Questions?

REQUEST A MEDICAL SCIENCE LIAISON (MSL)

Questions?

REQUEST A MEDICAL SCIENCE LIAISON (MSL)

A Retrospective Database Analysis

Comparative Effectiveness of UPTRAVI® and Oral Treprostinil on Hospitalization in Patients With PH in the US1

UPTRAVI® WAS ASSOCIATED WITH A 47% RELATIVE RISK REDUCTION OF FIRST PAH-RELATED HOSPITALIZATION COMPARED WITH ORAL TREPROSTINIL IN A RETROSPECTIVE CLAIMS ANALYSIS1

Objective

Compare the effects of oral treprostinil with UPTRAVI® on PAH-related hospitalization among patients with PAH based on a retrospective claims database analysis.

Methods

Retrospective claims analysis of the Optum® Clinformatics® Data Mart database containing both medical and pharmacy administrative claims for privately insured US patients.*

  • A multivariable Cox hazard regression model was used to compare time to first PAH-related hospitalization for oral treprostinil vs UPTRAVI®, adjusting for age, gender, geographic region, insurance type, Charlson comorbidity score, baseline PAH medication, certain comorbidities, and baseline inpatient and outpatient visits

Outcome measures

The primary outcome was PAH-related hospitalization‡ with a PH diagnosis code at any position in the medical claim.

Study design

Patients initiated UPTRAVI® or oral treprostinil between the identification period of January 1, 2015, and September 30, 2017.

Retrospective claims analysis desktop study design

Patient selection

Inclusion criteria included the following:

  • Age ≥18 years
  • Continuous enrollment with ≥1 medical claim with ICD diagnosis code for PH† in the baseline period of ≥6 months prior to the index date
  • New initiation of UPTRAVI® or oral treprostinil; could not have prior oral PPA treatment in the 6 months before index date
  • Could not switch oral PPA during the study period
  • Continuous treatment based on prescription claim with subsequent claim ≤45 days following the end of the days’ supply of the previous claim

Study limitations and considerations

  • This retrospective claims analysis compared risk of PAH-related hospitalization and does not assess or compare product safety or efficacy. There have been no head-to-head clinical trials comparing the efficacy or safety of UPTRAVI® and oral treprostinil. No direct evaluation of comparative clinical profiles can be made
  • Due to the limitations, it is not possible to draw firm conclusions regarding causality of the association found in this study. Controlled studies are recommended to confirm findings
  • Results should be considered as hypothesis generating and should not be taken as the basis for influencing clinical practice
  • This research was sponsored by Actelion Pharmaceuticals US, Inc., a Janssen Pharmaceutical Company. The sponsor was involved in the data analysis and interpretation, funded medical writing and editorial support to the authors, and was involved in the decision to publish the finished manuscript
  • Prevalence of comorbidities and PAH diagnosis were obtained from administrative claims data that have not been clinically validated. Administrative claims do not provide information on whether the prescriptions were filled and taken as prescribed
  • There are no unique ICD-9-CM or ICD-10-CM codes for PAH. Both coding systems have a diagnostic code for primary PH, which corresponds to idiopathic PAH in the current PAH classification. However, they have no codes that differentiate other PAH subgroups from non-PAH forms of PH. Since patients were identified based on the diagnosis code for PH, there may be an unknown percentage of non-PAH patients included in the study
  • Patients were excluded from switching between oral treprostinil and UPTRAVI®
  • This study included US patients who are privately insured, thus generalizability of results to other populations such as patients with different coverage, to the US population as a whole, or to populations residing out of the US is not clear
  • Despite covariate adjustments in the multivariate Cox proportional hazard model, unmeasured confounders, such as WHO FC, exercise capacity, right ventricular function and structure, hemodynamics, brain natriuretic peptide, and other biomarkers, may impact the study results

Baseline patient characteristics1

Retrospective claims analysis baseline characteristics mobile table
After adjusting for certain confounders, UPTRAVI® was associated with a 47% relative risk reduction of first PAH-related hospitalization (HR: 0.53; 95% Cl: 0.31, 0.93) compared with oral treprostinil1
Probability of first PAH-related hospitalization event mobile curve

Reference group: oral treprostinil; the Cox proportional hazards models were adjusted for age, gender, geographic region, insurance type, Charlson comorbidity score, PAH medication, PAH-associated comorbidities, other selected comorbidities, and baseline hospitalization and outpatient visits.

  • This retrospective claims analysis compared risk of PAH-related hospitalization and does not assess or compare product safety or efficacy. Prevalence of comorbidities and PAH diagnosis were obtained from administrative claims data that have not been clinically validated
  • There have been no head-to-head clinical trials comparing the efficacy or safety of UPTRAVI® and oral treprostinil. No direct evaluation of comparative clinical profiles can be made
  • Results should be considered as hypothesis generating and should not be taken as the basis for influencing clinical practice

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Concomitant use of strong inhibitors of CYP2C8 (eg, gemfibrozil) with UPTRAVI® is contraindicated.

