Description
Anal fistula plugs (AFPs) are biosynthetic devices used to promote healing and prevent recurrence of anal fistulas. They are proposed as an alternative to procedures including fistulotomy, endorectal advancement flaps, seton drain placement, and use of fibrin glue in the treatment of anal fistulas.

For individuals who have anal fistula(s) who receive placement of AFP(s), the evidence includes 3 randomized comparative trials (RCTs), a number of comparative and noncomparative nonrandomized studies, and systematic reviews of these studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, and treatment-related morbidity. Two RCTs comparing AFP with surgical flap treatment have reported disparate findings: one found significantly higher rates of fistula recurrence with AFP; the other found similar rates of recurrence for AFP and surgical treatment. Another RCT, which compared AFP to seton drain removal alone for patients with fistulizing Crohn's disease, found no significant difference in healing rates at 12 weeks between groups. Systematic reviews of AFP repair of anal fistulas have demonstrated a wide range of success rates and heterogeneity in study results. Nonrandomized studies have also reported conflicting results. The evidence is insufficient to determine the effects of the technology on health outcomes. 

Background 
ANAL FISTULAS
An anal fistula is an abnormal communication between the interior of the anal canal or rectum and the skin surface. Rarer forms may communicate with the vagina or other pelvic structures, including the bowel. Most fistulas begin as anorectal abscesses, which are thought to arise from infection in the glands around the anal canal. When the abscess opens spontaneously in the anal canal (or has been opened surgically), a fistula may occur. Studies have reported that 26% to 37% of cases of perianal abscesses eventually form anal fistulas.¹

Other causes of fistulas include tuberculosis, cancer, prior radiotherapy, and inflammatory bowel disease. Fistulas may occur singly or in multiples. Symptoms include a purulent discharge and drainage of pus and/or stool near the anus, which can irritate the outer tissues causing itching and discomfort. Pain occurs when fistulas become blocked, and abscesses recur. Flatus may also escape from the fistulous tract.

The most widely used classification of anal fistulas is the Parks classification system, which defines anal fistulas by their position relative to the anal sphincter as transsphincteric, intersphincteric, suprasphincteric, or extrasphincteric. More simply, anal fistulas are described as low (present distally and not extending up to the anorectal sling) or high (extending up to or beyond the anorectal sling). The repair of high fistulas can be associated with incontinence. Diagnosis may involve a fistula probe, anoscopy, fistulography, ultrasound, or magnetic resonance imaging.     

Regulatory Status 
Several plugs for fistula repair have received clearance for marketing from the U.S. Food and Drug Administration through the 510(k) process and are outlined in Table 1.

Table 1: Devices for Anal Fistula Repair

FDA: Food and Drug Administration; PGA:TMC: polyglycolide-co-trimethylene carbonate; SIS: small intestinal submucosa. 

Policy
Biosynthetic fistula plugs, including plugs made of porcine small intestine submucosa or of synthetic material, are investigational and/or unproven and are therefore considered NOT MEDICALLY NECESSARY for all indications including, but not limited to, repair of anal and rectal fistulas

Policy Guidelines
See the Codes table for details.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African American, Asian, Black, Latino and Native American]; LGBTQIA [lesbian, gay, bisexual, transgender, queer, intersex, asexual]; women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.”

Anal Fistula Repair
Clinical Context and Therapy Purpose
The purpose of placing anal fistula plugs (AFPs) in individuals who have anal fistulas is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with anal fistulas.

The prevalence of anal fistulas is not well characterized. The mean age of individuals presenting with anal abscess and fistula is 40 years (range, 20 to 60). Men are more likely to develop an abscess and fistula than women.²

Interventions
The therapy being considered is an AFP.

Fistula plugs are designed to provide a structure that acts as a scaffold for new tissue growth. The scaffold, which can be derived from animal (eg, porcine) tissue or a synthetic copolymer fiber, is degraded by hydrolytic or enzymatic pathways as healing progresses. The plug is pulled through the fistula tract and secured at the fistula’s proximal opening. The fistula tract is left open at the distal opening to allow drainage. Several fistula plugs have been cleared for marketing by the U.S. Food and Drug Administration (FDA) (see Regulatory Status section).

A fistula plug derived from autologous cartilage tissue has been investigated in a small (N = 10) pilot study.³

Comparators
The following therapies are currently being used to treat anal fistulas: fistulotomy or fistulectomy, endorectal or anal sliding flaps, seton drains, and fibrin glue.

Treatment is aimed at repairing the fistula without compromising continence.

