Efficacy and Adverse Effects of Solifenacin in the Treatment of Lower Urinary Tract Symptoms in Patients With Overactive Bladder

Transcription

1 Urol Sci 21;21(1):38 43 ORIGINAL ARTICLE Efficacy and Adverse Effects of Solifenacin in the Treatment of Lower Urinary Tract Symptoms in Patients With Overactive Bladder Yih-Chou Chen, Chia-Yen Chen, Hann-Chorng Kuo* Department of Urology, Buddhist Tzu Chi General Hospital and School of Medicine, Tzu Chi University, Hualien, Taiwan Objective: Solifenacin is an anticholinergic agent selective to M3 cholinergic receptor and has been widely used to treat overactive bladder (OAB). In this study, the efficacy and safety of solifenacin in patients with OAB were evaluated. Materials and Methods: A prospective study for evaluating the therapeutic results of solifenacin in patients with OAB dry (OAB without urge incontinence) or OAB wet (OAB with urge incontinence) was performed. Solifenacin 5 mg daily was given and the endpoint was set at the 6th month to evaluate the changes in urgency severity score (USS) after treatment. The measured parameters, including urinary frequency, nocturia, USS, maximum flow rate (Qmax), voided volume, post-voiding residual volume (PVR) and functional bladder capacity (FBC), were recorded at every visit. Patients were further categorized into OAB wet (USS, 4) and OAB dry (USS, 1, 2 and 3), and the effect and adverse events of solifenacin treatment were analyzed. Results: A total of 54 patients was enrolled in this study and completed all follow-up visits. Significant improvements of USS, daytime urinary frequency and nocturia were noted in both OAB dry and OAB wet groups. The urinary frequency and nocturia episodes also improved significantly after taking solifenacin. Mean USS improved from 3.28 ±.94 to 2.2 ± 1.62 (p <.1), and Qmax increased significantly from 13.9 ± 8.9 ml/s to 15.8 ± 9.6 ml/s (p =.4) at baseline and 6 months, respectively. FBC and voiding volume were also found to have significant improvement; however, no significant change in PVR was noted from baseline to endpoint. The therapeutic efficacy showed no significant difference between the OAB dry and OAB wet groups. Minor adverse effects were noted in only seven patients (13.%), and the most common complaint was difficult urination (5.6%). Conclusion: This study demonstrated that solifenacin is an effective antimuscarinic for treatment of OAB with few adverse effects. Patients with either OAB wet or OAB dry can benefit from solifenacin treatment, in terms of improvement in USS, frequency, nocturia episodes and bladder capacity, without compromising voiding efficiency. Only 13.% of patients had minor adverse effect, typically dysuria. Received: April 21, 29 Revised: May 15, 29 Accepted: June 19, 29 KEY WORDS: overactive bladder; solifenacin *Corresponding author. Department of Urology, Buddhist Tzu Chi General Hospital, 77, Section 3, Chung Yang Road, Hualien 97, Taiwan. hck@tzuchi.com.tw Taiwan Urological Association. Published by Elsevier Taiwan LLC.

