The purposeof this study is to investigate and compare the effects of 5-mg once-daily tadalafil versus 5-mg alternate-day tadalafil in men with moderate-to-severe erectile dysfunction (ED) and lower urinary tract symptoms (LUTS). Between January 2012 and June 2013, 144 men presenting with an International Index of Erectile Function-5 (IIEF-5) score of <18 and an International Prostate Symptom Score (IPSS) of >8 were enrolled to the study. Patients were allocated the simple alternate randomization into Group I (5-mg once-daily tadalafil) and Group II (5-mg alternate-day tadalafil). Changes in IIEF scores, Sexual Encounter Profile Question 3 (SEP Q3) percentage, IPSS, uroflowmetry and post void residual at the first visit (V1), week 4 (V2) and week 12 (V3) were compared. No significant difference was found between the baseline patient characteristics of Group I and Group II. Treatment with 5-mg daily tadalafil demonstrated improvement in IIEF, SEP Q3 percentage and IPSS score between V1 and V2, and that between V1 and V3. Patients receiving 5-mg alternate-day tadalafil also showed a significant improvement in IIEF, SEP Q3 percentage, and IPSS score between V1 and V2, and that between V2 and V3. However, no significant improvements were found in any other parameters. There were no significant differences between Group I and Group II apart from IIEF scores in V2 (19.4 versus 17.9, respectively). The SEP Q3 percentage was also higher at the V2 visit for Group I and Group II (35.6 versus 30.9%). Even with no placebo control and short of LUTS medication control, the use of 5-mg once-daily or alternate-day treatment with tadalafil was well tolerated in patients and effectively improved the IIEF score, IPSS score and SEP Q3 percentage. Management of patients with 5-mg alternate-day tadalafil could be adequate for regular use in patients with ED and LUTS.
Erectile dysfunction (ED) is a prevailing condition defined as the constant inability to obtain and sustain an erection sufficiently to achieve satisfactory sexual performance.1
For most men with ED, the use of a medication that inhibits phosphodiesterase type 5 (PDE5) is a currently widely recognized first-line therapy, providing a noninvasive, efficient and well-tolerated treatment for ED.2 Currently, various PDE5 inhibitors are taken before sexual activity, as needed. However, 30–40% of patients fail to respond to or are not satisfied with the on-demand treatment even after correction of the ED.3, 4
Although PDE5 inhibitors are easy to use, men should take these oral agents when they wish to engage in sexual activity, and therefore, they should remain temporally linked to treatment. For some patients and their partners, planning sexual activity around drug intake is troublesome. The concept of daily administration of PDE5 inhibitors was established to provide an alternative treatment option that is closer to a natural sexual life.
Tadalafil differs from other PDE5 inhibitors in its unique long-elimination half-life.5 Because of its Tmax of 2 h, tadalafil is effective within 16–60 min following ingestion and improves erectile function for 18 h, in contrast to 4–5 h with sildenafil and vardenafil. It also has the ability to preserve one or several erections over a 36-h period following intake.6, 7
The prolonged half-life of tadalafil and effective steady-state serum concentration makes it ideally suited for daily dosing. Therefore, low-dose tadalafil of 5 mg was first approved for daily administration instudies by Porst8 and Forgue9
The relationship between lower urinary tract symptoms (LUTS) and ED has been strongly investigated for the high incidence of both conditions in elderly men.10
Although the sites of action are incompletely known, inhibition of PDE5 seems to affect different pathways involved in LUTS. PDE5 inhibitors affect the bladder, resulting in reduced afferent signaling, which is the final common pathway in the development of LUTS, and can relax the smooth muscle of the bladder at its outflow region.11 Many investigatiuons have shown safety, efficacy and cost-effectiveness of chronic use of PDE5-Is either as a primary treatment or in combination with conventional therapies. However, these studies have not established whether constant administration of low-dose PDE5 inhibitors offers a sustainable benefit to patients with LUTS and ED after discontinuation of treatment or changing the medication interval.
Thus, the objective of this study was to investigate the sustainable effect of 5-mg alternate-day tadalafil versus 5-mg once-daily tadalafil for 12 weeks on ED and LUTS beyond the treatment period.
Materials and methods
We conducted a prospective, open-label study by the simple alternate randomization under no restrictions at a single hospital. We obtained written permission from patients for participation in this study, and the study was performed according to the procedure approved by the ethical and research committee. Between January 2012 and June 2013, we enrolled 180 men with ED. Of the 180 patients, 144 completed the 12-week clinical trial.
