Objectives: This study assessed pulmonary hypertension (PH)-related hospitalizations, including readmissions, among US patients with pulmonary arterial hypertension (PAH), a rare disease characterized by high morbidity and premature mortality.
Study Design: Analysis of claims data (January 1, 2007—April 30, 2011) from adult enrollees with commercial or Medicare Advantage with Part D coverage from a large US health plan.
Methods: Patients with PAH were identified based on ≥1 medical claim with a PH-related diagnostic code (International Classification of Diseases, Ninth Edition, Clinical Modification code 416.0 for primary pulmonary hypertension or 416.8 for other chronic pulmonary heart disease) and ≥1 pharmacy claim for a medication indicated for PAH or frequently used in PAH. Data were analyzed for patients with ≥1 hospitalization with a primary or secondary diagnostic code of PH. PH-related hospitalizations were defined as those with ≥1 PH-related diagnostic code. The principal diagnosis was defined as the diagnosis most frequently in the first-listed position on a hospitalization’s facility claims. Total hospitalization costs (inflated to 2011 US$) and length of stay (LOS) were analyzed. A subgroup analysis evaluated readmissions.
Results: Of 4009 enrollees meeting inclusion criteria, 2275 had ≥1 PH-related hospitalization during follow-up: 56.9% were female, 59.4% were <65 years old, and 67.8% had commercial insurance. Mean (SD) costs across all hospitalizations were $46,118 ($135,137) for commercially insured and $16,319 ($30,046) for Medicare Advantage enrollees; LOS was 10.9 (20.4) and 12.8 (21.2) days, respectively. Costs and LOS were higher for admissions with a principal diagnosis of PH compared with other principal diagnoses: $61,922 ($213,596) versus $42,455 ($108,925) and 14.2 (32.3) versus 10.2 (16.4) days, respectively, for the commercially insured, and $19,584 ($29,501) versus $15,904 ($30,097) and 16.7 (25.7) versus 12.3 (20.5) days, respectively, for Medicare Advantage enrollees. Of the 954 patients who experienced ≥1 PH-related readmission within the first year after discharge from the initial hospitalization, 483 (50.6%), 246 (25.8%), and 225 (23.6%) patients had 1, 2, and ≥3 readmissions, respectively.
Conclusions: PH-related hospitalizations incur substantial healthcare costs and require long hospital stays for patients with PAH; many are readmitted within 1 year. Improved treatment approaches are needed to reduce PAH disease progression leading to costly and burdensome inpatient stays.
Am J Manag Care. 2015;21:S47-S58Pulmonary arterial hypertension (PAH) is a rare and debilitating chronic disease of the pulmonary vasculature, with an annual incidence of 2.3 cases per million and a prevalence of 12.4 cases per million in the United States.1 PAH is characterized by vascular proliferation and remodeling of the small pulmonary arteries.2 These changes result in a progressive increase in pulmonary vascular resistance, ultimately leading to right heart failure (HF) and premature death.2
PAH-related morbidity results from disease progression that frequently requires hospitalization, which is recognized to be an important measure of clinical worsening.3 PAH-related hospitalization has been linked to increased mortality among patients in clinical practice.4 Although few studies have provided healthcare cost data for PAH, especially for important morbidity events such as hospitalizations, the available evidence from retrospective database studies in the United States, in which patients with PAH were identified based on medical claims for inpatient and outpatient services and treatments, indicates that hospitalization costs greatly exceed pharmacy costs in this population.5-8
The scarcity of cost data for PAH is partly due to the challenge of ascertaining patients with PAH in healthcare databases in the absence of a unique diagnostic code to distinguish PAH from other forms of pulmonary hypertension (PH).9 The coding currently used in the United States, the International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM), includes the code 416.0 for primary PH, which corresponds to idiopathic PAH (IPAH) and heritable PAH (HPAH) in the current clinical classification system for PH,10 and the code 416.8 for other chronic pulmonary heart disease, which encompasses not only other PAH etiologies but also forms of PH not classified as PAH.9 Consequently, prior retrospective database studies have had to use algorithms to identify potential patients with PAH.5-8
