As WHO-FC IV indicates a functional status where further deterioration is not possible due to a ceiling effect, WHO-FC IV was always regarded as a functional deterioration event, also when it had been present at baseline. To describe the longitudinal event incidence of the end points, the longitudinal event rate per 100 person-years was calculated for each component and for the composite of these using the following formula: event rate per 100 person-years = total number events/(total observation time/100). In this analysis, patients could experience multiple events and were censored at death or end of follow-up. A separate event rate analysis was performed involving first events only, with censoring at time of the event or end of follow-up. Cumulative event incidence curves were depicted for the separate end point components. To assess the relationship between the soft and hard end point components, the prognostic value of the first occurring soft CW components 3, 4 and 5 were assessed using time-dependent Cox regression analysis with the hard end point death or LTx as the dependent analysis outcome (component 1+2). To describe the timing of CW in relation to death or LTx, both survival and event-free survival were reported and compared using Kaplan-Meier analysis. To align the study sample with the specific setting of a clinical trial, all analyses were repeated for a subgroup of what we called trial-eligible patients. These patients were defined as not hospitalized, not in WHO-FC IV and/or not immediately started on IV prostanoids at baseline. The results from these analyses were presented as Supplementary Material. 9 Results Patient characteristics In total, 70 patients were included in this study. The expected nationwide representation is confirmed by the fact that the current sample size over a 14-year period is inline with several reports on annual PAH incidence (reports ranging from one to three cases per million; the Dutch pediatric population approximately 3 million). 2,44,45 Patient characteristics at treatment initiation (baseline) are shown in Table 1. Median age was

7 212 Chapter 9 Table 1. Baseline Characteristics Stratified by Diagnosis Total IPAH/HPAH APAH-CHD APAH-non-CHD n N=70 n N=37 n N=25 n N=8 P Age, y ( ) ( ) ( ) ( ) Male (34) (35) 25 5 (20) 8 6 (75) 18 a WHO-FC a I 4 (6) 4 (11) 0 (0) 0 (0) II 25 (36) 12 (32) 10 (40) 3 (38) III 28 (40) 16 (43) 10 (40) 2 (25) IV 13 (19) 5 (14) 5 (20) 3 (38) 6MWD, m ± ± ± ± NT-proBNP, ng/l ( ) ( ) (93-752) ( ) 87 Hemodynamics b mrap, mmhg ± ± ± ± mpap, mmhg 61 54± ± ± ± PVRi, WU*m ± ± ± ± CI, L/min/m ± ± ± ± Treatment >0.999 a Upfront monotherapy 66 (94) 34 (92) 24 (96) 8 (100) Upfront dual therapy 3 (4) 2 (5) 1 (4) 0 (0) Upfront triple therapy 1 (1) 1 (3) 0 (0) 0 (0) Baseline IV prostanoids (19) 37 8 (22) 25 2 (8) 8 3 (38) a Hospitalized at baseline c (14) 37 6 (16) 25 1 (4) 8 3 (38) 52 a Observation time, py N.A. Data are presented as n (%) or median (interquartile range) or mean±sd, unless otherwise indicated. IPAH=idiopathic pulmonary arterial hypertension; HPAH=hereditary pulmonary arterial hypertension; APAH-CHD=pulmonary arterial hypertension associated with congenital heart disease; APAH-non-CHD=pulmonary arterial hypertension associated with conditions other than congenital heart disease; WHO-FC=World Health Organization functional class; 6MWD=6-minute-walk-distance; mrap=mean right atrial pressure; mpap=mean pulmonary arterial pressure; PVRi=indexed pulmonary vascular resistance; CI=cardiac index; N.A.=not applicable; NT-proBNP=N-terminal B-type natriuretic peptide; py=person-years. a Fisher s exact test used to calculate P-value. b Right heart catheterization prior to treatment initiation (the median time from catheterization to treatment initiation was 1 month). c Non-elective PAH related hospitalization.