2 Solifenacin in treating OAB 1. Introduction Overactive bladder (OAB) is a condition characterized by symptoms of frequency, urgency, with or without urge incontinence. 1 OAB was estimated to occur in 12 17% of the population in Europe and USA, and the prevalence of OAB tends to increase with increasing age. 2,3 It was generally accepted that antimuscarinics are the first choice in the treatment of OAB. 4 Muscarinic receptors are identified to locate at the urothelium as well as detrusor muscle. 5 7 Among several antimuscarinics, the affinity of solifenacin to M3 receptor was greater than those of oxybutynin and tolterodine. 8,9 Patients with OAB dry (OAB without urge incontinence) and OAB wet (OAB with urge incontinence) have different clinical presentations. OAB dry has been considered as hypersensitive bladder, which is likely to cause by urothelial dysfunction or overexpression of sensory receptors in the urothelium. On the other hand, OAB wet might be a condition of detrusor dysfunction involving several possible mechanisms from detrusor to central nerve system, and the true mechanism of OAB has not been completely elucidated. 1 Yamaguchi et al. 11 defined OAB as a hypersensitivity disorder, because most patients could not differentiate urge to void from urgency exactly. 11 Although several studies have revealed good therapeutic effect of solifenacin in treating OAB compared with other antimuscarinics, only few studies have mentioned the efficacy of solifenacin in OAB dry and OAB wet. 17 This study was designed to compare the efficacy and adverse effects of solifenacin treatment in OAB wet and OAB dry. 2. Material and Methods This is a prospective study. Patients older than 18 years from either sex presenting with urinary frequency, or urgency with or without urge incontinence were eligible for recruitment. Exclusion criteria included active urinary tract infection, urinary retention, detrusor underactivity proven by urodynamic study, post-voiding residual volume (PVR) > 15 ml, and patients with severe chronic systemic disease. Solifenacin 5 mg once daily orally was prescribed to patients without escalating the dose during the treatment period. All patients were followed up at 1 week, and 1, 3 and 6 months after treatment. The primary endpoint was change in the urinary urgency severity score (USS; reported as to 4, representing none, mild, moderate severe urgency to urge incontinence) from baseline to 6 months after starting solifenacin treatment. The secondary endpoints measured the parameters, which included voiding frequency at daytime and nighttime, maximum flow rate (Qmax), voiding volume, functional bladder capacity (FBC), and PVR. USS and adverse events were evaluated by the same investigator during follow-up. The patients were further categorized based on USS into the OAB dry (USS, 1, 2 and 3) and OAB wet (USS, 4) groups. Statistical analysis was performed by multiple measurement test and paired t test for consecutive parameters. A p value of <.5 was considered statistically significant. The common adverse events of antimuscarinics, such as difficult urination, dry mouth, constipation, blurred vision, dizziness and dry eye, were also recorded at each visit. 3. Results A total of 125 patients were enrolled in this study, and 54 patients, including 11 women and 43 men, completed the study and were followed up at all time-points. The remaining 71 patients were not enrolled in this study, and they included 58 patients who did not return for follow-up (of whom 22 patients had improved lower urinary tract symptoms [LUTS] and 36 did not have), 11 patients who were still on treatment, and two patients who switched to other medications due to unimproved LUTS, were not enrolled in this study. No adverse effects were noted in the chart recording of these 71 patients. Twenty-five patients were categorized as having OAB dry (OAB dry group) and 29 as having OAB wet (OAB wet group). There was no significant difference in the mean age between the OAB dry and OAB wet groups. As shown in Table 1, the USS, daytime frequency and nocturia improved significantly from baseline to 6 months after solifenacin treatment. Qmax was also noted to increase significantly in the patients overall and in the OAB wet group but not OAB dry group (p =.3). The voided volume and FBC increased significantly (all p =.5), but PVR did not increase at 6 months either in the OAB dry or OAB wet group. Figure 1 shows the changes in USS and Qmax, and Figure 2 shows the changes in voided volume, PVR and FBC at