To date, no studies have assessed costs and length of stay (LOS) of PH-related hospitalizations by type of payer or principal diagnosis. Also, no previous studies have formally examined rates, LOS, and costs associated with readmissions in patients with PAH. Readmission soon after discharge for the same condition that prompted the initial hospitalization is common across diseases, and readmission LOS and costs have been shown to generally exceed those of initial hospitalizations.11 Policy makers in the United States have identified reducing readmission rates as a way to improve quality of care (assuming that a proportion of readmissions should be preventable) and reduce costs; accordingly, Medicare’s Hospital Readmissions Reduction Program penalizes hospitals that have “worse than expected” rates of readmission during the 30-day post discharge period.12
Understanding the burden of PH-related hospitalization in the United States is important to address growing interest in PAH among pharmacy benefit managers and payers. In 2013, PH ranked in the top 5 Medicare specialty therapy classes by per member per year spend.13 Given the clinical and economic relevance of hospitalizations and readmissions in PAH, the present retrospective database study was conducted to assess PH-related hospitalizations and readmissions in terms of timing, rates, costs, and LOS among patients with PAH identified in a large population of health-plan beneficiaries in the United States with commercial or Medicare coverage.
The data source for this study was the large, nationally representative Optum Research Database affiliated with Optum, which contains medical and pharmacy claims from US health plans providing commercial and Medicare Advantage with Part D insurance coverage. This study was conducted in compliance with the Health Insurance Portability and Accountability Act Privacy Rules. The database covered approximately 30 million lives during the study period, from January 1, 2007, to October 31, 2011.
Medical, pharmacy, and enrollment data from the database were abstracted for the purposes of this study. Medical claims data are available from all available healthcare sites, including hospitals (inpatient and outpatient visits), emergency departments, surgery centers, and physician offices. Medical claims and coding conform to insurance industry standards. Rigorous quality assurance checks were conducted during data set construction, including record-level verification of all data elements, double programming of certain portions of the data set, programming data edit checks, visual review of raw claims data against the constructed data elements, and review of analyses to assess the validity of results. Each medical claim includes the following information: multiple ICD-9-CM diagnosis codes (1 primary diagnosis code and up to 17 secondary diagnosis codes); procedure codes recorded with ICD-9-CM Current Procedural Terminology or Healthcare Common Procedure Coding System codes; site-of-service codes; provider specialty codes; revenue codes (for facilities); and paid amounts, including patient co-payments, third party payments (eg, from pharmacy benefit management organizations), and plan-reimbursed amounts. Healthcare costs for each PH-related hospitalization in the study period were calculated as the combined amounts paid by patients, third parties, and health plans.
Pharmacy claims data available include, among other items of information, drug name (branded and generic), dosage form, drug strength, and fill date.
Patient coverage eligibility in this study was determined on the basis of health plan enrollment data. The enrollment file includes for each patient a unique identifier, age, date of birth, gender, and dates of enrollment and (if applicable) disenrollment from the health plan. Patient characteristics at baseline (age, gender, and insurance type) were retrieved from the enrollment data file.