8 Clinical worsening in pediatric PAH years (IQR, years). In total, 37 patients were diagnosed with idiopathic PAH (IPAH) or heritable PAH (HPAH), 25 with PAH associated with congenital heart disease (APAH-CHD), and eight with PAH associated with conditions other than congenital heart disease (APAH-non-CHD). Of the 25 patients with APAH-CHD, 16 (64%) had Eisenmenger physiology. Patients were followed for a median of 39 months (IQR, months), for a total observation time of person-years. Event incidence During the observation time, 28 patients (40%) died and seven (10%) underwent LTx (Table 2). The soft end point components - hospitalizations, initiation of IV prostanoids and functional deterioration - occurred in 38 (54%), 26 (37%) and 50 (71%) patients, respectively. The longitudinal event rates of the separate components were as follows: 10.1 deaths, 2.5 times LTx, 21.4 hospitalizations, 9.4 initiations of IV prostanoids and 48.1 functional deteriorations per 100 person-years (Table 2). The corresponding cumulative event-incidence curves are depicted in Figure 1 and show that a substantial proportion of the patients experienced components 3 and 5 more than once. The composite CW end point occurred in 59 of 70 patients, with an event rate of 91.5 events per 100 person-years (Table 2). Defining the functional deterioration component alternatively as worsening WHO-FC only, yielded a composite event rate of Stratification by diagnostic groups showed a lower event rate of the composite CW end point in APAH-CHD and a higher event rate in APAH-non-CHD. Table 3 shows the event rates when only each first event of an individual is taken into account. This yielded an event rate of 55.5 CW events per 100 person-years. The event incidence analyses were repeated in the trial-eligible subgroup, consisting of 49 patients who were not hospitalized, not in WHO-FC IV and/or not immediately started on IV prostanoids at baseline. The results are presented as Supplementary Material (event rates in Supplementary Tables 1 and 2, cumulative event incidence curves in Supplementary Figure 1) and show that the event incidence of the separate components and the end point combinations were slightly lower in this subgroup. 9 Prognostic value of soft components The occurrences of either PAH-related hospitalization, initiation of IV prostanoids, or functional deterioration were significantly associated with death or LTx, also after adjusting for diagnosis (P<01 for all models) (Table 4). A merge of these three soft components into a soft composite end point, in which the first occurrence of one of the three components was regarded as the event of interest, was also significantly associated with death or LTx (hazard ratio, 19.1; P<01). Analysis of alternative combinations of these soft end points, such as a combination without functional deterioration, yielded significant associations as well (P<01 for all analyzed combinations). An interaction

9 214 Chapter 9 Table 2. Event Rate of Separate and Combined End point-components Stratified by Diagnosis: All Events Total N=70 IPAH/HPAH N=37 APAH-CHD N=25 APAH-non-CHD N=8 Patients Event rate Patients Event rate Patients Event rate Patients Event rate n (%) n/100 py n (%) n/100 py n (%) n/100 py n (%) n/100 py (1) Death 28 (40) (38) (36) (63) 42.5 (2) Lung-transplantation 7 (10) (11) (12) (0) (3) Hospitalization a 38 (54) (57) (44) (75) 76.5 (4) Initiation of IV prostanoids 26 (37) (49) (16) (50) 34.0 (5) Functional deterioration (5A) WHO-FC b 44 (63) (73) (44) (75) 76.5 (5AB) WHO-FC b or 6MWD c 50 (71) (81) (56) (75) 93.5 End point combinations (1)(2)(3)(4) 51 (73) (78) (60) (88) (1)(2)(3)(4)(5A) 56 (80) (89) (64) (88) (1)(2)(3)(4)(5AB) (CW-composite) 59 (84) (95) (68) (88) Data are presented as n (%) or number of events per 100 person-years. IPAH=idiopathic pulmonary arterial hypertension; HPAH=hereditary pulmonary arterial hypertension; APAH-CHD=pulmonary arterial hypertension associated with congenital heart disease; APAH-non-CHD=pulmonary arterial hypertension associated with conditions other than congenital heart disease; IV=intravenous; WHO-FC=World Health Organization functional class; 6MWD=6-minute-walk-distance; py=person-years; CW=clinical worsening. a Non-elective PAH related hospitalization. b Worsening of WHO functional class. WHO functional class IV was always regarded as a functional deterioration event. c 15% decrease in 6-minute-walk-distance.

