Periurethral Bulking Agents for the Treatment of Urinary Incontinence
Chapter: Medicine: Treatments
© Blue Cross and Blue Shield of Montana
Current Effective Date: 03/16/2011
Original Effective Date: 03/16/2011
Revised Dates: [RevisedDates]
Periurethral bulking agents are substances that are injected periurethrally to increase tissue bulk as a treatment of stress incontinence. Patients receive one or several treatment sessions. A number of products have been developed and are commercially available; key factors in determining the optimal product are biocompatibility, durability, and absence of migration.
Improvement in stress incontinence with bulking agents is achieved by increasing the tissue bulk and thereby increasing resistance to the outflow of urine. The bulking agent is injected into the periurethral tissue as a liquid that then solidifies into a spongy material to bulk the urethral wall. Bulking agents may be injected over a course of several treatments until the desired effect is achieved. Periurethral bulking agents have been widely used for incontinence in women. Men have also been treated, typically those with post-prostatectomy incontinence. Except for Contigen®, however, bulking agents are indicated by the U.S. Food and Drug Administration (FDA) for use only in women, specifically those with stress urinary incontinence due to intrinsic sphincter deficiency.
Biocompatibility, durability, and absence of migration are key factors in the success of bulking agents. Cross-linked collagen (e.g., Contigen) has been commercially available for many years. Collagen is slowly absorbed over time and symptoms may recur, requiring additional injections. Carbon-coated beads (e.g., Durasphere) and ethylene vinyl alcohol copolymer implants (e.g., Uryx®, marketed under the trade name Tegress® starting in 2005) received approval (1999 and 2004, respectively) from the FDA for use as periurethral bulking agents. Both were thought to be more durable than collagen. Tegress was later voluntarily removed from the market due to safety concerns.
In 2005, a bulking agent composed of spherical particles of calcium hydroxylapatite (CaHA) in a gel carrier (Coaptite®) received FDA approval for use in women. Polydimethylsiloxane (silicone, Macroplastique®) received FDA approval in 2006 “for transurethral injection in the treatment of adult women diagnosed with stress urinary incontinence (SUI) primarily due to intrinsic sphincter deficiency.” The FDA approvals are conditional on the enrollment of a minimum of 200–250 patients into a 5-year registry to further evaluate safety and efficacy.
Q-Med has been collecting data in Europe for a dextranomer/hyalyuronic (Dx/HA) copolymer (Zuidex™) together with an injection system (Implacer™) for treatment of incontinence. A Dx/HA formulation (Deflux™) from the same company has been commercially available for a number of years for the treatment of vesicoureteral reflux in children. About 30,000 children with vesicoureteral reflux have been treated with Dx/HA with no emergent safety concerns. (1)
Autologous fat and autologous ear chondrocytes have also been used as periurethral bulking agents; autologous substances do not require FDA approval. Polytetrafluoroethylene (Teflon®) has been investigated as an implant material but has not received FDA approval.
A more recently explored alternative is cellular therapy with myoblasts, fibroblasts, or stem cells (muscle-derived or adipose-derived). In addition to their use as periurethral bulking agents, it is hoped that transplanted stem cells will undergo self-renewal and multipotent differentiation, which could result in regeneration of the sphincter and its neural connections.
Several periuretheral bulking agents have been approved by the FDA through the premarket approval process. These devices are indicated for the treatment of stress urinary incontinence due to intrinsic sphincter deficiency; other than Contigen, approval is only for use in adult women. Products include:
• In 1993, Contigen (Allergan, Inc.), a cross-linked collagen, was approved. A supplemental approval in 2009 limited the device’s indication to treatment of urinary incontinence due to intrinsic sphincter deficiency in patients (men or women) who have shown no improvement in incontinence for at least 12 months.
• In 1999, Durasphere (Advanced UroScience), pyrolytic carbon-coated zirconium oxide spheres, was approved.
