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ORIGINAL RESEARCH—ED PHARMACOTHERAPY A Comparative Randomized Prospective Study to Evaluate Efficacy and Safety of Combination of Tamsulosin and Tadalafil vs. Tamsulosin or Tadalafil Alone in Patients with Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia Dig Vijay Singh, MS, MCh, Uttam Kumar Mete, MS, DNB, MCh, FRCSEd, Arup Kumar Mandal, MS, MCh, and Shrawan Kumar Singh, MS, MCh Department of Urology, Post Graduate Institute of Medical Education & Research, Chandigarh, India DOI: 10.1111/jsm.12357
ABSTRACT
Introduction. Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and erectile dysfunction are common disorders of advancing age. Aim. To evaluate the efficacy and safety of tamsulosin and tadalafil in patients with LUTS due to BPH. Methods. In this prospective randomized study, 133 men complaining of LUTS due to BPH were included. Forty-five patients received tamsulosin 0.4 mg/day alone (Group A), 44 patients received tadalafil 10 mg/day (Group B), and combination therapy (tamsulosin and tadalafil both) was instituted in 44 patients (Group C). After a 2-week medication free run-in period, they were evaluated for International Prostatic Symptom Score (IPSS), International Index of Erectile Function score (IIEF5), quality of life (IPSS QoL), maximum urinary flow rate (Qmax), post-void residual urine (PVR) volume, and safety parameters before and at 3 months of treatment. Main Outcome Measures. There were primary (IPSS, IPSS QoL index, Qmax, and PVR) and secondary (erectile function [EF] domain scores from IIEF5) efficacy end points. Safety assessment included laboratory tests and patient’s reporting of adverse event. Results. A significant improvement in IPSS score was observed in all the 3 groups A, B, and C (−50.90%, P < 0.05; −33.50%, P < 0.05; and −53.90%, P < 0.05, respectively). IIEF5 score increased significantly in these three groups (+39.28%, P < 0.05; +45.96%, P < 0.05; and +60.23%, P < 0.05, respectively). A significant increase in Qmax and decrease in PVR were also observed (33.99%, P < 0.05; 29.78%, P < 0.05; and 37.04%, P < 0.05) and (−60.90%, P < 0.05; −49.45%, P < 0.05; and −62.97%, P < 0.05, respectively). The QoL scores improved significantly (−73.35%, P < 0.05; −70.26%, P < 0.05; and −79.65%, P < 0.05, respectively). Side effects were dyspepsia, heartburn, headache, flushing, myalgia, and backache. Adverse effect dropout was 3.7%. No participant experienced any severe or serious adverse events. Conclusions. In patients with LUTS due to BPH, tamsulosin and tadalafil alone or in combination cause a significant improvement in patients with LUTS. Their EF also improves with these medications. The improvement is better with combination therapy compared with single agent alone. Singh DV, Mete UK, Mandal AK, and Singh SK. A comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. J Sex Med 2014;11:187–196. Key Words. Tamsulosin; Tadalafil; Benign Prostatic Hyperplasia; Lower Urinary Tract Symptoms; Erectile Dysfunction; Medical Therapy
© 2013 International Society for Sexual Medicine
J Sex Med 2014;11:187–196
188 Introduction
L
ower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are common disorders whose prevalence increases with advancing age. Recent large-scale epidemiological studies reported a statistically significant association between these two conditions, independent of age and cardiovascular comorbidities [1–3]. Furthermore, a significant association between the increased severity of LUTS and the increased severity of ED has been confirmed [4]. The exact mechanisms responsible for this association remain controversial. It has been suggested that this association may be psychosocial [5] because the psychological impact of LUTS on the quality of life (QoL) might alter a patient’s erectile function (EF). Conversely, other authors suggested some pathophysiologic common components that may be involved. Four theories supporting biological plausibility currently exist: (i) the reduced production of nitric oxide synthase/NO in the pelvis, which includes both the penis and prostate; (ii) the autonomic hyperactivity and metabolic syndrome effects on LUTS, prostate growth, and ED; (iii) the presence of an increased rho-kinase activation/endothelin activity; and (iv) the diffuse atherosclerosis of prostate, penis, and bladder [6]. Considering the high incidence of ED and BPH in aging men and the same pathophysiology and the probability to treat both disorders with the same treatment (alpha blockers and/or phosphodiesterase type 5 [PDE5] inhibitors), numerous authors evaluated the actions of PDE5 inhibitors in improving the symptoms of LUTS [7–10] and in vitro and in vivo role of alpha blockers and PDE5 inhibitors for ED improvement [11,12].
Aim
To offer another clinical evaluation in order to verify the safety and efficacy of the combination of tamsulosin 0.4 mg/day plus tadalafil 10 mg/day vs. either of the drug alone to treat patients with LUTS due to BPH. Material and Methods
Patients and Study Design This was a 3-month, randomized, open-label, three-arm study conducted at a single center from October 2010 to December 2012. The study was J Sex Med 2014;11:187–196
Singh et al. conducted in accordance with the guidelines of the International Conference on Harmonization/ World Health Organization Good Clinical Practice Standards and the principles of the Declaration of Helsinki. An ethical review board approved the study protocol for this site, and the patients granted written informed consent before any study procedures. Men over the age of 45 years presenting to our urologic outpatient clinic with a history of LUTS secondary to BPH of 6 months or longer, an International Prostatic Symptom Score (IPSS) of >8, total serum prostatic specific antigen (PSA) ≤4.0 ng/mL, maximum urinary flow rate (Qmax) >5 mL/second and 125 mL at screening, and willing and able to give written informed consent and comply with study procedures were enrolled. Patients agreed not to use BPH medications during the research other than the study medications. The exclusion criteria were contraindications to investigational drugs including patients with known allergies/allergy to drugs under study, use of finasteride/dutasteride and other investigational drugs or prohibited medications like alpha adrenergic—agonist, history of syncope, and orthostatic hypotension—bladder outlet obstruction due to cancer, calculi or stricture, previous transurethral resection of the prostate, any neurological disorders affecting storage and voiding functions, prostatic disease like prostatitis or cancer, PSA greater than 4 ng/mL, an episode of acute urinary retention within 4 weeks of study initiation, documented urinary tract infection, poorly controlled diabetes mellitus, or poorly controlled hypertension. At the first visit (visit 0), a detailed clinical history was taken including medical history of present and past diseases, sexual life, and concomitant drug treatments. Patients using BPH drugs or medications that could interfere with bladder function (alpha blockers, anticholinergics, sympathomimetic drugs, antihistamines, and herbal preparations) or PDE5 inhibitors underwent a 2-week medication free run-in period before the study treatment as specified in previous studies [13]. Prior to commencing therapy, all participants completed questionnaires including International Index of Erectile Function (IIEF5) and IPSS. Other efficiency variables included Qmax and post-void residual urine volume (PVR). After 2 weeks (visit 1; baseline), digital rectal examination, abdominal ultrasound, basic
Comparative Efficacy of Tamsulosin and Tadalafil in BPH laboratory investigations (hematology, renal function tests, urine analysis), serum PSA, and uroflowmetry were performed. An IPSS of 8 points or more and a Qmax of 5–15 mL/second on a voided volume of 125 mL or more were required for study continuation. The treatments were given to the eligible patients according to computergenerated random table and underwent randomized allocation to either tamsulosin 0.4 mg once a day (Group A), tadalafil 10 mg once a day (Group B), or the combination of both (Group C). Patients were instructed to take the study medication at approximately the same time every day without restrictions of food intake or timing of sexual activity. Compliance and drug-related side effects were assessed at visit 2 and visit 3 (1 and 3 months, respectively after starting the treatment).
