PDE-5 inhibitors - non-RCT evidence

Clinical bottom line

There are very considerable amounts of information available in the form of observational studies. For sildenafil, the first in class, there were more than 33,000 men in observational studies, compared with under 4,000 in randomised trials.

Background

Evidence from systematic reviews of good quality randomised trials may be the highest form of evidence, but it is not the only evidence available to us. There may be circumstances in which randomisation is not ethical, for instance when efficacy has been established in general terms, but where evidence in special circumstances needs to be assessed. Another example is for ascertainment of rare but serious adverse events, where even the most comprehensive collection of randomised trials could lack sufficient numbers of patients or events.

Searching

To examine the amount of evidence, PubMed was searched for original studies of two main types - randomised studies not included in the systematic review for some reason, and for any cohort or cross sectional studies - involving sildenafil, tadalafil, and vardenafil published between 2000 and 2005. The results are shown in the tables below.

Randomised studies not included in systematic reviews

Ten sildenafil studies with 561 patients were not included in a recent systematic review (Table 1). All were randomised, and three were double blind. One was a withdrawal design demonstrating that beneficial effects of sildenafil were lost on stopping the drug, one in Parkinson's disease where hypotension stopped the study, and one crossover study in congestive heart failure. The other studies were either declared to be open, or were not convincingly double blind.

Table 1: Randomised studies with sildenafil not included in a recent systematic review

Study Type	Reference	Condition	Number of men	Outcome	Country
R, DB, withdrawal study	Christiansen E et al. Int J Impotence Res 2000 12:177-182	ED treated with sildenafil	99	Improvements maintained with continued treatment, lost with withdrawal	UK, Norway, France
R, DB, crossover	Hussain IF et al. J Neurol Neurosurg Psychiatry 2001 71:371-374	Parkinsonism (Parkinson's disease or multiple system atrophy)	18	IIEF scores improved, but hypotension stopped study in multiple system atrophy	UK
R, DB, crossover	Bocchi EA et al. Circulation 2002 106:1097-1103	Congestive heart failure	23	Single 50 mg dose decreased HR and BP on standing, increased exerecise capacity	Brazil
R, crossover, not effectively DB	Webster LJ et al. Arch Intern Med 2004 164:514-520	Congestive heart failure	35	IIEF, QoL and depression scores improved. No symptomatic hypotension	Canada
R, open	Perimenis P et al. Int J Impotence Res 2004 16:256-260	ED	15	IIEF scores improved more with sildenafil than continuous positive airways pressure, but less than sildenafil in the general population	Greece
R	Mancini M et al Int J Impot Res 2004 16:8-12	ED vasulogenic and nonvasculogenic	22	IIEF scores increased for both sildenafil and alprostadil, not placebo. Cavernosous arterial insufficiency improved for vasculogenic patients only	Italy
R, open, crossover	Perimenis P et al. Int J Impot Res 2004 16:2-7	ED arteriogenic	43	Sildenafil better than apomorphine for successful attempts and satisfaction	Greece
R, open, crossover	Eardley I et al. BJU International 2004 93:1271-1275	ED	139	IIEF and satisfaction better for sildenafil than apomorphine	UK
R, open, parallel	Ugarte F et al. Int J Impot Res 2002 14:S48-S53	ED	123	IIEF scores and success better for sildenafil than phentolamine	Mexico
R, crossover	Lammers PI et al. Int J Impot Res 2002 14:54-60	ED	44	No sig diff in efficacy for sildenafil and combinations of apomorphine, phentolamine and paparavine	Mexico
R= randomised; DB = double blind; ED = erectile dysfunction; IIEF = international index of erectile function

These studies from Europe and central and south America, were mostly small, with seven having fewer than 50 patients. Two of the larger and two of the smaller studies compared sildenafil directly with apomorphine or phentolamine, and found sildenafil to be more effective.

One study was found for tadalafil (Table 2), with 4,262 patients in a European study examining dosing preferences. No such studies were found for vardenafil.

Table 2: Randomised study with tadalafil excluded from the systematic review, and cohort studies with tadalafil and vardenafil

Study Type	Reference	Condition	Number of men	Outcome	Country
Tadalafil
R, open, crossover	Mirone V et al Eur Urol 2005 47:846-854.	ED	4262	More preferred on-demand than 3times a week dosing	Europe
Prospective cohort	Del Popolo et al. Spinal Cord 2004 42:643-648.	Spinal cord injury	28	Tadalafil effecive	Italy
Prospective cohort	Montorsi F et al. Eur Urol 2004 45:339-344.	ED	1173	Open-label extension of RCT, with 42% completing 24 months. AE discontinuations 6%	Europe
Vardenafil
Prospective cohort	Potempa AJ. Eur Urol 2004 46:73-79.	ED	398	Titration study. 80-90% effective, with low asverse event rates	Germany
Prospective cohort	Stief C et al. In J Clin Pract 2004 58:230-239.	ED	566	Extension of RCTs. Good sustained efficacy	Germany
R= randomised; DB = double blind; ED = erectile dysfunction; IIEF = international index of erectile function

Cohort or cross-sectional studies

Twenty-five sildenafil studies with 33,708 patients were found (Table 3). There were 17 prospective cohort studies with 3,668 men, six retrospective cohorts with 29,352 men, and two cross-sectional studies with 127 men.