10 Clinical worsening in pediatric PAH 215 A 1.0 B 1.0 Cumulative event incidence Cumulative event incidence C 1.0 1st event 2nd event 3rd event D 1.0 Cumulative event incidence Cumulative event incidence E Cumulative event incidence st event 2nd event 3rd event 4th event F Cumulative event incidence st event 2nd event 3rd event 4th event 5th event Figure 1. Cumulative event incidence of separate end point-components. A: Component 1, death. B: Component 2, lung-transplantation. C: Component 3, non-elective PAH related hospitalization. D: Component 4, initiation of IV prostanoids. E: Component 5A, functional deterioration (defined as worsening of WHO functional class only). F: Component 5AB, functional deterioration (defined as worsening of WHO functional class and/or 15% decrease in 6-minute-walk-distance). Since the end point-components 3 (panel C) and 5 (panel E/F) could occur repetitive, the occurrence of every second, third, fourth and fifth are also depicted.

11 216 Chapter 9 Table 3. Event Rate of Separate and Combined End point-components Stratified by Diagnosis: First Events Total N=70 IPAH/HPAH N=37 APAH-CHD N=25 APAH-non-CHD N=8 Patients Event rate Patients Event rate Patients Event rate Patients Event rate n (%) n/100 py n (%) n/100 py n (%) n/100 py n (%) n/100 py (1) Death 28 (40) (38) (36) (63) 42.5 (2) Lung-transplantation 7 (10) (11) (12) (0) (3) Hospitalization a 38 (54) (57) 2 11 (44) (75) 74.0 (4) Initiation of IV prostanoids 26 (37) (49) (16) (50) 38.0 (5) Functional deterioration (5A) WHO-FC b 44 (63) (73) (44) (75) 77.7 (5AB) WHO-FC b or 6MWD c 50 (71) (81) (56) (75) 77.7 End point combinations (1)(2)(3)(4) 51 (73) (78) (60) (88) 10 (1)(2)(3)(4)(5A) 56 (80) (89) (64) (88) (1)(2)(3)(4)(5AB) (CW-composite) 59 (84) (95) (68) (88) Data are presented as n (%) or number of events per 100 person-years. IPAH=idiopathic pulmonary arterial hypertension; HPAH=hereditary pulmonary arterial hypertension; APAH-CHD=pulmonary arterial hypertension associated with congenital heart disease; APAH-non-CHD=pulmonary arterial hypertension associated with conditions other than congenital heart disease; IV=intravenous; WHO-FC=World Health Organization functional class; 6MWD=6-minute-walk-distance; py=person-years; CW=clinical worsening. a Non-elective PAH related hospitalization. b Worsening of WHO functional class. WHO functional class IV was always regarded as a functional deterioration event. c 15% decrease in 6-minute-walk-distance.