Main Outcome Measures At 3 months of the treatment, same efficacy variables were reassessed for comparison. Primary efficacy end points included subjective (IPSS, IPSS QoL index) and objective (Qmax and PVR) changes from baseline. Secondary efficacy end points included changes from baseline in their EF using the EF domain scores from the IIEF5. Safety assessment included laboratory tests (hematology, clinical biochemistry, and urinalysis) and patient’s reporting of adverse event. Medical history, physical examination, and electrocardiogram were performed at study entry, at 1 month, 3 months, and discontinuation. Statistical Analysis Statistical analyses were performed using a commercially available analysis program: SPSS version 16.0 (SPSS Inc., Chicago, IL, USA). The data has been expressed as the mean (standard error of the mean) with n indicating number of experiments. Statistical significance was determined by paired t-test, and subgroup analysis was performed within the framework of one-way analysis of variance (Anova) model and post hoc test with P value < 0.05 considered to indicate significance. The study was designed to provide 80% power to detect a difference of 3.0 for change in IPSS, IIEF, and 2 mL/second for Qmax assuming a standard deviation of 5.0 and a one-sided alpha of 0.05. The purpose of this study was to establish proof of principle in anticipation of subsequent larger and more definitive trials. As such, this protocol prespecified the use of one-sided tests of signifi-
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cance for evaluating the efficacy end points. No adjustments were made for multiple comparisons. Assuming that 85% of patients would complete the study, a randomized sample of 123 subjects were required. Our sample size came out to be at least 35 subjects per group. Results
Patient Population There were a total 178 BPH patients, but 45 cases were excluded that did not meet the inclusion criteria. A total of 133 men of more than 45 years old (mean age 62 years) were included in the study on a prospective basis with 45 randomized to the tamsulosin group (Group A), 44 to the tadalafil group (Group B), and 44 to the combination therapy group (Group C). Eight patients (6.01%) dropped out because of adverse events (n = 5) or noncompliance (n = 3); therefore, the study population for efficacy comparison consisted of 125 patients (43 in tamsulosin group, 40 in tadalafil group, and 42 in combination group) (Figure 1). Demographic and baseline characteristics were similar between the three groups (Table 1). Study Outcomes EF An IIEF5 questionnaire was not done in eight patients in absence of sexual activity, so assessment was done in 117 patients (drug A: n = 40; drug B: n = 38; drug C: n = 39) (Figure 1). Three patients had no ED (IIEF5 score >22). EF improved with tamsulosin (+39.28% [P < 0.05]), tadalafil (+45.96% [P < 0.05]), and tamsulosin and tadalafil combination (+60.23% [P < 0.05]) (Figure 2A, B; Table 2). On Anova and post hoc tests, the impact of combination regimen on EF was significantly greater than tamsulosin alone (P < 0.05) but not when compared with tadalafil group (P = 0.125), whereas tadalafil improved EF better than tamsulosin monotherapy (P < 0.05). IPSS Changes Significant decrease in the IPSS score was observed in all the three groups. However, maximum benefit was noted among patients receiving combination therapy. A significant decrease in IPSS score was observed in monotherapy of tamsulosin (−50.90% [P < 0.05]), tadalafil (−33.50% [P < 0.05]), and with combined therapy of tamsulosin and tadalafil J Sex Med 2014;11:187–196
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Singh et al. Assessed for eligibility (N = 178)
Randomized (N = 133) Mean age 62 years
Allocated to tamsulosin (N = 45) Completed study (N = 43)
IPSS IPSS QoL index Qmax PVR
Allocated to tadalafil (N = 44) Completed study (N = 40)
Patient withdrew (N = 4) Reason: worsening of LUTS (N = 1) severe myalgia and backache (N = 1) flushing, headache, myalgia, hypotension (N = 1) Increase in IOP in diagnosed patient of glaucoma (N = 1)
Noncompliance (N = 2) (Lost to follow-up)
Primary outcome analysis (N = 43)
Failed inclusion criteria (N = 45)
Secondary outcome analysis (N = 40)
Absence of sexual activity (N = 3) IIEF assessment done only in sexually active patients (N = 30)
Primary outcome analysis (N = 40)
IPSS IPSS QoL index Qmax PVR
Secondary outcome analysis (N = 38)
Absence of sexual activity (N = 2) IIEF assessment done only in sexually active patients (N = 28)
Allocated to tamsulosin and tadalafil combination (N = 44) Completed study (N = 42)
Noncompliance (N = 1) (Lost to follow-up) Patient withdrew (N = 1) Reason: severe myalgia and backache (N = 1)
Primary outcome analysis (N = 42)
IPSS IPSS QoL index Qmax PVR
Secondary outcome analysis (N = 39)
Absence of sexual activity (N = 3) IIEF assessment done only in sexually active patients (N = 29)
Figure 1 Consort diagram representing patient population and main outcome measures. IIEF5 = International Index of Erectile Function 5; IOP = intraocular pressure; IPSS = International Prostatic Symptom Score; LUTS = lower urinary tract symptoms; PVR = post-void residual urine; Qmax = maximum urinary flow rate; QoL = quality of life.
(−53.90% [P < 0.05]) (Figure 2C, D; Table 2). On applying Anova, tamsulosin monotherapy and combination regimen were significantly better than tadalafil monotherapy (P < 0.05), whereas combination regimen may not be statistically significant but better than tamsulosin regimen (P = 0.147).
Table 1
IPSS QoL QoL scores were significantly decreased (greater QoL) with tamsulosin (−73.35% [P < 0.05]) and tadalafil (−70.26% [P < 0.05]) but maximally with tamsulosin and tadalafil combination (−79.65% [P < 0.05]) (Figure 2E, F; Table 2). There in between-group comparison by Anova and post
Patients’ baseline characteristics Total population (N = 133)
Age (years) ≤60 years (%) >60 years (%) Comorbidities NO HT DM IPSS IIEF Qmax PVR QoL
61.61 ± 6.981 48.9 (n = 65) 51.1 (n = 68) 48.5 32.4 19.1 21.01 10.8 9.3 101.22 5.66
Drug A (n = 45)
Drug B (n = 44)
59.50 ± 6.048 53.3 (n = 24) 46.7 (n = 21)
63.42 ± 8.09 47.7 (n = 21) 52.3 (n = 23)
43.5 34.8 21.7 20.93 10.08 9.15 79.11 5.59
52.2 26.1 21.7 20.33 11.77 8.83 98.92 5.75
Drug C (n = 44) 61.92 ± 6.291 47.7 (n = 21) 52.3 (n = 23) 50 36.4 13.6 21.73 10.61 9.88 126.31 5.65
P value NS NS NS NS NS NS NS NS NS NS NS
DM = diabetes mellitus; HT = hypertension; IIEF5 = International Index of Erectile Function 5; IPSS = International Prostatic Symptom Score; NO = no comorbidity; NS = not significant; PVR = post-void residual urine volume; Qmax = maximum urinary flow rate; QoL = quality of life
J Sex Med 2014;11:187–196
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Figure 2 Subjective parameters. (A) IIEF5 mean score before and after treatment; (B) Percentage change IIEF5 mean score posttreatment at 3 months; (C) IPSS mean before and after treatment; (D) Percentage change IPSS mean posttreatment at 3 months; (E) QoL mean score before and after treatment; (F) Percentage change posttreatment at 3 months. DRUG A = tamsulosin; DRUG B = tadalafil; DRUG C = tamsulosin and tadalafil combination; IIEF5 = International Index of Erectile Function 5; IPSS = International Prostatic Symptom Score; QoL = quality of life.
