Real-world experience of selexipag titration in pulmonary arterial hypertension

Br J Cardiol 2021;28:105–8doi:10.5837/bjc.2021.032 Leave a comment
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First published online 14th July 2021

Selexipag is an oral selective prostacyclin-receptor agonist that was approved for use in patients with World Health Organisation (WHO) functional class II–III pulmonary arterial hypertension (PAH). Treatment with individualised doses of selexipag resulted in significant reductions in the composite end point of death or a complication related to PAH in the phase III GRIPHON (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) study. In order to better understand the real-world approach to selexipag titration and to establish the individualised maintenance regimens used in our centre, we performed this retrospective study of the first 20 patients prescribed selexipag. Baseline characteristics differed from the GRIPHON study, with more combination therapy and comorbidities at drug initiation. Maintenance doses were stratified as low-dose in 10% (n=2), medium-dose in 70% (n=14) and high-dose in 20% (n=4). This study highlights that selexipag can be safely initiated, titrated and transitioned in an outpatient setting to achieve an individualised dosing regimen.

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Introduction

Pulmonary arterial hypertension (PAH) is a devastating disease characterised by irreversible pulmonary vascular proliferation and remodelling, resulting ultimately in right heart failure. Current therapy targets the nitric oxide, endothelin and prostacyclin pathways to promote pulmonary vasodilatation and reduce right ventricular afterload.1,2 Selexipag is an oral selective prostacyclin-receptor agonist that is used in the treatment of PAH. In the GRIPHON (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) trial the optimum dose of selexipag for maximum therapeutic benefit frequently differed between individual patients. It is postulated that this relates to variations in prostacyclin (IP) receptor expression and density.3-5 Selexipag is initiated at 200 µg twice daily and titrated weekly until a total daily dose of 3,200 µg is achieved or side effects become intolerable and an individual maximum tolerated dose is established. In the GRIPHON study, individualised maximum tolerated doses were stratified to low-, medium- and high-dose strata. Twice-daily doses were defined as low if they fell within a 200 µg to 400 µg range, medium if 600 µg to 1,000 µg and high if within a 1,200 µg to 1,600 µg range. This individualised dosing strategy demonstrated consistent efficacy.6 In clinical trials, treatment with selexipag was associated with improvements in six-minute walk distance (6MWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiac index (CI) and pulmonary vascular resistance (PVR), and a significant reduction was noted in the composite morbidity and mortality end point at a median of 70.7 weeks of treatment.6,7 In order to better understand the real-world approach to selexipag titration we performed a retrospective analysis of the clinical and treatment characteristics of the first 20 patients prescribed selexipag in our centre.

Objective

To perform a retrospective analysis of the clinical and treatment characteristics of the first 20 patients prescribed selexipag in our centre, with specific reference to drug titration and individualised maintenance doses.

Method

Table 1. Baseline characteristics of patients, prior to the initiation of selexipag

Characteristic N=20
Gender: male/female, n (%) 7 (35)/13 (65)
Mean age, years ± SD 55 ± 17
Time since PAH diagnosis, years ± SD 4 ± 4
Mean 6MWD*, m ± SD 331 ± 165
PAH classification, n (%)
IPAH 12 (60)
CTD-PAH 6 (30)
Group 5 PH (sarcoid) 1 (5)
Mixed disease 1 (5)
WHO functional class, n (%)
I 0
II 10 (50)
III 10 (50)
IV 0
Risk stratification, n (%)
Low risk 5 (25)
Intermediate risk 13 (65)
High risk 2 (10)
Baseline medications for PAH, n (%)
ERA + PD5 inhibitors 17 (85)
ERA + sGC stimulator 1 (5)
ERA + PD5 inhibitors + PGI2 therapy 2 (10)
Baseline medications (excluding targeted PAH medication), n (%)
None 1 (5)
1–2 10 (50)
3–6 7 (35)
≥7 2 (10)
Comorbidities, n (%)
None 3 (15)
Respiratory 11 (55)
Cardiovascular 4 (20)
Gastrointestinal 4 (20)
*Note data regarding 6MWD (N=16).
Key: 6MWD = six-minute walk distance; CTD = connective tissue disease; ERA = endothelin receptor antagonist; IPAH = idiopathic pulmonary arterial hypertension; PAH = pulmonary arterial hypertension; PD5 = phosphodiesterase type 5; PGI2 = prostacyclin; SD = standard deviation; sGC = soluble guanylate cyclase; WHO = World Health Organisation

A retrospective search of the hospital database was performed to identify patients with confirmed PAH who commenced selexipag therapy, outside of a clinical trial, until June 2020. Paper charts and the hospital information technology service (PatientCentre) were used to collect data that were subsequently fully anonymised. Patients were excluded if they were commenced on selexipag therapy in the context of a clinical trial, as their experience might not reflect ‘real-world’ practice.

