Int Urogynecol J DOI 10.1007/s00192-017-3278-7
REVIEW ARTICLE
Intraurethral bulking agents for the management of female stress urinary incontinence: a systematic review Zain A. Siddiqui 1 & Hamid Abboudi 2
&
Ruairidh Crawford 2 & Shahzad Shah 2
Received: 3 December 2016 / Accepted: 16 January 2017 # The International Urogynecological Association 2017
Abstract Introduction and hypothesis The object of this review was to assess the efficacy and safety of urethral bulking agents (UBA), principally Macroplastique and Bulkamid, in the treatment of female stress urinary incontinence (SUI). Methods MEDLINE® and EMBASE® databases were systematically searched up to June 2016. Year of publication, study type, outcome measures, urodynamics before and after the procedure, number of participants, procedure complications, proportion requiring repeat injections or surgical procedures, frequency of follow-up, and results were analysed. Results The use of Bulkamid and Macroplastique for the treatment of female SUI was described in 26 studies. Studies used modalities including the visual analogue scale, Likert scale, International Consultation on Incontinence Modular Questionnaire (ICIQ), Patient Global Improvement Questionnaire (PGIQ) and Incontinence Impact Questionnaire (IIQ) and showed success rates ranging from 66% to 89.7% at 12 months follow-up. Objective improvements in patient symptoms were measured using urodynamics, 24-h pad tests, cough tests and voiding diaries. Studies showed variable objective success rates ranging from 25.4% to 73.3%. Objective findings for UBAs remain less well documented than those for the midurethral sling procedure. Conclusions There are a range of complications associated with UBAs, the most common being urinary tract infection.
* Hamid Abboudi [email protected]
1
Department of Urology, Birmingham City Hospital, Dudley Road, Birmingham B18 7QH, UK
2
Department of Urology, Watford General Hospital, Vicarage Road, Watford WD80 0HB, UK
However, it remains a very well tolerated procedure in the majority of patients. UBAs should be considered as an alternative in patients unsuitable for more invasive procedures and those willing to accept the need for repeat injections. The majority of the literature focuses on subjective improvement measures rather than objective improvement measures. Further randomized controlled trials directly comparing UBAs are required to indicate the most effective agent. Keywords Bulkamid . Incontinence . Macroplastique . Urethral bulking agent
Introduction Stress urinary incontinence (SUI) is a common socially debilitating condition predominantly affecting women with a prevalence of between 10% and 40% [1]. Managing and treating SUI comes at a significant cost to the UK’s National Health Service (NHS), estimated at approximately £353.6 million per annum [2]. Normal urinary continence relies on the functional coordination of the anatomy by the nervous system. The pelvic floor creates the support required by the bladder and urethra to sustain transmission of abdominal pressure to the proximal urethra, ultimately resulting in continence [3]. It has been hypothesized that reductions in the urethral closure pressure superimposed on the transmission of pressure from the abdomen to the urethra results in SUI [4]. Furthermore, recent findings have highlighted the role of midurethral support in the maintenance of continence [5]. Risk factors include advancing age, higher parity, vaginal delivery, obesity and postmenopausal status [6]. The current gold standard treatment of SUI is placement of a midurethral sling via either the retropubic or the transobturator route. These procedures aim to provide support at the midurethral level with the sling acting as a hammock preventing the urethra
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from dropping. Typically, a synthetic mesh is positioned posterior to the proximal urethra lifting the urethra up into a position where it can withstand increases in intraabdominal pressure so that continence is maintained [3]. The use of midurethral tapes has come under scrutiny recently in relation to mesh complications including infection, chronic pain and erosion. Midurethral tapes have been withdrawn from use in the NHS in Scotland pending further investigation, but not in the rest of the UK. These concerns have led to the focus being shifted to existing urethral bulking agents (UBAs) and their development for use in the treatment of SUI The American Urology Association has recommended the use of UBA in elderly patients, patients with an increased risk of anaesthetic complications, and patients reluctant to undergo a more invasive procedure [7]. In addition, the National Institute for Health and Clinical Excellence (NICE) [8] advises that UBAs be considered in patients with significantly decreased urethral mobility and patients who have a history of failed conservative treatment [8]. In 2011 glutaraldehyde-treated bovine collagen (Contigen) was withdrawn worldwide due to its tendency to be absorbed leading to recurrence of symptoms. This resulted in the need for new agents, most notably polydimethylsiloxane (Macroplastique) and polyacrylamide hydrogel (Bulkamid) [9, 10]. UBAs provide additional support when injected into the mid-urethra. Once implanted into the urethral submucosa they provide a cushion helping to increase urethral sphincter pressure thus improving continence [11]. This aim of this systematic review was to assess the efficacy and safety of UBAs alone, principally Macroplastique and Bulkamid. We compared the two UBAs to determine whether either is superior in the treatment of women with SUI.
June 2016) and EMBASE (2006 to June 2016) databases. The keywords used included: ‘bulking agent’, ‘bulkamid’, ‘macroplastique’ and ‘urinary stress incontinence’. In addition to studies obtained via the databases, further studies were acquired from the references cited in recent review articles. Study selection and data collection One reviewer (Z.S.) independently screened the abstracts of the studies identified in the database search to identify those that were potentially relevant. The full text of each potentially relevant paper was then independently reviewed by two authors (Z.S. and H.A.) to determine whether the paper included certain topics of interest such as bulking agents, human studies, SUI, and follow-up on safety and efficacy. Conflicts between reviewers were discussed until there was 100% agreement on the studies finally to be included. Data extraction and analysis From each study certain information was extracted and entered into a table for summary and analysis. Information extracted included: year of publication, type of study, outcome measures, urodynamics before and after the procedure, number of study participants, procedure complications, proportion of subjects requiring repeat injections or surgical procedures, frequency of follow-up, and results.
Results Study selection
Materials and methods This systematic review was conducted in accordance with the guidelines provided in the Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) statement (http://www.prisma-statement.org).
A total of 223 potentially relevant publications were identified from the literature search, but, following abstract review this was brought down to 53. Full text analysis led to the exclusion of a further 27 studies due to duplication, lack of relevance or lack of full text journal publication. Thus, a final count of 26 studies were included in the systematic review (Fig. 1).
Study eligibility criteria
Bulkamid
Studies outlining the use, efficacy and safety of UBAs in the treatment of female SUI as an alternative to more invasive traditional surgical procedures were included. Review articles, conference abstracts, letters, animal studies and studies involving the use of models were excluded.