12 Clinical worsening in pediatric PAH 217 Table 4. Association of Soft End point-components With Death or Lung-Transplantation Interaction Analysis d Comparison with IPAH/HPAH Time-dependent Model 2 Adjusted for diagnosis Time-dependent Model 1 Univariable analysis APAH-non-CHD P HR (95% CI) P HR (95% CI) P APAH-CHD P Death (1) and Lung-transplantation (2) used as combined analysis end point (3) Hospitalization a 9.4 ( ) < ( ) < (4) Initiation of IV prostanoids 6.2 ( ) < ( ) < (5) Functional deterioration (5A) WHO-FC b 14.3 ( ) < ( ) < (5AB) WHO-FC b or 6MWD c 14.4 ( ) < ( ) < Soft end point combinations (3)(4) 12.3 ( ) < ( ) < (3)(4)(5A) 14.1 ( ) < ( ) < (3)(4)(5AB) 19.1 ( ) < ( ) < Data are presented as hazard ratio (95% confidence interval) or P-values. IPAH=idiopathic pulmonary arterial hypertension; HPAH=hereditary pulmonary arterial hypertension; APAH-CHD=pulmonary arterial hypertension associated with congenital heart disease; APAH-non-CHD=pulmonary arterial hypertension associated with conditions other than congenital heart disease; WHO-FC=World Health Organization functional class; 6MWD=6-minute-walk-distance; IV=Iintravenous; py=person-years. a Non-elective PAH related hospitalizations. b Worsening of WHO functional class. WHO functional class IV was always regarded as a functional deterioration event. c 15% decrease in 6-minutewalk-distance. d P-values <5 indicate significant differences in the associations across the diagnostic groups. 9

13 218 Chapter 9 analysis revealed that the effect size of the found associations did not significantly differ between the diagnostic groups. Similar associations with death or LTx were found in the trial-eligible subgroup (Supplementary Table 3). CW compared to death/ltx Figure 2 shows event-free survival curves for six end point-combinations. The composite CW end point occurred early and in a higher proportion of patients, compared to the other end point combinations. The event-free survival curves were similar in the trialeligible subgroup (Supplementary Figure 2). 1.0 Freedom from: component 1 component component component component A component AB (CW-endpoint) Cumulative survival Figure 2. Event-free survival of 6 end point combinations. Only the first occurrence of end point-components are incorporated as events. Component 1 = death; Component 2 = lung-transplantation; Component 3 = non-elective PAH-related hospitalization; Component 4 = initiation of IV prostanoids; Component 5A = functional deterioration (defined as worsening of WHO functional class only); Component 5AB = functional deterioration (defined as worsening of WHO functional class and/or 15% decrease in 6-minute-walk-distance); CW-end point = Full composite clinical worsening end point consisting of death, lung-transplantation, non-elective PAH related hospitalization, initiation of IV prostanoids and functional deterioration.

14 Clinical worsening in pediatric PAH 219 Discussion In this study, a proposed definition of CW was evaluated as a potential end point in pediatric PAH, which consisted of the following end point components: death, LTx, nonelective PAH-related hospitalization, initiation of IV prostanoids, and functional deterioration. The results show that CW occurs with a high event incidence and that all soft end point components are highly predictive of death or LTx. The first CW events occurred early in the disease course, supporting the usefulness of CW as a study end point and also as an early clinical warning sign. A study end point should be a clinically meaningful outcome, defined as a direct or surrogate measure of how a patient feels, functions or survives. 9 To date, no validated surrogates for survival are available in PAH and multiple well-established predictors of survival in adults have recently been shown to fail to comply with criteria for surrogacy. 13,16,46 48 CW consists of components that are all clinically meaningful outcomes in themselves. LTx, hospitalization, initiation of IV prostanoids, and functional deterioration are all undesirable events associated with major impairment in daily life (i.e., how a patient functions ), thereby making CW a valid and useful composite end point. An important criticism of CW is that the definitions used in clinical trials have not been completely consistent. 18,49 Death and LTx have been included in most definitions. The same holds true for hospitalizations, although definitions may vary. For example, in the recent REVEAL Registry substudy 40 in which CW was evaluated in adults, all-cause hospitalizations were included, whereas, in many trials, nonelective PAH-related hospitalizations have been used. It might be debated whether the REVEAL Registry definition is best for future trial designs, as hospitalizations due to comorbidities or social reasons should not be regarded as CW events. 49 The need for additional PAH therapy has been a common CW component throughout the trials, but has not always exclusively been defined as initiation of IV prostanoids. In this respect, it is important to realize that dose increments and addition of oral drugs might be part of currently changing, more aggressive, and goal-oriented treatment strategies, and are not necessarily induced by actual worsening of the disease. Moreover, in contrast to the initiation of continuous IV therapy, the addition of an oral therapy not necessarily affects a patient s ability to function in daily life. Therefore, inclusion of these events may distort the validity of CW as a clinically meaningful end point. Various definitions of functional deterioration have been used, including decrease in 6MWD only, worsening of WHO-FC only, either worsening of WHO-FC or decrease in 6MWD, and decrease in 6MWD with concurrent worsening of WHO-FC. The latter definition was proposed by the (adult) task forces on end points and clinical trial design that met at the fourth and fifth World Symposium on Pulmonary Hypertension. 42,43 However, as 6MWD is not feasible in the youngest children, 7 the either/or definition seems most preferable in pediatric PAH. Last, symptomatic progres- 9

