Treatment patterns and healthcare system burden of managed care patients with suspected pulmonary arterial hypertension in the United States

Abstract

Objectives:

To describe treatment patterns and healthcare burden among individuals with suspected pulmonary arterial hypertension (PAH), as identified through a practice guideline-based healthcare claims algorithm.

Methods:

Adults with evidence of PAH from 1 January 2004 (commercial and Medicaid) or 1 July 2006 (Medicare Advantage) through 30 June 2008 were identified. Given the lack of an ICD-9 code for PAH, an algorithm was developed requiring: (1) ≥1 claim for PAH medication (index date); (2) ≥1 claim with a pulmonary hypertension diagnosis code in the 6-month pre-index period (baseline) or within 90 days post-index; (3) a right heart catheterization or pulmonary hypertension-related inpatient stay during baseline or within 90 days post-index; and (4) continuous health plan enrollment for 6 months pre-index and ≥6 months post-index. Patients with PAH-specific medications during baseline were excluded. Treatment patterns, healthcare utilization, and costs were assessed during the period ending with the earlier of health plan disenrollment or 31 December 2008.

Results:

Among the 521 included patients, 69% were female. Most patients (94%) initiated treatment with monotherapy (most commonly sildenafil or bosentan), and 12.7% of all patients augmented their therapy by the end of the observation period. The medication possession ratio was 0.96 each for ambrisentan (SD = 0.04), bosentan (SD = 0.04), and sildenafil (SD = 0.05). Overall, 72.6% of patients discontinued therapy with a mean of 149 (SD = 170) days until discontinuation. A mean (SD) of 2.14 (1.82) all-cause office and 1.64 (1.98) outpatient visits occurred per patient per month. Mean PAH-related healthcare costs were $6617 per patient per month, comprising 71% of all-cause costs. The guideline-based algorithm may not have perfectly captured patients with PAH.

Conclusions:

Patients with suspected PAH were likely to initiate treatment with oral monotherapy, had high compliance rates, and received close ambulatory follow-up. PAH-related costs constituted the majority of all-cause healthcare costs.

Key words::

• Claims analysis
• Health expenditures
• Pulmonary hypertension

Introduction

Pulmonary arterial hypertension (PAH) is a rare condition characterized by restricted flow through the pulmonary arteries, resulting in increased pulmonary vascular resistance and ultimately in right heart failure1. Its prevalence in the US general population is relatively unknown. One study estimated a prevalence of 109 cases per million privately-insured individuals under age 65 and 451 cases per million Medicare beneficiaries2. This seems substantially higher than estimated prevalences in Europe, which range from 15–50 cases per million population3,4. Approximately 80% of patients represented in US PAH registries5–7 are women and 74–80% of patients are classified as functional class III or IV of the World Health Organization/New York Heart Association8 at diagnosis3,5–7. The median survival for US registry patients enrolled between 1982–2006 was 3.6 years, with corresponding survival rates of 84% at 1 year and 58% at 5 years5; survival rates were slightly higher among patients enrolled between 1991–2007 (86% at 1 year; 61% at 5 years)7.

The diagnostic algorithm for PAH requires a variety of clinical studies. Right heart catheterization, however, is the gold standard assessment of hemodynamics in patients with pulmonary hypertension and US and European guidelines recommend using it to confirm the PAH diagnosis9,10. Differentiating PAH from other clinical groups of pulmonary hypertension is critical because therapy differs depending on the diagnosis.

PAH pharmacy treatment currently comprises four drug classes: endothelin receptor antagonists (ERAs: bosentan, ambrisentan), prostanoids (epoprostenol, treprostinil), phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil), and calcium channel blockers. Calcium channel blockers are currently recommended only for the few patients with positive acute vasoreactivity testing9–13. Combinations of ERAs, prostanoids, and PDE-5 inhibitors might be considered. According to current guidelines initial combination therapy is reasonable for patients with an advanced functional class10,14, whereas sequential combination therapy should be considered for patients who demonstrate an inadequate clinical response to initial monotherapy9–11,14.