An overview of the studies identified in which Bulkamid was used for the treatment of female SUI is presented in Table 1. The review showed that Bulkamid treatment improves patient quality of life (QoL) as shown in terms of subjective success measured using various methods including the visual analogue scale, Likert scale, International Consultation on Incontinence Modular Questionnaire (ICIQ), Patient Global Improvement Questionnaire (PGIQ and Incontinence Impact Questionnaire (IIQ). One study showed a high subjective success rate of 74.4% [18]. In another study with 25 subjects Bulkamid improved subjective symptoms in all patients
Information sources and search Using the NICE Healthcare Databases Advanced Search (https:// www.evidence.nhs.uk) a broad search of the English literature was conducted in June 2016 via the MEDLINE (2006 to
Int Urogynecol J Fig. 1 Study selection
Records idenfied through searching MEDLINE and EMBASE (n=243)
Addional records idenfied through other sources (n=5)
Records aer duplicates removed (n=223)
Records screened (n=223)
Records excluded aer abstract review (n=170)
Full-text arcles assessed for eligibility (n=53)
Full-text arcles excluded aer full-text review (n=27)
Studies included in final analysis (n=26)
except two who felt that the treatment had affected their social life [16]. In other studies subjective cure rates varied over time: at 1, 6, and 12 months the rates were 87%, 71%, and 66% respectively [22]. Finally, one study highlighted the variability in QoL following treatment with Bulkamid: QoL was found to be considerably improved in 40% of patients, slightly improved in 21%, unchanged in 29% and worsened in 10% [21]. Considering sexual function specifically, one study demonstrated an improvement following treatment with Bulkamid. In this study, 23 of 29 women treated continued to be sexually active and the subjective success rate was 89.7% at 12 months [20]. In the Bulkamid studies, objective success was measured using urodynamics, the 24-h pad test, the cough test and the number of incontinence episodes. In one study, full continence as defined by a negative cough test was achieved in 14 of 46 patients (30.4%) following treatment [12]. The same study showed a significant reduction in urine leakage, ranging from −61.5 ml to −197.5 ml as demonstrated by the pad test, but showed no significant changes in urodynamic parameters except for a reduction in voided volume [12]. Another study investigated the use of Bulkamid in 60 women who had previously had a failed midurethral sling procedure. In that study, 56.7% of the women had a negative cough test and 50% in 53 of 63 (79%) patients according to the 1-h pad test. In another study, the objective cure rate decreased from 55% at 6 months to 44% at 12 months. Voiding diaries showed that the number of incontinence episodes over 3 days decreased from 15.2 ± 6.6 to 7.9 ± 7.7 after treatment. However, the same
52
25
4
82
Martan et al. [15] Retrospective
Prospective
Prospective
Mouritsen et al. [16]
Krause et al. [17]
Leone Roberti Prospective Maggiore et al. [18] Yes
No
Yes
Yes
Yes
No
Yes
No
Yes
Yes 345 (229 Bulkamid, 116 Contigen)
Randomized controlled trial
Sokol et al. [14]
Yes
After the procedure
No
60
Prospective
Zivanovic et al. [13]
Yes
Before the procedure
Urodynamics
Yes
46
Prospective
Krhut et al. [12]
No. of patients
Type
24-h pad test, ICIQ, voiding diary, Likert scale
Cough test, ultrasonography1-h pad test, VAS
10% required repeat Bulkamid treatment
1, 3, 6, 12 months ICIQ, IIQ, patient global improvement questionnaire
5% offered repeat Bulkamid treatment
Not stated
King’s Health 8% required repeat Questionnaire, pelvic Bulkamid treatment. examination, USS, 28% required tape urine dipstick/MCS, procedure 48-h voiding diary, 24-h pad test Immediately after Physical examination the procedure
8 years
Results
Subjective success rate 74.4% at 1 year. ICIQ and IIQ scores significantly improved at 1 year. Frequency or leakage episodes/24 h significantly reduced at 1 year. No alteration in uroflowmetry at 1 year
75% cured/improved, 25% unchanged/worse. Results of the King’s Health Questionnaire similar to those reported 1 year after treatment. Only two women felt that their incontinence affected their social life Three of four women dry postoperatively and remained continent at discharge
Cough test negative in 19.6% (22 months). ICIQ dry rate 15.7% and dry/improved rate 45.1%. Mean VAS 51.3 ± 38.3. Likert scale cured or improved in 54.9%
30.4% achieved full continence. Significant reduction in 24-h pad weight and questionnaire scores. No significant changes in urodynamics except voided volume Not stated Cured/improved rates 93.3% (56/60), 88.3% (53/60), and 83.6% (46/55) at 1, 6, and 12 months Not stated; however, >50% decrease at 12 months in offered repeat leakage/incontinence episodes in injections (up to two) 53.2% (Bulkamid). 12-month if not dry after zero stress incontinence rates bulking agent 47.2% (Bulkamid). 12-month cured/improved rate 77.1% (Bulkamid)
Repeat procedure
ICIQ, patient perception Not stated of bladder condition questionnaire, 3-day voiding diary, 24-h pad test, cough test
Outcome measures
Average ICIQ, VAS, cough test, 22 months Likert scale (min 6 months, max 50 months)
1, 3, 6, 9, 12 months
1, 6, 12 months
3, 12, 24 months
Follow-up
Overview of studies in which Bulkamid was used in the treatment of female stress urinary incontinence
Reference
Table 1
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29
54
Leone Roberti Prospective Maggiore et al. [20]
Prospective
Prospective
Prospective
Trutnovsky et al. [21]
Lose et al. [22]
Lose et al. [23]
Yes
Yes
No
Yes
Yes
Before the procedure
Urodynamics
Yes
Yes
No
Yes
Yes
After the procedure
1, 3, 12 months
1, 6, 12 months
9 months
12 months
12 months
Follow-up
Results
35% required repeat Bulkamid treatment
26% required repeat Bulkamid treatment
31% required repeat Bulkamid treatment
38% subjectively dry and a further 43% improved. Urine leakage/24 h decreased by 93% and number of incontinence episodes by 87%. Quality of life measures improved significantly in all domains other than general health perception. No significant changes in urodynamic variables
Subjective success rate 89.7% and objective success 79.3% at 1 year. Mean number of incontinence episodes/24 h at 1 year significantly lower than at baseline. Mean (±SD) urine leakage/24 h significantly lower at 1-year (7.9 ± 8.0 g) than at baseline Considerable improvement (40%), slight improvement (21%), no change (29%), worsening (10%) Subjective response rates (cured/improved) after 1, 6 and 12 months 87%, 71% and 66%, respectively. Median incontinence episodes and urine leakage reduced significantly from baseline
Pad test negative in 73.2% after Not stated; however, treatment. Subjective offered repeat improvement in general health injections at 6 weeks and role limitations if procedure failed
Repeat procedure
Physical examination, 65% required repeat urine dipstick, 48-h Bulkamid treatment voiding diary, 24-h pad test, King’s Health Questionnaire
Pelvic examination, 24-h pad test, 3-day voiding diary, ICIQ, VAS
IOQ
King’s health Questionnaire, VAS, 2-h pad test, urethral pressure profile Pelvic examination, cough test, 3-day voiding diary, 24-h pad test, ICIQ, IIQ, VAS
Outcome measures
ICIQ International Consultation on Incontinence Modular Questionnaire, IIQ Incontinence Impact Questionnaire, IOQ Incontinence Outcome Questionnaire, MCS microscopy, culture and sensitivity, USS urgency severity scale, VAS visual analogue scale. Stamey grade is a way of grading the severity of stress incontinence: Grade 1: leakage of urine with sudden rises in intrabdominal pressure e.g. sneezing Grade 2: leakage of urine with lesser degrees of stress e.g. walking Grade 3: leakage of urine unrelated to activity or position e.g. lying at rest.
