The clinical evidence: efficacy of tadalafil in ED
The most important outcome for an ED therapy is the patient’s perception of success. When patients with ED experience a successful intercourse after treatment, they feel cured of their problem. Furthermore, they express the desire of unplanned, unpremeditated or spontaneous sexual intercourse. In this sense, one possible use of the self-administered questionnaire International Index of Erectile Function – Erectile Function domain (IIEF-EF) score is to ascertain whether patients return to normal erectile function after treatment, with scores of 26–30 representing the normal ranges. Integrated analysis of data from phase III trials demonstrated that tadalafil, at doses from 5 mg to 20 mg versus placebo, significantly improved erectile function (EF) by all measures. In particular, 50%–65% of patients, regardless of ED severity at baseline, returned to normal erectile function with almost 60%–90% of success rate at intercourse attempts during active treatment.
In the community-based Massachusetts Male Aging Study (MMAS), 52% of 1290 men aged 40 to 70 years were found to have some degree of ED. The probability was 9.6% in the whole sample, and higher in men aged 60–69 years (40%) and in those treated for heart diseases (39%), diabetes (28%), or hypertension (15%). This indicates that ED is often a symptom present in cardiovascular disease and diabetes. Analogously, in the majority of the studies reported in this review the population selected is similar, as far as age and causes of ED are concerned, to that of MMAS.
With the purpose of assessing efficacy and safety of tadalafil (Cialis) in the treatment of ED, an integrated analysis of five randomized double-blind placebo controlled parallel group trials was conducted. An update of this analysis has been made with six newest tadalafil studies including an additional group of 1215 men with ED. The final analysis included eleven studies with 2102 patients (mean age 56 years, age range 22–88 years) who had a minimum 3-month history of mild (36%), moderate (27%), or severe (33%) ED, of organic (58%), psychogenic (12%), or mixed etiology (31%). Hypertension, diabetes mellitus, and hyperlipidemia were the most common comorbidities.
The subjects were randomly allocated to a 12-week treatment with placebo (n=638) or cheap tadalafil at fixed daily doses of 2.5 mg (n=74), 5mg (n=151), 10 mg (n=321), and 20 mg (n=1143). The doses of 2.5 mg and 5 mg were included only in the “five studies analysis”. Treatment was self administered as needed before sexual intercourse with no restrictions on food or alcohol intake or timing of sexual activity. Exclusion criteria were impotence due to radical prostatectomy, pelvic surgery, penile deformities, or recent history of stroke or spinal cord trauma, severe cardiovascular diseases and/or clinically significant renal or hepatic insufficiency. Men treated with nitrates, antiandrogens or cancer chemotherapy agents were also excluded from study participation. The international index of erectile function (IIEF) (Rosen et al 1999), that includes the domains of EF, intercourse satisfaction, orgasmic function, sexual desire and overall satisfaction, was used to globally evaluate EF. In particular, ED severity in the EF domain is scored mild (22–25), moderate (11–21), and severe (≤10). The diary Sexual Encountered Profile (SEP) that consists of 6 and 4 yes/no questions to be answered by the patient and the partner respectively, and Global Assessment Question (GAQ) related to improvement of erections and ability to engage in sexual activity, were also administered at baseline and following treatment to evaluate the effect of therapy on successful completion of intercourse and satisfaction. Compared with placebo, tadalafil significantly enhanced, in a dose-dependent manner, in patients of different ages, all efficacy outcomes across disease etiologies and severities. The primary efficacy outcome measure was the EF domain that consists of 6 questions with possible score range from 1 (worse function) to 30 (normal function). The score increase was <0.1 for placebo, and respectively 3.2, 4.6, 6.5, and 8.6 for tadalafil 2.5 mg, 5 mg, 10 mg, and 20 mg (p<0.05–0.001 vs placebo). Two other co-primary efficacy variables were the mean changes from baseline to end-point on the ability in penetration and length of erection for a successful intercourse, measured by questions 2 (“were you able to insert your penis into your partner’s vagina?”) and 3 (“did your erection last long enough for you to have successful intercourse?”) of the SEP diary. The change of positive response to the questions 1 and 2 significantly increased from 2.3% and 8% for placebo, to 15% and 20%, 16% and 22%, 24% and 34%, 30% and 46% respectively, for tadalafil 2.5 mg, 5 mg, 10 mg, and 20 mg (p<0.001 vs placebo). Across all patients on tadalafil 10 mg and 20 mg, 71% and 84% reported improved erection (GAQ) versus 33% in the placebo group. The total number of successful attempts, as a proportion of the total number of attempts made, was 61% and 72% respectively, compared with 34% of placebo (p<0.001). Both 20 mg and 10 mg doses were significantly better than placebo in improving patients’ EF. Based on the cause of ED, there was a similar trend in the IIEF–EF domain score improvements, with the 20 mg group that had numerically greater mean changes across all severity groups than the 10 mg group. The greatest percentage of tadalafil treated patients having normal EF at end-point were those with mild baseline ED, followed by those with moderate and severe ED.