• In 2004, Uryx (CR Bard), vinyl alcohol copolymer implants, was approved. In 2005, approval was given to market the device under the trade name Tegress. In 2007, Tegress was voluntarily removed from the market due to safety concerns.
• In 2005, Coaptite (BioForm Medical, Inc.), spherical particles of calcium hydroxylapatite, suspended in a gel carrier, was approved for soft tissue augmentation in the treatment of stress urinary incontinence due to intrinsic sphincter deficiency in adult females.
• In 2006, Macroplastique (Uroplasty), polydimethylsiloxane, was approved.
Prior authorization is recommended. To authorize, call Blue Cross and Blue Shield of Montana (BCBSMT) Customer Service at 1-800-447-7828 or fax your request to the Medical Review Department at 406-437-7863. A retrospective review is performed if services are not prior authorized.
BCBSMT considers the use of cross-linked collagen, carbon-coated spheres, calcium hydroxylapatite, or polydimethylsiloxane medically necessary to treat stress urinary incontinence in men and women who have failed appropriate conservative therapy. See Policy Guidelines.
Not Medically Necessary
BCBSMT considers the use of cross-linked collagen, carbon-coated spheres, calcium hydroxylapatite, or polydimethylsiloxane not medically necessary to treat stress urinary incontinence in men and women who have not tried or had an adequate response to appropriate conservative therapy.
Advanced Member Notice of Financial Liability for Denied Services
When the criteria for coverage is not met, BCBSMT encourages all participating providers to have a member complete and sign an Advanced Member Notification (AMN) form stating that BCBSMT will not cover this service, supply, device, or drug. If an AMN is signed prior to delivery of the service, participating providers can balance bill the patient. If an AMN is not signed, participating providers are financially liable and cannot balance bill the BCBSMT member for denied services. Services provided by an out-of-state provider that are denied as not medically necessary are the financial responsibility of the patient even if an AMN is signed.
Refer to the Advanced Member Notification medical policy for more information. The AMN form is available at www.bcbsmt.com (Click on Providers and then Forms).
Patients should have had inadequate response to conservative therapy or therapies; in general, these treatments should have been used for at least 3 months. Conservative therapy for stress incontinence includes pelvic floor muscle exercises and behavioral changes, such as fluid management and moderation of physical activities that provoke incontinence. Additional options include intravaginal estrogen therapy, use of a pessary, and treatment of other underlying causes of incontinence in patients amenable to these treatments.
BCBSMT considers use of the following investigational:
• Autologous cellular therapy (e.g., myoblasts, fibroblasts, muscle-derived stem cells, or adipose-derived stem cells), autologous fat, and autologous ear chondrocytes to treat stress urinary incontinence
• Any other periurethral bulking agent, including, but not limited to Teflon®, to treat stress urinary incontinence
• Periuretheral bulking agents to treat urge urinary incontinence
Federal mandate prohibits denial of any drug, device or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP). In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone.
An initial literature search was performed in 1995. The policy was updated regularly with a literature review using MEDLINE; most recently, the literature was searched from August 2009 through August 2010. Following is a summary of literature to date on use of periurethral bulking agents to treat urinary incontinence.