As with other rare diseases, the epidemiology and disease burden associated with PAH has generally been limited to patient registries3,5,6,15, which tend to be less focused on outcome data such as treatment patterns and health economic burden. Healthcare claims databases may be a viable alternative to registries for assessing the disease burden associated with PAH by examining treatment patterns, healthcare utilization, and costs. Given that there is currently no International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis code specific to PAH, some researchers have used claims data-based algorithms that combine codes indicating pulmonary hypertension with other claims-based criteria to identify patients with PAH2,16. Using a claims data-based algorithm that is based on practice guidelines for the diagnosis and treatment of PAH9,10 may further help to identify patients with PAH. The objectives of this study were to describe the treatment patterns and healthcare burden associated with managed-care patients with suspected PAH, as identified through a practice guideline-based healthcare claims data algorithm9,10.

Methods

Data source

De-identified healthcare claims data, including enrollment information and medical and pharmacy claims data, from the Life Sciences Research Database affiliated with OptumInsight (formerly Innovus) were used in this retrospective study. The database included information on geographically-diverse commercial, Medicaid or Medicare Advantage health plan members in the US, with concentrations of enrollees in the South and Midwest. During the study identification period (2004–2008), more than 33 million enrollees were represented in the database. The study protocol was approved by an institutional review board.

Study sample identification

Eligibility was determined based on healthcare claims, with service dates during the identification periods 1 January 2004–30 June 2008 for commercial and Medicaid patients and 1 July 2006–30 June 2008 for Medicare Advantage patients. The first criterion in the patient identification algorithm was presence of at least one claim for a PAH medication of interest during the identification period. Pharmacy and medical claims were used to identify ambrisentan, bosentan, inhaled iloprost, intravenous or subcutaneous treprostinil, intravenous epoprostenol, and sildenafil. Identification of sildenafil was limited to patients with claims for the trade name and dose approved for PAH (sildenafil 20 mg, Revatio, Pfizer Inc., New York, NY). This criterion was intended to differentiate use of sildenafil for PAH from use for other indications; sildenafil is not available in generic form. The date of the first observed PAH medication claim was defined as the index date, and the medication was the index PAH treatment. Patients were required to be continuously enrolled in their health plan for 6 months prior to and at least 6 months following the index date (baseline and follow-up periods, respectively). In order to evaluate treatment patterns starting with the initial PAH diagnosis, patients with claims for PAH treatment in the 6-month period preceding the index date (baseline period) were excluded. The patient sample was further refined by including only patients who had at least one medical claim with an ICD-9-CM diagnosis code for pulmonary hypertension (416.0 or 416.8) in the baseline period or within the first 90 days of follow-up and had claims-based evidence of a right heart catheterization (ICD-9-CM procedure code 37.21 or 37.23; Current Procedural Terminology [CPT] codes 93501, 93526–93529) or pulmonary hypertension-related inpatient stay (inpatient facility stay with a primary or secondary diagnosis of pulmonary hypertension) in the baseline period or within the first 90 days post-index. Patients were required to be at least 18 years of age.

To further ensure a cohort of suspected PAH patients without acute vasoreactivity who were receiving PAH-specific medication, calcium channel blockers and the sildenafil brand approved for erectile dysfunction (Viagra, Pfizer Inc., New York, NY) were excluded from the patient identification algorithm and assessment of PAH-specific treatment patterns. Calcium channel blockers are recommended for patients with positive acute vasoreactivity9–13, and are also used to treat other cardiovascular conditions, leading to potential misclassification of subjects. The PDE-5 inhibitor tadalafil was approved for PAH after the study period (2009) and therefore was not included in this study.

Patient characteristics

Enrollment information and healthcare claims data from the baseline period were used to determine demographic and clinical characteristics of patients in the study sample. The baseline comorbidity burden is described based on the Quan-Charlson comorbidity index17 and comorbidities identified using Clinical Classifications Software (http://www.hcup-us.ahrq.gov/toolssoftware/ccs/ccs.jsp) from the Agency for Healthcare Research and Quality (2009 version). The five most prevalent comorbidities identified among the study patients are reported.