To evaluate the efficacy of tadalafil in men with ED by demographic and ED characteristics, Lewis and colleagues (2005) extended post-hoc the analysis of the “eleven double-blind trials”. In particular, etiology, severity, duration, presence of comorbid conditions such as obesity, diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, depression, benign prostatic hyperplasia (BPH), or concomitant treatment with antihypertensive or antidepressant drugs have been considered. Younger patients (<65 years) had numerically better scores than older patients on each of the efficacy measures, although the differences were small after accounting for the slightly better baseline characteristics in younger patients. When age was considered, the percentage of patients attaining normal EF at end-point (IIEF–EF domain ≥26) was significantly superior in the younger treatment groups (p<0.001). Overall, canadian tadalafil proved to be effective in improving erectile function across a variety of patient demographics and illness characteristics including ED etiology, duration, severity, comorbidity, and concomitant treatments. Obesity is generally associated with increased risk of medical conditions such as diabetes mellitus, hypertension, depression or cardiovascular diseases, and BPH. This was reflected in these ED studies with 66% of obese patients (Body Mass Index [BMI] >30) affected from these concomitant illnesses in comparison to the BMI <30 subjects that were affected by 53% (p<0.001). The obese subgroup had a statistically nonsignificant lower score on each of the efficacy measures with respect to the rest of the sample. The group of patients with organic ED etiology had lower baseline scores on both IIEF–EF and SEP-Q3 and accounts for the 67% of severe ED compared with the mixed (25%) and psychogenic subgroups (8%). As already expected (Emmick et al 2002; Saenz De Tejada et al 2002), whether affected from diabetes or hypertension, these subgroups had lower baseline and end-point scores. Both tadalafil doses showed statistically greater improvement than placebo for each ED severity level, with more pronounced amelioration in the moderate and severe ED patients because of the lower baseline scores. The subgroups of patients with comorbid conditions taking tadalafil 20 mg showed significant improvements from baseline to end-point.
Early treatment success may be important in enhancing self-confidence to continue successful treatment. An integrated post-hoc analysis of the “five double-blind studies” examined the first dose success, the cumulative success by dose and the maintenance of success among men taking generic tadalafil. The SEP diary questions assessed these three perspectives. With the first dose, significantly greater proportions of men taking tadalafil 10 mg and 20 mg versus placebo achieved successful erection (SEP-Q1: 85% and 90% vs 66% respectively), successful penetration (SEP-Q2: 74% and 79% vs 47% respectively), successful intercourse (SEP-Q3: 56% and 67% vs 31 % respectively), and were satisfied overall with their sexual experience (SEP-Q5: 36% and 47% vs 15%, respectively; all p<0.001). Regardless of the ED severity or patient age, continued dosing increased the proportion of men achieving first success, reaching a plateau between dose 4th and 8th at approximately 95% (SEP-Q2), 90% (SEP-Q3), and 81% (SEP-Q5). After first-dose success, success rate in a 12-week period was significantly greater for men taking tadalafil versus placebo (SEP-Q2: 85% and 91% vs 75%; SEP-Q3: 81 and 88% vs 64%, respectively; p<0.001). Note the high proportion of patients attaining initially a successful erection while on placebo. This success was not maintained under the measures of successful penetration, intercourse, and satisfaction.
