Periurethral bulking agents are substances that are injected periurethrally to increase tissue bulk around the urethra as a treatment of stress incontinence. Improvement in stress incontinence 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. However, men have also been treated, typically those with post-prostatectomy incontinence. Except for Contigen, bulking agents are indicated by the U.S. Food and Drug Administration (FDA) for use only in women 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® since 2005) are thought to be more durable and have received approval (1999 and 2004, respectively) from the U.S. Food and Drug Administration (FDA) for use as periurethral bulking agents.

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, ethylene vinyl alcohol copolymers, 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®, autologous fat, and autologous ear chondrocytes is considered investigational.

The use of autologous cellular therapy (e.g., myoblasts, fibroblasts, muscle-derived stem cells or adipose-derived stem cells) 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.

Periurethral bulking agents are recognized as treatment options for both men and women with stress urinary incontinence (SUI). (2-4) 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. (5)

A double-blind randomized study comparing carbon-coated beads to cross-linked collagen was reported as part of the FDA-approval process for Durasphere™. (6, 7) 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. 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.” (8) 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.

Autologous fat and autologous ear chondrocytes 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 periurethral fat injections did not appear to be more efficacious than placebo for treating stress incontinence. (9) 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 50% of patients remained dry for 12 months after receiving a single outpatient injection of harvested autologous auricular cartilage. (10) 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.

2007 Update

Coaptite® (CaHA) and Macroplastique® (polydimethylsiloxane) were FDA approved based partly on results from single-blind randomized non-inferiority comparisons with collagen. The effectiveness at 12 months was similar for the Coaptite and control groups (296 women), with 39% and 37% reporting that they were dry and 50% and 46% reporting improvement by 1 grade, respectively. (11) In a multicenter trial, 34.6% of the 130 women randomized to Macroplastique reported that they were dry and 58% reported improvement by 1 grade compared with 24% and 47% of the 130 women randomized to the control treatment. (12)

A search of the MEDLINE database for the period of January 2005 through February 2007 identified a number of publications on the topic of bulking agents for treatment of incontinence. One randomized clinical trial compared the efficacy of collagen injections with surgery in 133 women. (13) 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.

The literature indicates continued search for a more effective and durable bulking agent. The Zuidex-Implacer is a system to inject Dx/HA in the outpatient clinic without the need for endoscopy. 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. (1) Magnetic resonance imaging in a subset of 16 patients determined that 78% of Implacer injections were deposited in the desired location within the urethral wall. (14) This study is limited by a 24% dropout rate, an unrepresentative patient population, and lack of a comparison group. The efficacy of the Implacer has not been established outside of this single trial, and Zuidex is not currently FDA approved for use in the United States.

Notably, there was 1 report of a poor overall response rate (10.5%) and urethral erosion in 7 of 19 patients following treatment with the ethylene vinyl alcohol copolymer (Tegress™). (15) Although there are too few subjects from this single report for firm conclusions, the high percentage of serious adverse events associated with this copolymer is concerning. No other reports of use of this compound were identified.

2008 Update
A search of the MEDLINE database was performed for the period of March 2007 through March 2008. An updated Cochrane review of 12 trials, (5 added since the prior review) found that greater symptomatic improvement was observed after surgery, but that this advantage needed to be balanced against higher risks. (16) The authors concluded that the moderate quality of the studies reviewed still 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. (17)

References:

1. 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.
2. 1994 TEC Assessment: Collagen Implantation for the Treatment of Urinary Incontinence; Tab 14.
3. Cespedes RD. Collagen injection or artificial sphincter for postprostatectomy incontinence: collagen. Urology 2000; 55(1):5-7.
4. Litwiller SE, Kim KB, Fone PD et al. Post-prostatectomy incontinence and the artificial urinary sphincter: a long-term study of patient satisfaction and criteria for success. J Urol 1996; 156(6):1975-80.
5. Agency for Health Care Policy and Research. Clinical Practice Guideline. Urinary Incontinence in Adults. Department of Health and Human Services, Rockville, Md., 1996.
6. Durasphere package insert, Advanced UroSciences, St. Paul, Minn.
7. 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.
8. Uryx. FDA Summary of Safety and Effectiveness. http://www.fda.gov/cdrh/PDF3/p030030b.pdf.
9. 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.
10. 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.
11. U.S. Food and Drug Administration. Summary of safety and effectiveness data for Coaptite. Accessible at: http://www.fda.gov/cdrh/pdf4/P040047.html
12. U. S. Food and Drug Administration. Summary of safety and effectiveness data for Macroplastique. Accessible at: http://www.fda.gov/cdrh/pdf4/p040050.html
13. 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.
14. Fianu-Jonasson A, Edwall L, Wiberg MK. Magnetic resonance imaging to evaluate NASHA/Dx gel (Zuidex) for stress urinary incontinence. Int J Clin Pract 2006; 60(10):1181-6.
15. 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.
16. Keegan PE, Atiemo K, Cody J et al. Periurethral injection therapy for urinary incontinence in women. Cochrane Database Syst Rev 2007; (3):CD003881.
17. 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.
18. 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.
19. 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.

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™