all time-points from baseline to 6 months. The changes in USS and voiding parameters improved gradually from baseline to 1 month and became stably improved after 3 months treatment. Figure 3 shows the differences in the measured parameters between OAB dry and OAB wet groups. There were no significant differences in all parameters between these two groups. The mean USS decreased by 46% and 34% in the OAB dry and OAB wet groups, respectively. The mean daytime frequency and nocturia decreased, and the voided volume and FBC increased in both OAB dry and OAB wet groups at 6 months. After treatment with solifenacin for 6 months, the USS decreased by at least 1 scale point in 12 patients with OAB dry (48%; i.e., 2% by 3 scale points, 24% by 2 scale points, and 4% by 1 scale point) and 13 with OAB wet (44.8%; i.e., 2.7% by 4 scale points, 13.8% by 3 scale points, 3.4% by 2 scale points, and 6.9% by 1 scale point). Based on the change in primary end-point, there was no significant difference in therapeutic efficacy between the OAB wet and OAB dry groups (p =.54). Vol. 21, 38 43, March 21 39

3 Y.C. Chen, et al Table 1 Comparison of the changes in parameters between OAB-dry and OAB-wet subgroups* Total (n = 54) OAB dry (n = 25) OAB wet (n = 29) Baseline 6 months Baseline 6 months Baseline 6 months USS 3.28 ± ± ± ± ± ± 1.72 Daytime frequency 7.44 ± ± ± ± ± ± 2.3 Nocturia 4.4 ± ± ± ± ± ± 1.24 Qmax (ml/s) 13.9 ± ± ± ± ± ± 1.4 PVR (ml) 52.9 ± ± ± ± ± ± 81.2 Voided volume (ml) 24 ± ± ± ± ± ± 117 FBC (ml) 257 ± ± ± ± ± ± 128 *Data are presented as mean ± standard deviation; p <.5 compared with the baseline data. OAB = overactive bladder; USS = urgency severity score; Qmax = maximum flow rate; PVR = post-voiding residual volume; FBC = functional bladder capacity. A Figure 1 A B Qmax (ml/s) Time Time Total OAB wet OAB dry The changes in (A) urgency severity score (USS) and (B) maximum flow rate (Qmax) during follow-up period B PVR Volume FBC Figure 2 Changes in post-voiding residual volume (PVR), voided volume and functional bladder capacity (FBC) in (A) overactive bladder (OAB) dry group and (B) OAB wet group during all follow-up time-points. The adverse events at all time-points are listed in Table 2. The incidence of adverse events did not increase from 3 months to 6 months after treatment. At 6 months, only seven patients (13.%) complained of any adverse effect. Difficult urination was the most common complaint (three of 54 patients, 5.6%). Other adverse events, including dry mouth, constipation, dizziness and gastrointestinal upset, occurred in one patient each (1.9%). 4. Discussion This study demonstrated that solifenacin is effective in treatment of patients with OAB. There was no difference in therapeutic efficacy between the OAB wet and OAB dry groups. The USS, daytime frequency and nocturia improved significantly after treatment. Voided volume and FBC were also noted to have significant improvement without affecting voiding efficacy. The results of this study is consistent with previous reports. 15,17 19 Solifenacin is considered to be a better antimuscarinic agent than other antimuscarinics because of its higher affinity to M2 and M3 muscarinic receptors, which might play a major role in bladder contractility. 9 One previous study has shown that the mean frequency of micturition decreased by 21% and 19.5% in patients receiving tolterodine and oxybutynin, respectively, for 12 weeks. 2 The results of this study confirmed the same therapeutic 4 Vol. 21, 38 43, March 21

4 Solifenacin in treating OAB A 12 1 p =.94 21% 23% Baseline 6 mo 8 6 p =.53 46% 34% p =.6 29% 37% OAB dry OAB wet OAB dry OAB wet OAB dry OAB wet B USS Day me frequency Nocturia p =.41 3% 22% p =.51 1% 31% p =.8 27% 27% OAB dry OAB wet OAB dry OAB wet OABdry OAB wet Voided volume PVR Func onal bladder capacity C p =.76 11% 16% OAB dry Qmax OAB wet Figure 3 Therapeutic effects on frequency, urgency symptoms and voiding parameters between overactive bladder (OAB) dry and OAB wet groups. (A) Changes in parameters of urgency severity score (USS), daytime frequency and nocturia, (B) changes in parameters of functional bladder capacity (FBC), post-voiding residual volume (PVR) and voiding volume, and (C) changes in maximum flow rate (Qmax) from baseline to 6 months. effects of solifenacin in both OAB dry and OAB wet patients. Muscarinic receptors have been found to be located on the bladder urothelium and suburothelium structure in addition to the detrusor muscles. 