Treatment patterns

Patterns of treatment with PAH medications were assessed during the follow-up period, which varied in duration and ended with health plan disenrollment or on 31 December 2008, whichever occurred earlier. Due to the post-index continuous enrollment requirement, follow-up was at least 6 months in duration.

The index PAH medication regimen was described as monotherapy or combination therapy depending on evidence of medication use in the first 90 days of follow-up. As described in the patient identification algorithm, index monotherapy could be ambrisentan, bosentan, iloprost, treprostinil, epoprostenol, or sildenafil (PAH-specific indication). Index combination therapy was defined as evidence of two or more PAH-specific medications in the first 90 days that were each supplied for at least 45 days and that overlapped by at least 30 days.

Evidence of index medication switch, augmentation, and dose escalation was used to describe treatment progression during the study period, as was use of supportive therapies. A switch in index PAH treatment was defined as commencement of a non-index PAH-specific treatment with no subsequent claims for the index treatment. For patients with index combination therapy, a switch occurred if one or all treatments met this definition. Index treatment augmentation was defined as commencement of a non-index PAH-specific treatment with at least one subsequent claim for the index PAH treatment(s). Dose escalation during the treatment period was examined for the oral and inhaled medications. The dose associated with each oral or inhaled PAH medication fill was defined as the quantity of drug dispensed multiplied by the strength divided by the number of days supplied. A subsequent dose greater than the dose calculated for the index PAH medication fill was defined as escalation. The initiation of PAH-related supportive therapies (warfarin, diuretics, digoxin, calcium channel blockers, or oxygen) was captured. The number of days from the index date to the date of the first observed switch, augmentation, dose escalation, or use of supportive therapy was counted.

Index treatment compliance and discontinuation were assessed over the follow-up period. The medication possession ratio (MPR)18 was used to measure treatment compliance among patients with oral or inhaled index PAH monotherapy. MPR was calculated as the total days supply of index medication divided by the number of days in the treatment period (i.e. from the index date until the earlier of a treatment change or the end of follow-up). The MPR calculation was corrected for inpatient events, under the assumption that medication was supplied by the facility during a hospitalization. The MPR for intravenous and subcutaneous prostanoids was not determined because patient weight, which is used to determine dosing for these medications, was not available in the claims data.

Discontinuation of index therapy was defined as a supply gap equal to at least half the number of days supplied in the fill preceding the gap. For parenteral medications, the period between service dates was considered to equal the number of days supplied, unless the period was greater than 90 days, in which case the supply was considered to be 90 days.

Healthcare service utilization

The number of all-cause and PAH-related healthcare visits during follow-up was determined. Visits were categorized as office visits, outpatient visits, emergency department visits, or inpatient admissions. The length of inpatient stays was also calculated. Healthcare service utilization based on claims with diagnosis codes 416.0 or 416.8 in any position or medical claims with codes associated with PAH-specific medication use was considered PAH-related. Utilization was computed per patient per month to account for varying lengths of follow-up.

Healthcare costs

All-cause and PAH-related healthcare costs were computed as combined health plan- and patient-paid amounts during follow-up. Costs were calculated per patient per month to account for varying follow-up durations and adjusted to reflect inflation through 200819. PAH-related medical costs were costs from claims used to identify PAH-related utilization (i.e. based on claims with pulmonary hypertension diagnosis codes or associated with PAH-specific medication). Medical costs include costs for services (such as right heart catheterization) performed during physician office visits, outpatient visits, emergency department visits, and inpatient admissions, as well as ‘other’ products or services (e.g. durable medical equipment or home health assistance) that are not associated with specified healthcare settings. Parenteral prostanoid administration costs were included with medical costs when the drug was administered in a hospital or clinic, and with pharmacy costs when a patient received the medication by filling a prescription. All-cause and PAH-related pharmacy costs were based on pharmacy claims. PAH-related pharmacy costs included PAH medications and supportive therapies obtained via outpatient pharmacy (warfarin, diuretics, digoxin, calcium channel blockers). Total healthcare costs are the sum of medical and pharmacy costs.