J Sex Med 2014;11:187–196
192 Table 2
Singh et al. Mean change of parameters from baseline and after 3 months of treatment
IIEF5 score Baseline 3 months % change IPSS Baseline 3 months % change IPSS QoL score Baseline 3 months % change Qmax Baseline 3 months % change PVR Baseline 3 months % change
Drug A
Drug B
Drug C
10.08 ± 5.064 14.04 ± 5.254 +39.28 (P < 0.05)
11.77 ± 6.384 17.27 ± 6.826 +45.96 (P < 0.05)
10.61 ± 5.582 17.00 ± 5.705 +60.23 (P < 0.05)
20.93 ± 4.607 10.26 ± 3.218 −50.90 (P < 0.05)
20.33 ± 5.662 13.50 ± 3.856 −33.50 (P < 0.05)
21.73 ± 5.876 10.00 ± 2.898 −53.90 (P < 0.05)
5.59 ± 0.501 1.48 ± 0.509 −73.35 (P < 0.05)
5.75 ± 0.442 1.71 ± 0.550 −70.26 (P < 0.05)
5.65 ± 0.562 1.15 ± 0.368 −79.65 (P < 0.05)
9.15 ± 3.022 12.26 ± 3.537 +33.99 (P < 0.05)
8.83 ± 3.535 11.46 ± 3.867 +29.78 (P < 0.05)
9.88 ± 3.581 13.54 ± 5.587 +37.04 (P < 0.05)
79.11 ± 55.924 30.93 ± 22.103 −60.90 (P < 0.05)
98.92 ± 84.497 50.00 ± 36.056 −49.45 (P < 0.05)
126.31 ± 78.507 46.77 ± 36.362 −62.97 (P < 0.05)
IIEF5 = International Index of Erectile Function 5; IPSS = International Prostatic Symptom Score; PVR = post-void residual urine volume; Qmax = maximum urinary flow rate; QoL = quality of life
hoc test revealed that combination regimen has greater impact than tamsulosin (P = 0.041) and tadalafil (P = 0.020) regimens.
Qmax Improvement Qmax on uroflowmtery improved with tamsulosin and tadalafil combination (+37.04% [P < 0.05]), tamsulosin only (+33.99% [P < 0.05]), and tadalafil only (+29.78% [P < 0.05]) (Figure 3A, B; Table 2). However, there was not a statistical significant difference on Anova (P = 0.307). PVR Change Significant reduction in PVR was observed with combination of tamsulosin and tadalafil (−62.97% [P < 0.05]), tamsulosin only (−60.90% [P < 0.05]), and tadalafil only group (−49.45% [P < 0.05]) (Figure 3C, D; Table 2). Anova test concluded no regimen superior in reducing PVR (P = 0.053). Safety Out of the total number of 133 patients randomized for the study, 5 patients (3.7%) dropped out because of adverse events. One patient due to worsening of LUTS in tadalafil group, two with severe myalgia and backache (one each in tadalafil only and combination of tamsulosin and tadalafil group), one due to flushing, headache, myalgia, and hypotension, and another due to increase in intraocular pressure (IOP) in already diagnosed patient with glaucoma (both in tadalafil group) left the treatment. No dropout occurred from tamsulosin regimen because of any drug-related side effects (Figure 1). J Sex Med 2014;11:187–196
Four patients in tadalafil only group and six patients in tamsulosin and tadalafil combination group complained of heartburn and dyspepsia, which were relieved with proton pump inhibitors. Flushing, headache, and myalgia were noted in four patients, two each in tadalafil and combination group. None of patients in tamsulosin group complained of drug-related complication. There were no severe or serious adverse events. Discussion
As the prevalence of both ED and LUTS increases with age [14–16], physicians could be in the position to manage these two conditions simultaneously. Moreover, medical therapies for either one of these conditions can affect the other. Alpha blockers are considered the most effective monotherapy for LUTS suggestive of BPH [17]. PDE5 inhibitors are the first-line treatment for ED [18,19]. As a consequence, because of the strong association between LUTS and ED, the simultaneous administration of these drugs is increasing. The current study is designed to evaluate the efficacy of the combined regimen of tamsulosin and tadalafil compared with either of the drug to evaluate effect on both of the conditions, which often coexist. The reason to favor tamsulosin to combine with PDE5 inhibitor was because some authors demonstrated that the combination tamsulosin 0.4 mg + tadalafil (10 or 20 mg) did not show significant hemodynamic changes [20]. In
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Figure 3 Objective parameters. (A) Qmax mean before and after treatment; (B) Percentage change Qmax mean posttreatment at 3 months; (C) PVR mean before and after treatment; (D) Percentage change PVR mean posttreatment at 3 months. DRUG A = tamsulosin; DRUG B = tadalafil; DRUG C = tamsulosin and tadalafil combination; PVR = post-void residual urine; Qmax = maximum urinary flow rate.
addition, tamsulosin was the only alpha blocker accepted by the Food and Drug Administration to be used in combination with tadalafil [21]. Also, prolonged duration of action of tadalafil suits more compared with sildenafil and vardenafil to mitigate some of the psychosocial barriers that interfere with treating ED and provides some men with ED and their partners a treatment option that may offer greater flexibility and potentially less anxiety surrounding the resumption of sexual activity [22].
In a study by Porst et al. [23], efficacy parameters 20 mg dose was not superior to 10 mg dose even with increased adverse effects. Daily doses of 20 mg of tadalafil have been associated with a high percentage of headaches that could probably be reduced using smaller doses of tadalafil [24–26]. In addition to this, the study also highlighted that once-daily tadalafil improved EF in sexually active men with ED and BPH-LUTS, both overall and in clinically relevant patient subgroups [27]. MoreJ Sex Med 2014;11:187–196
194 over, tadalafil 10 mg daily has better patient compliance as compared with alternate day therapy as compared with the study by Liguori et al. where alternate day regimen was used [28]. In a small pilot study, De Rose et al. demonstrated significant increase of IIEF in 78.6% of the patients treated with the combination of doxazosin and sildenafil [29]. In a pilot study by Bechara et al., crossover comparison of two groups to receive tamsulosin 0.4 mg/day vs. tamsulosin 0.4 mg/day plus tadalafil 20 mg/day was done and concluded that improvements of IPSS score and IPSS-QOL were significant with both treatments but greater with the drug combination [26]. Both regimens similarly improved the Qmax and decreased the PVR volume from baseline (P < 0.001) with no significant differences between tamsulosin alone vs. tamsulosin and tadalafil (P > 0.05). The IIEF improved with tamsulosin plus tadalafil (P < 0.001) but not with tamsulosin alone (P > 0.05). In our study, all three regimens improved EF based on IIEF5 questionnaire to a statistical significance but maximally with combination of tamsulosin and tadalafil. Also, there is a significant impact of combination of tamsulosin and tadalafil on EF improvement when compared with tamsulosin alone but not when compared tadalafil alone. These results are in concordance with earlier studies [26,28]. The improvement in EF by tamsulosin can be explained by the same pathophysiological mechanism of LUTS due to BPH and ED [6]. The mechanism by which combination therapy produced greater improvements than either monotherapy is not yet fully defined. It was postulated that both alpha-1 blockers and PDE5 inhibitors, acting by two different mechanisms of action on common urogenital target organs, may have a synergistic effect on LUTS and ED. Alpha-1 blockers, by blocking alpha-1-adrenergic receptors and reducing the sympathetic tone in penile smooth muscle and prostate/bladder neck, could enhance the NO-mediated relaxant influence of PDE5 inhibitors [9,11,26,28,30,31]. Similarily, there is evidence that PDE5 inhibitors enhance the inhibitory effects of alpha-1 blockers on neurogenic contractions of human prostate and bladder neck [32]. We found that IPSS and IPSS QOL improved significantly in all the three groups comparable with the study by Bechara et al. [26]. However, it is unlikely that symptoms relief was simply a psychological benefit because change in IPSS and IIEF5 J Sex Med 2014;11:187–196