Study Design and Cohort Selection
The study design, patient ascertainment algorithm, and data analysis plan were developed a priori. Patients likely to have PAH were identified on the basis of at least 1 medical claim with evidence of PH and at least 1 pharmacy claim for a medication used to treat PAH, using a multi-step process (Figure 1). Specifically, to be included in the study cohort, a health plan enrollee was required to have at least 1 medical claim with a primary or secondary diagnosis code for PH (ICD-9-CM 416.0 or 416.8) from July 1, 2007, through April 30, 2011 (the identification period). Although ICD-9-CM code 416.0 (Primary PH. Idiopathic pulmonary arteriosclerosis. Pulmonary hypertension [essential] [idiopathic] [primary]) is specific to PAH (ie, referring to the etiologies of IPAH and HPAH), ICD-9-CM code 416.8 (Other chronic pulmonary heart disease. Pulmonary hypertension, secondary) encompasses not only other PAH etiologies but also non-PAH forms of PH.9 Therefore, the specificity of the patient selection process for PAH was increased by applying the additional inclusion criterion of at least 1 pharmacy claim during the identification period for a medication indicated to treat PAH, defined as a medication of interest. Eligible drugs marketed during the study period were the phosphodiesterase type-5 (PDE-5) inhibitors sildenafil and tadalafil, the endothelin receptor antagonists (ERAs) bosentan and ambrisentan, and the prostacyclins epoprostenol, treprostinil, and iloprost (Table 1). Because the PDE-5 inhibitors are also marketed under brand names that are indicated for erectile dysfunction (ED) but may potentially also be prescribed to patients with PAH, a further criterion was applied: Viagra (sildenafil) fills had to have a daily dose of at least 60 mg, and Cialis (tadalafil) fills had to have a daily dose of at least 40 mg (ie, the daily doses approved for PAH14,15). The index date was defined as the date of the first PAH drug prescription during the identification period; the medication received on the index date was the index medication.
Additional patient inclusion criteria were at least 6 months of continuous enrollment with medical and pharmacy coverage both before and after the index date (baseline period and follow-up period, respectively; Figure 1). For each included patient, the follow-up period ended with health plan disenrollment or October 31, 2011, whichever occurred earlier. Thus, the study period was January 1, 2007, to at the latest October 31, 2011. In addition, eligible patients were required to have experienced 1 or more PH-related hospitalization after the index date, defined as a hospitalization with an ICD-9-CM code of 416.0 or 416.8 in any position on a medical claim. Finally, all patients were required to be at least 18 years of age as of the year of the identification date.
Enrollees were excluded from the cohort if they had any medical claims with a diagnosis code for pregnancy, labor, or delivery (ICD-9-CM 630-676.xx, 679.xx, 796.5, V22.x-V24.x, V27.x-V28.xx, V61.6-V61.7, V72.42, V91. xx) during the entire study period, because the management of patients with evidence of these conditions differs substantially from that of others. Patients with dual coverage by commercial insurance and Medicare were included in the overall sample but were excluded from all analyses comparing outcomes for the 2 types of coverage.
All analyses reported in this paper included only hospitalizations with at least 1 PH-related diagnostic code in any position in the claims for that inpatient stay—ie, all hospitalizations were deemed to be PH-related. The first PH-related hospitalization that occurred after the index date was defined as the initial PH-related hospitalization (Figure 1). The period after discharge from the initial PH-related hospitalization was defined as the post initial PH-related hospitalization period. In a subgroup analysis to assess readmissions, patients with at least 1 additional PH-related hospitalization within the post-initial PH-related hospitalization period were identified. Results in terms of costs and LOS were analyzed for patients with at least 1 readmission within 1 year of discharge from the initial PH-related hospitalization. The 1-year period for analysis of readmissions was chosen to correspond to a plan year relevant to payers.
As a sensitivity analysis, results were limited to patients who never had a prescription for Viagra or Cialis during the study period. The inclusion in the ascertainment algorithm of patients taking these drugs was intended to ensure an adequate sample size, but it created the potential for capturing off-label prescribing; by excluding these patients, the sensitivity analysis was intended to assess the robustness of the main analysis findings.
Statistical Analysis and Calculations
Because no hypotheses were prespecified, no analyses of statistical significance were performed. Descriptive statistics were used to describe the cohort and study outcomes both for the main analysis and the subgroup of patients included in the readmission analysis: counts and percentages for discrete variables, and mean and standard deviation (SD) or standard error (SE) for continuous variables.