A 2007 Cochrane review on periurethral bulking agents for urinary incontinence in women identified 12 trials that included bulking agents in at least one of the study arms. (2) The studies varied in their patient eligibility criteria. Several of the studies required that women had experienced incontinence for a specified period of time e.g., 6 or 12 months and/or had already used conservative therapy; one study further specified that conservative therapy had to have been used for at least 3 months. Data from the trials were not suitable for pooling. The authors concluded that the generally small size and moderate quality of the studies reviewed provided an unsatisfactory basis for practice, but “pending further evidence, injection therapy may represent a useful option for short-term symptomatic relief among selected women with co-morbidity that precludes anesthesia—two or three injections are likely to be required to achieve a satisfactory result.” Another systematic review of various non-surgical treatments concluded (on the basis of only 4 randomized trials) that the results of injectable bulking agents were inconsistent. (2)
Bulking Agents Approved by the U.S. Food and Drug Administration (FDA)
Cross-linked collagen (Contigen®)
Contigen® was the first bulking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of urinary incontinence. No randomized trials comparing Contigen to conservative therapy or placebo were identified. The 1996 Clinical Practice Guidelines for Urinary Continence in Adults, developed by the Agency for Health Care Policy and Research (AHCPR, now Agency for Healthcare Research and Quality), concluded that periurethral collagen is curative in 32% of men and 62% of women. (3) A randomized clinical trial published in 2005 compared the efficacy of collagen injections with surgery in 133 women. (4) Eligibility criteria included stress incontinence for at least 6 months, or one year after delivery. Twelve-month success rates for collagen treatment were lower than for surgery (53% vs. 72%). Also, there were also significantly fewer adverse events in the collagen-treated group (36% vs. 63%). Results from this study support informed decision making in the choice between bulking agents and surgical intervention for stress urinary incontinence.
Carbon-coated beads (e.g. Durasphere™)
A double-blind randomized study comparing carbon-coated beads to cross-linked collagen was reported as part of the FDA-approval process for Durasphere™. (5, 6) The study found no difference in efficacy or in the number of treatments between the groups, although the trial length of 12 months may not have been long enough to assess comparative durability.
Ethylene vinyl alcohol copolymer (EVA, e.g., Uryx™ marketed as Tegress™)
The copolymer implant (Uryx™/ Tegress™) received FDA approval based on a study that randomized 237 women with stress urinary incontinence to undergo periurethral bulking with Uryx or to a “currently marketed absorbable bulking agent.” (7) The effectiveness at 12 months was similar in the 2 groups, with 18.4% of those receiving Uryx reporting that they were dry and 48.7% reporting improvement by 1 grade, compared to 16.5% and 53.2% in the control group. A repeat injection was necessary in 75% of these patients to achieve satisfactory results. Following reports of adverse effects (8), Tegress was voluntarily withdrawn from the market by CR Bard as of January 31, 2007.
Calcium hydroxylapatite, CAHA (Coaptite®)
Coaptite® (CaHA) received FDA approval based partly on results from a single-blind randomized non-inferiority comparison with collagen among women with stress urinary incontinence. (9) This study was later published and reported on findings from 231 (78%) of 296 enrolled women. For the primary outcome measure, 83 (63%) patients treated with calcium hydroxylapatite and 57 (57%) control patients treated with collagen showed an improvement of one grade or more on the four-grade Stamey Urinary Incontinence Scale at 12-month follow-up. Similar results were obtained by intent-to-treat analysis, with non-inferiority of calcium hydroxylapatite to collagen for improvement of at least one Stamey Grade (58% vs. 51%, respectively) and decrease in pad weight (51% vs. 38%) of 50% or more.
Polydimethylsiloxane (silicone, Macroplastique®)
FDA approval of Macroplastique® (polydimethylsiloxane) was also partly based on a randomized non-inferiority comparison with collagen in women with stress urinary incontinence. Results of this trial were published in 2009. (10) The trial was single-blind; patients, but not providers, were blinded. At 12 months, Macroplastique was found to be non-inferior to collagen in terms of the primary efficacy variable, improvement in the Stamey incontinence grade. Seventy-five of the 122 patients (61.2%) in the Macroplastique group and 60 of 125 patients (48%) in the collagen group improved at least one Stamey grade (p<0.001 for non-inferiority). Twelve of the 247 randomized patients were excluded from the analysis.
Two-year data on 67 of the 75 women who responded to treatment with Macroplastique were published in 2010. (11) Fifty-six of the 67 (84%) patients had sustained treatment success at 24 months, defined as an improvement of at least one Stamey grade compared to baseline. Forty-five of the 67 (67%) patients evaluated at 24 months were dry (Stamey grade 0). The long-term analysis is limited because it only included a portion of responders from one arm of the trial. The analysis included 67 of 122 (55%) patients originally randomized to receive Macroplastique and did not provide data on the patients in the comparison group.
