Bulking Agents in the Treatment of Stress Urinary Incontinence: History, Outcomes, Patient Populations, and Reimbursement Profile

Abstract

Stress urinary incontinence (SUI) can be defined as involuntary loss of urine during a period of increased abdominal pressure and in the absence of detrusor activity. Bulking agents used in the urethra are one of the newer but established technologies for the treatment of SUI. An understanding of the demographics of SUI will help in the selection of patients for bulking agent therapy. Knowledge of available materials, including their positive and negative aspects, is also required. Autologous fat, silicone beads, collagen, carbon particles, and polytetrafluoroethylene paste have all demonstrated success to some degree, but none have met both criteria for success (remaining efficacious over time and maintaining a low side-effect profile). An implantable solution of ethylene vinyl alcohol suspended in dimethyl sulfoxide, currently in clinical testing and review, shows minimal foreign body reaction and is one option being investigated to address patient needs for improved bulking therapy.

With a significant number of Americans experiencing urinary incontinence and more than 60% of those exhibiting some component of stress urinary incontinence (SUI), treatment has evolved, over time, in response to need. There are now newer technologies following the advent of updated treatment protocols, but no single treatment type is applicable to all patients, and there is often greater benefit from combination therapy. Bulking agents used in the urethra are one of the relatively newer but established technologies. An understanding of the demographics of SUI (85% female, 56% younger than 65 years) helps shape discussions regarding patient selection for bulk ing agents. Likewise, knowledge of available materials, including their positive and negative aspects, as well as reimbursement issues, must be clearly understood in terms of patient selection and necessary testing.

Demographics of SUI

Stress urinary incontinence can be defined as a brief involuntary loss of urine associated with an increase of abdominal pressure and in the absence of detrusor activity. Historically, patients have been divided into 2 groups: those with urethral hypermobility and those with intrinsic sphincteric deficiency (ISD). ISD, a term defined in 1992,¹ is used to describe damage to the urethral sphincteric mechanism, regardless of etiology. The urethra might be damaged owing to fixation (as in cases of spina bifida), prior surgery, or denervation or muscle damage during childbirth. We now know that ISD and hypermobility can exist concomitantly as well as alone. The number of patients with stress incontinence has been roughly estimated at 25 million, with approximately 10% to 15% suffering from ISD. We expect these figures to continue to change as our understanding of the process and diagnostic acumen improve.

Urinary incontinence exacts a high price, both financially and in terms of quality of life, and has a substantial impact on individual patients, health care organizations, insurers, and society as a whole. The Alliance for Aging Research, in conjunction with the National Association for Continence, noted in a report to Congress that incontinence was 1 of the top 4 disease entities that detrimentally affect quality of life for our nation’s seniors. In the Agency for Health Care Policy and Research Guidelines Update of 1996, Dr. T.W. Hu of the University of California, Berkeley, reported his data on the economic impact of incontinence.² Studying the population over 64 years of age only, Dr. Hu reported that routine costs of the condition were $10.2 billion. The majority of those costs were attributable to purchase of disposable products, such as pads, briefs, and catheters, as well as laundry charges. Other costs included treatment for urinary tract infections ($4.2 billion), care for injuries (eg, falls) resulting from attempts to reach the bathroom ($58 million), and longer hospital stays and additional hospital admissions ($7.8 billion). Total annual direct costs reached a record $23.6 billion per year for the Medicare-aged population alone. Indirect costs, such as lost time from work for a patient or caregiver, added $4.2 billion to the bill, for a total of $27.8 billion.

Incontinence is also a valid predictor of heavy nursing home use. Nursing home costs are between $39,000 and $43,000 per year, two thirds of which is covered by Medicare and Medicaid, thus adding to the financial impact of incontinence.³

Bulking Agents: History and Outcomes Data

Bulking agents have a long medical history in fields outside of urology. They have been used for gastroesophageal reflux, for scars and wrinkles, as well as for patients with glottic insufficiency.^4–6 A variety of compounds have been used, with varying degrees of success. When bulking agents are used in the urethra, the goal is coaptation of the urethra during the storage phase, and maintenance of that coaptation during periods of increased abdominal pressure. Materials are implanted via the periurethral route (alongside the urethra) or, as in most cases, transurethrally. Implantation has to be accomplished without disturbing the patient’s natural ability to void. The success of any product can be defined as its efficacy over time while maintaining a low side-effect profile. The ideal material should be biocompatible, nonimmunologic, and hypoallergenic. It should retain its bulking characteristics for a prolonged interval and not biodegrade or migrate. Additionally, it should be easy to prepare and implant. Although safety is a main advantage of bulking agents, the most common complications are pain during injection and transient urinary retention and voiding dysfunction after implantation.

