NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of closure of anal fistula using a suturable bioprosthetic plug Surgical repair of anal fistula with a bioprosthetic plug Anal fistula is an abnormal opening between the anal canal and the skin around the anus. It may cause symptoms such as pain or discomfort and leaking of blood or pus. In this procedure, a specially designed plug is inserted into the fistula and stitched in place. Introduction The National Institute for Health and Clinical Excellence (NICE) has prepared this overview to help members of the Interventional Procedures Advisory Committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This overview was prepared in February Procedure name Closure of anal fistula using a suturable bioprosthetic plug. Specialty societies Association of Coloproctology of Great Britain and Ireland British Society of Gastroenterology. Description Indications and current treatment High trans-sphincteric or deeper anal fistula (fistula-in-ano). Anal fistula is an abnormal passageway between the anal canal and the skin around the anus (or neighbouring structures such as the vagina). It may cause symptoms such as pain or discomfort in the anal area, and leakage of blood or pus. It usually results from previous anal abscesses (cryptoglandular) but can also be associated with other conditions such as Crohn s disease and cancer. Page 1 of 23

2 Anal fistulae can be classified according to their relationship with the external sphincter. Intersphincteric fistulae are the most common type and cross only the internal sphincter. Trans-sphincteric fistulae pass through the internal and external sphincter. Usually only a small proportion of the external sphincter is involved, but some fistulae may involve a much larger proportion. Treatment of anal fistulae usually involves surgery. The type of surgery depends on the location and complexity of the fistulae. For trans-sphincteric anal fistulae, the most common treatment is a fistulotomy. This procedure is usually carried out under regional or general anaesthesia, but very small fistulae can be treated under local anaesthesia. An incision is made through the skin into the fistula tract, which is opened up after curettage, allowing the tissues to heal from the inside out. For recurrent fistulae or deeper fistulae that involve a lot of muscle, a seton (a piece of suture material or rubber sling) may be used, either alone or in combination with fistulotomy. The seton is passed from the external skin opening, along the fistula tract, through the internal opening in the anal canal and out through the anus. It is then tied in a loop and may be left loose to act as a wick, promoting drainage and formation of scar tissue, or it may be gradually tightened over a period of weeks to slowly cut through the muscle and to help heal the fistula. Fistulae that cross the external sphincter at a high level are sometimes treated with a mucosal advancement flap. This involves excision of the internal opening, curettage and suture ligation of the fistula, followed by advancement of a flap of healthy mucosa and submucosa over the internal opening, which is sutured in place without tension. Another option for treating anal fistulae, which is currently less commonly used, is injection of fibrin glue (a solution of fibrinogen and thrombin). The aim of the procedure is for the glue to form a clot within the fistula, in order to promote healing. Techniques that involve dividing the sphincter muscle to treat the fistulae are associated with a risk of postoperative incontinence. What the procedure involves Insertion of a suturable bioprosthetic plug into an anal fistula is usually performed with the patient under general anaesthesia. Before the procedure patients may undergo mechanical bowel preparation, and they generally receive antibiotics and thromboprophylaxis. The fistula tract is identified and the external and internal openings are located using a fistula probe or imaging techniques. The tract is initially cleaned by irrigating with hydrogen peroxide or sterile saline. A conical plug made of porcine intestinal submucosa is then pulled into the tract from the internal opening until the thicker end of the plug securely blocks the internal opening. Excess material is trimmed away and both ends of the plug are sutured in place. The external opening is not completely sealed so that drainage of the fistula can continue. The aim is for the plug to act as a scaffold for new tissue to grow into. Page 2 of 23

3 One of the advantages of this procedure is that the sphincter muscle is left intact. If the procedure is unsuccessful, patients can be offered other procedures subsequently. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to closure of anal fistula using a suturable bioprosthetic plug. Searches were conducted of the following databases, covering the period from their commencement to 24/09/2010: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Table 1 Inclusion criteria for identification of relevant studies Characteristic Criteria Publication type Clinical studies were Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patient Patients with anal fistula. Intervention/test Insertion of a suturable bioprosthetic plug. Outcome Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Language Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. List of studies included in the overview This overview is based on approximately 1111 patients from 1 systematic review, 2 randomised controlled trials (RCTs), 3 non-randomised comparative studies and 2 case series 1 8. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. Page 3 of 23

4 India Table 2 Summary of key efficacy and safety findings on closure of anal fistula using a suturable bioprosthetic plug Abbreviations used: CI, confidence intervals; MRI, magnetic resonance imaging; RR, relative risk. Study details Key efficacy findings Key safety findings Comments Garg P (2010) 1 Number of patients analysed: 317 Abscess formation (sepsis / suppuration) = Systematic review Overall success rate (patient cure rate): 24 92% 4 29% (11/108) Search date: 2009 Study population: patients with anal fistulae n = 317 (12 studies) Inclusion criteria: all randomised / nonrandomised, controlled / non-controlled clinical trials, which studied anal fistula plug or compared anal fistula plug with other treatment methods for anal fistulae, and which reported clinical healing of the fistula as the outcome. No RCTs were found. Follow-up: months Conflict of interest/source of funding: none Overall tract closure rate: 61 90% Success rates in different parameters Parameter No. of studies No. of patients Successful cases Studies with follow-up 6 months Complex fistula Recurrent fistula Crohn s disease Single tract fistula Multiple tract fistula Excluding patients with plug extrusion Range of success rates (%) Study design issues: The primary outcome measure was the success rate of the plug procedure. Secondary outcomes were plug extrusion rate and abscess formation / sepsis rate. Because of heterogeneity among the included studies, it was not possible to perform a weighted analysis to get a summary estimate of the efficacy of the procedure. Other issues: One study reporting the use of an acellular extracellular matrix was not included because the material used was different to the Surgisis anal fistula plug. The authors noted that there was a lack of uniformity and quantity of data to allow the following factors to be analysed: the impact of seton insertion before the plug procedure, role of antibiotics, the effect of the procedure on incontinence, objective pain assessment after the procedure and the efficacy of multiple plug procedures in the same patient. Plug extrusion rate: 4 41% (43/232) Page 4 of 23