21,22 The binding of antimuscarinics to receptors on the detrusor muscles and the binding of the metabolite of antimuscarinics excreted in urine to the receptors on the urothelium play an important role in treating OAB. 23,24 The expression of muscarinic receptors, typically the M2 and M3 subtypes, on the bladder urothelium and detrusor muscle has been found to increase in rats with bladder outlet obstruction and metabolic syndrome, the conditions of both of which might predispose to detrusor overactivity Solifenacin is a highly lipophilic agent, is completely oral bioavailable, and is metabolized by the cytochrome P45 3A isozyme. Fifty percent of the oral dose of solifenacin will be eliminated renally as the parent compound, which is higher than that of darifenacin and tolterodine. 28 A recent report also revealed that when the solifenacin is metabolized and excreted in human urine, its metabolite provides a better pharmacologic advantage for treating detrusor overactivity in rats than tolterodine Vol. 21, 38 43, March 21 41

5 Y.C. Chen, et al Table 2 Adverse events at all time-points* Adverse effect 1 week 1 month 3 months 6 months Difficult urination 1 (1.9) 3 (5.6) 3 (5.6) Dry mouth 1 (1.9) 1 (1.9) Constipation 1 (1.9) 1 (1.9) Hematuria 1 (1.9) Skin itching 1 (1.9) Residual urine 1 (1.9) sensation Dizziness 2 (3.7) 1 (1.9) GI upset 1 (1.9) Total (n = 54) (%) 3 (5.6) 8 (14.8) 7 (13.) *Data are presented as n (%); percentages may not add up to total because of rounding. GI = gastrointestinal. or darifenacin. 29 The result of this study showed no significant difference between OAB dry and OAB wet, which might be explained by the high affinity of solifenacin on muscarinic receptors on the urothelium and detrusor muscles and a higher metabolite concentration of the parent compound of solifenacin in urine. This study also revealed that the change in USS decreased gradually with time and became stably decreased after 3 months treatment. The treatment course of antimuscarinics on OAB needs at least 3 months to reach a plateau. It is because the therapeutic effect of antimuscarinics is not only attributed to direct receptor blocking effects but also influenced by the drug concentration reaching to a maximal steady state. Solifenacin needs at least 2 3 months to reach a maximal stable therapeutic effect as for other types of antimuscarinics. 9 In our study, only 48% of the patients with OAB dry and 45% with OAB wet had USS decreased by at least 1 scale point at 6 months, suggesting that the dose of solifenacin should be escalated if the maximal effect is not reached after 3 months of treatment. Therefore, if there is no significant improvement after taking solifenacin for an initial 3 months, increasing the dosage to 1 mg daily could be considered. 15,18,19,3 Concerning the adverse effects of solifenacin, only minor adverse events occurred in 13.% of the patients overall at 6 months after treatment, indicating that solifenacin at a dosage of 5 mg daily is safe for treating patients with OAB. An incidence of adverse effects of less than 15% was noted during the follow-up period, and this result was better than in other previous reports, in which the incidences of dry mouth and constipation were reported to be 21.4% and 13.3%, respectively, after solifenacin treatment. 18 We found fewer adverse effects occurring in this study in comparison with a 25% discontinuation rate in patients treated with oxybutynin in another study. 3 The fewer adverse effects in this study may be due to the following: (1) the small sample size of 54 patients would introduce bias; (2) patients took solifenacin 5 mg orally per day, and the lower dosage of solifenacin would cause minor adverse effects; and (3) as patients who sought help often focused on their LUTS, and once the LUTS improved, the tolerable adverse effects might be ignored. In conclusion, patients with either OAB wet or OAB dry can benefit from solifenacin treatment, in terms of improvement in USS, frequency and nocturia episodes, and bladder capacity without compromising voiding efficiency. Only 13% of the patients had minor adverse effects, typically dysuria. References 1. Abrams P, Cardozo L, Fall M, et al. The standardization of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 22;21: Stewart EF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 23;2: Irwin DE, Milsom I, HunsKaar S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 26;5: Adersson KE. Antimuscarinics for treatment of overactive bladder. Lancet Neurol 24;3: Anderson KE, Yoshida M. 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