Coverage Policy Manual
Policy #: 2010020
Category: Surgery
Initiated: April 2010
Last Review: December 2018
  Plugs for Anal Fistula Repair

Description:
Anal fistula plugs are biosynthetic devices used to promote healing and prevent recurrence of anal fistulas (fistula-in-ano). The conical-shaped plug is anchored in the anal fistula and acts as a scaffold into which new tissue can grow to close the fistula. The plug is absorbed into the body in 6 to 8 weeks. The procedure may require 12–24 hours observation postoperatively. The procedure can be repeated in case of failure.
 
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 into the anal canal (or has been opened surgically), a fistula may occur. Other causes of fistulas include tuberculosis, cancer, 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. Anal fistulas are described as low (present in the lower part and not extending up to the anorectal sling) or high (extending up to or beyond the ano-rectal sling). The repair of high fistula can be associated with incontinence. Diagnosis may involve fistula probe, anoscopy, fistulography, ultrasound, or magnetic resonance imaging.
 
Treatment is aimed at repairing the fistula without compromising continence. Surgical treatments for anal fistulas include fistulotomy/ fistulectomy, endorectal/anal sliding flaps, ligation of the intersphincteric fistula tract (LIFT) technique, seton drain, and fibrin glue. Fistulotomy involves 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 carries the risk of incontinence. A seton is a thread placed through the fistula tract for the purpose of draining fistula material and preventing the development of a perianal infection. Draining setons can control sepsis, but few patients 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 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 LIFT 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 (Campbell, 2013). Fibrin glue is a combination of fibrinogen, thrombin, and calcium in a matrix, which is injected into the fistula track. The glue induces clot formation within the tract, which is then closed through overgrowth of new tissue. Evidence for new treatments must allow comparison with conventional treatment on outcomes including symptoms, change in disease status, morbid events, functional outcomes (ie, sphincter function), and treatment-related morbidity.
 
 
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 fistulas proximal opening; the fistula tract is left open at the distal opening to allow drainage.
 
Regulatory Status
Several plugs for fistula repair have received clearance for marketing from FDA through the 510(k) process and are outlined in Table 1.
 
Table 1: Devices for Anal Fistula Repair
Device   SIS Fistula Plug (Cook Biotech Inc.)  
Year   March 2005
Description  Manufactured from porcine SIS
Indication(s)  Repair of anal, rectal and enterocutaneous fistulas
Predicate Device(s) SURGISIS® Soft Tissue Graft (Cood Biotech Ic.)
FDA Product Code FTM
 
Device   Surgisis RVP Recto-Vaginal Fistula Plug  (Cook Biotech Inc.)
Year   October 2006
Description Manufactured from porcine SIS; tapered configuration with a button to provide increased plug retention and improved blockage of the fistula
Indication(s)  Reinforce soft tissue for the repair of rectovaginal fistulas
Predicate Device(s) SIS Fistula Plug (Cook Biotech Inc.)
FDA Product Code FTM
 
Device   Surgisis Biodesign Enterocutaneous Fistula Plug (Cook Biotech, Inc.)
Year   February 2009
Description Manufactured from porcine SIS; tapered configuration with a flange to provide increased retention of the plug and improved blockage of the fistula
Indication(s)  Reinforce soft tissue for the repair of enterocutaneous fistulas
Predicate Device(s) SIS Fistula Plug (Cook Biotech Inc.)
FDA Product Code FTM
 
Device   Gore Bio-A Fistula Plug (W.L. Gore & Associates Inc.
Year   March 2009
Description  Manufactured from bioabsorbable polyglucolide-cotrimethylene carbonate (PGA:TMC) copolymer;  Supplied in a 3- dimensional configuration of a disk with attached tubes
Indication(s)  Reinforce soft tissue for the repair of anorectal fistulas
Predicate Device(s) Gore Bioabsorbable Mesh (W.L. Gore & Associates Inc.) SIS Fistula Plug (Cook Biotech Inc.)
FDA Product Code FTL
  
Beginning in 2010, there is a specific CPT code for use of these plugs in repair of an anorectal fistula:  (46707). Prior to 2010, this was reported with a category III code – 0170T.
 