The study participants had an age range of 42–67 years and a history of ED for at least 3 months, an international index of erectile function-5 (IIEF-5) score of <18 (representing an ED status of ‘moderate-to-severe’) and an International Prostate Symptom Score (IPSS) score of >8 (representing a LUTS status of ‘moderate-to-severe’).
Medications that could influence voiding parameters, such as anticholinergics or sympathomimetics were washed out at least 2 weeks before commencing the study.
The exclusion criteria included ED from neurological problem; hypersensitivity reactions to PDE5; a history of medication affecting erectile function such as 5α reductase inhibitors, androgens or anti-androgens within 1 month of enrollment to the study; a history of urologic surgery, prostate or bladder cancer; urinary retention; bladder neck or urethral stricture; concomitant use of nitrates or nitric oxide donors; anticoagulants; or any kind of treatment for ED.
IIEF and IPSS scores were estimated at the first visit (V1), week 4 (V2) and week 12 (V3) after treatment had begun.
IIEF scores, Sexual Encounter Profile Question 3 (SEP Q3) percentage, IPSS score, uroflowmetry and post void residual of Groups I and II were assessed before treatment (week 0), during treatment (week 4) and after treatment (week 12).The SEP Q3 used was ‘Did your erection last long enough for you to have successful intercourse?’
Safety evaluation in the study included taking medial history, physical examination and recording of adverse effects. Any association between the use of tadalafil and adverse effects was determined.
Data were analyzed to identify any differences in erectile and LUTS improvement. The differences in variables between the two different treatment regimens were compared before and after the use of tadalafil using the paired and independent t-tests. All statistical analyses were performed by SPSS 12.0 (SPSS, Chicago, IL, USA) and P-values <0.05 were considered statistically significant.
Figures 1 and 2 show the reasons participants dropped out before completion of the study. Of the180 patients recruited to the study, only 144 completed treatment program (80.0%). Dropout rates were 18.9% (17/90) in Group I (5-mg tadalafil once-daily group) and 21.1% (19/90) in Group II (5-mg tadalafil every other day group). Patient characteristics are shown in Table 1. The mean patient age in the study was 56.8 years. No significant differences were found between Groups I and II for age, body mass index, proportions of underlying disease, IIEF, proportions of SEP Q3-positive patients, IPSS, Qmax and post void residual.
Comparison of follow-up results between Groups I and II are shown in Table 2. Group I was found to have an improved IIEF (+6.3), SEP Q3 percentage (+23.4%) and IPSS (−4.9). Daily treatment with tadalafil also significantly improved IIEF (+8.8), SEP Q3 percentage (+26.1%) and IPSS (−6) between V1 and V3.However, treatment effect was not significantly different between V2 and V3.
Alternate-day treatment with 5-mg tadalafil also significantly improved IIEF (+ 4.2), SEP Q3 percentage (+19.6%) and IPSS (−4.8) between V1 and V2. Similar improvement was also found during V1 and V3: IIEF (+ 7.1), SEP Q3 percentage (+23.9%) and IPSS (−5.4). However, no significant difference in improvement was observed in any parameter between V2 and V3 in Group II. Serial changes of IIEF score, SEP Q3 percentage and IPSS score in every visit are shown in Figure 1.
No significant differences were noted in any parameter between Groups I and II, except for IIEF(19.4 versus 17.9, respectively) at the V2 visit and SEP Q3 percentage change at the V2 visit (35.6 versus30.9%, respectively).
Side effects were similar in both of groups. Group I had two patients with headache and one with flushing, so the incidence was 3.3% (3/90). On the other hand, Group II had one patient with headache and one with flushing, so the incidence was 2.2% (3/90).
No difference in any other parameter was found between Groups I and II during the study period.
Sexual arousal does not occur at an expected time or at a fixed period. Therefore, various therapeutic options have been introduced for the treatment of ED in order to provide the patient with a more natural and spontaneous rather than scheduled sexual life.12, 13 In addition, people want to recover their sexual activity and improve spontaneous erectile function and regain normal sexual activity, rather than rely on erectile support through medication.14 Daily administration of PDE5 inhibitors provides an excellent solution for such medical needs. Currently, there are various first-line treatment options for ED using PDE5 inhibitors available with different characteristics in their clinical efficacy, safety and medication availability.
