|MP 7.01.19||Injectable Bulking Agents for the Treatment of Urinary Incontinence|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/ 10:2013
|Return to Medical Policy Index|
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Bulking agents are injectable substances used to increase tissue bulk. They can be injected periurethrally to treat urinary incontinence and perianally to treat fecal incontinence. A number of products have been developed, and there are several U.S. Food and Drug Administration (FDA)-approved options for treating urinary incontinence. One product is commercially available to date for treating fecal incontinence.
Injectable bulking agents are space-filling substances used to increase tissue bulk. When used to treat stress urinary incontinence (SUI), bulking agents are injected periurethrally to increase the tissue bulk and thereby increase 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.
Following the success of periurethral bulking agents for treating SUI, bulking agents injected into the anal canal have been proposed for treating fecal incontinence. In particular, bulking agents are a potential treatment for passive fecal incontinence associated with internal anal sphincter (IAS) dysfunction. The bulking agent is injected into the submucosa of the anal canal to increase tissue bulk in the area, which narrows the opening of the anus. Current treatment options for fecal incontinence include conservative measures e.g., dietary changes, pharmacotherapy and pelvic floor muscle exercises, sacral nerve stimulation, and surgical interventions to correct an underlying problem.
Key factors in determining the optimal product are biocompatibility, durability, and absence of migration. A number of periurethral bulking agents to treat urinary incontinence have been cleared for marketing by the U.S. Food and Drug Administration (FDA). Except for Contigen®, bulking agents are indicated by FDA for use only in women, specifically those with stress urinary incontinence due to intrinsic sphincter deficiency. 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. Other periurethral bulking agents cleared by the FDA for urinary incontinence include carbon-coated beads (e.g., Durasphere®), spherical particles of calcium hydroxylapatite (CaHA) in a gel carrier (Coaptite®), polydimethylsiloxane (silicone, Macroplastique®), and ethylene vinyl alcohol copolymer implants (e.g., Uryx®, marketed under the trade name Tegress® starting in 2005). Tegress was later voluntarily removed from the market due to safety concerns.
Several agents identical to or similar to those used for urinary incontinence e.g., Durasphere, silicone biomaterial, etc. have been studied for the treatment of fecal incontinence. To date, only one bulking agent has been approved by the FDA for treating fecal incontinence. This is a formulation of non-animal stabilized hyaluronic acid/dextranomer in stabilized hyaluronic acid (NASHA Dx) and is marketed by Q-Med as Solesta. A hyaluronic acid/dextranomer 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).
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 periurethral bulking agents have been approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process 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.
One bulking agent was approved by the FDA through the premarket approval process for treating fecal incontinence. In 2011, non-animal stabilized hyaluronic acid/dextranomer in stabilized hyaluronic acid (NASHA Dx) marketed as Solesta® (Q-Med) is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy.
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 who have failed appropriate conservative therapy.
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 to treat stress urinary incontinence is considered investigational.
The use of any other periurethral bulking agent, including, but not limited to Teflon®, to treat stress urinary incontinence is considered investigational.
The use of periuretheral bulking agents to treat urge urinary incontinence is considered investigational.
The use of perianal bulking agents to treat fecal incontinence 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.
Effective in 2013, there is a HCPCS code for perianal bulking agent – L8605: Injectable bulking agent, dextranomer/hyaluronic acid copolymer implant, anal canal, 1 ml, includes shipping and necessary supplies. The physician services associated with perianal bulking agents might be reported with CPT code 45335 (Sigmoidoscopy, flexible; with directed submucosal injection(s), any substance) or code 46999 (unlisted procedure, anus). Code 46999 is recommended on the company’s website.
Effective April 1, 2013, there is a HCPCS “C” code that was created for the Solesta procedure:
C9735 Anoscopy; with directed submucosal injection(s), any substance
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.
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 on bulking agents to treat urinary incontinence was performed in 1995. The policy was updated regularly with a literature review using the MEDLINE database. The policy was expanded to include fecal incontinence in 2013. The most recent literature review searched MEDLINE through February 12, 2013. Following is a summary of literature to date on use of injectable bulking agents to treat urinary and fecal incontinence.