Statistical analyses

Treatment patterns, healthcare utilization, and costs were analyzed descriptively. Utilization and costs of patients with index monotherapy were compared with those of patients with index combination therapy using t-tests and a Wilcoxon rank-sum non-parametric test. The threshold for significance for all statistical comparisons was set at p < 0.05. Sensitivity analysis was conducted to assess whether excluding patients who received the sildenafil trade name indicated for erectile dysfunction was likely to exclude patients who in fact were receiving treatment for PAH: demographic and clinical variables were compared between patients whose index medication was PAH-specific sildenafil and those whose PAH medication was the sildenafil brand indicated for erectile dysfunction but otherwise fulfilled the inclusion criteria. Analyses were conducted using SAS 9.2 (SAS, Cary, NC).

Results

Baseline characteristics

The study sample selection process showing the steps in the algorithm used to identify patients with suspected PAH is presented in Figure 1. A total of 521 patients fulfilled the inclusion criteria. Baseline demographic and clinical characteristics of patients in the study sample are shown in Table 1. The mean age was 57.7 years (SD = 13.5), with the majority of patients aged 45–64 years. Approximately 69% of the patients were female. Most patients were commercially-insured and, like the source database population, from the South or Midwest. The high proportion of patients with Quan-Charlson comorbidity index scores of 2 or greater and the presence of different comorbidities suggest that many of the patients in the study had diminished health. The mean duration of follow-up was ∼1.4 years (528, SD = 303 days).

Figure 1.  Sample attrition.

Table 1.  Demographic and clinical characteristics of the study sample (n = 521).

Characteristic	n	%
Age
18–44	86	16.51
45–64	280	53.74
≥65	155	29.75
Gender
Male	162	31.09
Female	359	68.91
Insurance type
Commercial	450	86.37
Medicare Advantage	65	12.48
Medicaid	6	1.15
Region
Northeast	45	8.64
Midwest	195	37.43
South	217	41.65
West	64	12.28
Quan-Charlson Comorbidity Index
0	5	0.96
1	71	13.63
2	125	23.99
3	118	22.65
4	80	15.36
≥5	122	23.42
Comorbid conditions*
Diseases of the heart	519	99.62
Other lower respiratory disease	492	94.43
Hypertension	368	70.63
Diseases of arteries; arterioles; and capillaries	268	51.44
COPD and bronchiectasis	232	44.53

*Identified using Clinical Classifications Software for ICD-9-CM.

COPD, chronic obstructive pulmonary disease.

Comparisons between patients with claims for the sildenafil brands with different indications showed that demographic characteristics of the group that received sildenafil indicated for erectile dysfunction (n = 152) differed from those of the group that received PAH-specific sildenafil. Specifically, the patient group that received sildenafil indicated for erectile dysfunction included a greater proportion of men (91% vs 36%; p < 0.001) and a lower proportion of patients with comorbid ‘diseases of the heart’ (90% vs 100%; p < 0.001) than did the group that received PAH-specific sildenafil, suggesting that medication claims for the erectile dysfunction-specific sildenafil were unlikely to represent true use for PAH and that excluding these patients does not weaken our assessment of patients with suspected PAH.

Treatment patterns

Treatment progression

As shown in Figure 2, index PAH treatment was typically monotherapy, with 489 (94%) of patients initiating therapy with a single agent. Only 32 (6%) patients had index combination therapy.

Figure 2.  Distribution of index PAH medications.

Over the follow-up period, 19.8% of patients switched to a different PAH-specific medication, 12.7% augmented their index therapy, and 39.9% had evidence of a dose escalation. Among these types of regimen changes, dose escalation occurred the earliest, with a mean (SD) time to dose escalation of 84 (113) days. The mean time to switch was 203 (152) days, and the mean time to augmentation was 283 (236) days.

Among the supportive therapies, initiating a diuretic (81.4%) or oxygen (62.8%) occurred most commonly and within the shortest time frame, on average: 61 (SD = 124) days and 58 (SD = 133) days, respectively. Approximately half (48.9%) of patients with suspected PAH initiated warfarin during the post-index period, 36.1% initiated a calcium channel blocker, and 18.4% had evidence of digoxin use. Anticoagulants, calcium channel blockers, and digoxin were initiated at a mean (SD) of 91 (181) days, 90 (188) days, and 103 (171) days, respectively, following the index date.