Surgical treatments for anal fistulas include fistulotomy or fistulectomy, endorectal or anal sliding flaps, ligation of the intersphincteric fistula tract (LIFT) technique, seton drain, and fibrin glue. Fistulotomy involves a division of the tissue over the fistula and laying open of the fistula tract. Although fistulotomies are widely used for low fistulas, lay-open fistulotomies in high fistulas carry the risk of incontinence. A seton is a thread placed through the fistula tract to drain fistula material and preventing the development of a perianal infection. Draining setons can control sepsis, but few individuals heal after removal of the seton, and the procedure is poorly tolerated long-term. A “cutting seton” refers to the process of regular tightening of the seton to encourage the gradual cutting of the sphincteric muscle with subsequent inflammation and fibrosis. Cutting setons can cause continence disturbances. Endorectal advancement flaps involve the advancement of a full or partial thickness flap of the proximal rectal wall over the internal (rectal) opening of the fistula tract. The intersphincteric fistula tract technique involves identifying the intersphincteric plane and then dividing the fistula tract; its use has been reported in small studies, but long-term follow-up is unavailable.⁴ Fibrin glue is a combination of fibrinogen, thrombin, and calcium in a matrix, which is injected into the fistula tract. The glue induces clot formation within the tract, which is then closed through the overgrowth of new tissue.

Outcomes
The general outcomes of interest are fistula repair and healing, elimination of symptoms, treatment-related complications (e.g., abscess), and fistula recurrence.

Short-term postsurgical follow-up can range between 2 and 12 weeks while longer-term follow-up monitoring can range from weeks to months.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Cheung et al. (2021) completed a systematic review and meta-analysis of all the available evidence (N = 28 studies) on the surgical management of adults with non-Crohn-related perianal fistulas.⁵ The primary outcomes were fistula recurrence and fecal incontinence. Since the included studies had a range of different comparison groups, pooling of data from all 28 studies was not possible. In the review, 2 studies (van Koperen et al. [2011]6 and Ortiz et al. [2009]⁷ described in the Randomized Controlled Trials section) compared fistula plug with advancement flap, with an increased recurrence rate in the plug group. Pooled data analysis on recurrence revealed an odds ratio (OR) favoring the advancement flap (OR, 4.22; 95% confidence interval [CI], 1.76 to 10.13; p = .03). No difference in incontinence scores between groups was noted.

Narang et al. (2016) published a systematic review of the Gore Bio-A plug for anal fistulas, which included 6 studies (N = 221) in a qualitative synthesis.⁸ Fistula healing rates ranged from 15.8% to 72.7%. Reviewers assessed the overall quality of the underlying studies as poor.

Nasseri et al. (2016) reported on a systematic review of AFP for patients with Crohn disease and anal fistulas.⁹ Twelve studies were included: 8 nonrandomized prospective studies and 4 retrospective studies (N = 84 ; range, 1 to 20 patients per study). Due to study heterogeneity, reviewers did not perform a weighted analysis with summary efficacy estimates. The total success rate of AFPs was 49 (58.3%) of 84 placed (95% CI, 47% to 69%).

Xu et al. (2016) reported on a meta-analysis of 10 comparative studies of AFPs and mucosal advancement flaps (MAFs) for complex anal fistulas (N = 778 ).¹⁰ Three studies were randomized trials; the remaining were observational studies or did not describe designs. In the pooled analysis, there were no significant differences in healing rates at the end of follow-up between the AFP and MAF groups (OR, 0.79; 95% CI, 0.36 to 1.73; p = .55, I2 = 74%). None the 7 studies reporting on recurrence rates found significant differences in rates (OR, 2.29; 95% CI, 0.59 to 8.88; p = .23, I2 = 83%). However, conclusions were limited by shortcomings in the underlying evidence base.

Randomized Controlled Trials
Jayne et al. (2021) compared the use of porcine AFPs (Biodesign Surgisis) with surgeon's preference (advancement flap, cutting seton, fistulotomy, or Ligation of the Intersphincteric Fistula Tract [LIFT] procedure) in 304 patients with transsphincteric fistulas in the pragmatic, multicenter, randomized FIAT trial.¹¹ The primary outcome was fecal incontinence quality of life (FIQoL) at 12 months. Secondary outcome measures included fistula healing, incontinence rates, and complications. No significant differences were seen in FIQoL between groups at 12 months. Clinical fistula healing was reported in 66/122 (54%) of the AFP group and 66/119 (55%) of the surgeon's preference group at 12 months. Marginal improvement in fecal incontinence rates was observed in both groups. Frequent complications and reinterventions were observed, with significantly more complications in the AFP group at 6 weeks (49/142 (35%) vs. 25/137 (18%); p = .002).

