Abstract
Introduction
There have been a number of reports on dose increase therapy (DI-T) with the alpha 1 adrenoceptor antagonists (α1-blockers) naftopidil and tamsulosin for lower urinary tract symptoms associated with benign prostatic hyperplasia.
Methods and Results
The reports on DI-T (naftopidil 75 mg/d, tamsulosin 0.4 mg/d) in non-responders to low-dose initial therapy (LI-T, naftopidil 50 mg/d, tamsulosin 0.2 mg/d) were summarized. In each study, a non-responder was defined as a patient without sufficient improvements on the International Prostate Symptom Score (IPSS), IPSS Quality of Life, maximum flow rate of urine, or treatment satisfaction. These reports showed that 22.4-76.1% of patients were non-responders to LI-T, indicating that a novel treatment strategy for such patients is important. Moreover, 22.5-90.0% of non-responders to LI-T showed a response to DI-T, which achieved the same level of efficacy as low-dose maintenance therapy. Specifically, the improvements of the IPSS voiding symptom sub-score and maximum flow rate of urine were superior. The predictive factors for non-response to α1-blockers LI-T were insufficient improvement of subjective symptoms and objective findings during LI-T. These patients require high-dose initial therapy or DI-T at an early stage, since adverse events associated with naftopidil and tamsulosin do not show a dose-response relationship.
Conclusions
DI-T with α1-blockers has high potential as an essential treatment strategy for lower urinary tract symptoms associated with benign prostatic hyperplasia.
Key Words: Lower urinary tract symptoms, Dose increase therapy, Benign prostatic hyperplasia, Naftopidil, Tamsulosin, Alpha 1 adrenoceptor antagonist
Introduction
Lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) are progressive and common in elderly men [1]. Alpha 1 adrenoceptor antagonists (α1-blockers) are among the first-line drugs for the treatment of LUTS/BPH [2,3,4,5].
In Western countries, α1-blockers in common use are the uro-selective drugs, tamsulosin and silodosin [5,6,7]. Naftopidil is a uro-selective α1-blocker launched in 1999 in Japan, which is widely used for LUTS/BPH treatment in Japan, Korea, China, and India. The dosage of naftopidil is 25-75 mg/d, with the optimal dose being 50 or 75 mg/d [8,9,10]. Naftopidil has a 3-fold higher affinity for the α1D adrenoceptor subtype than for the α1A adreno-ceptor subtype. In contrast, tamsulosin has a high affinity for the α1A adrenoceptor subtype [11]. There are reports that the α1D adrenoceptor subtype contributes to bladder function [12,13]. Naftopidil has been reported to be effective for storage symptoms through inhibition of the α1D adrenoceptor subtype in the bladder [14,15].
There are many reports that α1-blockers do not improve symptoms in some patients. Switch therapy to another α1-blocker or additional therapy with drugs that have other mechanisms of action have been reported for non-responders to α1-blockers [16,17,18,19,20]. However, polypharmacy is a problem with additional therapy because LUTS/BPH is a disease of elderly persons [21].
There have been several reports on the efficacy of α1-blocker dose increase therapy (DI-T) [22,23,24,25,26,27,28,29]. In nafto-pidil DI-T, the dose was increased to 75 mg/d in non-re-sponders to naftopidil 50 mg/d low-dose initial therapy (LI-T), because of the wide dosage range of naftopidil [10,22,23,24,25,26]. A dosage of 0.2 mg/d tamsulosin is commonly used in Japan and Korea, but the most common dosage in Western countries is 0.4 or 0.8 mg/d [30]. In non-responders to tamsulosin 0.2 mg/d LI-T, there have been a few reports that the dosage was increased from 0.2 to 0.4 mg/d as tamsulosin DI-T in Korea [27,28,29].
These reports on naftopidil and tamsulosin DI-T, including our report, were summarized, and this review shows the re-analysis of our data for the new clinical questions related to DI-T.
Purpose and Definition of Efficacy in These Studies
A prospective study of DI-T was first performed by Yoshida et al. [22]. Naftopidil 50 mg/d as LI-T was administered for 4 weeks in 45 patients. For a further 4 weeks, the dose was increased to 75 mg/d as DI-T for non-responders, defined as patients with an improvement of less than 1 point in the International Prostate Symptom Score (IPSS) Quality of Life (IPSS-QoL) at weeks 4 and 8.
