Oral Prostacyclin Pathway Agents Used in PAH: A Targeted Literature Review.

Purpose: Pulmonary arterial hypertension (PAH) is a rare and progressive pulmonary vascular disease that can result in right heart failure and death. Oral prostacyclins play an important role in the management of intermediate-low risk PAH. This targeted literature review (TLR) aimed to identify and compare evidence supporting use of oral prostacyclin pathway agents (PPAs: selexipag and oral treprostinil) in intermediate-low risk PAH. Methods: A targeted literature review was conducted. Literature databases (MEDLINE, Embase, and Cochrane reviews) were searched for studies describing clinical practice and treatment outcomes for oral treprostinil and selexipag globally, published in English (2012 to 2022). Electronic searches were supplemented by manual-searches of targeted conferences (2020 to 2022), and reference lists of identified publications were reviewed. One reviewer assessed studies for eligibility. Results: In total, 95 publications met inclusion criteria: 47 full-text articles (selexipag n = 22; oral treprostinil n = 16; selexipag and oral treprostinil n = 9) and 48 conference materials. Selexipag and oral treprostinil target the prostacyclin pathway differently; their label-supporting trials had different primary endpoints (disease progression and hospitalization vs exercise capacity and disease progression), differing baseline therapy (0, 1 or 2 vs 0 or 1 baseline treatments), titration duration and dosing (personalized dose capped at 1600 ug twice daily (BID) vs increasing doses over time with no maximum dose), respectively. While both oral PPAs have demonstrated reduced risk of disease progression, only selexipag showed reduction in hospitalization rates. Oral PPAs have been shown to reduce healthcare costs in real-world clinical practice. This difference is reflected in labeled indications. Conclusion: Given differences in trial- and real-world outcomes, number of prior therapies, and dosing, personalizing the choice of oral PPA is critical to maximizing the benefit for individual patients.

PAH is a condition that causes heart failure. It is important to take medicines to slow down this process. For people with early disease, there are some medicines that can be taken as a tablet rather than as an injection to slow down disease progression. The differences between two of the tablet options ­ selexipag and oral treprostinil, are unclear. We reviewed publications describing how, when and why these medicines are used and how well they work, to improve our understanding of the value of these medicines to people with PAH.

US commercial health plan coverage dynamics in pulmonary arterial hypertension therapies.

BACKGROUND: Health plan coverage is central to patient access to care, especially for rare, chronic diseases. For specialty drugs, coverage varies, resulting in barriers to access. Pulmonary arterial hypertension (PAH) is a rare, progressive, and fatal disease. Guidelines suggest starting or rapidly escalating to combination therapy with drugs of differing classes (phosphodiesterase 5 inhibitors [PDE5is], soluble guanylate cyclase stimulators [sGC stimulators], endothelin receptor antagonists [ERAs], and prostacyclin pathway agents [PPAs]). OBJECTIVE: To assess the variation in commercial health plan coverage for PAH treatments and how coverage has evolved. To examine the frequency of coverage updates and evidence cited in plan policies. METHODS: We used the Tufts Medical Center Specialty Drug Evidence and Coverage database, which includes publicly available specialty drug coverage policies. Overall, and at the drug and treatment class level, we identified plan-imposed coverage restrictions beyond the drug's US Food and Drug Administration label, including step therapy protocols, clinical restrictions (eg, disease severity), and prescriber specialty requirements. We analyzed variation in coverage restrictiveness and how coverage has changed over time. We determined how often plans update their policies. Finally, we categorized the cited evidence into 6 different types. RESULTS: Results reflected plan coverage policies for 13 PAH drugs active between August 2017 and August 2022 and issued by 17 large US commercial health plans, representing 70% of covered lives. Coverage restrictions varied mainly by step therapy protocols and prescriber restrictions. Seven plans had step therapy protocols for most drugs, 9 for at least one drug, and 1 had none. Ten plans required specialist (cardiologist or pulmonologist) prescribing for at least one drug, and 7 did not. Coverage restrictions increased over time: the proportion of policies with at least 1 restriction increased from 38% to 73%, and the proportion with step therapy protocols increased from 29% to 46%, with generics as the most common step. The proportion of policies with step therapy protocols increased for every therapy class with generic availability: 18% to 59% for ERAs, 33% to 77% for PDE5is, and 33% to 43% for PPAs. The proportion of policies with prescriber requirements increased from 24% to 48%. Plans updated their policies 58% of the time annually and most often cited the 2019 CHEST clinical guidelines, followed by randomized controlled trials. CONCLUSIONS: Plan use of coverage restrictions for PAH therapies increased over time and varied across both drugs and plans. Inconsistency among health plans may complicate patient access and reduce the proportion who can persist on PAH treatments.

Factors associated with discontinuation of treatment for pulmonary arterial hypertension in the United States.