5 Abbreviations used: CI, confidence intervals; MRI, magnetic resonance imaging; RR, relative risk. Study details Key efficacy findings Key safety findings Comments Ortiz H (2009) 2 Randomised controlled trial Spain Recruitment period: 2007 Study population: patients with high anal fistula of cryptoglandular aetiology n = 43 (21 fistula plug vs 22 endorectal anal flap) Mean age: 46.5 years (range 30 76) Sex: 62.5% (20/32) male Patient selection criteria: high fistula-in-ano of cryptoglandular origin. Patients with secondary tracts, fistulae with any suggestion of infection, horseshoe, anovaginal or rectourethral fistulae and those with Crohn s disease were excluded. Technique: All patients underwent full mechanical bowel preparation and received antibiotic prophylaxis. Lyophilized porcine submucosal plug (Surgisis anal fistula plug, Cook Surgical, USA) was used for the fistula plug procedure. Curettage of the fistula tract was not performed. The flap technique comprised a complete fistulectomy followed by creation of a curvilinear flap consisting of mucosa, submucosa and a few muscular fibres. Follow-up: 1 year Conflict of interest/source of funding: not reported Number of patients analysed: 31 (15 vs 16) (11 patients did not receive allocated intervention: 5 abscess at surgery, 4 internal opening not identified, 1 Crohn s disease suspected at surgery and 1 arrhythmia at surgery) Fistula recurrence (1-year follow-up): Fistula plug = 80% (12/15) Endorectal anal flap = 12.5% (2/16) RR 6.40, 95% CI 1.7 to 24.0, p <0.001 All recurrences were detected during the first 3 months after surgery. Fistulae recurred in 9 of 16 patients who had previously undergone fistula surgery (8 of the 9 patients were in the fistula plug group). The recurrent fistula healed in 7 patients, 6 treated with an endorectal anal flap and 1 with a fistula plug. Among patients who had a fistula plug, recurrence was diagnosed by: Presence of abscess in the same area as the original fistula at 2 weeks after surgery = 6.7% (1/15) Extrusion of plug (at 2 and 4 weeks) = 20% (3/15) Persistent leakage around the plug, such that the fistula could not close = 53.3% (8/15) In the flap group, both recurrences were diagnosed by the presence of an abscess arising in the same area as the original fistula. No complications were reported. Follow-up issues: 1 patient was lost to follow-up (plug group) Patients were followed up at 2, 4, 8, 12 and 24 weeks, and 1 year after surgery by means of an interview and physical examination. Study design issues: Patients were assigned randomly to treatment by a computer-generated table of random numbers in the outpatient department. Follow-up was performed by an independent observer. To avoid a learning curve effect, the first 5 consecutive patients treated with a plug were excluded from the study. The required sample size was calculated as 93 patients per group, based on a recurrence rate of 35% with the plug and 17.5% with the flap. Inclusion into the trial was discontinued early because of an unusually high number of recurrences in the plug group. Study population issues: The 2 groups were well matched for demographic data and fistula characteristics (all had a single internal and external opening). 16 patients had a history of fistula surgery. 5 patients in the plug group and 6 in the flap group did not receive the allocated intervention. Other issues: The authors note that the closure rate in the fistula plug group was at the lower end of the published range of 14 87%. Page 5 of 23

6 Abbreviations used: CI, confidence intervals; MRI, magnetic resonance imaging; RR, relative risk. Study details Key efficacy findings Key safety findings Comments A ba-bai-ke-re MMTJ (2010) 3 Number of patients analysed: 90 (45 vs 45) The report noted that no severe adverse Randomised controlled trial effect occurred in the patients. China Recruitment period: Study population: patients with complex anorectal fistulae n = 90 (45 fistula plug vs 45 endorectal advancement flap) Age range: years Sex: 54% (49/90) male Patient selection criteria: patients aged years with 2 6 cm long intrasphincteric and transsphincteric anorectal complex fistulae were Patients with no internal opening found during surgery and those with human immunodeficiency virus, Crohn s disease, malignant cause, tuberculosis, hydradenitis suppurativa, severe cardiovascular state, diabetes, pregnancy and sepsis were excluded. Technique: fistula tracts were cleaned with curettage and hydrogen peroxide. The fistula plug procedure was done using acellular dermal matrix (J-I, JY Life Tissue Engineering Co. Ltd., China). All patients were required to have a warm Sitz bath 3 times a day and were given intravenous broad-spectrum antibiotics and metronidazole for 3 days after surgery. Median follow-up: 6 months Conflict of interest/source of funding: not reported Success rate (defined as closure of all external openings, absence of drainage without further intervention, and no abscess formation): Fistula plug = 82.2% (37/45) Endorectal advancement flap = 64.4% (29/45), p<0.05 Fistula recurrence: Fistula plug = 4.4% (2/45) Endorectal advancement flap = 28.9% (13/45), p = Early extrusion of the plug occurred in 4 patients and late extrusion in 1 patient (not further defined). Quality of life scores: (assessed using the Fecal Incontinence Quality of Life Scale; higher scores indicate better quality of life) Fistula plug = 85.9 ± 5.3 Endorectal advancement flap = 65.3 ± 8.9 p < Faecal incontinence: Fistula plug = 2.2% (1/45) Flap = 8.9% (4/45) p = 0.36 Anal deformity: Fistula plug = 0% (0/45) Flap = 6.7% (3/45) p = 0.24 Postoperative pain time (days): Fistula plug = 1.5 ± 0.5 Flap = 7.5 ± 1.8 p < Healing time (days): Fistula plug = 7.5 ± 3.5 Flap = 24.5 ± 5.5 p < Drainage surgery: Fistula plug = 2.2% (1/45) Flap = 11.1% (5/45) Follow-up issues: There were no losses to follow-up. Follow-up examination was done at 2 days, 2, 4, 6 and 12 weeks, and 5 months after surgery. Quality of life scores prior to the procedure are not available Study design issues: Randomisation was performed during surgery after the internal opening of the fistula was identified. Computergenerated random codes were used to produce envelopes containing the information about the allocated treatment. Patients were blinded to treatment allocation. The required sample size was calculated as 44 patients per group, based on a success rate of 87% with the plug and 37% with the flap. The primary endpoint of the trial was fistula closure rate. Postoperative pain was scored using a visual analogue scale. Study population issues: There were no statistically significant differences between the groups with regard to age, sex and fistula type. 36patients had intrasphincteric fistulae (evenly divided between groups) Page 6 of 23

