Hospitalization Among Pulmonary Arterial Hypertension Patients With and Without Connective Tissue Disease Comorbidities Prescribed Oral Selexipag

This study examined hospitalization rate, PAH disease progression, medical costs, and healthcare utilization among PAH patients with and without CTD comorbidities who were prescribed oral selexipag. Historically, PAH treatment appeared less effective in CTD-associated PAH patients compared to IPAH patients [3, 6, 12]. However, the results from this study suggested that risks of all-cause hospitalization, PAH hospitalization, or PAH disease progression, were not statistically significantly different between PAH patients with and without CTD comorbidities among oral selexipag users. The results of this study complement the data that were observed in the GRIPHON post-hoc analysis that showed the treatment effects of oral selexipag for morbidity and mortality were consistent between CTD-associated patients, IPAH patients, and the overall study population. Further, the GRIPHON post hoc analysis looked at CTD-associated PAH based on the CTD subtype specifically patients with PAH-SSc and PAH-SLE were examined. That post hoc analysis showed that despite the differences in CTD subtypes, the treatment benefits such as reducing risk of PAH disease progression and hospitalization by oral selexipag utilization was consistent for the CTD subtypes and other PAH patients without CTD [6, 13]. However, the current study differed from the GRIPHON post hoc analysis in the groups that were compared. In this study, two groups of oral selexipag users were compared since a control group without oral selexipag is assumed to have less severe disease leading to introduction of selection bias (Table 3).

Table 3 Adjusted healthcare resource utilization and costs for CTD-associated PAH patients and PAH patients not associated with CTD who were prescribed oral selexipag

There are not many other studies that have investigated the impact of PAH medication on health outcomes among CTD-associated PAH. Rhee et al. conducted a meta-analysis of 11 RCTs to compare the effect of PAH therapy between IPAH and CTD-associated PAH. They found the effect of PAH treatment was less effective in improving 6-min walk distance and preventing clinical worsening in CTD-associated PAH patients compared to IPAH. However, several trials that were included in this meta-analysis had patients that did not receive background PAH therapies. Since the publication of this meta-analysis, new novel therapies such as oral prostacyclin pathway agents were introduced in the treatment landscape and combination therapy is now regarded as the standard of care in PAH. A recent meta-analysis of 11 RCTs and 19 registries found a similar risk reduction in morbidity and mortality between CTD-associated PAH and the overall PAH population, suggesting a potential benefit from currently available PAH therapies. This meta-analysis included trials of modern therapy to date as well as the more frequent use of combination therapy. In our study, about 86.25% of CTD-associated PAH patients were on combination therapy at baseline. Previous studies have indicated that combination therapy is effective in CTD-associated PAH patients [14, 15]. However, in this present study, we cannot determine the magnitude to which combination therapy helped improved the study outcomes in CTD-associated PAH patients.

In this study, PAH-related hospitalization and PAH disease progression were the primary and secondary outcomes, respectively. These selected outcomes are clinically important to PAH patients because PAH disease progression or hospitalization due to PAH events are potential risk factors for mortality [16]. Unlike the 6-min walk test outcome that was used in Rhee et al. meta-analysis to assess PAH treatment response, the composite PAH disease progression outcome that was measured in this study is potentially less influenced by non-cardiopulmonary manifestations of CTD [6].

In addition to examining clinical outcomes such as hospitalization and PAH disease progression, this study also examined the cost and utilization associated with PAH patients with or without CTD comorbidities who were prescribed oral selexipag. Adjusted all-cause healthcare utilization and PAH-related utilization were similar between the two cohorts; however, PAH patients with CTD were observed to have higher all-cause ER PPPM costs and higher mean total medical PPPM costs compared to PAH patients without CTD comorbidities. One possible explanation for the observed PPPM cost difference, in part, is due to the additional comorbidities that are prevalent in patients with CTD. In our study, PAH patients with CTD comorbidities had approximately three times the proportion of patients with interstitial lung disease compared to PAH patients without CTD comorbidities and may affect the all-cause healthcare PPPM costs. PAH-related costs for PAH patients with CTD comorbidities were higher than PAH patients without CTD comorbidities, but the difference was not statistically significant.

The strength of the study comes from the administrative claims database, which covers multiple providers and physician visits well recorded in claims data as patient consent is not necessary for collecting administrative claims data.

A limitation of the study is the lack of specificity of ICD codes in the World Health Organization PAH clinical classification and PAH etiology. Furthermore, there are no specific ICD codes for PAH and therefore we require all patients in the study to receive at least one PAH medication to increase the specificity of the patient selection for PAH.

Replication of this study utilizing EMR data or hospital derived data, which may include clinical data points such as right heart catheterization, echocardiogram, and hemodynamic results, and radiologic patterns for PAH diagnosis and progression, would further validate findings of this study.

It is also important to note that the ICD-9 codes do not distinguish PAH from CTEPH and therefore patients with CTEPH diagnosis in the baseline were excluded and CTEPH diagnosis in the follow-up was used as a censoring event. However, the impact would be minimal given the time period contributing to patient identification prior to ICD CM code change was short.

Another limitation of the study pertains to those observed in the claims data. The presence of a diagnosis code on a medical claim is not a positive presence of disease. The presence of a claim for a filled prescription does not indicate whether the medication was consumed or that it was taken as prescribed. The lack of completeness of the mortality data in the Optum Clinformatics® DoD database may lead to underrepresentation of the death data in the current study. The clinical and disease-specific parameters not captured in claims data could influence the study outcomes, for e.g., severity of the patients which cannot be determined in the claims data.

The definition of PAH disease progression may vary across different studies, which may result in conflicting information on PAH disease progression. The definition of disease progression used in this study could only capture serious changes in PAH disease progression so results should be interpreted with this consideration. Also, the Optum Clinformatics® database reports a ‘standardized cost’ figure that is related to allowable charges and should not be interpreted as the cost of services or medications. It might have under-represented the costs for commercially insured patients and conversely overestimated costs for Medicare patients with supplemental coverage.

This study did not consider undifferentiated CTD, which could have introduced misclassification of PAH patients in some cases. However, this is usually a small proportion and therefore the impact would be minimal. Further, this study did not examine CTD subtypes and CTD medication use due to small sample size of PAH with CTD cohort. Future studies with sufficient sample could adjust for severity of PAH with CTD patients by CTD subtypes and CTD-related medication use.

This study reported and adjusted for PAH therapies at baseline but did not investigate CTD medications. Such study could provide insight into PAH patients with CTD but since the objective of the study was to compare PAH patients with CTD and PAH patients without CTD this limitation would have had a minimal impact.

Due to small sample size, the analysis may be underpowered to detect small differences between PAH with and without CTD. Interpretation of the results should be made with some caution, especially because adjustment for multiple testing was not performed. Finally, the comparability between the two groups might have been affected due to the discrepancy in the sample size of the groups.

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