A 2012 Cochrane review on periurethral bulking agents for urinary incontinence in women identified 14 randomized controlled trials (RCTs) with sample sizes ranging from 30 to 355 patients that included bulking agents in at least one of the study arms. (1) This was an update of a 2007 review. All trials included women with a urodynamic diagnosis of stress incontinence, and 7 trials limited eligibility to stress incontinence due to intrinsic sphincter deficiency. The studies varied in the type of bulking agent and comparison intervention used. Eight studies compared 2 bulking agents, 2 compared bulking agents to surgery, 1 compared a bulking agent to pelvic floor exercise, and 1 trial used a placebo comparison group. 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. The authors stated that data from the trials were not suitable for pooling due to heterogeneity among studies. They concluded that the updated review indicates insufficient evidence to guide practice and recommend that additional RCTs with a placebo group or conservative treatment arm be conducted.
A 2011 systematic review by Davila identified 20 studies meeting their inclusion criteria (prospective clinical studies or RCTs conducted among women with stress urinary incontinence and published in English). (2) Nine studies (total n=682) evaluated the bulking agent cross-linked collagen. Rates of patients considered cured or improved in individual studies ranged from 21% to 81% at 12 months, 7% to 52% at 2 years, and 30% to 43% at more than 4 years. There were 8 trials (n=507) using cross-linked polydimethylsiloxane injection. Cure rates ranged from 20% to 71% at 12 months and 18% to 40% at long-term follow-up up to 60 months. The authors concluded that bulking agents have demonstrated effectiveness at 1 year, but results, particularly with older agents, diminish over time, and repeated injections can restore or enhance improvement.
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 [AHRQ]), concluded that periurethral collagen is curative in 32% of men and 62% of women. (3) A randomized controlled 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 1 year after delivery. Twelve-month success rates for collagen treatment were lower than for surgery (53% vs. 72%, respectively). However, there were significantly fewer adverse events in the collagen-treated group (36% vs. 63%, respectively). 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) 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 randomly assigned 237 women with stress urinary incontinence to undergo periurethral bulking with Uryx or to a “currently marketed absorbable bulking agent.” (6) 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%, respectively, in the control group. A repeat injection was necessary in 75% of these patients to achieve satisfactory results. Following reports of adverse effects, (7) 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 SUI. (8) 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 1 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 1 Stamey grade (58% vs. 51%, respectively) and decrease in pad weight (51% vs. 38%, respectively) 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 (SUI). Results of this trial were published in 2009. (9) 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 1 Stamey grade (p<0.001 for non-inferiority). Twelve of the 247 randomly assigned 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. (10) Fifty-six of the 67 (84%) patients had sustained treatment success at 24 months, defined as an improvement of at least 1 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 includes a portion of responders from one arm of the trial. The analysis included 67 of 122 (55%) patients originally randomly assigned to receive Macroplastique and did not provide data on the patients in the comparison group.
Dextranomer/hyaluronic (Dx/HA, 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 that compared 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 an equal to or greater than 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 randomly assigned 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. (12) 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. (13) 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. (14) 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; 4 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 that compared 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. (15) 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. (16) 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 SUI. (17) 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. (18) 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.
Conclusions: A number of RCTs and a Cochrane review of RCTs evaluating periurethral bulking agents for the treatment of urinary incontinence have been published. The trials vary in the bulking agent used and the comparison intervention e.g., placebo, conservative therapy, or another bulking agent. Due to this heterogeneity among studies, and the small number of studies in each category, the Cochrane review was unable to make specific conclusions about the efficacy of specific bulking agents compared to alternative treatments. Cross-linked collagen is the most established bulking agent that is currently available. The evidence on cross-linked collagen is sufficient to conclude that it is effective in some patients who fail conservative treatment and therefore, is a reasonable alternative to more risky surgical procedures. Results from available trials suggest that carbon-coated spheres, calcium hydroxylapatite, and polydimethylsiloxane have efficacy for treating incontinence that is similar to cross-linked collagen. For other agents, such as autologous cellular therapy, autologous fat, autologous ear chondrocytes, and Teflon, there are few RCTs and little evidence of efficacy.
