briefly , the reveal registry is a multicenter observational , prospective registry involving 55 university - affiliated and community hospital - based pulmonary hypertension centers in the united states .
each of the participating sites received institutional review board approval ( e - table 1 ) .
patients with pah ( who group 1 pulmonary hypertension ; venice 2003 definition ) , confirmed by right - sided heart catheterization , were enrolled consecutively from march 2006 through december 2009 after providing informed consent . for this analysis we evaluated only patients with
newly diagnosed disease with qualifying right - sided heart catheterization within 90 days of enrollment with hemodynamics measured at rest . only patients with pulmonary capillary wedge pressure  15 mm hg were included .
first - time postenrollment hospitalizations were independently reviewed by three investigators ( c. d. b. , p. k. l. , and r. e. s. ) and categorized as pah related or not primarily related to pah ( hereafter referred to as 
pah unrelated  ) based on information in case report forms ( dates of hospital admission and discharge , primary discharge diagnosis , reason for hospitalization , disease characteristics , and treatments prior to admission ) .
secondary diagnoses were not available , so the determination of pah related vs pah unrelated was made based only on the primary diagnosis .
categories for pah - related hospitalization were determined before review , and any one of these categories would have constituted a pah - related hospitalization .
categories for the pah - unrelated hospitalizations were also determined before review , but some modifications were made afterward to cover all categories with more than one admission 
any single discharge diagnosis that did not fit in a category was classified as  other . 
more than one category could have been present at any given admission , and in those situations the primary discharge diagnosis was the determinate of hospitalization causality .
group differences in patient demographics and disease characteristics determined at enrollment were tested with pearson  , mantel - haenszel  , or t tests for binary , ordinal , and continuous variables , respectively . for variables with highly skewed distributions ,
kaplan - meier estimates for freedom from hospitalization and for survival were computed for distinct at - risk periods : ( 1 ) for the full cohort ( ie , hospitalized and nonhospitalized patients ) , the risk period began at enrollment ; ( 2 ) for patients with a first - time hospitalization , the risk period ( for freedom from event following hospitalization ) began at hospital discharge ; ( 3 ) for patients event - free through the first year of follow - up , the at - risk period for future follow - up began at 365 days after enrollment .
of 862 patients in the analysis cohort , 490 ( 56.8% ) had at least one hospitalization during follow - up on study , and 372 ( 43.2% ) had none ( fig 1 ) .
of the 490 first - time hospitalizations , 257 ( 52.4% ) were for causes clearly related to pah , 214 ( 43.7% ) were for pah - unrelated causes that were considered related to comorbidity , and 19 ( 3.9% ) could not be characterized as pah related or unrelated because of insufficient data ( fig 1 ) .
the median time from right - sided heart catheterization diagnosis to study enrollment was 26 days .
pah = pulmonary arterial hypertension ; pcwp = pulmonary capillary wedge pressure ; reveal = registry to evaluate early and long - term pah disease management . among the 257 patients hospitalized for pah - related causes , congestive heart failure ( n = 81 , 31.5% ) and placement or removal of a central venous catheter ( n = 63 , 24.5% ) were the two most common causes cited at admission ( table 1 ) .
other common causes for first - time hospitalization were the initial iv line insertion ( n = 30 , 11.7% ) , which represents the initiation of iv therapy , and the escalation of therapy for pah ( n = 23 , 8.9% ) . a total of 21 pah - related hospitalizations ( 8.2% ) were associated with catheter infection : 11 occurring in the first year , three in the second year , and seven in the third year or later . reasons for first - time hospitalization related and unrelated to pah reasons are not mutually exclusive ; a patient could have been hospitalized for more than one reason .
. includes angina and myocardial infarction . among the 214 patients hospitalized for pah - unrelated causes , non - line - related infections were cited most commonly : pah - unrelated infections ( n = 38 , 21.1% ) and pneumonia ( n = 34 , 15.9% ) ( table 1 ) .
other common diagnoses at the time of first hospitalization were surgery / procedures ( n = 24 , 11.2% ) and hemorrhage ( n = 19 , 8.9% ) .
patients hospitalized for any reason were more likely than patients not hospitalized to have comorbidities ( diabetes and depression ) and to have more severe pah at enrollment , as measured by functional class , presence of pericardial effusion , higher mean atrial pressure , lower cardiac index , and higher reveal registry risk score .
patients with hospitalizations also had significantly longer follow - up from enrollment than patients without hospitalizations ( table 2 ) .
patient demographics and disease characteristics at enrollment all patients with  1 hospitalization ( c ) includes patients with pah - related ( a ) and pah - unrelated ( b ) hospitalizations .
