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Sildenafil

Phosphodiesterases inactivate cyclic adenosin and guanosin monophosphate, the second messengers of prostacyclin and NO, and therfore may augment and prolong the vascular effects of for instance prostacyclin, which in turn acts via activation of adenylate cyclase (1). The selective phosphodiesterase-5 inhibitor sildenafil has been approved for treatment of erectile dysfunction (2). Generally, sildenafil causes only slight systemic and hemodynamic changes (3). Recent case series have confirmed the theoretical considerations with respect to the potential benefits in PH of an increase in guanosin monophosphate by demonstrating an additive and longer lasting effect of oral sildenafil in various doses in addition to aerosolized iloprost (4, 5).

Sildenafil at a single dose of 50 mg was shown to decrease PVR by 24 % in patients on iv epoprostenol for an average of three years and at a mean dose of 26 ng/kg/min, in contrast to NO, which had no significant effect (6). Long-term addition of sildenafil to iv epoprostenol reduced PVR by 14 to 41% in three patients (7).

In a first small cross over trial in 22 patients, oral sildenafil in daily doses from 25 to 100 mg tid. resulted in an increase in exercise time, an improvement of hemodynamics and quality of life (8). Recently, the large randomized, double-blind, placebo-controlled SUPER-1 trial has demonstrated that all three doses of sildenafil, e. g. 20, 40, and 80 mg tid, respectively, improved the 6-minute walking distance by 45, 46, and 50 m, respectively, with no significant difference between the three treatment regimens (9). In addition, there was an improvement in WHO/NYHA functional class and hemodynamics. Although there was no difference in time to clinical worsening, the proportion of hospitaliziations for PH was significantly lower with sildenafil (p=0.02). Another small randomized cross over trial in 20 patients with severe PAH also found a significantly improved WHO/NYHA functional class, 6-minute walking distance, and hemodynamic parameters (10). As a consequence of the SUPER-1 trial sildenafil 20 mg tid. (Revatio®) has become the accepted dose in patients with PAH.

Although all the previous at least 8 open trials of sildenafil in PH have used the dose of 50 mg tid. (11), the SUPER-1 trial failed to show a dose dependency of the effect of sildenfafil on the 6-minute walking distance (9). Notwithstanding, many experts have seen deteriorations in patients who were switched from the 50 mg tid to the 20 mg tid sildenafil dose (personal communications). In addition, it should be emphasized that so far there are no long-term data with the lower sildenafil dose, since in the SUPER-1 extension trial (SUPER-2 trial), which demonstrated an impressive 1-year survival of 96 % compared with an expected of 71 % (12), all except two of these patients had been up-titrated to receive the highest dose of 80 mg tid (Corris P. personal communication). Hence, down titration of patients on 50 mg tid. of Viagra® should be performed with caution, and an increase in dosage may be necessary in patients on Revatio® 20 mg tid. who fail to respond to treatment, especially those already on bosentan, because the latter decreases the area under the curve of sildenafil by more than 60 % (13).

So far, there is no clinical experience with other phosphodiesterase inhibitors. Thus, notwithstanding the advantage of more convenient dosing, these drugs can not be recommended at the present time. Moreover, it has to be emphasized that for instance tadalafil has no selectivity for the pulmonary circulation compared to sildenafil and vardenafil (14).


Table 3. Randomized controlled trials of oral sildenafil

Trial	Sastry 2004 (8)	Galie, 2005 (9)	Singh, 2006 (10)
Treatment	Sildenafil	Sildenafil	Sildenafil
Patients (n)	22	278	20
Etiology of PH  IPAH / CTD / CHD	100 / 0 / 0	64 / 30 / 6	50 / 0 / 50
NYHA II / III / IV (%)	0 / 82 / 18	39 / 58 / 3	40 / 55 / 5
Duration (m)	1.5 (crossover)	3	1.5 (crossover)
Primary endpoint	Exercise time	6-MW
Improvement  in 6-MW (m)  compared to controls	+44%	+50	+65
Improvement in  other enpoints	Hemodyn  QOL	Hemodyn   NYHA	Hemodyn  NYHA
Side effects	-	-	-

 
References:

1. Matsumoto T, Kobayashi T, Kamata K. Phosphodiesterases in the vascular system. J Smooth Muscle Res 2003;39:67-86.

2. Salonia A, Rigatti P, Montorsi F. Sildenafil in erectile dysfunction: a critical review. Curr Med Res Opin 2003;19:241-262.

3. Raja SG, Nayak SH. Sildenafil: emerging cardiovascular indications. Ann Thorac Surg 2004;78:1496-1506.

4. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, Weissmann N, Ghofrani S, Enke B, Seeger W, Grimminger F. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158-164.

5. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M, Sybrecht GW, Schermuly RT, Roehl A, Weissmann N. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001;104:1218-1222.

6. Kuhn KP, Wickersham NE, Robbins IM, Byrne DW. Acute effects of sildenafil in patients with primary pulmonary hypertension receiving epoprostenol. Exp Lung Res 2004;30:135-145.

7. Stiebellehner L, Petkov V, Vonbank K, Funk G, Schenk P, Ziesche R, Block LH. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003;123:1293-1295.

8. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004;43:1149-1153.

9. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005;353:2148-2157.

10. Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 2006;151:851 e851-855.

11. Lee AJ, Chiao TB, Tsang MP. Sildenafil for pulmonary hypertension. Ann Pharmacother 2005;39:869-884.

12. Corris P, Burgess G, Parpia T, Barst R. Sildenafil effects on 1-year survival of patients with idiopathic pulmonary arterial hypertension (IPAH). Eur Respir J 2005;26:475s.

13. Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 2005;60:107-112.

14. Ghofrani HA, Voswinckel R, Reichenberger F, Olschewski H, Haredza P, Karadas B, Schermuly RT, Weissmann N, Seeger W, Grimminger F. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol 2004;44:1488-1496.

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