Data regarding patient demographics, PAH subtype, duration of PAH diagnosis, comorbidities and regular medications were collected retrospectively. World Health Organisation (WHO) functional class (FC), patient risk-stratification category (using the 2015 ESC [European Society of Cardiology]/ERS [European Respiratory Society] PAH guidelines risk table) and 6MWD were also recorded.2 Details regarding selexipag indication, titration, maintenance doses, reported side effects and compliance were also recorded from patient records. Standard deviations were represented as SD (±).

Statistical analysis was performed using GraphPad online statistical software. Fisher’s exact test was employed to assess the statistical significance for categorical variables and t-test was used to calculate significance between means. A value p<0.05 was considered statistically significant.

Results

Table 2. Characteristics of selexipag titration and maintenance doses at the end of the titration period and at six months post-selexipag initiation

Selexipag dosing
Mean titration period, days ± SD 67 ± 26
Maintenance dose post-titration – mean daily dose, μg ± SD 1,830 ± 548
Subsequent dose changes at 6 months, n (%)
No change 15 (75)
Dose increase 2 (10)
Dose reduction 2 (10)
Data missing 1 (5)
Drug discontinuation 0
Maintenance dose at 6 months – mean daily dose, μg ± SD 1,758 ± 620
Key: SD = standard deviation

Patient selection

The first 20 patients prescribed selexipag in our centre, outside the setting of a clinical trial, were included in this analysis.

Baseline characteristics

Of the 20 patients, 65% (n=13) were female, the mean age was 55 (± 17) years, and 60% (n=12) had a diagnosis of idiopathic PAH (IPAH), 30% (n=6) PAH associated with connective tissue disease (CTD-PAH) and 10% (n=2) were defined as other. Patients reported WHO FC II symptoms in 50% (n=10) and FC III in 50% (n=10) at baseline. Baseline risk assessment was stratified as low in 25% (n=5), intermediate in 65% (n=13) and high risk in 10% (n=2). Double combination therapy was prescribed in 90% (n=18) and triple combination therapy consisting of inhaled iloprost in 10% (n=2). Comorbidities and additional baseline medications were common and are displayed in table 1.

Table 3. Maintenance dose ranges obtained at the end of the initial titration period, which are classified as low (200–400 μg twice daily), medium (600–1,000 μg twice daily) and high (1,200–1,600 μg twice daily)

Maintenance doses
(N=20)
Twice-daily dose (μg) Patients
n (%)
Low-dose stratum 200 0
400 2 (10)
Medium-dose stratum 600 1 (5)
800 6 (30)
1,000 7 (35)
High-dose stratum 1,200 2 (10)
1,400 2 (10)
1,600 0

Selexipag dosing

Selexipag was commenced at 200 µg twice daily, following the protocol used in the GRIPHON study, increasing by 200 µg twice daily every seven days if side effects were tolerable.6 The mean time to reach an individual maintenance dose was 67 (± 26) days and the mean total daily maintenance dose was 1,830 (± 548) µg at the end of the titration period (table 2). Maintenance doses were stratified as low-dose in 10% (n=2), medium-dose in 70% (n=14) and high-dose in 20% (n=4) (table 3). Selexipag doses were reviewed at six months post-initiation to ascertain if there were any subsequent dose titrations. These were not significantly different from individual maintenance doses established at the end of the titration period (p=0.699) (table 2). The minimum patient follow-up in this study was six months. However, the average duration of patient follow-up was typically longer, with a mean duration of follow-up of 416 (± 90) days.

Transitioning between prostacyclin therapies

Two patients were prescribed triple combination therapy at baseline, including inhaled iloprost at doses of 5 µg six times a day. In both cases, when selexipag was initiated at 200 µg twice daily, iloprost was simultaneously reduced to 5 µg four times a day by excluding the morning and the evening iloprost doses. Iloprost was then reduced to 5 µg twice daily in the second week, when selexipag was increased to 400 µg twice daily. This was well tolerated, and inhaled iloprost was discontinued by week three, with ongoing uptitration of selexipag until individual maintenance doses were achieved. Final doses of 1,200 µg twice daily and 1,400 µg twice daily were achieved in these cases, which was higher when compared with doses achieved by other patients in our centre.

