Efficacy and safety of combination therapy with mirodenafil and α1-blocker for benign prostatic hyperplasia-induced lower urinary tract symptoms accompanied by erectile dysfunction: a multicenter, open-label, prospective study


This study was conducted to determine whether mirodenafil 100 mg, when administered on demand to patients with benign prostatic hyperplasia (BPH) who are receiving α1-blocker therapy, is safe with regard to the cardiovascular system and whether it improves lower urinary tract symptoms (LUTS) and sexual function. The study involved 121 LUTS/BPH patients who had been treated for at least 3 months with α1-blockers before being administered with mirodenafil 100 mg on demand. Before the start of mirodenafil administration, the blood pressure, heart rate, international prostate symptom score (IPSS)/quality of life (QoL), peak urine flow rate (Qmax), post-voiding residual urine volume (PVR), and international index of erectile function-5 (IIEF-5) of each patient were measured. At 4 and 8 weeks after commencing mirodenafil administration, the blood pressure and heart rate were measured again, any adverse effects of mirodenafil were assessed, and sexual function and voiding symptoms were re-evaluated. Of the 121 patients, 73 (60.3%) completed the 8-week clinical trial. Significant changes in blood pressure and heart rate were not observed during the study. Significant improvements in the IIEF-5 and the IPSS/QoL, but not the Qmax or PVR, were observed. The results of this study suggest that the administration of mirodenafil 100 mg on demand may induce few hypotensive interactions and may be acceptably effective with regard to improving LUTS and sexual function.


The prevalences of ED and the lower urinary tract symptoms (LUTS) that are induced by benign prostate hyperplasia (BPH) increase with age, and several epidemiological surveys have shown that there is high comorbidity between LUTS and ED.1, 2, 3, 4 Other studies have also suggested that the same pathophysiological mechanisms may underlie both ED and BPH-induced LUTS (LUTS/BPH): these mechanisms may involve nitric oxide synthase/nitric oxide pathways, endothelin-1, autonomic overactivity, rhokinase activity and α1-adrenergic receptors.5, 6, 7 With regard to the latter, as α1-adrenergic blockers (α1-blockers) inhibit the α1-adrenergic receptors of smooth muscles of the prostate and bladder neck, and induce the relaxation of these muscles, these blockers alleviate LUTS.8 In addition, when the activity of nitric oxide is improved by a PDE5i, erection is induced. Although it has been reported that α1-blockers and PDE5i act synergistically to improve both ED and LUTS/BPH, it remains unclear whether α1-blockers can improve ED on their own, and although one study found that they have a positive effect on ED,9 several others have shown that α1-blockers do not affect libido or erectile function.10 By contrast, several clinical studies suggest that PDE5i on their own improve LUTS/BPH.11 At present, α1-blocker monotherapy is highly recommended for the treatment of LUTS/BPH,12 and PDE5i are a first-line treatment for ED.13 Given this, it is important to understand the safety and efficacy of PDE5i/α1-blocker combination therapy in patients with concurrent LUTS/BPH and ED, particularly with regard to hypotension hemodynamic interactions. Indeed, several studies with middle-aged patients with LUTS/BPH and ED have shown that combination therapy with PDE5i and α1-blockers improve the symptoms of both ED and LUTS/BPH without inducing any hypotensive hemodynamic interactions.14 Furthermore, an in vitro study has reported that such combination therapy relaxes human prostate smooth muscles more potently than monotherapy.15

