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.