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Sildenafil (Viagra) for erectile dysfunction update

 

Clinical bottom line

Sildenafil was effective in treating men with erectile dysfunction of mixed aetiology, and with diabetes or spinal cord lesions, at home. For those with mixed aetiology the NNT was 2. About 75% of men treated at home had erections suitable for intercourse, at an increased rate than with placebo, and about as frequently as men with no erectile dysfunction. Adverse event withdrawals were rare.


Searching

Searching was done using PubMed, Medline and the Cochrane Library, up to end 2000. Randomised trials in which sildenafil was compared with placebo were sought. Details of the trials were abstracted and quality scoring done with a 5 point scale. For crossover or partial crossover designs, details of the first phase were used (as a parallel group trial) where possible, and where this was not possible the full crossover data was used.

The outcome sought was patient/partner judgement of satisfactory erections suitable for intercourse, or actual intercourse, at home. Ideally this was on a patient basis, rather than on event basis, which was a secondary outcome. Relative risk and NNT were calculated using standard methods.

Results

There were four trials in three papers in men with erectile dysfunction of mixed aetiology, and two reports each for men with erectile dysfunction caused by spinal cord lesion or diabetes (Table 1). These trials used the IIEF questionnaire, and usually reported the results of important questions as means. This is of little value, because while it tells us that sildenafil was better than placebo, or that a value rose from X to 2X, it does not tell us the number or proportion of men achieving an adequate outcome. However, the number of men achieving erections satisfactory for vaginal intercourse was given, and in most cases this did result in intercourse, so it is a useful surrogate for the outcome we most want.

Doses of sildenafil were either fixed at 25, 50, or 100 mg, or were adjusted by the patients to 25, 50, or 100 mg starting with 50 mg. The results given are predominantly those from the final four weeks of the treatment period.

Table 1: Details of randomised trials of sildenafil

Study

Design

Quality score

Patients

Treatment

Outcome

Result

Adverse events

Erectile dysfunction of mixed aetiology
Dinsmore et al, 1999 Randomised, double blind, parallel group

4

Men with erectile dysfunction of six months or more. Mean age 55 years Oral sildenafil (25, 50 or 100 mg optional) or placebo for 12 weeks, plus nondrug control of men without erectile dysfunction IIEF and other diary records about erections Global efficacy 46/57 sildenafil and 10/54 placebo. 1.7 vs 0.6 erections hard enough for penetration a week, and 73% vs 30% successful attempts at intercourse for sildenafil and placebo respectively No adverse event discontinuations. Otherwise mild
Goldstein et al, 1998 Study 1 Randomised, double blind, parallel group

3

532 men with erectile dysfunction of mixed aetiology. Mean age 58 years Oral sildenafil 25mg , 50mg or 100 mg fixed dose or placebo for 24 weeks IIEF and other diary records about erections Improved erections 54/96 on 25 mg, 81/105 on 50 mg, 84/101 on 100 mg and 50/199 on placebo. Over 85% of these resulted in successful intercourse. Number per week was 1.1 with 25 mg, 1.7 with 50 mg, 1.7 with 100 mg and 0.8 with placebo 4/316 adverse event discontinuations with sildenafil and 1/216 with placebo
Goldstein et al, 1998 Study 2 Randomised, double blind, parallel group

3

329 men with erectile dysfunction of mixed aetiology. Mean age 60 years Oral sildenafil (25, 50 or 100 mg optional) or placebo for 12 weeks IIEF and other diary records about erections Improved erections 101/136 on sildenafil and 23/118 on placebo. Over 70% of these resulted in successful intercourse. 1/163 adverse event discontinuations with sildenafil and 1/166 with placebo
Montorsi et al, 1999 Randomised, double blind, parallel group

4

514 men with erectile dysfunction of mixed aetiology. Mean age 56 years Oral sildenafil 25mg , 50mg or 100 mg fixed dose or placebo for 12 weeks IIEF and other diary records about erections Improved erections 86/128 on 25 mg, 103/132 on 50 mg, 109/127 on 100 mg and 30/127 on placebo. Over 65% of these resulted in successful intercourse. Number per week was 1.1 to 1.4 with sildenafil and 0.4 with placebo Adverse event discontinuations were 0/128 with 25 mg, 1/132 with 50 mg, 5/127 with 100 mg and 1/127 with placebo
Erectile dysfunction from spinal cord lesion or diabetes
Derry et al, 1998 Randomised, double blind, parallel group