Mirodenafil (5-ethyl-3,5-dihydro-2-[5-[[4-(2-hydroxyethyl)-1-piperazinyl]sulfonyl]-2-propoxyphenyl]-7-propyl-4H-pyrrolo[3,2-d]pyrimidin-4-one; Mvix®, SK Chemical, Seoul, Korea) is the most recently developed oral PDE5i and has been shown to be potent, reversible and selective.16 In Korea, this drug has been commercially available since 2007. It has a Tmax of 1.25 h and a T1/2 of 2.5 h and a preclinical study has shown it has high selectivity.17 The selectivity of mirodenafil is 10 times higher than that of sildenafil and its inhibitory effects on other PDEs are very small and its action time is 6 h, similar to sildenafil or vardenafil.18 At the previous study it was demonstrated that mirodenafil, in doses of 50 or 100 mg, significantly improved erectile function and was well tolerated in men with broad-spectrum ED of various etiologies and severities.19 In general, mirodenafil 50 or 100 mg was recommended to be administrated 4 h to 30 min before the sexual intercourse and maximally once a day. However, to the best of our knowledge, studies examining the clinical efficacy and safety of combination therapy composed of mirodenafil and α1-blockers have not yet been performed. Therefore, this study is designed to determine whether administering mirodenafil to patients who are being treated with α1-blockers can effectively treat LUTS/BPH and ED without inducing hypotensive interactions.

Patients and methods

Subjects and study design

This study included 121 men with ED and LUTS/BPH who visited our urological clinics between October 2009 and August 2010. All patients had been given α1-blockers (tamsulosin 0.2 mg or alfuzosin 10 mg) to treat LUTS/BPH for more than 3 months before the study commenced. The study was an open-label, prospective and non-comparative study that was conducted in five medical institutions in Korea. The study was approved by the Institutional Review Board.

All subjects were assessed by using the five-item version of the international index of erectile function (IIEF-5). The following subjects were excluded from the study: (1) those who had shown hypersensitivity reactions to PDE5i, (2) those who were being treated with drugs that are known to affect erectile function (for example, antiandrogens and 5 α-reductase inhibitors), (3) those who had been diagnosed with ED and had undergone surgery, (4) those who taken a PDE5i for a month before our study (5) those who were being treated with nitrate preparations and nitric oxide providers and (6) those who did not take a mirodenafil at the day before visit.

Before enrolment in the study (V0), patients were screened for 2 weeks to determine whether they met the inclusion and exclusion criteria. Information regarding the duration of illness, smoking/drinking status and past medical history was collected. V0 also included a physical examination in which the blood pressure and heart rate were measured and 12-lead electrocardiography, routine hematological tests, and urinalysis were performed. Thereafter, at the start of the study (designated as V1), all patients were then given two oral mirodenafil doses of 100 mg per week, to be taken before intercourse. They were asked not to take the drug more than twice in a week and were instructed with regard to its administration, if possible. It was emphasized that the patients should take mirodenafil at least 6 h after they had taken their α1-blocker. In addition, all patients were explained that each visit should be the day after the last medication. The efficacy and safety of this regimen were assessed 4 (V2) and 8 weeks (V3) after commencing mirodenafil administration.

Assessment of efficacy and safety

The efficacy of the combination treatment with regard to ED was assessed at V1, V2 and V3 by using the IIEF-5 together with the question 2 and 3 of the sexual encounter prole (SEP2: were you able to insert your penis into your partner's vagina? SEP3: did your erection last long enough for you to have a successful intercourse?) and global assessment question (GAQ: has the treatment you have taken over the past 8 weeks improved your erections?). The efficacy of the combination treatment with regard to LUTS/BPH was assessed by determining the international prostate symptom score (IPSS) and by measuring the post-voiding residual urine volume (PVR) and the peak urine flow rate (Qmax). The quality of life (QoL) score was also determined.

The safety of the combination treatment was assessed at V1, V2 and V3 by taking the patient's history, performing a physical examination that included determining the sitting and standing systolic and diastolic blood pressures and the heart rate, and recording the adverse effects.

Statistical analysis

The age and body mass index (BMI) of the subjects were analyzed. Statistical comparisons of IPSS, Qmax and PVR before and after commencing mirodenafil administration were made by using the Student's t-test. Statistical analyses were performed by using Open Office.org Calc (Open Office.org® version 3.2.0, Oracle, Redwood Shores, CA, USA) and MedCalc (MedCalc® version, MedCalc Software, Mariakerke, Belgium). A P-value of <0.05 was considered statistically significant.


