Sildenafil in the treatment of pulmonary hypertension

Figures & data

Table 1 Revised clinical classification of pulmonary hypertension

1.	Pulmonary arterial hypertension (PAH)
	1.1	Idiopathic (IPAH)
	1.2	Familial (FPAH)
	1.3	Associated with (APAH):
		1.3.1	Collagen vascular disease
		1.3.2	Congenital systemic-to-pulmonary shunts
		1.3.3	Portal hypertension
		1.3.4	HIV infection
		1.3.5	Drugs and toxins
		1.3.6	Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)
	1.4	Associated with significant venous or capillary involvement
		1.4.1	Pulmonary veno-occlusive disease (PVOD)
		1.4.2	Pulmonary capillary hemangiomatosis (PCH)
	1.5	Persistent pulmonary hypertension of the newborn
2.	Pulmonary hypertension (PH) with left heart disease
	2.1	Left-sided atrial or ventricular heart disease
	2.2	Left-sided valvular heart disease
3.	PH associated with lung disease and/or hypoxemia
	3.1	Chronic obstructive pulmonary disease
	3.2	Intersitial lung disease
	3.3	Sleep-disordered breathing
	3.4	Alveolar hypoventilation disorders
	3.5	Chronic exposure to high altitude
	3.6	Development abnormalities
4.	PH due to chronic thrombotic and/or embolic disease
	4.1	Thromboembolic obstruction of proximal pulmonary arteries
	4.2	Thromboembolic obstruction of distal pulmonary arteries
	4.3	Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)
5.	Miscellaneous
	Sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangiomatosis, compression of pulmonary vessels by adenopathy, tumor fibrosing mediastinitis, or other process

Adapted with permission from Simonneau G, Galie N, Rubin LJ, et al. 2004. Clinical classification of pulmonary hypertension. J Am Coll Cardiol, 43:5S–12S. © 2004 Elsevier.

Figure 1 Mechanism of vasodilatory and antiproliferative effects of sildenafil. NO from vascular endothelial cells stimulates the activity of sGC which produces cGMP from GTP. Sildenafil inhibits the breakdown of cGMP to GMP by PDE 5, increasing cellular concentrations of cGMP which increases the formation of PKG. Competitive inhibition of PDE inhibits breakdown of cAMP which stimulates increased production of PKA. Vasodilation results primarily from modulation of ion channel activity by cGMP with a lesser contribution from increased levels of cAMP. Inhibition of smooth muscle cell proliferation occurs via increased levels of PKA and PKG.

Abbreviations: AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; PDE 5, phosphodiesterase type 5, PKA, cAMP dependent protein kinase; PKG, cGMP dependent protein kinase; sGC, soluble guanylate cyclase.

Table 2 Summary of randomized controlled trials of sildenafil in the treatment of PAH (Bharani et al 2003; Sastry et al 2004; Galiè et al 2005)

	Baharani 2003	Sastry 2004	Galiè 2005
Trial design	Randomized, placebo controlled, double blind, crossover	Randomized, placebo controlled, double blind, crossover	Randomized double blind, placebo controlled
No (male)	9 (4)	22 (10)	277 (68)
Etiology (number)	Idiopathic PAH (3)	Idiopathic PAH (22)	Idiopathic PAH (175)
	Left to right shunt (3)		CTD (84)
	Thromboembolism (1) ILD (2)		Left to right shunt (18)
Duration	2 weeks	6 weeks	12 weeks
Primary outcome	6 min walk 170 m at end of placebo phase vs 266 m at end of sildenafil phase, p<0.005	Exercise treadmill time 475±168 s at end of placebo phase vs 686±224 s at end of sildenafil phase, p<0.0001	Placebo corrected increase in mean 6 min walk distance 20, 40, and 80 mg; 45, 46, and 50 m (p<0.001)
Secondary outcomes	Significant improvement in Borg dyspnea score and PASP	Significant improvement in cardiac index and QOL, no change in PASP	Significant improvement in mPAP, CI (40 and 80 mg dose), PVR,WHO functional class, no change in time to worsening or Borg dyspnea scale
Adverse effects	None reported	Similar to placebo	Increased rate of headache and epistaxis in sildenafil group

Abbreviations: CTD, connective tissue disease; ILD, interstitial lung disease; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PASP, pulmonary artery systolic pressure; PVR, pulmonary vascular resistance; QOL, quality of life.

Table 3 Results of the Super-1 trial showing improvements in hemodynamics and 6 minute walk test with use of sildenafil

Effect at 8 weeks	Placebo (95% confidence interval)	20 mg (95% confidence interval)	40 mg (95% confidence interval)	80 mg (95% confidence interval)
6 minute walk distance (placebo corrected, in meters)		45 (21, 70)	46 (20, 72)	50 (23, 77)
Mean pulmonary artery pressure (mmHG)	0.6 (−0.8, 2.0)	−2.1 (−4.3, 0.0)	−2.6 (−4.4, −0.9)	−4.7 (−6.7, −2.8)
Cardiac index (L·min^−1·m^−2)	−0.02 (−0.17, 0.13)	0.21 (0.04, 0.8)	0.24 (0.05, 0.42)	0.37 (0.20, 0.55)
PVR (dynes·s^−1·cm^−5)	49 (−54, 153)	−22 (−217, −27)	−143 (−218, −69)	−261 (−365, −157)

Abbreviations: PVR, pulmonary vascular resistance.

SimonneauGGalieNRubinLJClinical classification of pulmonary hypertensionJ Am Coll Cardiol2004435S12S15194173

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BharaniAMathewVSahuAThe efficacy and tolerability of sildenafil in patients with moderate-to-severe pulmonary hypertensionIndian Heart J20035555912760589

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SastryBKSNarasimhanCReddyNKClinical efficacy of sildenafil in primary pulmonary hypertension:A randomized, placebo-controlled, double-blind, crossover studyJ Am Coll Cardiol20044311495315063421

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GalièNGhofraniHATorbickiASildenafil citrate therapy for pulmonary arterial hypertensionN Engl J Med200535321485716291984

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