Improvement in quality of life after botulinum toxin-A injections for idiopathic detrusor overactivity: results from a randomized double-blind placebo-controlled trial

Authors


Prokar Dasgupta, Department of Urology, 1st floor Thomas Guy House, Guy’s Hospital and KCL School of Medicine, London SE1 9RT, UK.
e-mail: prokarurol@gmail.com

Abstract

OBJECTIVE

To determine whether botulinum toxin-A (BTX-A) treatment has an effect on the quality of life (QoL) of patients with overactive bladder (OAB) refractory to anticholinergics.

PATIENTS AND METHODS

This was a single centre, randomized, double-blind, placebo-controlled trial. Participants were men and women with idiopathic detrusor overactivity (IDO). Participants were randomised to receive either 200 U of BTX-A (Botox®, Allergan Inc., Irvine, CA, USA; n = 16) or placebo (n = 18) via a trigone-sparing flexible cystoscopic technique. QoL was assessed using the King’s Health Questionnaire (KHQ) at baseline and at 4 and 12 weeks, after injection. At 12 weeks patients were ‘unblinded’ and a further open-label follow-up in the BTX-A group occurred at 24 weeks. The changes in the subdomains of the KHQ were assessed over the study period.

RESULTS

Overall QoL was significantly improved in the BTX-A treated patients compared with placebo in the blinded part of the study. When analysing the KHQ subdomains, ‘Incontinence Impact’, ‘Emotions’, ‘Physical Limitations’, ‘Social Limitations’ and ‘Severity Measures’ were significantly improved in those that received BTX-A compared with placebo. The ‘Symptom Severity’ domain was also significantly improved at 4 weeks but not at 12 weeks. At 12 weeks ‘Role Limitations’ also became statistically significant in favour of BTX-A. The open-label extension study suggested these benefits last for at least 24 weeks.

CONCLUSIONS

BTX-A bladder injections at 200 U appear to improve QoL in patients with OAB symptoms and IDO refractory to anticholinergics for at least 24 weeks. As well as the improvement seen in clinical parameters with this form of therapy, perhaps of more importance to the patient, is the improvement in QoL.

Abbreviations
OAB

overactive bladder

BTX(-A)

botulinum toxin (-type A)

QoL

quality of life

(I)(N)DO

(idopathic) (neurogenic) detrusor overactivity

KHQ

King’s Health Questionnaire

MID

minimally important difference

IIQ-7

Incontinence impact questionnaire short form 7

UDI-6

Urogenital distress inventory short form 6

sd

standard deviation.

INTRODUCTION

Traditionally management of overactive bladder (OAB) involves lifestyle modification, ‘bladder training’ and anticholinergics. If this approach is not successful, options include sacral neuromodulation, botulinum toxin (BTX) injections into the bladder and in intractable cases, surgery in the form of clam ileocystoplasty or urinary diversion. The overall aim is to reduce OAB symptoms and improve quality of life (QoL) for patients. Bladder injections of BTX-A, derived from the Gram-positive anaerobic organism Clostridium botulinum, is establishing itself as an effective second-line treatment for OAB in patients refractory to anticholinergics.

Evidence from randomized placebo-controlled trials [1,2] have shown BTX-A to be effective in treating neurogenic detrusor overactivity (NDO). In this population group BTX-A injections are repeatable with equal efficacy between injections [3–5]. We have previously reported on the significant improvements in OAB symptoms and urodynamic variables in patients with idiopathic DO (IDO) treated with BTX-A [6]. The purpose of the present study was to report on QoL outcomes from the same study measured by the King’s Health Questionnaire (KHQ).

PATIENTS AND METHODS

Patients of either sex with symptoms of OAB for ≥6 months and urodynamically confirmed IDO were recruited into this randomized, double-blind, placebo-controlled trial. The study was conducted at Guy’s Hospital, London, UK between May 2004 and February 2006 after receiving the relevant Ethics Committee approval (registration no. 10/03/04; ISCRTN no. 16995641). The full details have been previously reported [6]. In brief, all patients had failed a trial of anticholinergics for ≥6 weeks before randomization, due to either poor efficacy or tolerability. Patients with mixed urinary incontinence were allowed into the study if the symptoms of urge were greater than those of stress.

