Department of Urology, Leeds General Infirmary, Leeds
Royal Free Hospital, London
Genito-Urinary Medicine Department, Royal Victoria Hospital, Belfast
Pfizer Ltd, Sandwich, Kent
Correspondence: Ian Eardley, Department of Urology, Leeds General Infirmary, Leeds LSI 3EX. Tel: 01132 923561; Fax: 01132 926347
Declaration of interest Research supported by Pfizer Inc.
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ABSTRACT |
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Aims To evaluate the efficacy, tolerability and frequency of use of sildenafil citrate in men with mild to moderate erectile dysfunction of no established organic cause.
Method This double-blind, randomised, placebo-controlled, flexible-dose, two-way crossover study was conducted at four centres in the UK in 44 men with mild to moderate erectile dysfunction of no clinically obvious organic cause. The study included two 28-day treatment periods, during which time sildenafil or placebo (25-75 mg, based on efficacy) was taken as required.
Results Compared with placebo, sildenafil was associated with increases in frequency of use, erections adequate for sexual intercourse and level of sexual satisfaction (P<0.0001). More patients receiving sildenafil stated they would use the treatment again compared with those receiving placebo (P<0.0001). There were no discontinuations due to sildenafil treatment.
Conclusions Sildenafil is effective and well tolerated in men with mild to moderate erectile dysfunction of no clinically identifiable organic cause.
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INTRODUCTION |
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METHOD |
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Study design
This double-blind, placebo-controlled, flexible-dose, randomised, two-way
crossover study of sildenafil, taken as needed, was conducted at four centres
in the UK. The study included two 28-day, double-blind treatment periods not
separated by a washout period, and a 2-week follow-up period.
Randomisation and blinding
Randomisation to one of the two treatment sequences was undertaken in a
double-blinded fashion prior to the study start date. Subjects were allocated
to a treatment sequence group, and blocks were assigned to each centre to
ensure adequate balance of subjects to sequences within each centre. Other
than the project statistician and the pharmacist who packaged the study drug,
all study investigators and other staff were blinded to the sequence
allocation.
Dosing
Patients received 25 mg doses of sildenafil or matching placebo, and were
instructed to take the study drug 30 to 60 minutes before anticipated sexual
activity, but not more than once daily, and to record the actual time of
dosing in the patient diary. Dosage could be increased incrementally to a
total of three 25 mg tablets to increase efficacy if necessary. Patients were
instructed to decrease the dose if the study drug was not well tolerated.
Clinical assessments
For assessment of efficacy, patients completed a detailed daily diary
recording erectile activity for 7 days before the first treatment period and
for the two consecutive 28-day treatment periods. Data from patients' logs
were used as a primary source of assessment because sexual function is best
assessed in a natural setting with self-report techniques
(Andersen & Broffitt,
1988). Based on recommendations by the National Institutes of
Health Consensus Conference on Impotence (1993), records included information
deemed important in the assessment of patients with erectile dysfunction, such
as timing and number of doses of study dug taken; time of onset, duration and
quality of erections; whether the erection was associated with sexual
stimulation; occurrence of satisfactory sexual intercourse; and whether other
sexual activity occurred. The quality of erections was graded on a four-point
scale: 1, increase in size but not hard; 2, hard but not hard enough for
penetration; 3, hard enough for penetration (but not completely hard); 4,
completely hard.
Erectile activity was also assessed by yes/no responses to a two-item global efficacy questionnaire (GEQ; Goldstein et al, 1998) administered at the end of each 28-day treatment period: (GEQ1) "Has the treatment you have been taking over the last 28 days improved the quality of your erections?" and (GEQ2) "If this treatment were available would you want to take it?" As part of the patient diary, patients' partners were asked if treatment improved their partner's erections and, if so, were they satisfied with the quality of the patient's erections during the 28-day treatment period.
Safety assessments
All observed and volunteered adverse events were recorded by the
investigator and assessed for severity and relationship to study medication.
Objective test findings, including standard laboratory tests (haematology,
biochemistry and urinalysis) and physical examinations (supine blood pressure
and pulse rate) were performed at each clinic visit (screening, Day 0, Day 28
of both first- and second-treatment periods and follow-up); a 12-lead
electrocardiogram was performed at the screening and follow-up visits.