Autologous fat, silicone beads, collagen, carbon particles, and polytetrafluoroethylene (Teflon®) paste have all demonstrated success to one degree or another. However, none have met both success criteria of effectiveness over time and limited side effects. Autologous fat is difficult to harvest and is reabsorbed from the injection site at an unacceptably high rate.⁷ The rare complication of fat embolization, with death, has also been reported. Silicone beads have demonstrated efficacy in some hands, but a possible association with development of some types of collagen vascular disease, as reported by patients after breast implants, remains an unanswered concern. This, and the issue of the worrisome migration of silicone particles, has slowed testing and delayed submission for US Food and Drug Administration (FDA) approval.⁸ In the 1970s, Berg⁹ described the use of Teflon for correction of urinary incontinence. Although it has a long history of successful use by subureteric injection in the treatment of reflux in children,¹⁰ Teflon has not been approved in the United States, again owing to concern for particle migration/embolization and induction of inflammatory reactions such as granuloma formation.¹¹ Glutaraldehyde cross-linked (GAX) collagen has stood the test of time for safety. However, reimplantation requirements for collagen, as for all currently available bulking agents, diminish longterm efficacy of this therapy. After implantation of GAX collagen, neovascularization, accompanied by recruitment of host fibroblasts, can be seen. These fibroblasts might in fact replace the collagen and be responsible, ultimately, for continued continence when the presence of collagen can no longer be demonstrated.¹²

Carbon-coated bead suspensions demonstrate continence rates similar to those with GAX collagen. However, no preinjection antigenic testing is required. The beads can be cumbersome to inject. The biogel that suspends the beads flows fairly easily through the injection needle without carrying the beads along at a steady rate. The beads then tend to clog the needle, and the remaining material in the syringe is rendered useless. Sterile abscess formation has been reported with carbon-coated beads, but this might be an issue with many injectables that remain in a solid phase.¹³

Newer formulations look promising but must withstand the test of time. Liquid compounds that are inert and have limited foreign body reactions, as well as gels that precipitate to create bulk upon interaction with tissue or interstitial fluid, are being tested. These include hyaluronic acid and dextranomer microspheres.¹⁴ An implantable solution of ethylene vinyl alcohol suspended in dimethyl sulfoxide shows minimal foreign body reaction and looks favorable. Interestingly, this solution has been used successfully in the treatment of brain aneurysms by direct implantation into the aneurysm itself. A mild foreign body response is elicited, but to date no untoward side effects in the brain have been noted. In clinical testing, the same solution has exhibited promising results after implantation into the urethra.¹⁴

Special Patient Populations: Collagen as a Case Study

Shortliffe and coworkers¹⁵ first reported GAX collagen for intraurethral use in 1989. After FDA approval in 1993, it was widely used for urethral ISD. The patient profile suggested older women with leakage at abdominal pressures of less than 65 cm H₂O. Originally, collagen was thought to be ineffective in patients with urethral hypermobility. Most initial data therefore excluded this group of patients. A skin test with non-crosslinked collagen was required to elicit any possible allergic reactions. Implantation was initially performed periurethrally, although over time the transurethral route was increasingly preferred by surgeons. Many studies have demonstrated that transurethral implantation also requires less material than the periurethral method. The procedure can be performed in the hospital with sedation or in the office setting, with a periurethral local block in combination with viscous lidocaine per urethra. Most patients void immediately after surgery. The few side effects observed include hematuria, urinary retention (transient), urinary tract infections, and urgency/frequency. Indwelling catheter treatment is avoided because it disrupts the newly recreated mucosal seal as the collagen molds itself around the catheter. The ideal patient in the early studies was thought to be an elderly woman with a fixed, open urethra, who otherwise could not tolerate a more invasive open surgical procedure.