The mean age of the 121 subjects was 58.17±6.35 years and the mean duration of ED was 12.87±5.64 months. The mean BMI was 25.26±2.19 kg m−2 and the mean abdominal circumference was 89.42±6.28 cm. On average, 2.14 mirodenafil doses were taken per week (range 0–5). At V2 and V3, 23 men (19.01%) and 25 men (25.51%) dropped out of the study (Figure 1). Consequently, by V3, 73 men had completed the study. A total of 51 men were taking tamsulosin 0.2 mg and 22 men alfuzosin 10 mg daily.

Figure 1

This 10-week study involved a 2-week screening period and an 8-week treatment phase. The figure shows the reasons for drug discontinuation in our study.

With regard to efficacy in terms of ED, at V1, V2 and V3, the mean IIEF-5 score was 7.78±4.30, 11.22±4.19 and 15.22±4.00, respectively (V1 vs V2, P<0.001; V1 vs V3, P<0.001). In terms of the five questions that make up the IIEF-5 score, the scores for all five questions were significantly higher at V2 and V3 compared with at V1. Thus, the combination treatment was associated with significant improvements in erectile function. In respect of the SEP2 and SEP3, 61 (62.24%) and 55 men (56.12%) reported ‘yes’ at V2, and 59 (80.82%) and 62 men (84.93%) reported ‘yes’ at V3. With regard to the GAQ, 71 men (72.45%) reported ‘yes’ at V2 and 66 men (90.41%) reported ‘yes’ at V3.

With regard to the LUTS/BPH efficacy parameters, at V1, V2 and V3, the mean IPSS score was 15.60±7.79, 11.29±5.77 and 9.01±4.86, respectively (V1 vs V2, P<0.001; V1 vs V3, P<0.001), the mean QoL was 3.22±0.89, 2.86±0.90 and 2.42±0.96, respectively (V1 vs V2, P=0.001; V1 vs V3, P<0.001), the mean Qmax was 14.54±3.26, 14.42±3.35 and 14.55±3.17 ml s−1, respectively (V1 vs V2, P=0.098; V1 vs V3, P=0.472), and the mean PVR was 22.10±28.75, 17.66±15.07 and 18.71±16.65 ml, respectively (V1 vs V2, P=0.229; V1 vs V3, P=0.343) (Table 1). Thus, mirodenafil treatment was associated with significant improvements in the IPSS and QoL but no marked changes in the Qmax or PVR were observed. The subjects were then divided into two subgroups according to difference of IIEF-5 between V3 and V1: those with difference of IIEF-58 (group 1, 35 men) and those with difference of IIEF-5>8 (group 2, 38). In group 1, for V1, V2 and V3, the mean IPSS was 16.06±6.69, 11.03±5.18 and 8.91±4.51, respectively (V1 vs V3, P<0.001; V1 vs V3, P<0.001). In group 2, for V1, V2 and V3, the mean IPSS was 15.18±8.75, 11.53±6.33 and 9.11±5.21, respectively (V1 vs V2, P<0.001; V1 vs V3, P<0.001). However, there were no significant differences in the two groups in difference of IPSS between V1 and V3 (group 1: 7.14±4.94, group 2: 6.08±5.75, P=0.401) (Table 2).