17
135
514
Prospective
Mohr et al. [19]
No. of patients
Type
Reference
Table 1 (continued)
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Prospective
Prospective
Ghoniem et al. [26]
Zullo et al. [27]
ter Meulen et Randomized 47 (24 Macroplastique al. [28] controlled trial (2 withdrew) and 21 pelvic floor exercises)
27
75
23
Retrospective
Lee et al. [25]
No. of patients
35
Type
Yes
Yes
Yes
Yes
Yes
No
After the procedure
Yes
Yes
Yes
Yes
Before the procedure
Urodynamics
3, 12 months
6 m, 12 months
12, 24 months
6–34 months
6 weeks, 12–62 months
Follow-up
Repeat procedure
Urinalysis, I-QOL, 11% required repeat Stamey grade, Macroplastique frequency/volume treatment chart, 1-h pad test, physical examination
VAS, 3-day voiding Not stated diary, cough test, physical examination
Sandvik questionnaire, 9% required repeat Macroplastique VAS, I-QOL, benefit, treatment and 13% satisfaction and had a further tape willingness to procedure continue questionnaire Stamey grade, pad test, 44% required repeat I-QOL, voiding diary Macroplastique treatment
Not stated Pelvic examination, 24-h pad test, 3-day voiding diary, I-QOL, IIQ-7, UDI-6
Outcome measures
Overview of studies in which Macroplastique was used in the treatment of female stress urinary incontinence
Gumus et al. Prospective [24]
Reference
Table 2
No significant difference in pad weight at 3 months between treatment arms. Number of pads used at 3 months in the Macroplastique group decreased significantly compared to control group. Number of women “cured” or “markedly improved” at 3 months significantly higher than that in the control group (70.8% vs. 28.5%)
At 6 months 55% patients were cured and 15% reported no improvement. At 12 months objective cure rate 44%, improvement rate 33% and failure rate 22%. No statistically significant difference between 6 and 12 months
At 12 and 24 months 57% and 67% respectively, were dry (Stamey grade 0). Compared to baseline 85% considered themselves dry or markedly improved on the Patient Global Impression of Improvement, 8% considered themselves slightly improved and 8% were unchanged. 79% improved from baseline with at least 50% decrease in urine loss
Differences between median I-QOL, IIQ-7, and UDI-6 scores before and after treatment statistically significant, suggesting subjective improvement in symptoms At a median follow-up of 10 months, 34.8% were cured. 92% reported benefit and 77% were satisfied
Results
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Prospective
Prospective
Plotti et al. [30]
Tamanini et al. [31]
Yes
Yes
Yes
Yes
Yes
Yes
After the procedure
Before the procedure
Urodynamics
Cough test, voiding diary, physical examination, VAS
Physical examination, 3-day voiding diary, I-QOL, 1-h pad test, Stamey grade
Outcome measures
6, 12, 24, 60 months Physical examination, King’s Health Questionnaire, Stamey grade, pad usage, 1-h pad test
6, 12 months
1, 3, 6, 12 months
Follow-up
Not stated
Not stated
Not stated, however, allowed after 3 m if symptoms not improved
Repeat procedure
I-QOL Incontinence Quality-of-Life Questionnaire, IIQ-7 Incontinence Impact Questionnaire-7, UDI-6 Urogenital Distress Inventory-6, VAS visual analogue scale
21
24
Randomized 247 (122 controlled trial Macroplastique, 125 Contigen, 12 excluded
Ghoniem et al. [29]
No. of patients
Type
Reference
Table 2 (continued)
Subjective success rate 80%. At 60 months, pad usage reduced from a mean of 3.5/day to 0.9/day, and 1-h pad weight decreased from 53.8 to 5.9 g. Valsalva leak-point pressure testing demonstrated cure/improvement rate of 73.3%
At 12 months cure rate 42%, improvement rate 42%, failure rate 16%. Preoperative VAS values significantly lower at 12 months than postoperatively. Frequency of incontinence according to the 3-day voiding diary significantly reduced following treatment
Of all patients, 61.5% of those treated with Macroplastique and 48% of controls showed improvement of at least one Stamey grade at 12 months, demonstrating that Macroplastique is not inferior to Contigen. Average decreases in urine loss from baseline 25.4 ± 39.4 ml for Macroplastique, 22.8 ± 35.0 ml for Contigen
Results
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study did not show any significant changes in urodynamic parameters after treatment (peak flow 18.8 ± 3 ml/s vs. 19 ± 2 ml/s, flow time 21.6 ± 2.9 s vs. 19.3 s, postvoid residual volume 21.8 ± 10.1 ml vs. 20.8 ± 6.7 ml). However, maximum urethral closure pressure improved significantly from 22.2 ± 10.1 cm H2O to 30 ± 10.2 cm H2O, indicating restored continence [27]. In the study by Plotti et al. [30], 10 of 24 patients were cured of SUI and were negative on the cough test. In addition, there was a significant reduction in the number of incontinence episodes over 3 days after treatment (14.5 ± 5.8 to 4.3 ± 7.9). However, maximum urethral closure pressure improved significantly from 26.4 ± 23.5 cm H 2O to 36.3 ± 24.4 cm H2O after treatment, indicating restored continence. Finally, in the study by Tamanini et al. [31], patients showed objective improvement in terms of pad usage which decreased significantly from 3.5 per day to 0.9 per day, and 1-h pad weight which decreased significantly from 53.8 to 5.9 g. Valsalva leak point pressure also improved, indicating a 73.3% rate of cure/improvement. Safety of Bulkamid and Macroplastique We also evaluated the side effect profile of both UBAs. The most common adverse effect was urinary tract infection for both Bulkamid and Macroplastique (11% and 9%, respectively). Bulkamid caused more of each of the most commonly occurring adverse effects than Macroplastique, except for acute urinary retention (3% vs. 9%) and dysuria (1% vs 7%). It is difficult to compare the two agents with confidence given the difference in the total numbers of patients treated with Bulkamid (n = 777) and with Macroplastique (n = 351). The most common adverse effects associated with the two bulking agents are listed in Table 3.