7 Abbreviations used: CI, confidence intervals; MRI, magnetic resonance imaging; RR, relative risk. Study details Key efficacy findings Key safety findings Comments Chung W (2009) 4 Number of patients analysed: 232 (27 vs 23 vs 86 vs 96) No complications were reported. Non-randomised comparative study Canada Recruitment period: Study population: patients with high transsphincteric fistulae of cryptoglandular origin n = 232 (27 fistula plug, 23 fibrin glue, 86 seton drain, 96 flap advancement) Median age: 47 years (range 21 82) Sex: 78% (181/232) male Patient selection criteria: inclusion criteria were age above 18 years and high transsphincteric fistulae of cryptoglandular origin (including direct, horseshoe and supralevator fistulae). Exclusion criteria were simple fistulae, rectovaginal fistulae and fistulae associated with Crohn s disease. Technique: all procedures were performed under general anaesthesia. The fistula plug procedure used the Surgisis anal fistula plug (Cook Surgical, USA). Follow-up: 12 weeks Conflict of interest/source of funding: one of the authors received presentation expenses from an unrestricted education grant provided by Cook. Healing rates at week 12: Fistula plug = 59.3% (16/27) Fibrin glue = 39.1% (9/23) Seton drain = 32.6% (28/86) Flap advancement = 60.4% (58/96) p < 0.05 between the treatment groups Further follow-up of patients in the fistula plug group showed continued improvement with a healing rate of 70.4% (19/27) at 24 weeks. The other groups were not assessed at 24 weeks. Of the 11 fistula plug patients with persistent fistulae at 12 weeks, 3 had infection and 5 had plug extrusion (all occurring within 4 weeks). Follow-up issues: All patients were evaluated in the outpatient clinic. Study design issues: Retrospective design; all patients treated for anal fistulae by a single colorectal surgeon were identified from a database. Patient selection was not described. The primary endpoint was full healing defined as closure of the external fistula opening with no drainage or infection at 12 weeks postoperatively (healing for the seton drain group was defined as a persistent fistula opening at the seton site but absence of drainage or infection). Study population issues: There was no significant difference in age between the treatment groups. The fibrin glue group had a significantly higher proportion of men than the other groups (p = 0.04). Page 7 of 23

8 Abbreviations used: CI, confidence intervals; MRI, magnetic resonance imaging; RR, relative risk. Study details Key efficacy findings Key safety findings Comments Hyman N (2009) 5 Number of patients analysed: 245 Complications: Urinary retention = Non-randomised comparative study (registry Number of fistulae healed at 3 months: 0.4% (1/245) data) Fistula plug = 32% (14/43), p<0.001 Urinary tract Fistulotomy = 87% (104/120) infection = 1.6% USA Staged fistulotomy = 50% (18/36), p = (4/245) Recruitment period: Draining seton only = 5% (1/21), p<0.001 Bleeding = 1.2% Cutting seton = 69% (9/13), p = (3/245) Fibrin glue = 80% (4/5), p = Other (all minor) = Advancement flap = 75% (3/4), p = % (8/245) Study population: patients with anal fistulae (77 intersphincteric, 87 low transsphincteric, 52 high transsphincteric, 20 horseshoe fistulae, 4 suprasphincteric, 2 extrasphincteric, 3 unrecorded) n = 245 (43 fistula plug, 120 fistulotomy, 36 staged fistulotomy, 21 draining seton only, 13 cutting seton, 5 fibrin glue, 4 advancement flap, 1 other, 1 unrecorded) Median age: 46 years (range 18 85) Sex: 66% (162/245) male Patient selection criteria: none stated. Technique: not reported Follow-up: 3 months Conflict of interest/source of funding: not reported Note: p values relate to the healing rate compared with fistulotomy. 28.4% (65/245) of patients required at least 1 additional unplanned operation, such as abscess drainage or alternative fistula treatment. 73% of primary fistulae were healed at 3 months vs 41% of recurrent fistulae. Patient-specific factors associated with non-healing at 3 months (multivariate analysis) Factor p value Age 0.78 Female gender 0.04 Recurrent fistula 0.03 Multiple tracts 0.27 smoking 0.07 Crohn s disease 0.89 Type of fistula 0.90 There were no unplanned admissions. The complications were not broken down by type of operation performed. Study design issues: Patient selection was not described. The registry included data from 25 surgeons in 13 different practices. The surgical approach was not standardised; it is likely that different techniques were used at each centre. The discussion implies that fistulotomy was the first choice option with other treatments being used if the patient was not suitable for fistulotomy Study population issues: 75 (31%) of patients were being treated for a recurrent fistula and 51 (21%) had multiple tracts. 10% (24/245) of patients had Crohn s disease. Page 8 of 23