6mwd = 6-min walk distance ; bnp = brain natriuretic peptide ; chd = congenital heart disease ; ctd = connective tissue disease ; iqr = interquartile range ; mpap = mean pulmonary arterial pressure ; mrap = mean right atrial pressure ; nyha = new york heart association ; poph = portopulmonary hypertension ; pvod = pulmonary veno - occlusive disease ; pvr = pulmonary vascular resistance .
the total number of patients in each cohort with data at enrollment for each parameter is assumed to be 257 ( a ) , 214 ( b ) , 471 ( c ) , and 372 ( d ) , unless otherwise noted .
comparison between pah - related and pah - unrelated groups revealed few differences at enrollment .
in particular , patients with pah - related hospitalizations were less likely than patients with pah - unrelated hospitalizations to be < 18 years of age and more likely to have more severe pah , as measured by functional class and lower cardiac index .
length of follow - up from enrollment was also shorter for the pah - related group ( table 2 ) .
hospitalization - related characteristics were similar overall between the pah - related and pah - unrelated groups , with the notable exception that patients with pah - related hospitalizations were more likely to be on parenteral therapy , to be in functional class iii or iv prior to hospitalization , and to have a higher reveal registry risk score prior to hospitalization ( table 3 ) .
further description of the type and timing of pah - related hospitalizations , including distribution of specific causes for hospitalization over time , is provided in the online supplement ( e - figs 1 , 2 , e - table 2 ) .
characterization of hospitalizations , by type of hospitalization all patients with  1 hospitalization ( c ) includes patients with pah - related ( a ) and pah - unrelated ( b ) hospitalizations .
see table 1 legend for expansion of other abbreviation . the total number of patients in each cohort with data at enrollment for each parameter is assumed to be 257 ( a ) , 214 ( b ) , and 471 ( c ) , unless otherwise noted .
p value is computed using fisher exact test . for the entire analysis cohort at 3 years from enrollment
, 45.4%  1.8% of patients remained free from hospitalization ( fig 2a ) . among patients who were hospitalized and discharged alive following the first hospitalization , 25.4%  3.2% of patients with pah - related and 31.0%  4.0% of patients with pah - unrelated first hospitalization remained free from a second hospitalization at 3 years postdischarge ( p = .11 ) ( fig 2b ) . for patients who remained hospitalization - free for 1 year postenrollment
, 53.7%  2.5% remained free from admission after an additional 3 years of follow - up ( fig 2c ) .
a - c , kaplan - meier estimates of freedom from hospitalization for ( a ) all patients from time of enrollment ; ( b ) patients with a first - time hospitalization from time of discharge , by type of hospitalization ; and ( c ) patients with no hospitalization in the first year of follow - up ( including patients with no hospitalizations and patients with first - time hospitalizations occurring after the first year of follow - up ) from 1 y after enrollment .
mortality was significantly higher for pah - related hospitalizations compared with pah - unrelated hospitalizations ( 5.4% vs 1.4% , p = .024 ) ( table 3 ) . among those discharged alive following first - time hospitalization ,
the survival estimate at 3 years postdischarge was lower for patients with pah - related hospitalization than for patients with pah - unrelated hospitalization ( 56.8%  3.5% vs 67.8%  3.6% , p = .037 ) ( fig 3a ) . among patients who remained hospitalization - free for 1 year postenrollment ,
survival after 3 additional years of follow - up was 77.8%  1.9% ( fig 3b ) .
a , b , kaplan - meier estimates of survival for ( a ) patients with a first - time hospitalization from time of discharge , by type of hospitalization ; and ( b ) patients with no hospitalization in the first year of follow - up ( including patients with no hospitalizations and patients with first - time hospitalizations occurring after the first year of follow - up ) from 1 y after enrollment .
of 862 patients in the analysis cohort , 490 ( 56.8% ) had at least one hospitalization during follow - up on study , and 372 ( 43.2% ) had none ( fig 1 ) .