Information on factors leading to pulmonary arterial hypertension (PAH) treatment discontinuation is limited. This study analyzed 12,902 new PAH medication users to identify predictors of treatment discontinuation. Treatment by accredited pulmonary hypertension centers and combination therapy with PAH agents from different classes were less likely to result in discontinuation.

Economic Burden of Delayed Diagnosis in Patients with Pulmonary Arterial Hypertension (PAH).

BACKGROUND: The aim of this study was to assess health care resource utilization (HRU) and costs associated with delayed pulmonary arterial hypertension (PAH) diagnosis in the United States. METHODS: Eligible adults with newly diagnosed PAH from Optum's de-identified Clinformatics® Data Mart Database (2016-2021) were assigned to mutually exclusive cohorts based on time between first PAH-related symptom and first PAH diagnosis (i.e., ≤12 months' delay, >12 to ≤24 months' delay, >24 months' delay). All-cause HRU and health care costs per patient per month (PPPM) were assessed during the first year following diagnosis and compared across cohorts using regression analysis adjusted for baseline covariates. Sensitivity analyses were conducted to assess outcomes during all available follow-up post-diagnosis. RESULTS: Among 538 patients (mean age: 65.6 years; 60.6% female), 60.8% had ≤12 months' delay, 23.4% had a delay of >12 to ≤24 months, and 15.8% had >24 months' delay. Compared with ≤12 months, delays of >12 to ≤24 months and >24 months were associated with increased hospitalizations (incidence rate ratio [95% confidence interval]: 1.40 [1.11-1.71] vs 1.71 [1.29-2.12]) and outpatient visits (1.17 [1.06-1.30] vs 1.26 [1.08-1.41]). Longer delays were also associated with more intensive care unit (ICU) stays and 30-day readmissions. Diagnosis delays translated into excess costs PPPM of US$3986 [1439-6436] for >12 to ≤24 months and US$5366 [2107-8524] for >24 months compared with ≤12 months' delay; increased hospitalization costs (US$3248 [1108-5135] and US$4048 [1401-6342], respectively) being the driver. Sensitivity analyses yielded similar trends. CONCLUSIONS: Delayed PAH diagnosis is associated with significant incremental economic burden post-diagnosis, driven by hospitalizations including ICU stays and 30-day readmissions, highlighting the need for increased awareness and a potential benefit of earlier screening.

Impact of selexipag use within 12 months of pulmonary arterial hypertension diagnosis on hospitalizations and medical costs: A retrospective cohort study.

BACKGROUND: Oral selexipag, a prostacyclin pathway agent (PPA), is effective in patients with pulmonary arterial hypertension (PAH). The objective of this study is to assess the impact of initiating oral selexipag within 12 months of diagnosis on health outcomes. METHODS: This retrospective cohort study used data from Optum's de-identified Clinformatics® Data Mart Database. PAH patients between 1 October 2015 and 30 September 2019 were included. Patients were also required to have received PAH medication within 12 months of their initial diagnosis. Study groups included patients who initiated selexipag within 12 months of PAH diagnosis (SEL ≤ 12) and those who did not initiate any PPA within 12 months of PAH diagnosis (No PPA ≤ 12). Inverse probability of treatment weighting was used to remove potential confounding between groups. Cox and Poisson regression models were used to compare hospitalization and disease progression. Generalized linear model with gamma distribution and log link was used to compare costs. RESULTS: SEL ≤ 12 had lower rate of all-cause hospitalizations (rate ratio: 0.76, 95% confidence interval [CI]: 0.60, 0.96) versus no PPA ≤ 12, but no differences in PAH-related hospitalization rate (rate ratio: 1.03, 95% CI: 0.79, 1.33) or risk of disease progression (hazard ratio: 1.01, 95% CI: 0.71, 1.44). SEL ≤ 12 incurred lower all-cause (mean difference: -$23 623; 95% CI: -35 537, -8512) and PAH-related total medical costs (mean difference: -$12 927; 95% CI: -19 559, -5679) versus no PPA ≤ 12. CONCLUSION: Selexipag initiation within 12 months of PAH diagnosis demonstrated reductions in all-cause hospitalization rate and medical costs.

Hospitalization-related costs associated with oral agents targeting the prostacyclin pathway for pulmonary arterial hypertension.