9 Abbreviations used: CI, confidence intervals; MRI, magnetic resonance imaging; RR, relative risk. Study details Key efficacy findings Key safety findings Comments Christoforidis D (2010) 6 Number of patients analysed: 80 (37 vs 43) No serious complications occurred Non-randomised comparative study in the fistula plug group. USA Recruitment period: Study population: patients with transsphincteric anal fistulae of cryptoglandular origin n = 80 (37 fistula plug vs 43 endorectal advancement flap) Mean age (years): 48 (plug), 47 (flap) Sex: 55% (44/80) male Patient selection criteria: exclusion criteria were rectovaginal fistulae, fistulae that did not involve the external sphincter, fistulae related to Crohn s disease, and fistulae related to surgery. Patients who underwent either procedure more than once were included only for the first procedure. Technique: surgery was performed electively and in the absence of uncontrolled sepsis. For the plug procedure, the fistula was usually irrigated with hydrogen peroxide but not curetted. The plug (Surgisis anal fistula plug, Cook Surgical, USA) was secured at the external opening in 30% (11/37) of patients. Mean follow-up (months): 14 (plug), 56 (flap) (p < ) Conflict of interest/source of funding: one of the authors received an educational grant from Cook Medical Inc., another author received an honorarium for research consulting from Cook Medical. Success rate: (defined as a closed external opening in the absence of symptoms at minimum 6-month follow-up) Fistula plug = 32.4% (12/37) Endorectal advancement flap = 62.8% (27/43), p = In a time-to-failure analysis, failure occurred less frequently in the advancement flap group (failures reached a plateau after 9 to 12 months). Early extrusion of the plug occurred in 7 patients. Success rate excluding patients with early extrusion of fistula plug: Fistula plug = 40.0% (12/30) Endorectal advancement flap = 62.8% (27/43), p = Fistula recurrence: (following temporary healing later than 6 months after surgery) Fistula plug = 13.5% (5/37) Endorectal advancement flap = 7.0% (3/43) Functional outcome: (among patients with healed fistula) Fistula plug: 6 out of 7 patients reported normal or near normal continence. 1 patient reported daily gas and liquid incontinence, but these symptoms were present prior to fistula plug repair. Advancement flap: 48% (11/23) of patients had no continence disturbance or gas/liquid incontinence less than once a month; 35% (8/23) of patients had occasional gas incontinence with rare liquid incontinence. 4 patients had lifestyle alterations with frequent liquid stool incontinence and/or occasional solid stool incontinence (2 patients reported this prior to the fistula repair and 1 patient did not recall his continence status prior to the repair). 5 patients in the fistula plug group were treated with antibiotics postoperatively because of pain and increased drainage. 2 patients in the advancement flap group required reoperation for bleeding on postoperative days 5 and 7 respectively. Some of these patients are likely to be included in the systematic review (Garg et al, 2010) 1. Follow-up issues: 6 patients in the advancement flap group were excluded because of insufficient follow-up. The questionnaire response rate among patients with healed fistula was 58% (7/12) in the plug group and 85% (23/27) in the flap group. Study design issues: Retrospective design. Incontinence scores were not collected prior to the fistula repair procedure. The time-periods of patient inclusion differ between the 2 groups as the plug was not used until Study population issues: There were no statistically significant differences between the groups with regard to age, sex, smoking status, fistula type, and previous failed treatments although there was a trend for more sphincter involvement and more female patients in the advancement flap group. 30 patients (12 vs 18) had prior failed repairs. The follow-up was statistically significantly longer in the flap group versus the plug group. Other issues: The authors note that these data include their initial experience with the fistula plug. Page 9 of 23

10 Abbreviations used: CI, confidence intervals; MRI, magnetic resonance imaging; RR, relative risk. Study details Key efficacy findings Key safety findings Comments McGee MF (2010) 7 Number of patients analysed: 41 (42 fistula tracts) There were no adverse events and no reports Successful closure = 43% (18/42) of incontinence discovered at USA 20 patients had initial success at 6 months but 2 of these postoperative clinic experienced failure at 9 and 12 months respectively. visits. Recruitment period: Study population: patients with transsphincteric cryptoglandular fistulae n = 41 patients (42 fistula tracts) Mean age: 42 years (range 22 88) Sex: 63% (26/41) male Patient selection criteria: patients with suspected transsphincteric cryptoglandular fistulae were Patients with Crohn s disease were excluded. Technique: all patients had a draining seton placed before fistula plug repair was attempted for a mean duration of 4 months. Previously placed setons were left in place at the start of the operation to aid in visualising the tract and subsequent fistula plug placement. The Surgisis anal fistula plug (Cook Surgical, USA) was used. Postoperative Sitz baths were encouraged as needed. Mean follow-up: 24.5 months (range 7 43) Conflict of interest/source of funding: none Closures and failures by fistula tract length Tract Tract Total >4 cm <4 cm Successful closure 61% (n = 14) 21% (n = 4) 43% (n = 18) p = Failed closure 39% (n = 9) 79% (n = 15) 57% (n = 24) Cause of failure: Drainage n = 9 n = 13 n = 22 Plug n = 0 n = 2 n = 2 extrusion Timing of failure: <6 months n = 8 n = 14 n = 22 >6 months n = 1 n = 1 n = 2 Patients age, gender, fistula location, length of seton placement, and duration of follow-up did not influence rates of closure (the authors note, however, that there may have been other confounding factors such as smoking, diabetes and amount of sphincter involvement that were not analysed). Follow-up issues: Office-based anoscopy was done at 3 and 6 months after the procedure. Patients with success at 6-month follow-up were subsequently called in November 2009 and asked scripted questions about any persistent symptoms. Study design issues: Patient selection was not described. A group of 5 surgeons performed the procedures 1 was present for all procedures to ensure adherence to a standardised technique. Fistula tract length was determined by subtracting the length of trimmed excess plug material from the original plug length. Failure was defined as either patient reports of persistent drainage, anoscopic identification of persistent abscess or external fistula opening, or development of an abscess or infection requiring additional surgery. Other issues: The authors noted that they have subsequently changed their practice and no longer attempt repair of short fistulae with a plug. Page 10 of 23