Discussion Bulkamid and Macroplastique were designed to provide a less invasive treatment for SUI in women. However, their use has
Table 3 Most common adverse effects in 777 patients treated with Bulkamid and 651 patients treated with Macroplastique
Urinary tract infection Implantation site pain Acute urinary retention De novo urgency Dysuria Persistent urge urinary Incontinence Haematuria
been scrutinized and questions have been asked about their effectiveness and safety. Our findings showed that UBAs can relieve the symptoms in patients with SUI. However, the degree of symptom relief depends on whether subjective or objective measurements are used. Subjective success was often achieved much sooner than objective success. For example, in two of the studies, immediately after the procedure [17] and at 1 month [22] subjective success rates were 75% and 87%, respectively. This might be explained by the outcome measures used in the studies. The first used physical examination immediately after the procedure which does not take into account the patient’s own view of success and instead focuses on that of the examiner. Furthermore, the time at which outcome is measured may not be long enough for the true success rate to become apparent. As shown previously, the success rate, whether subjective or objective, deteriorates over time. The second study used questionnaires including ICIQ and QoL and VAS. It is important to remember that patients experiencing any improvement in symptoms will score lower on the questionnaires. However, subjective responses may be prone to error; for example, if two patients show the same reduction in the amount of urine leaked after the procedure, the patient leaking more urine before the procedure may report a lower degree of success using the questionnaire. When comparing interventions, subjective and objective methods can give different results. However, achieving the best possible outcome for the patient is only possible if treatment goals are discussed and subjective perceptions identified. Much variability was also noted in the results at about 12 months after the procedure. In addition to the outcome method used, as described above, there are a number of factors which may have been responsible for this. Firstly, patient demographics play an important role. One study [25] showed a subjective cure rate of 34% at a median follow-up of 10 months, but another study [26] showed a rate of 57%. This discrepancy might be explained by the fact that all of the patients included in the first of these studies [25] had previously had a failed midurethral sling procedure for SUI, which may indicate increased complexity of their condition. Secondly, given that the efficacy of UBA treatment does
Bulkamid, n (%)
Macroplastique, n (%)
85 (11) 76 (10) 27 (3) 18 (2) 5 (1) 8 (1) 9 (1)
33 (9) 6 (2) 32 (9) 11 (3) 24 (7) 7 (2) 9 (3)
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reduce over time, it is not unreasonable to imagine that individuals will require repeat therapy sooner or later than others. This may also be one of the factors accounting for the variability in success rate found at about 12 months.
infection being the most common adverse effect. This study further highlights the advantages and disadvantages of UBAs, but further randomized controlled trials directly comparing UBAs are required to indicate the most effective agent.
Strengths and limitations
Compliance with ethical standards
There are certain limitations in the quality of the evidence provided by the studies identified. With regard to the hierarchy of evidence, there were only three randomized controlled trials found, none of which directly compared Bulkamid and Macroplastique. Instead these randomized controlled trials used Contigen as the control, a UBA that is no longer available. Although we tried to compare outcomes at 12 months based on case series, raw data were not reported in all studies making comparisons difficult. As such, it is still unclear whether either bulking agent is superior to the other as a treatment for SUI. In addition, the aim of this systematic review was not to compare UBA with the current gold standard therapy for SUI, midurethral tape procedures. Finally, with regard to methodological variability, many of the studies reviewed reported subjective measures of success, whereas fewer reported objective findings, with fewer still reporting both.
Conflicts of interest None.
Implications for future research We believe that given the recent rise in interest in UBAs as a less invasive option for improving QoL and providing symptomatic relief in patients with SUI, future studies should directly compare the efficacy of popular UBAs on the market. Furthermore, study methodology should be changed to reflect the need to provide more objective measures of success. It would also be useful to divide patients into cohorts reflecting the severity of their condition, to help better gauge which patient group stands to gain the most from UBA therapy. Lastly, given the decline in efficacy of UBAs over time, follow-up periods should be longer to allow more accurate investigation of this issue.
Financial disclaimer None.
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Conclusion SUI is a common debilitating condition in women. Current standard treatment involves the surgical option of midurethral sling procedures. For those who cannot undergo such an invasive procedure or for those who want to avoid a synthetic mesh procedure and for whom there is acceptance that repeat treatments may be required, interest in the use of UBA has started to increase. Two of the more popular agents, Bulkamid and Macroplastique, have shown significant promise with studies showing statistically significant improvements in subjective QoL. However, improvements in objective measurements are not as well documented in the literature. We have shown that their safety profiles are similar, with urinary tract
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Martan A, Masata J, Svabík K, Krhut J. Transurethral injection of polyacrylamide hydrogel (Bulkamid®) for the treatment of female stress or mixed urinary incontinence. Eur J Obstet Gynecol Reprod Biol 2014;178:199–202. Mouritsen L, Lose G, Møller-Bek K. Long-term follow-up after urethral injection with polyacrylamide hydrogel for female stress incontinence. Acta Obstet Gynecol Scand. 2014;93(2):209–212. Krause HG, Lussy JP, Goh JT. Use of periurethral injections of polyacrylamide hydrogel for treating post-vesicovaginal fistula closure urinary stress incontinence. J Obstet Gynaecol Res. 2014;40(2):521–525. Leone Roberti Maggiore U, Alessandri F, Medica M, Gabelli M, Venturini PL, Ferrero S. Outpatient periurethral injections of polyacrylamide hydrogel for the treatment of female stress urinary incontinence: effectiveness and safety. Arch Gynecol Obstet. 2013;288(1):131–137. Mohr S, Siegenthaler M, Mueller MD, Kuhn A. Bulking agents: an analysis of 500 cases and review of the literature. Int Urogynecol J 2013;24(2):241–247. Leone Roberti Maggiore U, Alessandri F, Medica M, Gabelli M, Venturini PL, Ferrero S. Periurethral injection of polyacrylamide hydrogel for the treatment of stress urinary incontinence: the impact on female sexual function. J Sex Med. 2012;9(12):3255–3263. Trutnovsky G, Tamussino K, Greimel E, Bjelic-Radisic V. Quality of life after periurethral injection with polyacrylamide hydrogel for stress urinary incontinence. Int Urogynecol J. 2011;22(3):353–356. Lose G, Sørensen HC, Axelsen SM, Falconer C, Lobodasch K, Safwat T. An open multicenter study of polyacrylamide hydrogel (Bulkamid®) for female stress and mixed urinary incontinence. Int Urogynecol J. 2010;21(12):1471–1477. Lose G, Mouritsen L, Neilsen JB. A new bulking agent (polyacrylamide hydrogel) for treating stress urinary incontinence in women. BJU Int 104 100;98(1).