4

Men with documented spinal cord injury causing erectile dysfunction. Age range 21 to 49 years Oral sildenafil 50 mg or placebo for four weeks about one hour before sexual activity Global efficacy about improved erections Global efficacy 9/12 sildenafil and 1/14 placebo. 1.8 vs 0.4 erections hard enough for penetration a week, and 30% vs 15% successful attempts at intercourse for sildenafil and placebo respectively No significant adverse events
Giuliano et al, 1999 Randomised, double blind, crossover

5

Men with documented spinal cord injury causing erectile dysfunction. Age range 21 to 49 years Oral sildenafil (25, 50 or 100 mg optional) or placebo for 6 weeks Global efficacy about improved erections, plus successful intercourse attempts Improved erections 127/168 with sildenafil and 7/168 with placebo. 73/175 on sildenafil reported successful intercourse for more than 60% of attempts, and 6/174 with placebo. 3/178 adverse event discontinuations with sildenafil, 1/178 with placebo
Price et al, 1998 Randomised, double blind, crossover

3

21 diabetic men with erectile dysfunction of at least six months duration. Mean age 51 years Oral sildenafil 25mg or 50mg fixed dose or placebo daily for 10 days Erections sufficient for intercourse over 10 days Mean number of erections 0.6 for placebo, 1.3 for 25 mg and 1.6 for 50 mg sildenafil 1 severe adverse event with placebo, 3 with 25 mg and vive with 50 mg sildenafil
Rendell et al, 1999 Randomised, double blind, parallel group

4

269 men with diabetes. Mean age 57 years Oral sildenafil (25, 50 or 100 mg optional) or placebo for 12 weeks IIEF and other diary records about erections Improved erections 74/131 with sildenafil and 13/127 with placebo. At least one successful attempt at intercourse 71/117 with sildenafil and 25/114 with placebo. Adverse event withdrawals 1/132 placebo and 1/136 sildenafil

Erectile dysfunction of mixed cause

The four trials enrolled nearly 1,400 men, 879 of whom received sildenafil and 498 placebo. Erections at home predominantly resulting in intercourse occurred in 664/879 men (76% 95% CI 73-78%) with sildenafil and 113/498 (23% 95% CI 19 to 26%) with placebo (Figure 1). The relative benefit was 3.3 (2.8 to 3.9). The number needed to treat was 1.9 (1.7 to 2.1). This means that one of every two men treated with sildenafil will have erections at home suitable for intercourse who would not have done with placebo.

Figure 1: L'Abbé plot for sildenafil versus placebo in dysfunction of mixed aetiology

(red symbols mixed aetiology, cyan spinal cord lesions and yellow diabetes)

 In these trials the average successful attempts at intercourse was 1.3 to 1.7 times with sildenafil, compared with 0.4 to 0.8 times with placebo.

Figure 2: Number of successful attempts at intercourse a week in thee different trials

Erectile dysfunction with spinal cord lesion

Of the two studies that examined this, one was small but the other large. 45% of men with spinal cord lesions reported successful intercourse for more than 6/10 of the attempts made, compared with just a few percent with placebo. 76% of men reported improved erections with sildenafil compared with 4% with placebo. The relative benefit was 17 (9-34) and the NNT 1.4 (1.3 to 1.6).

Erectile dysfunction with diabetes

One large study reported outcomes of interest. At least one successful attempt at intercourse was made by 61% of men on sildenafil and 22% of men on placebo. Improved erections were reported by 56% of men on sildenafil and 10% of men on placebo. The relative benefit was 5.5 (3.2 to 9.4) and the NNT 2.2 (1.8 to 2.8).

Comment

Aficionados of systematic reviews will spot that there have been several instances of duplicated publication of trials in the reference lists below. Some potentially includable trials have been omitted because of a likelihood that they were part publication of multicentre trails.