Healthcare costs for each hospitalization were retrieved from the medical claims data and computed as the combined amounts paid by patients, third parties, and health plans. All costs were adjusted to 2011 US dollars based on the Consumer Price Index for Urban Consumers. LOS for each hospitalization was calculated from facility claims as the number of days between admission date and discharge date.
Although every hospitalization was PH-related by virtue of having at least 1 PH code (ICD-9-CM 416.0 or 416.8) in its claims, no unique diagnosis code was available from the database to identify the main reason for a given hospitalization. Therefore, each hospitalization was assigned a single principal diagnosis, determined to assess the likely primary reason for that hospital stay, based on the diagnosis code most commonly found as the primary diagnosis (ie, in the first position) on all facility claims related to that hospitalization. Hospitalization costs and LOS were stratified by PH versus other principal diagnosis based on this definition.
Since US healthcare costs vary considerably by payer, costs across any enrollee cohort with heterogeneous coverage are dependent on the specific mix of insurers in the cohort and are thus difficult to generalize; accordingly, hospitalization-related results were reported stratified by insurance type (ie, commercial or Medicare Advantage).
For the subgroup analysis of readmissions in patients with at least 1 readmission post initial hospitalization, the Kaplan-Meier curve of time to first PH-related readmission was also determined. In addition, the percentage of patients with at least 1 readmission was determined for the overall cohort.
The patient selection and attrition for the study cohort is presented in Figure 2. A total of 4009 enrollees had at least 1 PH-related medical claim, received a medication of interest, and were 18 years or older during the identification period, thus fulfilling the inclusion criteria. Of these, 2275 (56.7%) had at least 1 PH-related hospitalization in the follow-up period (as defined in the Methods section) and were included in analyses.
Table 2 reports patient characteristics for the sample of all patients with at least 1 hospitalization. A majority of patients were female (57%), older than 50 years (78%), and had commercial insurance (68%). As expected, the mean (SD) age was higher among patients with Medicare Advantage coverage (which primarily covers elderly people) than among those with commercial coverage: 69.6 (11.5) versus 56.7 (13.4) years, respectively. The proportion of males was higher among the commercially insured than among Medicare Advantage enrollees: 50.4% versus 27.7%, respectively.
A total of 5582 PH-related hospitalizations were identified post index date: 3322 among enrollees with commercial insurance and 2244 among those with Medicare Advantage coverage. As shown in Figure 3, mean (SD) hospitalization costs averaged across all admissions (ie, initial hospitalization, N = 2273, and readmissions, N = 3293) were nearly 3-fold higher among patients with commercial insurance compared with costs for patients enrolled in Medicare Advantage: $46,118 ($135,137) versus $16,319 ($30,046), respectively. Figure 3 also shows that LOS was shorter for commercially insured patients than for Medicare Advantage enrollees: 10.9 (20.4) versus 12.8 (21.2) days, respectively.
Considering only the initial hospitalization after the index date, the mean (SD) cost was more than twice as high among patients with commercial insurance than among Medicare Advantage enrollees: $39,576 ($96,707) versus $16,496 ($31,301), respectively. As for all hospitalizations, LOS for the initial hospitalization was shorter for commercially insured patients than for Medicare Advantage enrollees: 10.0 (14.8) versus 12.7 (21.0) days, respectively.
