University of Groningen

Prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary arterialhypertensionPloegstra, Mark-Jan

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Chapter 1General introduction and aims of this thesis

General introduction and aims 11

1I. IntroduCtIon to PedIAtrIC PulMonAry ArterIAl hyPertensIon

Pulmonary hypertension

Under normal conditions, pulmonary arterial (PA) blood pressure is much lower than the systemic arterial pressure (SAP), despite the fact that the pulmonary circulation receives the same amount of ventricular output as the systemic circulation.1,2 Mean PA pressure (mPAP) normally ranges from 12-18 mmHg,1 about one-sixth of mean SAP. Key features of the pulmonary circulation, unique in the human body, are high-flow, low-pressure, high-compliance and low-resistance.2 Due to the high responsiveness to vasoactive mediators, the capacity to recruit unperfused vessels, and the high vascular compliance, the pulmonary vasculature has an enormous physiologic reserve to accommodate fluctuations in pulmonary blood flow, pulmonary vascular resistance (PVR), or both. The right ventricle (RV) is a crescentic- and triangularly shaped thin-walled flow generator, specifically adapted for the perfusion of this highly compliant low-pressure circulation.3 This design allows the RV to easily accommodate large changes in blood flow, but makes it less tolerable for increases in afterload.

When the physiological reserve of the pulmonary circulation is exceeded due to pathological circumstances causing a rise of PVR or pulmonary blood flow, pulmonary hypertension (PH) can result.4,5 This is a serious pathophysiological phenomenon indi-cating abnormally increased arterial pressure in the pulmonary vasculature. PH causes an afterload burden on the RV, which leads to RV failure.6 The progressive contractile dysfunction eventually leads to RV decompensation and death.7 At an international level, it has been agreed to define PH as mPAP ≥25 mmHg as assessed by right heart catheterization (RHC).8,9

The complex problem of PH can develop from several underlying diseases, which are categorized in “The World Symposium on Pulmonary Hypertension (WSPH) Clinical Classification” (Table 1).10 Disorders causing PH are categorized into 5 groups, based on similar pathological and hemodynamic characteristics and management approaches. WSPH Group 1 encompasses the various subgroups of pulmonary arterial hypertension (PAH). Groups 2-5 include PH secondary to: left heart disease (Group 2), lung disease / hypoxemia (Group 3), chronic thromboembolic disease (Group 4), and various condi-tions with unclear / multifactorial underlying mechanisms (Group 5). This thesis has a particular focus on pediatric PAH, as represented in WSPH Group 1.

12 Chapter 1

table 1. Updated Clinical Classification of Pulmonary Hypertension (Nice, 2013)

1. Pulmonary arterial hypertension (PAh)

1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2

1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3

1.2.3 Unknown

1.3 Drug and toxin induced

1.4 Associated with:

1.4.1 Connective tissue disease

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart diseases

1.4.5 Schistosomiasis

1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

1’’ Persistent pulmonary hypertension of the newborn (PPhn)

2. Pulmonary hypertension due to left heart disease

2.1 Left ventricular systolic dysfunction

2.2 Left ventricular diastolic dysfunction

2.3 Valvular disease

2.4 Congenital / acquired left heart inflow / outflow tract obstruction and congenital cardiomyopathies

3. Pulmonary hypertension due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4. Chronic thromboembolic pulmonary hypertension (CtePh)

5. Pulmonary hypertension with unclear multifactorial mechanisms

5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoral obstruction, fibrosingmediastinitis, chronic renal failure, segmental PH

BMPRII = Bone morphogenetic protein receptor type II, CAV1=caveolin-1, ENG=endoglin, HIV=human immuno-deficiency virus, PAH = pulmonary arterial hypertension. (Reproduced from [10])

General introduction and aims 13

1Pulmonary arterial hypertension

Within the context of PH, PAH can be regarded a distinct disease entity that merits spe-cial consideration. Unlike the other four WSPH Groups, PAH is a progressive disease of the precapillary pulmonary arteries, characterized by typical histopathological changes. Relief of the underlying conditions causing PH Groups 2-5 can result in regression of PH, which is generally not the case with PAH. In addition to medial hypertrophy and muscularization of arterioles, which also occurs in other forms of PH, concentric laminar intimal fibrosis and plexogenic lesions are specific hallmarks of PAH.11,12 The progressive arterial remodeling process in PAH causes increasing luminal obstruction and stiffening of the pulmonary vasculature, which leads to a rise in PVR, subsequently resulting in increased RV afterload, RV failure and death.