Aficionados will also note that the L'Abbé plot shows remarkable concordance between trials, a result of the size and similarity of the trial designs. Despite this, outcomes were reported as mean values, pretty useless when answers to specific and meaningful questions have been reduced to (meaningless) numbers and then meaned. Ye gods, we yearn for more simplicity. Perhaps this is the real exemplar about making the important measurable rather than making what has been measured important.

The bottom line, though, is that sildenafil is an effective treatment for erectile dysfunction in men with problems because of mixed aetiology, and in those with diabetes or spinal cord lesions. The NNT of about 2 is probably slightly generous because the outcome of erections satisfactory for intercourse is not quite the same as intercourse, but in the end that may be something of a quibble, and of little relevance to people.

The comparison with health age-matched men (Dinsmore et al, 1998) is interesting, because it allows comparison with that population at baseline and after treatment. In a rather simplified summary, it shows that men with erectile dysfunction treated with sildenafil become about the same as men of the same age without erectile dysfunction.

We have not drawn together the adverse event data, but will examine two reviews of sildenafil adverse events to see if they can be abstracted sensibly. Adverse event withdrawals were rare in the trials, though.

References

Reference

Notes

Derry FA, Dinsmore WW, Fraser M et al. Efficacy and safety of oral sildenafil (Viagra) in men with erectile dysfunction caused by spinal cord injury. Neurology 1998; 51(6):1629-33. Considered for review
Dinsmore WW, Hodges M, Hargreaves C, Osterloh IH, Smith MD, Rosen RC. Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects [published erratum appears in Urology 1999 May;53(5):1072]. Urology 1999; 53(4):800-5. Considered for review
Giuliano F, Hultling C, El Masry WS et al. Randomized trial of sildenafil for the treatment of erectile dysfunction in spinal cord injury. Sildenafil Study Group. Ann Neurol 1999; 46(1):15-21. Considered for review
Goldstein I, Lue TF, Padma-Nathan H et al. Oral sildenafil in the treatment of erectile dysfunction. The New England Journal of Medicine 1998; 338(Number 20):1397-404. Considered for review
Maytom MC, Derry FA, Dinsmore WW et al. Sildenafil (ViagraTM) - a two-stage, double-blind, placebo-controlled study in men with erectile dysfunction (ED) caused by tramautic spinal cord injury (SCI). Spinal Cord 1999; 37(2):110-6. Duplicate of Derry et al, 1998
Montorsi F, McDermott TE, Morgan R et al. Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies. Urology 1999; 53(5):1011-8. Considered for review
Padma Nathan H, Steers WD, Wicker PA. Efficacy and safety of oral sildenafil in the treatment of erectile dysfunction: a double-blind, placebo-controlled study of 329 patients. Sildenafil Study Group [see comments]. Int J Clin Pract 1998; 52(6):375-9. Duplicate of study 1 in Goldstein et al, 1998
Price DE, Gingell JC, Gepi Attee S, Wareham K, Yates P, Boolell M. Sildenafil: study of a novel oral treatment for erectile dysfunction in diabetic men. Diabet Med 1998; 15(10):821-5. Considered for review
Rendell MC, Rafjer J, Wicker PA et al. Sildenafil for treatment of erectile dysfunction in men with diabetes. A randomized controlled trial. JAMA 1999; 281-(No. 5):421-426. Considered for review
 