McGuire and Appell¹⁶ reported on their observation of 98 women and 89 men at 1 year after surgery and 45 women and 33 men at 2 years after surgery. They concluded that collagen implants dramatically improved the ability of the urethra to resist abdominal pressure increases without changing the voiding pressure required to allow bladder emptying (Table 1). After implantation, male patients similarly demonstrated an increase in abdominal pressure required to cause leakage; however, the data for men were not supported in further reports. Overall, men had lower success rates and required more collagen to render them dry. Herschorn and coworkers¹⁷ reported on 31 women and 10 men with a mean follow-up of 8 and 6 months, respectively (Table 2). A follow-up study was published by this group on 181 women, mean age 64 years and mean follow-up 21 months. In this study, patients with hypermobility were included. For those with ISD alone, the dry rate was 23%, improvement at 52%, and failure at 25%.¹⁸ Cross and colleagues¹⁹ reported on 139 women (median age, 72 years) with ISD, of whom 73% had grade 3 incontinence. Seventy-four percent and 20% were “substantially improved” and “improved,” respectively, with a median follow-up of 18 months. Eleven percent required “booster” injections at more than 6 months. These findings substantiated the need for repeated collagen implantation to maintain continence in many patients. Cross and colleagues¹⁹ generated Kaplan-Meier curves to examine the relationship between grade of incontinence and probability of remaining dry. There was an inverse correlation, although it was not found to be statistically significant. The mean volume of collagen required to render patients dry increased as the grade of incontinence increased.

Table 1.

Outcome Data from a Study of Transurethral Collagen Injection for Urinary Incontinence

Authors	Patient Population	Results	Conclusions	Comments/Findings
McGuire and Appell,	98 women, 89 men	Over 1 y:	Collagen injection dramatically	Urethral leakage that results
199416	over 1 y;	ISD women:	improves the ability of the	when abdominal pressure
	45 women, 33 men	Base ALPP:	urethra to resist abdominal	is elevated indicates
	at 2-y follow-up	29 cm H2O	pressure without changing	dysfunction due to poor
		Last ALPP	voiding pressure required	closure mechanism or
		w/collagen:	to induce voiding.	urethral hypermobility.
		66 cm H2O
		ISD men:	Injectable materials should	Surgery designed to restore
		Base ALPP:	not be considered a	and hold the urethra in
		43 cm H2O	minor treatment for	normal position during
		Last ALPP	minor incontinence, nor	high abdominal pressure
		w/collagen:	should they be considered	does not often resolve
		70 cm H2O	competitive with other	leakage due to poor
		At 2 y:	treatments, including	closure mechanism.
		ISD women:	pubovaginal slings.
		Base ALPP:		Generally, leakage at very
		30 cm H2O	Injectables can be used in	low abdominal pressures
		Last ALPP	conjunction with slings	indicates poor proximal
		w/collagen:	or artificial sphincters.	urethral sphincter
		90 cm H2O		function
		ISD men:
		Base ALPP:		Patients with improvement
		34 cm H2O		often did not want or
		Last ALPP		need further therapy.
		w/collagen:
		101 cm H2O		Complete dryness is not
				always necessary for
				success.

ISD, intrinsic sphincteric deficiency; ALPP, abdominal leak point pressure.

Table 2.

Outcome Data from a Study of Intraurethral Collagen Injection for Urinary Incontinence

Authors	Patient Population	Results	Conclusions	Comments/Findings
Herschorn et al,	31 women followed	Women:	Intraurethral injection of	Female mean leak point
199217	for 3–15 mo	48% dry	collagen is a safe and	pressure increased from 31 cm
	(mean 8 mo);	42% improved	benign procedure,	H2O to 85 cm H2O, post-
	10 men followed	10% no improvement	offering greatest benefit	treatment.
	for 3–11 mo	Average volume used	to female patients.
	(mean 6 mo)	for dry/improved		The transurethral technique
		cases: 12.7 mL,		was used for men.
	Median patient	2 sessions
	age: 58 y			For the majority of women,
		Men:		the periurethral technique
		20% dry		was used.
		50% improved
		30% no improvement		Complications were minimal.
		Average volume used
		for dry/improved
		cases: 51.8 mL,
		6 sessions

Herschorn and colleagues¹⁸ report that intraurethral collagen injection is shown to be a safe and well-tolerated procedure that works equally well in younger and older women. Pretreatment bladder instability seems to be an adverse factor, whereas hypermobility is not, because patients with all types of incontinence fared similarly. Long-term durability of a successful result has been demonstrated, and repeat injections might restore success.¹⁸ Additional studies suggest that some, but not all, patients with hypermobility do well.