To assess QoL, patients completed the short forms of the Incontinence Impact Questionnaire (IIQ-7), Urogenital Distress Inventory (UDI-6) (previously reported [6]) and the KHQ. An independent statistician generated the randomization code using SAS version 8.2 software. The code was sent to a pharmacist at Guy’s Hospital who randomized patients to either BTX-A (Botox®, Allergan Inc., Irvine, CA, USA) 200 U reconstituted in 20 mL 0.9% normal saline or placebo (20 mL 0.9% normal saline).

BTX-A or placebo was administered with a flexible injection needle via a flexible cystoscope (Olympus Keymed, Milton Keynes, UK). Before the injections, three biopsies were taken from the bladder base 2 cm above the left ureteric orifice. These were taken for another study to assess histological and neuronal effects of treatment. This minimally invasive technique [7] involved 20 injections at 10 U/mL/injection site: five in the midline posterior bladder wall, five each along the left and right lateral walls, and five across the dome of the bladder, sparing the trigone. Injections were into the detrusor muscle or suburothelium. After the injections, patients were observed for a minimum of 30 min and if well, were discharged with a 3-day prescription of oral ciprofloxacin 250 mg twice daily.

Patients taking anticholinergics, despite poor efficacy, were asked to continue unless they felt it unnecessary, and to inform the investigators when this occurred. Those not taking anticholinergics were advised not to restart unless instructed to by the investigators.

Patients were followed-up by telephone at 1 week, and QoL KHQ assessments at 4- and 12-weeks after injection. In addition, three more biopsies were taken from the same bladder site at 4 and 12 weeks. The study was unblinded at 12 weeks, and patients receiving BTX-A were assessed again for QoL at 24 weeks using the KHQ.

For statistical analysis the Wilcoxon paired test to compare within groups and the Mann–Whitney test to compare between groups were used. Values are given as the median (interquartile range). All significance tests were carried out at the two-sided 5% interval; a P < 0.05 was considered to indicate statistical significance. The Spearman’s rank method was used for the correlation analysis with significance accepted for P < 0.05 on a one-tailed test.

RESULTS

In all, 97 patients were screened for the trial in our clinic but 38 did not meet the inclusion/exclusion criteria (Table 1) and 23 refused to participate. Thus, 36 patients were randomized to treatment, 18 to BTX-A and 18 to placebo. Two patients in the BTX-A group were excluded from analysis as they did not meet the inclusion criteria (no evidence of DO in one; NDO in the other) and did not complete the trial. The baseline demographics of the two groups and concomitant anticholinergic use at baseline are outlined in Table 2. Five of six patients in the BTX-A group who were taking anticholinergics were able to stop them, compared with none in the placebo group before unblinding. In the BTX-A group, four patients were prescribed anticholinergics (either trospium chloride 20 mg twice daily or tolterodine XL 4 mg once daily) by 4 months and seven by 6 months to further improve symptoms.

Table 1.  Inclusion/exclusion criteria
InclusionExclusion
  1. CISC, clean intermittent self-catheterization.

Age 18–80 yearsOAB secondary to neurological disease
Symptoms of OABEvidence of BOO
Proven DO on urodynamicsAnticoagulant therapy (e.g. heparin or warfarin)
Failed anticholinergics therapyPregnancy or planned pregnancy within a year
Able and willing to perform CISCPainful bladder syndrome or interstitial cystitis
Indwelling catheter
Previous urological use of BTX
Previous bladder surgery (e.g. cystoplasty)
Other bladder pathology (e.g. TCC, current UTI)
Neuromuscular transmission disorder (e.g. myasthenia gravis, Eaton–Lambert syndrome)
Table 2. 
Baseline demographic data
 BTX-APlacebo
  1. od, once daily; bd, twice daily; tds, three times daily.