To evaluate the efficacy of naftopidil DI-T in non-re-sponders to LI-T, Funahashi et al. [23] gave naftopidil 50 mg/d as LI-T for 12 weeks to 122 patients. The dose was increased to 75 mg/d as DI-T for non-responders to LI-T for a further 12 weeks. Non-responders were defined as patients with an improvement of less than 5 points in IPSS at weeks 12 and 24.
Mizusawa et al. [24] compared the efficacy of naftopidil DI-T for non-responders to LI-T with naftopidil low-dose maintenance therapy (LM-T) that was maintained at 50 mg/d for responders to LI-T [24]. Naftopidil LI-T was used for 4 weeks. The non-responders and responders to LI-T were treated with DI-T and LM-T for a further 4 weeks, respectively. Non-responders were defined as patients who were not satisfied with their urinary status at week 4.
The predictors of the efficacy of naftopidil DI-T were evaluated in the INFORM study [25]. There were 92 patients who were treated with naftopidil LI-T for 4 weeks. All patients were increased to 75 mg/d for a further 4 weeks. Non-responders were defined after 4 and 8 weeks based on the criteria in the Japanese Urological Association Clinical Guidelines for BPH [3].
Naftopidil LI-T was given for 8 weeks to 95 patients to evaluate the efficacy of naftopidil DI-T [26]. The non-re-sponders and responders to naftopidil LI-T were treated with DI-T and LM-T, respectively, for a further 8 weeks. Non-responders were defined as patients with IPSS-QoL scores ≥ 4 at week 8, or patients whose improvement of the IPSS-QoL from baseline to week 8 was < 2.
In 133 patients, Chung et al. [27] administered tam-sulosin 0.2 mg/d as LI-T for 8 weeks to compare the efficacies of tamsulosin LM-T and DI-T. Tamsulosin 0.4 mg/d as DI-T and 0.2 mg/d as LM-T were given to the non-responders and responders to LI-T, respectively, for a further 8 weeks. Non-responders to LI-T were defined as patients with changes in the IPSS total score < 20% and in the maximum flow rate of urine (Qmax) < 20%, aggravation of the IPSS-QoL score, or development of clinically significant complications at week 8.
With 174 patients, Kim et al. [28] conducted a similar study comparing tamsulosin DI-T in the non-responders and LM-T in the responders to LI-T. Tamsulosin LI-T was administered for 12 weeks, and DI-T in the non-re-sponders and LM-T in the responders to LI-T were given for a further 26 weeks. Non-responders were defined as patients who desired DI-T or needed DI-T based on an objective assessment at week 12.
Park et al. [29] administered tamsulosin LI-T to 120 patients for 8 weeks to evaluate the efficacy of tamsulosin DI-T. In non-responders to LI-T, DI-T was administered for a further 8 weeks. Non-responders were defined as patients with improvement in the IPSS total score < 3 at weeks 8 and 16. These studies are shown in Table 1.
Table 1.
Definitions of efficacy
| Author | Agent | LI-T |
Definition of non-responders | DI-T |
Purpose | ||
|---|---|---|---|---|---|---|---|
| n | Dose (period) | n | Dose (period) | ||||
| Yoshida et al. [22] | naftopidil | 45 | 50 mg/d (4 weeks) | patients who showed improvement in IPSS-QoL < 1 at week 4 | 10 | 75 mg/d (4 weeks) | response rate to DI-T for non-responders to LI-T |
| Funahashi et al. [23] | naftopidil | 181 | 50 mg/d (12 weeks) | patients who showed improvement in IPSS-TS < 5 at week 12 | 58 | 75 mg/d (12 weeks) | responders vs. non-responders to 75 mg/d |
| Mizusawa et al. [24] | naftopidil | 53 | 50 mg/d (4 weeks) | patients who were not satisfied with their urinary status at week 4 | 35 | 75 mg/d (4 weeks) | LM-T vs. DI-T |