Compliance and discontinuation

Compliance was high for all oral monotherapies and inhaled iloprost. The MPR (SD) value for each therapy was: 0.96 (0.04) for ambrisentan, 0.96 (0.04) for bosentan, 0.96 (0.05) for sildenafil, and 0.97 (0.03) for iloprost.

The overall discontinuation rate for PAH medication was 72.6%. The average number of days until discontinuation was 149 (SD = 170); the median was 90 days.

Healthcare service utilization

Counts of all-cause and PAH-related healthcare visits are shown in Table 2. On average, a patient with suspected PAH had contact with the healthcare system for any reason ∼1–2 times per month in ambulatory venues and had approximately one inpatient stay per year (mean of 0.11 inpatient admissions per month; Table 2). Less than one physician office visit per patient per month was attributable to PAH (Table 2). The proportion of all-cause utilization that is attributable to PAH appears to be greatest for inpatient stays (∼72.7% for inpatient vs 11.8–26.2% for ambulatory). A large proportion of the sample utilized healthcare resources: 90% of patients had a PAH-related physician office visit and more than half of patients had at least one PAH-related inpatient visit during follow-up (Table 2).

Table 2.  All-cause and PAH-related healthcare utilization during follow-up (n = 521).

	All-cause				PAH-related
	Mean	SD	Median	% of patients*	Mean	SD	Median	% of patients*
Physician office visits (number PPPM)	2.14	1.82	1.75	99	0.48	0.52	0.37	90
Outpatient visits (number PPPM)	1.64	1.98	1.12	97	0.43	0.55	0.25	76
Emergency department visits (number PPPM)	0.17	0.62	0.07	63	0.02	0.08	0.00	17
Inpatient admissions (number PPPM)	0.11	0.15	0.07	64	0.08	0.12	0.04	55
Length of inpatient stay (days)	1.12	2.25	0.31	–	0.86	1.86	0.18	–

*Percentage of patients with at least one healthcare encounter in the designated category.

PAH, pulmonary arterial hypertension; PPPM, per patient per month; SD, standard deviation.

Patients on index combination therapy had significantly more all-cause outpatient visits per month than did patients on monotherapy (mean 2.8 vs 1.6; p = 0.022), but no other significant differences in all-cause utilization were detected. The comparisons may be under-powered due to the small sample size in the combination therapy group.

Costs

All-cause healthcare costs averaged $9295 per patient per month, and PAH-related costs averaged $6617 per patient per month (Figure 3); thus, PAH-related healthcare costs constituted 71.2% of all-cause healthcare costs, on average. Within both all-cause and PAH-related costs, medical costs accounted for a larger portion of total costs than did pharmacy costs. Among all-cause medical cost components, the highest per-patient per-month costs were attributable to inpatient admissions ($3701, SD = $12,320) and outpatient visits ($1363, SD = $5017). All-cause medical costs did not differ significantly between patients with index monotherapy and those with index combination therapy (mean = $5889, SD = $12,694 vs $14,556, SD = $28.230; p = 0.094), but pharmacy costs were significantly greater for combination therapy users than for monotherapy users (mean = $6695, SD = $3832 vs $2623, SD = $2069; t-test and Wilcoxon rank-sum p < 0.001). The contribution of costs of combination therapy users to overall costs may be under-estimated given the small sample size in the combination therapy group. For PAH-related costs, the highest medical costs were attributable to inpatient admissions and other costs (Table 3).

Figure 3.  All-cause and PAH-related healthcare costs during follow-up.

Table 3.  PAH-related per-patient per-month total healthcare costs during follow-up (n = 521).