Statistical analysis
Sample size was based on the primary efficacy variable and used data from a
previous study that had compared multiple doses of sildenafil with placebo and
indicated that a sample size of 36 subjects was sufficient to detect a 60%
difference in weekly erection count with probability 0.80 when testing at the
5% level of significance. All analyses were controlled for the differing
effects between centres. The inter-action effect of centre with both treatment
and sequence was assessed when the analysis was able to do so; these effects
were found to be not significant, and therefore were removed from the model.
Intent-to-treat analyses were performed on efficacy variables and included all
randomised patients who had a baseline measurement of erectile dysfunction and
at least one efficacy assessment after the start of each treatment. All tests
of significance were two-sided and evaluated at the 5% significance level. The
mean number of Grade 3 or 4 erections was log transformed and analysed using
an analysis of variance model and included appropriate terms for sequence,
subject, period and treatment. The mean number of doses per week was also
subjected to an analysis of variance model. The number of occurrences of
satisfactory sexual intercourse as a proportion of the number of doses taken
and the number of satisfactory Grade 3 or 4 erections as a proportion of doses
taken were analysed using logistic regression. The odds of a satisfactory
event were calculated as a/b, with a=X(100-X) where X is the percentage of
satisfactory events with sildenafil treatment, and b=Y/(100-Y) where Y is the
percentage of satisfactory events with placebo treatment. The results of the
investigator questionnaire and the partner question were analysed using the
MainlandGart test for contingency tables
(Mainland, 1963; Gart, 1969), which investigated
each 28-day period and treatment effects. No interim analysis was
undertaken.
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RESULTS |
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Efficacy of treatment
As assessed from the patients' diary data, analyses of the frequency of
study drug use included the distribution of number of doses taken over the
entire study period and the average number of doses taken per week by the
intent-to-treat population (see Table
2). Whereas the distribution of dosages of study drug showed
little variability in the number of doses of sildenafil taken for the overall
study period, more doses of placebo were taken at the higher dosage level. The
average number of doses taken per week was significantly higher for treatment
with sildenafil compared with placebo (P=0.001). The mean values of
time between doses showed a shorter median time for sildenafil compared with
placebo (50.2 v. 56.7 hours, respectively). A similar pattern was
observed for the minimum time between doses, with a lower mean for sildenafil
than placebo (23.9 and 32.7 hours, respectively).
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The geometric mean number of Grade 3 or 4 erections per week was significantly higher for treatment with sildenafil compared with placebo (P<0.0001, see Fig. 1). The average number of Grade 3 or 4 sexually stimulated erections was also higher for patients receiving sildenafil than for patients receiving placebo (see Fig. 1). Of all responders to sildenafil, 85% were able to have intercourse more than 75% of the time. The majority of non-sexually stimulated erections were nocturnal or early morning erections for both treatments.
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The estimated proportion of occurrences of satisfactory Grade 3 or 4 erections per number of doses was 94% for sildenafil and 68% for placebo, with a highly significant overall treatment effect for sildenafil (P<0.0001, see Fig. 2). The odds of achieving a satisfactory erection while taking sildenafil were 7.9 times greater than the corresponding odds for placebo (P<0.05). The estimated occurrence of satisfactory sexual intercourse per number of doses was 62% for sildenafil and 12% for placebo (P<0.0001, see Fig. 2). Thus, the odds of having satisfactory sexual intercourse while taking sildenafil were on average 12 times greater than the corresponding odds for placebo (P<0.02).
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Of the 36 patients included in the analysis of GEQ1, responders to treatment included 34 (94%) who recorded improved erections while taking sildenafil, and nine (25%) while taking placebo (P<0.0001, Fig. 3). This analysis included patients who recorded improvement with sildenafil but not placebo (n=25), both treatments (n=9) or neither treatment (n=2). Of the 35 patients included in the analysis of GEQ2, 33 (94%) stated they would take sildenafil if it was available, and 13 (37%) stated they would take placebo (P<0.0001 for treatment effect). This analysis included patients who stated they would take sildenafil but not placebo (n=20), both treatments (n=13) or neither treatment (n=2).