| Tanuma et al. [25] | naftopidil | 92 | 50 mg/d (4 weeks) | the criteria of the Japanese Urological Associationa | 83 | 75 mg/d (4 weeks) | predictors that affected the efficacy of DI-T |
| Yamaguchi et al. [26] | naftopidil | 95 | 50 mg/d (8 weeks) | patients with IPSS-QoL > 3, or IPSS-QoL = 3 whose score had improved by < 2 at week 8 | 27 | 75 mg/d (8 weeks) | LM-T vs. DI-T |
| Chung et al. [27] | tamsulosin | 133 | 0.2 mg/d (8 weeks) | patients with a change in IPSS-TS < 20% or Qmax < 20%, aggravation of IPSS-QoL, or developed clinically significant complications at week 8 | 26 | 0.4 mg/d (8 weeks) | LM-T vs. DI-T |
| Kim et al. [28] | tamsulosin | 174 | 0.2 mg/d (12 weeks) | patients who desired DI-T or needed DI-T based on objective assessment at week 12 | 64 | 0.4 mg/d (36 weeks) | LM-T vs. DI-T |
| Park et al. [29] | tamsulosin | 120 | 0.2 mg/d (8 weeks) | patients who showed improvement in IPSS-TS < 3 at week 8 | 64 | 0.4 mg/d (8 weeks) | responders vs. non-responders to 0.4 mg/d |
The Japanese Urological Association clinical guidelines for BPH: The efficacy for symptoms was classified by the ratio of post- and pre-treatment IPSS as excellent ≤ 0.25, good ≤ 0.5, fair ≤ 0.75, and poor/worse > 0.75. The efficacy for QoL was classified by the changes in pre- and post-treatment IPSS-QoL as excellent ≥ 4, good 3, fair 2 or 1, and poor/worse ≤ 0. The efficacy for function was classified by the changes in post- and pre-treatment Qmax as: excellent ≥ 10 ml/s, good ≥ 5 ml/s, fair ≥ 2.5 ml/s, and poor/worse ≤ 0.5 ml/s. Overall efficacy is the median of the efficacy grade of the 3 items of symptoms, QoL, and function.
It is a problem that each of the reports on DI-T differed in the definition of the response and the treatment period. Thus, it is necessary to standardize the criteria of the evaluation method and the period in LUTS/BPH therapy.
Response Rate
In 30 patients who could be evaluated, Yoshida et al. [22] reported that 33.3% were non-responders to naftopidil LI-T, and the response rate to DI-T was 90.0%. Funahashi et al. [23] reported that 58/122 patients (47.5%) were non-responders to naftopidil LI-T, and 9/40 patients (22.5%) available for evaluation showed improvement with naftopidil DI-T. Tanuma et al. [25] showed that 37/83 patients (44.6%) who could be evaluated were non -responders to naftopidil LI-T, and DI-T was effective in 17 (45.9%) of the non-responders.
Because there are few reports on the number of re-sponders to DI-T, we re-analyzed the data from our previous paper on naftopidil DI-T [26]. It was found that naftopidil LM-T was given to 59/86 responders to LI-T who could be evaluated for naftopidil LI-T, and 52 patients (88.1%) were improved. On the other hand, there were 27 (31.4%) non-responders to naftopidil LI-T, and 22 patients (81.5%) were improved with DI-T. The response rate showed no significant difference between DI-T in the non-responder group and LM-T in the re-sponder group (p = 0.409, unpublished data).
Park et al. [29] reported that non-response to tamsulosin LI-T was seen in 64/93 patients (68.8%), and 31/60 patients (51.7%) who could be evaluated were improved with DI-T. Mizusawa et al. [24], Chung et al. [27], and Kim et al. [28] reported that the percentages of non-re-sponders to naftopidil or tamsulosin LI-T were 76.1, 22.4, and 38.7%, respectively. However, the response rate to DI-T was not evaluated. These studies are shown in Table 2.
Table 2.