After the first introduction of sildenafil citrate, many drugs have been developed and more than 30 million men with ED have taken these drugs.15
Tadalafil was approved for clinical practice in the United States in 2003, after sildenafil and vardenafil approval. After drug administration, tadalafil reaches the peak plasma concentration within 2 h rather than ∼1 h as with the other PDE5 inhibitors. Although peak plasma concentrations are achieved in 2 h, the onset of effect has been reported to within 15 min of medication.9 Tadalafil is also unique in that it has a long elimination half-life of ∼18 h. This prolonged half-life of tadalafil is due to the low volume of distribution, slow clearance by liver and nearly 80% bioavailability of the drug and the pharmacologic effect may persist for up to 36 h.16
Because of this retention by the metabolism, many studies have been performed to optimize the therapeutic effect of tadalafil through modification in drug administration and dosage intervals, illustrating the differences between on-demand and daily treatment.
Examination of tadalafil concentration–time profiles have demonstrated that the plasma steady state is essentially attained by day 5 of administration with a plasma concentration 1.6 times that obtained with a single dose. In the steady state, 5-mg tadalafil taken once daily reached plasma concentrations similar to that at 24 h after a dosage regimen of 20-mg tadalafil taken two to three times a week.17
The use of daily tadalafil (10 or 20 mg) was first described in 2004.18 One hundred and twelve men, who responded poorly to treatment with 20-mg tadalafil, showed substantial improvement in mean international index of IIEF-EF scores from 10.3 to 14.9 following a 4-week on-demand regimen, and this increased to 23.1 after 12 weeks of daily dose therapy. Favorable responses to SEP3 also increase from 14% (baseline) to 21% after on-demand therapy. Favorable responses reported were 58% for 10-mg tadalafil daily therapy and 52% for daily 20-mg therapy. A similar report using 2.5 mg and 5 mg tadalafil daily medication versus placebo, also showed significantly successful intercourse rate (46 and 55%, respectively) on their initial attempt compared with 29% of men in the placebo group.19
Tadalafil is approved for daily administration for the treatment of ED and most popular even though udenafil daily dose is currently available on the market in Korea. In addition, only tadalafil has been approved for the secondary treatment of LUTS. Several clinics have reported that PDE5 inhibitors can improve benign prostatic hyperplasia-related LUTS. Investigation on 281 men: 5 mg tadalafil once daily for 6 weeks, followed by dose escalation to 20 mg once daily for another 6 weeks, or placebo for 12 weeks. The increment of IIEF was significant for tadalafil (+8.4) than placebo (+1.6). Moreover, IPSS improvement was greater with tadalafil (49.3%, 60.9%) than placebo (36.4%, 42.7%) at week 6, 12.11
Patients received tadalafil 2.5, 5, 10, 20 mg or placebo once daily and IIEF improved +5.59 for tadalafil 2.5 mg, +6.97 for tadalafil 5 mg, +7.98 for tadalafil 10 mg and +8.34 for tadalafil 20 mg than the placebo (+2.2). Mean changes of IPSS were also significantly different for all tadalafil doses: −3.9 for tadalafil 2.5 mg, −4.9 for tadalafil 5 mg, −5.2 for tadalafil 10 mg and −5.2 for tadalafil 20 mg compared with placebo (−2.3).20
One study on the efficacy, onset and safety of daily 5-mg tadalafil use over a 12-week period resulted in a clinically important reduction in the total IPSS as early as 1 week following commencement of therapy and achieved significance after 4 weeks in men with benign prostatic hyperplasia.21 In addition, the efficacy of 5 mg daily tadalafil resulted in significant and similar improvements in benign prostatic hyperplasia symptoms, comparable to that observed with 0.5 mg of tamsulosin once daily versus placebo throughout a 12-week treatment period.22
In more conclusive systematic review study including 2250 patients, PDE5-Is significantly ameliorate IPSS (−2.8) and IIEF score (+5.5 ) versus placebo.23 Similliar to our regimen adjustment, tadalafil 20 mg treatment on demand or three times a week for 5–6 weeks were also compared. In this study, 57.8% of men preferred the on-demand regimen of tadalafil 20 mg, a substantial number (42.2%) preferred the three times a week treatment. The two regimens provide additional treatment options by giving men with ED.24 Our data on the similar effectiveness of 5-mg alternate-day versus 5-mg once-daily tadalafil on LUTS are also promising in the clinical field.