Overall, 15% of principal diagnoses were for PH (ICD-9-CM 416.0 or 416.8); the most frequent among the numerous types of other principal diagnoses were congestive HF (ICD-9-CM 428.0; 7%), pneumonia (ICD- 9-CM 486; 4%), obstructive chronic bronchitis with exacerbation (ICD-9-CM 491.21; 3%), and acute and chronic respiratory failure (ICD-9-CM 518.84; 3%). Within each insurance type, hospitalization costs and LOS were substantially higher for hospitalizations with a principal diagnosis of PH compared with other principal diagnoses (Figure 3), although the differences in costs were much greater in patients with commercial insurance. Among patients with commercial insurance, mean (SD) hospitalization costs and LOS were $61,922 ($213,596) and 14.2 (32.3) days for hospitalizations with a principal diagnosis of PH compared with $42,455 ($108,925) and 10.2 (16.4) days for hospitalizations with other principal diagnoses. Among patients with Medicare Advantage, hospitalization costs and LOS were $19,584 ($29,501) and 16.7 (25.7) days for hospitalizations with a principal diagnosis of PH compared with $15,904 ($30,097) and 12.3 (20.5) days for hospitalization with other principal diagnoses.
Readmission Subgroup Analysis
A total of 1203 patients (52.9% of subjects with hospitalizations) had 1 or more readmissions at any time during the total follow-up period after discharge from the initial PH-related hospitalization. As shown in Figure 4, among these 1203 readmitted patients, approximately one-fifth (21.2%) were readmitted within 30 days of discharge from the initial hospitalization, with the cumulative proportion of readmitted patients rising to 59.1% by 6 months and 79.3% by 1 year. Calculated across all 2275 patients with at least 1 hospitalization, patients were readmitted within the following time periods after initial discharge: 11.2% within 30 days, 17.2% within 60 days, 22.2% within 90 days, 26.0% within 120 days, 31.2% within 180 days, and 41.9% within 1 year.
Of the 1203 patients with readmissions during followup, 954 (79.3%) had 1 or more readmissions within the first year after discharge from the initial hospitalization and were included in the readmitted subgroup. In this subgroup, 483 (50.6%), 246 (25.8%), and 225 (23.6%) experienced 1, 2, and 3 or more readmissions in the first year, respectively. Patient characteristics for this subset of patients with readmissions within 1 year of initial discharge were similar to those for all patients in the main analysis (Table 2).
As for all patients with admissions, among the readmitted subgroup, hospitalization costs were higher and LOS was shorter for commercially insured patients compared with Medicare Advantage enrollees. As can be seen in Figure 5, readmissions accounted for the vast majority of 1-year hospitalization costs in this subgroup (ie, including the cost of the initial admission): 70.6% for commercially insured patients and 68.9% for those enrolled in Medicare Advantage.
Averaged over all 2275 patients with at least 1 hospitalization, the mean (SD) readmission costs (ie, excluding the initial hospitalization) within 1 year after discharge from the initial hospitalization were $35,188 ($152,006) for commercially insured patients and $19,170 ($41,905) for Medicare Advantage enrollees. Averaged over only the 954 patients in the readmitted subgroup, the respective 1-year readmission costs were $95,254 (238,506) and $36,543 (52,106), respectively.
After patients with a prescription for Viagra or Cialis were excluded, the patient population was reduced to 1202 (62.4%) commercially insured patients and 725 (37.6%) patients with Medicare Advantage coverage, of whom 756 (62.9%) and 524 (72.3%), respectively, were female. For these subgroups, the mean (SD) costs of all hospitalizations were $37,156 ($136,170) and $14,507 ($26,193), respectively; LOS was 10.19 (23.33) versus 11.46 (18.73) days, respectively.
Overall, the results of this study confirm the high burden of PAH. More than half of the identified patients with PAH (56.7%) had a PH-related hospitalization during a mean follow-up period of 35.1 months (after index prescription). A key finding was that patients with commercial insurance had much higher mean PH-related hospitalization costs compared with Medicare Advantage enrollees ($46,118 versus $16,319, respectively), likely reflecting the differential reimbursement rates between Medicare and commercial insurance. Patients with Medicare Advantage spent on average nearly 2 more days in the hospital per admission, possibly attributable to the higher mean age and associated comorbidity in this population relative to the commercial population.