Although the morphological findings and presentation may be similar in patients with PAH, there is a wide variety in the underlying disease mechanisms, associated conditions, and treatment approaches. In view of this, the WSPH Clinical Classification of PH provides a further subcategorizing of this Group (Table 1). This detailed sub-categorization can roughly be summarized as the distinction between (1) PAH with an unknown or genetic cause, termed idiopathic or hereditary PAH (IPAH/HPAH), (2) PAH that occurs in association with congenital heart disease (APAH-CHD) and (3) PAH that occurs in association with other underlying conditions (APAH-other).

Idiopathic and heritable PAh

IPAH is a diagnosis per exclusionem, as this indicates the type of PAH with unknown origin. HPAH is diagnosed in case of an indisputable family history of PAH or when spe-cific PAH gene mutations have been identified. Familial cases of PAH have already been reported since 1954.13 In 2000, it was shown that in 80% of families with multiple cases of PAH, mutations of the bone morphogenic protein receptor type 2 (BMPR2) gene can be identified.14 Other mutations that have been brought into relation with the develop-ment of PAH include: ALK-1, ENG, TBX4, KCNQ3, EIF2AK4 and Caveolin-1.15–17

PAh associated with congenital heart disease

In APAH-CHD, long-standing increased pulmonary blood flow due to systemic-to-pulmonary shunting induces shear stress and circumferential stretch, which trigger the development of PAH. There are many underlying cardiac defects that can cause PAH, making APAH-CHD a very heterogeneous subgroup with regards to cardiac anatomy, physiology and the clinical presentation.18 Patients with post-tricuspid shunts such as caused by large ventricular septal defect or patent ductus arteriosus are more likely to develop advanced PAH than patients with pre-tricuspid shunts such as caused by atrial septal defects.19–22 Timely repair of the cardiac defect in a stage when the pulmonary vascular disease (PVD) is still reversible can prevent the progression to advanced PAH.

14 Chapter 1

As part of the WSPH Clinical Classification of PH, APAH-CHD is subdivided into four physiologic subtypes (Table 2). Type 1, Eisenmenger syndrome, represents the severe end-spectrum of APAH-CHD.23 In this condition, PVR becomes high enough to reverse the shunting across the defect, leading to pulmonary-to-systemic shunting with sub-sequent systemic desaturation. Although the cyanotic complications of Eisenmenger syndrome are associated with significant morbidity,24 the preserved cardiac output as a result of the pulmonary-to-systemic shunting explains the suggestions of a more favorable life-expectancy when compared to other types of PAH.25,26 Type 2 includes PAH patients with systemic-to-pulmonary shunts and normal resting saturation. Type 3 includes PAH patients that have small shunts that are not considered to cause severe PAH and are therefore regarded as “coincidental”. As the exact underlying PAH etiology of these patients is unknown, these patients are often considered and treated as IPAH patients. Type 4 includes patients that have unexpectedly developed PAH following suc-cessful correction of their cardiac shunt-defect. In contrast to the circumstances of type 1-3 where elevations of right sided pressures can be released at the level of the open cardiac defect, this is not possible when the defect has been closed, leading to a similar or even worse disease course and prognosis compared to IPAH.

Although the categorization of APAH-CHD into these four subtypes is useful and im-portant, the WSPH Clinical Classification of PH has several limitations when it comes to pulmonary vascular disease in the context of CHD. First, the four subtypes do certainly not represent homogeneous patient groups, as there still is considerable variety with re-gard to the location, size, repair status and age at repair of the defect, and the presence or absence of associated cardiac and extracardiac anomalies.18 Consequently, there is no such thing as a “typical patient” with APAH-CHD type 1, 2, 3 or 4. Second, there are CHD patients that cannot be fit in these categories, such as patients with transposition of the great arteries who have undergone a neonatal switch operation that subsequently developed PAH. Third, it has to be recognized that in the pediatric age-group, so-called

table 2. Clinical Classification of Pulmonary Arterial Hypertension As-sociated With Congenital Heart Disease

1. Eisenmenger Syndrome

2. Left to right shunts

Operable

Inoperable

3. PAH with co-incidental CHD

4. Post-operative PAH

PAH = pulmonary arterial hypertension, CHD = congenital heart disease. (Reproduced from [10])

General introduction and aims 15

1“flow-PAH” occurs frequently in the setting of uncorrected congenital heart defects and represents early reversible stages of PVD associated with shunts, that may resolve after correction of the cardiac defect.