of the 490 first - time hospitalizations , 257 ( 52.4% ) were for causes clearly related to pah , 214 ( 43.7% ) were for pah - unrelated causes that were considered related to comorbidity , and 19 ( 3.9% ) could not be characterized as pah related or unrelated because of insufficient data ( fig 1 ) .
the median time from right - sided heart catheterization diagnosis to study enrollment was 26 days .
pah = pulmonary arterial hypertension ; pcwp = pulmonary capillary wedge pressure ; reveal = registry to evaluate early and long - term pah disease management . among the 257 patients hospitalized for pah - related causes , congestive heart failure ( n = 81 , 31.5% ) and placement or removal of a central venous catheter ( n = 63 , 24.5% ) were the two most common causes cited at admission ( table 1 ) .
other common causes for first - time hospitalization were the initial iv line insertion ( n = 30 , 11.7% ) , which represents the initiation of iv therapy , and the escalation of therapy for pah ( n = 23 , 8.9% ) . a total of 21 pah - related hospitalizations ( 8.2% ) were associated with catheter infection : 11 occurring in the first year , three in the second year , and seven in the third year or later . reasons for first - time hospitalization related and unrelated to pah reasons are not mutually exclusive ; a patient could have been hospitalized for more than one reason .
. includes angina and myocardial infarction . among the 214 patients hospitalized for pah - unrelated causes , non - line - related infections were cited most commonly : pah - unrelated infections ( n = 38 , 21.1% ) and pneumonia ( n = 34 , 15.9% ) ( table 1 ) .
other common diagnoses at the time of first hospitalization were surgery / procedures ( n = 24 , 11.2% ) and hemorrhage ( n = 19 , 8.9% ) .
patients hospitalized for any reason were more likely than patients not hospitalized to have comorbidities ( diabetes and depression ) and to have more severe pah at enrollment , as measured by functional class , presence of pericardial effusion , higher mean atrial pressure , lower cardiac index , and higher reveal registry risk score .
patients with hospitalizations also had significantly longer follow - up from enrollment than patients without hospitalizations ( table 2 ) .
patient demographics and disease characteristics at enrollment all patients with  1 hospitalization ( c ) includes patients with pah - related ( a ) and pah - unrelated ( b ) hospitalizations .
6mwd = 6-min walk distance ; bnp = brain natriuretic peptide ; chd = congenital heart disease ; ctd = connective tissue disease ; iqr = interquartile range ; mpap = mean pulmonary arterial pressure ; mrap = mean right atrial pressure ; nyha = new york heart association ; poph = portopulmonary hypertension ; pvod = pulmonary veno - occlusive disease ; pvr = pulmonary vascular resistance .
the total number of patients in each cohort with data at enrollment for each parameter is assumed to be 257 ( a ) , 214 ( b ) , 471 ( c ) , and 372 ( d ) , unless otherwise noted .
comparison between pah - related and pah - unrelated groups revealed few differences at enrollment .
in particular , patients with pah - related hospitalizations were less likely than patients with pah - unrelated hospitalizations to be < 18 years of age and more likely to have more severe pah , as measured by functional class and lower cardiac index .
length of follow - up from enrollment was also shorter for the pah - related group ( table 2 ) .
hospitalization - related characteristics were similar overall between the pah - related and pah - unrelated groups , with the notable exception that patients with pah - related hospitalizations were more likely to be on parenteral therapy , to be in functional class iii or iv prior to hospitalization , and to have a higher reveal registry risk score prior to hospitalization ( table 3 ) .
further description of the type and timing of pah - related hospitalizations , including distribution of specific causes for hospitalization over time , is provided in the online supplement ( e - figs 1 , 2 , e - table 2 ) .
characterization of hospitalizations , by type of hospitalization all patients with  1 hospitalization ( c ) includes patients with pah - related ( a ) and pah - unrelated ( b ) hospitalizations .
the total number of patients in each cohort with data at enrollment for each parameter is assumed to be 257 ( a ) , 214 ( b ) , and 471 ( c ) , unless otherwise noted .
for the entire analysis cohort at 3 years from enrollment , 45.4%  1.8% of patients remained free from hospitalization ( fig 2a ) . among patients who were hospitalized and discharged alive following the first hospitalization ,
25.4%  3.2% of patients with pah - related and 31.0%  4.0% of patients with pah - unrelated first hospitalization remained free from a second hospitalization at 3 years postdischarge ( p = .11 ) ( fig 2b ) . for patients who remained hospitalization - free for 1 year postenrollment , 53.7%  2.5% remained free from admission after an additional 3 years of follow - up ( fig 2c ) .