Number of patients1618
Mean age, years49.850.8
Gender, M : F 7:9 8:10
Anticholinergic current use, n 611
 tolterodine XL, 4 mg od 4 8
 trospium chloride, 20 mg bd 2 1
 oxybutynin, 5 mg tds 0 2

QoL

A reduction in score for the KHQ indicates better QoL. Overall, there was a significant improvement in the overall KHQ score in favour of BTX-A compared with placebo at 4 weeks (P = 0.002) and 12 weeks (P = 0.006). At 24 weeks in the open-label extension part of the study BTX-A was significantly better than baseline values (P = 0.006). Analysis of the individual domain scores for the KHQ in the blinded part of the study, showed a significant improvement in six of the 10 scores at both 4 weeks and 12 weeks in the BTX-A group. This included ‘Incontinence Impact’, ‘Physical Limitations’, ‘Social Limitations’, ‘Emotions’ and ‘Severity Measures’ at both time points. In addition, the ‘Symptom Severity’ score had improved at both time points in favour of BTX-A, although it only reached statistical significance at 4 weeks. By 12 weeks ‘Role Limitations’ was also statistically significant in favour of BTX-A. There was an improvement for ‘Personal Relationship’ and ‘Sleep/Energy’ scores in patients from the BTX-A arm, but these did not quite reach a statistically significant level. This is summarized in Table 3. In the open-label extension study, all domains except ‘General Health Perception’ and ‘Incontinence Impact’ were significantly improved compared with baseline in the BTX-A group at 24 weeks (Fig. 1).

Table 3.  Median (interquartile range) KHQ domain scores at baseline and changes from baseline score at 4 and 12 weeks
KHQ domainBTX-APlaceboP
  1. All domains scored on a 0–100 scale except symptom severity which is on a 0–30 scale.

General health perception   
 Baseline score 25 (25–50) 25 (0–43)0.17
 Change at 4 weeks  0 (0–25)  0 (−19–0)0.37
 Change at 12 weeks  0 (0–25)  0 (0–0)0.40
Incontinence impact   
 Baseline score100 (92–100)100 (100–100)0.69
 Change at 4 weeks 33 (0–67)  0 (0–25)0.03
 Change at 12 weeks 35 (0–67)  0 (0–0)0.04
Role limitations   
 Baseline score 83 (50–100) 83 (54–100)0.92
 Change at 4 weeks 33 (17–67) 17 (4–33)0.16
 Change at 12 weeks 33 (13–75) 17 (−17–17)0.02
Physical limitations   
 Baseline score 75 (50–100) 83 (54–100)0.94
 Change at 4 weeks 50 (17–67)  0 (0–17)0.001
 Change at 12 weeks 33 (13–67)  0 (−17–17)0.002
Social limitations   
 Baseline score 72 (54–78) 67 (17 to75)0.23
 Change at 4 weeks 44 (11–67) 17 (−11–22)0.005
 Change at 12 weeks 33 (11–67)  0 (−19–17)0.003
Personal relationships   
 Baseline score 67 (25–83) 33 (0–50)0.27
 Change at 4 weeks 33 (0–42)  0 (0–17)0.20
 Change at 12 weeks 17 (0–50)  0 (0–0)0.06
Emotions   
 Baseline score100 (67–100) 78 (39–89)0.018
 Change at 4 weeks 44 (33–64)  6 (−8–22)<0.001
 Change at 12 weeks 33 (2–67)  0 (−28–22)0.002
Sleep/energy   
 Baseline score 83 (67–100) 67 (67–96)0.38
 Change at 4 weeks 16 (0–33)  0 (− 12–17)0.14
 Change at 12 weeks 25 (0–50)  0 (0–17)0.07
Severity measures   
 Baseline score 67 (52–93) 67 (42–83)0.57
 Change at 4 weeks 20 (10–37)  0 (−7–12)0.007
 Change at 12 weeks 33 (−2–67)  0 (−7–7)0.03
Symptom severity   
 Baseline score 17 (12–19) 13 (12–19)0.50
 Change at 4 weeks  7 (4–13)  3 (−1–4)0.007
 Change at 12 weeks  5 (−1–15)  0 (−1–3)0.09
Figure 1.

