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 U.S. Food and Drug Administration (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 (see policy No. 7.01.102 on the treatment of vesicoureteral reflux with bulking agents). 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. 

The use of cross-linked collagen, carbon-coated spheres, calcium hydroxylapatite, or polydimethylsiloxane may be considered medically necessary to treat stress urinary incontinence in men and women.

The use of any other periurethral bulking agent, including, but not limited to Teflon is considered investigational.

The use of autologous cellular therapy (e.g., myoblasts, fibroblasts, muscle-derived stem cells or adipose-derived stem cells), autologous fat, and autologous ear chondrocytes is considered investigational.

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. See coding section below.

BlueCard/National Account Issues

Periurethral bulking agents may benefit both men and women with stress urinary incontinence. However, only Contigen has FDA approval for use in men and women.

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 March 2008 through August 2009. Following is a summary of literature to date on use of periureteral bulking agents to treat urinary incontinence.

A Cochrane review identified 12 trials which evaluated periurethral bulking agents in at least one of the study arms. Data from the trials were not suitable for pooling. (1) 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 amongst 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)

FDA-approved bulking agents

Cross-linked collagen (Contigen®)

This was the first FDA-approved bulking agent 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) Twelve-month success rates for collagen treatment were lower than for surgery (53% vs. 72%). However, 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 2 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) was FDA-approved 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 4-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. 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 60/125 (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.

Non-FDA approved products

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 (Q0Med) randomized non-inferiority trial comparing the Zuidex/Implacer system to Contigen conducted in North America was published in 2009. (11) 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 3 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 earlier 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. (12) This study also had a high dropout rate (24%), as well as an unrepresentative patient population, and lack of a comparison group.

Polytetrafluoroethylene (Teflon)

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. (13) 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. (14) 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. (15) 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. (16) 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.

Summary

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. There is insufficient published evidence on the efficacy of autologous cellular therapy, autologous fat, autologous ear chondrycytes and other treatments such as Teflon; thus, these are considered investigational.

References:

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. 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 Aug 4 [Epub ahead of print].
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.

Collagen, Treatment of Urinary Incontinence
Durasphere
Incontinence, Treatment with Bulking Agents
Teflon®, Periurethral Injection for Urinary Incontinence
Uryx, Treatment of Urinary Incontinence
Tegress, Treatment of Urinary Incontinence
Ethylene Vinyl Alcohol Copolymer,Treatment of Urinary Incontinence
Coaptite®)
CalciumH,Treatment of Urinary Incontinence
Macroplastique®
Polydimethylsiloxane,Treatment of Urinary Incontinence
Dextranomer/ Hyaluronic Copolymer,Treatment of Urinary Incontinence
Zuidex™
Implacer™