Table 4. Side effects reported during selexipag titration

Side effects, N=20 n (%)
Nausea, GERD, vomiting 13 (65)
Diarrhoea 13 (65)
Headache 13 (65)
Jaw discomfort 9 (45)
Myalgia, arthralgia 7 (35)
Abdominal cramps 3 (15)
Weight loss 2 (10)
Flushing 2 (10)
Clinical worsening of PAH 1 (5)
Other* 3 (15)
* Three patients classified as “other” reported increased thirst (n=1), insomnia (n=1) and cold intolerance (n=1)
Key: GERD = gastroesophageal reflux disease; PAH = pulmonary arterial hypertension

Side effects and tolerance

All patients reported side effects during the titration phase, which had an average duration of 67 (± 26) days. These generally improved during the maintenance phase when patients were established on individualised doses. The most frequent reported side effects were nausea, gastroesophageal reflux (GERD) and vomiting in 65% (n=13), diarrhoea in 65% (n=13) and headache in 65% (n=13). Jaw discomfort occurred in 45% (n=9). Clinical worsening occurred in one case, in a patient with CTD-PAH with FC III symptoms and high-risk features at baseline. This patient required hospitalisation for management of right heart failure (table 4). No patients discontinued selexipag due to side effects or adverse events and there were no reported deaths. There was one reported case of new thyroid dysfunction (defined as subclinical hyperthyroidism).

Discussion

The discovery of prostacyclin in 1976, and subsequent development of synthetic analogues, revolutionised the field of PAH.8,9 These analogues include epoprostenol, iloprost and treprostinil, which target IP receptors to stimulate adenylate cyclase, increase cyclic adenosine monophosphate and promote beneficial downstream effects including pulmonary vasodilatation. Interestingly, these agents are not specific for the IP receptor and bind additional prostaglandin receptors that have diverse functions.1,10 Selexipag differs from these analogues, as it is structurally distinct from prostacyclin and is a selective agonist of the IP receptor.6 In our centre, patients initiated on selexipag were more likely to be older (mean age 54 ± 16 years), with comorbidities and additional baseline medications, when compared with patients included in the GRIPHON study. Additionally, all patients were already on double combination therapy (90%, n=18) or triple therapy (10%, n=2) at baseline, reflective of current international best practice. These treatment characteristics emphasise the importance of clear guidelines on drug initiation and a standardised approach to transitioning between prostacyclin agents, as this is increasingly encountered in clinical practice.11-17

The TRANSIT-1 (Tolerability and the Safety of the Transition From Inhaled Treprostinil to Oral Selexipag in Patients With Pulmonary Arterial Hypertension) study was an open-label phase IIIb study that prospectively enrolled 34 patients with clinically stable PAH and transitioned from inhaled treprostinil to oral selexipag.15 Dose reductions were implemented at the discretion of the investigators, highlighting that even in a controlled environment there can be considerable variability in titration approaches due to individual patient factors, including baseline prostacyclin requirements and reported side effects. In our centre, two patients were transitioned from inhaled iloprost to oral selexipag. There is a paucity of published data, limited to case reports detailing the transition of iloprost to selexipag.18 Iloprost is a stable analogue of prostacyclin, that can be administered via nebulisation six to nine times a day to preferentially vasodilate well-ventilated lung, with effects lasting 30 to 90 minutes.19 Aerosolised iloprost is generally well tolerated as it typically avoids the systemic side effects of intravenous (IV), subcutaneous or oral routes of prostacyclin administration. However, there is some evidence that the cessation of nebulised iloprost overnight is associated with a deterioration in haemodynamic parameters.20 In our cohort, two patients transitioned from inhaled iloprost by reducing the frequency of drug administration, rather than reducing the dose administered or duration of treatment sessions. This method was well tolerated, with complete drug cessation by week three in both cases. The final selexipag doses achieved in these two cases were higher than those achieved by patients who were prostacyclin naïve, which one could speculate reflects iloprost-associated IP receptor desensitisation or a higher tolerance of prostacyclin.