a - c , kaplan - meier estimates of freedom from hospitalization for ( a ) all patients from time of enrollment ; ( b ) patients with a first - time hospitalization from time of discharge , by type of hospitalization ; and ( c ) patients with no hospitalization in the first year of follow - up ( including patients with no hospitalizations and patients with first - time hospitalizations occurring after the first year of follow - up ) from 1 y after enrollment . see figure 1 legend for expansion of abbreviation .
in - hospital mortality was significantly higher for pah - related hospitalizations compared with pah - unrelated hospitalizations ( 5.4% vs 1.4% , p = .024 ) ( table 3 ) . among those discharged alive following first - time hospitalization , the survival estimate at 3 years postdischarge was lower for patients with pah - related hospitalization than for patients with pah - unrelated hospitalization ( 56.8%  3.5% vs 67.8%  3.6% , p = .037 ) ( fig 3a ) . among patients who remained hospitalization - free for 1 year postenrollment , survival after 3 additional years of follow - up was 77.8%  1.9% ( fig 3b ) .
a , b , kaplan - meier estimates of survival for ( a ) patients with a first - time hospitalization from time of discharge , by type of hospitalization ; and ( b ) patients with no hospitalization in the first year of follow - up ( including patients with no hospitalizations and patients with first - time hospitalizations occurring after the first year of follow - up ) from 1 y after enrollment .
the reveal registry represents the largest database so far of patients newly diagnosed with pah ( who group 1 ) analyzed for characteristics of first - time hospitalization .
the burden of disease in patients with pah is substantial , as evidenced by the high incidence of hospitalization ( 57% ) in this cohort of patients with newly diagnosed disease from the prospective reveal registry .
our findings clearly demonstrate that all - cause hospitalization is very common among patients with newly diagnosed disease . in particular ,
the rate of pah - unrelated hospitalizations in this reveal registry cohort is relatively high , suggesting that the term  pah - unrelated  is a misnomer and that this category of hospitalization actually reflects a degree of risk conferred by the pah comorbidity .
for example , a primary discharge diagnosis of  pneumonia  on the case report form would result in a categorization of that patient s hospitalization as pah - unrelated .
however , if pah predisposes the patient to non - line - related infections such as pneumonia or if an infection such as pneumonia were to precipitate congestive heart failure , then one could argue that the hospitalization is truly pah related .
although 53% of patients had first - time hospitalizations that were clearly related to pah , it is unclear what proportion of so - called  pah - unrelated  hospitalizations were truly incidental or precipitated by the pah comorbidity to some extent .
patients in this analysis who were hospitalized for any reason had a higher prevalence of comorbidities and more severe pah at enrollment , as measured by functional class , pericardial effusion , mean right atrial pressure , and reveal registry risk score , compared with patients without hospitalizations .
fewer differences at enrollment distinguished between patients with pah - related and pah - unrelated hospitalizations , although patients with pah - related hospitalizations presented with more severe pah at the time of first admission .
the lack of differences between the pah - related and pah - unrelated groups at enrollment is an important point , given our finding that both in - hospital and postdischarge survival are significantly worse for patients hospitalized for pah - related reasons , despite the similar frequencies at which pah - related and pah - unrelated hospitalizations occur .
the worse outcomes were seen in the pah - related group despite > 46% use of parenteral prostanoids at the time of the first hospitalization compared with 22% in the pah - unrelated group .
hospital readmission is common for patients with pah , especially those whose first hospitalization was pah related .
only 25.4% of patients discharged after a pah - related hospitalization remained free from readmission 3 years later .
furthermore , hospitalization for any cause increases overall risk of death , an association that has been documented previously . even for patients with no hospitalizations in the first year after enrollment , almost one - half experience at least one hospitalization over the subsequent 3 years , despite treatment of pah , indicating that surviving the first year hospitalization - free does not strongly relate to the likelihood of future hospitalization .
mean total hospital days in the year after first admission ( inclusive of first admission ) for all patients with at least one hospitalization was 15.3 days ( median , 7.0 days ) , which represents a significant burden for both the health - care system as a whole and for individual patients .