11 Abbreviations used: CI, confidence intervals; MRI, magnetic resonance imaging; RR, relative risk. Study details Key efficacy findings Key safety findings Comments Ellis CN (2010) 8 Number of patients analysed: 63 No safety outcomes were reported. Some of these patients are likely to be included in the systematic review (Garg et Success of initial plug = 76% (48/63) al, 2010) 1. USA Recruitment period: Study population: patients with complex anal fistula (defined as a fistula whose treatment poses an increased risk for a change in continence) n = 63 Mean age: 46 years (range 22 68) Sex: 70% (44/63) male Patient selection criteria: all patients whose anal fistula was managed by use of a bioprosthetic plug. All patients had a minimum of 1 year of follow-up since their last treatment. Technique: a draining seton had been in place for at least 6 weeks in 95% (60/53) of patients. To perform the fistula closure procedure, the Surgisis anal fistula plug (Cook Surgical, USA) was used. Follow-up: minimum 12 months (range 12 24) Conflict of interest/source of funding: the first author is a consultant for and has received a research grant from Cook Surgical Inc. Types of failure: Technical issues (plug extruded within 1 week of placement) = 1.6% (1/63) Primary failure (plug not extruded but fistula failed to heal) = 15.9% (10/63) Late failure (fistula healed but subsequently recurred during follow-up; median time to recurrence was 7 months ) = 6.4% (4/63) In the 1 patient whose plug failed for technical reasons, replacement of the plug was successful. Of the 10 patients with primary failure, 6 had posterior fistulae and 1 had an anovaginal fistula. Of these 10 patients, 7 were male, 4 had Crohn s disease and 8 smoked tobacco. Repeat use of the plug was unsuccessful in all these patients. Of the 4 patients with late failure, 3 had posterior fistulae and 1 had an anovaginal fistula. 3 of these 4 patients were male, 1 had Crohn s disease, and 3 smoked tobacco. Repeat use of the plug was successful in 2 patients. In 6 out of 8 patients with clinical long-term healing undergoing MRI, healing of the fistula was confirmed. Multivariate analysis of factors predictive of failure Hazard ratio (95% p CI) Male gender 1.41 (0.98 to 2.26) 0.06 Crohn s disease 5.50 (0.69 to 13.9) 0.07 Posterior fistula 4.28 (1.7 to 9.7) Tobacco smoking 5.35 (2.55 to 10.9) <0.001 Previous plug failure 12.9 (6.68 to 35.3) <0.001 Follow-up issues: Longer-term follow-up was determined by clinic visit or telephone interview. All patients whose fistula was clinically healed at 1 year were offered MRI to confirm healing of the fistula. Study design issues: Retrospective analysis. Consecutive patients. Clinical healing was defined as the absence of drainage with no evidence of residual fistula tract. Study population issues: 12 patients had an anovaginal fistula. The fistula plug was used as the first treatment modality (excluding placement of a loose seton for drainage) in all patients. 19% (12/63) of patients had a history of Crohn s disease. Page 11 of 23

12 Efficacy Successful fistula closure A systematic review of 12 studies including 317 patients reported an overall success rate ranging from 24% to 90% 1. An RCT of 90 patients treated by a suturable bioprosthetic plug or endorectal advancement flap reported successful fistula closure in 82% (37/45) and 64% (29/45) of patients respectively at 6-month follow-up (p <0.05) 3. A non-randomised comparative study of 232 patients treated by a suturable bioprosthetic plug, fibrin glue, seton drain or flap advancement reported healing rates of 59% (16/27), 39% (9/23), 33% (28/86) and 60% (58/96) of patients respectively at 12-week follow-up (p < 0.05 between the groups) 4. Of the 11 patients with persistent fistulae in the bioprosthetic plug group, 3 had infection and 5 had plug extrusion (all occurring within 4 weeks). A non-randomised comparative study of 245 patients treated by a suturable bioprosthetic plug, fistulotomy, staged fistulotomy, draining seton, cutting seton, fibrin glue or flap advancement reported healing rates of 32% (14/43), 87% (104/120), 50% (18/36), 5% (1/21), 69% (9/13), 80% (4/5) and 75% (3/4) of patients respectively at 3-month follow-up (p < for fistula plug versus fistulotomy) 5. A non-randomised comparative study of 80 patients treated by a suturable bioprosthetic plug or endorectal flap advancement reported successful fistula closure in 32% (12/37) and 63% (27/43) of patients respectively after follow-up of at least 6 months (p = 0.008) 6. Early extrusion of the plug occurred in 7 patients. A case series of 41 patients (42 fistula tracts) reported successful closure in 43% (18/42) after a mean follow-up of 24.5 months 7. Rates of successful closure were significantly higher when the fistula tract was >4 cm long (61% vs 21%, p = 0.004). Another case series of 63 patients reported successful closure in 76% (48/63) of patients after a minimum follow-up of 12 months 8. Healing of the fistula was confirmed by MRI in 6 out of 8 patients with clinical long-term healing. Recurrence The systematic review including 317 patients reported the plug extrusion rate ranged from 4 to 41% 1. An RCT of 31 patients treated by a suturable bioprosthetic plug or endorectal flap advancement reported fistula recurrence in 80% (12/15) and 12.5% (2/16) of patients respectively at 1-year follow-up (p<0.001). 3 of the recurrences in the bioprosthetic plug group were due to extrusion of the plug within 4 weeks of surgery and 8 were due to persistent leakage around the plug. The trial was discontinued early because of the high recurrence rate in the fistula plug group 2. Page 12 of 23