Table 1 Comparison of urodynamic parameters and IPSS/QoL at V1a, V2b and V3c
Table 2 Comparison of IPSS between group 1 and 2

At V1, V2 and V3, the mean sitting systolic blood pressure was 123.75±10.70, 124.49±9.94 and 124.67±8.94 mm Hg, respectively (V1 vs V2, P=0.068; V1 vs V3, P=0.061), the mean sitting diastolic blood pressure was 74.38±8.38, 74.27±7.43 and 74.30±6.78 mm Hg, respectively (V1 vs V2, P=0.066; V1 vs V3, P=0.260), the mean standing systolic blood pressure was 126.79±12.05, 126.70±10.22 and 127.36±9.23 mm Hg, respectively (V1 vs V2, P=0.920; V1 vs V3, P=0.583), the mean standing diastolic blood pressure was 78.05±9.49, 78.90±7.84 and 79.10±7.29 mm Hg (V1 vs V2, P=0.280; V1 vs V3, P=0.078), and the mean heart rate was 73.41±9.36, 72.49±7.58 and 72.77±8.11 beats per min, respectively (V1 vs V2, P=0.297; V1 vs V3, P=0.488) (Table 3). Thus, the mean sitting and standing systolic and diastolic blood pressures and the mean heart rate did not change significantly over the course of the trial.

Table 3 Hemodynamic parameters at V1a, V2b and V3c

Adverse effects were observed in four men (4.08%) at V2 and in four men (5.48%) at V3. Facial flushing was the most common adverse effect (three men at V2; two men at V3), followed by headache (one man each at V2 and V3) and dizziness (one man at V3). None of the subjects dropped out of the study because of adverse effects.


For patients with LUTS/BPH, α1-blockers serve as the first-line medical treatment. As both α1-blockers and PDE5i can affect blood pressure, clinicians must be careful that any combination therapies involving these two drugs do not induce any hemodynamic interactions.9 At present, there is controversy regarding the concomitant administration of α1-blockers and PDE5i for treating concurrent LUTS and ED. The European Association of Urology guidelines on male sexual dysfunction recommend that α1-blockers should not be administered within 4 h of the use of sildenafil 50 or 100 mg; they also state that tadalafil is contraindicated for patients who are being treated with any α1-blocker apart from tamsulosin 0.4 mg.13 Similarly, in the United States, combination therapy composed of α1-blockers and vardenafil is not used in clinical practice. However, several studies have shown that the appropriate use of PDE5i/α1-blocker combination therapy in healthy men or BPH patients cannot induce the development of significant hypotension.

One of these was the study by Auerbach et al., where 22 patients being treated with tamsulosin in the morning also received vardenafil or placebo in the evening.20 Analyses of the systolic/diastolic blood pressure and heart rate suggested that vardenafil/tamsulosin combination therapy does not induce clinically significant hypotension. Another study by Kloner et al. examined the safety of the doxazosin 8 mg and tadalafil 20 mg combination and the tamsulosin and tadalafil 10 or 20 mg combination. This study showed that tadalafil 20 mg augmented the hypotensive effect of doxazosin 8 mg, but did not affect patients in the tamsulosin group. Thus, it was concluded that tamsulosin/tadalafil combination therapy is hemodynamically safe. Similarly, when Giuliano et al. conducted the study of healthy men who were administered alfuzosin 10 mg daily for 7 days and tadalafil 20 mg or a placebo on the seventh day, it was concluded that a combination of alfuzosin 10 mg and tadalafil 20 mg does not induce hemodynamic interactions in middle-aged healthy men.21 However, one study reported that PDE5i/α1-blocker combination therapy does induce hemodynamic interactions. This study by Nieminen et al.22 involved 16 patients with enlarged prostates and LUTS who were treated with tamsulosin 0.4 mg and/or sildenafil 100 mg. On their own, tamsulosin did not affect the hemodynamics but sidenafil decreased blood pressure in the supine position. When they were combined, the two drugs reduced the systemic vascular resistance in the supine position. However, Nieminen et al. emphasized that such changes may be due to multifactorial causes such as associated cardiovascular disease(s) or concurrent medication. In the present study, patients with LUTS/BPH who were receiving α1-blockers were treated with mirodenafil 100 mg on demand twice a week and their hemodynamic changes were evaluated. The safety and efficacy of mirodenafil combined with α1-blockers (tamsulosin or alfuzosin) have not been determined previously, however, we did not detect any significant changes in systolic/diastolic blood pressure and heart rate in our study. This supports the observations of the many previous studies described above that have examined the safety of other PDE5i/α1-blocker combinations. It should be noted that during the screening period, it was emphasized to the patients that they were to take the mirodenafil at least 6 h after taking the α1-blocker; whether this rule was followed was also ascertained at the follow-up visits.