There have been 3 published RCTs evaluating bulking agents for treatment of fecal incontinence. Two were placebo or sham-controlled trials, and 1 compared injections of bulking agents to biofeedback. The RCTs are described below:
In 2013, Dehli and colleagues in Norway published findings of an RCT evaluating Solesta, an FDA-approved non-animal stabilized hyaluronic acid/dextranomer in stabilized hyaluronic acid (NASHA Dx) bulking agent.(19) A total of 126 adults with fecal incontinence were randomized to receive injectable bulking agents (n=62) or a 6 month biofeedback intervention (n=64). Patients in the bulking agent group who reported minor or no symptom improvement at 3 months received a second injection. The primary efficacy outcome was incontinence severity, as measured by the St. Mark’s score, which can range from 0 (perfect continence) to 24 (maximal incontinence). A St. Mark’s score of at least 4 was required for study participation. Ten patients (8%) dropped out of the study before 6 months. At the 6-month follow-up, the mean St. Mark’s score in the biofeedback group had decreased from 12.6 points (95% confidence interval [CI]: 11.4-13.8) at baseline to 9.2 points (95% CI: 7.9-10.5). In the bulking agents group, mean scores were 12.9 (95% CI: 11.8-14.0) at baseline and 8.9 (95% CI: 7.6-10.2) at 6 months. The difference between groups in St. Mark’s score reduction at 6 months was not statistically significant. In addition, change in St. Marks’s score did not differ between groups at 24 months; only 61 patients (49%) completed the 24-month follow-up. Three of the first 10 patients in the bulking agent group got infections at the injection site and underwent treatment; subsequent patients in this group received prophylactic antibiotics.
In 2011, Graf and colleagues published an industry-sponsored multicenter RCT that compared Solesta to sham treatment in 206 adult patients. (20) To be eligible for inclusion, patients needed to have a Cleveland Clinic Florida fecal incontinence score (CCFIS) of 10 or higher, at least 4 documented incontinence episodes in 2 weeks, symptoms for at least 12 months and have failed at least 1 medically supervised conservative treatment (which could include dietary modification, fiber supplements or loperamide hydrochloride). Patients received an initial injection, and those with persistent symptoms, and no substantial adverse effects at 1 month were offered a second injection. A total of 112 patients (86%) in the active treatment group and 61 patients (87%) in the sham group received a second procedure. Response to treatment was defined as a reduction in the number of incontinence episodes by 50% or more compared to baseline. The study was double-blind for the first 6 months of follow-up; at 6 months, patients in the sham group were offered active treatment. Thus, the primary efficacy outcome was assessed at 6 months.
A total of 197/206 (96%) of randomized patients completed the 6-month follow-up and were included in the primary efficacy analysis. Seventy-one (52%) in the active treatment group and 22 (31%) in the sham group had a 50% or greater reduction in incontinence episodes at 6 months. The difference between groups was statistically significant (odds ratio [OR]: 2.36, 95% CI: 1.24 to 4.47, p=-0.009). Findings on secondary outcomes at 6 months were mixed. For example, the mean increase in number of incontinence-free days was significantly higher in the active treatment group than the sham group (3.1 versus 1.7, respectively; p=0.016), but the median decrease in number of incontinence episodes did not differ significantly between groups (6.0 vs. 3.0, respectively; p=0.09). Moreover, change in the CCFIS did not differ significantly at 6 months; (2.5 points in the active treatment group versus 1.7 points in the sham treatment group). Quality of life was measured by the fecal incontinence quality of life (FIQL) instrument, which has 4 subscales. One of the 4 subscales (coping and behavior) improved significantly more in the treatment than the sham group at 6 months. Change in scores on the other 3 subscales (lifestyle, depression and self-perception, and embarrassment) did not differ significantly between groups at 6 months. The authors did not report the proportion of patients who were continent at follow-up, either as a primary or secondary outcome.
During the 6-month blinded treatment phase, 128 adverse events were reported in the active treatment group and 29 in the sham group. The most common adverse event in the active treatment group was proctalgia, which occurred in 19 patients (14%). In contrast, 2 patients (3%) in the sham group reported proctalgia. Moreover, 10 patients (7%) in the active treatment group and 1 patient (1%) in the sham group had rectal hemorrhage. Infection site bleeding occurred in 12 patients (17%) in the sham group and 7 patients (5%) in the active treatment group. Two serious adverse events were reported, both in the active treatment group; there was 1 rectal abscess and 1 prostate abscess.
In 2007, Siproudhis and colleagues in France published a small, single center, placebo-controlled, double-blind RCT a non-U.S. Food and Drug Administration (FDA)-approved silicone bulking agent, (polydimethylsiloxane). (21) A total of 44 patients with severe fecal incontinence were treated with a bulking agent or saline control. Follow-up was for 3 months, and the primary outcome was the percent of patients with successful treatment, defined as a CCFIS score of less than 8. A secondary outcome measure was the mean CCFIS score at 3 months. There were not statistically significant differences on either outcome measure. The percent of patients with a successful treatment outcome was 27% in the bulking agent group compared to 23% in the placebo group (p=0.73). The mean CCFIS score decreased from 13.8 at baseline to 11.7 at 3 months in the bulking agent group compared to a mean score of 14.6 at baseline and 11.4 at 3 months in the placebo group (p=0.79).
