Table 2.
Patients, etiology, end points, treatment effects, and adverse reactions in the Pivotal Phase III randomized controlled trials of the US Food and Drug Administration approved endothelin-1 receptor antagonists for the treatment of pulmonary arterial hypertension in adults.
| Channick et al. [27] | BREATHE-1 [28] | EARLY [29] | ARIES-1 [30] | ARIES-2 [30] | SERAPHIN [31] | |
|---|---|---|---|---|---|---|
| Patients (no.) | 32 | 213 | 185 | 202 | 192 | 742 |
| Drug | BOSENTAN | AMBRISENTAN | MACITENTAN | |||
| Dosing/route | 62.5–125 mg bid/os | 62.5–250 mg bid/os | 62.5–125 mg bid/os | 5 or 10 mg qd/os | 2.5 or 5 mg qd/os | 3 or 10 mg qd/os |
| Follow-up (months) | 3 | 4 | 6 | 3 | 3 | 24 |
| Etiology (%)* | ||||||
| IPAH | 85 | 70 | 58 | 63 | 65 | 56 |
| CTD | 15 | 30 | 20 | 29 | 30 | 30 |
| CHD | — | — | 17 | — | — | 8 |
| HIV | — | — | 5 | 5 | 3 | 1 |
| Anorexigen use | — | — | — | 3 | 2 | 3 |
| Functional class (%) | ||||||
| NYHA/WHO II | — | — | 100 | 30 | 45 | 52 |
| NYHA/WHO III | 100 | 91 | — | 60 | 52 | 46 |
| NYHA/WHO IV | 9 | — | 10 | 3 | 2 | |
| Primary end point | 6MWD | 6MWD | 6MWD Hemodynamics |
6MWD | 6MWD | Composite/events† |
| Treatment effects | ||||||
| Δ6MWD (m) | 76 | 44 | 19 | 31 and 51 | 32 and 59 | 17 and 22 |
| Hemodynamics | Improved | N/A | Improved | No change | No change | Improved |
| Clinical worsening | Reduced | Reduced | Reduced | Reduced | Reduced | Reduced |
| Adverse reactions | Headache, flushing, syncope, anemia, and elevated liver aminotransferase values | Peripheral edema, nasal congestion, and flushing | Anemia, headache, and nasopharyngitis | |||
BREATHE: Bosentan Randomized Trial of Endothelin Antagonist THErapy; EARLY: Endothelin Antagonist tRial in mildLY symptomatic pulmonary arterial hypertension patients; ARIES: Ambrisentan in pulmonary arterial hypertension, RandomIzed, double-blind, placebo-controlled, multicenter, efficacy study; SERAPHIN: Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve cliNical outcome; bid: twice daily; qd: once-daily; os: oral; *sum of percentage may not be 100% for rounding to the nearest unit; 0.5 is rounded to the upper unit; IPAH: idiopathic pulmonary arterial hypertension; CTD: connective tissue disease; CHD: congenital heart disease (congenital systemic-to-pulmonary shunts); HIV: human immunodeficiency virus; NYHA: New York Heart Association; WHO: World Health Organization; 6MWD: 6 min walking distance; †primary end point, time from the initiation of treatment to the first occurrence of a composite of death, atrioseptostomy, lung transplantation, initiation of prostanoids, or worsening of PAH; Δ: mean (or median) change from baseline.