Table 1.
Randomized clinical studies of the phosphodiesterase-5 inhibitors in pulmonary arterial hypertension
| Author | n | PAH definition | PAH class/type | Study regimen(s) | Control regimen(s) | Concomitant medications |
Results |
||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Exercise capacity | MPAP/SPAP | CI/CO | Functional class | QOL | |||||||
| Galiè (SUPER study)27 | 278 | MPAP ≥ 25 and PCWP ≤ 15 | WHO Class I–IV | Sildenafil (3 study doses): 20, 40, or 80 mg PO TID × 12 weeks. Long-term study phase: all patients titrated to 80 mg PO TID. | Placebo | Conventional therapy allowed (specific drugs N/A) | ↑ | ↓ | ↑ | ↓ | N/A |
| Galiè (PHIRST study)35 | 405 | MPAP ≥ 25, PVR ≥ 3, PCWP ≤15 | WHO Class I–IV | Tadalafil 2.5 mg, 10 mg, 20 mg, 40 mg or placebo PO daily × 16 weeks. | Placebo | Bosentan: maximal use 125 mg twice daily for minimum of 12 weeks at time of screening | ↑ | ↓ | ↑ (CI) 40 mg group only | ↔ | ↑ 40 mg group only |
| Simmonneau28 | 267 | N/A | WHO Class I–IV) | IV epoprostenol + sildenafil 20 mg PO TID × 4 weeks, increased to 40 mg PO TID × 4 weeks, 80 mg PO TID × 4 weeks. | Placebo + epoprostenol | None | ↑ | ↓ | ↑ (CO) | N/A | N/A |
| Bharani36 | 11 | SPAP > 35 | WHO Class II–III | Tadalafil 20 mg once daily or placebo × 4 weeks, followed by 2-week drug-free interval, then crossed over to other regimen. | Placebo | Diuretics, oral anticoagulants, digoxin | ↑ | ↓ (SPAP) | N/A | ↔ | N/A |
| Bharani29 | 9 | SPAP ≥ 35 | NYHA II–IV | 25 mg PO BID × 2 weeks; with 2-week washout, then crossover × 2 weeks. | Placebo | Digoxin, diuretics, oral anticoagulants, nifedipine | ↑ | ↓ (SPAP) | N/A | ↔ | N/A |
| Sastry30 | 22 | MPAP ≥ 30 | NYHA II and III | Weight-based dosing: <26 kg = 25 mg PO TID; 26–50 kg = 50 mg PO TID; >50 kg = 100 mg PO TID × 6 weeks. Crossover between sildenafil and placebo, then by another 6 weeks. | Placebo | Digoxin, diuretics, oral anticoagulants | ↑ | ↔ (SPAP) | ↑ | N/A | ↑ |
| Wilkins (SERAPH study)31 | 26 | MPAP ≥ 25 | NYHA III only | 50 mg PO BID × 4 weeks; 50 mg PO TID × 12 wks. (all sildenafil patients were transitioned to open-label bosentan in fifth month) | Bosentan: 62.5 mg PO BID × 4 weeks; 125 mg PO BID × 12 weeks. Open-label bosentan in fifth month. | Digoxin, diuretics, oral anticoagulants, calcium channel blockers | ↑ | N/A | ↔ | N/A | |
| Singh32 | 20 | N/A | NYHA II–IV | Adults: 25 mg × 1; repeated 6 hours. If tolerated, 100 mg PO TID × 6 weeks; 2-week wash-out then crossover × 6 weeks. (Children very detailed regimen) | Placebo | N/A | ↑ | ↓ | N/A | ↓ | N/A |
| Ghofrani33 | 30 | MPAP > 40 | NYHA III–IV | Sildenafil 12.5 mg; sildenafil 12.5 mg + iloprost 2.8 μg; sildenafil 50 mg; sildenafil 50 mg + iloprost 2.8 μg. Iloprost administered 1 hour after sildenafil dose. | iNO administered, iloprost administered after hemodynamic values returned to baseline. | None | N/A | ↓(dose-depend) | ↑(increase x 5% 12.5 mg and 13.2% 50 mg) | N/A | N/A |
| Ghofrani34 | 60 | N/A | NYHA II–IV | Sildenafil 50 mg × 1; vardenafil 10 mg × 1; vardenafil 20 mg × 1; tadalafil 20 mg × 1; tadalafil 40 mg × 1; or tadalafil 60 mg × 1 | iNO 20–40 ppm | N/A | N/A | ↓ (all treatments) | N/A | N/A | N/A |
Abbreviations: BID, twice daily; CI, cardiac index; CO, cardiac output; iNO, inhaled nitric oxide; IV, intravenous; LV, left ventricle; MPAP, mean pulmonary arterial hypertension; N/A, not reported; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; QOL, quality of life; SPAP, systolic pulmonary arterial hypertension; TID, three times daily; WHO, World Health Organization; ↑, increased effect/variable; ↓, decreased effect/variable; ↔, no effect.