AIMS: Pulmonary arterial hypertension (PAH) is a rare, progressive, and ultimately fatal form of the broader condition pulmonary hypertension. ESC/ERS guidelines recommend therapy targeting the prostacyclin pathway for patients not achieving low-risk mortality status. Currently, only oral selexipag (OS) and oral treprostinil (OT) have this mechanism of action and are available in the United States (US). A recent database analysis has shown significantly lower hospitalization risk for patients treated with OS versus OT. Nevertheless, differences in hospitalization and treatment costs among PAH patients taking oral prostacyclin pathway agents (PPAs) in the US healthcare system remain unclear. This study aims to estimate the difference in costs for patients who achieve a stable maintenance dose from a US payer perspective. MATERIALS AND METHODS: We developed a cost calculator including direct medical costs from the US third-party payer perspective to estimate PAH-related hospitalizations and costs associated with oral PPA use over 2 years, in a hypothetical US payer plan with 1 million members. The treatment-eligible population was estimated from real-world epidemiological data. Treatment-specific hospitalizations were estimated from a study using the Optum Clinformatics administrative claims database. Influence of each model parameter was tested in one-way sensitivity analyses (OWSA), while scenario analysis tested the impact of key assumptions. RESULTS: For 78 PAH patients included in the model, the base case scenario estimated total costs of $46,736,768 with 98 PAH-related admissions for OS, and total costs of $60,113,620 and 161 PAH-related admissions over 2 years for OT. Using OS was associated with 22.3% cost reduction and 39.1% hospitalizations averted; the number of patients needed treated with selexipag to avoid one hospital admission was 1.23. OWSA indicated medication cost was the most sensitive parameter, followed by population parameters. LIMITATIONS AND CONCLUSIONS: OS use over 2 years would result in lower total, drug, and hospitalization-related costs compared with OT, thus providing financial savings for payers.

Impact of the COVID-19 pandemic on care disruptions, outcomes, and costs in patients receiving pulmonary arterial hypertension-specific therapy in the United States of America: An observational study.

Regular expert follow-up, risk assessment, and early therapeutic intervention minimize worsening of pulmonary arterial hypertension (PAH). COVID-19 lockdown measures were challenging for chronic disease management. This retrospective, longitudinal analysis used US claims data (January 12, 2016 to September 11, 2021) for patients treated with PAH-specific medication to compare in-person outpatient and specialist visits, telemedicine visits, and PAH-related tests during 6-month assessment periods pre- and immediately post-COVID-19. Hospitalizations, costs, and outcomes were compared in patients with and without care disruptions (no in-person or telemedicine outpatient visits in immediate post-COVID-19 period). Patients in the immediate post-COVID-19 (N = 599) versus the pre-COVID-19 period (N = 598) had fewer in-person outpatient visits (mean 1.27 vs. 2.12) and in-person specialist visits (pulmonologist, 22.9% vs. 37.0% of patients; cardiologist, 27.5% vs. 33.8%); and more telemedicine visits (mean 0.45 vs. 0.02). In the immediate post-COVID-19 period, patients were less likely to have a PAH-related test versus the pre-COVID-19 period (incidence rate ratio: 0.700; 95% confidence interval: 0.615-0.797), including electrocardiograms (41.7% vs. 54.2%) and 6-minute walk distance tests (16.2% vs. 24.9%). In the immediate post-COVID-19 period, 48 patients had care disruptions and, in the following year, required more hospital days than those without care disruptions (N = 240) (median 10 vs. 5 days in total) and had higher overall hospitalization costs (median US$34,755 vs. US$20,090). Our findings support the need for minimizing care disruptions to potentially avoid incremental post-disruption healthcare utilization and costs among patients with serious chronic diseases such as PAH.

Real-World Treatment Patterns Among Patients with Connective Tissue Disorder-Related Pulmonary Arterial Hypertension in the United States: A Retrospective Claims-Based Analysis.

INTRODUCTION: Connective tissue disorders (CTDs) are the most frequent diseases associated with pulmonary arterial hypertension (PAH). Despite advances in treatment, the prognosis of CTD-related PAH remains poor. To help identify areas for improvement in the management of CTD-related PAH, this study assessed real-world PAH treatment patterns in this population in the US. METHODS: Eligible adult patients with PAH initiated on a PAH treatment (index date: 1st initiation date) were identified from Optum's de-identified Clinformatics® Data Mart Database (10/01/2015-09/30/2021) and categorized into mutually exclusive cohorts (CTD + PAH; PAH) based on the presence of CTD diagnosis claims. Treatment patterns were assessed from the index date to the earliest of death or end of continuous insurance eligibility, or data availability. Treatment persistence was assessed using Kaplan-Meier analysis. RESULTS: A total of 4751 patients were included (CTD + PAH: n = 728, mean follow-up of 18.8 months; PAH: n = 4023, mean follow-up of 19.6 months). For both cohorts, the most common first treatment regimens were sildenafil (CTD + PAH: 38.7%; PAH: 51.5%), tadalafil (10.0%; 9.4%), and macitentan (8.1%; 5.4%) monotherapy; these were also the most frequent agents included in any of the first 3 treatment regimens. Combination therapy was more frequent in the CTD + PAH versus PAH cohort (any regimen: 40.9% vs. 27.2%; 1st treatment regimen: 26.9% vs. 18.5%; 2nd: 52.8% vs. 42.0%; 3rd: 55.2% vs. 48.5%). Treatment persistence was similar across cohorts and the first three treatment regimens, with persistence rates ranging from 42.6 to 49.7% at 12 months. CONCLUSIONS: Treatment patterns were generally similar between the CTD + PAH and PAH cohorts, although combination therapy was more frequent in the CTD + PAH cohort. Both cohorts may benefit from broader use of all available PAH treatment classes, including combination therapy. Considering the life-threatening nature of PAH, our findings also highlight the need to address the low persistence rates with PAH therapies regardless of etiology.