15 220 Chapter 9 sion has been proposed and occasionally used as a separate CW component, 43 but we argue that this is likely to be captured in WHO-FC. Recently, time to clinical failure has been introduced as primary end point in a clinical trial evaluating combination therapy in adult PAH. 50 An important difference with the CW end point is the inclusion of the component unsatisfactory clinical response. As evidence from adults and children suggest that there are prognostic implications associated with failure to achieve predefined treatment goals, this might be an interesting concept for future end point definitions. 17,51,52 CW as defined and evaluated in this study seems to provide a feasible and valid alternative end point for future pediatric studies. Notwithstanding, the authors feel the following remarks should be taken into account with regard to the design of future studies. To allow comparison of pediatric studies using CW as an end point, definitions of CW should be consistent in different studies. The currently evaluated definition appears suitable. A prerequisite for a consistent implementation is a broad consensus within the pediatric field regarding the exact definition of CW. 18,42 Each of the components might need to be defined as objectively and unequivocally as possible. 19 Accuracy and consistency of reporting CW events are of utmost importance. Therefore, to guarantee the integrity of studies using CW as an end point, the use of blinded independent adjudication committees is recommended. 19,43,49 For example, it should be ensured that hospitalizations and functional deteriorations are indeed caused by worsening PAH and not by comorbidities or other causes. Patients with unstable disease can usually not be included in clinical trials, which might lead to discrepancies in included patients and event rates between registries and trials. This is illustrated by a comparison of the REVEAL Registry and the event-driven Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial that used CW as a primary end point. 37,40 In REVEAL, 64% of the patients experienced an event within 2 years, whereas in the SERAPHIN trial, only 39% had an event over a median period of 115 weeks. However, the results from the current study show only minor differences between the full cohort and the trial-eligible subgroup: 84% of the full cohort experienced CW (Table 2), compared to 78% of the trial-eligible subgroup (Supplementary Table 1). This confirms that PAH can progress more quickly in children compared with adults, 8 and suggests that the use of CW allows for pediatric study designs with an achievable number of children. Study limitations Evaluation of alternative end points is important though hampered by the extremely limited data on pediatric PAH. The Dutch National Network for Pediatric Pulmonary Hypertension is a national prospective registry with complete follow-up that encompasses all diagnosed children with PAH in the Netherlands. 53 Despite the relatively small

16 Clinical worsening in pediatric PAH 221 number of patients in our study, limiting our analyses, we found strong associations between the soft end point components and death or LTx. The highly standardized and complete longitudinal follow-up allowed for time-dependent Cox regression, which is an appropriate method for evaluating the prognostic value of time-varying variables such as the CW end point components. 54 Inherent to the analytical approach, censoring of deceased patients was taken into account rather than the competing risk of death. Although all subsequent CW events were captured in the cumulative event-incidence curves and longitudinal event rates, only the soft CW-events that occurred first could be analyzed in time-dependent Cox regression analysis. The sample size and analytic approach did not allow for an identification of which CW component carried the most prognostic value. Conclusion CW occurs early and frequently in the follow-up of children with PAH. Each of the soft end point components was highly predictive of death or LTx, as was the CW composite. This strongly supports the usefulness of CW as a patient-centered, composite study end point and allows for pediatric study designs with an achievable number of required children. Regarding its prognostic value, CW could also serve as an early clinical warning sign. 9