13 An RCT of 90 patients treated by a suturable bioprosthetic plug or endorectal flap advancement reported fistula recurrence in 4% (2/45) and 29% (13/45) of patients respectively at 6-month follow-up (p = 0.005) 3. A non-randomised comparative study of 80 patients treated by a suturable bioprosthetic plug or endorectal flap advancement reported fistula recurrence in 14% (5/37) and 7% (3/43) of patients respectively after follow-up of at least 6 months (p = not reported) 6. Quality of life An RCT of 90 patients reported significantly higher quality of life scores (assessed using the Fecal Incontinence Quality of Life Scale) in patients treated by a suturable bioprosthetic plug compared with those treated by endorectal flap advancement (85.9 vs 65.3) at 6-month follow-up (p < 0.001) 3. Safety The systematic review including 317 patients reported that the abscess formation/sepsis rate ranged from 4 to 29% 1. In the RCT of 31 patients, 1 of the 15 patients treated by a bioprosthetic plug had an abscess at the same site as the original fistula at 2 weeks after surgery 2. In the non-randomised comparative study of 80 patients, 14% (5/37) of patients in the fistula plug group were treated with antibiotics postoperatively because of pain and increased drainage 6. Validity and generalisability of the studies The evidence includes heterogeneous populations both within and between studies. Five studies excluded patients with Crohn s disease 2,3,4,6,7. The systematic review excluded one study reporting the use of an acellular extracellular matrix because the material used was different to the Surgisis anal fistula plug that was used in the other studies 1. Two studies reported that a proportion of patients had a history of prior fistula surgery 2,6, and one stated that a proportion of patients had recurrent fistulae 5. Only 1 study assessed closure of fistulae using MRI, and this was only done in a small proportion of patients 8. One of the RCTs was stopped prematurely because of a high fistula recurrence rate in the bioprosthetic plug group of patients 2. One study specifically noted that the data were part of their initial experience with the bioprosthetic plug and that there may be a learning curve effect 6. Several studies did not describe how patients were selected for treatment by the bioprosthetic plug. Page 13 of 23

14 In 1 case series, a proportion of patients had an anovaginal fistula rather than an anorectal fistula 8. One of the RCTs used a different type of bioprosthetic plug to the other 6 studies 3. In 3 studies, some or all of the patients had a draining seton placed for a period of time before the fistula repair was done 6,7,8. Curettage of the fistula tract was described in only 1 study 3. Two studies specifically stated that curettage was not performed 2,6. Existing assessments of this procedure A consensus statement on the Surgisis anal fistula plug was published in 2008, following a Consensus Conference held in Chicago 9. The recommendations stated that contraindications for the plug included conventional, uncomplicated intersphincteric fistula, pouch-vaginal and recto-vaginal fistula, fistula with a persistent abscess cavity, fistula with any suggestion of infection and inability of the surgeon to identify both the external and internal openings. The Panel concluded that patient selection, avoidance of local infection, and meticulous technique were required to achieve the highest possibility of success. It was recognised that even in patients with apparent healing, the rate of subsequent recurrence was unknown. The Panel agreed that the procedure should be undertaken only by trained surgeons familiar with anorectal anatomy and experienced in conventional anal fistula surgery and in the management of its complications. Conflict of interest statement: all of the participants in the conference received reimbursement for their expenses through Cook Medical Inc. (USA) and everyone received an honorarium. Related NICE guidance Below is a list of NICE guidance related to this procedure. Appendix B gives details of the recommendations made in each piece of guidance listed. Interventional procedures Closure of anorectal fistula using a suturable bioprosthetic plug. NICE interventional procedures guidance 221 (2007). Available from [current guidance] Specialist Advisers opinions Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and does not represent the view of the society. Mr D Bartolo, Mr R Philips, Mr J Scholefield (Association of Coloproctology of Great Britain and Ireland). Page 14 of 23

