ABSTRACT
Selexipag is an oral prostacyclin receptor agonist approved for pulmonary arterial hypertension (PAH). This single‐center, retrospective study described oral selexipag dosing patterns and persistence, overall and stratified by history of methamphetamine (meth) use, at an expert center in California, USA, using a multidisciplinary, nurse‐directed protocol entailing frequent follow‐up and individualized side effect management. Medical charts of patients with PAH initiating oral selexipag between January 2016 and March 2023 were abstracted. Patient characteristics and dosing patterns were described up to 14 months post‐initiation. The individualized maintenance dose (IMD) was the first dose maintained for ≥ 14 days after reaching the maximum tolerated dose. Persistence was described using Kaplan–Meier analysis. A total of 200 patients initiated oral selexipag (median age 52 years; 69.5% female; 54.5% White; 70.5% on triple therapy; 41% with a history of meth use). Most patients (89.0%) achieved maintenance (median IMD: 900 μg twice daily; median time to maintenance: 2.5 months). Selexipag persistence at 1 year was 76.2%, with most discontinuations occurring within 2 months of initiation. Similar proportions of patients with and without a history of meth use achieved maintenance (85.4% vs. 91.5%; p = 0.3) and persisted on selexipag at 1 year (74.0% vs. 77.5%; p = 0.9). Using a multidisciplinary nurse‐directed protocol, most patients with PAH were titrated to their IMD and persisted on oral selexipag, including those with a history of meth use. These findings highlight the importance of frequent patient contact for dose adjustment and side effect management, particularly earlier in the titration process.
Keywords: electronic medical record, methamphetamine, prostacyclins, pulmonary hypertension, retrospective studies
1.
Pulmonary arterial hypertension (PAH) is a rare, progressive disease that ultimately leads to right ventricular failure and death [1, 2, 3, 4, 5]. Though there have been significant advances in PAH therapy, modern registries continue to demonstrate substantial morbidity, with a 3‐year mortality of approximately 20% [6]. The etiology of PAH may be idiopathic, but can also be heritable and is associated with a diverse array of conditions, including connective tissue disease, congenital heart disease, human immunodeficiency virus, portal hypertension, and certain drug/toxin exposures [7, 8]. Methamphetamine (meth) use is an increasingly recognized cause of PAH (Meth‐APAH), especially in the Western United States of America (USA) [9, 10], and is associated with worse outcomes compared to patients with idiopathic disease [11, 12, 13]. Despite these data, patients with Meth‐APAH remain an understudied, at‐risk population, facing greater disparities in care, including reduced likelihood of receiving triple therapy regimens [12, 13, 14].
Selexipag is an oral prostacyclin receptor agonist that has been demonstrated to delay PAH disease progression and reduce the risk of hospitalization [15, 16]. Based on the GRIPHON trial protocol, the USA label recommends selexipag initiation at 200 µg twice daily (BID) and titration in increments of 200 µg BID, usually at weekly intervals, to a patient's individualized maintenance dose (IMD), and up to a maximum dose of 1600 µg BID [15, 17]. As selexipag titration and maintenance may be affected by side effects common to the prostacyclin pathway, frequent patient touchpoints and multidisciplinary collaboration are essential to make dose adjustments, manage adverse events (AEs), and foster persistence on therapy [18, 19]. Notably, selexipag showed similar efficacy across low‐, medium‐, and high‐dose strata in GRIPHON, suggesting that persistence is the most important factor for disease management, irrespective of the individualized dose that a patient can tolerate [15].
The prospective SelexiPag: tHe usErs dRug rEgistry (SPHERE) and EXPloratory Observational Study of Uptravi in Real‐lifE (EXPOSURE) registries have provided insights into real‐world selexipag dosing and titration patterns [20, 21, 22, 23]. However, minimal data are available on specific institutional approaches to selexipag titration that incorporate patient‐specific factors and side effect management strategies, particularly among at‐risk populations such as those with a history of meth use, who are often underrepresented in pivotal clinical trials and cohort studies [14].
Recognizing the importance of selexipag titration, the Adult Pulmonary Hypertension Comprehensive Care Center (PHCCC) at the University of California, San Francisco (UCSF) developed a multidisciplinary, nurse‐directed protocol to enhance therapy titration and persistence. The multidisciplinary team at UCSF PHCCC includes physician, nursing, social work, and pharmacy collaboration. Registered and Advanced Practice Registered Nurses are able to provide comprehensive care coordination, patient education, and support with medication‐related side effects to optimize treatment and patient adherence [18, 19]. Further, UCSF PHCCC has extensive experience treating patients with a history of meth use, who comprise a sizeable proportion of their PAH patient cohort.
Thus, the present study aimed to depict real‐world selexipag dosing patterns and persistence, and examine how a history of meth use might impact these metrics. We hypothesized that, at this expert center using a nurse‐directed protocol including frequent patient engagement and in‐depth nursing assessment, most patients with PAH initiated on selexipag, including those with a history of meth use, would be able to reach their IMD and persist on treatment.