Singh et al. scores did not correlate significantly following monotherapy. The change in IPSS was significantly greater with combination group and tamsulosin compared with tadalafil monotherapy. Also, combination regimen was better than tamsulosin; however, it was not statistically significant as mentioned in earlier studies [12,26,28]. The benefit in Qmax and PVR is statistically significant in the three regimens concordant to study by Bechara et al. [26]. No one was significantly better between groups; however, the change in Qmax and PVR was greater in the combination regimen compared with monotherapy in which tamsulosin group behaved marginally better than tadalafil group. These results stipulate the findings of Liguori et al. [28] and Bechara et al. study [26]. In agreement with other authors, our results showed that the combination of tamsulosin and tadalafil did not produce significant changes in Qmax and PVR when compared with alpha blocker monotherapy [7,8,26] and with tadalafil only group. Clearly, an improvement in Qmax was equally observed with all three schemes of drugs, however, not to the extent of IPSS and IPSS QoL improvement, suggesting that PDE5 inhibitors may increase the effects of tamsulosin in reducing LUTS but may be not enough to act over the different pathophysiological mechanisms to increase Qmax [26]. Eight patients (6.01%) dropped out because of adverse events (n = 5) or noncompliance (n = 3). Heartburn and dyspepsia were most common complications (7.5%), four in tadalafil and six in combination group. Flushing, headache, and myalgia were noted in four patients, two each in tadalafil and combination group. Lesser complication of headache compared with previous studies was probably due to 10 mg instead of 20 mg/day dose [23–26]. The 10 mg daily dose used might explain some of the side effects that patients experienced, and one can postulate that there would have even been less side effects if a 5 mg dose was used, but at the cost of lesser benefit in LUTS and/or ED as depicted in the study by Porst et al. [23]. Out of the total number of 133 patients randomized for the study, 5 patients (3.7%) dropped out because of adverse events. Out of this, backache and myalgia were the most common that occurred in three patients. Similarly, in Liguori et al.’s study [28], the most common cause of dropout was backache and myalgia (3 out of the total 66 patients). However, one patient left the treatment in tadalafil group due to increase in IOP
Comparative Efficacy of Tamsulosin and Tadalafil in BPH in general tadalafil not known to cause this side effect. It may be a coincidental finding. None of the patient in tamsulosin group had any complication. There were no severe or serious adverse events in any of the groups. Although randomized, our study is open label and not placebo controlled, and as such, contains restrictions in ascertaining direct drug-related effects on symptoms; nevertheless, it demonstrates a significant and positive effect of combination therapy on LUTS and ED score as assessed not only by the IPSS, QOL, and IIEF5 questionnaires but also by urinary flow rates and PVR, which are an objective outcome evaluation. Other limitations are that it is not a crossover design and the number of patients is too small to get a solid conclusion, and that the men enrolled in the trial may represent a highly motivated sample seeking medical advice rather than the overall male LUTS/BPH population. Also, a patient in combination regimen has the tendency to have greater psychogenic effect of improvement compared with monotherapy that may lead to greater perceived benefit in subjective parameters. We think that in order to conduct a large multicenter trial and to follow a standardized approach, the addition of a medication acceptability tool is also required, which may be accomplished by including measurement of patient satisfaction or preference of medication, measures of acceptability, and relationship between acceptability and adherence. Categorization of patients in different socioeconomic strata, their drug adherence, and overall response would be logical for assessing economic accessibility.
Conclusion
Although at this time there are limited data to support recommending the routine use of combination therapy for patients with LUTS and ED, our preliminary results seem to confirm the data of previous studies that is the combination of alpha-1 blockers with a PDE5 inhibitor is more effective than monotherapy for ED in men with LUTS/BPH. However, in agreement to previous studies, our study stipulates the combination regimen to be more effective compared with monotherapy of tamsulosin or tadalafil for LUTS improvement, but in disagreement of some pioneer studies like of Amado et al. We have not gained a statistical significant change in both IPSS and QoL in combination group compared with
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either of the monotherapy. We think that combination regimen might become a future therapy, if monotherapy for a given patient is not satisfactorily effective especially when patient has significant component of ED. Moreover, we think that a common approach for managing LUTS and ED is mandatory: urologists should be aware of the association between LUTS and ED, especially in patients with ED risk factors. Prospective, randomized, large placebocontrolled, long-lasting clinical trials are ensured to explain the role of combination therapy in patients with LUTS and ED.
Acknowledgment
We would like to thank all the residents of departments of urology, PGIMER, Chandigarh, India for the enrollment of patients and Mrs. Kusum Lata for the statistical work of this study. Corresponding Author: Dig Vijay Singh, MS, MCh, Department of Urology, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, India. Tel: +91 172 2756321; +91 9876616318; Fax: +91 172 2744401; E-mail: [email protected] Conflict of Interest: The author(s) report no conflicts of interest.
Statement of Authorship
Category 1 (a) Conception and Design Dig Vijay Singh; Uttam K. Mete; Shrawan K. Singh (b) Acquisition of Data Dig Vijay Singh; Uttam K. Mete (c) Analysis and Interpretation of Data Dig Vijay Singh; Uttam K. Mete; Shrawan K. Singh; Arup K. Mandal
Category 2 (a) Drafting the Article Dig Vijay Singh; Uttam K. Mete; Shrawan K. Singh; Arup K. Mandal (b) Revising It for Intellectual Content Dig Vijay Singh; Shrawan K. Singh
Category 3 (a) Final Approval of the Completed Article Dig Vijay Singh; Uttam K. Mete; Shrawan K. Singh; Arup K. Mandal J Sex Med 2014;11:187–196
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Singh et al.