Characteristics of patients with pulmonary arterial hypertension from an innovative, comprehensive real-world patient data repository.

Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease. PAH registries provide real-world data that complement clinical trial data and inform treatment decisions. The TRIO comprehensive, integrated patient data repository (TRIO CIPDR), is an innovative US repository capturing data on contemporary patients diagnosed with pulmonary hypertension and receiving US Food and Drug Administration-approved PAH therapies. This repository uniquely combines clinical data from electronic medical records with the ability to track drug-prescription and drug-dispensing characteristics, and includes 946 adult patients with PAH (data collected January 2019 to December 2020) enrolled from nine representative US specialist tertiary care centers. Potentially eligible patients were identified based on dispensing data from specialty pharmacies. Hemodynamic and clinical data, as well as dispensing information on prescribed PAH medications, were provided by tertiary centers. At enrollment, 75% of patients were female, 67% were White, median age at PAH diagnosis was 53 years (median time from diagnosis to enrollment was 5 years), and 37% were obese. Comorbidity profiles were as expected for a PAH population, although the proportion with atrial fibrillation (34%) was higher than expected. Overall, 38% of patients had idiopathic PAH and 30% had connective tissue disease-related PAH. Among 917 patients receiving PAH-specific therapy, 40% were on monotherapy, 43% on dual therapy, and 17% on triple therapy. Longitudinal data from this repository will allow tracking of the PAH treatment journey in relation to clinical characteristics and outcomes.

A claims-based, machine-learning algorithm to identify patients with pulmonary arterial hypertension.

Many patients with pulmonary arterial hypertension (PAH) experience substantial delays in diagnosis, which is associated with worse outcomes and higher costs. Tools for diagnosing PAH sooner may lead to earlier treatment, which may delay disease progression and adverse outcomes including hospitalization and death. We developed a machine-learning (ML) algorithm to identify patients at risk for PAH earlier in their symptom journey and distinguish them from patients with similar early symptoms not at risk for developing PAH. Our supervised ML model analyzed retrospective, de-identified data from the US-based Optum® Clinformatics® Data Mart claims database (January 2015 to December 2019). Propensity score matched PAH and non-PAH (control) cohorts were established based on observed differences. Random forest models were used to classify patients as PAH or non-PAH at diagnosis and at 6 months prediagnosis. The PAH and non-PAH cohorts included 1339 and 4222 patients, respectively. At 6 months prediagnosis, the model performed well in distinguishing PAH and non-PAH patients, with area under the curve of the receiver operating characteristic of 0.84, recall (sensitivity) of 0.73, and precision of 0.50. Key features distinguishing PAH from non-PAH cohorts were a longer time between first symptom and the prediagnosis model date (i.e., 6 months before diagnosis); more diagnostic and prescription claims, circulatory claims, and imaging procedures, leading to higher overall healthcare resource utilization; and more hospitalizations. Our model distinguishes between patients with and without PAH at 6 months before diagnosis and illustrates the feasibility of using routine claims data to identify patients at a population level who might benefit from PAH-specific screening and/or earlier specialist referral.

Predicting Risk of 1-Year Hospitalization Among Patients with Pulmonary Arterial Hypertension.