1. Methods
1.1. Study Design
This was a retrospective chart review of adult patients with a primary diagnosis of PAH who initiated oral selexipag at UCSF PHCCC. De‐identified data on patient demographics, clinical characteristics, and selexipag dosing patterns and persistence—including reasons for discontinuation and presence of AEs—were collected. The index date was the initiation date of selexipag for PAH, and the observation period spanned from index to the earliest of 14 months post‐index, the last assessment, lung transplant, or death.
The study was approved by the UCSF institutional review board, and a waiver of informed consent was granted.
1.2. Study Population and Subgroups
A list of patients receiving oral selexipag at UCSF was obtained from two specialty pharmacies for screening. Patients were included in the study if they (1) initiated oral selexipag for PAH between January 1, 2016, and March 31, 2023; (2) were aged ≥ 18 years at index with a primary diagnosis of World Health Organization (WHO) Group 1—PAH; (3) had no evidence of selexipag use at UCSF (or other centers) in the month prior to index; (4) had accessible medical record data; and (5) had ≥ 1 documented follow‐up within 2 weeks of selexipag initiation. Patients were excluded if they were enrolled in an interventional clinical trial at any time during the observation period or did not have a WHO Group 1—PAH diagnosis. Patients with comorbidities such as left heart disease or lung disease could be included if they were deemed to have Group 1—PAH as their primary diagnosis.
Patients were stratified into two subgroups: patients with a history of meth use, defined as any mention of meth use recorded in the medical record, and patients with no history of meth use.
1.3. Nurse‐Directed Protocol
The UCSF PHCCC's multidisciplinary, nurse‐directed protocol is depicted in Figure 1. The protocol was developed iteratively by PHCCC nursing, in collaboration with the pharmacy team and pulmonary hypertension (PH) physicians, based on prior experience with prostacyclin pathway agents. The result was a template for communication for specialty pharmacy nurses to complete after obtaining standardized assessment information at each patient visit, including vitals, symptoms, side effects, current dose, number of tablets/strength of medication, and other information that could affect selexipag titration and persistence. Patients were proactively followed for side effect management after each assessment (see Table 1 for common side effects and their proposed management strategies and Table E1 for the study definitions of AE severity).
Figure 1.
Multidisciplinary, nurse‐directed protocol for oral selexipag titration. BID, twice daily; QHS, once daily at bedtime.
Table 1.
Management strategies for common prostacyclin pathway side effects. a
| Side effect | Intervention | Consideration/rationale |
|---|---|---|
| Pain management | Non‐pharmacologic interventions (i.e., heating pad, massage, acupuncture, acupressure, relaxation techniques) | First‐line options to relieve pain |
| Pharmacologic interventions (i.e., acetaminophen, ibuprofen [if not contraindicated], gabapentin, pregabalin, tramadol) | Second‐line options to relieve pain | |
| Slow titration or decrease the dose | Dose‐limiting side effect | |
| Refer to psychiatry, pain management, or palliative care if refractory pain | Pain management is better trained and equipped to manage severe long‐term pain | |
| Ensure doses are taken 12 h apart | Taking doses < 12 h apart will result in higher serum levels and increased effect of medication including side effects | |
| Leg pain | Acetaminophen | Take 30 min prior to dose and PRN during the day (no more than 3000 mg/day in patients with normal liver function) |
| Obtain basic metabolic panel | Evaluate electrolytes in the setting of other side effects, such as diarrhea, as hyponatremia, hypokalemia, and/or hypomagnesemia can cause leg cramping | |
| Ensure doses are taken 12 h apart | Taking doses < 12 h apart will result in higher serum levels and increased effect of medication, including side effects | |
| Jaw pain | Usually no interventions needed; reassure patient that this will improve with time | Not a dose‐limiting side effect, loss of jaw pain may indicate the need for up‐titration |
| Take slow bites or sips of water, suck on saltine cracker or hard candy, chew gum before eating | Jaw pain is intermittent and generally occurs with the first bite of the meal | |
| Headache | Pre‐treat before oral prostacyclin doses | Used to prevent headaches or lessen their severity |
| Acetaminophen | Use the smallest amount for the shortest amount of time and monitor liver function tests | |
| Tramadol | Reduce the dose in patients with cirrhosis | |
| Avoid alcohol | The vasodilatory effects of alcohol can worsen headaches | |
| Refer to neurology if titration becomes limited or headache becomes chronic | May be helpful with patients who have a history of migraines | |
| Evaluate for secondary cause (i.e., check INR, brain imaging, referral to specialist) | Rule out life‐threatening causes of acute onset or worsening headache | |
| Slow titration or decrease dose | Dose‐limiting side effect | |
| Ensure doses are taken 12 h apart | Taking doses < 12 h apart will result in higher serum levels and increased effect of medication, including side effects | |
| Dizziness/hypotension | Decrease blood pressure medication and/or diuretics | Prostacyclins can lower blood pressure |
| Assess and manage dehydration or over‐diuresis, obtain labs to check renal function and electrolytes | Diuretics combined with fluid and sodium restriction can occasionally lead to dehydration; side effect of diarrhea can cause hypotension | |