Policy/
Coverage:
Effective November 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Biosynthetic fistula plugs, including plugs made of porcine small intestine submucosa or of synthetic material meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for repair of anal and rectal fistulas meeting all of the following criteria:  
 
    1. Complex anal fistulas*  that are either:
 
        • High fistulas; OR
        • Anterior fistulas; OR
        • Fistulas that transverse a significant portion of the anal sphincter muscle (greater than or equal to 30% of sphincter)
 
 
AND
 
 
2. The patient has a high risk of incontinence
 
 
*Complex anal fistulas refer to fistulas that have a high risk of treatment failure and cannot be treated safely (have a high risk for incontinence) by routine fistulotomy (Garg, 2017).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
Biosynthetic fistula plugs, including plugs made of porcine small intestine submucosa or of synthetic material for the repair of anal and rectal fistulas other than those listed above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, biosynthetic fistula plugs, including plugs made of porcine small intestine submucosa or of synthetic material for the repair of anal and rectal fistulas other than those listed above, are considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective April 2010 - October 2018
Biosynthetic fistula plugs, including plugs made of porcine small intestine submucosa or of synthetic material for all indications including, but not limited to, repair of anal and rectal fistulas do not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, biosynthetic fistula plugs, including plugs made of porcine small intestine submucosa or of synthetic material are considered investigational for all indications including, but not limited to, repair of anal and rectal fistulas.  Investigational services are exclusions in most member benefit certificates of coverage.
 

Rationale:
Conventional treatments for anal fistula include fistulotomy/fistulectomy, endorectal/anal sliding flaps, seton drain, and fibrin glue. Evidence for new treatments must allow comparison with conventional treatment on outcomes including safety, healing, fistula recurrence, and sphincter function.
 
There is limited published data on outcomes of anal plug procedures, and in all of the published studies, fistula plugs were made of porcine small intestinal submucosal tissue. Search of the MEDLINE database found 1 randomized controlled trial and 3 retrospective comparative studies. Ortiz and colleagues in a European trial compared use of porcine submucosal (Surgisis) anal fistula plug (AFP) with an endorectal anal flap (ERAF) procedure in a randomized controlled trial (RCT) with 43 patients who had high anal fistula (Ortiz, 2009). 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 recurrences in the fistula plug group led to premature closure of the trial. After 1 year, fistula recurrence was seen in 12 of 15 patients treated with an anal fistula plug versus 2 of 16 patients who underwent the flap procedure. Fistulas recurred in 9 of 16 patients who had previously undergone fistula surgery; 8 of the 9 patients had an AFP. A trend for more sphincter involvement and more females in the ERAF group was noted. Complications were not reported in this paper.
 
Christoforidis et al performed a retrospective analysis of patients from a U.S. center with transsphincteric fistulas treated with ERAF (n=43) or anal plug (Surgisis) (n=37) between January 1996 and April 2007 (Christoforidis, 2009). Success was defined as closed external opening in absence of symptoms at minimal follow-up of 6 months. The success rate was 63% in the ERAF group and 32% in the in AFP group after a mean follow-up of 56 months for ERAF and 14 (range, 6–22) months. After exclusion of patients with early AFP extrusion, which may by considered a technical failure, the ERAF advantage did not meet statistical significance. 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 prior to the procedure and low response rate in the AFP group prohibit valid comparisons on functional outcomes. Complication rates were low in both groups; 2 patients in the ERAF group required reoperation for bleeding. No serious complications occurred in the AFP group. The authors conclude that “randomized trials are needed to further elucidate the efficacy and potential functional benefit of AFP in the treatment of complex anal fistulas.”
 
Wang et al compared outcomes of all patients with transsphincteric fistulas treated with AFP from July 2005 to December 2006 (n=29) and compared them with historical controls treated with ERAF (2001–2005) (n=26) (Wang, 2009). 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 the additional treatments for failed initial procedures). Closure rates were 34% for plugs (mean follow-up 279 days) and 62% for flaps (median follow-up 819 days). Complications were not reported. The authors conclude that a systematic randomized trial with long-term follow-up comparing advancement flaps with fistula plugs is needed, and they calculate that 112 patients would need to be randomized to detect a statistically significant difference in success rates for each procedure. Because the fistula plugs are costly, the authors recommend that cost-benefit analysis be performed.
 