Systematic Reviews: At least 3 systematic reviews have been published; all conducted literature searches prior to the publication of the RCTs evaluating the FDA-approved bulking agent for treating fecal incontinence. The systematic reviews included other RCTs that compared different types of bulking agents, and/or different types of delivery of bulking agents.
A 2010 Cochrane review on perianal injectable bulking agents for treating fecal incontinence identified 4 RCTs with a total of 176 patients. (22) The trials included patients with anal sphincter dysfunction or passive fecal incontinence who had failed previous conservative treatments e.g. anti-diarrheal medications, pelvic floor muscle training, etc. One trial was placebo-controlled, 2 compared 2 different bulking agents and another compared 2 methods of injecting the same agent. Due to heterogeneity among trials, study findings were not pooled. The Cochrane investigators stated that the single placebo-controlled trial [the study by Siproudhis et al., described above (21)] was too small to detect between-group differences in any outcome. Of the 2 trials comparing bulking agents, 1 had only 10 participants, which is too few to detect between-group differences. The other trial found significantly greater improvement in fecal incontinence at 6 and 12 months using silicone material compared to carbon-coated beads. A limitation of the latter trial is that injectable bulking agents were not compared to placebo or an alternative treatment. None of the agents used in the RCTs were approved by the FDA.
In 2011, 2 systematic reviews were published that included observational studies and RCTs evaluating bulking agents for treating fecal incontinence. (23, 24) Both systematic reviews identified the 4 RCTs included in the Cochrane review. Additionally, the Hussain review included one RCT that did not publish results for the control group, but only for the treatment group, and therefore does not allow conclusions about comparative efficacy of bulking agents. Although data from RCTs are needed to draw conclusions about efficacy of bulking agents, data from observational studies are useful for analysis of safety outcomes. Hussain and colleagues included 1,070 patients from 39 studies in a safety analysis. Adverse events occurred in 139 patients (13.5%). The most common complication was pain, which occurred in 67 patients (6.5%) followed by leakage of injected material, which was reported by 58 patients (5.6%). The authors did not report the number of serious adverse events.
Conclusions: Three RCTs evaluating bulking agents for the treatment of fecal incontinence have been published; 2 of these used the FDA-approved product, NASHA Dx (Solesta). Two of the 3 trials (including 1 evaluating Solesta) did not show that bulking agents provided significant benefit compared to the comparison intervention. One RCT using Solesta found that a significantly greater proportion of patients receiving active treatment compared to sham had at least a 50% reduction in incontinence episodes at 6 months. Secondary outcomes were mixed, and the authors did not report the number of patients who attained continence. Moreover, outcomes were not compared in the treatment and sham groups beyond 6 months, and side effects were more prevalent in the treatment group. Systematic reviews published prior to the largest RCT have concluded that there is little evidence for the efficacy of these agents. Overall, this evidence is not sufficient to conclude whether bulking agents are an effective treatment for fecal incontinence. Corroboration of the single positive trial is needed, and trials with longer follow-up are important to determine the durability of any treatment effect.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received through 4 physician specialty societies and 4 academic medical centers while this policy was under review in 2013. Although the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. There was consensus agreement with all of the policy statements among reviewers who provided responses. In particular, for the statement added in 2013 that perianal bulking agents to treat fecal incontinence is considered investigational, there was unanimous agreement among the respondents.
There is sufficient evidence to conclude that cross-linked collagen improves the net health outcome (i.e. effective in some patients who failed conservative treatment with fewer adverse events than surgery). Moreover, there is evidence that carbon-coated spheres, calcium hydroxylapatite, and polydimethylsiloxane have efficacy for treating incontinence and have efficacy and safety similar to cross-linked collagen. Thus, these bulking agents may be considered medically necessary for patients with urinary incontinence who have failed 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. Therefore, use of these agents to treat urinary incontinence is considered investigational.
There is insufficient evidence that injectable bulking agents improve the net health outcome for patients with fecal incontinence. The available evidence from randomized controlled trials has not consistently found that perianal bulking agents improve health outcomes compared to a comparison intervention; 1 of 2 trials evaluating the FDA-approved product found benefit, but had limitations. Thus, injectable bulking agents are considered investigational for treating fecal incontinence.