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Gumus II, Kaygusuz I, DerbentA, Simavli S, Kafali H. Effect of the Macroplastique Implantation System for stress urinary incontinence in women with or without a history of an anti-incontinence operation. Int Urogynecol J. 2011;22(6):743–749 25. Lee HN, Lee YS, Han JY, Jeong JY, Choo MS, Lee KS. Transurethral injection of bulking agent for treatment of failed mid-urethral sling procedures. Int Urogynecol J. 2010;21(12): 1479–1483. 26. Ghoniem G, Corcos J, Comiter C, Westney OL, Herschorn S. Durability of urethral bulking agent injection for female stress urinary incontinence: 2-year multicenter study results. J Urol. 2010;183(4):1444–1449. 27. Zullo MA, Ruggiero A, Montera R, Plotti F, Muzii L, Angioli R, et al. An ultra-miniinvasive treatment for stress urinary incontinence in complicated older patients. Maturitas. 2010;65(3):292– 295. 28. ter Meulen PH, Berghmans LCM, Nieman FHM, van Kerrebroeck PEVA. Effects of Macroplastique® Implantation System for stress urinary incontinence and urethral hypermobility in women. Int Urogynecol J 2009;20(2):177–183. 29. Ghoniem G, Corcos J, Comiter C, Bernhard P, Westney OL, Herschorn S. Cross-Linked Polydimethylsiloxane Injection for Female Stress Urinary Incontinence: Results of a Multicenter, Randomized, Controlled, Single-Blind Study. J Urol 2009;181(1): 204–210. 30. Plotti F, Zullo MA, Sansone M, Calcagno M, Bellati F, Angioli R, et al. Post radical hysterectomy urinary incontinence: a prospective study of transurethral bulking agents injection. Gynecol Oncol. 2009;112(1):90–94. 31. Tamanini JT, D’Ancona CA, Netto NR. Macroplastique implantation system for female stress urinary incontinence: long-term follow-up. J Endourol. 2006;20(12):1082–1086.
REVIEW ARTICLE
Intraurethral bulking agents for the management of female stress urinary incontinence: a systematic review Zain A. Siddiqui 1 & Hamid Abboudi 2
&
Ruairidh Crawford 2 & Shahzad Shah 2
Received: 3 December 2016 / Accepted: 16 January 2017 # The International Urogynecological Association 2017
Abstract Introduction and hypothesis The object of this review was to assess the efficacy and safety of urethral bulking agents (UBA), principally Macroplastique and Bulkamid, in the treatment of female stress urinary incontinence (SUI). Methods MEDLINE® and EMBASE® databases were systematically searched up to June 2016. Year of publication, study type, outcome measures, urodynamics before and after the procedure, number of participants, procedure complications, proportion requiring repeat injections or surgical procedures, frequency of follow-up, and results were analysed. Results The use of Bulkamid and Macroplastique for the treatment of female SUI was described in 26 studies. Studies used modalities including the visual analogue scale, Likert scale, International Consultation on Incontinence Modular Questionnaire (ICIQ), Patient Global Improvement Questionnaire (PGIQ) and Incontinence Impact Questionnaire (IIQ) and showed success rates ranging from 66% to 89.7% at 12 months follow-up. Objective improvements in patient symptoms were measured using urodynamics, 24-h pad tests, cough tests and voiding diaries. Studies showed variable objective success rates ranging from 25.4% to 73.3%. Objective findings for UBAs remain less well documented than those for the midurethral sling procedure. Conclusions There are a range of complications associated with UBAs, the most common being urinary tract infection.
* Hamid Abboudi [email protected]
1
Department of Urology, Birmingham City Hospital, Dudley Road, Birmingham B18 7QH, UK
2
Department of Urology, Watford General Hospital, Vicarage Road, Watford WD80 0HB, UK
However, it remains a very well tolerated procedure in the majority of patients. UBAs should be considered as an alternative in patients unsuitable for more invasive procedures and those willing to accept the need for repeat injections. The majority of the literature focuses on subjective improvement measures rather than objective improvement measures. Further randomized controlled trials directly comparing UBAs are required to indicate the most effective agent. Keywords Bulkamid . Incontinence . Macroplastique . Urethral bulking agent
Introduction Stress urinary incontinence (SUI) is a common socially debilitating condition predominantly affecting women with a prevalence of between 10% and 40% [1]. Managing and treating SUI comes at a significant cost to the UK’s National Health Service (NHS), estimated at approximately £353.6 million per annum [2]. Normal urinary continence relies on the functional coordination of the anatomy by the nervous system. The pelvic floor creates the support required by the bladder and urethra to sustain transmission of abdominal pressure to the proximal urethra, ultimately resulting in continence [3]. It has been hypothesized that reductions in the urethral closure pressure superimposed on the transmission of pressure from the abdomen to the urethra results in SUI [4]. Furthermore, recent findings have highlighted the role of midurethral support in the maintenance of continence [5]. Risk factors include advancing age, higher parity, vaginal delivery, obesity and postmenopausal status [6]. The current gold standard treatment of SUI is placement of a midurethral sling via either the retropubic or the transobturator route. These procedures aim to provide support at the midurethral level with the sling acting as a hammock preventing the urethra
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from dropping. Typically, a synthetic mesh is positioned posterior to the proximal urethra lifting the urethra up into a position where it can withstand increases in intraabdominal pressure so that continence is maintained [3]. The use of midurethral tapes has come under scrutiny recently in relation to mesh complications including infection, chronic pain and erosion. Midurethral tapes have been withdrawn from use in the NHS in Scotland pending further investigation, but not in the rest of the UK. These concerns have led to the focus being shifted to existing urethral bulking agents (UBAs) and their development for use in the treatment of SUI The American Urology Association has recommended the use of UBA in elderly patients, patients with an increased risk of anaesthetic complications, and patients reluctant to undergo a more invasive procedure [7]. In addition, the National Institute for Health and Clinical Excellence (NICE) [8] advises that UBAs be considered in patients with significantly decreased urethral mobility and patients who have a history of failed conservative treatment [8]. In 2011 glutaraldehyde-treated bovine collagen (Contigen) was withdrawn worldwide due to its tendency to be absorbed leading to recurrence of symptoms. This resulted in the need for new agents, most notably polydimethylsiloxane (Macroplastique) and polyacrylamide hydrogel (Bulkamid) [9, 10]. UBAs provide additional support when injected into the mid-urethra. Once implanted into the urethral submucosa they provide a cushion helping to increase urethral sphincter pressure thus improving continence [11]. This aim of this systematic review was to assess the efficacy and safety of UBAs alone, principally Macroplastique and Bulkamid. We compared the two UBAs to determine whether either is superior in the treatment of women with SUI.