Changes in the median KHQ Domain scores over the study period: (i) ‘General Health Perception’ (GHP) and ‘Incontinence Impact (II); (ii) ‘Role limitations’ (RL), ‘Physical Limitations’ (PL) and ‘Social Limitations’ (SL); (iii) ‘Personal Relationships’ (PR), ‘Emotions’ (E) ‘Sleep/Energy’ (S/E) and ‘Severity Measures’ (SM); (iv) ‘Symptom Severity’ score (SSS).

These benefits in QoL were then analysed and correlated with changes in OAB symptoms and urodynamic variables, previously reported in these patients [6]. There was a significant relationship between the percentage improvement in OAB symptoms and the overall KHQ score. At 4 weeks, urgency and urge urinary incontinence were statistically correlated with improvements in QoL and at 12 weeks with frequency and urgency. There was no correlation with QoL and changes in mean maximum cystometric capacity; however, maximum detrusor pressure during filling cystometry was statistically significant at both 4 and 12 weeks. This is summarized in Table 4.

Table 4.  Correlation of the percentage improvements in overall KHQ score with OAB symptoms and urodynamic variables at 4 (n = 14) and 12 weeks (n = 16). (Pearson’s correlation, one-tailed)
Variable% Improvement in KHQ score at:
4 weeksSpearman’s r (P)12 weeksSpearman’s r (P)
  1. MCC, maximum cystometric capacity; MDP, maximum detrusor pressure during filling cystometry; *statistically significant.

Frequency0.38 (0.088)0.59 (0.008)*
Urgency0.64 (0.007)*0.78 (<0.001)*
Urge UI0.75 (0.001)*0.42 (0.054)
MCC0.40 (0.078)0.01 (0.478)
MDP0.56 (0.006)*0.47 (0.033)*

DISCUSSION

The ICS has recommended that QoL measures should be included in the assessment of therapies in treating lower urinary tract dysfunction [8]. For the purposes of assessing BTX-A in treating refractory IDO we used the KHQ. The KHQ was first developed and validated in assessing women with UI at King’s College Hospital, London [9]. Since then it has also been validated for OAB [10]. The KHQ is split into three sections; (i) general health and overall health related to urinary symptoms (‘General Health Perception’ and ‘Incontinence Impact’), (ii) specific domains of quality of life (‘Role, Physical And Social Limitations’, ‘Personal Relationships’, ‘Emotions’, ‘Sleep/Energy’ and ‘Severity Measures’), and (iii) bother and impact of urinary symptoms (‘Symptom Severity’). It has been given a grade A recommendation by the ICS indicating that the questionnaire is valid, reliable and responsive to change as assessed by standard psychometric testing [11].

The overall KHQ scores suggested significant improvements in QoL in patients treated with BTX-A at each time-point in the present study compared with placebo, confirming open-label published data that BTX-A is effective in improving QoL in patients with OAB with IDO refractory to anticholinergics (Table 5) [12–19].

Table 5.  QoL outcomes after treatment with BTX-A in patients with IDO or non-neurogenic OAB
AuthorStudy typePatient numbers/ diagnosisFormulationBTX-A dose, UQoL measure and outcome
  1. RDBPCT, randomized double-blind placebo-controlled trial; SSI, Symptom severity index; SII, Symptom impact index; BFLUTS, Bristol female LUTS questionnaire; Uds, urodynamics; ES, external sphincter, II, ‘Incontinence Impact’; RL, ‘Role limitations’; PL, ‘Physical Limitations’; SL, ‘Social Limitations’; E, ‘Emotions’; S/E, ‘Sleep/Energy’; SM, ‘Severity Measures’; SSS, ‘Symptom Severity’ score.