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21 226 Chapter 9 A 1.0 B 1.0 Cumulative event incidence Cumulative event incidence C 1.0 1st event 2nd event 3rd event D 1.0 Cumulative event incidence Cumulative event incidence E Cumulative event incidence st event 2nd event 3rd event 4th event F Cumulative event incidence st event 2nd event 3rd event 4th event 5th event Supplementary Figure 1. Cumulative event incidence of separate end point components in trial-eligible subgroup (n=49). A: Component 1, death. B: Component 2, lung-transplantation. C: Component 3, nonelective PAH related hospitalization. D: Component 4, initiation of intravenous prostanoids. E: Component 5A, functional deterioration (defined as worsening of WHO functional class only). F: Component 5AB, functional deterioration (defined as worsening of WHO functional class and/or 15% decrease in 6-minutewalk-distance). Since the endpoint-components 3 (panel C) and 5 (panel E/F) could occur repetitive, the occurrence of every second, third, fourth and fifth are also depicted.

22 Clinical worsening in pediatric PAH Freedom from: component 1 component component component component A component AB (CW-endpoint) Cumulative survival Supplementary Figure 2. Event-free survival of 6 endpoint combinations in trial-eligible subgroup (n=49). Only the first occurrence of endpoint-components are incorporated as events. Component 1 = death; Component 2 = lung-transplantation; Component 3 = non-elective PAH-related hospitalization; Component 4 = initiation of intravenous prostanoids; Component 5A = functional deterioration (defined as worsening of WHO functional class deterioration only); Component 5AB = functional deterioration (defined as worsening of WHO functional class and/or 15% decrease in 6-minute-walk-distance); CW-endpoint = Full composite clinical worsening endpoint consisting of death, lung-transplantation, non-elective PAH related hospitalization, initiation of intravenous prostanoids and functional deterioration. 9

23 228 Chapter 9 Supplementary Table 1. Event Rate of Separate and Combined End Point Components Stratified by Diagnosis: All Events in Trial-Eligible Subgroup Total N=49 IPAH/HPAH N=26 APAH-CHD N=19 APAH-non-CHD N=4 Patients Event rate Patients Event rate Patients Event rate Patients Event rate n (%) n/100 py n (%) n/100 py n (%) n/100 py n (%) n/100 py (1) Death 12 (25) (27) (21) (25) 9.5 (2) Lung-transplantation 5 (10) (12) (11) (0) (3) Hospitalization a 24 (49) (54) (37) (75) 57.0 (4) Initiation of IV prostanoids 10 (20) (35) (5) (0) (5) Functional deterioration (5A) WHO-FC b 27 (55) (73) (26) (75) 57.0 (5AB) WHO-FC b or 6MWD c 32 (65) (81) (42) (75) 66.5 End point combinations (1)(2)(3)(4) 30 (61) (69) (47) (75) 66.5 (1)(2)(3)(4)(5A) 35 (71) (85) (53) (75) (1)(2)(3)(4)(5AB) (CW-composite) 38 (78) (92) (58) (75) Data are presented as n (%) or number of events per 100 person-years. The results are from an analysis within the trial-eligible subgroup (n=49), that consists of patients who were not hospitalized, not in WHO functional class IV and/or not immediately started on intravenous prostanoids at baseline. IPAH=idiopathic pulmonary arterial hypertension; HPAH=hereditary pulmonary arterial hypertension; APAH-CHD=pulmonary arterial hypertension associated with congenital heart disease; APAH-non-CHD=pulmonary arterial hypertension associated with conditions other than congenital heart disease; IV=intravenous; WHO-FC=World Health Organization functional class; 6MWD=6-minutewalk-distance; py=person-years; CW=clinical worsening. a Non-elective PAH related hospitalization. b Worsening of WHO functional class. WHO functional class IV was always regarded as a functional deterioration event. c 15% decrease in 6-minute-walk-distance.