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Diagnosis and treatment recommendations. J Urol 2003;170: 530–47. Lue TF, Giuliano F, Montorsi F, Rosen RC, Andersson KE, Althof S, Christ G, Hatzichristou D, Hirsch M, Kimoto Y, Lewis R, McKenna K, MacMahon C, Morales A, Mulcahy J, Padma-Nathan H, Pryor J, de Tejada IS, Shabsigh R, Wagner G. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2004;1:6–23. Porst H, Burnett A, Brock G, Ghanem H, Giuliano F, Glina S, Hellstorm W, Martin-Morales A, Salonia A, Sharlip I; ISSM Standards Committee for Sexual Medicine. SOP conservative (medical and mechanical) treatment of erectile dysfunction. J Sex Med 2013;10:130–71. Kloner R, Jackson G, Emmick J, Mitchell M, Bedding A, Warner M, Pereira A. Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men. J Urol 2004;172: 1935–40. Kloner R. Cardiovascular effects of the 3 phosphodiesterase-5 inhibitors approved for the treatment of erectile dysfunction. Circulation 2004;110:3149–55. Dunn ME, Althof SE, Perelman MA. Phosphodiesterase type 5 inhibitors’ extended duration of response as a variable in the treatment of erectile dysfunction. Int J Impot Res 2007;19: 119–23. Porst H, McVary KT, Montorsi F, Sutherland P, ElionMboussa A, Wolka AM, Viktrup L. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol 2009;56:727–35. McMahon C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to on-demand tadalafil. J Sex Med 2004;1:292–300. Brock GB, Mcmahon CG, Chen KK, Costigan T, Shen W, Watkins V, Anglin G, Whitaker S. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: Results of integrated analyses. J Urol 2002;168:1332–6. Bechara A, Romano S, Casabé A, Haime S, Dedola P, Hernandez C, Rey H. Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot study. J Sex Med 2008;5:2170–8. Porst H, Rajfer J, Casabé A, Feldman R, Ralph D, Vieiralves LF, Esler A, Wolka AM, Klise SR. Long-term safety and efficacy of tadalafil 5 mg dosed once daily in men with erectile dysfunction. J Sex Med 2008;5:2160–9. Liguori G, Trombetta C, De Giorgi G, Pomara G, Maio G, Vecchio D, Ocello G, Ollandini G, Bucci S, Belgrano E. Efficacy and safety of combined oral therapy with tadalafil and alfuzosin: An integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. Preliminary report. J Sex Med 2009;6:544–52. De Rose AF, Giglio M, Traverso P, Lantieri P, Carmignani G. Combined oral therapy with sildenafil and doxazosin for the treatment of nonorganic erectile dysfunction refractory to sildenafil monotherapy. Int J Impot Res 2002;14:50–3. Carson CC. Combination of phosphodiesterase-5 inhibitors and alpha-blockers in patients with benign prostatic hyperplasia: Treatments of lower urinary tract symptoms, erectile dysfunction, or both? BJU Int 2006;97(2 suppl):39–43. Giuliano F. Lower urinary tract symptoms and sexual dysfunction: A common approach. BJU Int 2008;101(3 suppl):22–6. Angulo J, Cuevas P, Fernández A, La Fuente JM, Allona A, Moncada I, Saenz de Tejada I. Tadalafil enhances the inhibitory effects of tamsulosin on neurogenic contractions of human prostate and bladder neck. J Sex Med 2012;9:2293– 306.
ORIGINAL RESEARCH—ED PHARMACOTHERAPY A Comparative Randomized Prospective Study to Evaluate Efficacy and Safety of Combination of Tamsulosin and Tadalafil vs. Tamsulosin or Tadalafil Alone in Patients with Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia Dig Vijay Singh, MS, MCh, Uttam Kumar Mete, MS, DNB, MCh, FRCSEd, Arup Kumar Mandal, MS, MCh, and Shrawan Kumar Singh, MS, MCh Department of Urology, Post Graduate Institute of Medical Education & Research, Chandigarh, India DOI: 10.1111/jsm.12357
ABSTRACT
Introduction. Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and erectile dysfunction are common disorders of advancing age. Aim. To evaluate the efficacy and safety of tamsulosin and tadalafil in patients with LUTS due to BPH. Methods. In this prospective randomized study, 133 men complaining of LUTS due to BPH were included. Forty-five patients received tamsulosin 0.4 mg/day alone (Group A), 44 patients received tadalafil 10 mg/day (Group B), and combination therapy (tamsulosin and tadalafil both) was instituted in 44 patients (Group C). After a 2-week medication free run-in period, they were evaluated for International Prostatic Symptom Score (IPSS), International Index of Erectile Function score (IIEF5), quality of life (IPSS QoL), maximum urinary flow rate (Qmax), post-void residual urine (PVR) volume, and safety parameters before and at 3 months of treatment. Main Outcome Measures. There were primary (IPSS, IPSS QoL index, Qmax, and PVR) and secondary (erectile function [EF] domain scores from IIEF5) efficacy end points. Safety assessment included laboratory tests and patient’s reporting of adverse event. Results. A significant improvement in IPSS score was observed in all the 3 groups A, B, and C (−50.90%, P < 0.05; −33.50%, P < 0.05; and −53.90%, P < 0.05, respectively). IIEF5 score increased significantly in these three groups (+39.28%, P < 0.05; +45.96%, P < 0.05; and +60.23%, P < 0.05, respectively). A significant increase in Qmax and decrease in PVR were also observed (33.99%, P < 0.05; 29.78%, P < 0.05; and 37.04%, P < 0.05) and (−60.90%, P < 0.05; −49.45%, P < 0.05; and −62.97%, P < 0.05, respectively). The QoL scores improved significantly (−73.35%, P < 0.05; −70.26%, P < 0.05; and −79.65%, P < 0.05, respectively). Side effects were dyspepsia, heartburn, headache, flushing, myalgia, and backache. Adverse effect dropout was 3.7%. No participant experienced any severe or serious adverse events. Conclusions. In patients with LUTS due to BPH, tamsulosin and tadalafil alone or in combination cause a significant improvement in patients with LUTS. Their EF also improves with these medications. The improvement is better with combination therapy compared with single agent alone. Singh DV, Mete UK, Mandal AK, and Singh SK. A comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. J Sex Med 2014;11:187–196. Key Words. Tamsulosin; Tadalafil; Benign Prostatic Hyperplasia; Lower Urinary Tract Symptoms; Erectile Dysfunction; Medical Therapy
© 2013 International Society for Sexual Medicine
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188 Introduction
L
ower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are common disorders whose prevalence increases with advancing age. Recent large-scale epidemiological studies reported a statistically significant association between these two conditions, independent of age and cardiovascular comorbidities [1–3]. Furthermore, a significant association between the increased severity of LUTS and the increased severity of ED has been confirmed [4]. The exact mechanisms responsible for this association remain controversial. It has been suggested that this association may be psychosocial [5] because the psychological impact of LUTS on the quality of life (QoL) might alter a patient’s erectile function (EF). Conversely, other authors suggested some pathophysiologic common components that may be involved. Four theories supporting biological plausibility currently exist: (i) the reduced production of nitric oxide synthase/NO in the pelvis, which includes both the penis and prostate; (ii) the autonomic hyperactivity and metabolic syndrome effects on LUTS, prostate growth, and ED; (iii) the presence of an increased rho-kinase activation/endothelin activity; and (iv) the diffuse atherosclerosis of prostate, penis, and bladder [6]. Considering the high incidence of ED and BPH in aging men and the same pathophysiology and the probability to treat both disorders with the same treatment (alpha blockers and/or phosphodiesterase type 5 [PDE5] inhibitors), numerous authors evaluated the actions of PDE5 inhibitors in improving the symptoms of LUTS [7–10] and in vitro and in vivo role of alpha blockers and PDE5 inhibitors for ED improvement [11,12].