A retrospective study of 232 patients treated in Canada between 1997 and 2008 by a variety of methods for high transsphincteric anal fistulas was reported (Chung, 2009). Postoperative healing rates at the 12-week follow-up for the fistula plug, fibrin glue, flap advancement, and seton drain groups were 59.3%, 39.1%, 60.4%, and 32.6%, respectively. They conclude that closure of the primary fistula opening using a biological anal fistula plug and anal flap advancement result in similar fistula healing rates in patients with high transsphincteric fistulas, and that these strategies are superior to seton placement and fibrin glue. “Given the low morbidity and relative simplicity of the procedure, the anal fistula plug is a viable alternative treatment for patients with high transsphincteric anal fistulas.” The 12-week follow-up time in this study is likely too short to evaluate the durability of treatment.
 
The remainder of the published evidence for anal fistula plug consists of case series, most with small numbers of subjects. A 2009 systematic review reports a wide range of success rates (Garg, 2009). In the 12 included studies, all case series, reported success rates for the AFP procedure were from 24% to 92%. Success rates in treating complex fistula-in-ano in the 8 prospective studies reviewed were 35%–87%. Other papers report treatment of very small numbers of patients with rectovaginal fistulas, endoscopic treatment of postoperative enterocutaneous fistulas after bariatric surgery, a colocutaneous fistula, and a recurrent tracheoesophageal fistula treated with fistula plug.
 
A number of clinical trials are proposed or recruiting patients, including a study in which 300 patients will be randomized to receive either the Surgisis plug or placement of a cutting seton drain, and an industry- sponsored study comparing the Surgisis plug with advancement flap surgery (Clinical Trials. Gov).  
 
Summary: Evidence of efficacy of anal fistula plug treatment is quite limited. An RCT and retrospective comparisons did not demonstrate that anal plugs improved healing rates or reduced recurrence of anal fistulas. Case series report a wide range of results. Randomized controlled trials with sufficient numbers of patients and with at least 6 months of follow-up reporting healing and recurrence rates and sphincter function before and after procedures are required. In light of the limited data available and inconsistent outcomes reported the impact of anal fistula plugs on net health outcome is not known.
 
Technology Assessments, Guidelines and Position Statements
The most recent (2005) Practice Parameters for the Treatment of Perianal Abscess and Fistula-in-Ano from the American Society of Colorectal Surgeons does not mention treatment with an anal plug (Whiteford, 2005).
 
The National Institute for Health and Clinical Excellence (NICE) published guidance on the suturable bioprosthetic plug in June 2007. NICE determined that while there are no major safety concerns, evidence on the efficacy of the procedure is not adequate for it to be used without special arrangements for consent and for audit or research. Further, clinicians wishing to perform the procedure should inform the clinical governance leads in their Trust, ensure that patients understand the uncertainty about the procedure’s efficacy and provide them with clear written information, and audit and review clinical outcomes, ideally through collaborative data collection. Publication of safety and efficacy outcomes would be useful.
 