Hypersensitivity to the active substance or to any of the excipients is contraindicated.

WARNINGS AND PRECAUTIONS

Pulmonary Edema with Pulmonary Veno-Occlusive Disease (PVOD)

Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue UPTRAVI®.

ADVERSE REACTIONS

Adverse reactions more frequent compared to placebo (≥3%) seen with UPTRAVI® Tablets are headache (65% vs 32%), diarrhea (42% vs 18%), jaw pain (26% vs 6%), nausea (33% vs 18%), myalgia (16% vs 6%), vomiting (18% vs 9%), pain in extremity (17% vs 8%), flushing (12% vs 5%), arthralgia (11% vs 8%), anemia (8% vs 5%), decreased appetite (6% vs 3%), and rash (11% vs 8%).

These adverse reactions are more frequent during the dose titration phase.

Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI® Tablets and in none of the patients on placebo.

DRUG INTERACTIONS

CYP2C8 Inhibitors

Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant use of UPTRAVI® with strong inhibitors of CYP2C8 is contraindicated.

Concomitant administration of UPTRAVI® with clopidogrel, a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7–fold. Reduce the dosing of UPTRAVI® to once daily in patients on a moderate CYP2C8 inhibitor.

CYP2C8 Inducers

Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI® dose, up to twice, when co-administered with rifampin. Reduce UPTRAVI® when rifampin is stopped.

DOSAGE AND ADMINISTRATION

Recommended Dosage

Recommended starting dose is 200 mcg twice daily for UPTRAVI® Tablets. Tolerability may be improved when taken with food. Increase by 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If dose is not tolerated, reduce to the previous tolerated dose.

Patients With Hepatic Impairment

For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of UPTRAVI® Tablets is 200 mcg once daily. Increase by 200 mcg once daily at weekly intervals, as tolerated. Avoid use of UPTRAVI® in patients with severe hepatic impairment (Child-Pugh class C).

Co-administration With Moderate CYP2C8 Inhibitors

When co-administered with moderate CYP2C8 inhibitors (eg, clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI® to once daily.

Dosage Strengths

UPTRAVI® tablet strengths:
200, 400, 600, 800, 1000, 1200, 1400, and 1600 mcg.

Additional Important Safety Information for UPTRAVI® IV

Use UPTRAVI® for injection in patients who are temporarily unable to take oral therapy.

Administer UPTRAVI® for injection twice daily by intravenous infusion at a dose that corresponds to the patient’s current dose of UPTRAVI® Tablets (see Table 1 in full Prescribing Information). Administer UPTRAVI® for injection as an 80-minute intravenous infusion.

Adverse Reactions: Infusion-site reactions (infusion-site erythema/redness, pain and swelling) were reported with UPTRAVI® for injection.

INDICATION

UPTRAVI® (selexipag) is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

Effectiveness of UPTRAVI® Tablets was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms.

Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), and PAH associated with congenital heart disease with repaired shunts (10%).

Please see full Prescribing Information for UPTRAVI®.

cp-126160v5

*Sample selection and creation of analytic variables were performed using the Instant Health Data platform, and statistical analyses were undertaken with R, version 3.2.1. Baseline patient characteristics were compared between the 2 treatment groups using Student’s t-test for continuous variables and chi square or Fisher’s exact test for categorical variables, as appropriate.

†Diagnosis codes included ICD-9-CM 416.0, 416.8, 416.9 and ICD-10-CM I27.0, I27.2, I27.89, I27.9.

‡This study targets the PAH population, but references hospitalizations as “PH-related” due to this methodology limitation in identifying patients. PAH does not have a specific diagnosis code; therefore the PH-specific diagnosis code plus other criteria (the use of PAH-specific medications) are applied to identify patients in this population.

§ERAs include ambrisentan, macitentan, and bosentan.

‖PDE-5is include sildenafil and tadalafil.

Inhaled or parenteral PGl2s include parenteral epoprostenol or treprostinil, inhaled treprostinil, and inhaled iloprost.

#sGC stimulators include riociguat.

CHD=congenital heart disease; CI=confidence interval; COPD=chronic obstructive pulmonary disease; CTD=connective tissue disease; ERA=endothelin receptor antagonist; FC=Functional Class; HR=hazard ratio; ICD=International Classification of Diseases; ICD-9-CM=International Classification of Diseases, Ninth Revision, Clinical Modification; ICD-10-CM=International Classification of Diseases, Tenth Revision, Clinical Modification; PDE-5i=phosphodiesterase type-5 inhibitor; PGI2=prostacyclin; PH=pulmonary hypertension; PPA=prostacyclin pathway agent; sGC=soluble guanylate cyclase; WHO=World Health Organization.

Reference: 1. McConnell JW, Tsang Y, Pruett J, Drake W III. Comparative effectiveness of oral prostacyclin pathway drugs on hospitalization in patients with pulmonary hypertension in the United States: a retrospective database analysis. Pulm Circ. 2020;10(4):2045894020911831. doi:10.1177/2045894020911831