Senejoux et al. (2016) reported on a RCT comparing AFP with seton removal alone in 106 patients who had Crohn disease with non- or mildly active disease but at least 1 anoperitoneal fistula drained for at least 1 month.¹² The trial was powered for the superiority of AFP, and the analysis was intention-to-treat. At 12 weeks of follow-up, in the AFP group (n = 54), the clinical remission rate was 31.5% compared with 23.1% in the control group (relative risk, 1.31; 95% CI, 0.59 to 4.02; p = .19). Fistula tract healing rates on magnetic resonance imaging did not differ significantly between groups at 12 weeks.

Van Koperen et al. (2011) reported on a double-blind, multicenter, randomized trial comparing AFP with MAF in 60 patients with high perianal fistulas.⁶ At 11-month follow-up, trialists reported fistula recurrence in 22 (71%) patients in the AFP group and in 15 (52%) patients in the advancement flap group; these rates did not differ significantly (p = .126). Postoperative pain scores, quality of life after surgery, and functional outcomes did not differ significantly between groups. Despite disappointing results, trialists indicated the plug might be considered as an initial treatment option because the procedure is simple and minimally invasive.

Ortiz et al. (2009) compared the use of porcine submucosal (Surgisis) AFPs with an endorectal anal flap (ERAF) procedure in a RCT of 43 patients with high anal fistula.7 The primary endpoint was fistula healing. Recurrence was defined as the presence of an abscess in the same area or obvious evidence of fistulization. Five patients in the AFP group and 6 in the ERAF group did not receive the allocated intervention, leaving 32 patients. One patient in the AFP group was lost to follow-up. A large number of fistula recurrences in the fistula plug group led to the premature closure of the trial. After 1 year, fistula recurrence was seen in 12 of 15 patients treated with an AFP versus 2 of 16 patients who underwent the flap procedure (relative risk, 6.40; 95% CI, 1.70 to 23.97; p < .001). A trend for more sphincter involvement and more women in the ERAF group was noted. Complications were not reported.

Nonrandomized Comparative Studies
Because several RCTs exist, non-randomized studies will be summarized briefly below only if they capture longer periods of follow-up- (>1 year), larger populations, or particular subgroups of interest.

Retrospective Studies
Christoforidis et al. (2009) retrospectively analyzed patients from a U.S. center with transsphincteric fistulas treated with ERAF (n = 43) or anal plug (Surgisis; n = 37) between 1996 and 2007.¹³ Success was defined as a closed external opening in the absence of symptoms at minimal follow-up of 6 months. The success rate was 63% in the ERAF group and 32% in the AFP group after a mean follow-up of 56 months (range, 6 to 136 months) for ERAF and 14 months (range, 6 to 22 months) for AFP. After the exclusion of patients with early AFP extrusion, which may be considered a technical failure, the ERAF advantage was not statistically significant (p = .06). Twenty-three of 27 patients who had ERAF and 7 of 12 patients who had AFP responded to a questionnaire addressing functional outcomes. In the ERAF group, 11 of 23 patients had no continence disturbance versus 6 of 7 in the AFP group. The lack of prospectively collected incontinence scores before the procedure, and a low response rate in the AFP group does not permit valid comparisons on functional outcomes. Complication rates were low in both groups; only 2 patients in the ERAF group required reoperation for bleeding.

Wang et al. (2009) compared outcomes for patients who had transsphincteric fistulas treated using an AFP from 2005 to 2006 (n = 29) with historical controls treated with ERAF (2001-2005) (n = 26).¹⁴ Of 26 initial flap procedures, 10 failed and 16 healed. Of 29 initial plug procedures, 19 failed and 10 healed. In total, 30 advancement flaps and 34 plug procedures were performed (including additional treatments for failed initial procedures). Closure rates were 34% for plugs (mean follow-up, 279 days; range, 110 to 690 days) and 62% for flaps (median follow-up, 819 days; range, 93 to 1928 days; p = .045). Complications were not reported.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Colon and Rectal Surgeons
The 2022 practice guideline on the treatment of anorectal abscess, fistula-in-ano, and rectovaginal fistula from the Society provided a strong recommendation based on moderate-quality evidence that anal fistula plug and fibrin glue are relatively ineffective treatments for fistula-in-ano.¹⁵

National Institute for Health and Care Excellence
In 2019, the National Institute for Health and Care Excellence updated its guidance on the suturable bioprosthetic plug.¹⁶ The Institute determined that "evidence on the safety and efficacy of bioprosthetic plug insertion for anal fistula is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent, and audit." Though, it was noted that "the procedure should only be done by a surgeon experienced in managing anal fistulas."