Response rates to LI-T, LM-T, and DI-T
| Author | Drug | Response rate to LI-T |
Response rate to LM-T or DI-T |
|||
|---|---|---|---|---|---|---|
| Rate (%) | Therapy | Rate (%) | ||||
| Yoshida et al. [22] | naftopidil | responders non-responders |
66.7% (20/30) 33.3% (10/30) |
DI-T | responders non-responders |
90.0% (9/10) 10.0% (1/10) |
| Funahashi et al. [23] | naftopidil | responders non-responders |
52.5% (64/122) 47.5% (58/122) |
DI-T | responders non-responders |
22.5% (9/40) 77.5% (31/40) |
| Mizusawa et al. [24] | naftopidil | responders non-responders |
23.9% (11/46) 76.1% (35/46) |
LM-T DI-T |
− | − |
| Tanuma et al. [25] | naftopidil | responders non-responders |
55.4% (46/83) 44.6% (37/83) |
DI-T DI-T |
responders non-responders responders non-responders |
82.6% (38/46) 17.4% (8/46) 45.9% (17/37) 54.1% (20/37) |
| Yamaguchi et al. [26] and re-analyzed data | naftopidil | responders non-responders |
68.6% (59/86) 31.4% (27/86) |
LM-T DI-T |
responders non-responders responders non-responders |
88.1% (52/59)# 11.9% (7/59)# 81.5% (22/27)# 18.5% (5/27)# |
| Chung et al. [27] | tamsulosin | responders non-responders |
77.6% (90/116) 22.4% (26/116) |
LM-T DI-T |
− − |
− − |
| Kim et al. [28] | tamsulosin | responders non-responders |
61.3% (95/155) 38.7% (60/155) |
LM-T DI-T |
− − |
− − |
| Park et al. [29] | tamsulosin | responders non-responders |
31.2% (29/93) 68.8% (64/93) |
− DI-T |
− responders non-responders |
− 51.7% (31/60)## 48.3% (29/60)## |
−: The response rate was not evaluated.
Chi-squared test: p = 0.409
4/64 non-responders lost to follow-up.
Thus 22.5-90.0% of non-responders to LI-T could benefit from DI-T, though the individual study designs showed a different result. DI-T was concluded to be a useful and important treatment strategy for non-responders, since it achieved approximately the same response rate as LM-T. Conversely, the response rate to LI-T was 23.9-77.6%. It is important that α1-blockers should be started with LI-T to establish an effective dose that is as low as possible for safety reasons and to avoid unnecessary overdosage, because LI-T improves many patients.
Subjective and Objective Efficacy of DI-T
At the end of naftopidil LI-T (week 4), Mizusawa et al. [24] reported a significantly improved IPSS total score (IPSS-TS) and IPSS voiding symptom (IPSS-VS) sub-score in the LM-T group compared with the DI-T group (p = 0.041, p = 0.016, respectively). However, similar levels of improvement were seen in the 2 groups at the study endpoint (week 8).
The INFORM study showed that the changes in IPSS-TS, IPSS-VS, and IPSS storage symptoms (IPSS-SS) at the study endpoint (week 8) were significantly improved in responders to naftopidil LI-T compared with non-responders (p < 0.001, p = 0.001, p < 0.001, respectively). This suggested that DI-T was more effective in responders to LI-T. The change in Qmax of responders to LI-T was significantly improved in comparison to non-responders at the end of LI-T (week 4, p < 0.001). However, the change in Qmax showed no significant difference between the groups at the study endpoint (week 8). Naftopidil DI-T was effective for objective findings in the non-responders to LI-T [25].
At the end of naftopidil LI-T (week 8), we reported that changes in IPSS-TS, IPSS-VS and IPSS-SS were significantly improved in the LM-T group compared to the DI-T group (p = 0.004, p = 0.013, p = 0.038, respectively). However, these showed similar efficacy in the 2 groups at the study endpoint (week 16). Change in Qmax was significantly improved at the study endpoint (week 16) compared with the end of LI-T (week 8) in the DI-T group (p = 0.015). In contrast, it was significantly increased between the baseline and the end of LI-T (week 8, p < 0.01), but not significantly improved between the end of LI-T (week 8) and the study endpoint (week 16) in the LM-T group [26].
At the end of tamsulosin LI-T (week 8), Chung et al. [27] reported significantly improved IPSS-TS and Qmax in the LM-T group compared with the DI-T group (p < 0.001, p < 0.001 respectively). However, both groups showed similar levels of improvement at the study end-point (week 16).
In the tamsulosin LM-T group, Kim et al. [28] reported significant improvement of the change in IPSSTS compared with the DI-T group at the study endpoint (week 24, p < 0.01). In addition, tamsulosin DI-T caused a greater change in IPSS-VS, and this led to a greater change in IPSS-TS for patients receiving tamsulosin 0.4 mg/d. However, these levels at the baseline were significantly different between the groups. The evaluation of DI-T by subjective symptoms is difficult. The changes of subjective symptoms and objective findings are shown in Table 3, 4.
Table 3.