INTRODUCTION: US claims-based analyses emphasize the substantial hospitalization burden of patients with pulmonary arterial hypertension (PAH) and the significant need for improved monitoring and more timely interventions. A claims-based predictive model may be useful to assist healthcare providers and payers in identifying patients with PAH at increased hospitalization risk. To address this aim, we constructed statistical models using baseline patient variables available in administrative healthcare claims to predict patients' risk for all-cause and PH-related hospitalization within 1 year of initiating ≥ 1 PAH indicated medication. METHODS: Adult patients with PAH who newly initiated ≥ 1 PAH indicated medication were selected from the MarketScan Commercial and Medicare Supplemental databases (January 1, 2009-January 31, 2019). Cox regression models were built with a randomly selected training set and evaluated using a validation set of remaining patients. Predictive variables for the models were selected in three steps: clinical knowledge, univariate analysis, and backward stepwise selection. RESULTS: Within 1 year of initiating ≥ 1 PAH indicated medication, 1502/3872 (38.8%) had an all-cause hospitalization and 950/3872 (24.5%) had a pulmonary hypertension (PH)-related hospitalization. Predictive risk factors for all-cause hospitalization were Quan-Charlson Comorbidity Index (CCI) score 2-3 [hazard ratio (HR) 1.229; P = 0.038] and ≥ 4 (HR 1.531; P < 0.001), claims-based frailty index (CFI) score > 1 (highest frailty level; HR 1.301; P = 0.018), hemoptysis (HR 1.254; P = 0.016), malaise/fatigue (HR 1.150; P = 0.037), history of PH-related hospitalization (HR 1.171; P = 0.011), non-PH-related ER visit (HR 1.713; P = 0.014), and higher non-PH-related outpatient visit cost (HR 1.069; P < 0.001). Predictive risk factors for PH-related hospitalization were female sex (HR 1.264; P = 0.004), Quan-CCI score ≥ 4 (HR 1.408; P = 0.008), portal hypertension (HR 1.565; P = 0.019), CFI score > 1 (HR 1.522; P = 0.002), dyspnea (HR 1.259; P = 0.023), and history of PH-related hospitalization (HR 1.273; P = 0.002). CONCLUSIONS: The US claims-based predictive models showed acceptable performance to predict 1-year hospitalization among patients with PAH.

Economic burden of illness among patients with pulmonary arterial hypertension (PAH) associated with connective tissue disorders (CTD).

Pulmonary arterial hypertension (PAH) is commonly associated with connective tissue disorders (CTDs). This study provides a contemporary assessment of the economic burden of CTD + PAH and PAH in the United States. Eligible adult patients identified from Optum's deidentified Clinformatics® Data Mart Database (10/01/2015-09/30/2021) were classified into mutually exclusive cohorts based on recorded diagnoses: (1) CTD + PAH, (2) PAH, (3) CTD, (4) control without CTD/PAH. The index date was a randomly selected diagnosis date for PAH (CTD + PAH, PAH cohorts) or CTD (CTD cohort), or a random date (control cohort). Entropy balancing was used to balance characteristics across cohorts. Healthcare costs and healthcare resource utilization (HRU) per patient per month (PPPM) were assessed for ≤12 months postindex and compared among balanced cohorts. A total of 552,900 patients were included (CTD + PAH: n = 1876; PAH: n = 8177; CTD: n = 209,156; control: n = 333,691). Average total all-cause costs were higher for CTD + PAH than PAH cohort ($16,854 vs. $15,686 PPPM; p = 0.02); both cohorts incurred higher costs than CTD and control cohorts ($4476 and $2170 PPPM; all p < 0.001). Average HRU PPPM was similar between CTD + PAH and PAH cohorts (inpatient stay: 0.15 vs. 0.15, outpatient visits: 4.23 vs. 4.11; all p > 0.05), while CTD and control cohorts incurred less HRU (inpatient stay: 0.07 and 0.03, outpatient visits: 2.67 and 1.69; all p < 0.001). CTD + PAH and PAH are associated with a substantial economic burden. The incremental burden attributable to PAH versus the general population and patients with CTD without PAH highlights significant unmet needs among PAH patients.

Comparative evaluation of costs and healthcare resource utilization of oral selexipag versus inhaled treprostinil or oral treprostinil in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH), a rare vasculopathy progressively leading to right heart failure and death, is associated with considerable economic burden. Oral prostacyclin pathway agents (PPAs) like selexipag and treprostinil address an underlying PAH pathway, yet are often under-utilized. Data on head-to-head cost comparison of various PPAs is lacking. METHODS: In this retrospective study using a large health claims database, we compared the per-patient-per-year (PPPY) costs and healthcare resource utilization (HRU) among PAH patients taking either oral selexipag, inhaled treprostinil or oral treprostinil in the United States between July 2015 and March 2020. Patients with ≥1 prescription for one of the drugs of interest, ≥1 in-patient pulmonary hypertension (PH) diagnosis, or ≥ 2 outpatient PH diagnoses were included in this study. Baseline differences between the three groups were adjusted using an inverse probability of treatment weighting approach. 411 patients were selected for the final study cohorts. RESULTS: All-cause hospitalization costs were highest for oral treprostinil ($39,983) compared to oral selexipag ($20,635) and inhaled treprostinil ($16,548; p = .037). Total PAH-related medical costs were 40% lower for patients on oral selexipag compared to patients on oral and inhaled treprostinil ($24,351 vs. $40,398 and $40,339, respectively; p = .006). PAH-related outpatient visits were lowest for patients on oral selexipag (14 PPPY visits) compared to oral treprostinil (16 PPPY visits) and inhaled treprostinil (22 PPPY visits; p = .001). CONCLUSIONS: Compared to oral and inhaled treprostinil, oral selexipag may incur lower medical costs and reduce PAH related outpatient visits for patients with PAH.