2011 Update  
A retrospective study from the Mayo Clinic described 20 patients who had anal plug closure, 17 of whom had the plug as the only procedure, with a success rate of 24%, and perianal sepsis rate of 29% (Lawes, 2008).  A New England registry reported by the University of Vermont, reviewed the effectiveness of various treatments for anal fistulae and found that anal plugs had only a 32% healing rate at 3 months, whereas 80% of patients with fistulotomy were healed at 3 months (Hyman, 2009).  A retrospective study of 36 patients from the Cleveland Clinic found a success rate at a mean of 124 days of 13.9% (Safar, 2008).  A retrospective study at the University of South Alabama of 63 patients who received the plug found a healing rate of 81% (Ellis, 2010).  A 2010 systematic review from India looked at 12 studies (total of 317 patients) and concluded that the AFP procedure had a success rate ranging from 24% to 92%.  In complex fistula-in-ano prospective studies (8 of the 12), the success rate was 35-87%.  The success rate in patients with Crohn’s disease was 29-86%.  The success rate in patients with single tracts was 44-93%, and in patients with multiple tracts, success ranged from 20% to 71%.  The abscess formation/sepsis rate was 4-29% (11/108) and the plug extrusion rate was 4-41% (42/232).  They concluded, “further randomized controlled trials studying objective parameters of fistula healing are needed to substantiate these findings” (Garg, 2010).  A randomized trial from The Netherlands compared the plug with mucosal advancement flap, and the plug was significantly better (Koperen, 2011). It is difficult to interpret this from the standpoint that out of the 245 procedures reported to the New England Registry, there were only 4 procedures done using the mucosal advancement flap technique.  A retrospective study of 37 patients reported from Denmark found a cure rate of 46%.  The authors concluded, “Current knowledge suggests that the AFP is a good choice for 1st line measurement of complex fistula-in-ano, but further evaluation is needed (Kleif, 2011).  A clinical trial investigating the effectiveness of the plug versus the seton (NCT00450671) is ongoing at the University of Southern California, and a trial comparing the plug versus ligation of the intersphincteric fistula tract (NCT00830661) is ongoing at the University of Pennsylvania, Massachusetts General Hospital, and the University of Ottawa. Both studies have statements such as “Anal fistulae are a difficult problem to treat. The optimal treatment for fistula involving the anal sphincter is unclear.” Both studies are scheduled to be reported in 2012.  Because of the conflict in outcomes in reported trials, and the fact that the treatment is being studied in randomized trials, anal plugs for treatment of fistula remains investigational.
 
2012 Update
A search of the MEDLINE database was conducted through September 2012.  There was no new information identified that would prompt a change in the coverage statement. Two documents were identified that support the coverage statement.
 
The 2011 Practice Parameters for the Treatment of Perianal Abscess and Fistula-in-Ano from the American Society of Colon and Rectal Surgeons gives treatment with an anal fistula plug for complex anal fistulas a weak recommendation. The guidelines note the available evidence is of moderate quality with success rates of <50% in the majority of studies (Steele, 2011).
 
The National Institute for Health and Clinical Excellence (NICE) published updated guidance on the suturable bioprosthetic plug in November 2011. (NICE, 2011) NICE determined that while there are no major safety concerns, evidence on the efficacy of the procedure is not adequate for it to be used without special arrangements for consent and for audit or research. Further, clinicians wishing to perform the procedure are encouraged to enroll patients into the Fistula-In-Ano Trial (FIAT) (Available online at: www.hta.ac.uk/project/1998.asp or www.controlled-trials.com/ISRCTN78352529). If the clinician chooses to perform the procedure outside of a clinical trial, the clinician should inform the clinical governance leads in their Trust, ensure that patients understand the uncertainty about the procedure’s efficacy and provide them with clear written information (NICE recommends the information it developed for patients be provided) and audit and review clinical outcomes.
 
2013 Update
A search of the MEDLINE database through 2013 did not reveal any new literature that would prompt a change in the coverage statement.
 
In 2012, 3 reviews were published comparing AFP to conventional surgical treatment for anal fistulas (Pu, 2012; Leng, 2012; O’Riordan, 2012). Pu and colleagues undertook a meta-analysis of 5 studies (2 RCTs and 3 retrospective studies) published through April 2012. Treatment options in the conventional arm of this review included endorectal/mucosal advancement flaps, fibrin glue, and seton drains (Pu, 2012). The 2 RCTs included in this analysis (Ortiz, 2009; van Koperen, 2011) are discussed below under randomized controlled trials. On combined analysis, AFP patients had a higher recurrence rate (62%) compared to those undergoing conventional treatment options (47%) after 3 months of follow-up (5 studies, 428 patients; p=0.004, odds ratio [OR]: 1.91; 95% confidence interval [CI]: 1.23-2.97).
 