15 One Specialist Adviser had performed the procedure at least once, one performs it regularly, and the other had never performed it. Two Specialist Advisers consider the procedure to be novel and of uncertain safety and efficacy; one considers it to be the first in a new class of procedure. Appropriate comparators would be advancement flap repair or seton lay-open of fistula. There is considerable debate over the efficacy of this procedure with differing success rates reported in the literature. One Specialist Adviser noted that the different success rates may be due to variation in assessment of suitable patients and variation in insertion technique. Adverse events known from reports or experience include new abscess formation and extrusion of the plug. Anecdotal adverse events include discharge from the site of insertion of the plug for 6 weeks Key efficacy outcomes include healing (clinically and on MRI scanning) and faecal incontinence. One Specialist Adviser considered that the procedure should be restricted to a few specialised centres with a high-volume fistula practice until more information is available. Two Specialist Advisers thought that the procedure is likely to have a moderate impact on the NHS, in terms of numbers of patients eligible for treatment and use of resources; the other thought it was likely to have a major impact. Patient Commentators opinions NICE s Patient and Public Involvement Programme was unable to gather patient commentary for this procedure. Issues for consideration by IPAC The Fistula-In-Ano Trial (FIAT) is an ongoing UK multicentre RCT, comparing Surgisis anal fistula plug versus the surgeon s preference. The trial started in January 2010 and the anticipated end date is January The target number of participants is 500. Page 15 of 23

16 References 1. Garg P, Song J, Bhatia A et al. (2010) The efficacy of anal fistula plug in fistula-in-ano: a systematic review. Colorectal disease 12: Ortiz H, Marzo J, Ciga MA et al. (2009) Randomized clinical trial of anal fistula plug versus endorectal advancement flap for the treatment of high cryptoglandular fistula in ano. British Journal of Surgery 96: Ba-bai-ke-re A, Wen H, Huang H-G et al. (2010) Randomized controlled trial of minimally invasive surgery using acellular dermal matrix for complex anorectal fistula. World Journal of Gastroenterology 16: Chung W, Kazemi P, Ko D et al. (2009) Anal fistula plug and fibrin glue versus conventional treatment in repair of complex anal fistulas. American Journal of Surgery 197: Hyman N, O'Brien S, Osler T. (2009) Outcomes after fistulotomy: results of a prospective, multicenter regional study. Diseases of the Colon & Rectum 52: Christoforidis D, Pieh MC, Madoff RD et al. (2009) Treatment of transsphincteric anal fistulas by endorectal advancement flap or collagen fistula plug: a comparative study. Diseases of the Colon & Rectum 52: McGee MF, Champagne BJ, Stulberg JJ et al. (2010) Tract length predicts successful closure with anal fistula plug in cryptoglandular fistulas. Diseases of the Colon & Rectum 53: Ellis CN, Rostas JW, Greiner FG. (2010) Long-term outcomes with the use of bioprosthetic plugs for the management of complex anal fistulas. Diseases of the Colon & Rectum 53: Corman ML, Abcarian H, Bailey HR et al. (2008) The surgisis AFP anal fistula plug: Report of a consensus conference. Colorectal Disease 10: Page 16 of 23

17 Appendix A: Additional papers on closure of anal fistula using a suturable bioprosthetic plug The following table outlines the studies that are considered potentially relevant to the overview but were not included in the main data extraction table (table 2). It is by no means an exhaustive list of potentially relevant studies. Article Adamina M, Hoch JS, Burnstein MJ. (2010)To plug or not to plug: a cost-effectiveness analysis for complex anal fistula. Surgery 147: Champagne BJ, O'Connor LM, Ferguson M et al. (2006) Efficacy of anal fistula plug in closure of cryptoglandular fistulas: long-term follow-up. Diseases of the Colon & Rectum 49: Number of patients/ follow-up Non-randomised comparative study n = 24 (12 vs 12) Follow-up = 7 m n = 46 Follow-up = 12 m Direction of conclusions Complex anal fistulae Success rate: Fistula plug = 50% (6/12) Endoanal advancement flap = 33% (4/12), p = 0.68 High cryptoglandular anorectal fistulae Success rate = 83% Reasons for noninclusion in table 2 original overview. Christoforidis D, Etzioni DA, Goldberg SM et al. (2008) Treatment of complex anal fistulas with the collagen fistula plug. Diseases of the Colon & Rectum 51: Chung W, Ko D, Sun C et al. (2010) Outcomes of anal fistula surgery in patients with inflammatory bowel disease. American Journal of Surgery 199: Echenique I, Mella JR, Rosado F et al. (2008) Puerto Rico experience with plugs in the treatment of anal fistulas. Boletin - Asociacion Medica de Puerto Rico 100: El-Gazzaz G, Zutshi M, Hull T. (2010) A retrospective review of chronic anal fistulae treated by anal fistulae plug. Colorectal Disease 12: n = 47 Follow-up = 6.5 m Non-randomised comparative study n = 51 (4 fistula plug) Follow-up = 12 weeks n = 23 Follow-up = not reported n = 33 Follow-up = 222 days Complex anal fistulae Success rate = 31% per procedure (43% per patient) An increased amount of external sphincter involvement was associated with a higher failure rate (p<0.05) Patients with inflammatory bowel disease Healing rates at 12 weeks: Fistula plug = 75% Fibrin glue = 0% Flap advancement = 20% Seton drain = 28% Continence scores were not altered. Anal fistulae (excluding patients with inflammatory bowel disease) Success rate = 60% (14/23) Complex anal fistulae (61% cryptoglandular, 39% Crohn s disease) Success rate = 25% (8/32) Reasons for failure = sepsis (87%) and plug dislodgment (13%) systematic review 1. systematic review 1. systematic review 1. Page 17 of 23