Hospitalizations with a principal diagnosis of PH were found to have higher mean total costs and longer mean LOS per patient than hospitalizations for other reasons, demonstrating the increased healthcare burden of hospitalizations for PH. The mean cost was $46,070 for initial hospitalizations and $73,066 for readmissions with a principal diagnosis of PH among commercially insured patients, which is substantially higher—even if inflation is considered—than the mean HF-related hospitalization cost recently reported by Korves et al for commercially insured patients in 2004-2008, which was $31,998 for the initial hospitalization and $22,048 to $24,839 for readmissions. 16 Similarly, the mean cost of hospitalizations with a principal diagnosis of PH for patients with PAH with Medicare Advantage coverage in the present study ($17,627 for initial hospitalizations and $20,995 for readmissions) was much higher than the HF-related hospitalization cost reported by Korves et al among Medicare enrollees with HF ($12,427 for the initial hospitalization and $9132 to $10,040 for readmissions).16
Among Medicare enrollees, 117 in 495 (23.6%) patients with PAH with a readmission were readmitted within 30 days of discharge from their initial hospitalization, the time period over which Medicare assesses readmissions to determine reimbursement reduction to penalize excessive readmission.12 This 30-day readmission rate is similar to that reported by Ross et al (23%) for an HF population of fee-for-service Medicare patients 65 years or older17 and within the range for other chronic conditions as reported in a paper by Jencks et al of fee-for-service Medicare beneficiaries (26.9% for HF, 20.1% for pneumonia, 22.6% for chronic obstructive pulmonary disease, 24.6% for psychoses, and 19.2% for gastrointestinal problems).11
When averaged over all 2275 patients with at least 1 hospitalization, mean 1-year readmission costs were similar to costs for the initial hospitalizations: $35,188 versus $39,576, respectively, for the commercially insured and $19,170 versus $16,496, respectively, for those with Medicare Advantage coverage. Thus, although not all patients were readmitted, the 1-year cost of readmissions was comparable to that of initial hospitalization, confirming the high burden of hospitalizations and readmissions in these patients.
The potential of advanced drug-based treatment strategies to reduce the clinical and economic burden of PAH-related hospitalizations has been reported recently. Statistically significant reductions in hospitalization were demonstrated for macitentan versus placebo in the SERAPHIN study (Study with Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome), which included treatment- naïve patients and patients on background PAH therapy.18 Compared with placebo, macitentan 10 mg reduced the risk of PAH-related hospitalization by 52% (P <.0001), the rate of PAH-related hospitalization by 50% (P <.0001), and the mean number of annual hospital days for PAH-related hospitalizations by 52% (P = .0003). Reductions in PAH-related hospitalization with macitentan were seen in treatment-naïve patients and those on existing PAH-specific therapies.18
This study is subject to some limitations. Results are based on patients with commercial or Medicare Advantage with Part D coverage health plans with Optum, so they may not be representative of all patients with PAH in the United States. However, the results for commercially insured and Medicare Advantage enrollees subgroups can be expected to be generally representative of patients in other health plans.
A limitation common to this study and all other retrospective analyses of US claims databases in PAH is that the codes used to identify patients with PAH are not specific.9 Because of the lack of a unique ICD-9-CM code for PAH, patients had to be identified based on an algorithm, which led to a potential overestimation of the sample. Although the majority of patients were female (56.9% of patients with PH-related hospitalizations), the cohort included more males than expected based on the sex ratio observed in the US-based REVEAL (Registry to Evaluate Early And Long-Term PAH Disease Management) registry, the largest prospective registry in PAH (79.5% female).19 This may be due to the inadvertent inclusion of men taking PDE-5 inhibitors to treat ED because generic drug names were used as part of the cohort selection criteria, even though careful attention was paid to only include patients taking these drugs at doses appropriate in PAH. Notably, a sensitivity analysis in which patients with prescriptions for Viagra or Cialis were excluded led to a gender ratio (66.4% female) more similar to that observed in REVEAL, with mean PH-related hospitalization costs being somewhat lower than for all patients included in the main analysis: $37,156 versus $46,118, respectively, for commercially insured patients, and $14,507 versus $16,319, respectively, for Medicare Advantage enrollees. Although it is impossible to be certain that the patients with Viagra or Cialis prescriptions were not taking these drugs for ED, it is more likely that they were being treated with these agents for more severe (and thus costly) conditions, specifically left-sided HF or other cardiovascular diseases, as in recent years the use of PDE-5 inhibitors has been expanded to the therapeutic management of cardiovascular disorders.20,21
Given that a PH-related medical claim (which could relate to a hospitalization) was an inclusion criterion for ascertaining patients with PAH, this study may have overestimated the hospitalization rate in the overall PAH population. However, overestimation is unlikely because patients with PAH require regular visits every 3 to 6 months22 and are therefore likely to incur frequent medical claims regardless of whether they had a hospitalization.