| Close monitoring of blood pressure by patient in the home with parameters to call clinic | Establish a pattern of low blood pressure | |
| Caution about sudden change in position | Orthostatic hypotension | |
| Avoid inadvertent increased prostacyclin dose, increase fluids, vasopressors if needed | Bolus can lead to hypotension and/or syncope | |
| If pre‐syncopal or syncope event, evaluate in clinic or hospital | May indicate clinical worsening | |
| Slow titration or decrease dose | Dose‐limiting side effect | |
| Ensure doses are taken 12 h apart | Taking doses < 12 h apart will result in higher serum levels and increased effect of medication, including side effects | |
| Nausea/vomiting/acid reflux | Encourage patients to take medication with a balanced meal | Side effects more prominent when medications are taken on an empty stomach or with fatty foods |
| Anti‐emetics (i.e., ondansetron) | Vomiting can lead to vagal event and should be avoided | |
| H2 antagonist, proton pump inhibitor | Manage GERD symptoms to improve tolerance to medication; drug‐drug interactions may occur, choose class or medication without drug‐drug interactions | |
| Avoid alcohol | Alcohol intake can worsen all GI‐related side effects, including loss of appetite, nausea, diarrhea, and GERD | |
| Rule out pregnancy | Pregnancy can be life‐threatening in pulmonary hypertension | |
| Refer to gastroenterologist | Rule out other causes | |
| Slow titration or decrease dose | Dose‐limiting side effect | |
| Ensure doses are taken 12 h apart | Taking doses < 12 h apart will result in higher serum levels and increased effect of medication including side effects | |
| Diarrhea | Encourage patients to take medication with a balanced meal | Side effects more prominent when medications are taken on an empty stomach or with fatty foods |
| Loperamide | Take PRN for diarrhea, can take prior to dose to decrease side effects | |
| Decrease diuretic | Avoid hypovolemia | |
| Rule out other causes, such as C. diff, obtain chemistry panel | To evaluate renal function and electrolytes in setting of chronic or worsening diarrhea | |
| Refer to GI | Rule out other conditions/complications | |
| Slow titration or decrease dose | Dose‐limiting side effect | |
| Ensure doses are taken 12 h apart | Taking doses < 12 h apart will result in higher serum levels and increased effect of medication including side effects |
Abbreviations: GERD, gastroesophageal reflux disease; GI, gastrointestinal; H2, histamine; INR, international normalized ratio; PRN, pro re nata (as needed).
This table is adapted from Kingman et al, Pulm Circ, 2017; 7(3):598‐608 (1), licensed under CC BY 4.0 [18].
1.4. Statistical Analyses
Patient demographics, clinical characteristics, and selexipag dosing patterns, including frequency and severity of AEs, were summarized using descriptive statistics. Definitions for selexipag titration and dosing variables were adapted from the SPHERE registry [20, 21]. Specifically, the maximum tolerated dose (MTD) was defined as the highest observed dose within 6 months of selexipag initiation, and the IMD was defined as the first dose maintained for ≥ 14 days after reaching MTD. The titration phase was defined as the period from selexipag initiation to the day before achieving maintenance. The maintenance phase was defined as the period from day 1 of IMD (if lower than MTD) or day 8 after first IMD (if equal to MTD) until discontinuation of selexipag or end of observation period. Dose strength was categorized as low (200– < 600 µg BID), medium (600– < 1200 µg BID), high (1200–1600 µg BID), or other (< 200 or > 1600 µg BID). MTD and IMD doses were presented as BID, based on the total daily dose divided in half. In the real‐world setting, patients could receive different doses within the same day (e.g., 400 µg in the morning and 600 µg in the evening), making it possible to see BID doses that are not multiples of 200 μg (e.g., 500 µg BID).
Kaplan–Meier analysis was used to describe time to maintenance and persistence (overall and among those who achieved maintenance) during the observation period; patients were censored at the date of last assessment, lung transplant, or death.
Subgroup analyses were conducted among patients with and without a history of meth use. Differences in time to maintenance and persistence between subgroups were evaluated using log‐rank tests. Adjustment for multiple testing was not applied.
Finally, a multivariable Cox regression analysis was conducted to identify demographic and clinical characteristics associated with selexipag discontinuation at any point during the observation period.
All analyses were carried out using SAS version 9.4 and R version 4.3.0.
2. Results
2.1. Patient Characteristics
A total of 200 patients met the eligibility criteria and were included in the analysis (Figure E1). Demographic and clinical data are presented in Table 2. The median age was 52 years, with 69.5% female, and the most common race/ethnicities included White (54.5%), Hispanic/Latino (20.5%), Asian (10.0%), and Black (8.5%). Most (60.0%) patients were WHO functional class III/IV at index. The most common PAH etiologies were drug or toxin‐induced PAH (41.5%), idiopathic (16.0%), and connective tissue disease (12.0%). Among patients with available data (74.5%), the median time from PAH diagnosis to selexipag initiation was 1.5 years. The most common comorbidities were hypertension (35.0%) and obstructive sleep apnea (28.5%). Most patients (70.5%) received selexipag as part of triple therapy, and 12.0% transitioned from another prostacyclin pathway agent to selexipag.
Table 2.