PAh associated with other conditions

PAH can also occur in association with connective tissue diseases, such as systemic sclerosis and systemic lupus erythematosus. These autoimmune diseases cause fibros-ing of pulmonary vascular tissue, leading to vascular remodeling and increases in PVR. Although not very common in children, connective tissue disease is one of the main known causes of PAH in adults.27 Other conditions that can cause PAH are human immu-nodeficiency virus infection, portal hypertension and schistosomiasis. Also, a significant number of drugs and toxins have been described that are potentially associated with the development of PAH, such as aminorex and fenfluramine.28

Pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis and persistent pulmonary hypertension of the newborn are classified within WSPH group 1, but have remarkable differences in presentation and clinical course when compared to all other forms of PAH. To account for these differences in the clinical classification, these diseases are designated as separate 1’ and 1” subcategories.

Children are not small adults

Despite the same underlying disease mechanisms, there are important differences between adults and children with PAH. Pediatric PAH has specific features that preclude a simple extrapolation of adult data to a child with PAH. In children with PAH, pulmonary vascular injury occurs during susceptible periods of growth and development of the car-diopulmonary system.29 Also, important pathobiological contributing factors uniquely relate to the pediatric age group, such as perinatal hypoxia and hemodynamic stress conditions during the transition from fetal to postnatal life.

Epidemiological studies have shown that there are important differences regard-ing the distribution of etiologies between children and adults. A comparison of the adult “Registry to evaluate early and long-term pulmonary arterial hypertension disease management” (REVEAL) and the international pediatric “Tracking Outcomes and Prac-tice in Pediatric PH” (TOPP) registry shows that the proportion of IPAH/HPAH is similar, but that APAH-CHD is more frequent in children, whereas APAH-other is rare in children compared to adults (Figure 1).27,30 An explanation for the substantially larger proportion of APAH-CHD in children is the fact that pediatric PAH encompasses a broad spectrum of patients with cardiac defects, including complex heart disease, that have not always sur-vived into adulthood. APAH-CHD is also more heterogeneous in children compared to adults, and includes early disease stages of PAH where the pulmonary vascular disease can still be reversed after correction of the shunt defect.

16 Chapter 1

Children with PAH further differ from adults regarding their clinical presentation and disease course. Although dyspnea on exertion and fatigue are the most frequent presenting symptoms in both adults and children, syncope occurs twice as often in children.30 Comorbidities such as lung diseases and chromosomal and other (extra-cardiac) congenital anomalies are frequent in children with PAH, complicating diagnosis and clinical classification. Children with PAH can deteriorate very quickly and survival rates remain unsatisfactory, despite the introduction of PAH targeted drugs.26 In both diagnosis and management, the physiology of a growing and developing child needs to be taken into account.

epidemiology and prognosis

Pediatric PAH is a rare condition. In the Netherlands, Van Loon et al. have reported an-nual incidence rates of 0.7 cases of IPAH/HPAH and 2.2 cases of APAH-CHD per million children. Prevalence rates were 4.4 cases of IPAH/HPAH and 15.6 cases of APAH-CHD per million.26 In the United Kingdom, incidence and prevalence of pediatric IPAH have been estimated to be 0.48 and 2.2 cases per million, respectively.31

Before the era of PAH-targeted therapies, children with IPAH died within 1 to 2 years after diagnosis.32 Figure 2 shows survival of children from the Dutch National

12%

39%49%

b

dfe

40% 53%

7%a b c f

IPAH/HPAH APAH-other:a. CTD c. PVOD / PCH e. HIV b. Portal hypertension d. drugs / toxins f. OtherAPAH-CHD

a

Adult PAH – REVEAL registry Pediatric PAH – TOPP registry

Figure 1. Comparison of etiology in adult and pediatric pulmonary arterial hypertension. REVEAL = regis-try to evaluate early and long-term pulmonary arterial hypertension disease management, TOPP = track-ing outcomes and practice in pediatric pulmonary hypertension, IPAH = idiopathic pulmonary arterial hypertension, HPAH = hereditary pulmonary arterial hypertension, APAH = associated pulmonary arterial hypertension, CHD = congenital heart disease, CTD = connective tissue disease, PVOD = pulmonary veno-occlusive disease, PCH = pulmonary capillary hemangiomatosis, HIV = human immunodeficiency virus. (Percentages extracted from [27] and [30])