Leng and Jin undertook a meta-analysis of 6 studies published through April 2011 (3 RCTs, 2 retrospective studies, and one cohort study) involving 408 patients comparing AFP with mucosal advancement flap (MAF) (Leng, 2012). Two of the RCTs in this analysis were included in the review by Pu and colleagues above; the third RCT was a Chinese trial of 90 patients comparing AFP (manufactured in China and similar in design to the SURGISIS®) to the MAF. On combined analysis, the differences in the overall success rates (6 studies) and incidence of fistula recurrence (4 studies including 3 RCTs) were not statistically significant between the AFP and MAF (risk difference [RD]: -0.12; 95% CI: -0.39 - 0.14; RD: 0.13; 95% CI: -0.18 - 0.43, respectively) (Leng, 2012). The risk of continence postoperatively (3 studies including 2 RCTs), however, was reported to be lower with AFP (RD: -0.08; 95% CI: 0.15 to -0.02). In addition to the small numbers of controlled studies and limited follow-up, the findings of this meta-analysis were further limited by significant heterogeneity across studies (Leng, 2012).
 
O’Riordan and colleagues undertook a systematic review of AFP (20 studies including 2 RCTs by Ortiz and van Koperan) for patients with Crohn’s and non-Crohn’s-related anal fistulas (O’Riordan, 2012).  The follow-up period across studies ranged from 3 months to 24.5 months. The pooled proportion of patients achieving fistula closure in patients with non-Crohn’s anal fistula was 0.54 (95% CI: 0.50-0.59). The proportion achieving closure in patients with Crohn’s disease was similar (0.55, 95% CI: 0.39-0.70) (O'Riordan, 2012). There were no reported cases of any significant change in continence after AFP insertion in any of the study patients (n=196). The findings of this systematic review are limited by the variability of operative technique and perioperative care across studies, which may influence the probability of success or failure associated with the AFP (O’Riordan, 2012).
 
Ongoing Clinical Trials
A search of online site clinicaltrials.gov identified at least 5 randomized controlled trials on anal fistula plugs. In NCT00830661, a biodegradable porcine anal fistula plug will be compared to ligation of the intersphincteric fistula tract (LIFT) procedure (LIFT vs. PLUG) in 124 randomized patients at 4 North American institutions. The estimated completion date of this trial was March 2012; however, its recruitment status is presently unknown because the information has not been verified as of May 2009. In another RCT, the SURGISIS® anal fistula plug will be compared to the advancement flap procedure in 86 randomized patients in Germany (NCT 00545441). This trial is completed, but not recruiting participants; study results have not been published.
 
The University of California, Los Angeles is conducting a trial to compare the SURGISIS® plug to cutting seton drain in 300 patients (NCT00450671). The estimated completion date of this trial was February 2012; however, its recruitment status is presently unknown because the information has not been verified as of March 2007. In NCT 01021774, an unspecified collagen plug will be compared to advancement flap in 100 randomized patients in Sweden. This trial is currently recruiting participants with an estimated completion date of December 2013. And finally, the LIFT procedure will be compared to LIFT combined with the anal fistula plug in China in 240 patients (NCT01478139). The estimated completion date of this trial was February 2013; however, its recruitment status is presently unknown because the information has not been verified as of November 2011.
 
2014 Update
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2013, Cirocchi et al published results of a systematic review and meta-analysis of studies that compared biologically derived products for fistula repair, including fibrin glue, AFPs, and acellular dermal matrix, with surgical therapy for fistula repair (Cirocchi, 2013). Seven studies were considered eligible for their evidence review, 4 of which included comparisons of AFPs with surgery, and 2 of which were RCTs (Ortiz 2009 and van Koperen 2011, described next). In combined analysis, AFP placement was not significantly different than surgical treatment in terms of rates of healing (pooled risk ratio [RR]=1.19, 95% confidence interval [CI], 0.51 to 2.76). Recurrence of anal fistulas was not significantly different between patients treated with AFP compared with those treated with surgery, although the confidence interval for the pooled analysis was very wide (pooled odds ratio [OR]=3.12, 95% CI, 0.52 to 18.83).
 
Several systematic reviews of studies of AFP repair of anal fistulas demonstrate a wide range of success rates and heterogeneity in study results. The net benefit of a strategy using AFP compared with open surgical repair is a lack of high-quality trials and uncertainty related to the tradeoff between a less invasive procedure and a higher fistula reoccurrence rate.
 