Dextranomer/hyalyuronic (DxHA, Zuidex™) with an injection system (Implacer™)
The Zuidex-Implacer is a system to inject Dx/HA in the outpatient clinic without the need for endoscopy.
An industry-sponsored (Q-Med) randomized non-inferiority trial comparing the Zuidex/Implacer system to Contigen conducted in North America was published in 2009. (12) Patients were blinded to treatment group. The primary study outcome was the proportion of women who had >50% reduction in urinary leakage on provocation testing from baseline to 12 months after the final treatment (up to three treatments were permitted). The primary outcome was achieved by 65% of Zuidex-treated women compared to 84% in the Contigen group; non-inferiority of Zuidex was not established. The study is limited by a high rate of missing data; primary outcome data were missing for 35% of randomized patients.
An open multicenter study from Europe reported a 12-month 77% positive response rate (reduction ≥50% for provocation test urinary leakage) with the Dx/HA Zuidex-Implacer system in 142 women who met strict inclusion/exclusion criteria. (13) Similar to the North American trial, this study had a high dropout rate (24%), as well as an unrepresentative patient population, and lack of a comparison group. Twenty-one women recruited as part of this study were followed for a mean of 6.7 years after treatment with the Zuidex-Implacer system. (14) At this long-term follow-up, 7 of 21 (33%) were continent of urine, but 6 of the 7 had undergone other continence procedures since their Zuidex injections.
Polyacrylamide hydrogel (Bulkamid®)
Bulkamid is a gel containing 2.5% cross-linked polyacrylamide and 97.5% apyrogenic water. Findings from a multicenter European case series were published in 2010. (15) A total of 135 adult women with symptomatic stress (n=67) or mixed (n=68) incontinence for at least 12 months and at least 1 episode of incontinence per day were included. Ninety-eight (73%) completed the 12-month follow-up; four additional patients were excluded from the per-protocol analysis due to protocol violations. The primary outcome was response to treatment, defined as patients self-reporting that they considered themselves “improved” or “cured”. The response rate at 6 and 12 months was 71% and 66%, respectively. Corresponding cure rates were 16% and 24%. The study lacked a comparison group with which to compare these outcomes; a comparison group is particularly important with a subjective outcome such as the one used in the study. There were 32 treatment-related adverse effects including 2 cases of urinary retention requiring hospitalization and 10 cases of urinary tract infection (UTI).
No published clinical trials were identified.
Products That Do Not Require FDA Approval
Autologous fat and autologous ear chondrocytes
These are other materials that have been used as bulking agents but have not demonstrated sustained effectiveness comparable to cross-linked collagen or carbon-coated beads. In a randomized, double-blind clinical trial of 56 female patients comparing periurethral injections of autologous fat (treatment group) to saline (placebo group), Lee and colleagues found that periurethral fat injections did not appear to be more efficacious than placebo for treating stress incontinence. (16) At 3 months, only 6 of 27 patients (22.2%) in the treatment group and 6 of 29 (20.7%) in the placebo group were cured or improved. In addition, 1 death occurred as a result of a pulmonary fat embolism. In another clinical trial of 32 female patients, Bent and colleagues reported that 50% of patients remained dry for 12 months after receiving a single outpatient injection of harvested autologous auricular cartilage. (17) While autologous substances have a non-immunogenic advantage, their use may be limited by resorption and fibrous replacement along with local discomfort associated with harvesting procedures.
Autologous cellular therapy
In 2007, Strasser et al published the first randomized study on autologous cell therapy for treating stress urinary incontinence. (18) This study has been widely cited as an important advance in the field. However, in September 2008, the Lancet published a statement that they were retracting publication of this study due to ethical and quality concerns. (19) The Lancet retraction states “…in our view, the conclusions of this official investigation pinpoint so many irregularities in the conduct of their (Strasser et al) work that, taken together, the paper should be retracted from the public record.” Because of this retraction, findings from this study will no longer be cited as evidence in this policy.