General introduction and aims 17

1Network for Pediatric PH that were started on PAH targeted therapy between 2000 and 2008, together with predicted survival based on the historical National Institutes of Health registry equation.33 The comparison suggests that children with PAH have benefited from the availability of PAH targeted therapies, but also demonstrates that mortality rates are still unsatisfactory. Common causes of death are RV failure, hemopty-sis, sudden death and arrhythmias.34

Clinical disease manifestation

In the initial disease stage of PAH, dyspnea on exertion and fatigue are the most fre-quently reported symptoms in children with PAH. These symptoms are non-specific and often mimic more common respiratory conditions such as asthma, which may delay diagnosis. The clear relationship with activity reflects the inability of the RV to increase cardiac output for the higher demand in workload. Chest pain as a result of ischemia can develop due to insufficient systolic right coronary artery flow in the setting of RV hy-pertrophy.35 Hemoptysis, assumed to result from rupture of frail hypertrophic bronchial arteries or from dilated pulmonary arteries,36 is not uncommon in children with PAH and has been shown to be associated with poor outcome.37 Syncope is a frequent presenting symptom specifically in children without shunts, and is the result of insufficient cardiac output. In the specific setting of Eisenmenger syndrome with systemic desaturation due to pulmonary-to-systemic shunts, cyanosis is very common.23 When the disease progresses, symptoms of RV failure can emerge, including dyspnea in rest, peripheral edema and ascites. Atrial and ventricular arrhythmias can occur and can lead to sudden

100

80

60

40

20

0

Cum

ulat

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surv

ival

(%)

Time from second-generation drug availability (yrs)0 2 4 6 8 10

42 27 13

Observed survival (n=45)Predicted survival using NIH registry equation

Figure 2. Observed current era survival of children with pulmonary arterial hypertension, compared to predicted survival using historical National Institutes of Health (NIH) registry equation. Dotted lines repre-sent 95% confidence interval. (Reproduced from [33])

18 Chapter 1

death. Clinical evidence of RV failure is a hallmark of the end stage of the disease and is associated with a poor prognosis.27

Clinical management

PAH is not curable with the currently available therapies. Treatment of PAH consists of supportive therapies and PAH-targeted therapies.28 Supportive therapies include diuretics, supplemental oxygen and anticoagulation. PAH-targeted therapies are subdivided in “first generation” and “second generation” agents, on the basis of their historical availability: calcium channel blockers are first generation agents and are of benefit when prescribed in high doses in patients who have shown an acute response to vasoreactivity testing during cardiac catheterization. Second generation agents have become available during the past two decades, and do not only have vasodila-tor properties but are believed to also improve pulmonary vascular remodeling. These agents target the following three molecular pathways: the nitric oxide, prostacyclin and endothelin-1 pathway. Surgical interventions that are carried out in children that do not improve despite maximal therapy include atrial septostomy, Potts shunt, and (heart-)lung transplantation. As an extension to the introduction of this thesis, the treatment of pediatric PAH is reviewed in detail in Chapter 2.

Current treatment strategies in pediatric PAH are predominantly based on the ex-perience and consensus of clinicians and extrapolation of evidence from adult studies. Controlled trials in pediatric PAH are almost non-existent, hampering an evidence-based treatment for pediatric PAH. An important reason is the lack of validated clinical end-points. In view of the improved survival rates in recent observational studies, pediatric PAH seems to have benefited from the PAH-targeted drugs that have been tested in adults. However, morbidity and mortality remain unsatisfactory.

II. Current ChAllenges In PedIAtrIC PAh

In the current era with increased availability of PAH-targeted drugs, one of the major challenges for clinicians is to tailor optimal treatment regimens for the individual pa-tient with PAH.38,39 Multiple drugs targeting different pathways are now available, but there is a paucity of data on how and when the available treatments should be used. Challenging questions are which type of drugs to start in different patient groups, or when it is better to consider upfront combination therapy targeting multiple pathways at the same time. Risk stratification is essential to allow tailoring of treatment, but there is a lack of evidence-based prognostic factors. Also, important challenges are the evaluation of treatment success, the appropriate timing of therapy escalation during follow-up, and adequate timing of surgical interventions such as Potts shunts or (heart-)

General introduction and aims 19

1lung transplantation. A standardized treatment strategy is much desired, but requires the identification of clinically and prognostically relevant treatment goals. The available drugs are barely tested in children as pediatric clinical trial design is challenged by a lack of appropriate clinical endpoints.