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Partners' opinions of the effect of each 28-day treatment on the patient's erections also showed a highly significant positive response for sildenafil compared with placebo (P<0.0001, see Fig. 3). Of the 37 partners included in this analysis, 34 (92%) recorded that the patient's erections had improved while taking sildenafil and seven (19%) reported improved erections while the partner was taking placebo. Overall, 28 partners recorded improvement with sildenafil but not placebo, one recorded improvement with placebo but not sildenafil, and six recorded improvement with both sildenafil and placebo.
Safety and tolerability
Treatment with sildenafil was well tolerated during the two 28-day periods.
Twenty-three patients receiving sildenafil and 14 receiving placebo reported
adverse events of all causes. Most treatment-emergent adverse events were mild
to moderate in nature (see Table
3). Two severe adverse events (palpitations and flushing) were
reported with sildenafil, both of which resolved without treatment.
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Of the five discontinuations in this study, four were due to protocol violation or because the patient was lost to follow-up. The only discontinuation due to a serious adverse event involved a patient who suffered a myocardial infarction while receiving placebo during the second 28-day treatment period. Clinical laboratory test abnormalities were reported for eight of the 43 patients on sildenafil and six of 41 patients on placebo. However, there were no discontinuations due to laboratory test abnormalities.
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DISCUSSION |
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Erectile dysfunction has been associated with a number of organic, psychogenic and lifestyle factors that can show varying degrees of interdependence. Indeed, numerous psychogenic and other non-organic factors may contribute to or be associated with erectile dysfunction. Various psychological processes can impair erectile function by reducing erotic focus or awareness of sensory experience. Stress and anxiety, resulting from work-related problems, relationship conflict or performance fears, can cause increased sympathetic outflow and elevated catecholamine levels, thereby increasing penile smooth muscle tone and opposing the smooth muscle relaxation required for erection (Krane et al, 1989). Conversely, problems with erectile function, as may result from subtle but significant organic changes, can generate varying degrees of anxiety (Smith, 1988). Not only is clinical depression a well-recognised cause of decreased sexual desire and of erectile dysfunction (Feldman et al, 1994), but erectile dysfunction itself may result in depression (Shabsigh et al, 1998). Compounding this complex, dynamic and bidirectional relationship, erectile dysfunction can be induced as a side-effect of medications used to treat depression (e.g. tricyclic antidepressants, lithium, monoamine oxidase inhibitors and serotonin reuptake inhibitors) and other classes of psychotropics (e.g., phenothiazines, butyrophenones, opiates and amphetamines) (Bennett & Melman, 1995; Margolese & Assalian, 1996). Suppression and expression of anger, overrestrictive upbringing and substance misuse have also been associated with the development of erectile dysfunction (Smith, 1988; Feldman et al, 1994; Bennett & Melman, 1995). Regardless of its aetiology, erectile dysfunction can adversely affect quality of life, self-esteem and partner relationships if the condition is not successfully treated, that is, effectively and with minimal adverse effects (National Institutes of Health Consensus Development Panel on Impotence, 1993; Hanson-Divers et al, 1996).
Sildenafil, a selective inhibitor of phosphodiesterase type 5, enables a natural erection after sexual stimulation (Boolell et al, 1996). The efficacy, safety and tolerability of sildenafil have been demonstrated in large clinical trials (Goldstein et al, 1998; Morales et al, 1998; Padma-Nathan et al, 1998), in which a therapeutic response of similar magnitude was observed in men with erectile dysfunction of various aetiologies. To date, evaluations of sildenafil in patient subsets have predominantly focused on men with erectile dysfunction due to an organic cause, for example radical prostatectomy (Zippe et al, 1998), diabetes (Rendell et al, 1999), cardiovascular disease (Cheitlin et al, 1999) and spinal cord injury (Maytom et al, 1999).