Aim
To offer another clinical evaluation in order to verify the safety and efficacy of the combination of tamsulosin 0.4 mg/day plus tadalafil 10 mg/day vs. either of the drug alone to treat patients with LUTS due to BPH. Material and Methods
Patients and Study Design This was a 3-month, randomized, open-label, three-arm study conducted at a single center from October 2010 to December 2012. The study was J Sex Med 2014;11:187–196
Singh et al. conducted in accordance with the guidelines of the International Conference on Harmonization/ World Health Organization Good Clinical Practice Standards and the principles of the Declaration of Helsinki. An ethical review board approved the study protocol for this site, and the patients granted written informed consent before any study procedures. Men over the age of 45 years presenting to our urologic outpatient clinic with a history of LUTS secondary to BPH of 6 months or longer, an International Prostatic Symptom Score (IPSS) of >8, total serum prostatic specific antigen (PSA) ≤4.0 ng/mL, maximum urinary flow rate (Qmax) >5 mL/second and 125 mL at screening, and willing and able to give written informed consent and comply with study procedures were enrolled. Patients agreed not to use BPH medications during the research other than the study medications. The exclusion criteria were contraindications to investigational drugs including patients with known allergies/allergy to drugs under study, use of finasteride/dutasteride and other investigational drugs or prohibited medications like alpha adrenergic—agonist, history of syncope, and orthostatic hypotension—bladder outlet obstruction due to cancer, calculi or stricture, previous transurethral resection of the prostate, any neurological disorders affecting storage and voiding functions, prostatic disease like prostatitis or cancer, PSA greater than 4 ng/mL, an episode of acute urinary retention within 4 weeks of study initiation, documented urinary tract infection, poorly controlled diabetes mellitus, or poorly controlled hypertension. At the first visit (visit 0), a detailed clinical history was taken including medical history of present and past diseases, sexual life, and concomitant drug treatments. Patients using BPH drugs or medications that could interfere with bladder function (alpha blockers, anticholinergics, sympathomimetic drugs, antihistamines, and herbal preparations) or PDE5 inhibitors underwent a 2-week medication free run-in period before the study treatment as specified in previous studies [13]. Prior to commencing therapy, all participants completed questionnaires including International Index of Erectile Function (IIEF5) and IPSS. Other efficiency variables included Qmax and post-void residual urine volume (PVR). After 2 weeks (visit 1; baseline), digital rectal examination, abdominal ultrasound, basic
Comparative Efficacy of Tamsulosin and Tadalafil in BPH laboratory investigations (hematology, renal function tests, urine analysis), serum PSA, and uroflowmetry were performed. An IPSS of 8 points or more and a Qmax of 5–15 mL/second on a voided volume of 125 mL or more were required for study continuation. The treatments were given to the eligible patients according to computergenerated random table and underwent randomized allocation to either tamsulosin 0.4 mg once a day (Group A), tadalafil 10 mg once a day (Group B), or the combination of both (Group C). Patients were instructed to take the study medication at approximately the same time every day without restrictions of food intake or timing of sexual activity. Compliance and drug-related side effects were assessed at visit 2 and visit 3 (1 and 3 months, respectively after starting the treatment).
Main Outcome Measures At 3 months of the treatment, same efficacy variables were reassessed for comparison. Primary efficacy end points included subjective (IPSS, IPSS QoL index) and objective (Qmax and PVR) changes from baseline. Secondary efficacy end points included changes from baseline in their EF using the EF domain scores from the IIEF5. Safety assessment included laboratory tests (hematology, clinical biochemistry, and urinalysis) and patient’s reporting of adverse event. Medical history, physical examination, and electrocardiogram were performed at study entry, at 1 month, 3 months, and discontinuation. Statistical Analysis Statistical analyses were performed using a commercially available analysis program: SPSS version 16.0 (SPSS Inc., Chicago, IL, USA). The data has been expressed as the mean (standard error of the mean) with n indicating number of experiments. Statistical significance was determined by paired t-test, and subgroup analysis was performed within the framework of one-way analysis of variance (Anova) model and post hoc test with P value < 0.05 considered to indicate significance. The study was designed to provide 80% power to detect a difference of 3.0 for change in IPSS, IIEF, and 2 mL/second for Qmax assuming a standard deviation of 5.0 and a one-sided alpha of 0.05. The purpose of this study was to establish proof of principle in anticipation of subsequent larger and more definitive trials. As such, this protocol prespecified the use of one-sided tests of signifi-
189
cance for evaluating the efficacy end points. No adjustments were made for multiple comparisons. Assuming that 85% of patients would complete the study, a randomized sample of 123 subjects were required. Our sample size came out to be at least 35 subjects per group. Results
Patient Population There were a total 178 BPH patients, but 45 cases were excluded that did not meet the inclusion criteria. A total of 133 men of more than 45 years old (mean age 62 years) were included in the study on a prospective basis with 45 randomized to the tamsulosin group (Group A), 44 to the tadalafil group (Group B), and 44 to the combination therapy group (Group C). Eight patients (6.01%) dropped out because of adverse events (n = 5) or noncompliance (n = 3); therefore, the study population for efficacy comparison consisted of 125 patients (43 in tamsulosin group, 40 in tadalafil group, and 42 in combination group) (Figure 1). Demographic and baseline characteristics were similar between the three groups (Table 1). Study Outcomes EF An IIEF5 questionnaire was not done in eight patients in absence of sexual activity, so assessment was done in 117 patients (drug A: n = 40; drug B: n = 38; drug C: n = 39) (Figure 1). Three patients had no ED (IIEF5 score >22). EF improved with tamsulosin (+39.28% [P < 0.05]), tadalafil (+45.96% [P < 0.05]), and tamsulosin and tadalafil combination (+60.23% [P < 0.05]) (Figure 2A, B; Table 2). On Anova and post hoc tests, the impact of combination regimen on EF was significantly greater than tamsulosin alone (P < 0.05) but not when compared with tadalafil group (P = 0.125), whereas tadalafil improved EF better than tamsulosin monotherapy (P < 0.05). IPSS Changes Significant decrease in the IPSS score was observed in all the three groups. However, maximum benefit was noted among patients receiving combination therapy. A significant decrease in IPSS score was observed in monotherapy of tamsulosin (−50.90% [P < 0.05]), tadalafil (−33.50% [P < 0.05]), and with combined therapy of tamsulosin and tadalafil J Sex Med 2014;11:187–196
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Singh et al. Assessed for eligibility (N = 178)
Randomized (N = 133) Mean age 62 years
Allocated to tamsulosin (N = 45) Completed study (N = 43)
IPSS IPSS QoL index Qmax PVR
Allocated to tadalafil (N = 44) Completed study (N = 40)
Patient withdrew (N = 4) Reason: worsening of LUTS (N = 1) severe myalgia and backache (N = 1) flushing, headache, myalgia, hypotension (N = 1) Increase in IOP in diagnosed patient of glaucoma (N = 1)
Noncompliance (N = 2) (Lost to follow-up)
Primary outcome analysis (N = 43)
Failed inclusion criteria (N = 45)
Secondary outcome analysis (N = 40)
Absence of sexual activity (N = 3) IIEF assessment done only in sexually active patients (N = 30)
Primary outcome analysis (N = 40)
IPSS IPSS QoL index Qmax PVR
Secondary outcome analysis (N = 38)
Absence of sexual activity (N = 2) IIEF assessment done only in sexually active patients (N = 28)
Allocated to tamsulosin and tadalafil combination (N = 44) Completed study (N = 42)
Noncompliance (N = 1) (Lost to follow-up) Patient withdrew (N = 1) Reason: severe myalgia and backache (N = 1)
Primary outcome analysis (N = 42)
IPSS IPSS QoL index Qmax PVR
Secondary outcome analysis (N = 39)
Absence of sexual activity (N = 3) IIEF assessment done only in sexually active patients (N = 29)
Figure 1 Consort diagram representing patient population and main outcome measures. IIEF5 = International Index of Erectile Function 5; IOP = intraocular pressure; IPSS = International Prostatic Symptom Score; LUTS = lower urinary tract symptoms; PVR = post-void residual urine; Qmax = maximum urinary flow rate; QoL = quality of life.
(−53.90% [P < 0.05]) (Figure 2C, D; Table 2). On applying Anova, tamsulosin monotherapy and combination regimen were significantly better than tadalafil monotherapy (P < 0.05), whereas combination regimen may not be statistically significant but better than tamsulosin regimen (P = 0.147).
