By 30 November 2022, 535 out of 698 (77%) patients had data allowing for risk assessment calculation at baseline. Of these, 14% (N = 76) were in the low risk group, 31% (N = 168) in the intermediate-low risk group, 34% (N = 182) in the intermediate-high risk group and 20% (N = 109) in the high risk group. The demographics and baseline characteristics of these patients are outlined in Table 1.

Overall, the population was predominantly female (71%), with idiopathic/heritable PAH (I/HPAH; 56%) or PAH associated with connective tissue disease (CTD-PAH; 27%), with a median age of 60 years and prevalent (2 years) PAH disease. Across the groups from low to high risk, there was an increase in the proportion of CTD-PAH and in age—ranging from 12%–40% and 46–68 years, respectively, and a decrease in the proportion of I/HPAH and in the time from diagnosis—ranging from 71%–52% and 3.2–1.6 years, respectively. There was a history of cardiovascular risk factors across all risk groups. The most prominent were history of smoking, systemic hypertension and obesity, which were reported in 13–18% of patients in the low risk group and 29–47% of patients in the higher risk groups (Fig. S1). Overall, the haemodynamic parameters worsened with increasing risk group. Diffusing capacity of lung for carbon monoxide, although only captured in a third of patients, decreased with increasing risk group. Values for the parameters used to calculate the risk score (WHO FC, 6MWD and NT-proBNP) worsened with increasing risk group, as expected. Demographics and baseline characteristics for the overall selexipag group are provided in Table 1 and Fig. S1.

The median (interquartile range [Q1, Q3]) duration of selexipag titration was comparable across all four risk groups, with a slightly shorter duration for patients in the high risk group compared to the other risk groups (low risk 1.9 [0.9, 3.0] months; high risk 1.6 [0.6, 2.4] months) (Table 2). The majority of patients in all risk groups completed their titration (85–93%), 1–10% were ongoing and 5–10% discontinued selexipag (Table 2). The median individualised dose was 800 µg b.i.d. for patients in the low, intermediate-low and intermediate-high risk groups, with a slightly lower dose for patients at high risk (median [Q1, Q3]: 600 [400, 1000] µg b.i.d.) (Table 2). The distribution of dose groups is outlined in Table S2. The proportion of patients with further dose adjustments after titration was comparable between the risk groups (28–35%) (Table 2), over a median of 4.2–6.1 months.

At 6 months prior to baseline, the majority of patients in all risk groups were on double combination PAH-specific therapy (57–63%). At baseline, the vast majority of patients in all risk groups initiated selexipag as part of triple combination therapy (range 74–81%), mainly with both an ERA and a PDE5i (Fig. 1). A detailed overview of therapies at baseline is provided in Table S3. This escalation to triple combination therapy with selexipag tended to occur within a shorter time from diagnosis for patients at high risk versus low risk (median [Q1, Q3]: 1.6 [0.5, 4.1] vs 3.2 [1.4, 9.3] years, respectively). Reasons for the initiation of selexipag are outlined in Table S4; expectation of further improvement was the main reason across all risk groups. Selexipag titration, dosing and treatment patterns for the overall selexipag group are displayed in Table 2 and Fig. 1.

PAH-specific treatment patterns at baseline. *Includes 163 patients who did not have sufficient data to allow for risk evaluation. †Includes patients with therapies that have missing start and end dates, and patients for whom it cannot be determined if the treatments are prior or concomitant. ERA endothelin receptor antagonist, PAH pulmonary arterial hypertension, PDE5i phosphodiesterase 5 inhibitor, PGI2 prostacyclin and its analogues, sGC soluble guanylate cyclase

The median (Q1, Q3) selexipag exposure duration was slightly longer for patients in the lower risk groups compared to the higher risk groups (low risk 11.5 [4.0, 25.3] months; intermediate-low risk 11.4 [4.0, 26.4]; intermediate-high risk 10.1 [3.7, 24.1]; high risk 9.0 [2.8, 17.2]) (Table 3). Over the selexipag exposure period, the proportion of patients hospitalised increased with increasing risk status (16%, 23%, 34%, 42% for the low, intermediate-low, intermediate-high and high risk groups, respectively) (Table 3). A greater proportion of hospitalisations were deemed PAH-related for patients in the high risk group (71%) compared to patients in the other risk groups (47–54%) (Table 3). The incidence rate for PAH-related hospitalisations was 6.0 (95% CI: 2.2, 13.1) per 100 person-years for patients at low risk and increased incrementally to 33.6 (95% CI: 22.2, 48.4) per 100 person-years for patients at high risk (Table 3). This indicates that for 100 patients over 1 year, 6.0 and 33.6 patients will have at least one PAH-related hospitalisation in the low risk and high risk groups, respectively. At 1-year, 88%, 84%, 69% and 58% patients were free from hospitalisation in the low, intermediate-low, intermediate-high and high risk groups, respectively (Fig. 2). Hospitalisations for the overall selexipag group are provided in Table 3 and Fig. S2.

Time to first all-cause hospitalisation during selexipag exposure illustrated using KM curves. Each curve is cut at the first timepoint where < 10% of patients in the group are left at risk. Patients with a hospitalisation ongoing at baseline were excluded from the KM analysis. KM estimates (95% CI) shown at 12 and 24 months. For the high risk group, patient numbers were insufficient at 24 months to calculate a KM estimate. CI confidence interval, KM Kaplan–Meier

There were 1, 7, 22 and 23 deaths reported in the low, intermediate-low, intermediate-high and high risk groups, respectively. Of these, 0%, 71%, 65% and 80% were deemed PAH-related, as per judgement of the treating physician (Table 3). The majority of deaths were described as disease progression/PAH worsening for patients in the intermediate-high and high risk groups and right heart failure for patients in the intermediate-low risk group (Table 3). The mortality rate per 100 person-years (95% CI) increased incrementally with increasing risk group: 1.0 (0.0, 5.5), 3.1 (1.2, 6.3), 9.5 (5.9, 14.3) and 20.3 (12.9, 30.5) for patients at low, intermediate-low, intermediate-high and high risk, respectively (Table 3). KM estimates of survival in the respective risk groups were 98%, 98%, 93% and 80% at 1-year and 98%, 92%, 81% and 67% at 2-years. KM estimates of survival at 3-years were 98%, 92% and 76% for patients at low, intermediate-low and intermediate-high risk, respectively (Fig. 3). Survival for the overall selexipag group is provided in Table 3 and Fig. S3.

Time to all-cause death during selexipag exposure illustrated using KM curves. Each curve is cut at the first timepoint where < 10% of patients in the group are left at risk. KM estimates (95% CI) shown at 12, 24 and 36 months. For the high risk group, patient numbers were insufficient at 36 months to calculate a KM estimate. CI confidence interval, KM Kaplan–Meier

The proportion of patients that discontinued selexipag because of tolerability/AE during the exposure period was 12%, 14%, 15% and 23% for patients at low, intermediate-low, intermediate-high and high risk, respectively (Table 4). Other main reasons for discontinuation were PAH disease progression (5–9%) for all risk groups, and death for patients in the intermediate-high and high risk groups (12% and 21%, respectively) (Table 4). The most frequently reported AEs in all risk groups were consistent with targeting the prostacyclin pathway: diarrhoea and headache (Table 4). For patients in the high risk group, cardiac failure was also one of the most frequently reported AEs (6%; n = 6) (Table 4). Safety for the overall selexipag group is provided in Table 4.