Any changes to baseline PAH therapy, including the initiation of oral prostacyclin therapy, should involve careful patient selection and multi-parametric risk assessment.2 All patients selected for selexipag therapy in this study were prevalent patients, with a mean time since diagnosis of four years, which may have implications for treatment response. A post-hoc analysis of patients included in the GRIPHON study demonstrated more pronounced treatment effects in patients who initiated therapy closer to their PAH diagnosis.21 The importance of patient selection, individual assessment and consideration of haemodynamic parameters was highlighted by Yanaka et al. in a study of eight patients transitioned from IV epoprostenol to oral selexipag.16 At evaluation approximately 4.4 months post-selexipag transitioning, there was a significant reduction in cardiac index in these patients.22 To address the knowledge gaps surrounding patient selection for oral prostacyclin therapy, an expert consensus statement on the treatment of PAH with oral prostacyclin agents was published.23 This suggested 13 specific situations where oral selexipag may be suitable, with reference to patients with IPAH and CTD-PAH, with WHO FC II–III and associated low-to-intermediate risk features. Parenteral prostacyclin was recommended for patients with high-risk haemodynamics or with WHO FC IV symptoms.

Selexipag initiation was accompanied by extensive patient education of anticipated side effects during the titration period and comprehensive supervision by experienced PAH nurse specialists who were familiar with individual patients. In our study, the majority of patients (73%, n=16) achieved maintenance doses in the medium-dose stratum, with fewer individual maintenance doses categorised in the high-dose stratum when compared with the GRIPHON study. This is likely multi-factorial in nature and reflects differences in patient demographics and baseline characteristics, including older age, more comorbidities and additional baseline medications in our cohort. Prostacyclin-type side effects were common, and led to drug discontinuation in twice as many participants when compared with placebo in the GRIPHON study.6 Interestingly, there were no cases of drug discontinuation in our cohort. Selexipag does not appear to lead to IP receptor desensitisation over time, potentially due to partial antagonism of the IP receptor, and, therefore, future titrations are generally not required once a maintenance dose is established.24,25 In our cohort, there was no significant difference between maintenance doses at the end of the titration period and doses at six months post-drug initiation; however, this is a relatively short interval and extended follow-up would be required to support this.

Important limitations of this study include its retrospective descriptive nature and the absence of long-term follow-up. Due to the COVID-19 pandemic, a considerable proportion of clinical assessments were performed using telemedicine technology and, therefore, haemodynamic data were not included. Nevertheless, this study reflects ‘real-world’ experience of selexipag and describes appropriate patient selection for oral prostacyclin therapy and an approach to transitioning between prostacyclin agents. Additionally, as selexipag titration was safely performed in an outpatient setting, guided by experienced PAH nurse specialists, this has important implications for resource utilisation and patient autonomy.

Conclusion

This study of the first 20 patients prescribed selexipag in our centre demonstrates that selexipag can be safely initiated, titrated and transitioned in an outpatient setting to achieve an individualised dosing regimen. Prostacyclin side effects were common, but improved in the maintenance phase. There were no drug discontinuations or deaths in this study, but close observation and multi-parametric risk assessment is essential following any changes in drug therapy.

Key messages

  • Selexipag is an oral selective prostacyclin-receptor agonist that was approved for use in patients with World Health Organisation (WHO) functional class II–III pulmonary arterial hypertension (PAH)
  • In the GRIPHON (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) study, selexipag demonstrated consistent efficacy for individualised doses in low-, medium- and high-dose stratums
  • Real-world experience of selexipag dosing and transitioning from other prostacyclin agents is limited
  • This study demonstrates that selexipag can be safely initiated, titrated and transitioned in an outpatient setting to achieve an individualised dosing regimen and adds to limited literature regarding transitioning from inhaled iloprost

Conflicts of interest

None declared.

Funding

Dr Sarah Cullivan is the Janssen Pharmaceuticals Newman Fellow in Pulmonary Hypertension and Translational Medicine. Janssen Pharmaceuticals had no input in the creation of this manuscript and no funding was received for same.

Acknowledgements

We would like to thank Ms Diane Moran, Caitriona Minnock and Denise Lennon, pulmonary hypertension nurse specialists, for their expertise, compassion and dedication to the care of patients in the National Pulmonary Hypertension Unit in Ireland.

Study approval

This study received ethical approval from the Mater Misericordiae University Hospital institutional ethical review board (IRB:1/378/2179 TMR) and as patient data was fully anonymised, individual patient consent was not required.

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