June 2016) and EMBASE (2006 to June 2016) databases. The keywords used included: ‘bulking agent’, ‘bulkamid’, ‘macroplastique’ and ‘urinary stress incontinence’. In addition to studies obtained via the databases, further studies were acquired from the references cited in recent review articles. Study selection and data collection One reviewer (Z.S.) independently screened the abstracts of the studies identified in the database search to identify those that were potentially relevant. The full text of each potentially relevant paper was then independently reviewed by two authors (Z.S. and H.A.) to determine whether the paper included certain topics of interest such as bulking agents, human studies, SUI, and follow-up on safety and efficacy. Conflicts between reviewers were discussed until there was 100% agreement on the studies finally to be included. Data extraction and analysis From each study certain information was extracted and entered into a table for summary and analysis. Information extracted included: year of publication, type of study, outcome measures, urodynamics before and after the procedure, number of study participants, procedure complications, proportion of subjects requiring repeat injections or surgical procedures, frequency of follow-up, and results.
Results Study selection
Materials and methods This systematic review was conducted in accordance with the guidelines provided in the Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) statement (http://www.prisma-statement.org).
A total of 223 potentially relevant publications were identified from the literature search, but, following abstract review this was brought down to 53. Full text analysis led to the exclusion of a further 27 studies due to duplication, lack of relevance or lack of full text journal publication. Thus, a final count of 26 studies were included in the systematic review (Fig. 1).
Study eligibility criteria
Bulkamid
Studies outlining the use, efficacy and safety of UBAs in the treatment of female SUI as an alternative to more invasive traditional surgical procedures were included. Review articles, conference abstracts, letters, animal studies and studies involving the use of models were excluded.
An overview of the studies identified in which Bulkamid was used for the treatment of female SUI is presented in Table 1. The review showed that Bulkamid treatment improves patient quality of life (QoL) as shown in terms of subjective success measured using various methods including the visual analogue scale, Likert scale, International Consultation on Incontinence Modular Questionnaire (ICIQ), Patient Global Improvement Questionnaire (PGIQ and Incontinence Impact Questionnaire (IIQ). One study showed a high subjective success rate of 74.4% [18]. In another study with 25 subjects Bulkamid improved subjective symptoms in all patients
Information sources and search Using the NICE Healthcare Databases Advanced Search (https:// www.evidence.nhs.uk) a broad search of the English literature was conducted in June 2016 via the MEDLINE (2006 to
Int Urogynecol J Fig. 1 Study selection
Records idenfied through searching MEDLINE and EMBASE (n=243)
Addional records idenfied through other sources (n=5)
Records aer duplicates removed (n=223)
Records screened (n=223)
Records excluded aer abstract review (n=170)
Full-text arcles assessed for eligibility (n=53)
Full-text arcles excluded aer full-text review (n=27)
Studies included in final analysis (n=26)
except two who felt that the treatment had affected their social life [16]. In other studies subjective cure rates varied over time: at 1, 6, and 12 months the rates were 87%, 71%, and 66% respectively [22]. Finally, one study highlighted the variability in QoL following treatment with Bulkamid: QoL was found to be considerably improved in 40% of patients, slightly improved in 21%, unchanged in 29% and worsened in 10% [21]. Considering sexual function specifically, one study demonstrated an improvement following treatment with Bulkamid. In this study, 23 of 29 women treated continued to be sexually active and the subjective success rate was 89.7% at 12 months [20]. In the Bulkamid studies, objective success was measured using urodynamics, the 24-h pad test, the cough test and the number of incontinence episodes. In one study, full continence as defined by a negative cough test was achieved in 14 of 46 patients (30.4%) following treatment [12]. The same study showed a significant reduction in urine leakage, ranging from −61.5 ml to −197.5 ml as demonstrated by the pad test, but showed no significant changes in urodynamic parameters except for a reduction in voided volume [12]. Another study investigated the use of Bulkamid in 60 women who had previously had a failed midurethral sling procedure. In that study, 56.7% of the women had a negative cough test and 50% in 53 of 63 (79%) patients according to the 1-h pad test. In another study, the objective cure rate decreased from 55% at 6 months to 44% at 12 months. Voiding diaries showed that the number of incontinence episodes over 3 days decreased from 15.2 ± 6.6 to 7.9 ± 7.7 after treatment. However, the same
52
25
4
82
Martan et al. [15] Retrospective
Prospective
Prospective
Mouritsen et al. [16]
Krause et al. [17]
Leone Roberti Prospective Maggiore et al. [18] Yes
No
Yes
Yes
Yes
No
Yes
No
Yes
Yes 345 (229 Bulkamid, 116 Contigen)
Randomized controlled trial
Sokol et al. [14]
Yes
After the procedure
No
60
Prospective
Zivanovic et al. [13]
Yes
Before the procedure
Urodynamics
Yes
46
Prospective
Krhut et al. [12]
No. of patients
Type
24-h pad test, ICIQ, voiding diary, Likert scale
Cough test, ultrasonography1-h pad test, VAS
10% required repeat Bulkamid treatment
1, 3, 6, 12 months ICIQ, IIQ, patient global improvement questionnaire
5% offered repeat Bulkamid treatment
Not stated
King’s Health 8% required repeat Questionnaire, pelvic Bulkamid treatment. examination, USS, 28% required tape urine dipstick/MCS, procedure 48-h voiding diary, 24-h pad test Immediately after Physical examination the procedure
8 years
Results
Subjective success rate 74.4% at 1 year. ICIQ and IIQ scores significantly improved at 1 year. Frequency or leakage episodes/24 h significantly reduced at 1 year. No alteration in uroflowmetry at 1 year
75% cured/improved, 25% unchanged/worse. Results of the King’s Health Questionnaire similar to those reported 1 year after treatment. Only two women felt that their incontinence affected their social life Three of four women dry postoperatively and remained continent at discharge
Cough test negative in 19.6% (22 months). ICIQ dry rate 15.7% and dry/improved rate 45.1%. Mean VAS 51.3 ± 38.3. Likert scale cured or improved in 54.9%
30.4% achieved full continence. Significant reduction in 24-h pad weight and questionnaire scores. No significant changes in urodynamics except voided volume Not stated Cured/improved rates 93.3% (56/60), 88.3% (53/60), and 83.6% (46/55) at 1, 6, and 12 months Not stated; however, >50% decrease at 12 months in offered repeat leakage/incontinence episodes in injections (up to two) 53.2% (Bulkamid). 12-month if not dry after zero stress incontinence rates bulking agent 47.2% (Bulkamid). 12-month cured/improved rate 77.1% (Bulkamid)
Repeat procedure
ICIQ, patient perception Not stated of bladder condition questionnaire, 3-day voiding diary, 24-h pad test, cough test