Hence, prognostic factors are required for risk stratification, treatment goals are required for defining treatment strategies, and clinical endpoints are required for the design of clinical trials. In the following sections, these three topics are introduced.

Prognostic factors for risk stratification

Children with PAH present at different stages of disease and at different levels of risk for disease progression and mortality. It appears to make sense to choose more aggressive treatment regimens (e.g. early intravenous therapy or combination therapy) for sicker and higher risk children. Thus, risk stratification is an essential first step, and this requires clinical measurements that are valid prognosticators of disease outcome.

The most widely used, but not all validated, clinical measurements in adult and pediatric PAH include the following. Functional capacity can be evaluated by World Health Organization (WHO) functional class (a scale of symptom severity and degree of functional limitation), 6-minute walk distance (6MWD) and cardiopulmonary exercise testing.27,40 These are established predictors of outcome in adults with PAH, but cur-rently available data in children are scarce and contradictory.33,41Biomarkers suggested to be associated with mortality in PAH include serum levels of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) and uric acid.42–46 Both adult and pediatric studies have shown correlations of these biomarkers with outcome. Imaging modalities, including echocardiography and cardiac magnetic resonance imaging, have only been studied anecdotally and incompletely in pediatric PAH.47–49 However, in adults with PAH, imaging derived parameters including right atrial and RV dimensions, eccentricity index, RV frac-tional area change, RV myocardial performance index, RV dyssynchrony, the presence or absence of pericardial effusion, RV ejection fraction, and tricuspid annular plane systolic excursion have all been suggested to correlate with outcome.27,50–56Cardiac catheteriza-tion is performed to define PAH at time of diagnosis, and yields several hemodynamic characteristics with prognostic value that are currently used to tailor initial treatment. In both adults and children, among other hemodynamic measurements, mean right atrial pressure, indexed PVR (PVRi) and cardiac index have been shown to correlate with mortality in multiple observational studies.27,33,57–59 Assessment of the response to vasoreactivity testing is crucial, as responders are at lower risk and can be treated with high-dose calcium channel blockers.60 There is a need for additional diagnostic and prognostic tools that can complement hemodynamics, and that can provide more insight in the actual state of the pulmonary vasculature. Measurements that take ac-count of the pulsatile characteristics of the pulmonary vasculature, such as PA stiffness

20 Chapter 1

indices,61,62 may prove of added value in this respect, as these are not incorporated in conventional hemodynamic measurements such as PVRi and mPAP (these assume steady flow, whereas the pulmonary vasculature is a pulsatile flow system).63

With regard to risk stratification, there are specific unmet needs for the field of pediatric PAH. Studies on prognostic factors in pediatric PAH are available but limited, as these are mostly based on relatively small patient series and there are contradictory findings between the cohorts. When considering the utility of these reported prognostic factors for risk stratification in pediatric PAH, it is of utmost importance to evaluate the available literature as a whole, and to evaluate potential causes of the discrepancies. In addition, specific clinical measurements that are promising for risk stratification in children (e.g. based on adult data), have not yet been sufficiently studied in pediatric PAH. For example, the prognostic value of echocardiography and serum biomarkers requires further investigation.

To allow for clinical monitoring of the disease over time, there is a need for clinical measurements that are not only informative at time of diagnosis or time of treatment initiation, but also during follow-up. In longitudinal studies in adults with PAH, some of the aforementioned clinical measurements have been shown to remain prognostic during follow-up (e.g. hemodynamics, 6MWD).64 This supports the usefulness of such measurements for monitoring a patient over time. In children, however, there is a lack of data regarding the prognostic value of repeated measurements. Reliable disease mark-ers fluctuate according to the severity of the disease. Therefore, clinical measurements that are candidates for monitoring a child with PAH over time, require evaluation in a longitudinal fashion.