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

INTRODUCTION: Patients with connective tissue disorders (CTD) and pulmonary arterial hypertension (PAH) have a poorer prognosis than those with other PAH etiologies. This study assessed the impact of CTD on healthcare outcomes among PAH patients with and without CTD comorbidities that were treated with oral selexipag. METHODS: The study utilized Optum's de-identified Clinformatics® Data Mart Database (2007-2021) from January 1, 2014 to June 30, 2019, and identified patients with PAH without CTD and PAH with CTD treated with oral selexipag. Patients had ≥ 12-month baseline period with no requirement for a minimum follow-up period. Patients were followed until any of the following events: discontinuation of oral selexipag, or health plan disenrollment, or death, or presence of a diagnosis claim for CTEPH, or study end date, whichever occurred first. PAH-related hospitalizations, PAH disease progression, and healthcare utilizations and costs were assessed in the follow-up period. The Cox proportional hazards model was used to evaluate the time to hospitalization and generalized linear models were used to examine healthcare costs and utilization between the two cohorts. RESULTS: In the analysis, 237 PAH without CTD, and 80 PAH patients with CTD comorbidities prescribed oral selexipag were included. The PAH without CTD comorbidities cohort was older (65 vs. 63 years old), had proportionately less females (72 vs. 83%), and higher comorbidity burden than PAH with CTD comorbidities (mean CCI index 3 vs. 2). After adjusting for potential confounders, the risk for PAH-related hospitalization (hazard ratio (HR) 1.13, p value 0.641), all-cause hospitalization (HR 1.09, p value: 0.765), and PAH disease progression (HR 1.14, p value 0.522) between the two cohorts were similar. After adjusting for baseline demographic and clinical characteristics, PAH with CTD comorbidities incurred higher total mean all-cause PAH-related medical care costs compared to PAH without CTD comorbidities. CONCLUSIONS: In this real-world study, the risk of hospitalization and PAH disease progression were similar between the two cohorts who received oral selexipag. The results from this study corroborate findings of the GRIPHON post hoc analysis of PAH-associated CTD patients and support oral selexipag use in PAH-CTD patients.

Real-World Persistence and Time to Next Treatment With Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Including Patients at High Risk for Atrial Fibrillation or Stroke.

BACKGROUND: Atrial fibrillation (AF) is a recognized adverse consequence associated with all Bruton's tyrosine kinase inhibitors used to treat chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); however, real-world time to discontinuation (TTD) and time to next treatment (TTNT) of CLL/SLL patients with a high baseline AF/stroke risk remain unknown. MATERIALS AND METHODS: Patients with CLL/SLL from a nationwide electronic health record-derived database (February 12, 2013-January 31, 2021) initiating first-line (1L) or second or later-line (2L+) treatment with ibrutinib or other regimens on or after February 12, 2014 (index date) were analyzed. Kaplan-Meier survival analysis was used to assess TTD and TTNT among all patients, patients with high AF risk (CHARGE-AF risk score ≥10.0%), and patients at high risk of stroke (CHA2DS2-VASc risk score ≥3 [females] or ≥2 [males]). RESULTS: In 1L/2L+, 2190/1851 patients received ibrutinib and 4388/4135, were treated with other regimens. Median TTD for ibrutinib was similar regardless of AF/stroke-related risk (1L: all patients, 15.7 months; high AF risk, 11.7 months; high stroke risk, 13.7 months; similar results in 2L+). Median TTNT was significantly longer for ibrutinib vs. other regimens (1L: not reached vs. 45.9 months; 2L+: not reached vs. 23.6 months; both P < .05), including among those with high AF/stroke risk. TTNT was similar between all patients and high-risk cohorts in 1L and 2L+ (all P > .05). CONCLUSION: This study highlights that elevated baseline AF/stroke-related risk does not adversely impact TTD and TTNT outcomes associated with ibrutinib use. Additionally, TTNT was significantly longer for patients treated with ibrutinib vs. other regimens.