Noncomparative Studies
Blom et al reported results from a retrospective analysis of outcomes after AFP placement (with the Biodesign plug) at 4 hospitals (Blom, 2013). The authors identified 126 patients who underwent AFP placement who were followed over a median of 13 months (range 1-47). At the time of the last assessment, 30/126 patients (24%) had no symptoms indicative of fistula (pain at the fistula site or drainage). Anterior fistulas were less likely to have successful closure (12%) than posterior (32%) or lateral (41%) fistulas.
 
Cintron et al reported results from a prospective evaluation of 73 patients who received a porcine AFP (SurgiSIS AFP) for anorectal fistulas of various etiologies (Cintron, 2013). Patients with anorectal fistulas were offered participation in the study, although it is not noted how many patients were approached to participate. Seventy-eight plugs were inserted in 73 patients, and there were 7 plug fallouts (9.6% patient fallout rate). There were 45 treatment failures at a mean follow-up of 15 months (61.6% patient failure rate). The authors note that prior series of AFPs report a wide range in success rates from 24% to 88%.
 
Tan et al reported results from a prospective study with longer term follow-up (median 59 weeks) of patients who received the SurgiSIS AFP for anal fistulas thought to result from cryptoglandular abscesses (Tran, 2013). Twenty-six patients with 30 fistulas were included. Most fistulas (86.7%) were transsphincteric. At last follow-up, 26 fistulas (86.7%) had reccurred.
 
Ongoing and Unpublished Clinical Trials
A search of online database ClinicalTrials.gov in July 2014 identified the following comparative trials\ evaluating anal fistula plugs:
  • A Randomized Clinical Trial Comparing Surgisis AFP to Advancement Flap for the Repair of Anal Fistulas (SurgiSIS AFP) (NCT00545441) – This is a randomized, open-label trial to compare a fistula plug (Surgisis AFP) to advancement flap surgery for the repair of transsphincteric, suprasphincteric, or extrasphincteric anal fistulas. Enrollment is planned for 86 subjects; the estimated study completion date was April 2013, but no results have been posted.
  • Ligation of Intersphincteric Fistula Tract (LIFT) Versus LIFT-plug Procedure for Anal Fistula Repair (NCT01478139) – This is a randomized, open-label trial to compare the LIFT procedure with LIFT with a bioprosthetic plug in patients with a transsphincteric fistula tract determined to be of cryptoglandular origin. Enrollment is planned for 240 patients; the estimated study completion date was November 2013, but no results have been posted.
  • Anal Fistula Treatment Outcome - Collagen Plug Versus Advancement Flap Surgery (NCT01021774) – This is a randomized, single-blinded trial to compare a collagen plug (device not specified) with advancement flap surgery for the treatment of perianal fistulas. Enrollment is planned for 100 subjects; the estimated study completion date is December 2015.
 
A search of the International Standard Randomised Controlled Trial Number Register identified an additional randomized trial evaluating anal fistula plugs:
  • The Fistula-In-Ano Trial (FIAT) comparing Surgisis® anal fistula plug versus surgeon's preference (advancement flap, fistulotomy, cutting seton) for transsphincteric fistula-in-ano (ISRCTN78352529) – This is an RCT to evaluate the SurgiSIS AFP with standard care for management of high anal fistulas. Enrollment is planned for 500 subjects; the estimated study completion date is May 2015.
 
2015 Update
A literature search conducted through September 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Nonrandomized Comparative Studies
A number of nonrandomized studies have compared AFP with various alternative treatments for anal fistula. Hall and colleagues reported results from another larger study, which reported on a multicenter registry of prospectively-collected data on 240 operations for anal fistula, including those conducted with AFPs (Hall, 2013). Rates of utilization of fistulotomy, LIFT procedure, advancement flap, AFP placement, draining seton, and cutting seton were 61%, 18%, 6.3%, 4.2%, 8.3%, and 0.83%, respectively. The healing rate for patients treated with AFPs was 20% (95% CI 5 to 50%), compared with 95% after fistulotomy (95% CI 89 to 97%), 79% after LIFT procedure (95% CI 65 to 88%), 100% after cutting seton placement (95% CI 34 to 100%) and 60% after endorectal advancement flap (95% CI 33 to 77%).
 