ISD and Hypermobility

Because bulking agents were originally considered to have greatest utility in patients with ISD, and subsequent reimbursement followed along those lines, it was some time before patients with hypermobility were studied in the United States in any detail. Herschorn and coworkers^17,18 in Toronto demonstrated that the patient with hypermobility could derive benefit. In fact, no significant difference in outcomes was seen in patients with or without hypermobility (P = .2889) in their studies. Interestingly, patients with hypermobility required less collagen for a successful outcome. Monga and colleagues²⁰ reported on 60 women with genuine stress incontinence and urethral excursion (“mobility”) up to 25 mm. Objective cure rates (according to urodynamic assessment) were 61% at 3 months and 48% at 24 months. Subjective success rates were 86% and 68% at 3 months and 24 months, respectively. Another report on 40 patients,²¹ 23% with ISD, revealed that the hypermobile group required a similar number of implant procedures and volume of collagen compared with their counterparts with ISD alone. A logical conclusion derived from these studies is that ISD can exist in the presence of hypermobility and that this alone should not be a criterion for exclusion from bulking therapy. Bladder instability seems to be a predictor of a poorer outcome with bulking therapy. Patients with bladder instability should be appropriately evaluated.^18,19 Not all studies support the conclusion of poorer clinical results with bulking therapy in patients with unstable bladders, but common sense would dictate careful attention during patient selection and good medical management of the instability, both pre- and perioperatively.²⁰

Male Incontinence

Closer examination of men with ISD resulted in several observations.^22–25 Patients with severe incontinence were unlikely to enjoy significant success with bulking therapy. Bladder neck contractures and scarring were associated with poorer continence status postoperatively. Unfortunately, men suffering from ISD were likely to be either postsurgical or postirradiation patients in whom scarring was often present. An antegrade implant method via a suprapubic tract proved superior in terms of finding a tissue plane that could accommodate implantation of a bulking agent. Yet durability of the implant still remained an issue even with this alternative implant technique (Table 3).

Table 3.

Outcome Data from Three Studies of Transurethral Collagen Injection for Male Urinary Incontinence

	Patient
Authors	Population	Results	Conclusions	Comments/Findings
Elsergany and Ghoniem,	35 men with ISD	20 % dry	Transurethral collagen	Procedures were performed
199823	(mean age 69 y)	31 % improved	injection is a safe and	under local anesthesia
	followed for 3–22	49% no improvement	reasonable option	with monitored
	mo (mean 18 mo)	Average volume used	for men with ISD.	anesthesia care.
		for dry/improvement
		cases: 8.2 mL,	History of pelvic	Abdominal leak point
		2 sessions	irradiation, urethral	pressure increased
			stricture, or involuntary	significantly after
			bladder contractions	injection, from 69 cm
			can jeopardize results.	H2O to 116 cm H2O.
				Complications are low.
Cummings et al,	19 men with post-	21 % dry	Collagen injection can
199624	radical prostatec-	37 % improved	be helpful for men
	tomy stress incon-	42 % no improvement	with stress incon-
	tinence, followed	Average volume used	tinence induced by
	for 3–15 mo	for dry/improved	radical prostatectomy.
	(mean 10 mo)	cases: 13.8 mL,
		1.8 sessions	Tissue scarring and
			preoperative severity
			of leakage affect results.
Aboseif et al, 199622	88 men with ISD	48 % dry	Transurethral collagen	Collagen was injected
	(men age 68 y)	37 % improved	injection is effective	slowly, under direct
	followed for	15 % no improvement	and safe in carefully	supervision, on both
	6–12 mo (mean	Average volume	selected patients	sides until coaptation
	10 mo)	used for dry/	with ISD.	was achieved.
		improved cases:
		22.7 mL, 3.4	Tissue scarring and	Treatment endpoint
		sessions	preoperative severity	was cure of 5
			of leakage affected	injections.
			outcomes.
				Most injections were
			No significant	performed under
			morbidity is	local anesthesia.
			associated with
			collagen injection.

ISD, intrinsic sphincteric deficiency.

Elderly Populations

Several reports have been dedicated to the appropriate application of bulking therapy for elderly women. The definition of “elderly” has been subject to varied interpretation throughout the medical literature. Studies, at times, have labeled the average 65-year-old woman as “elderly.” Today, the term “elderly” is more appropriately applied to those age 75 years or older. In this group and for those older women with significant health issues, a minimally invasive procedure for incontinence certainly is very appealing. Faerber²⁶ reported successful outcomes for elderly women with type I stress incontinence. Winters and coworkers²⁷ studied patients with an average age of 73.2 years. One to four implant procedures were required for continence, and the average volume required was 14.6 mL. Elderly women were more likely to have recurrent incontinence. The interval between therapy and recurrence was shorter than for their younger counterparts. Counseling of all patients is recommended.

Historical View of Medicare Reimbursement

Bulking therapy has a well-established reimbursement profile and a successful track record of payment history within federal and private pay insurer systems. Medicare reimbursement for bulking therapy is predicated upon demonstration of ISD and very low Valsalva leak point pressures (VLPP). Private insurance carriers have followed suit, awarding reimbursement across the country. Fortunately, at the onset of coverage for this therapy, criteria for ISD were not strictly defined, because diagnostic testing performed by urogynecologists and gynecologists tended to vary from that performed by urologists.