Service	Cost
	Mean	SD	Median
Medical costs	$4284*	$12,058	$666
Physician office visits	$72	$116	$36
Outpatient visits	$294	$563	$68
Emergency department visits	$8	$50	$0
Inpatient admissions	$3175	$11,452	$151
Other costs	$734	$2,407	$4
Pharmacy costs	$2333	$2,366	$1408
Total costs	$6617	$12,163	$3638

*Mean medical component costs do not sum to $4284 due to rounding.

SD, standard deviation.

Discussion

In this study, we found that oral monotherapy was the most frequently used initial therapy regimen after PAH diagnosis, and compliance with PAH-specific therapy was high. Monthly PAH-related healthcare utilization and costs of patients with PAH are substantial relative to all-cause costs.

Healthcare claims data are a readily-available source of information that reveal real-world clinical practice and treatment patterns, but identifying patients with conditions of interest is limited by the codes used to describe care. The algorithm created to identify patients with suspected PAH required an ICD-9-CM diagnosis code for pulmonary hypertension and receipt of medication used to treat PAH, similar to the criteria used by Angalakuditi et al.16. In addition, we required evidence of a right heart catheterization or an inpatient stay related to pulmonary hypertension in order to more accurately capture patients with suspected PAH. Kirson et al.2 also employed a right heart catheterization criterion, as well as exclusionary diagnoses, but they did not use pharmacy information. Based on clinical practice guidelines, including right heart catheterization as a criterion should increase the specificity of the algorithm for identifying patients with PAH. However, reliance on that criterion might lead to an under-estimation of the number of patients with suspected PAH if catheterization is not in fact carried out as recommended, and this is the reason our algorithm also captured patients who had an inpatient stay related to pulmonary hypertension.

To facilitate investigation of treatment trends in PAH, the patient identification algorithm was designed to capture newly-diagnosed patients and new users of PAH medications. Most of the identified patients received monotherapy. Monotherapy is typically recommended for patients with less advanced PAH, but it is also considered a useful and effective initial therapy for patients with more advanced functional class9,10. Conversely, combination therapies are generally reserved for patients with more advanced functional class or inadequate response to monotherapy10,11,14. Although information regarding functional class was not available for the study sample, the relative scarcity of patients on infused therapy or combination therapy, along with the identification criteria regarding new treatment and diagnosis, suggest that the identified patient population comprised patients with less advanced PAH. In addition to functional class, other factors that could influence the initial therapy selection include comorbidity and concerns regarding polypharmacy and potential drug interactions, the risk of hemodynamic intolerance to vasodilators, and costs.

In this study, ∼85% of patients received monotherapy with sildenafil, bosentan, or ambrisentan, and compliance for these oral medications was high (MPR = 0.96). In this patient population, good adherence is expected to decrease patient symptoms, improve prognosis, and lead to a more stable course of the disease. Although our analysis suggests that patients with PAH-specific monotherapy tend to follow their prescribed regimens, claims data provide indirect support because pharmacy claims do not indicate whether the patient took the medication as prescribed.

It is also important to recognize that the patient sample described in this study appears to differ from the population represented in registries such as REVEAL, and thus comparisons between these studies may be limited6. Patients in this study were older, on average, than the population represented in the REVEAL registry and other observational registries such as the Pulmonary Hypertension Connection registry5,6. Even though the disease can manifest at any age, this finding may represent a more frequent later onset of the disease, a delay of patients to consult, or a delay of diagnosis and initiating PAH treatment. Only a small percentage of patients in our study sample had evidence of combination therapy use—ranging from 6% with an index combination to 13% with an augmented PAH-specific regimen by the end of follow-up. In contrast, 41% of patients were on two or more PAH medications at the time of enrollment in REVEAL6. Possible explanations for these apparently different treatment patterns include differences in the patient populations and treatment settings: only 14% of REVEAL patients were newly diagnosed and more than half were in New York Heart Association/World Health Organization functional class III or IV6. Patients in the REVEAL registry were enrolled from specialty treatment centers and, because efficacy and safety of combination therapies are still under investigation, some guidelines currently recommended that only expert centers institute combination treatment10. On the other hand, patients in our study could have received treatment at any type of facility.