Demographic and clinical characteristics among patients with PAH initiating oral selexipag.
| Overall (N = 200) | History of meth use (N = 82) | No history of meth use (N = 117) | |
|---|---|---|---|
| Age at index (years) | |||
| Mean ± SD | 52.3 ± 13.9 | 50.3 ± 8.3 | 53.9 ± 16.5 |
| Median (IQR) | 52.0 (43.0, 62.5) | 50.0 (43.3, 56.8) | 57.0 (38.0, 68.0) |
| Sex – Female, n (%) | 139 (69.5%) | 47 (57.3%) | 91 (77.8%) |
| Race/ethnicitya , b, n (%) | |||
| White | 109 (54.5%) | 57 (69.5%) | 52 (44.4%) |
| Hispanic/Latino | 41 (20.5%) | 11 (13.4%) | 29 (24.8%) |
| Asian | 20 (10.0%) | n.r. | n.r. |
| Black/African American | 17 (8.5%) | 5 (6.1%) | 12 (10.3%) |
| American Indian or Alaska Native | 5 (2.5%) | n.r. | n.r. |
| Other | 15 (7.5%) | 5 (6.1%) | 10 (8.5%) |
| Unknown | 7 (3.5%) | n.r. | n.r. |
| WHO functional class at index, n (%)c | |||
| Class I | 26 (13.0%) | 11 (13.4%) | 14 (12.0%) |
| Class II | 54 (27.0%) | 17 (20.7%) | 37 (31.6%) |
| Class III | 108 (54.0%) | 47 (57.3%) | 61 (52.1%) |
| Class IV | 12 (6.0%) | 7 (8.5%) | 5 (4.3%) |
| PAH WHO Group 1 etiology at indexa , b, n (%) | |||
| Drug or toxin‐induced | 83 (41.5%) | 76 (92.7%) | 7 (6.0%) |
| Idiopathic | 32 (16.0%) | n.r. | n.r. |
| Connective tissue disease | 24 (12.0%) | n.r. | n.r. |
| Adult congenital heart disease | 17 (8.5%) | n.r. | n.r. |
| Heritable | 12 (6.0%) | n.r. | n.r. |
| PoPH | 10 (5.0%) | n.r. | n.r. |
| HIV | 5 (2.5%) | n.r. | n.r. |
| Patients with known PAH diagnosis dated, n (%) | 149 (74.5%) | 61 (74.4%) | 87 (74.4%) |
| Time from PAH diagnosis to index (years) | |||
| Mean ± SD | 3.4 ± 4.8 | 3.3 ± 3.6 | 3.6 ± 5.6 |
| Median (IQR) | 1.5 (0.7, 4.1) | 1.7 (0.9, 3.7) | 1.4 (0.5, 4.8) |
| Comorbidities at or before indexa , b, n (%) | |||
| Hypertension | 70 (35.0%) | 31 (37.8%) | 39 (33.3%) |
| Obstructive sleep apnea | 57 (28.5%) | 26 (31.7%) | 31 (26.5%) |
| Coronary artery disease | 43 (21.5%) | 18 (22.0%) | 25 (21.4%) |
| Obesity | 36 (18.0%) | 18 (22.0%) | 18 (15.4%) |
| Diabetes mellitus | 31 (15.5%) | 10 (12.2%) | 21 (17.9%) |
| Atrial fibrillation | 23 (11.5%) | 9 (11.0%) | 14 (12.0%) |
| Interstitial lung disease | 21 (10.5%) | n.r. | n.r. |
| Chronic obstructive pulmonary disorder | 18 (9.0%) | 7 (8.5%) | 11 (9.4%) |
| Active meth user at index, n (%) | 17 (8.5%) | 17 (20.7%) | 0 (0%) |
| REVEAL Lite 2 risk score at indexe | |||
| Mean ± SD | 6.1 ± 2.2 | 5.9 ± 2.2 | 6.4 ± 2.2 |
| Median (IQR) | 6.0 (4.0, 8.0) | 6.0 (4.0, 8.0) | 6.0 (5.0, 8.0) |
| REVEAL Lite 2 based risk stratificationf, n (%) | |||
| High | 13 (31.7%) | 6 (31.6%) | 7 (31.8%) |
| Intermediate | 12 (29.3%) | n.r. | n.r. |
| Low | 16 (39.0%) | 9 (47.4%) | 7 (31.8%) |
| Initiated on triple therapy at index, n (%) | 141 (70.5%) | 63 (76.8%) | 78 (66.7%) |
| Transitioned from another prostacyclin pathway agent to oral selexipag, n (%) | 24 (12.0%) | 5 (6.1%) | 19 (16.2%) |
Abbreviations: HIV, human immunodeficiency virus; IQR, interquartile range; meth, methamphetamine; n.r., not reported; PAH, pulmonary arterial hypertension; PoPH, pulmonary arterial hypertension associated with portal hypertension; SD, standard deviation; WHO, World Health Organization.
Categories are not mutually exclusive, except for “Unknown.”
Data not reported for categories with < 5 patients.
Total may not sum to 100% due to rounding.
Missing data for PAH diagnosis date in 51 (25.5%) patients overall, including 21 (25.6%) patients with a history of meth use and 30 (25.6%) patients with no history of meth use.
