Side effects and tolerance
All patients reported side effects during selexipag titration. The most frequent reported side effects were nausea, gastroesophageal reflux (GERD) and vomiting in 65% (n=13), diarrhoea (65%, n=13) and headache in 65% (n=13). Jaw discomfort occurred in 45% (n=9). Clinical worsening occurred in 1 case, in a patient with CTD-PAH with FC III symptoms and high risk features at baseline, and required hospital admission for treatment 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), with co-morbidities and additional baseline medications, when compared to 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 study was an open-label phase IIIb study that prospectively enrolled 34 patients with clinically stable PAH and assessed the transition 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 a 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 IV, subcutaneous or oral routes of prostacyclin administration, however there is some evidence that the cessation of iloprost overnight is associated with a deterioration in hemodynamic 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 3 in both cases. The final selexipag doses achieved in these two cases were significantly 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 multiparametric risk assessment.2 All patients selected for selexipag therapy in this study were prevalent patients, with a mean time since diagnosis of 4 years, which may have implications for treatment response, as 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 hemodynamic parameters was highlighted by Yanaka et al in a study of 8 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 NYHA FC II-III and associated low to intermediate risk features. Parenteral prostacyclin was recommended for patients with high-risk hemodynamics or with NYHA FC IV symptoms.
Selexipag initiation was accompanied by extensive patient education of anticipated side effects during the titration period and comprehensive supervision by experienced PH nurse specialists who were familiar with individual patients. Individual maintenance doses were established by 67 days on average. In our study the majority of patients (73%, n=16) achieved maintenance doses in the medium-dose stratum, with fewer individual maintenance doses categorized in the high-dose stratum when compared to the GRIPHON study. This is likely multifactorial 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 are common and led to drug discontinuation in twice as many participants when compared to placebo in the GRIPHON study.6 Interestingly there were no cases of drug discontinuation in our cohort. Interestingly selexipag does not appear to lead to IP receptor desensitization over time, potentially due to partial antagonism of the IP receptor, and therefore future titrations are generally not be 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 6 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 hemodynamic data was not included. Nevertheless this study reflects ‘real-world’ experience of selexipag and helps to highlight 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.