Some of the study data are comparable to those reported by Angalakuditi et al.16, who conducted another claims data-based study of treatment patterns among patients with PAH. Although the authors used the same data source as this study and the study samples have similar mean age, their patient identification algorithm did not require right heart catheterization and only patients who had index treatment with bosentan or sildenafil were included. The authors identified a higher proportion of combination therapy users (18%) than in our study (6%), but, unlike our study, calcium channel blockers were considered in their analysis of combinations, which might at least partially explain the difference16. The mean counts of PAH-related emergency department visits, ambulatory visits, and inpatient stays were similar between the study performed by Angalakuditi et al.16 and our study, as was the duration of inpatient stays. These counts, which indicate frequent contact with the healthcare system, are consistent with the close follow-up that patients with PAH usually require. The cost estimates from both studies suggest that monthly PAH-related healthcare costs of PAH patients are substantial relative to all-cause costs, and our estimate of a mean of $6617 per patient per month for total healthcare costs appeared to be driven by medical costs. In our analysis, costs associated with drug administration in a hospital or clinic, such as intravenous administration of a prostanoid, are classified as medical costs. This might help to explain the high proportion of total costs attributable to medical costs. In addition, our mean PAH-related cost estimates are ∼$2000 per patient per month greater than those reported by Angalakuditi et al.16, which could be due to the inclusion of patients with index prostanoid medications in our study. These estimates might not reflect the full economic burden of PAH because patients with severe disease might be under-represented.

Consistent with treatment guidelines and previous registry studies, PDE-5 inhibitor and ERA classes were the most commonly used medications for patients with suspected PAH; particularly sildenafil and bosentan. Further comparison between the observed treatment patterns and guideline recommendations is limited, however, because current recommendations for initiating therapy are based on the acute vasoreactivity test result and the patient’s functional class9,10. Our investigation could not incorporate such clinical information because it is not available in the claims data.

The results of this retrospective, claims data-based analysis must be interpreted in the context of several limitations. Our selective guideline-based patient-identification algorithm was intended to find patients with newly-diagnosed PAH, but because real-world clinical practice does not always reflect adherence to clinical guidelines some PAH patients might not have been captured. It is possible that patients with pulmonary hypertension in a classification other than Group 1 who used PAH-specific drugs off-label might have been included in the study sample; the sensitivity analysis of patients who had sildenafil suggested that patients with evidence of having the brand approved for erectile dysfunction were unlikely to represent patients with PAH. The study included only patients with suspected PAH, and thus was not structured for regression analysis. In addition to limitations regarding patient identification, our assessment also lacked clinical information such as reasons for adjusting therapy. Patients may change therapies or adjust their regimen in cases of treatment progression or because of intolerance; without such information the appropriateness of treatment adjustments cannot be assessed. Finally, generalizability is limited to individuals with newly-diagnosed PAH. Only a small number of combination therapy users met study criteria, and the contributions of patients on combination therapy to the overall economic burden of PAH may be under-estimated.

Conclusions

Patients initiating treatment for suspected PAH were likely to be treated with monotherapy consisting of an oral medication such as sildenafil or bosentan. Monotherapy was associated with a high compliance rate. Patients received a close ambulatory follow-up and PAH-related medical costs were substantial relative to all-cause medical costs.

Transparency

Declaration of funding

This study and manuscript preparation were funded by Novartis Pharma, Basel, Switzerland.

Declaration of financial/other relationships

RC and AW were both employees of OptumInsight (formerly Innovus) while the study was conducted. OptumInsight was contracted by Novartis to conduct the study. AC is an employee of Novartis. MLM was Medical Director at PharmaNet/i3 (formerly i3) while the study was conducted, and does not have any financial relationships to disclose.

Acknowledgments

The authors thank Jim Hartje (OptumInsight) for data analysis and programming, Laura Becker (OptumInsight) for assistance with data analysis, Adam Lowy (Novartis) for assistance with the study design, Elizabeth J. Davis, PhD (OptumInsight) for medical writing assistance, and RG McAllister, MD (Executive Director of Medical Affairs at PharmaNet/i3) and Rachel Halpern, PhD (OptumInsight) for thoughtful review of the manuscript.