Changes in IPSS and Qmax
| Author | Drug | Group | IPSS-TS |
Qmax |
||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | End of LI-T | Endpoint | Intragroup# | Baseline | End of LI-T | Endpoint | Intragroup# | |||
| Mizusawa et al. [24] |
naftopidil | LM-T (n = 11) DI-T (n = 35) intragroup |
14.2 ± 5.1 18.1 ± 7.2 NS |
7.6 ± 3.0 12.4 ± 7.3 0.041 |
7.4 ± 4.5 10.3 ± 7.3 NS |
NS 0.019 NS |
− − − |
− − − |
− − − |
− − NS |
| Tanuma et al. [25] (Change from baseline) |
naftopidil | responders at week 4 (n = 46) non-responders at week 4 (n = 37) intergroup |
0 0 − |
−8.0 ± 5.5 0.3 ± 5.5 < 0.001 |
−9.0 ± 6.4 -2.4 ± 6.1 < 0.001 |
0.040 0.023 NS |
0 0 − |
3.0 ± 7.4 -2.0 ± 4.6 < 0.001 |
3.6 ± 7.1 2.0 ± 10.0 NS |
NS NS NS |
| Yamaguchi et al. [26] (Change from baseline) | naftopidil | LM-T DI-T intergroup | 0 (n = 59) 0 (n = 27) | −9.6 ± 4.7 (n = 59) −6.0 ± 4.7 (n = 27) 0.004 | −10.0 ± 5.3 (n = 59) −10.0 ± 3.9 (n = 27) NS | NS < 0.001 NS | 0 (53) 0 (n = 24) | 7.1 ± 7.6 (n = 53)* 0.6 ± 4.8 (n = 24) NS | 4.7 ± 7.5 (n = 53) 3.3 ± 4.5 (n = 27) NS | NS 0.015 NS |
| Chung et al. [27] | tamsulosin | LM-T (n = 90) DI-T (n = 26) intergroup | 23.8 ± 7.0 22.4 ± 5.3 NS | 17.1 ± 3.7 21.9 ± 3.7 < 0.001 | 16.8 ± 4.5 17.4 ± 3.4 NS | no data reported no data reported NS | 7.9 ± 2.6 7.4 ± 1.9 NS | 10.6 ± 2.1 8.3 ± 2.1 < 0.001 | 12.8 ± 2.0 12.6 ± 2.4 NS | no data reported no data reported NS |
| Kim et al. [28] | tamsulosin | LM-T (n = 95) DI-T (n = 60) intergroup | 18.3 ± 7.6 23.2 ± 6.3 < 0.01 | 13.3 ± 6.6 19.7 ± 6.5 < 0.01 | 10.3 ± 5.0 13.5 ± 7.0 < 0.01 | no data reported no data reported NS | 14.2 ± 6.1 11.0 ± 5.3 | − − − | 16.8 ± 5.3** 15.3 ± 6.6** no data reported | no data reported no data reported NS |
End of LI-T versus end point; NS = not significant; −: no evaluation.
The amount of change in Qmax was significantly increased between before and after LI-T in the LM-T group (p < 0.01)
the amount of change in Qmax was significantly increased in the DI-T group compared to the LM-T group (p = 0.01).
Table 4.