Headache, dyspepsia, back pain, gastroesophageal reflux, sinusitis and myalgia were the most frequently reported side effects of PDE5I.25 Our data showed 3.3% (3/90) in Group I, 5-mg once-daily tadalafil users, and 2.2% (3/90) in Group II, 5-mg alternate-day tadalafil users. The incidences are similar and low. In general, tadalafil has good safety profile with a relative risk of side effects from tadalafil similar to those reported with vardenafil or sildenafil (2.27 versus 1.86 versus 1.22, respectively). In addition, the occurrence of serious side effects was rare for all PDE5-Is (1.1%, 1.85% and 1.05% for the tadalafil, vardenafil and sildenafil subgroups, respectively).26
It has been speculated that retention of PDE5 inhibitors in cells, but not serum, and/or continuation of the cellular effects of PDE5 inhibitors may lead to constant erection-potentiating activity, even after serum levels of PDE5 inhibitors have declined from therapeutic level.14 These effects were due to an improvement in endothelial function and the oxygenation of penile tissues. For instance, following treatment with sildenafil once daily, which has a comparatively shorter half-life, several endothelial molecular markers that affect EF have been detected.27
Furthermore, there may be a difference between the blood concentration and tissue concentration after administration PDE5 inhibitors in patients.28 Previous studies on animals found differences in the concentrations of PDE5 inhibitors in the plasma and the corpus cavernosum, and the pharmacokinetic parameters did not correspond. Therefore, various studies on the effects of once-daily treatment cannot be determined by only considering the blood concentration and half-life of the agent.29 Increasing the frequency of medication could be burdensome to patients and may decrease patient compliance. For example, maintenance of recommended long-term treatment regimens among patients with a chronic disease was found to be suboptimal and unsatisfactory.30 It has been suggested that medication compliance may be as low as 50%.31
In light of this, decreasing medication frequency may improve patient compliance. Furthermore, treatment cost is an important factor for compliance particularly in low-income patient, regardless of the fact that the treatment is highly effective.32 The influence of costs on daily use of PDE5 inhibitors has not yet been determined in men with ED but could negatively influence patient compliance.33
In the present study, efficacy in 5-mg tadalafil taken once every other day versus once daily was comparable and can be explained by the highly selective nature of the agent and comparatively long half-life that allows the drug to remain in the blood at a therapeutic concentration of higher than the minimal effective concentration.
Another possible mechanism could include the difference of drug concentrations between plasma and erectile tissue, with an improvement in endothelial function and oxygenation of penile tissues.
Our study has some limitations. No placebo or control group was included in the study for comparison with the groups that received treatment. In addition, the study period was relatively short, and the strict control of LUTS medication was relatively insufficient, including finasteride, because this can lead to permanent ED in a significant proportion of men. However, our modified standard daily drug regimen seems to be cost-effective and increased patient compliance, without loss of treatment efficacy.
Daily administration of a PDE5 inhibitor provides a treatment option that could be suitable for difficult cases of ED, as well as providing the possibility for spontaneity that does not require consideration of the timing of sexual activity with therapeutic dose. Considering the number of patients undergoing medical therapy for ED associated with LUTS is increasing, our findings on the 5-mg tadalafil once every other day regimen that achieves sustainable effects on LUTS and ED could be a reasonable alternative treatment.
Chronic, continuous use of PDE5 inhibitors is likely to continue as life expectancy increases. Therefore, diverse treatment alternatives are warranted for different causes. Until now, tadalafil daily dosing was the first and unique ED treatment approved for chronic usage. There will be numerous changes in the use of medication for the treatment of ED and in the use over the long term.
In this study, we compared the efficacy and safety of 5 mg tadalafil daily and 5-mg once every other day in men with coexisting ED and LUTS. Both treatments were well tolerated and effectively improved IIEF, IPSS and SEP Q3 percentage. Treatment with 5-mg tadalafil on alternate days is an acceptable alternative to once-daily use of PDE5 inhibitors. Although alternative-day use of tadalafil may not necessarily be the optimal management scheme for every man with ED, exciting challenges in dosing options with PDE5 inhibitors have great potential for long-term study. Our data provides one piece of such a trend. More clinical trials are needed to expand on data available on the efficacy of tadalafil on LUTS and ED.
Tadalafil 5-mg once-daily or alternate-day treatment effectively improved the IIEF score, IPSS score and SEP Q3 percentage. Management of patients with 5-mg alternate-day tadalafil could be sufficient for regular use in patients with ED and LUTS.
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The authors declare no conflict of interest.
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Choi, H., Kim, JH., Shim, JS. et al. Comparison of the efficacy and safety of 5-mg once-daily versus 5-mg alternate-day tadalafil in men with erectile dysfunction and lower urinary tract symptoms. Int J Impot Res 27, 33–37 (2015). https://doi.org/10.1038/ijir.2014.19
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