Table 1
IPSS QoL QoL scores were significantly decreased (greater QoL) with tamsulosin (−73.35% [P < 0.05]) and tadalafil (−70.26% [P < 0.05]) but maximally with tamsulosin and tadalafil combination (−79.65% [P < 0.05]) (Figure 2E, F; Table 2). There in between-group comparison by Anova and post
Patients’ baseline characteristics Total population (N = 133)
Age (years) ≤60 years (%) >60 years (%) Comorbidities NO HT DM IPSS IIEF Qmax PVR QoL
61.61 ± 6.981 48.9 (n = 65) 51.1 (n = 68) 48.5 32.4 19.1 21.01 10.8 9.3 101.22 5.66
Drug A (n = 45)
Drug B (n = 44)
59.50 ± 6.048 53.3 (n = 24) 46.7 (n = 21)
63.42 ± 8.09 47.7 (n = 21) 52.3 (n = 23)
43.5 34.8 21.7 20.93 10.08 9.15 79.11 5.59
52.2 26.1 21.7 20.33 11.77 8.83 98.92 5.75
Drug C (n = 44) 61.92 ± 6.291 47.7 (n = 21) 52.3 (n = 23) 50 36.4 13.6 21.73 10.61 9.88 126.31 5.65
P value NS NS NS NS NS NS NS NS NS NS NS
DM = diabetes mellitus; HT = hypertension; IIEF5 = International Index of Erectile Function 5; IPSS = International Prostatic Symptom Score; NO = no comorbidity; NS = not significant; PVR = post-void residual urine volume; Qmax = maximum urinary flow rate; QoL = quality of life
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Figure 2 Subjective parameters. (A) IIEF5 mean score before and after treatment; (B) Percentage change IIEF5 mean score posttreatment at 3 months; (C) IPSS mean before and after treatment; (D) Percentage change IPSS mean posttreatment at 3 months; (E) QoL mean score before and after treatment; (F) Percentage change posttreatment at 3 months. DRUG A = tamsulosin; DRUG B = tadalafil; DRUG C = tamsulosin and tadalafil combination; IIEF5 = International Index of Erectile Function 5; IPSS = International Prostatic Symptom Score; QoL = quality of life.
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192 Table 2
Singh et al. Mean change of parameters from baseline and after 3 months of treatment
IIEF5 score Baseline 3 months % change IPSS Baseline 3 months % change IPSS QoL score Baseline 3 months % change Qmax Baseline 3 months % change PVR Baseline 3 months % change
Drug A
Drug B
Drug C
10.08 ± 5.064 14.04 ± 5.254 +39.28 (P < 0.05)
11.77 ± 6.384 17.27 ± 6.826 +45.96 (P < 0.05)
10.61 ± 5.582 17.00 ± 5.705 +60.23 (P < 0.05)
20.93 ± 4.607 10.26 ± 3.218 −50.90 (P < 0.05)
20.33 ± 5.662 13.50 ± 3.856 −33.50 (P < 0.05)
21.73 ± 5.876 10.00 ± 2.898 −53.90 (P < 0.05)
5.59 ± 0.501 1.48 ± 0.509 −73.35 (P < 0.05)
5.75 ± 0.442 1.71 ± 0.550 −70.26 (P < 0.05)
5.65 ± 0.562 1.15 ± 0.368 −79.65 (P < 0.05)
9.15 ± 3.022 12.26 ± 3.537 +33.99 (P < 0.05)
8.83 ± 3.535 11.46 ± 3.867 +29.78 (P < 0.05)
9.88 ± 3.581 13.54 ± 5.587 +37.04 (P < 0.05)
79.11 ± 55.924 30.93 ± 22.103 −60.90 (P < 0.05)
98.92 ± 84.497 50.00 ± 36.056 −49.45 (P < 0.05)
126.31 ± 78.507 46.77 ± 36.362 −62.97 (P < 0.05)
IIEF5 = International Index of Erectile Function 5; IPSS = International Prostatic Symptom Score; PVR = post-void residual urine volume; Qmax = maximum urinary flow rate; QoL = quality of life
hoc test revealed that combination regimen has greater impact than tamsulosin (P = 0.041) and tadalafil (P = 0.020) regimens.
Qmax Improvement Qmax on uroflowmtery improved with tamsulosin and tadalafil combination (+37.04% [P < 0.05]), tamsulosin only (+33.99% [P < 0.05]), and tadalafil only (+29.78% [P < 0.05]) (Figure 3A, B; Table 2). However, there was not a statistical significant difference on Anova (P = 0.307). PVR Change Significant reduction in PVR was observed with combination of tamsulosin and tadalafil (−62.97% [P < 0.05]), tamsulosin only (−60.90% [P < 0.05]), and tadalafil only group (−49.45% [P < 0.05]) (Figure 3C, D; Table 2). Anova test concluded no regimen superior in reducing PVR (P = 0.053). Safety Out of the total number of 133 patients randomized for the study, 5 patients (3.7%) dropped out because of adverse events. One patient due to worsening of LUTS in tadalafil group, two with severe myalgia and backache (one each in tadalafil only and combination of tamsulosin and tadalafil group), one due to flushing, headache, myalgia, and hypotension, and another due to increase in intraocular pressure (IOP) in already diagnosed patient with glaucoma (both in tadalafil group) left the treatment. No dropout occurred from tamsulosin regimen because of any drug-related side effects (Figure 1). J Sex Med 2014;11:187–196
Four patients in tadalafil only group and six patients in tamsulosin and tadalafil combination group complained of heartburn and dyspepsia, which were relieved with proton pump inhibitors. Flushing, headache, and myalgia were noted in four patients, two each in tadalafil and combination group. None of patients in tamsulosin group complained of drug-related complication. There were no severe or serious adverse events. Discussion
As the prevalence of both ED and LUTS increases with age [14–16], physicians could be in the position to manage these two conditions simultaneously. Moreover, medical therapies for either one of these conditions can affect the other. Alpha blockers are considered the most effective monotherapy for LUTS suggestive of BPH [17]. PDE5 inhibitors are the first-line treatment for ED [18,19]. As a consequence, because of the strong association between LUTS and ED, the simultaneous administration of these drugs is increasing. The current study is designed to evaluate the efficacy of the combined regimen of tamsulosin and tadalafil compared with either of the drug to evaluate effect on both of the conditions, which often coexist. The reason to favor tamsulosin to combine with PDE5 inhibitor was because some authors demonstrated that the combination tamsulosin 0.4 mg + tadalafil (10 or 20 mg) did not show significant hemodynamic changes [20]. In
Comparative Efficacy of Tamsulosin and Tadalafil in BPH
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Figure 3 Objective parameters. (A) Qmax mean before and after treatment; (B) Percentage change Qmax mean posttreatment at 3 months; (C) PVR mean before and after treatment; (D) Percentage change PVR mean posttreatment at 3 months. DRUG A = tamsulosin; DRUG B = tadalafil; DRUG C = tamsulosin and tadalafil combination; PVR = post-void residual urine; Qmax = maximum urinary flow rate.
addition, tamsulosin was the only alpha blocker accepted by the Food and Drug Administration to be used in combination with tadalafil [21]. Also, prolonged duration of action of tadalafil suits more compared with sildenafil and vardenafil to mitigate some of the psychosocial barriers that interfere with treating ED and provides some men with ED and their partners a treatment option that may offer greater flexibility and potentially less anxiety surrounding the resumption of sexual activity [22].