Several smaller or retrospective studies have also compared AFP and alternative treatments. Fischer and colleagues reported results of a retrospective study evaluating success rates after AFP (n=31) or endorectal advancement flap (n=40) in patients with anal fistula treated at a single institution from 2007 to 2012 (Fischer, 2015). For patients treated after May 2007, the Surgisis anal fistula plug was available. More patients treated with AFP had inflammatory bowel disease (IBD) (29.0% vs 5.0%; P=0.008). During follow-up, 12 (39%) patients treated with AFP and 17 (43%) treated with endorectal advancement flap had fistula recurrence (OR 0.94, 95% CI 0.32 to 2.72, P=1.00). Rates of complications did not differ significantly between groups.
 
Non-comparative Studies
Stamos and colleagues prospectively evaluated healing rates after treatment with a bioabsorbable AFP among 93 patients with complex trans-sphincteric anal fistulas (Stamos, 2015).  Seventy-three patients (78%) also received draining setons preoperatively at the surgeon’s discretion. Over 1 year of follow up, 13 patients were lost to follow up and 21 patients were withdrawn, most often due to need for an alternative treatment. Of the 66 patients examined 6 months after plug implantation, 30 had a healed fistula. Of the 55 patients examined 12 months after plug implantation, 36 had a healed fistula, but plug implantation failed in 18 patients before the 12-month visit. Overall continence scores improved from baseline (pre-surgery) to 6 months post-surgery.
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this policy are listed below:
 
Ongoing:
(NCT01021774) Comparison of Anal Fistula Treatment Outcome – Collagen Plug vs Advancement Flap Surgery. A Randomized prospective Blinded Multi-centre Study; planned enrollment 100; completion date December 2016.
 
Unpublished
(NCT01478139) Ligation of Intersphincteric Fistula Tract (LIFT) Versus LIFT-plug Procedure for Anal Fistula Repair: a Multicenter, Randomized, Open-label, Parallel Controlled Trial; planned enrollment 240; completion date November 2013 (last verified 2013)
 
(NCT00545441) industry sponsored or cosponsored trial. A Randomized Clinical Trial Comparing Surgisis AFP to Advancement Flap for the Repair of Anal Fistulas; planned enrollment 86; completed
 
(ISRCTN78352528) Surgisis® anal fistula plug versus surgeon's preference (advancement flap, fistulotomy, cutting seton) for transsphincteric fistula-in-ano: a multicentre phase III randomized controlled trial; planned enrollment 500; completed
 
The evidence for the use of anal fistula plug (AFP) placement for the treatment of individuals with anal fistulas includes 2 randomized comparative trials (RCTs), a number of comparative and noncomparative nonrandomized studies, and systematic reviews of these studies. Relevant outcomes include symptoms, change in disease status, morbid events, functional outcomes, and treatment-related morbidity. The 2 available RCTs comparing AFP with surgical flap treatment reported disparate findings: one reported significantly higher rates of fistula reoccurrence with AFP, while the other found similar rates of reoccurrence between AFP and surgical treatment. Systematic reviews of studies of AFP repair of anal fistulas demonstrate a wide range of success rates and heterogeneity in study results. The body of evidence consists of RCTs and nonrandomized studies that have conflicting results. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
2017 Update
A literature search conducted through September 2017 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Narang and colleagues published a systematic review of the Gore Bio-A plug for anal fistulas, which included 6 studies (total N=221 patients) in a qualitative synthesis (Narang, 2016). Fistula healing rates ranged from 15.8% to 72.7%. Reviewers assessed the overall quality of the underlying studies as poor.
 
Nasseri  and colleagues reported on a systematic review of AFP for patients with Crohn disease and anal fistulas (Nasseri, 2016). Twelve studies were included: 8 nonrandomized prospective studies and 4 retrospective studies (total N=84 patients; range, 1-20 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% confidence interval [CI], 47% to 69%).
 