Present studyRDBPCT16 (BTX-A) 18 (Placebo) IDOBotox200KHQ: II, PL and SL, E, SM and SSS significantly improved with BTX-A. RL and S/E were better in the BTX-A group at 12 but not 4 weeks. Open-label extension study suggested these benefits last for at least 24 weeks.
Jeffery et al. 2007 [12]Prospective, open-label25 IDODysport500KHQ: SM and II improved for 9 months; urgency and urge UI improved for up to 6 months.
Sahai et al. 2007 [6]RDBPCT16 (BTX-A) 18 (Placebo) IDOBotox200UDI-6/IIQ-7. Significant improvements vs placebo in the blinded part of the study, i.e. 1 and 3 months; Open-label extension study at 6 months, significant improvements vs baseline.
Lucioni et al. 2006 [14]Prospective, open-label40 (OAB including 7 patients with a neurological history; no UDs)Botox300UDI-6/IIQ-7. Significantly improved vs baseline at 3 weeks; combined UDI-6 and IIQ-7 scores significantly better at 6 months vs baseline.
Schmid et al. 2006 [17]Prospective, open-label100 at 1 month; 80 at 3 months; 20 at 9 months; (IDO n = 54 and sensory urgency n = 46)Botox100KHQ. Improvement in all urge related items at 1 and 3 months after injection. 90% reported improvement in at least 1 KHQ category in ability to travel, effect on sleep, participation in social life, accomplishment of household tasks and general effect on daily life.
Kalsi et al. 2006 [13]Prospective, open-label11 IDOBotox200UDI-6/IIQ-7. Significant improvements vs baseline at 4 and 16 weeks.
Schulte-Baukloh et al. 2005 [18]Prospective, open-label44 IDOBotox200–300 22 patients also received ES injection of 50–100 (no patient had >300 in total)UDI-6/SSI/SII. Significant improvements vs baseline in all questionnaires at 1, 3 and 6 months after treatment. Non-significant differences at 9 months.
Rajkumar et al. 2005 [15]Prospective, open-label15 IDOBotox300KHQ/BFLUTS. Significant improvements vs baseline at 6 weeks. Therapeutic response evident up to 24 weeks.
Werner et al. 2005 [19]Prospective, open-label26 at 1 month; 20 at 3 months; 5 at 9 monthsIDOBotox100KHQ. Significant improvement in all urge-related items at 1 and 3 months after treatment; Significant improvements vs baseline in improving at least 1 category with the KHQ for effect on life, household tasks, daily activities outside of home, ability to travel, social life, effect on sleep, embarrassment.
Rapp et al. 2004 [16]Prospective, open-label35 (OAB + including 6 with a neurological history; no UDs); 24 assessed at 6 monthsBotox300UDI-6/IIQ-7. Significant improvements vs baseline at 3 weeks; 14/24 patients assessed to have responded at 6 months follow-up. In these 14 patients, significant improvements vs baseline at 6 months.

The first part of the KHQ, ‘General Health Perception’, was not significantly altered throughout the study. In contrast ‘Incontinence Impact’, which asks the question ‘how much do you think your bladder affects your life?’ was significantly better in the BTX-A group compared with placebo in the blinded phase of the study, and although improved compared with baseline values in the BTX-A group at 24 weeks, this did not quite reach statistical significance (P = 0.06).

When assessing the specific QoL domain scores for the blinded part of the study four of the seven domains were significantly better in the BTX-A group at 4 weeks, increasing to five of the seven by 12 weeks. The ‘Role Limitations’ domain became significantly better at 12 weeks compared to placebo with significantly better scores than baseline at 24 weeks, suggesting a slight delay in the improvement for this domain. Although the ‘Sleep/Energy’ domain was not statistically different in the blinded part of the study, there did appear to be a trend towards improvement with BTX-A, and it was significantly better at 24 weeks in the extension study. This may be related to a delayed improvement in nocturia compared with other OAB symptoms, but as nocturia specifically was not quantified, we were unable to confirm this. The ‘Personal Relationships’ domain was also not significantly improved by BTX-A in the blinded part of the study but again by 24 weeks was significantly better than baseline values in the BTX-A group. This may reflect the time required for patients with OAB to adjust and increase their confidence with their personal relationships and family life. There was a similar trend in another OAB trial investigating the anticholinergic, solifenacin succinate, in patients with OAB [20]. In the open-label extension study, all seven specific QoL domains and overall eight of the 10 domains were better compared with baseline in the BTX-A group, suggesting long lasting effective QoL improvement in patients treated with BTX-A of at least 24 weeks.