Sildenafil: an oral drug for impotence. Med Lett Drugs Ther 1998; 40:51-2. Review
Sildenafil Viagra(R) UK-92480: Treatment of erectile dysfunction phosphodiesterase V inhibitor. DRUGS-FUTURE Drugs-of-the-Future. 1998; 23(2):242-3. Review
Aversa A, Mazzilli F, Rossi T, Delfino M, Isidori AM, Fabbri A. Effects of sildenafil (Viagra) administration on seminal parameters and post-ejaculatory refractory time in normal males. Hum Reprod 2000; 15(1):131-4. Study in normal volunteers
Barry MJ. Sildenafil improved sexual function in erectile dysfunction. EVID-BASED-MED Evidence-Based-Medicine. 1998; 3(6):184. Review
Berger A. The rise and fall of viagra. BMJ 1998; 317(7161):824. Review
Boolell M, Gepi-Attee S, Gingell JC, Allen MJ. Sildenafil, a novel effective oral therapy for male erectile dysfunction. British Journal of Urology 1996; 78:257-61. Lab not home setting 12 patients
Cheitlin MD. Sildenafil (viagra rho ): Use and precautions in patients with cardiovascular disease. CARDIOVASC-REV-REP Cardiovascular-Reviews-and-Reports. 1999; 20(3):143-5. Review
Cheitlin MD, Hutter AM Jr, Brindis RG et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999; 33(1):273-82. Review
Conti CR, Pepine CJ, Sweeney M. Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am J Cardiol 1999; 83(5A):29C-34C. Review
Derry F et al (Viagra): An oral treatment for erectile dysfunction caused by traumatic cord injury -a 28 day, double-blind, placebo controlled, parallel-group, dose response [Abstract]. Journal of the Neurological Sciences 1997; S270. Abstract
Derry F et al. Sildenafil (Viagra): an oral treatment for men with erectile dysfunction caused by traumatic spinal cord injury - a 28-day, double-blind, placebo-controlled, parallel-group, dose response study. Neurology 1997; 48(3:A215. Abstract
Derry F GCDWWFMGBMGMMOMOIaSM. Sildenafil (Viagra): a double-blind, placebo controlled, single dose, two-way crossover study in men with erectile dysfunction caused by traumatic spinal cord injury. J Neurol Sci 1997; 150:S134-S134. Abstract
Dunn A. Sildenafil: a new therapy for erectile dysfunction. Conn Med 1998; 62(7):413-6. Review
Eardley I, Brooks J, Yates PK, Ellis P, Boolell M. Sildenafil citrate (VIAGRA registered ): An oral treatment for erectile function with activity for up to four hours' duration. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):32-4. Lab, not home setting
Feldman R, Meuleman EJH, Steers W. Sildenafil citrate (VIAGRA registered ) in the treatment of erectile dysfunction: Analysis of two flexible dose-escalation studies. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):10-2. Possible duplicate
Gingell CJC, Jardin A, Olsson AM et al. A new oral treatment for erectile dysfunction: a double-blind, placebo-controlled, once daily dose response study. American Urological Association 1996; 155(Supp. 495A). Abstract
Giuliano F, Hultling C, El Masry WS et al. Sildenafil citrate (VlAGRA registered ): A novel oral treatment for erectile dysfunction caused by traumatic spinal cord injury. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):24-6. Definite duplicate
Goldenberg MM. Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction. Clin Ther 1998; 20(6):1033-48. Review
Hartmann U, Meuleman EJH, Cuzin B et al. Sildenafil citrate (VIAGRA registered ): Analysis of preferred doses in a European, six-month, double-blind, placebo-controlled, flexible dose-escalation study in patients with erectile dysfunction. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):27-9. Possible duplicate
Herschorn S. Sildenafil improved erections and increased successful sexual intercourse in diabetic men with erectile dysfunction. EVID-BASED-MED Evidence-Based-Medicine. 1999; 4(4):111. Review
Holmgren E, Giuliano F, Hulting C et al. Sildenafil (VIAGRATM) in the treatment of erectile dysfunction (ED) caused by spinal cord injury (SCI) a double-blind, placebo-controlled, flexible-dose,two-way crossover study. poster
Hultling C. Partners' perceptions of the efficacy of sildenafil citrate (VIAGRA registered ) in the treatment of erectile dysfunction. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):16-8. Retrospecive analysis