REVEAL Lite 2 scores were calculated based on the following components: WHO functional class, vital signs (systolic blood pressure and heart rate), 6‐min walking distance, B‐type natriuretic peptide (BNP)/N‐terminal‐proBNP, and renal insufficiency (estimated glomerular filtration rate). Score was calculated for 41 patients with i. no missing values, ii. missing values for only one of the six components, or iii. missing values for two or more of the following components: renal insufficiency, systolic blood pressure, and heart rate based on Benza (2021) [24], which showed good discrimination (c‐statistic > 0.70). REVEAL Lite 2 scores can range from 1 to 14.
A REVEAL Lite 2 score between 1 and 5 is considered low risk, a score of 6 or 7 is considered intermediate risk, and a score of 8 or higher is considered high risk.
2.2. Oral Selexipag Dosing Patterns and Persistence
Overall, 89.0% of patients completed their titration and achieved maintenance, with a median time to maintenance of 2.5 months (95% confidence interval [CI]: 2.2–2.9; Figure 2A). The IMD was distributed across dose categories (low: 22.5%; medium: 34.8%; high: 39.9%), with a median IMD of 900 μg BID. During titration, patients averaged 2.9 dose escalations and 0.2 dose step‐downs, with notable variability in the time between dose escalations (median: 14.0 days [interquartile range (IQR): 9.5–21.2], Table 3).
Figure 2.
Kaplan–Meier plot for time to reaching selexipag individualized maintenance dose, for (A) the overall sample and (B) subgroups based on history of meth use. CI, confidence interval; meth, methamphetamine.
Table 3.
Oral selexipag treatment characteristics and dosing patterns.
| Overall (N = 200) | History of meth use (N = 82) | No history of meth use (N = 117) | |
|---|---|---|---|
| MTD (µg BID) | |||
| Mean ± SD | 971 ± 510 | 878 ± 442 | 1031 ± 545 |
| Median (IQR) | 800 (600, 1450) | 800 (600, 1200) | 1000 (600, 1600) |
| MTD dose categories, n (%) | |||
| Low dose (200‐ < 600 µg BID) | 43 (21.5%) | 20 (24.4%) | 23 (19.7%) |
| Medium dose (600– < 1200 µg BID) | 76 (38.0%) | 37 (45.1%) | 39 (33.3%) |
| High dose (1200–1600 µg BID) | 75 (37.5%) | 25 (30.5%) | 49 (41.9%) |
| Other (< 200– > 1600 µg BID) | 6 (3.0%) | 0 (0.0%) | 6 (5.1%) |
| Dose escalations during the titration phase | |||
| Number of dose escalations | |||
| Mean ± SD | 2.9 ± 2.2 | 2.8 ± 2.2 | 3.0 ± 2.2 |
| Median (IQR) | 2.5 (1.0, 4.0) | 2.0 (1.0, 4.0) | 3.0 (1.0, 4.0) |
| Patients with ≥ 1 dose escalations, n (%) | 174 (87.0%) | 70 (85.4%) | 103 (88.0%) |
| Time between dose escalations (days) | |||
| Mean ± SD | 17.7 ± 13.7 | 18.5 ± 13.4 | 17.2 ± 14.0 |
| Median (IQR) | 14.0 (9.5, 21.2) | 14.5 (9.5, 24.8) | 14.0 (9.7, 19.0) |
| Patients who achieved maintenance, n (%) | 178 (89.0%) | 70 (85.4%) | 107 (91.5%) |
| IMD (µg BID) | |||
| Mean ± SD | 985 ± 520 | 849 ± 466 | 1069 ± 536 |
| Median (IQR) | 900 (600, 1600) | 800 (400, 1200) | 1000 (600, 1600) |
| IMD dose categories, n (%) | |||
| Low dose (200– < 600 µg BID) | 40 (22.5%) | 23 (32.9%) | 17 (15.9%) |
| Medium dose (600– < 1200 µg BID) | 62 (34.8%) | 25 (35.7%) | 37 (34.6%) |
| High dose (1200–1600 µg BID) | 71 (39.9%) | 22 (31.4%) | 48 (44.9%) |
| Other (< 200– > 1600 µg BID) | 5 (2.8%) | 0 (0.0%) | 5 (4.7%) |
| Patients who discontinued selexipag, n (%) | |||
| During the titration phase | 20 (10.0%) | 11 (13.4%) | 9 (7.7%) |
| During the maintenance phase | 30 (16.9%) | 10 (14.3%) | 20 (18.7%) |
Abbreviations: BID, twice daily; IMD, individualized maintenance dose; IQR, interquartile range; meth, methamphetamine; MTD, maximum tolerated dose; PAH, pulmonary arterial hypertension; SD, standard deviation.