Changes in IPSS-VS and IPSS-SS
| Author | Drug | Group | IPSS-VS |
IPSS-SS |
||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | End of LI-T | Endpoint | Intragroup# | Baseline | End of LI-T | Endpoint | Intragroup# | |||
| Mizusawa et al. [24] | naftopidil | LM-T (n = 11) DI-T (n = 35) intragroup | 5.0 ± 3.5 7.9 ± 4.3 NS | 2.1 ± 1.4 5.3 ± 4.1 0.016 | 4.2 ± 4.1 2.3 ± 1.9 NS | NS 0.047 NS | 7.5 ± 3.3 7.8 ± 3.6 NS | 4.8 ± 2.0 5.7 ± 3.5 NS | 4.4 ± 2.5 4.9 ± 3.6 NS | NS NS NS |
| Tanuma et al. [25] (Change from baseline) | naftopidil | responders at week 4 (n = 46) non-responders at week 4 (n = 37) intergroup | 0 0 − | −3.5 ± 4.3 0.6 ± 3.8 < 0.001 | −4.2 ± 4.4 −0.8 ± 3.6 0.001 | NS 0.017 NS | 0 0 | −3.1 ± 2.6 −0.5 ± 2.7 < 0.001 | −3.4 ± 3.0 −0.8 ± 2.5 < 0.001 | NS NS NS |
| Yamaguchi et al. [26] (Change from baseline) | naftopidil | LM-T (n = 59) DI-T (n = 27) intergroup | 0 0 − | −4.9 ± 2.9 −3.0 ± 3.5 0.013 | −5.3 ± 3.2 −5.1 ± 3.0 NS | NS 0.001 NS | − 0 0 | −3.1 ± 2.5 −2.0 ± 3.1 0.038 | −3.2 ± 2.6 −3.5 ± 3.0 NS | NS 0.023 NS |
| Kim et al. [28] | tamsulosin | LM-T (n = 95) DI-T (n = 60) intergroup | 8.8 ± 4.8 12.0 ± 3.9 < 0.01 | 6.1 ± 3.9 9.9 ± 4.0 < 0.01 | 5.0 ± 3.2 6.4 ± 4.0 < 0.02 | no data reported no data reported NS | 5.9 ± 3.2 7.3 ± 3.0 0.01 | 4.3 ± 2.7 6.2 ± 2.8 < 0.01 | 3.1 ± 1.8 4.8 ± 2.5 0.01 | no data reported no data reported NS |
End of LI-T versus end point; NS = not significant; −: no evaluation.
DI-T was thus improved to a similar level in comparison with LM-T in responders to LI-T, with particularly high rates of improvement suggested in IPSS-VS and Qmax. In Japan, however, it is necessary to be careful about the normal approved dosage of naftopidil, which is initially 25 mg/d, and the normal approved dosage of tamsulosin, which is 0.2 mg/d.
Adverse Events
The adverse event incidence rate of naftopidil was reported to be 8.9% (4/45) in patients given 75 mg/d by Yoshida et al. [22], 0.6% (1/181) and 6.9% (4/58) in patients given 50 and 75 mg/d, respectively, by Funahashi et al. [23], 9.4% (5/53) and 5.4% (2/37), respectively, by Mizusawa et al. [24], and only 1.1% (1 patient) at 50 mg/d in our study [26].
Adverse events with tamsulosin were reported in 11.1% (10/90) and 19.2% (5/26) of patients given 0.2 and 0.4 mg/d, respectively, by Chung et al. [27], and 21.6% (13/60) in patients given 0.4 mg/d by Park et al. [29].
In one report, the adverse event incidence rate in 286 patients given 25 to 75 mg/d of naftopidil did not differ with the dosage [10]. Adverse events resulting in withdrawal of tamsulosin 0.2 mg/d were reported in 5.7% (11/192) and 1.0% (1/103) by Kawabe et al. [32] and Lee et al. [33], respectively. In a study that compared 0.4 with 0.8 mg/d of tamsulosin via an oral controlled absorption system, adverse events resulting in withdrawal were re-ported in 3.9% (14/360) and 3.9% (28/722), respectively, by Chapple et al. [34]. Adverse events associated with naftopidil or tamsulosin showed no dose-response relationship in these reports. DI-T should therefore be actively considered for non-responders to LI-T.
An anti-muscarinic is often added for the α1-blocker non-responders who have BPH with an overactive bladder. The most common side-effect of anti-muscarinics is xerostomia, and increased postvoid residual urine may be seen [2,3,4,35]. The additional anti-muscarinic therapy has the possibility of increasing the risk of adverse events such as xerostomia and increased postvoid residual urine. Furthermore, taking multiple medications is related to not only an increased risk of side effects, but also greater health care costs, as well as increased risks of drug-interactions, medication non-adherence, reduced functional capacity, and multiple geriatric syndromes. In the examination of patients who took one or more drugs for chronic diseases for 3 months and were 65 years or older, 54.7% of patients took 5 or more different medicines, and 45.0% took 12 or more [36]. Such polypharmacy is a serious problem for LUTS/BPH patients, many of whom are elderly. For example, if switching from naftopidil 50 to 75 mg or tamsulosin 0.2 to 0.4 mg is possible, the risk of polypharmacy decreases compared to that with additional therapy.