Outcome measures
Average ICIQ, VAS, cough test, 22 months Likert scale (min 6 months, max 50 months)
1, 3, 6, 9, 12 months
1, 6, 12 months
3, 12, 24 months
Follow-up
Overview of studies in which Bulkamid was used in the treatment of female stress urinary incontinence
Reference
Table 1
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29
54
Leone Roberti Prospective Maggiore et al. [20]
Prospective
Prospective
Prospective
Trutnovsky et al. [21]
Lose et al. [22]
Lose et al. [23]
Yes
Yes
No
Yes
Yes
Before the procedure
Urodynamics
Yes
Yes
No
Yes
Yes
After the procedure
1, 3, 12 months
1, 6, 12 months
9 months
12 months
12 months
Follow-up
Results
35% required repeat Bulkamid treatment
26% required repeat Bulkamid treatment
31% required repeat Bulkamid treatment
38% subjectively dry and a further 43% improved. Urine leakage/24 h decreased by 93% and number of incontinence episodes by 87%. Quality of life measures improved significantly in all domains other than general health perception. No significant changes in urodynamic variables
Subjective success rate 89.7% and objective success 79.3% at 1 year. Mean number of incontinence episodes/24 h at 1 year significantly lower than at baseline. Mean (±SD) urine leakage/24 h significantly lower at 1-year (7.9 ± 8.0 g) than at baseline Considerable improvement (40%), slight improvement (21%), no change (29%), worsening (10%) Subjective response rates (cured/improved) after 1, 6 and 12 months 87%, 71% and 66%, respectively. Median incontinence episodes and urine leakage reduced significantly from baseline
Pad test negative in 73.2% after Not stated; however, treatment. Subjective offered repeat improvement in general health injections at 6 weeks and role limitations if procedure failed
Repeat procedure
Physical examination, 65% required repeat urine dipstick, 48-h Bulkamid treatment voiding diary, 24-h pad test, King’s Health Questionnaire
Pelvic examination, 24-h pad test, 3-day voiding diary, ICIQ, VAS
IOQ
King’s health Questionnaire, VAS, 2-h pad test, urethral pressure profile Pelvic examination, cough test, 3-day voiding diary, 24-h pad test, ICIQ, IIQ, VAS
Outcome measures
ICIQ International Consultation on Incontinence Modular Questionnaire, IIQ Incontinence Impact Questionnaire, IOQ Incontinence Outcome Questionnaire, MCS microscopy, culture and sensitivity, USS urgency severity scale, VAS visual analogue scale. Stamey grade is a way of grading the severity of stress incontinence: Grade 1: leakage of urine with sudden rises in intrabdominal pressure e.g. sneezing Grade 2: leakage of urine with lesser degrees of stress e.g. walking Grade 3: leakage of urine unrelated to activity or position e.g. lying at rest.
17
135
514
Prospective
Mohr et al. [19]
No. of patients
Type
Reference
Table 1 (continued)
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Prospective
Prospective
Ghoniem et al. [26]
Zullo et al. [27]
ter Meulen et Randomized 47 (24 Macroplastique al. [28] controlled trial (2 withdrew) and 21 pelvic floor exercises)
27
75
23
Retrospective
Lee et al. [25]
No. of patients
35
Type
Yes
Yes
Yes
Yes
Yes
No
After the procedure
Yes
Yes
Yes
Yes
Before the procedure
Urodynamics
3, 12 months
6 m, 12 months
12, 24 months
6–34 months
6 weeks, 12–62 months
Follow-up
Repeat procedure
Urinalysis, I-QOL, 11% required repeat Stamey grade, Macroplastique frequency/volume treatment chart, 1-h pad test, physical examination
VAS, 3-day voiding Not stated diary, cough test, physical examination
Sandvik questionnaire, 9% required repeat Macroplastique VAS, I-QOL, benefit, treatment and 13% satisfaction and had a further tape willingness to procedure continue questionnaire Stamey grade, pad test, 44% required repeat I-QOL, voiding diary Macroplastique treatment
Not stated Pelvic examination, 24-h pad test, 3-day voiding diary, I-QOL, IIQ-7, UDI-6
Outcome measures
Overview of studies in which Macroplastique was used in the treatment of female stress urinary incontinence
Gumus et al. Prospective [24]
Reference
Table 2
No significant difference in pad weight at 3 months between treatment arms. Number of pads used at 3 months in the Macroplastique group decreased significantly compared to control group. Number of women “cured” or “markedly improved” at 3 months significantly higher than that in the control group (70.8% vs. 28.5%)
At 6 months 55% patients were cured and 15% reported no improvement. At 12 months objective cure rate 44%, improvement rate 33% and failure rate 22%. No statistically significant difference between 6 and 12 months
At 12 and 24 months 57% and 67% respectively, were dry (Stamey grade 0). Compared to baseline 85% considered themselves dry or markedly improved on the Patient Global Impression of Improvement, 8% considered themselves slightly improved and 8% were unchanged. 79% improved from baseline with at least 50% decrease in urine loss
Differences between median I-QOL, IIQ-7, and UDI-6 scores before and after treatment statistically significant, suggesting subjective improvement in symptoms At a median follow-up of 10 months, 34.8% were cured. 92% reported benefit and 77% were satisfied
Results
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Prospective
Prospective
Plotti et al. [30]
Tamanini et al. [31]
Yes
Yes
Yes
Yes
Yes
Yes
After the procedure
Before the procedure
Urodynamics
Cough test, voiding diary, physical examination, VAS
Physical examination, 3-day voiding diary, I-QOL, 1-h pad test, Stamey grade
Outcome measures
6, 12, 24, 60 months Physical examination, King’s Health Questionnaire, Stamey grade, pad usage, 1-h pad test
6, 12 months
1, 3, 6, 12 months
Follow-up
Not stated
Not stated
Not stated, however, allowed after 3 m if symptoms not improved
Repeat procedure
I-QOL Incontinence Quality-of-Life Questionnaire, IIQ-7 Incontinence Impact Questionnaire-7, UDI-6 Urogenital Distress Inventory-6, VAS visual analogue scale
21
24
Randomized 247 (122 controlled trial Macroplastique, 125 Contigen, 12 excluded
Ghoniem et al. [29]
No. of patients
Type
Reference
Table 2 (continued)
Subjective success rate 80%. At 60 months, pad usage reduced from a mean of 3.5/day to 0.9/day, and 1-h pad weight decreased from 53.8 to 5.9 g. Valsalva leak-point pressure testing demonstrated cure/improvement rate of 73.3%
At 12 months cure rate 42%, improvement rate 42%, failure rate 16%. Preoperative VAS values significantly lower at 12 months than postoperatively. Frequency of incontinence according to the 3-day voiding diary significantly reduced following treatment
Of all patients, 61.5% of those treated with Macroplastique and 48% of controls showed improvement of at least one Stamey grade at 12 months, demonstrating that Macroplastique is not inferior to Contigen. Average decreases in urine loss from baseline 25.4 ± 39.4 ml for Macroplastique, 22.8 ± 35.0 ml for Contigen
Results