In a large population of men from Central and Eastern Europe and Eastern Mediterranean (mean age 52 years; range 21–82 years), after 12 weeks of on demand treatment, tadalafil 20 mg versus placebo has confirmed its superior efficacy, also after stratification of IIEF–EF severity class from mild and moderate to severe. Tadalafil patients achieved a normal IIEF–EF score at endpoint, compared with 16% of placebo patients (p<0.001), and compared with placebo, have a significantly higher end-point and a greater change from baseline across all domains of IIEF. The same conclusions on tadalafil 20 mg were yielded in similar trials with populations of different ethnicity (Allen et al 2004; Carson et al 2005). In particular, in a multicentric trial conducted both in Italy and UK, involving nearly 41% of severe ED patients (mean age 53; range 26–78 years), tadalafil 20 mg on-demand improved mean EF domain scores by 11.1, versus 0.4 of placebo (p<0.001), with 74% of successful intercourse attempts compared with 30% of placebo. This is the largest numerical improvement observed in the IIEF–EF domain with tadalafil. Cheap Tadalafil significantly improved IIEF satisfaction domain and GAQ overall effect on erection (82% vs 23%) and sexual activity (79% vs 17%). These results mirror those observed in the “five studies analysis”.
Regardless of the degree of ED, tadalafil professional 20 mg every other day for one month has been shown to improve endothelial function in patients with increased cardiovascular risk, since endothelial damage is a common marker of diseases of the cardiovascular system. The benefit was sustained two weeks after treatment discontinuation and was associated with an increase in nitrite/nitrate levels and a decrease in endothelin-1. Age itself is an important risk factor for vascular disease and ED, and thereby endothelial dysfunction. In elderly patients (60–70 years) affected by ED, with slight or no signs of carotid disease, resumption of spontaneous erections was obtained with chronic tadalafil 20 mg administered for three months on alternate days. One month after withdrawal from dosing, spontaneous improvement in sexual function was reported in 55%–65% of patients unaffected from carotid disease and in 16% of those with increase of carotid intimal thickness. Nocturnal penile tumescence rigidity monitoring and PDU parameters were inversely related to different degrees of carotid wall alteration and showed a significant improvement in those patients with atherosclerotic plaques, probably due to the amelioration of endothelial function during treatment.
A retrospective analysis of pooled data from 12 placebo-controlled trials was conducted to characterize the efficacy and safety of cheap tadalafil in men with diabetes mellitus. Baseline characteristics of ED severity, assessed by IIEF–EF, scored 12.6 in diabetics and 15 in nondiabetics (p<0.001). These scores correlated inversely with glycosylated hemoglobin (HbA1c) levels. Regardless of glycemic control and diabetic therapy, tadalafil 10 mg and 20 mg, compared with placebo, improved all primary efficacy outcomes in all patients. The subgroup receiving tadalafil 20 mg experienced a mean improvement of 7.4 in the IIEF–EF domain score from baseline versus 0.9 for placebo (p<0.001), reporting a 53% average of successful intercourse attempts, compared with 22% for placebo.
Tadalafil professional 20 mg was effectively administered in the treatment of 303 men suffering from ED following bilateral nerve sparing radical retropubic prostatectomy. Compared with placebo, a greater improvement on all the evaluated end-points was reported. IIEF–EF domain score increased by 5.3 (p<0.001 vs placebo), and positive response for SEP-Q2 and Q3 was for 54% and 41% of patients. A subgroup of patients with at least a post-operative tumescence, meaning a post-surgical minimal cavernous innervation damage, reported an increase of 5.9 points on the IIEF–EF and of 69% and 52% on SEP-Q2 and Q3.
In a randomized blind cross-over trial for the treatment of ED in 30 male spinal cord-injured patients (mean age 34.6, range 21–60 years) tadalafil 10 mg was compared with sildenafil 50 mg. In these patients, either psychogenic erections or reflexive spinally elicited erections or both are necessary for PDE5 inhibitor response. Canadian Tadalafil and canadian sildenafil allowed patients to achieve erections whit a mean total score on IIEF of 17.82 and 15.75 (increase from baseline of 58.41% and 40%) respectively. No significant differences were observed up to 12 h, while, as expected, normal sexual functioning and improved overall sex satisfaction up to 24 h post-dosing was better for tadalafil compared with sildenafil (p<0.01).