The prospective cohort studies were often large, and nine of them had more than 100 men. Almost all of them had measures of improvement in erectile function, most often using the standard IIEF outcomes. Improvement rates were typically above 70%, consistent with findings from the randomised trials.

With one exception, the retrospective studies had information on over 500 men each, with one having over 22,000 men. This UK study was designed to look for adverse events following the introduction of sildenafil in the UK, and is described in detail later.

Table 3: Prospective and retrospective cohort studies of sildenafil

Reference	Condition	Number of men	Outcome	Country
Prospective cohort
Sunwoo S et al. Int J Impot Res 2005 17:71-75	ED	572	80% reported improved erections with sildenafil, while six disontinued. 71 adverse events among 56 patients	Korea
Arandda P et al. Am J Hypertens 2004 17:139-145	Hypertension	291	IIEF scores improved	Spain
Fujisawa M et al. Arch Androl 2004 255-260	ED	44	Rate of improvement higher in youinger than older men with siildenafil	Japan
Sahin Y et al. Transplant Proc 2004 36:56-58	End-stage renal failure on haemodialysis	55	Overall response rate 75% with sildenafil 50 mg	Turkey
Benchekroun A et al. Int J Impot Res 2003 15 Suppl1:S18-24	ED	71	Dose escalation 25-100 mg, showed good efficacy and improve quality of life	Morocco
Fujisawa M et al. Arch Androl 2002 48:15-21	ED	40	QoL scores improved. Correlation with ED response	Japan
Sairam K et al. BMC Urology 2002 2:4	ED	147	90% successful, 80% willing to continue. High incidence of some adverse events	UK
Souverein PC et al. Int J Impot Res 2002 14:259-265	ED	317	Over 18 months 45% discont sildenafil. Factors associated with discont identified. Pts with history of prev drug treatment more likely to switch	Netherlands
Yenicerioglu Y et al. BJU Int 2002 90:442-443	End-stage renal disease	41	IIEF and QoL scores improved	Turkey
Raffaele R et al. Eur Urol 2002 41:382-386	Parkinson's disease	33	Improved erections in 84%. Improvement in depressive symptoms in 75%	Italy
Sters W et al. In J Impot Res 2001 13:261-267	ED, extension studies of RCTs	1008	90% improved erections over 36-52 weeks. Disocntinuations due to adverse events low, and cardiovascular adverse events below 1%	USA
Sanchez Ramos A et al. Spinal Cord 2001 39:637-643.	Spinal cord injuries	170	88% had improved erections	Spain
Gans WH et al. J Spinal Cord Med 2001 24:35-40	Spinal cord injuries	17	Significant improvement in erections. 1 discontinued	USA
Palumbo S et al. Eur Urol 2001 40:176-180	ED	380	77% response overall	Italy
Fagelman E et al. Urology 2001 57:1141-1144	ED	164	Improvement in 68%-81%	USA
McMahon CG et al. J Urol 2000 164:1192-1196	ED 27% psychogenic 73% organic	278	Erectile response and QoL scores improved	Australia
Green BG, Martin S. NeuroRehabilitation 2000 15:101-105	ED due to SCI or MS	40	Initial response: 36/40 improved erections, 15/40 complete intercourse. At 2 years 13/40 discontinued	USA
Retrospective cohort
Griffiths L et al J Clin Pharm Ther 2005 30:297-304	ED	513	78% prescibed for in accordance with Gov guidelines. Varaition between surgeries	UK
Boshier A et al BJU Int 2004 93:796-801	sildenafil prescribed	22473	Effective in 71%. Safety profile showed no unexpected events. No increase in deaths	UK
Russo D et al. J Nephrol 2004 17:291-295	Kidney transplant patients	20	IIEF scores improved	Italy
Sheu JY et al. J Chin Med Assoc 2003 66:480-486.	sildenafil prescribed	3168	Telephone interview of about half showed good efficacy, with high disontinuation because of lack of efficacy	Taiwan
Jiann B-P et al. Int J Impot Res 2003 15:412-417	ED and prescirbed sildenafil	1658	Information on usage, success rates, doses, effect of comorbidities	China
Lim PHC et al. Int J Urol 2002 9:308-315	ED	1520	83% had satisfactory erections. Differences in efficacy between races and comorbidities	Singapore
Cross-sectional
Monga M et al. Urology 2002 59:753-757	older men	73	ED prevalence inc with age. 660/976 men sexually active, 73 had used sildenafil at some time	USA
Muller MJ, Benkert O J Affect Disrord 2001 66:255-261	ED	54	Scores for depression better with sildenafil than no treatment	Germany

For tadalafil there were two prospective cohorts with 1201 men, and for vardenafil two more cohorts with 964 men (Table 2). In each case one of these was an open-label extension of randomised trials.

Comment

Thus for cohorts studies alone, there were almost ten times as many patients on sildenafil (33,708) as in the included randomised trials (under 4,000 in a recent systematic review). For tadalafil and vardenafil there was information from fewer men in cohort studies than in randomised trials (Figure 1), which is likely to increase as more randomised trials are published with these newer PDE-5 inhibitors.

Figure 1: Numbers of men in randomised trials in the systematic review, and in cohort studies

What this shows, interestingly, is that for a new treatment in an area where there was previously few effective treatments available, we might expect to see a considerable amount of observational information published, which can be useful and probably should not be overlooked.