Also in 2016, Xu and colleagues reported on a meta-analysis of comparative studies of AFPs and mucosal advancement flaps for complex anal fistulas, which included 10 studies (total N=778 patients) (Xu, 2016). Three studies were randomized trials; the remaining were observational studies or did not describe designs. In pooled analysis, there were no significant differences in healing rates at the end of follow-up between the AFP and mucosal advancement flap groups (odds ratio [OR], 0.79; 95% CI, 0.36 to 1.73; p=0.55, I2=74%). None the 7 studies reporting on recurrence rates found significant differences in recurrence rates (OR=2.29; 95% CI, 0.59 to 8.88; p=0.23, I2=83%). However, conclusions were limited by shortcomings in the underlying evidence base.
 
Senejoux and colleagues reported on an RCT comparing AFP to 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 (Senejoux, 2016). The trial was powered for superiority of AFP, and analysis was intention-to-treat. At 12 weeks of follow-up, in the AFP group (n=54), clinical remission rates were 31.5% compared with 23.1% in the control group (RR=1.31; 95% CI, 0.59 to 4.02; p=0.19). Fistula tract healing rates on magnetic resonance imaging did not differ significantly between groups at 12 weeks.
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in September 2017 did not identify any ongoing or unpublished trials that would likely influence this review.
     
2018 Update
A literature search was conducted through November 2018.  The following is a summary of the key identified literature.
 
Champagne et al (2006) performed a prospective study on the long-term efficacy of Surgisis anal fistula plugs in the closure of high cryptoglandular anorectal fistulas.  Additional variables recorded were number of fistula tracts and presence of setons. In the study, 46 patients underwent irrigation of the fistula tract by using hydrogen peroxide and each primary opening was occluded by using a Surgisis anal fistula plug, which was securely sutured in place at the primary opening and tacked to the periphery of the secondary opening. Follow-up was six months to two years (median, 12 months). At final follow-up, all fistula tracts had been successfully closed in 38 patients, for an overall success rate of 83 percent. Seven patients had multiple tracts, for a total of 55 fistula tracts in the series. Of the 55 individual tracts, 47 (85 percent) were closed at final follow-up. Patients with one primary opening were most likely to have successful closure by using the anal fistula plug, although this was not significant. Successful closure was not correlated with the presence of setons. The authors concluded that long-term closure of cryptoglandular anorectal fistula tracts using Surgisis anal fistula plug is safe and successful in 83 percent of patients and 85 percent of tracts.
 
Kockerling et al (2015) performed a systematic review of ten randomized controlled trials studying treatment of fistula-in-ano with a fistula plug with special attention paid to the technique. There were no significant differences in recurrence rates or incontinence rates in any of the studied comparisons. Studies were reviewed from PubMed, Medline, Embase, and the Cochrane medical database were searched up to July 2015. The reviewers found that healing rates of 50-60% can be expected for treatment of complex anal fistula with a fistula plug, with a plug-extrusion rate of 10-20%. Such results can be achieved not only with plugs made of porcine intestinal submucosa but also those made of other biological or synthetic bioabsorbable mesh materials. Important technical steps are firm suturing of the head of the plug in the primary opening and wide drainage of the secondary opening. The reviewers concluded that treatment of a complex fistula-in-ano with a fistula plug is an option with a success rate of 50-60% with low complication rate. Further improvements in technique and better studies are needed.
 
The 2017 practice guidelines on management of anal fistulas from the American Society of Colon and Rectal Surgeons did not evaluate use of plugs for anal fistula repair (Stewart et al, 2017). The 2016 practice guidelines on the treatment of anorectal abscess, fistula-in-ano, and rectovaginal fistula from the Society provided a weak recommendation with moderate-quality evidence (Vogel et al, 2016). With recent evidence of success rates of less than 50% in most studies for the treatment of complex anal fistulas with an anal fistula plug, the guidelines concluded that the fistula plug is relatively ineffective in the treatment of fistula-in-ano. However, despite the variability in healing with a fistula plug, the real possibility of success coupled with its sphincter-preserving nature allows this therapy to remain an option that may be considered for the treatment of fistula-in-ano.

CPT/HCPCS:
46707Repair of anorectal fistula with plug (eg, porcine small intestine submucosa [SIS])

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