The direct and indirect health care costs associated with pulmonary arterial hypertension among commercially insured patients in the United States.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, progressive, and fatal disease associated with considerable overall clinical and economic burden. Although the direct health care costs of PAH have been well described, there are few data regarding indirect costs and productivity loss associated with PAH. Patient data were assessed until the earliest of death, end of full-time employment, end of continuous enrollment, or end of study period. OBJECTIVES: To update data on the direct burden and address the knowledge gap regarding the indirect burden associated with PAH. METHODS: This is a retrospective case-control study with prevalent and incident patients with PAH aged 18-64 years identified from the MarketScan Commercial and Health and Productivity management datasets during the identification period (January 1, 2016, to November 30, 2018). Patients were required to have continuous enrollment for 12 months or longer from the baseline period and 1 month or longer from the follow-up (post-index) period. Among patients with PAH (cases), the first observed PAH diagnosis claim date during the identification period was the index date. Patients without PAH (controls) were selected and assigned a random index date during the same period. Controls were matched 1:1 by age, sex, and region to prevalent and incident PAH cases. Per patient per month (PPPM), all-cause health care resource utilization, costs, and short-term disability (STD) were examined for cases and controls during the follow-up period. Multivariable analysis was performed using the generalized linear model to determine the adjusted direct and indirect health care utilization and costs. RESULTS: A total of 1,293 prevalent and 455 incident patients with PAH were identified. During the follow-up period, prevalent patients with PAH had significantly higher total mean all-cause health care costs ($9,915 vs $359, P < 0.0001) and inpatient length of stay (0.63 vs 0.02 days, P < 0.0001) PPPM as compared with controls. Prevalent patients with PAH had significantly longer STD (6.0 vs 1.5 days, P < 0.0001) and higher STD-related costs ($1,226 vs $277, P < 0.0001) PPPM as compared with controls. Incident patients with PAH had significantly higher total mean all-cause health care costs ($9,353 vs $336, P < 0.0001) and inpatient length of stay (0.92 vs 0.01 days, P < 0.0001) PPPM as compared with controls. Incident patients with PAH also had longer STD (8.1 vs 1.5 days, P < 0.0001) and higher STD-related costs ($1,706 vs $263, P < 0.0001), as compared with controls. CONCLUSIONS: This study showed that incident and prevalent patients with PAH had significantly higher direct and indirect health care resource utilization and costs as well as productivity loss compared with patients without PAH. DISCLOSURES: Ms Ogbomo and Mr Mallampati were paid employees of STATinMED Research at the time of study completion; STATinMED Research is a paid consultant to Janssen Scientific Affairs, LLC. Drs Tsang and Panjabi are employees of Janssen Scientific Affairs LLC, a subsidiary of Johnson and Johnson, the study sponsor.

Development and evaluation of a predictive algorithm for unsatisfactory response among patients with pulmonary arterial hypertension using health insurance claims data.

OBJECTIVE: This study aimed to develop and validate a predictive algorithm for unsatisfactory response to initial pulmonary arterial hypertension (PAH) therapy using health insurance claims. METHODS: Adult patients with PAH initiated on a first PAH therapy (index date) were identified from Optum's de-identified Clinformatics Data Mart Database (1/1/2010-12/31/2019). A random survival forest algorithm was developed using patient-month data and predicted the "survival function" (i.e. risk of not having unsatisfactory response) over time. For each patient-month observation, risk factors were assessed in the 12 months prior. Unsatisfactory response was defined as the first instance of (1) new PAH therapy, (2) PAH-related hospitalization or emergency room visit, (3) lung transplant or atrial septostomy, (4) PAH-related death or (5) chronic oxygen therapy initiation. To facilitate use in clinical practice, a simplified risk score was also developed based on a linear combination of the most important risk factors identified in the algorithm. RESULTS: In total, 4781 patients were included (median age = 69.0 years; 58.6% female). Over a median follow-up of 14.0 months, 3169 (66.3%) had an unsatisfactory response. The most important risk factors included in the algorithm were healthcare resource use (i.e. PAH-related outpatient visits, pulmonologist visits, cardiologist visits, all-cause hospitalizations), time since first PAH diagnosis, time since index date, Charlson Comorbidity Index, dyspnea, and age. Predictive accuracy was good for the full algorithm (C-statistic: 0.732) but was slightly lower for the simplified risk score (C-statistic: 0.668). CONCLUSION: The present claims-based algorithm performed well in predicting time to unsatisfactory response following initial PAH therapy.

Real-world evidence for carfilzomib dosing intensity on overall survival and treatment progression in multiple myeloma patients.

INTRODUCTION: Carfilzomib dosing as a single agent or in combination with dexamethasone (Kd) has evolved from the initial 27 mg/m2 twice-weekly (legacy dose), to more recently approved doses of 56 mg/m2 twice-weekly and 70 mg/m2 once-weekly (optimized doses). The objective of this study was to evaluate the overall survival (OS), and time to next treatment (TTNT) among multiple myeloma patients treated with Kd optimized vs legacy doses. METHODS: A retrospective analysis of patients receiving Kd between 01/01/2013-07/31/2017 was conducted using IQVIA's oncology electronic medical records database. Kd dose was estimated based on body surface area. OS was measured from the Kd-initiation date until death. TTNT was defined as the time from Kd-initiation until the start of subsequent treatment. Kaplan-Meier analysis and Cox models were used to evaluate OS and TTNT. RESULTS: Of the 1,469 patients evaluated, 129 (8.8%) received optimized dose and 1,340 (91.2%) received legacy dose. Risk of mortality was 64% lower for patients receiving the optimized doses (HR: 0.36, 95% CI: 0.178-0.745). Patients receiving the optimized doses had significantly longer TTNT compared to patients receiving the legacy dose (median TTNT: 17.5 months [95% CI: 14.8-NE] and 13.2 months, [95% CI: 12.4-14.4], respectively; p = 0.023), and 33% lower risk of progressing to the subsequent treatment (HR: 0.67, 95% CI: 0.48-0.93). CONCLUSIONS: Patient outcomes could be improved if eligible MM patients are treated with the optimized, recently approved Kd doses (56 mg/m2 twice-weekly and 70 mg/m2 once-weekly).