The ‘Symptom Severity’ score of the KHQ asks questions related to symptoms and bother related to urinary symptoms such as OAB symptoms, stress and intercourse UI, nocturnal enuresis, UTI and bladder pain. This was significantly improved in the BTX-A group compared with placebo at 4 but by 12 weeks became statistically insignificant even though there was a trend towards improvement. In the extension study at 24 weeks the symptom severity score was again improved compared with baseline values. This correlated well with significant improvements in OAB symptoms in the same study population as assessed by 3-day voiding diaries at the same time points [6].

Kalsi et al.[13] in a population of patients with IDO and NDO reported significant improvements in QoL as assessed by the UDI-6 and IIQ-7 at 4 and 16 weeks after treatment compared with baseline. That study reported a statistically confirmed correlation between improvement in QoL with improvements in urgency and urge UI for patients with IDO and NDO, and also frequency in the NDO population alone. In the present study, there were similar findings, which re-enforces the positive correlation between improvement in QoL score and improvement in OAB symptoms. There was a positive correlation with urinary urgency, the defining symptom of OAB, at both time points tested and urge UI at 4 weeks and frequency at 12 weeks with QoL in our group of patients with IDO. Despite objective urodynamic improvement in the group of patients who received BTX-A [6], this only correlated statistically with improvements in QoL for maximum detrusor pressure during filling cystometry.

How significant are these improvements in QoL with BTX-A? Clinicians are becoming increasingly aware of the plethora of OAB and UI questionnaires available to assess treatment. It is important for the QoL tool to detect change but also to assess how this translates to the individual patient. This can be achieved by determining the minimally important difference (MID) of the questionnaire [21]. Kelleher et al.[22] in assessing this specifically for the KHQ reported that a change of ≥5 points indicated a clinically important difference in QoL. In the same study, using a distribution based approach and a 0.50 standard deviation (sd) criterion, the MID was 10–15 for all of the domains except ‘Symptom Severity’, which was 6–8 points. In the present study, all cases of statistical improvement in any of the KHQ domain scores with BTX-A had at least a mean reduction of 20 points and often significantly more (mean data not shown). Although some improvements of ≥5 points occurred in the placebo group, apart from ‘Social Limitations’, in no domain was it ≥10 points. This could be partly explained by the ‘placebo effect’ often observed in clinical trials in patients with OAB.

The main limitations of the present study were the use of concomitant anticholinergics and the relatively few patients. We felt that the stopping or re-instating of anticholinergics dependent on efficacy and patient symptoms was similar to everyday clinical practice and hence their inclusion in the original protocol. The sample size in the present study was originally designed to have 90% power to detect a mean difference of 50 mL in maximum cystometric capacity between BTX-A and placebo, assuming that the sd is 42 mL using a two-sided type I error of 5%. According to the power calculation, at least 32 patients (16 in each group) were required to complete the trial.

In conclusion, BTX-A at 200 U is effective in improving QoL as assessed by the KHQ in patients with refractory IDO compared with placebo. The beneficial effects appear to last for at least 24 weeks. Together with the improvement in subjective OAB symptoms and objective urodynamic variables, perhaps of most importance from the patient perspective is the improvement in QoL.

ACKNOWLEDGEMENTS

British Urological Foundation; Aseptics Unit, Pharmacy Department, Guy’s Hospital; Helen Lanka, Anna Bell – Urology Nurses; Iftekhar Khan for his help with the statistics.

The GKT Botulinum Study Group is composed of: Mr Arun Sahai, Mr Mohammad Shamin Khan, Mr Prokar Dasgupta, Mr Christopher Dowson, Dr Norman Gregson, Dr Yue Sun, Professor Kenneth Smith.

CONFLICT OF INTEREST

All authors are investigators for Allergan Ltd; Botulinum toxin-A was provided free for use in the present study.

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