Overall, 150 (75.0%) patients remained on selexipag throughout the observation period. Persistence on selexipag was 86.9% at 2 months and 76.2% at 1 year (Figure 3A). Among patients who achieved maintenance, persistence at 1 year was 84.8% (Figure 4A). Of the 50 patients who discontinued selexipag at any point during the observation period, 26 (52.0%) discontinued within the first 2 months following initiation. The most common reason for discontinuation was inability to tolerate treatment (68.0% [34/50]), most commonly due to headache (50.0% [17/34]), nausea (26.5% [9/34]), jaw pain (17.6% [6/34]), and muscle pain (17.6% [6/34]). Nevertheless, most patients were able to continue treatment despite AEs, as 90.5% experienced ≥ 1 AE and 42.5% experienced ≥ 1 severe AE at some point during the observation period. The most common AEs during the study period included headache (63.0%), muscle pain (37.5%), nausea (35.0%), and diarrhea (34.5%) (Table E2). AEs were also common among the 24 patients who transitioned from another prostacyclin pathway agent to selexipag, with 83.3% experiencing ≥ 1 AE and 37.5% experiencing ≥ 1 severe AE during the observation period.
Figure 3.
Kaplan–Meier plot for persistence on selexipag, for (A) the overall sample and (B) subgroups based on history of meth use. CI, confidence interval; meth, methamphetamine; NR, not reached.
Figure 4.
Kaplan–Meier plot for persistence among those who achieved maintenance, for (A) the overall sample and (B) subgroups based on history of meth use. CI, confidence interval; meth, methamphetamine; NR, not reached.
2.3. Subgroup Analysis by History of Meth Use
Among the 200 patients included in the cohort, 82 (41.0%) had a history of meth use, and 117 (58.5%) did not have a history of use. The history of meth use was not known in one patient who was excluded from the subgroup analyses. Patients with a history of meth use, relative to those with no history of use, were on average younger (median 50 vs. 57 years), had a lower proportion of females (57.3% vs. 77.8%), a higher proportion of White race (69.5% vs. 44.4%), and were more likely to be WHO functional class III/IV (65.8% vs. 56.4%; Table 2). Among patients with a history of meth use, 20.7% (17/82) reported active use at index.
A similar proportion of patients with and without a history of meth use achieved maintenance (85.4% vs. 91.5%), with most patients in both groups achieving maintenance within 3 months of initiation (median time to maintenance: 2.4 [95% CI: 2.1–3.3] vs. 2.6 [95% CI: 2.2–3.0] months, log‐rank p = 0.3; Figure 2B). Patients with a history of meth use tended to have a lower IMD than those without a history of use (median: 800 vs. 1000 μg BID; with 32.9% vs. 15.9% in the low‐dose category; Table 3).
Throughout the observation period, a similar proportion of patients with and without a history of meth use remained on treatment (74.4% vs. 75.2%). Selexipag persistence at 1 year was 74.0% vs. 77.5% among patients with versus without a history of meth use (log‐rank p = 0.9; Figure 3B). Among patients who completed their titration and achieved maintenance, persistence at 1 year among patients with a history of meth use was 85.6% versus 84.0% among those with no history of use (log‐rank p = 0.4; Figure 4B). Among the patients who discontinued selexipag at any point during the observation period, over half of patients both with and without a history of meth use did so within the first 2 months following initiation (52.4% [11/21] vs. 51.7% [15/29]). Among patients reporting active meth use at selexipag initiation, over half (52.9% [9/17]) remained on treatment throughout the observation period, with the majority (75.0% [6/8]) of discontinuations also occurring within the first 2 months following initiation.
As per the overall sample, most discontinuations were due to inability to tolerate treatment, both among patients with and without a history of meth use (76.2% [16/21] vs. 62.1% [18/29]). In both subgroups, common AEs leading to discontinuation, as well as proportions of patients experiencing ≥ 1 AE and ≥ 1 severe AE, were similar to those in the overall sample (Table E2).
2.4. Predictors of Treatment Discontinuation
The presence of severe AEs was associated with over fourfold higher risk of selexipag discontinuation (hazard ratio [HR]: 4.24 [95% CI: 2.08–8.65]; p < 0.001), while having multiple AEs was associated with a 32% lower risk of selexipag discontinuation (HR: 0.68 [95% CI: 0.55–0.85]; p < 0.001). In addition, although statistical significance was not reached, the risk of selexipag discontinuation was nearly 2.5 times higher among patients with chronic obstructive pulmonary disease at index (HR for selexipag discontinuation: 2.41 [95% CI: 0.99–5.84]; p = 0.05) (Table E3).
3. Discussion
In this retrospective study at an expert center using a multidisciplinary, nurse‐directed protocol for oral selexipag initiation and maintenance, most patients, including those with a history of meth use, reached their IMD, and nearly 80% persisted on treatment at 1 year. To our knowledge, this is the most comprehensive description of real‐world oral selexipag dosing patterns and clinical management in the USA published to date, and the first to specifically evaluate selexipag dosing patterns in patients with meth use, a population underrepresented in real‐world studies and clinical trials [14, 15]. The results suggest that a team‐based engagement approach, focused on individualized titration, frequent patient touchpoints, and side effect management, may help support persistence among patients with PAH and replicate persistence rates seen in randomized clinical trials [15, 25], including among at‐risk populations with a history of meth use.