Several studies have examined the efficacy of PDE5i/α1-blocker combination therapy for the LUTS/BPH patients. One of these was that of Kaplan et al., which was the study on the efficacy for new cases of LUTS and ED of a 12-week treatment regimen of alfuzosin 10 mg once a day (OAD) and/or sildenafil 25 mg OAD.23 In the combination therapy group, alfuzosin was administered each day after the same meal and sildenafil was administered at bed time. The combination therapy was associated with a greater improvement in the IPSS (24%) than either of the monotherapies (alfuzosin, 15.6%; sildenafil, 16.9%); the combination therapy also improved the IIEF significantly (P=0.002). Alfuzosin alone also significantly improved the Qmax (11.7%, P=0.03) but the combination therapy was even better (21.1%, P=0.02). Another study on the efficacy of PDE5i/α1-blocker combination therapy for LUTS/BPH was that by Bechara et al.,24 who performed a study with 27 BPH patients who had had LUTS for 6 months to examine the efficacy of tamsulosin 0.4 mg OAD monotherapy and tamsulosin 0.4 mg and tadalafil 20 mg OAD combination therapy. The treatment started with the monotherapy or combination therapy for 45 days, after which the therapy was switched to the other regimen for another 45 days. The combination therapy was associated with more significant improvements in the IPSS/QoL than the monotherapy. Both were also associated with significantly increased Qmax (both P<0.001) and did not differ significantly in this regard. In addition, only the combination therapy was associated with a significant improvement in the IIEF (P<0.001). Moreover, when Liguori et al.25 conducted a study with 66 BPH patients who had had LUTS for at least 6 months to determine the efficacy of alfuzosin 10 mg OAD and/or tadalafil 20 mg every other day, they found that while the IPSS was significantly improved in the alfuzosin monotherapy group (27.2%), it was even better in the combination therapy group (41.6%). Qmax was also improved in all three groups (21.7%, P=0.006 for alfuzosin; 9.5%, P=0.044 for tadalafil; 29.6%, P<0.001 for combination), with the combination group showing the best improvement. The IIEF-EF improved in the alfuzosin monotherapy group (15%), but the tadalafil and combination groups showed even greater improvements (36.3 and 37.6%, respectively). In addition, there was an open-label, prospective study by Chung et al.26 on the efficacy of udenafil 100 mg taken once or more weekly (mean, 2.2 times weekly) for 8 weeks in 82 patients with LUTS/BPH who were being treated with α1-blockers; these patients showed significant improvements in both the IPSS and IIEF. Qmax and PVR were not measured. Thus, these studies showed that PDE5i/α1-blocker combination therapy treats the LUTS/BPH patients more effectively than α1-blocker monotherapy. However, a recent study with 60 LUTS/BPH and ED has reported somewhat different results. This study by Tuncel et al.27 was a randomized, open-label, three-arm study on the efficacy of tamsulosin 0.4 mg and/or sildenafil 25 mg 4 days weekly and it showed that both combination therapy and tamsulosin monotherapy were associated with similar degrees of significant improvement in IPSS (40.1%, P<0.001 and 36.2%, P<0.001, respectively): they did not differ significantly from each other in this regard (P=0.206). However, although the Qmax was improved in all three groups, the combination therapy resulted in the most marked changes (42.0%, P<0.001 for the combination therapy; 26.9%, P<0.001 for sildenafil and 26.2%, P<0.001 for tamsulosin). The combination therapy and the sildenafil monotherapy were also associated with similar degrees of improvement in the sexual health inventory for men scores and the third and fourth questions of the IIEF. It was concluded that combination therapy is not superior to tamsulosin monotherapy in terms of improving voiding symptoms and it is similar to sildenafil monotherapy with regard to improving sexual function. However, it should be taken into consideration that this study was performed for 8 weeks on patients who had both a low IPSS and a high Qmax.