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
There are currently no relevant ongoing clinical trials of plugs for anal fistula repair in ClinicalTrials.gov through September 15, 2023.

References   

1. Simpson JA, Banerjea A, Scholefield JH. Management of anal fistula. BMJ. Oct 15 2012; 345: e6705. PMID 23069597
2. Sahnan K, Askari A, Adegbola SO, et al. Persistent Fistula After Anorectal Abscess Drainage: Local Experience of 11 Years. Dis Colon Rectum. Mar 2019; 62(3): 327-332. PMID 30451763
3. Ozturk E. Treatment of recurrent anal fistula using an autologous cartilage plug: a pilot study. Tech Coloproctol. May 2015; 19(5): 301-7. PMID 25850629
4. Campbell ML, Abboud EC, Dolberg ME, et al. Treatment of refractory perianal fistulas with ligation of the intersphincteric fistula tract: preliminary results. Am Surg. Jul 2013; 79(7): 723-7. PMID 23816007
5. Cheung XC, Fahey T, Rogers AC, et al. Surgical Management of Idiopathic Perianal Fistulas: A Systematic Review and Meta-Analysis. Dig Surg. 2021; 38(2): 104-119. PMID 33503621
6. van Koperen PJ, Bemelman WA, Gerhards MF, et al. The anal fistula plug treatment compared with the mucosal advancement flap for cryptoglandular high transsphincteric perianal fistula: a double-blinded multicenter randomized trial. Dis Colon Rectum. Apr 2011; 54(4): 387-93. PMID 21383557
7. Ortiz H, Marzo J, Ciga MA, et al. Randomized clinical trial of anal fistula plug versus endorectal advancement flap for the treatment of high cryptoglandular fistula in ano. Br J Surg. Jun 2009; 96(6): 608-12. PMID 19402190
8. Narang SK, Jones C, Alam NN, et al. Delayed absorbable synthetic plug (GORE(R) BIO-A(R)) for the treatment of fistula-in-ano: a systematic review. Colorectal Dis. Jan 2016; 18(1): 37-44. PMID 26542191
9. Nasseri Y, Cassella L, Berns M, et al. The anal fistula plug in Crohn's disease patients with fistula-in-ano: a systematic review. Colorectal Dis. Apr 2016; 18(4): 351-6. PMID 26749385
10. Xu Y, Tang W. Comparison of an anal fistula plug and mucosa advancement flap for complex anal fistulas: a meta-analysis. ANZ J Surg. Dec 2016; 86(12): 978-982. PMID 27680894
11. Jayne DG, Scholefield J, Tolan D, et al. A Multicenter Randomized Controlled Trial Comparing Safety, Efficacy, and Cost-effectiveness of the Surgisis Anal Fistula Plug Versus Surgeon's Preference for Transsphincteric Fistula-in-Ano: The FIAT Trial. Ann Surg. Mar 01 2021; 273(3): 433-441. PMID 32516229
12. Senejoux A, Siproudhis L, Abramowitz L, et al. Fistula Plug in Fistulising Ano-Perineal Crohn's Disease: a Randomised Controlled Trial. J Crohns Colitis. Feb 2016; 10(2): 141-8. PMID 26351393
13. Christoforidis D, Pieh MC, Madoff RD, et al. Treatment of transsphincteric anal fistulas by endorectal advancement flap or collagen fistula plug: a comparative study. Dis Colon Rectum. Jan 2009; 52(1): 18-22. PMID 19273951
14. Wang JY, Garcia-Aguilar J, Sternberg JA, et al. Treatment of transsphincteric anal fistulas: are fistula plugs an acceptable alternative?. Dis Colon Rectum. Apr 2009; 52(4): 692-7. PMID 19404076
15. Gaertner WB, Burgess PL, Davids JS, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Anorectal Abscess, Fistula-in-Ano, and Rectovaginal Fistula. Dis Colon Rectum. Aug 01 2022; 65(8): 964-985. PMID 35732009
16. National Institute for Health and Care Excellence (NICE). Bioprosthetic plug insertion for anal fistula [IPG662]. September 25, 2019; https://www.nice.org.uk/guidance/ipg662. Accessed September 15, 2023.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

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