An interesting topic that exclusively applies to PAH in children, is the influence of the disease on growth. Impaired growth is a determinant of disease severity and outcome in several severe pediatric diseases. Previous data have suggested that height is also impaired in children with PAH and that Z-scores for weight and height correlate with outcome.31 These findings provide clues that also growth could have a role in risk stratification in pediatric PAH. However, to allow adequate interpretation of growth measurements, the degree of growth impairment, trends over time, subgroups at risk for growth impairment, and associated determinants need further elucidation before measurements of growth can become useful in the context of risk stratification and tailoring treatment.

With respect to risk stratification, another important topic in PVD that almost exclusively applies to children is the assessment of disease reversibility.65 In the setting of uncorrected congenital heart defects, children may present with early stages of PVD in which the disease may still be reversible. To guide clinical-decision making in these early stages, clinical measurements are needed that can predict whether the disease will reverse or progress to advanced PAH in the future. Accurate prediction of disease

General introduction and aims 21

1progression is important, as shunt closure in irreversible disease stages has deleterious effects.25,26

treatment goals to define treatment strategies

Previously, patients with PAH were followed according to clinical parameters, and therapy was escalated in case of clinical deterioration. As PAH can develop very progres-sively, this conventional “waiting for clinical worsening” often leads to lagging behind events. A more aggressive goal-oriented treatment strategy is now recommended, in which clinically relevant goals are predefined.66,67 When treatment goals are not met during follow-up after initiation of first treatment, more aggressive treatment regimens are installed. Therapy can be escalated by adding other PAH-targeted treatments, and intravenous therapy may be considered in an earlier stage. When treatment goals are still not met despite intensive therapy regimens, surgical options such as Potts shunt or (heart-)lung transplantation are considered early.

In pediatric PAH, the design of such a goal oriented treatment strategy is ham-pered by the lack of validated treatment goals.68 The first step in defining such goals, is the identification of clinical measurements that are either directly clinically meaningful outcomes (i.e., how a patient feels, functions or survives),69 or are surrogates for such clinically meaningful outcomes.70,71 For example, the experience of PAH symptoms like dyspnea, chest pain and syncope are directly clinically meaningful, thus striving for improvement of these symptoms is a valid treatment goal.

Improving such symptoms does not necessarily lead to prolonged longevity. When improving survival is part of the overall treatment objective, then clinical mea-surements have to be identified that qualify as surrogates for mortality; improving such measurements using treatment may potentially lead to improved survival.

A strong correlation with outcome, even when this correlation persists during follow-up, does not necessarily indicate surrogacy for survival. In addition to a strong correlation with outcome, there are two additional basic criteria for surrogacy: (1) the clinical measurement must be modifiable by treatment and (2) treatment-induced changes in the clinical measurement correlate with outcome also.70,71 As longitudinal studies in both pediatric and adult PAH are scarce, there is a lack of evidence regarding the prognostic value of treatment-induced changes in clinical measurements, which hampers the definition of valid treatment goals.

endpoints for clinical trials

Most of the drugs that are currently being used in the treatment of pediatric PAH, have not yet been tested in randomized clinical trials (RCTs) in the pediatric age group. A crucial problem is the lack of appropriate clinical endpoints to evaluate treatment ef-ficacy, which hamper the design of RCTs.38,39,72

22 Chapter 1

Figure 3 provides an overview of endpoints that are used in adult trials in PH.73 The 6MWD has most frequently been used in the pivotal trials in adult PAH. However, 6MWD is not reliable in young children or in children with mental or physical disabilities, and depends on motivational issues. Therefore 6MWD is not feasible as a pediatric endpoint. Hemodynamics are also not attractive in children, in view of the associated risks of this invasive procedure and the need for sedation or general anesthesia.74 Clinical measure-ments that are considered as clinical endpoints need evaluation regarding the way in which they are directly or indirectly (a surrogate for) clinically meaningful outcomes.

“Clinical worsening” (CW) is a patient-centered composite endpoint consisting of clinically meaningful events that indicate clinical deterioration.75 CW consists of a combi-nation of hard unambiguous events such as death and (heart-)lung transplantation, and softer events, including hospitalizations, need for additional therapy, and worsening of function. This combined morbidity/mortality endpoint is gaining increasing interest in PAH and is now being used as primary or secondary endpoint in adult RCTs.76,77 CW is applicable throughout the full pediatric age range, but requires a comprehensive evalu-ation before it can qualify as a pediatric study endpoint. Essential information that is not yet available includes the incidence of the endpoint events of CW, the relation of the soft endpoint events with mortality, and the timing of the endpoint events throughout the disease course in pediatric PAH.

