Phosphodiesterase-5 inhibitors in management of pulmonary hypertension: safety, tolerability, and efficacy

Figures & data

Figure 1 Updated clinical classification system on the 2008 World Symposium.⁶

Abbreviations: ALK1, activin receptor-like kinase type 1; BMPR2, bone morphogenetic protein receptor type 2; HIV, human immunodeficiency virus.

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)^Citation27	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)^Citation35	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
Simmonneau^Citation28	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
Bharani^Citation36	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
Bharani^Citation29	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
Sastry^Citation30	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)^Citation31	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
Singh^Citation32	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
Ghofrani^Citation33	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
Ghofrani^Citation34	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.

Table 2 Phosphodiesterase-5 inhibitor pharmacokinetic profile^44–46

Drug	Bioavailability (%)	Time to peak onset (hours)	Metabolism (metabolite activity)	Half-life (hours)	Elimination	Protein binding (%)
Sildenafil	41	0.5–2	Hepatic (active)	4	Fecal (80%) Renal (13%)	96
Tadalafil	N/A	2–8	Hepatic (inactive)	15	Fecal (61%) Renal (36%)	94
Vardenafil	15	0.5–2	Hepatic (active)	4–5	Fecal (91%–95%) Renal (2%–6%)	95

Abbreviation: N/A, not available.

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