Kalinichenko SIu, Kozlov GI, Mel'nichenko GA, Dedov II. [Sildenafil citrate (viagra) treatment in patients with diabetes mellitus]. Ter Arkh 1999; 71(10):78-80. Russian
Kloner RA, Zusman RM. Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol 1999; 84(5B):11N-7N. Review
Langtry HD, Markham A. Sildenafil: a review of its use in erectile dysfunction. Drugs 1999; 57(6):967-89. Review
Lipshultz LI, Kim ED. Treatment of erectile dysfunction in men with diabetes. J-AM-MED-ASSOC Journal-of-the-American-Medical-Association. 1999 FEB 03; 281(5):465-6. Review
Meinhardt W, Kropman RE, Vermeij P. Comparative tolerability and efficacy of treatments for impotence. Drug Safety 1999; 20((2)):133-46. Review
Menarguez Puche JF, Martinez Bienvenido EM. [Sildenafil and erectile dysfunction]. Aten Primaria 1998; 22(6):379-86. Review
Merrick GS, Butler WM, Lief JH, Stipetich RL, Abel LJ, Dorsey AT. Efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology 1999; 53(6):1112-6. Not an RCT
Morales A, Gingell C, Collins M et al. Clinical safety of oral sildenafil citrate (VIAGRATM) in the treatment of erectile dysfunction. International Journal of Impotence Research 1998; 10:69-74. Review of AEs
Osterloh IH, Collins M, Wicker P, Wagner G. Sildenafil citrate (VIAGRA registered ): Overall safety profile in 18 double blind, placebo controlled, clinical trials. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):3-5. Review of AEs
Padma Nathan H. Oral sildenafil citrate (VIAGRA registered ) in the treatment of erectile dysfunction: Assessment of erections hard enough for sexual intercourse. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):13-5. Possible duplicate
Price D. Sildenafil citrate (Viagra registered ) efficacy in the treatment of erectile dysfunction in patients with common concomitant conditions. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):21-3. Review
Price D, Gingell J C, Gepi-Attee S, Wareham K, Yates P, Boolell M SO. Sildenafil (ViagraTM): a novel oral therapy for penile erectile dysfunction in patients with diabetes. Diabetes 1996. 45(suppl 2):6A. Abstract
Rendell MS, Moreno F. A double-blind, placebo-controlled, flexible dose-escalation study assessing the efficacy and safety of sildenafil (VIAGRATM) in men with erectile dysfunction and diabetes. American Diabetes Association 1998. Abstract
Rolf C, Nieschlag E. Sildenafil (Viagra(TM)) in erectile dysfunction. DTSCH-MED-WOCHENSCHR Deutsche-Medizinische-Wochenschrift. 1998 NOV 06; 123(45):1356-61. Review
Setter SM, Baker DE, Campbell RK, Johnson SB. Sildenafil (Viagra) for the treatment of erectile dysfunction in men with diabetes. Diabetes Educ 1999; 25(1):79-80, 83-4, 87 passim. Review
Shabsigh R. Efficacy of sildenafil citrate (VIAGRA registered ) is not affected by aetiology of erectile dysfunction. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):19-20. Possible duplicate
Virag R. Indications and early results of sildenafil (Viagra) in erectile dysfunction. Urology 1999; 54(6):1073-7. Not an RCT
Wagner G, Maytom M, Smith MD. Analysis of the efficacy of sildenafil (VIAGRATM) in the treatment of male erectile dysfunction in elderly patients. The Journal of Urology 159(No. 5). Abstract
Wasielewski S. Clinical testing of sildenafil: Two clinical studies on a pill for impotence. DTSCH-APOTH-ZTG Deutsche-Apotheker-Zeitung. 1998 JUN 25; 138(26):32-4. Review
Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999; 83(5A):21C-8C. RCT is a drug interaction study
Weber DC, Bieri S, Kurtz JM, Miralbell R. Prospective pilot study of sildenafil for treatment of postradiotherapy erectile dysfunction in patients with prostate cancer. J Clin Oncol 1999; 17(11):3444-9. Not an RCT
Young J. Sildenafil citrate (VIACRA registered ) in the treatment of erectile dysfunction: A 12-week, flexible-dose study to assess efficacy and safety. INT-J-CLIN-PRACT-SUPPL International-Journal-of-Clinical-Practice,-Supplement. 1999; -(102):6-7. Possible duplicate
Zippe CD, Kedia AW, Kedia K, Nelson DR, Agarwal A. Treatment of erectile dysfunction after radical prostatectomy with sildenafil citrate (Viagra). Urology 1998; 52(6):963-6. Not an RCT
Zusman Rm. Cardiovascular data on sildenafil citrate. The American Journal of Cardiology 1999; 83((5A)):1C-44C. This is a collection of papers already covered