Number of Trials0 50 100

PFTLaboratory values

CPEX6MWT

QOL indicesFunctional status

Cardiac MRIEchoRHC

Primary endpointSecondary endpoint

Figure 3. Outcome measures as endpoints in PH trials, 1995-2013. Number of trials (from total N = 126 identified in systematic literature review) reporting each outcome measure as a primary or secondary end-point. RHC = right heart catheterization, MRI = magnetic resonance imaging, QOL = quality of life, 6MWT = 6-minute walk test, CPEX = cardiopulmonary exercise testing, PFT = pulmonary function test. (Reproduced from [73])

General introduction and aims 23

1AIMs oF thIs thesIs

To address the unsatisfactory outcome in children with PAH, risk stratification, treatment strategies and clinical trial design should be improved. Therefore, the aims of this thesis were:– To identify prognostic factors, as these are essential for risk stratification and tailoring

of treatment. The identification of such prognostic factors starts with an overview of what has already been reported. We aim to evaluate the prognostic value of clini-cal measurements that have the potential to serve as prognostic factors, including echocardiography, a child’s growth, serum biomarkers, and PA stiffness indices.

– To identify treatment goals, as these are required for the design of pediatric goal-oriented treatment strategies. Therefore, we aim to investigate the prognostic value of treatment-induced changes in prognostic factors, and to identify prognostically distinctive threshold values.

– To identify clinical endpoints, as these are a prerequisite for the design of pediatric clinical trials. We aim to study clinical worsening as a candidate composite endpoint for pediatric PAH, including the evaluation of the incidence, timing and prognostic value of its endpoint components.

outlIne oF thesIs

In Chapter 2, current and advancing treatments for PAH are reviewed, as an extension to this general introduction. Potential treatment goals and strategies to guide treatment are also discussed.

In Chapter 3, currently available evidence regarding prognostic factors in pediatric PAH is systematically reviewed and combined. The available pediatric reports are scarce and sometimes contradictory, thus it is of great importance to identify, appraise, synthesize and combine the currently available data on prognostic factors in pediatric PAH. Ex-tracted data from the identified reports are combined using meta-analysis.

In Chapter 4, the potential of echocardiography in assessing disease severity and prog-nosis in children with PAH is evaluated. This widely used imaging modality is suited ideally to repeat throughout the course of the disease, but is insufficiently studied in pediatric PAH. Correlations are described between multiple transthoracic echocardiog-raphy variables and markers of disease severity and outcome.

24 Chapter 1

In Chapter 5, growth impairment in pediatric PAH is evaluated in a large longitudinal multi-registry study, together with the identification of its associated determinants. Growth is an easy and globally available indicator of a child’s health, but it is unclear how to interpret growth and its trends over time in an individual with PAH. In this chapter, the growth impairment in pediatric PAH is quantified and subgroups at risk and associated determinants are identified.

In Chapter 6, the value of serum uric acid as a prognostic biomarker is evaluated in children with PAH. Single measurements of uric acid have been shown to correlate with outcome in earlier studies, but the prognostic value of serially measured levels needs evaluation, including the clinical value of an incline over time. Associations with disease severity markers and mortality throughout the full course of the disease are described in a longitudinal fashion, and trends over time are evaluated.

In Chapter 7, a 20-year outcome study is reported that focuses not only on advanced PAH, but also on the earlier stages of PVD. In this chapter, the value of PA stiffness indices assessed by intravascular ultrasound are evaluated, with regards to prediction of future disease progression to advanced PAH and long-term mortality.

In Chapter 8, potential treatment goals in children with PAH are identified and evalu-ated, as a step towards the design of a goal oriented treatment strategy. The prognostic value of treatment-induced changes are assessed, and optimal prognostic thresholds are estimated.

In Chapter 9, clinical worsening is studied as a candidate composite study endpoint for future clinical trials in pediatric PAH. The usefulness of clinical worsening is evaluated by assessing the event incidence and prognostic value of each separate endpoint compo-nent, and of the composite clinical worsening endpoint.

In Chapter 10, a general discussion is provided together with future prospects, and the results of this thesis are summarized as part of the appendices.

General introduction and aims 25

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