The highly individualized approach to selexipag dosing was reflected in the substantial variability in the time between dose escalations as well as the wide range of achieved IMDs, encompassing low‐, medium‐, and high‐dose categories. These observations are largely congruent with the prospective, USA‐based SPHERE registry, as well as real‐world studies performed outside of the USA, including the prospective EXPOSURE study based in Europe and Canada and the Start Up program in France [20, 23, 26, 27, 28, 29, 30]. Notably, the time between successful dose titrations in the present study was often > 2 weeks, which is longer than the 1 week stipulated in the GRIPHON trial protocol [15]. This is similar to the results reported by the SPHERE registry, in which almost all patients (88%) titrated slower than the label‐recommended 200 µg BID per week, achieving a median IMD of 1000 µg BID, similar to our study (900 µg BID) [20]. Importantly, a high proportion of patients (22.5%) had IMDs in the low‐dose category, supporting that titration to higher doses of selexipag should not always be the priority and that persistence is more important than achieving the highest dose possible [15, 31].
In this study, nearly 80% of patients persisted on selexipag at 1 year, with similar findings among those with a history of meth use. Direct comparisons with prior studies are limited by differences in definitions of persistence, follow‐up duration, and patient populations. Nevertheless, the persistence observed in our cohort compares favorably with previously reported clinical trials and real‐world evidence. Our persistence was similar to that in the pivotal GRIPHON trial, in which 23% of patients discontinued selexipag prematurely [15], as well as the France Start Up program, which achieved a 19% discontinuation rate utilizing a nurse‐driven protocol in a real‐world setting [30]. However, our persistence was nearly 20% higher than that described in the pooled analyses of the real‐world SPHERE and EXPOSURE registries, where 43% of newly initiated patients discontinued therapy over a median of 11 months [32]. This suggests that persistence with selexipag remains a challenge in real‐world practice, particularly early in treatment. The relatively high 1‐year persistence observed in the present cohort—despite frequent AEs and a large proportion of patients with a history of meth use—may reflect the potential value of individualized titration schedules, frequent patient contact, and proactive side‐effect management within a multidisciplinary care model.
Notably, the discontinuation rate of selexipag in this study was highest in the first 2 months of treatment initiation. This could be partially attributable to more frequent AEs occurring earlier in the titration process with any prostacyclin pathway agent and higher percentage dose increases in the early phase of titration (i.e., an increase from 200 to 400 μg is a 100% increase, whereas an increase from 1200 to 1400 μg is only a 17% increase), which may be associated with more significant AEs. This study found that the presence of any severe AEs was associated with a higher risk of discontinuation; however, the presence of a greater number of different AEs was paradoxically associated with a lower risk of discontinuation, potentially indicating that these were mild‐to‐moderate AEs that were effectively managed by the nurse‐directed protocol. The high rate of early discontinuation highlights the importance of patient engagement and AE mitigation in the early stages of selexipag titration to prevent mild AEs from progressing to severe ones that could lead to discontinuation [30]. Indeed, novel strategies for titration should be considered, such as delayed titration schedules with longer periods between dose escalations upfront and shorter durations thereafter.
Historically, patients with Meth‐APAH have represented an at‐risk PAH population, facing unique challenges such as socioeconomic issues, disparities in healthcare access, and concerns with parenteral prostacyclin formulations (e.g., poor compliance, risk of infection, appropriate line/skin site care) [11, 12, 13]. Nevertheless, the present study demonstrates that selexipag treatment should not be withheld from patients with a history of meth use and that, in these patients managed with a nurse‐directed protocol, titration and persistence on therapy were quite similar to patients without a history of meth use—even with one‐fifth of patients with a history of meth use reporting active use at index enrollment.
Given the global increase in meth use [10, 33, 34] and the robust association between meth use and PAH [11], it is important to acknowledge that it is possible to successfully treat this at‐risk population. In this study, despite similar time to maintenance and comparable persistence levels, patients with a history of meth use had a slightly slower escalation schedule and lower IMDs than those without a history of use. Though we are unable to confirm the reason for this result, possible factors include increased sensitivity to selexipag titrations, as well as increased difficulties contacting and engaging with patients to confirm readiness for dose escalation. At UCSF PHCCC, the multidisciplinary team includes a social worker to provide additional psychosocial support to this complex population. The inclusion of social work professionals should be a priority of PH clinics that interface with Meth‐APAH patients and can aid in affording them resources in addition to direct medical care to optimize their health outcomes [19]. The provision of high‐quality and individualized care to all patients, irrespective of drug use history, is key to alleviating disparity and promoting equitable healthcare.
The success of the multidisciplinary, nurse‐directed protocol at UCSF PHCCC may be attributable to several factors. Execution of the protocol instills ownership among PH nurses and enables them to work at the highest scope of practice while collaborating with a multidisciplinary team of physicians, pharmacists, and social workers who are highly engaged. This fosters a streamlined and effective care model that moves care forward between official clinic visits and enhances care from specialty pharmacy nursing. Investing time into individualized patient communications and assessments is also a critical component of the protocol. Through validating patients’ symptoms, focusing on alleviating the side effect burden, and providing additional support, patients may be more engaged in their care, which in turn enhances treatment persistence. Improved persistence, even in patients who achieve a low‐dose IMD, is still of long‐term clinical benefit, as seen in the GRIPHON trial and its open‐label extension study [15, 16]. Further, with engaged patients who remain in constant contact with nurses, the center not only helps patients to continue their care but is also less likely to lose patients to follow‐up. UCSF PHCCC's experience highlights the potential clinical utility of a collaborative, nurse‐driven approach to patient selexipag titration, and this approach can easily be applied to other PAH therapies that require stepwise titration. Other PH centers can consider implementing similar protocols, tailoring the strategies to their individual institution's resources and patient populations.