Our study assessed the efficacy and safety of sildenafil in men with mild to moderate erectile dysfunction associated with no detectable organic cause and an age distribution similar to that of men with erectile dysfunction from the general population (Feldman et al, 1994). The patients' medical histories, the findings on physical examination and the results of diagnostic tests suggested that many of these men had erectile dysfunction of predominantly psychogenic origin. However, men with a history of depression were excluded from the study owing to the chronic nature of this disorder and the propensity of many medications used in the treatment of depression to induce erectile dysfunction.
Study findings
In our study, sildenafil was associated with significant improvements in
the quality and quantity of erections and levels of satisfactory intercourse.
The average number of sexually stimulated erections adequate for intercourse
were three-fold greater, and satisfactory sexual intercourse occurred more
frequently with sildenafil. Similar results were reported for patients with
erectile dysfunction of broad-spectrum aetiology
(Goldstein et al,
1998). Both the patients and partners in our study strongly agreed
that sildenafil was effective in improving erections, and most patients
indicated that they would continue treatment with sildenafil, if it was
available.
In general, sildenafil was well tolerated, with no discontinuations due to adverse events. The majority of adverse events were mild to moderate. The frequency of the most common adverse events associated with sildenafil was consistent with other published studies of men with erectile dysfunction of broad-spectrum aetiology (Goldstein et al, 1998; Morales et al, 1998; Padma-Nathan et al, 1998).
Limitations
Several limitations of this study merit acknowledgement. Although the
identification of an organic abnormality does not establish it as the cause of
erectile dysfunction in every individual
(Riley & Athanasiadis,
1997), mild organic disease causing changes in erectile function
of study participants may not have been detectable by the methods used at
screening. Moreover, the study was performed in a natural environment,
requiring a reliance on the study participants' own reports of efficacy;
although of great value, self-reported sexual function and symptomatology may
not be accurate in all settings.
The patients in our study preferred sildenafil and used this treatment 31% more frequently than placebo, which may have artificially increased the number of erections per week with sildenafil treatment. Additionally, not all erections recorded in this study were related to sexual intercourse, which likely explains why the odds ratio of achieving satisfactory intercourse with sildenafil was higher than that of achieving satisfactory erections. Indeed, the high number of nocturnal and early morning erections reported in this study suggests erectile dysfunction of predominant psychogenic aetiology. However, the study participants were not required to undergo a formal psychiatric evaluation, and presence of psychogenic factors contributing to the patients' erectile dysfunction was not confirmed.
Clinical implications
Erectile dysfunction is a multi-factorial disorder, and failure to identify
an organic cause does not prove a psychogenic origin
(Goldstein et al,
1998), but is generally associated with mild to moderate
dysfunction. Although emphasis has shifted to the role of organic factors in
the aetiology of erectile dysfunction, this should not reduce the importance
of assessment of erectile dysfunction in men with mild to moderate dysfunction
that may be of psychogenic origin or of no obvious organic cause. In the MMAS
(Feldman et al, 1994),
the largest population-based epidemiological survey of erectile dysfunction in
current literature, the majority of men with erectile dysfunction fell into
this category. In these men, the condition is likely to progress to severe
erectile dysfunction if an untreated psychogenic factor is contributing to the
pathology (Bennett & Melman,
1995).
Obviously, for optimal outcomes, the assessment and treatment of a multi-factorial disorder such as erectile dysfunction may require the participation of professionals who are trained and skilled in diverse disciplines. The purpose of performing pharmaceutical intervention studies is to help men with erectile dysfunction as part of a multi-disciplinary approach. It is not to promote drug use in place of cognitive-behavioural strategies for treating erectile dysfunction that is not due to a chronic illness, disease or surgery.
Although a presumptive diagnosis of psychogenic erectile dysfunction requires a medical assessment for organic factors that may contribute to the aetiology of the disorder and require treatment, the study findings cannot be interpreted to apply to all men who have clinically diagnosed erectile dysfunction of psychogenic origin. Rather, confirming and extending the findings of a smaller study undertaken in a similar population (Boolell et al, 1996), our study showed that oral sildenafil is an effective and well-tolerated treatment for men with erectile dysfunction that is mild to moderate in severity and may be either predominantly psychogenic or has an organic cause that has not been sufficiently established to be clinically manifest.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication February 1, 2000. Revision received July 3, 2000. Accepted for publication July 10, 2000.