Initially, to be eligible for reimbursement for GAX collagen implant therapy, VLPP was required to be 60 cm H₂O or less. The reimbursement criterion was revised upward to 100 cm H₂O in 1996, on the basis of data showing that patients with higher leak point pressures also derived benefit. Because collagen could be implanted in the office setting in many instances, performance of the procedure in ambulatory surgical facilities, such as hospital outpatient clinics, came under closer scrutiny.

In an effort to drive procedures to lower-cost environments and reduce overall health care system costs, the Centers for Medicare and Medicaid Services (CMS), the administrative body for Medicare, created a Hospital Outpatient Prospective Payment System (HOPPS) for many procedures, and Ambulatory Payment Classifications (APCs) were defined. Similar to the Diagnostic Related Groups (DRGs), the APC scheme classified “seemingly” similar procedures together for reimbursement.

In fiscal year 2001, ISD treatment was placed in the APC group with urethral repairs, including repair of a urethral injury (CPT 53505) and excision and fulguration of the Skene’s glands (CPT 53270). No other procedure requiring an implantable device or material fell within this APC group. This grouping generated a facility fee for the hospital but no reimbursement for the bulking implant itself, effectively rendering bulking therapy cost prohibitive for institutions and ambulatory care facilities, and thereby severely restricting patient access to this minimally invasive therapy. Not all physicians were comfortable performing bulking therapy in the office setting. For some office practices, nonavailability of the rigid cystoscopic equipment required for accurate intraurethral placement became a limiting factor. After public feedback at a CMS “Town Meeting,” a Medicare decision was reversed, and collagen was granted a “pass-through” reimbursement plan, which allowed payment of a facility fee and additional payment for every syringe used in a procedure. The physicians continued to bill separately for their technical services, using CPT code 51715. This reimbursement plan remained in effect for 2 years, until CMS determined that sufficient billing history was established to calculate more adequate payment levels for the therapy (Table 4).

Table 4.

Centers for Medicare and Medicaid Payment Services Payment Schedule for Procedures and Ambulatory Payment Classifications (APCs), 2004

		Physician’s	Physician’s
		Payment in the	Payment in the	Hospital Facility
HCPCS Code	Description	Office Setting	Hospital or ASC	Payment Mechanism
51715	Endoscopic injection	$299.82	$200.50	APC 0167
95028	Allergy skin tests	$8.83	N/A	APC 0370
Q3031	Skin test kit	N/A	N/A	N/A
L8603	Implant syringe	$351.34	N/A	Bundled into APC 0167

Payments shown are national averages. HCPCS, Healthcare Common Procedure Coding System; ASC, ambulatory surgical center; N/A, not applicable.

As of fiscal year 2004, the HOPPS regrouped bulking therapy with other genitourinary prosthetics in a category- based system. Fiscal year 2004 facility payment for outpatient hospital services, including the implant, now averages $1638, up from $1058 2 years earlier. In the office setting, reimbursement for bulking therapy continues under the Durable Medical Equipment Prosthetics, Orthotics and Supplies (DMEPOS) Schedule. There is no facility fee for in-office therapy, but each individual implant used in a procedure is covered separately. In an effort to move select procedures from the higher-cost hospital environment to the lower-cost office environment, CMS reimbursement of a physician’s technical fee for bulking therapy is 50% higher for an in-office procedure than for a hospital outpatient procedure. Payment is adjusted slightly by geographic region. According to the DMEPOS fee schedule, reimbursement per syringe is, on average, $351. There is a small reimbursement for placement of the skin test by a qualified health care provider, but there is no charge to the patient or the physician for the skin test material itself.

Main Points.

• A significant number of Americans experience urinary incontinence, with more than 60% of those exhibiting some component of stress urinary incontinence.

• Urinary incontinence exacts a high price in financial terms, relative to quality of life, but no single treatment is applicable to all patients, and there is often substantial benefit in combination therapy.

• A variety of bulking agents have been used with varying degrees of success in terms of providing nonimmunologic, hypoallergenic biocompatibility and bulking characteristics for prolonged periods without biodegradation or migration.

• Bulking agents, in addition to having a favorable safety profile, should be easy to prepare and implant.

• Intraurethral collagen injection has been demonstrated to be a safe, well-tolerated procedure equally effective in young and older women, with relatively long-term durability.

• Intrinsic sphincteric deficiency in the presence of hypermobility should not be a criterion for exclusion from bulking therapy.

• Bulking therapy has a well-established reimbursement profile and successful track record of payment history within both federal and private pay insurer systems.