Table 3.
Liver function tests, enzyme elevations, hepatic adverse events, and hepatic adverse events of special interest
| OPUS and OrPHeUS | ||
|---|---|---|
| Overall follow‐up set | PAH follow‐up seta | |
| N = 5650 | N = 4626 | |
| Liver function tests | ||
| Rate—per person‐year (95% CI) (entire macitentan exposure period) | 2.0 (2.0, 2.1) | 2.0 (1.9, 2.1) |
| Rate—per person‐year (95% CI) (first 6 months after macitentan initiation) | 2.6 (2.5, 2.7) | 2.5 (2.4, 2.6) |
| Patients with abnormal liver function testsb—KM estimates, % (95% CI) | ||
| At 3 months | 2.7 (2.3, 3.2) | 2.6 (2.2, 3.2) |
| Number at risk | 4484 | 3736 |
| At 6 months | 3.7 (3.2, 4.3) | 3.6 (3.1, 4.2) |
| Number at risk | 3865 | 3238 |
| Patients with ≥1 HAE—n (%) | 561 (9.9) | 457 (9.9) |
| Incidence rate—per person‐year (95% CI) | 0.07 (0.07, 0.08) | 0.07 (0.06, 0.08) |
| Most common HAEs (≥1% in either group)c | ||
| By Preferred Term—n (%) | ||
| Increased blood bilirubin | 113 (2.0) | 92 (2.0) |
| Increased AST | 104 (1.8) | 83 (1.8) |
| Increased ALT | 67 (1.2) | 57 (1.2) |
| Increased blood alkaline phosphatase | 66 (1.2) | 53 (1.1) |
| Laboratory values—n (%) | ||
| Patients with ALT/AST ≥ 3 × ULN | 186 (3.3) | 153 (3.3) |
| Patients with TBIL ≥ 2 × ULN | 227 (4.0) | 177 (3.8) |
| Patients with ≥1 HAESId— n (%) | 352 (6.2) | 281 (6.1) |
| Incidence rate—per person‐year (95% CI) | 0.04 (0.04, 0.05) | 0.04 (0.04, 0.05) |
| Most common HAESIs (≥1% in either group)c | ||
| By Preferred Term—n (%) | ||
| Increased blood bilirubin | 76 (1.3) | 64 (1.4) |
| Laboratory values—n (%) | ||
| Patients with TBIL ≥ 2 × ULN | 227 (4.0) | 177 (3.8) |
| Patients with ALT/AST ≥ 5 × ULN | 86 (1.5) | 67 (1.4) |
| Patients with ALT/AST ≥ 3 × ULN and TBIL ≥ 2 × ULN | 49 (0.9) | 36 (0.8) |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; HAE, hepatic adverse event; HAESI, hepatic adverse event of special interest; ILSDRB, Independent Liver Safety Data Review Board; KM, Kaplan–Meier; PAH, pulmonary arterial hypertension; TBIL, total bilirubin; ULN, upper limit of normal.
The PAH follow‐up set is part of the overall follow‐up set.
Defined as ALT ≥ 3 × ULN, AST ≥ 3 × ULN, and/or TBIL ≥ 2 × ULN.
Patients may appear in more than one row.
Of the 352 patients reporting HAESIs in the Overall follow‐up set, only two cases of increased liver enzymes were deemed by the ILSDRB to be possibly related to macitentan treatment.