There is a lack of large high-quality randomized controlled trials evaluating perurethral bulking agents for the treatment of urinary incontinence compared to placebo, conservative treatment, or one another. Existing evidence, although of moderate quality, suggests that the efficacy of carbon-coated spheres, calcium hydroxylapatite, and polydimethylsiloxane for treating incontinence may be similar to cross-linked collagen, an established treatment, and they may be considered medically necessary for patients who have failed appropriate conservative therapy. There is insufficient published evidence on the efficacy of autologous cellular therapy, autologous fat, autologous ear chondrocytes, and other treatments such as Teflon; thus, these are considered investigational.
Technology Assessments, Guidelines and Position Statements
In 2005, the American College of Obstetricians and Gynecologists (ACOG) issued a practice bulletin on urinary incontinence in women. (20) The practice bulletin included a recommendation for injection of bulking agents (i.e., collagen, carbon-coated beads and fat) as second-line therapy or in women with urinary incontinence who are ineligible for surgery. This recommendation was based on limited or inconsistent scientific evidence.
Medicare National Coverage
The Medicare National Coverage Determination for Incontinence Control Devices (230.10) addresses collagen implants but not other types of bulking agents. (20) Specific information on coverage of collagen implants is, as follows:
“Coverage of a collagen implant, and the procedure to inject it, is limited to the following types of patients with stress urinary incontinence due to ISD:
• Male or female patients with congenital sphincter weakness secondary to conditions such as myelomeningocele or epispadias;
• Male or female patients with acquired sphincter weakness secondary to spinal cord lesions;
• Male patients following trauma, including prostatectomy and/or radiation; and
• Female patients without urethral hypermobility and with abdominal leak point pressures of 100 cm H2O or less.
Patients whose incontinence does not improve with 5 injection procedures (5 separate treatment sessions) are considered treatment failures, and no further treatment of urinary incontinence by collagen implant is covered. Patients who have a reoccurrence of incontinence following successful treatment with collagen implants in the past (e.g., 6-12 months previously) may benefit from additional treatment sessions. Coverage of additional sessions may be allowed but must be supported by medical justification.”
Rationale for Benefit Administration
This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.
The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. Blue Cross and Blue Shield of Montana recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.
When using this policy to determine whether a service, supply, drug or device will be covered, please note that member contract language will take precedence over medical policy when there is a conflict.
There are HCPCS codes for the bulking agents used in this procedure. L8603 describes collagen implant material, such as Contigen, and L8606 describes synthetic bulking agents, such as carbon-coated beads or copolymers (Durasphere or Uryx). The physician services associated with urethral bulking agents are described by CPT code 51715.
51715 ENDOSCOPIC INJECTION/IMPLANT
L8603 INJECTABLE BULKING AGENT, COLLAGEN IMPLANT, URINARY TRACT, 2.5 ML SYRINGE, INCLUDES SHIPPING AND NECESSARY SUPPLIES
L8606 INJECTABLE BULKING AGENT, SYNTHETIC IMPLANT, URINARY TRACT, 1 ML SYRINGE, INLCUDES SHIPPING AND NECESSARY SUPPLIES
Q3031 COLLAGEN SKIN TEST
1.Keegan PE, Atiemo K, Cody J et al. Periurethral injection therapy for urinary incontinence in women. Cochrane Database Syst Rev 2007; (3):CD003881.
2.Shamliyan TA, Kane RL, Wyman J et al. Systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women. Ann Intern Med 2008; 148(6):459-73.
3.Agency for Health Care Policy and Research. Clinical Practice Guideline. Urinary Incontinence in Adults. Department of Health and Human Services, Rockville, Md., 1996.
4.Corcos J, Collet JP, Shapiro S et al. Multicenter randomized clinical trial comparing surgery and collagen injections for treatment of female stress urinary incontinence. Urology 2005; 65(5):898-904.