18 Article Ellis CN. (2007) Bioprosthetic plugs for complex anal fistulas: an early experience. Journal of Surgical Education 64: Number of patients/ follow-up Non-randomised comparative study n = 113 (18 fistula plug) Follow-up = 6 m Direction of conclusions Complex anal fistulae Fistula recurrence: Fistula plug = 12% (2/18) Advancement flap = 33% (31/95) Reasons for noninclusion in table 2 A more recent study from the same centre is original overview Garg P. (2009) To determine the efficacy of anal fistula plug in the treatment of high fistula-in-ano: an initial experience. Colorectal Disease 11: Johnson EK, Gaw JU, Armstrong DN. (2006) Efficacy of anal fistula plug vs. fibrin glue in closure of anorectal fistulas. Diseases of the Colon & Rectum 49: n = 23 Follow-up = 292 days Non-randomised comparative study n = 25 (15 vs 10) Follow-up = 3 m High cryptoglandular anal fistulae Success rate = 71% (15/21) High transsphincteric fistulae or deeper (excluding Crohn s disease) Persistence of fistula: Fistula plug = 13% (2/15) Fibrin glue = 60% (6/10) p < 0.05 systematic review 1., more recent original overview Ky AJ, Sylla P, Steinhagen R et al. (2008) Collagen fistula plug for the treatment of anal fistulas. Diseases of the Colon & Rectum 51: n = 45 Follow-up = 6.5 m Simple and complex anal fistulae Healing rate: 3 8 weeks = 84% 12 weeks = 62% 6.5 months = 55% Closure rate was significantly higher in patients with simple versus complex fistulae (71% vs 35%, p<0.02) and with non-crohn s disease versus Crohn s disease (67% vs 27%, p<0.02). SR. studies with longer follow-up are systematic review 1. Lawes DA, Efron JE, Abbas M et al. (2008) Early experience with the bioabsorbable anal fistula plug. World Journal of Surgery 32: n = 17 Follow-up = 7 m Postoperative complications = perianal abscess in 5 patients. Cryptoglandular anal fistulae Successful closure = 24% (4/17) Acute postoperative sepsis = 29% (5/17) systematic review 1. Page 18 of 23

19 Article O'Connor L, Champagne BJ, Ferguson MA et al. (2006) Efficacy of anal fistula plug in closure of Crohn's anorectal fistulas. Diseases of the Colon & Rectum 49: Number of patients/ follow-up n = 20 Direction of conclusions Crohn s anorectal fistulae Success rate = 80% (16/20) Reasons for noninclusion in table 2 original overview. Owen G, Keshava A, Stewart P et al. (2010) Plugs unplugged. Anal fistula plug: the Concord experience. ANZ Journal of Surgery 80: Safar B, Jobanputra S, Sands D et al. (2009) Anal fistula plug: initial experience and outcomes. Diseases of the Colon & Rectum 52: Schwandner O, Stadler F, Dietl O et al. (2008) Initial experience on efficacy in closure of cryptoglandular and Crohn's transsphincteric fistulas by the use of the anal fistula plug. International Journal of Colorectal Disease 23: Schwandner T, Roblick MH, Kierer W et al. (2009) Surgical treatment of complex anal fistulas with the anal fistula plug: a prospective, multicenter study. Diseases of the Colon & Rectum 52: Song WL, Wang ZJ, Zheng Y et al. (2008) An anorectal fistula treatment with acellular extracellular matrix: a new technique. World Journal of Gastroenterology 14: Thekkinkattil DK, Botterill I, Ambrose NS et al. (2009) Efficacy of the anal fistula plug in complex anorectal fistulae. Colorectal Disease 11: n = 32 Follow-up = 15 m n = 36 procedures Follow-up = 126 days n = 19 Follow-up = 279 days n = 60 Follow-up = 12 m n = 30 Follow-up = 14 days n = 43 Follow-up = 47 weeks Complex anal fistulae Success rate = 37% Complex anal fistulae Success rate = 14% (5/36) Reasons for failure: infection requiring drainage and seton placement (n = 8), plug dislodgement (n = 3), persistent drainage/tract and need for other procedures (n = 20). Transsphincteric anorectal fistulae (12 cryptoglandular, 7 Crohn s disease) Success rate at 9 months = 61% (11/18) No deterioration of continence was documented. There were significant improvements in quality of life factors. Single transsphincteric fistulae Success rate at 12 months = 62% The success rate was significantly lower in smokers and diabetics. Low anorectal fistulae Success rate = 100% Complex anorectal, rectovaginal and pouch vaginal fistulae Success rate = 44% SR. systematic review 1. studies or studies with longer follow-up are studies with longer follow-up are systematic review 1. Page 19 of 23

20 Article van Koperen PJ, D'Hoore A, Wolthuis AM et al. (2007) Anal fistula plug for closure of difficult anorectal fistula: a prospective study. Diseases of the Colon & Rectum 50: Wang JY, Garcia-Aguilar J, Sternberg JA et al. (2009) Treatment of transsphincteric anal fistulas: are fistula plugs an acceptable alternative? Diseases of the Colon & Rectum 52: Zubaidi A, Al-Obeed O. (2009) Anal fistula plug in high fistula-inano: an early Saudi experience. Diseases of the Colon & Rectum 52: Number of patients/ follow-up n = 17 Follow-up = 7 months Non-randomised comparative study n = 55 (29 vs 26) Follow-up = 279 days (plug) n = 22 (23 tracts) Follow-up = 12 m Direction of conclusions Complex high anorectal fistulae (therapyresistant) Healing rate = 41% (7/17) Transsphincteric, cryptoglandular anal fistulae Successful outcome: Fistula plug = 34% (10/29) Advancement flap (62% (16/26) p = High anorectal fistulae Success rate = 83% (19/23) Reasons for noninclusion in table 2 included Page 20 of 23