3.1. Limitations
Limitations of this study include the retrospective study design and reliance on routinely collected clinical data. As a result, there were key missing data from the medical records (e.g., risk parameters), and it is possible that other variables (e.g., dose escalations, AEs) were not fully captured. Second, this descriptive study did not include a control group, and thus it cannot be determined whether the collaborative, nurse‐driven model improved selexipag persistence. In addition, this study did not evaluate whether the care model impacts outcomes related to the clinical trajectory, including disease progression, hospitalizations, or deaths. Future studies are needed to confirm whether the care model to enhance selexipag persistence can improve patients’ clinical trajectory. Third, the study findings pertain to patients with a history of meth use documented in the medical record, and thus some patients with a history of meth use may have been missed. Additionally, the PAH etiology for patients with a history of meth use may not necessarily be Meth‐APAH, but due to other contributing conditions, especially as patients with PAH often present with multiple comorbidities and potential PH contributors. Lastly, our findings may not be generalizable to PAH populations outside of the present expert center, which has a high proportion of patients with a history of meth use.
4. Conclusions
In an expert center using a multidisciplinary, nurse‐directed protocol, nearly 80% of patients with PAH who initiated oral selexipag achieved maintenance and remained on treatment, including patients with a history of meth use. The time between dose titrations was often longer than 1 week, and the highest discontinuation rate was observed in the first 2 months of treatment, suggesting a slower, individualized titration schedule with side effect management, especially in the early stages of titration, may be conducive to treatment persistence. This study also found a median IMD of 900 μg BID, with dose ranges spanning across low‐, medium‐, and high‐dose strata, indicating that a tolerable IMD could be a valuable therapeutic target irrespective of the actual dose reached. These findings suggest that multidisciplinary care with frequent patient contact, individualized titration, and side effect mitigation may support selexipag persistence in patients with PAH, including among at‐risk populations with meth use. Future studies, including control groups will be valuable in determining the impact of these care models on improving persistence and clinical outcomes.
Author Contributions
S.B.B., A.S.H., and T.D.M. contributed to study conception and design, collection and assembly of data, and data analysis and interpretation. M.J.L., A.T., and J.T. contributed to collection and assembly of data and data analysis and interpretation. C.B., G.D., P.S., and S.W. contributed to study conception and design and data analysis and interpretation. A.S., G.M., H.B., and M.G.L. contributed to study conception and design, collection and assembly of data, and data analysis and interpretation. All authors reviewed and approved the final content of this manuscript.
Ethics Statement
The study was approved by the UCSF institutional review board, and a waiver of informed consent was granted.
Conflicts of Interest
A.S.H., M.J.L., A.T., and J.T. have no disclosures to report. S.B.B. has received research funding from and served as a consultant for Johnson & Johnson. G.D. is an employee and shareholder of Johnson & Johnson. C.B. and P.S. were employees of Johnson & Johnson at the time of the study and are shareholders of Johnson & Johnson. S.W. was an employee of Johnson & Johnson at the time of the study, is currently employed by Mineralys Therapeutics, and is a shareholder of Johnson & Johnson and Mineralys Therapeutics. A.S., G.M., H.B., and M.G.L. are employees of Analysis Group Inc., a consulting company that provided paid consulting services to Johnson & Johnson, which funded the development and conduct of this study. T.D.M. has served as a consultant for Corsair, Johnson & Johnson, Keros, Merck, Pulnovo, Tectonic, and United Therapeutics.
Guarantor
T.D.M.
Supporting information
Supporting File
Acknowledgments
The authors would like to thank Sara Bravo, RN, and Nimi Tarango, NP, of the University of California San Francisco for their care to the patients whose data were used for this study. Medical writing assistance was provided by medical writer, Flora Chik, PhD, MWC, an employee of Analysis Group Inc., a consulting company that has provided paid consulting services to Johnson & Johnson, which funded the development and conduct of this study and manuscript. Data in this manuscript were presented previously as poster presentations at the American Thoracic Society (ATS) 2025 International Conference held May 17‐21, 2025, in San Francisco, CA, USA based on interim data; and at the 2025 Pulmonary Hypertension Professional Network (PHPN) Symposium held September 18‐20, 2025, in Seattle, WA, USA based on final data. This study was supported by Johnson & Johnson. The study sponsor was involved in several aspects of the research, including the study design, interpretation of data, and writing of the manuscript. The final decision to submit the manuscript for publication was the sole decision of the authors.
Data Availability Statement
The data that support the findings of this study are available from Johnson & Johnson. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of Johnson & Johnson.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting File
Data Availability Statement
The data that support the findings of this study are available from Johnson & Johnson. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of Johnson & Johnson.