Practice Guidelines and Position Statements
In 2010, the Society of Obstetricians and Gynaecologists of Canada Urogynaecology Committee published a guideline on the evaluation and treatment of recurrent urinary incontinence after pelvic floor surgery. (25) The guideline recommends that conservative management be used as first-line therapy. It also stated that patients with significantly decreased urethral mobility may be managed with periurethral bulking agents as one of several treatment options.
In 2007, the National Institute for Health and Clinical Excellence (NICE) in the U.K. published guidance on injectable bulking agents for treating fecal incontinence. (26) The guidance stated that there is insufficient evidence to support the safety and efficacy of injectable bulking agents for fecal incontinence, and use of these products should take place in the context of a clinical trial.
In 2007, the American Society of Colon and Rectal Surgeons published practice parameters for the treatment of fecal incontinence. (27) The document included the following statement on bulking agents:
“When passive fecal incontinence caused by internal sphincter dysfunction is the predominant symptom, injectable therapy seems to be effective and safe, although its long-term efficacy has yet to be defined. Level of Evidence: II; Grade of Recommendation: B.”
In 2005 (reaffirmed 2009), the American College of Obstetricians and Gynecologists (ACOG) issued a practice bulletin on urinary incontinence in women. (28) 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. (29) 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 [intrinsic sphincteric deficiency]:
- 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 recurrence 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.”
No national coverage determination was identified on injectable bulking agents for treating fecal incontinence.
- Kirchin V, Page T, Keegan PE et al. Urethral injection therapy for urinary incontinence in women. Cochrane Database Syst Rev 2012; 2:CD003881.
- Davila GW. Nonsurgical outpatient therapies for the management of female stress urinary incontinence: long-term effectiveness and durability. Adv Urol 2011; 2011:176498.
- Agency for Health Care Policy and Research. Clinical Practice Guideline. Urinary Incontinence in Adults. Rockville, MD: Department of Health and Human Services;1996.
- 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.
- 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.
- URYX. FDA Summary of Safety and Effectiveness. Available online at: http://www.accessdata.fda.gov/cdrh_docs/pdf3/P030030b.pdf. Last accessed November, 2012.
- 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.
- 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.
- 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.
- 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.
- 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(4):771-5.
- 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.
- 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; 21(11):1359-64.
- Lose G, Sorensen HC, Axelsen SM et al. An open multicenter study of polyacrylamide hydrogel (Bulkamid) for female stress and mixed urinary incontinence. Int Urogynecol J 2010; 21(12):1471-7.
- 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.
- 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.
- 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.
- 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.
- Dehli T, Stordahl A, Vatten LJ et al. Sphincter training or anal injections of dextranomer for treatment of anal incontinence: a randomized trial. Scand J Gastroenterol 2013 [Epub ahead of print].
- Graf W, Mellgren A, Matzel KE et al. Efficacy of dextranomer in stabilised hyaluronic acid for treatment of faecal incontinence: a randomised, sham-controlled trial. Lancet 2011; 377(9770):997-1003.
- Siproudhis L, Morcet J, Laine F. Elastomer implants in faecal incontinence: a blind, randomized placebo-controlled study. Aliment Pharmacol Ther 2007; 25(9):1125-32.
- Maeda Y, Laurberg S, Norton C. Perianal injectable bulking agents as treatment for faecal incontinence in adults. Cochrane Database Syst Rev 2010; (5):CD007959.
- Hussain ZI, Lim M, Stojkovic SG. Systematic review of perianal implants in the treatment of faecal incontinence. Br J Surg 2011; 98(11):1526-36.
- Leung FW. Treatment of fecal incontinence - review of observational studies (OS) and randomized controlled trials (RCT) related to injection of bulking agent into peri-anal tissue. J Interv Gastroenterol 2011; 1(4):202-06.
- Lovatsis D, Easton W, Wilkie D. Society of Obstetricians Gynaecologists, of Canada Urogynaecology Committee. Guidelines for the evaluation and treatment of recurrent urinary incontinence following pelvic floor surgery. J Obstet Gynaecol Can 2010; 32(9):893-904.
- National Institute for Health and Clinical Excellence (NICE). Injectable bulking agents for faecal incontinence: February 2007. Available online at: http://www.nice.org.uk/nicemedia/live/11288/31713/31713.pdf. Last accessed November, 2012.
- Tjandra JJ, Dykes SL, Kumar RR et al. Practice parameters for the treatment of fecal incontinence. Dis Colon Rectum 2007; 50(10):1497-507.
- 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 August, 2011.