Finally, although all hospitalizations included in the present analysis were deemed to be PH related on the basis of including at least 1 claim with a PH-related code, it is possible that the reason for a given hospitalization was unrelated to PAH. The available data did not permit clinical confirmation of a relationship between hospitalization and PH.
The long durations and high incurred costs for PH-related hospitalizations, including readmissions, found in this study reveal the severe morbidity, healthcare, and patient burden of PAH. With the caution that patient populations and methods differed between studies, the burden of PH-related hospitalization found in this study was in line with previous analyses of HF. Improved patient management, incorporating advanced treatment options to reduce disease progression for patients with PAH, may lead to a reduction in hospitalizations (as demonstrated in SERAPHIN) and therefore have a positive impact on patient burden, healthcare resources, and associated costs.1. Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US Contemporary Registries. Chest. 2011;139(1):128-137.
2. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493-2537.
3. Galiè N, Simonneau G, Barst RJ, Badesch D, Rubin L. Clinical worsening in trials of pulmonary arterial hypertension: results and implications. Curr Opin Pulm Med. 2010; 16(suppl 1):S11-S19.
4. Burger CD, Long PK, Shah MR, et al. Characterization of first-time hospitalizations in patients with newly diagnosed pulmonary arterial hypertension in the REVEAL registry. Chest. 2014;146(5):1263-1273.
5. Copher R, Cerulli A, Watkins A, Laura Monsalvo M. Treatment patterns and healthcare system burden of managed care patients with suspected pulmonary arterial hypertension in the United States. J Med Econ. 2012;15(5):947-955.
6. Kirson NY, Birnbaum HG, Ivanova JI, et al. Excess costs associated with patients with pulmonary arterial hypertension in a US privately insured population. Appl Health Econ Health Policy. 2011;9(5):293-303.
7. Angalakuditi M, Edgell E, Beardsworth A, Buysman E, Bancroft T. Treatment patterns and resource utilization and costs among patients with pulmonary arterial hypertension in the United States. J Med Econ. 2010;13(3):393-402.
8. Said Q, Martin BC, Joish VN, Kreilick C, Mathai SC. The cost to managed care of managing pulmonary hypertension. J Med Econ. 2012;15(3):500-508.
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10. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 suppl):D34-D41.
11. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009;360(14):1418-1428.
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17. Ross JS, Chen J, Lin Z, et al. Recent national trends in readmission rates after heart failure hospitalization. Circ Heart Fail. 2010;3(1):97-103.
18. Channick RN, Delcroix M, Ghofrani HA, et al. Effect of macitentan on hospitalizations: results from the SERAPHIN trial. JACC Heart Fail. 2015;3(1):1-8.
19. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-387.
20. Guazzi M. Clinical use of phosphodiesterase-5 inhibitors in chronic heart failure. Circ Heart Fail. 2008;1(4):272-280.
21. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebocontrolled study. Circ Heart Fail. 2011;4(1):8-17.
22. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc, and the Pulmonary Hypertension Association. Circulation. 2009; 119(16):2250-2294.