Our study on the efficacy of PDE5i/α1-blocker combination therapy involved a relatively large number of BPH patients who completed the treatment course. After 8 weeks of the combination therapy, the IPSS had dropped from the baseline (15.60±7.79) by 57.8% to 9.01±4.86 (P<0.001) whereas the IIEF-5 had risen from the baseline (7.78±4.30) by 95.2% to 15.22±4.00 (P<0.001). Both of these observations are consistent with those of the previous studies described above. Qmax, however, which is an uroflowmetric factor, was 14.54±3.26 ml s−1 at baseline and 14.55±3.17 ml s−1 after 8 weeks of combination treatment; these two values did not differ significantly. These observations suggest that PDE5i may be more effective for irritative symptoms than for obstructive symptoms (indicated by Qmax and PVR, which are objective measures of BPH-related bladder-outlet obstruction).28 In the aforementioned studies, both PDE5i monotherapy and the combination therapy improved Qmax significantly (Table 4). This apparent discrepancy between our study and previous studies in terms of the effect of combination therapy on Qmax may relate to the fact that our study was performed on patients with LUTS/BPH who had taken α1-blockers for at least 3 months. It may be that in the previous studies, the obstructive symptoms were improved by combination therapy because the studies were conducted with patients without a history of previous treatment.29 Supporting this is that the baseline Qmax of 14.54±3.26 ml s−1 in the present study is high compared with those recorded in previous studies.23, 24, 25, 26 In comparison with Kaplan et al. and Tuncel et al., the full dose of mirodenafil, which we used might result in similar outcomes of improvement for LUTS despite only two times per week. In addition, we investigated two groups to examine correlation on improvement of IIEF-5 and IPSS. However, in group 1 and 2, difference of IPSS did not show significant differences. These statistical results might come from a relatively small sample size in each group.

Table 4 Effect of combination therapy on IPSSa and urodynamic parameters in previous studies

This study suffers from some limitations. First, a control group was lacking. Second, as this study was conducted with patients who had received α1-blockers for at least 3 months, the two drugs may have acted synergistically. Third, the study period was relatively short compared with those of previous studies. However, it is the first study on the efficacy and safety of a combination therapy composed of mirodenafil and α1-blockers OAD, and it supports previous studies that suggest that PDE5i/α1-blocker combination therapy may be of benefit in clinical settings.30 In addition, relatively short half-life and action time of mirodenafil might not induce severe adverse effects in combination therapy with α1-blocker. If patients with ED and LUTS/BPH keep medication schedule, mirodenafil may be effective and safe. Nevertheless, additional randomized, double-blind, placebo-controlled studies with longer follow-up periods are needed to confirm our results.


Combination therapy composed of mirodenafil and α1-blocker was safe for patients with both LUTS/BPH and ED. Hypotensive interactions and other adverse events were minimal and self-limited. The patients also showed significant improvements in both LUTS and ED.


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This study was sponsored by SK Chemical, Seoul, Korea.

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Correspondence to S W Lee.

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Lee, J., Cho, S., Oh, C. et al. Efficacy and safety of combination therapy with mirodenafil and α1-blocker for benign prostatic hyperplasia-induced lower urinary tract symptoms accompanied by erectile dysfunction: a multicenter, open-label, prospective study. Int J Impot Res 23, 249–256 (2011) doi:10.1038/ijir.2011.34

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  • adrenergic alpha-1 receptor antagonists
  • erectile dysfunction
  • mirodenafil
  • prostatic hyperplasia

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