In a study by Porst et al. [23], efficacy parameters 20 mg dose was not superior to 10 mg dose even with increased adverse effects. Daily doses of 20 mg of tadalafil have been associated with a high percentage of headaches that could probably be reduced using smaller doses of tadalafil [24–26]. In addition to this, the study also highlighted that once-daily tadalafil improved EF in sexually active men with ED and BPH-LUTS, both overall and in clinically relevant patient subgroups [27]. MoreJ Sex Med 2014;11:187–196
194 over, tadalafil 10 mg daily has better patient compliance as compared with alternate day therapy as compared with the study by Liguori et al. where alternate day regimen was used [28]. In a small pilot study, De Rose et al. demonstrated significant increase of IIEF in 78.6% of the patients treated with the combination of doxazosin and sildenafil [29]. In a pilot study by Bechara et al., crossover comparison of two groups to receive tamsulosin 0.4 mg/day vs. tamsulosin 0.4 mg/day plus tadalafil 20 mg/day was done and concluded that improvements of IPSS score and IPSS-QOL were significant with both treatments but greater with the drug combination [26]. Both regimens similarly improved the Qmax and decreased the PVR volume from baseline (P < 0.001) with no significant differences between tamsulosin alone vs. tamsulosin and tadalafil (P > 0.05). The IIEF improved with tamsulosin plus tadalafil (P < 0.001) but not with tamsulosin alone (P > 0.05). In our study, all three regimens improved EF based on IIEF5 questionnaire to a statistical significance but maximally with combination of tamsulosin and tadalafil. Also, there is a significant impact of combination of tamsulosin and tadalafil on EF improvement when compared with tamsulosin alone but not when compared tadalafil alone. These results are in concordance with earlier studies [26,28]. The improvement in EF by tamsulosin can be explained by the same pathophysiological mechanism of LUTS due to BPH and ED [6]. The mechanism by which combination therapy produced greater improvements than either monotherapy is not yet fully defined. It was postulated that both alpha-1 blockers and PDE5 inhibitors, acting by two different mechanisms of action on common urogenital target organs, may have a synergistic effect on LUTS and ED. Alpha-1 blockers, by blocking alpha-1-adrenergic receptors and reducing the sympathetic tone in penile smooth muscle and prostate/bladder neck, could enhance the NO-mediated relaxant influence of PDE5 inhibitors [9,11,26,28,30,31]. Similarily, there is evidence that PDE5 inhibitors enhance the inhibitory effects of alpha-1 blockers on neurogenic contractions of human prostate and bladder neck [32]. We found that IPSS and IPSS QOL improved significantly in all the three groups comparable with the study by Bechara et al. [26]. However, it is unlikely that symptoms relief was simply a psychological benefit because change in IPSS and IIEF5 J Sex Med 2014;11:187–196
Singh et al. scores did not correlate significantly following monotherapy. The change in IPSS was significantly greater with combination group and tamsulosin compared with tadalafil monotherapy. Also, combination regimen was better than tamsulosin; however, it was not statistically significant as mentioned in earlier studies [12,26,28]. The benefit in Qmax and PVR is statistically significant in the three regimens concordant to study by Bechara et al. [26]. No one was significantly better between groups; however, the change in Qmax and PVR was greater in the combination regimen compared with monotherapy in which tamsulosin group behaved marginally better than tadalafil group. These results stipulate the findings of Liguori et al. [28] and Bechara et al. study [26]. In agreement with other authors, our results showed that the combination of tamsulosin and tadalafil did not produce significant changes in Qmax and PVR when compared with alpha blocker monotherapy [7,8,26] and with tadalafil only group. Clearly, an improvement in Qmax was equally observed with all three schemes of drugs, however, not to the extent of IPSS and IPSS QoL improvement, suggesting that PDE5 inhibitors may increase the effects of tamsulosin in reducing LUTS but may be not enough to act over the different pathophysiological mechanisms to increase Qmax [26]. Eight patients (6.01%) dropped out because of adverse events (n = 5) or noncompliance (n = 3). Heartburn and dyspepsia were most common complications (7.5%), four in tadalafil and six in combination group. Flushing, headache, and myalgia were noted in four patients, two each in tadalafil and combination group. Lesser complication of headache compared with previous studies was probably due to 10 mg instead of 20 mg/day dose [23–26]. The 10 mg daily dose used might explain some of the side effects that patients experienced, and one can postulate that there would have even been less side effects if a 5 mg dose was used, but at the cost of lesser benefit in LUTS and/or ED as depicted in the study by Porst et al. [23]. Out of the total number of 133 patients randomized for the study, 5 patients (3.7%) dropped out because of adverse events. Out of this, backache and myalgia were the most common that occurred in three patients. Similarly, in Liguori et al.’s study [28], the most common cause of dropout was backache and myalgia (3 out of the total 66 patients). However, one patient left the treatment in tadalafil group due to increase in IOP
Comparative Efficacy of Tamsulosin and Tadalafil in BPH in general tadalafil not known to cause this side effect. It may be a coincidental finding. None of the patient in tamsulosin group had any complication. There were no severe or serious adverse events in any of the groups. Although randomized, our study is open label and not placebo controlled, and as such, contains restrictions in ascertaining direct drug-related effects on symptoms; nevertheless, it demonstrates a significant and positive effect of combination therapy on LUTS and ED score as assessed not only by the IPSS, QOL, and IIEF5 questionnaires but also by urinary flow rates and PVR, which are an objective outcome evaluation. Other limitations are that it is not a crossover design and the number of patients is too small to get a solid conclusion, and that the men enrolled in the trial may represent a highly motivated sample seeking medical advice rather than the overall male LUTS/BPH population. Also, a patient in combination regimen has the tendency to have greater psychogenic effect of improvement compared with monotherapy that may lead to greater perceived benefit in subjective parameters. We think that in order to conduct a large multicenter trial and to follow a standardized approach, the addition of a medication acceptability tool is also required, which may be accomplished by including measurement of patient satisfaction or preference of medication, measures of acceptability, and relationship between acceptability and adherence. Categorization of patients in different socioeconomic strata, their drug adherence, and overall response would be logical for assessing economic accessibility.
Conclusion
Although at this time there are limited data to support recommending the routine use of combination therapy for patients with LUTS and ED, our preliminary results seem to confirm the data of previous studies that is the combination of alpha-1 blockers with a PDE5 inhibitor is more effective than monotherapy for ED in men with LUTS/BPH. However, in agreement to previous studies, our study stipulates the combination regimen to be more effective compared with monotherapy of tamsulosin or tadalafil for LUTS improvement, but in disagreement of some pioneer studies like of Amado et al. We have not gained a statistical significant change in both IPSS and QoL in combination group compared with
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either of the monotherapy. We think that combination regimen might become a future therapy, if monotherapy for a given patient is not satisfactorily effective especially when patient has significant component of ED. Moreover, we think that a common approach for managing LUTS and ED is mandatory: urologists should be aware of the association between LUTS and ED, especially in patients with ED risk factors. Prospective, randomized, large placebocontrolled, long-lasting clinical trials are ensured to explain the role of combination therapy in patients with LUTS and ED.
Acknowledgment
We would like to thank all the residents of departments of urology, PGIMER, Chandigarh, India for the enrollment of patients and Mrs. Kusum Lata for the statistical work of this study. Corresponding Author: Dig Vijay Singh, MS, MCh, Department of Urology, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, India. Tel: +91 172 2756321; +91 9876616318; Fax: +91 172 2744401; E-mail: [email protected] Conflict of Interest: The author(s) report no conflicts of interest.
Statement of Authorship
Category 1 (a) Conception and Design Dig Vijay Singh; Uttam K. Mete; Shrawan K. Singh (b) Acquisition of Data Dig Vijay Singh; Uttam K. Mete (c) Analysis and Interpretation of Data Dig Vijay Singh; Uttam K. Mete; Shrawan K. Singh; Arup K. Mandal
Category 2 (a) Drafting the Article Dig Vijay Singh; Uttam K. Mete; Shrawan K. Singh; Arup K. Mandal (b) Revising It for Intellectual Content Dig Vijay Singh; Shrawan K. Singh
Category 3 (a) Final Approval of the Completed Article Dig Vijay Singh; Uttam K. Mete; Shrawan K. Singh; Arup K. Mandal J Sex Med 2014;11:187–196
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Singh et al.
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