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study did not show any significant changes in urodynamic parameters after treatment (peak flow 18.8 ± 3 ml/s vs. 19 ± 2 ml/s, flow time 21.6 ± 2.9 s vs. 19.3 s, postvoid residual volume 21.8 ± 10.1 ml vs. 20.8 ± 6.7 ml). However, maximum urethral closure pressure improved significantly from 22.2 ± 10.1 cm H2O to 30 ± 10.2 cm H2O, indicating restored continence [27]. In the study by Plotti et al. [30], 10 of 24 patients were cured of SUI and were negative on the cough test. In addition, there was a significant reduction in the number of incontinence episodes over 3 days after treatment (14.5 ± 5.8 to 4.3 ± 7.9). However, maximum urethral closure pressure improved significantly from 26.4 ± 23.5 cm H 2O to 36.3 ± 24.4 cm H2O after treatment, indicating restored continence. Finally, in the study by Tamanini et al. [31], patients showed objective improvement in terms of pad usage which decreased significantly from 3.5 per day to 0.9 per day, and 1-h pad weight which decreased significantly from 53.8 to 5.9 g. Valsalva leak point pressure also improved, indicating a 73.3% rate of cure/improvement. Safety of Bulkamid and Macroplastique We also evaluated the side effect profile of both UBAs. The most common adverse effect was urinary tract infection for both Bulkamid and Macroplastique (11% and 9%, respectively). Bulkamid caused more of each of the most commonly occurring adverse effects than Macroplastique, except for acute urinary retention (3% vs. 9%) and dysuria (1% vs 7%). It is difficult to compare the two agents with confidence given the difference in the total numbers of patients treated with Bulkamid (n = 777) and with Macroplastique (n = 351). The most common adverse effects associated with the two bulking agents are listed in Table 3.
Discussion Bulkamid and Macroplastique were designed to provide a less invasive treatment for SUI in women. However, their use has
Table 3 Most common adverse effects in 777 patients treated with Bulkamid and 651 patients treated with Macroplastique
Urinary tract infection Implantation site pain Acute urinary retention De novo urgency Dysuria Persistent urge urinary Incontinence Haematuria
been scrutinized and questions have been asked about their effectiveness and safety. Our findings showed that UBAs can relieve the symptoms in patients with SUI. However, the degree of symptom relief depends on whether subjective or objective measurements are used. Subjective success was often achieved much sooner than objective success. For example, in two of the studies, immediately after the procedure [17] and at 1 month [22] subjective success rates were 75% and 87%, respectively. This might be explained by the outcome measures used in the studies. The first used physical examination immediately after the procedure which does not take into account the patient’s own view of success and instead focuses on that of the examiner. Furthermore, the time at which outcome is measured may not be long enough for the true success rate to become apparent. As shown previously, the success rate, whether subjective or objective, deteriorates over time. The second study used questionnaires including ICIQ and QoL and VAS. It is important to remember that patients experiencing any improvement in symptoms will score lower on the questionnaires. However, subjective responses may be prone to error; for example, if two patients show the same reduction in the amount of urine leaked after the procedure, the patient leaking more urine before the procedure may report a lower degree of success using the questionnaire. When comparing interventions, subjective and objective methods can give different results. However, achieving the best possible outcome for the patient is only possible if treatment goals are discussed and subjective perceptions identified. Much variability was also noted in the results at about 12 months after the procedure. In addition to the outcome method used, as described above, there are a number of factors which may have been responsible for this. Firstly, patient demographics play an important role. One study [25] showed a subjective cure rate of 34% at a median follow-up of 10 months, but another study [26] showed a rate of 57%. This discrepancy might be explained by the fact that all of the patients included in the first of these studies [25] had previously had a failed midurethral sling procedure for SUI, which may indicate increased complexity of their condition. Secondly, given that the efficacy of UBA treatment does
Bulkamid, n (%)
Macroplastique, n (%)
85 (11) 76 (10) 27 (3) 18 (2) 5 (1) 8 (1) 9 (1)
33 (9) 6 (2) 32 (9) 11 (3) 24 (7) 7 (2) 9 (3)
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reduce over time, it is not unreasonable to imagine that individuals will require repeat therapy sooner or later than others. This may also be one of the factors accounting for the variability in success rate found at about 12 months.
infection being the most common adverse effect. This study further highlights the advantages and disadvantages of UBAs, but further randomized controlled trials directly comparing UBAs are required to indicate the most effective agent.
Strengths and limitations
Compliance with ethical standards
There are certain limitations in the quality of the evidence provided by the studies identified. With regard to the hierarchy of evidence, there were only three randomized controlled trials found, none of which directly compared Bulkamid and Macroplastique. Instead these randomized controlled trials used Contigen as the control, a UBA that is no longer available. Although we tried to compare outcomes at 12 months based on case series, raw data were not reported in all studies making comparisons difficult. As such, it is still unclear whether either bulking agent is superior to the other as a treatment for SUI. In addition, the aim of this systematic review was not to compare UBA with the current gold standard therapy for SUI, midurethral tape procedures. Finally, with regard to methodological variability, many of the studies reviewed reported subjective measures of success, whereas fewer reported objective findings, with fewer still reporting both.
Conflicts of interest None.
Implications for future research We believe that given the recent rise in interest in UBAs as a less invasive option for improving QoL and providing symptomatic relief in patients with SUI, future studies should directly compare the efficacy of popular UBAs on the market. Furthermore, study methodology should be changed to reflect the need to provide more objective measures of success. It would also be useful to divide patients into cohorts reflecting the severity of their condition, to help better gauge which patient group stands to gain the most from UBA therapy. Lastly, given the decline in efficacy of UBAs over time, follow-up periods should be longer to allow more accurate investigation of this issue.
Financial disclaimer None.
References 1.
2.
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4.
5.
6.
7.
8.
9.
10.
Conclusion SUI is a common debilitating condition in women. Current standard treatment involves the surgical option of midurethral sling procedures. For those who cannot undergo such an invasive procedure or for those who want to avoid a synthetic mesh procedure and for whom there is acceptance that repeat treatments may be required, interest in the use of UBA has started to increase. Two of the more popular agents, Bulkamid and Macroplastique, have shown significant promise with studies showing statistically significant improvements in subjective QoL. However, improvements in objective measurements are not as well documented in the literature. We have shown that their safety profiles are similar, with urinary tract
11. 12.
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