- Medicare Coverage Database. Available online at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=241&ncdver=1&CoverageSelection=National&KeyWord=incontinence+control+devices&KeyWordLookUp=Title&KeyWordSearchType=And&ncd_id=230.10&ncd_version=1&basket=ncd%253A230%252E10%253A1%253AIncontinence+Control+Devices&bc=gAAAABAAAAAA&. Last accessed November, 2012.
|CPT||46999||Unlisted procedure, anus|
|51715||Endoscopic injection of implant material into the submucosal tissues of the urethra and/or bladder neck|
|ICD-9 Procedure||49.99||Other operations on anus (it is unlikely the insertion of the perianal bulking material would be performed inpatient)|
|59.72||Injection of implant into urethra and/or bladder neck|
|ICD-9 Diagnosis||599.82||Intrinsic sphincter deficiency|
|625.6||Stress incontinence, female|
|788.32||Urinary incontinence, male|
|HCPCS||C9735||Anoscopy; with directed submucosal injection(s), any substance (new code 4/1/13)|
|L8603||Injectable bulking agent, collagen implant, urinary tract, 2.5 ml syringe, includes shipping and necessary supplies|
|L8605||Injectable bulking agent, dextranomer/hyaluronic acid copolymer implant, anal canal, 1 ml, includes shipping and necessary supplies (new code 1/1/13)|
|L8606||Injectable bulking agent synthetic implant, urinary tract, 1 ml syringe, includes shipping and necessary supplies|
|Q3031||Collagen skin test|
|ICD-10-CM (effective 10/1/14)||N39.3||Stress incontinence (female) (male)|
|R15.0-R15.9||Fecal incontinence code range|
|ICD-10-PCS (effective 10/1/14)||ICD-10-PCS codes are only used for inpatient services.|
|0DUQ7JZ, 0DUQ7KZ, 0DUQ8JZ, 0DUQ8KZ, 0DUQXJZ, 0DUZXKZ||Surgical, gastrointestinal system, supplement, anus, via natural or artificial opening, via natural or artificial opening endoscopic or external, codes for synthetic substitute and nonautologous tissue substitute|
|0TUC87Z, 0TUC8JZ, 0TUC8KZ||Surgical, urinary system, supplement, bladder neck, via natural or artificial opening endoscopic, codes for autologous tissue substitute, synthetic substitute, and nonautologous tissue substitute|
|Type of Service||Surgery|
|Place of Service||Inpatient
Collagen, Treatment of Urinary Incontinence
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
CalciumH,Treatment of Urinary Incontinence
Polydimethylsiloxane,Treatment of Urinary Incontinence
Dextranomer/ Hyaluronic Copolymer,Treatment of Urinary Incontinence
|12/01/95||Add to Surgery Section||New Policy|
|07/31/97||Replace policy||Reviewed with changes. Revised description|
|05/31/01||Replace policy||Policy re-titled and revised to include discussion of Durasphere|
|04/29/03||Replace policy||Policy updated; policy statement revised by including investigational agents, references added|
|4/1/05||Replace policy||Policy revised with literature review; policy statement expanded to indicate that the use of a copolymer (i.e., Uryx) would also be considered medically necessary. Reference 7 added.|
|04/17/07||Replace policy||Policy updated with literature review; reference numbers 1 and 11–15 added; policy statement revised to include newly FDA-approved bulking agents for use in men and women|
|05/08/08||Replace policy||Policy updated with literature review; reference numbers 16–19 added; policy statement added on autologous cell therapy|
|10/08/09||Replace policy||Policy updated with literature review; Ethylene vinyl alcohol copolymer (Tegress™) was withdrawn from the market and was removed from list of medically necessary agents; new references 10, 11 and 16 added; other references removed/renumbered.|
|10/08/10||Replace policy||Policy updated with literature review. Change in title from ‘incontinence’ to ‘urinary incontinence. Medically necessary policy statement changed to specify that it applies to patients who fail appropriate conservative therapy; new statement added that periuretheral bulking agents for urge incontinence is considered investigational. Reference numbers 11, 14, 15, 20 and 21 added; other references renumbered.|
|10/04/11||Replace policy||Policy updated with literature review. Reference numbers 2 and 20 added; other references renumbered or removed. No change in policy statements|
|03/14/13||Replace policy||Policy updated with literature review through February 12, 2013. Policy expanded to include fecal incontinence. Statement added that perianal bulking agents to treat fecal incontinence is investigational. Title changed to Injectable Bulking Agents for the Treatment of Urinary and Fecal Incontinence. Clinical input added. References 19-24, 26 and 27 added; other references renumbered.|