Discussion
Yoshida et al. [22] reported that the differences in patient characteristics between responders and non-responders to naftopidil LI-T were unknown, because no significant difference in each IPSS sub-score was seen at the baseline between the 2 groups. However, responders showed improvements of changes in IPSS-TS and IPSS-QoL during LI-T, whereas non-responders did not. In contrast, Kim et al. [28] showed that the predictors of non-response to tamsulosin LI-T were higher age, lower Qmax, and a higher IPSS frequency sub-score at the baseline. Mizusawa et al. [24] reported that a higher IPSS-VS at the baseline and less improvement in IPSS-QoL and nocturia during naftopidil LI-T were characteristic of non-responders to LI-T. In non-responders to naftopidil LI-T, the INFORM study showed that patients for whom DI-T was effective showed improvement of Qmax during LI-T [25]. Chung et al. [27] showed that IPSS-TS, IPSS-QoL, and Qmax at the baseline were not significantly different between responders and non-responders to tamsulosin LI-T. In responders to LI-T, however, changes in them during LI-T showed significant improvements in comparison with non-responders to LI-T. Thus, the appropriate use of DI-T should be considered based on changes in subjective symptoms and objective findings during LI-T.
Prostate volume (PV) does not affect α1-blockers efficacy in studies with follow-up periods < 1 year, but α1-blockers do seem to be more efficacious in patients with smaller prostates (< 40 ml) in longer-term studies [2]. In a systematic review, Malde et al. [31] showed that PV had low diagnostic accuracy for bladder outlet obstruction in men with LUTS. Also, we reported that PV at the baseline was significantly greater in non-responders than in responders to naftopidil LI-T (p < 0.01) [26]. Mizusawa et al. [24], Tanuma et al. [25], and Kim et al. [28] reported a similar result, but without a significant difference (Table 5). Accordingly, we re-analyzed our previously reported data using receiver operating characteristic curve analysis and found the cut-off level for PV to be 29.7 ml (Table 6, unpublished data). We probably need to recognize beforehand that patients with an enlarged PV are more likely to receive DI-T, and thus α1-blockers DI-T might be considered for patients with an enlarged PV in addition to combination therapy of α1-blockers and 5α-reductase inhibitors.
Table 5.
PV at the baseline of responders and non-responders to LI-T
| Author | Drug | PV at the baseline, ml |
Intergroup | |
|---|---|---|---|---|
| Responders | Non-responders | |||
| Yoshida et al. [22] | naftopidil | 35.2 ± 16.7 (n = 20) | 33.4 ± 8.9 (n = 10) | NS |
| Mizusawa et al. [24] | naftopidil | 25.0 ± 24.8 (n = 35) | 34.6 ± 24.9 (n = 11) | NS |
| Tanuma et al. [25] | naftopidil | 38.4 ± 24.3 (n = 44) | 43.9 ± 24.6 (n = 37) | NS |
| Yamaguchi et al. [26] | naftopidil | 26.9 ± 10.4 (n = 56) | 36.7 ± 14.5 (n = 26) | < 0.01 |
| Chung et al. [27] | tamsulosin | 27.1 ± 7.1 (n = 90) | 28.1 ± 4.4 (n = 26) | NS |
| Kim et al. [28] | tamsulosin | 30.6 ± 12.0 (n = 95) | 32.8 ± 11.9 (n = 60) | NS |
NS = Not significant.
Table 6.
Cut-off level of PV
| Cut-off level of PV | Sensitivity | 1–Specificity (Specificity) | AUC | p |
|---|---|---|---|---|
| 29.7ml | 76.0% | 37.5% (62.5%) | 0.714 | 0.002 |
AUC = Area under the curve.
Conclusion
In this paper, the efficacy and safety of α1-blockers DI-T were summarized, and new questions relating to DI-T were discussed based on a re-analysis of previous data.
1) Non-responders to LI-T were found to represent 31.4-53.3% of patients, and 22.5-90.0% of non-responders to LI-T showed a response to DI-T, which achieved the same level of efficacy as LM-T. DI-T is a good treatment strategy for non-responders to LI-T.
2) The predictors for non-responders to LI-T were insufficient improvements in subjective symptoms and objective findings during LI-T use. These patients need DI-T at an early stage.
3) Patients with an enlarged PV are probably the target for α1-blockers DI-T.
4) The adverse events associated with naftopidil and tamsulosin showed no dose-response relationship.
5) DI-T might decrease the risk of polypharmacy.
It was therefore concluded that DI-T has potential as an essential treatment strategy for LUTS/BPH.
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