5.Durasphere package insert, Advanced UroSciences, St. Paul, Minn.
6.Lightner D, Calvosa C, Andersen R et al. A new injectable bulking agent for treatment of stress urinary incontinence: results of a multicenter, randomized, controlled, double-blind study of Durasphere. Urology 2001; 58(1):12-5.
7.URYX. FDA Summary of Safety and Effectiveness. http://www.fda.gov/cdrh/PDF3/p030030b.pdf.
8.Hurtado E, McCrery R, Appell R. The safety and efficacy of ethylene vinyl alcohol copolymer as an intra-urethral bulking agent in women with intrinsic urethral deficiency. Int Urogynecol J Pelvic Floor Dysfunct 2007; 18(8):869-73.
9.Mayer RD, Dmochowski RR, Appell RA et al. Multicenter prospective randomized 52-week trial of calcium hydroxylapatite versus bovine dermal collagen for treatment of stress urinary incontinence. Urology 2007; 69(5):876-80.
10.Ghoniem G, Corcos J, Comiter C et al. Cross-linked polydimethylsiloxane injection for female stress incontinence: results from a multicenter, randomized, controlled single-blind study. J Urol 2009; 181(1): 204-10.
11.Ghoniem G, Corcos J, Comiter C et al. Durability of urethral bulking agent injection for female stress urinary incontinence: 2-year multicenter study results. J Urol 2010; 183(4):1444-9.
12. Lightner D, Rovner E, Corcos J et al. Randomized controlled multisite trial of injected bulking agents for women with intrinsic sphincter deficiency: mid-urethral injection of Zuidex via the Implacer versus proximal urethral injection of Contigen cystoscopically. Urology 2009; 74:771-7.
13.Chapple CR, Haab F, Cervigni M et al. An open, multicentre study of NASHA/Dx Gel (Zuidex) for the treatment of stress urinary incontinence. Eur Urol 2005; 48(3):488-94.
14.Lone F, Sultan AH, Thakar R. Long-term outcome of transurethral injection of hyaluronic acid/dextranomer (NASHA/Dx gel) for the treatment of stress urinary incontinence (SUI). Int Urogynecol J 2010 [Epub ahead of print].
15. Lose G, Sorensen HC, Axelsen SM et al. An open multicenter studyof polyacrylamide hydrogel (Bulkamid) for female stress and mixed urinary incontinence. Int Urogynecol J 2010 [Epub ahead of print].
16.Lee PE, Kung RC, Drutz HP. Periurethral autologous fat injection as treatment for female stress urinary incontinence: a randomized double-blind controlled trial. J Urol 2001; 165(1):153-8.
17.Bent AE, Tutrone RT, McLennan MT et al. Treatment of intrinsic sphincter deficiency using autologous ear chondrocytes as a bulking agent. Neurourol Urodyn 2001; 20(2):157-65.
18.Strasser H, Marksteiner R, Margreiter E et al. Autologous myoblasts and fibroblasts versus collagen for treatment of stress urinary incontinence in women: a randomised controlled trial. Lancet 2007; 369(9580):2179-86.
19.Kleinert S, Horton R. Retraction--autologous myoblasts and fibroblasts versus collagen [corrected] for treatment of stress urinary incontinence in women: a [corrected] randomized controlled trial. Lancet 2008; 372(9641):789-90.
20.American College of Obstetricians and Gynecologists (ACOG). Urinary incontinence in women. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2005. (ACOG practice bulletin; no. 63). Available online at www.guideline.gov. Last accessed September 15, 2010.
21.Medicare Coverage Database. Available online at http://www.cms.gov/mcd/viewncd.asp?ncd_id=230.10&ncd_version=1&basket=ncd%3A230%2E10%3A1%3AIncontinence+Control+Devices. Last accessed September 15, 2010.
History of Development
Previously addressed in the Urinary Incontinence, Treatment of medical policy.