Real-World Analysis of Treatment Patterns Among Hospitalized Patients with Pulmonary Arterial Hypertension.

INTRODUCTION: Hospitalization is an important clinical factor associated with survival and rehospitalization in patients with pulmonary arterial hypertension (PAH). Thus, this study examined treatment patterns before and after hospitalization in the US-specific population. METHODS: Adult PAH patients in the United States were identified using the Optum® Clinformatics® database from January 1, 2014, to June 30, 2019, and were required to have continuous health plan enrollment for at least 6 months prior to the first (index) hospitalization through at least 90 days post-discharge. Baseline patient characteristics were evaluated from 6 months prior to through the index hospitalization. PAH treatment patterns were examined from 30 days pre-index admission (pre-hospitalization) and 90 days post-index hospital discharge (post-hospitalization), and stratified by therapy type: monotherapy, double- or triple-combination therapy, or no PAH therapy. RESULTS: A total of 3116 hospitalized patients with PAH met selection criteria. The mean age and Charlson comorbidity index score were 68.1 years and 5.1, respectively. In the pre- and post-hospitalization periods (all-cause), respectively, patients prescribed monotherapy were most common (from 64.8% pre- to 51.9% post-hospitalization), followed by patients with no evidence of PAH therapy (from 14.6 to 28.5%). Among PAH-related hospitalizations, patients with monotherapy were also most common (from 60.8% pre- to 49.1% post-hospitalization), followed by patients with no evidence of PAH therapy (from 10.0 to 22.8%). The majority of patients with all-cause hospitalizations (72.8%) had no therapy modification; 20.0% de-escalated therapy (including 15.0% from monotherapy to no therapy) and 6.1% escalated therapy (including 2.2% from no therapy to monotherapy and 3.2% from monotherapy to double or triple therapy). CONCLUSION: Inpatient admissions did not appear to drive changes in PAH therapy management, as monotherapy predominated, and most patients had no therapy modification within 90 days of a hospitalization. These results warrant future research to understand the reasons behind the limited treatment intensification observed and the impact of post-hospitalization optimization on clinical and economic outcomes.

Health-Related and Economic Burden Among Family Caregivers of Patients with Acute Myeloid Leukemia or Hematological Malignancies.

INTRODUCTION: Acute myeloid leukemia (AML) is associated with lower survival and greater unmet need compared with some other hematologic malignancies (HMs). Despite differences in acuteness between AML and other HMs, the burden of family caregivers (FCs) of patients with these malignancies offer similar patient experiences. A targeted literature review was conducted to explore FC burden of patients with AML and HM with and without hematopoietic stem cell transplant (HSCT). Instruments to measure and interventions to address FC burden were identified. METHODS: Studies on economic burden and compromised health-related quality of life (HRQoL) associated with FC burden, family affairs, and childcare from 1 January 2010 to 30  June 2019 were identified through database and hand searches. Published English articles on randomized controlled trials or standardized qualitative or quantitative observational studies were included. FCs were those in close familial proximity to the patient (i.e., spouse, parents, children, relatives, other family members, significant others). RESULTS: Seventy-one publications were identified (AML, n = 3; HM, n = 29; HSCT, n = 39). Predominant burden categories included humanistic (n = 33), economic (n = 17), and interventions (n = 22); one study was classified as humanistic and economic. FCs lack sufficient resources to manage stressors and experience negative psychological, behavioral, and physiological effects. FCs of patients with HMs reported post-traumatic stress disorder, significant sleep problems, moderate-to-poor HRQoL, and negative impacts on family relationships. Instruments designed to measure caregiver burden were generic and symptom-specific. Educational, expressional, and self-adjustment interventions were used to improve FC burden. CONCLUSION: Findings indicate a need for additional research, public health approaches to support FCs, and effective interventions to address FC burden. Minimizing FC burden and improving quality of life may reduce the overall healthcare service use and allow FCs to more effectively fulfill caregiver tasks. Support systems to alleviate caregiver burden may create reinforced integrators, thus positively affecting quality of life and possibly the outcomes of patients.