for our analysis , we did not evaluate the burden of cost for pah - related hospitalization .
one retrospective study estimated total per - patient per - month costs ( including inpatient and outpatient costs ) at $ 4,021 for patients with pah . extrapolating from that figure , we calculate that total costs for pah were about $ 188 million in 2012 ( assuming a prevalence of 12.4 cases per million and 313.9 million people in the united states in 2012 ) . based on the attention currently paid to left - sided heart failure by regulatory and reimbursement third parties , for which total costs are estimated at $ 30 billion in the united states in 2013 , one might expect similar emphasis to be directed at pah - related hospitalizations , particularly those for heart failure .
first , the analysis presented here was retrospectively determined and may be limited by the biases inherent to any analysis that is not fully prespecified prospectively before the data are collected .
we chose to focus on patients with newly diagnosed disease to minimize survivor bias , but it must be noted that there was , typically , a delay of about 1 month between diagnosis and enrollment .
perhaps more importantly , at the time of the first hospitalization , patients no longer had newly diagnosed disease , but rather those results should be generalized to patients being discharged after their first postdiagnosis hospitalization .
second , the categorization of hospitalization as pah related or unrelated was made based on specific retrospective data available from the case report form , and in 42 cases ( 16.3% ) of hospitalization causality related to pah could not be determined .
access to full patient charts was not available at the time of investigator review of the data .
for example ,  placement or removal of a central venous catheter  may overlap with 
 some of the overlap was mitigated by ensuring that the category  pah - unrelated infection  excluded both 
( pah - unrelated hospitalization ) , so that these three categories of infection were considered separately .
fourth , the significantly longer period of follow - up for patients with hospitalizations , compared with patients without hospitalizations , may be a source of bias , since the likelihood of a hospitalization event increases with time .
pah is associated with a considerable burden of disease ( as measured by all - cause hospitalization ) .
patients who are more severely ill ( ie , with more severe pah or multiple comorbidities ) are at higher risk for all - cause hospitalization .
the degree of freedom from hospitalization is very poor after the first hospitalization , regardless of the cause .
prognosis is relatively better for patients with no hospitalizations in the first year or first hospitalization occurring after 1 year , but it nevertheless remains poor .
 background : hospitalization is an important outcome in pulmonary arterial hypertension ( pah ) , shown previously to correlate with survival . using the registry to evaluate early and long - term pah disease management ( reveal registry ) , we sought to characterize first - time hospitalizations and their effect on subsequent hospitalization and survival in patients with newly diagnosed disease.methods:patients with newly diagnosed pah ( n = 862 , world health organization group 1 ) were evaluated for first - time hospitalization . 
 the hospitalizations were categorized as pah related or pah unrelated based on the case report form . 
 categories for pah - related and pah - unrelated hospitalization were defined before independent review . 
 patient demographics and disease characteristics are described as well as freedom from hospitalization and survival.results:of 862 patients , 490 ( 56.8% ) had one or more hospitalizations postenrollment : 257 ( 52.4% ) pah related , 214 ( 43.7% ) pah unrelated , and 19 ( 3.9% ) of undetermined causes . 
 the most common causes of pah - related hospitalization were congestive heart failure and placement / removal of a central venous catheter . 
 patients with pah - related hospitalizations were more likely to receive parenteral therapy , be in functional class iii / iv , and have higher risk scores before hospitalization at enrollment . 
 following discharge , 25.4%  3.2% and 31.0%  4.0% of patients with pah - related and pah - unrelated first hospitalization , respectively , remained hospitalization - free for 3 years ( p = .11 ) . 
 survival estimates at 3 years postdischarge were 56.8%  3.5% and 67.8%  3.6% ( p = .037 ) for patients with pah - related and pah - unrelated hospitalization , respectively.conclusions:in the reveal registry , pah - related hospitalization was associated with relatively more rehospitalizations and worse survival at 3 years.trial registry : clinicaltrials.gov ; no . 
 : nct00370214 ; url : www.clinicaltrials.gov 
TRIAL REGISTRY:
Materials and Methods
Results
Causes of PAH-Related and PAH-Unrelated Hospitalizations
Patient Demographics and Disease Characteristics at Enrollment That Predict Hospitalization
Characterization of PAH-Related and PAH-Unrelated Hospitalizations
Freedom From Hospitalization
Survival
Discussion
Conclusions
Supplementary Material