So what do we know about published trials, however imperfect. A paradigm shift occurred in the mid-1990s in treatment of trans-sphincteric fistulas from fistulotomy to sphincter sparing operations. This is well documented in a 25-year time trends of fistula operations which documents a definite decline in fistulotomies commensurate with a steep rise in sphincter-sparing procedures [8]. Also because most of these procedures include closure of the primary opening, it seems that insertion of seton to drain the fistula tract and prior elimination of acute sepsis and preparation of the fistula for definitive procedure is mandatory. This has resulted in far greater use of setons than before [8]. Also if these procedures fail, the patient will have continued drainage or a new abscess which has to be treated with drainage and insertion of a new seton. In essence we have traded a single operation, i.e., fistulotomy for multiple procedures in an attempt to preserve continence. This fact must be stressed to the patient in the process of preoperative informed consent. And of course in addition to the risk of incontinence, anal fistulotomy does not afford 100 % cure rates. Recurrence rates of 2–13 % (median 11 %) have been reported in selected series and when the study was limited to trans-sphincteric fistulas, recurrence rates climbs to 13–37 % [9–11].

There are two published Cochrane reviews for anal fistulas. Malik and Nelson looked at the results of incision and drainage of anorectal abscess alone vs. combined with primary fistulotomy [12]. They found six studies with a total of 474 patients. The recurrence risk was 0.13 (0.07–0.24) and the incontinence risk was 3.06 (0.7–13.45). There are two problems with this study. One is the incidence of fistula found during incision and drainage of abscess which was seen in 88–100 % of the patients. This is a clearcut case of “overkill,” because the reports from multiple case series place the incidence of fistula in post-I&D patients around 30–37 %. The second problem is the very poor quality of the studies. The review concluded that primary fistulotomy significantly reduced the odds of persistent fistula and need for reoperation and a small number of patients may have transient minor incontinence. One has to be careful not to apply these conclusions to patient at high risk of incontinence such as women with anterior fistulas and patients with IBD or HIV or previous anorectal surgery [12].

The second Cochrane review attempted to look at surgical operations for anal fistula. However of the ten studies collected for review many addressed the trivial issue of radiofrequency vs. diathermy or fistulotomy plus/minus marsupialization. Other studies looking at flap procedures with or without glue reported very small number of patients and some no data or risk of recurrence and incontinence [13].

The following are chronologic listing of additional randomized trials not included in the two Cochrane reviews:

Zimmerman and associates studied the impact of two different types of anal retractors in fistula surgery, demonstrating that even an innocuous retraction during surgery may have delectations effects on resting pressure and continence. In this study of 30 patients Scott retractors (same as LoneStar^®) was compared with Parks’ retractors. Use of Scott retractors resulted in better resting pressure (p = 0.035) and better continence preservation (p = 0.038) [16]. Singer, Cintron, and colleagues studying fibrin sealant, randomized 75 patients with trans-sphincteric fistulas to three groups attempting to address causes of treatment failure: infection vs. glue extrusion due to large internal openings. Fibrin sealant is covered in Chap.​ 11. One group received fibrin sealant with antibiotics, the second fibrin sealant and closure of the internal opening, and the third had fibrin sealant plus both antibiotics and closure of the internal opening [17]. The results were worse than their previously published data on fibrin sealant alone (healing of 25–55 %) [18].

Perez and associates studied the clinical and manometric results of advancement flaps vs. fistulotomy with sphincter reconstruction in complex fistulas in 60 patients [19]. There were two recurrences (2/30) in each arm and the postoperative incontinence rate was similar [19]. Gustafson and Graf postulated that failure of advancement flap in fistula-in-ano was a result of infection. They randomized 83 patients to flap and implantation of gentamicin collagen beneath the flaps vs. flap alone. There was no added benefit from this modification (p = 0.45) [20]. Garcia-Olmo et al. have published the use of autologous adipose-derived stem cell in the treatment of complex fistulas. Injecting the stem cells suspended in fibrin sealant into the wall of the anal fistulas in Crohn’s disease, they reported a significantly higher incidence of healing in 49 patients randomized in the group with fibrin sealant and autologous stem cells,17/24 healed while in the fibrin glue alone arm 4/25 healed (OR = 4.43, CI 1.7–11.3) [21]. This topic is discussed in Chap.​ 18.

Hammond et al. reported on the use of cross-linked collagen suspended in fibrin sealant and compared them with fibrin sealant alone in 29 patients [22]. In the glue plus collagen arm 12/15 healed, while in the sealant alone group 7/13 healed, but the differences were not statistically significant (p = NS). Grimand Grimaud and colleagues compared fibrin sealant to no therapy in 71 patients with Crohn’s fistulae. This is a rare and possibly the only controlled trail comparing treatment with observation (placebo). There was some benefit reported as “remission” in 13/34 patients in the glue arm vs. 6/37 patients in observation group [23]. Khafagy et al. randomized flap treatments for closure of the internal opening between full thickness flap and mucosal flap in 40 patients. The full thickness flap comprised of mucosa and smooth muscle (internal sphincter or lower rectal wall) had a statically significantly higher rate of healing (18/20) compared with mucosal flap (12/20) p = 0.068. There were two cases of incontinence to flatus (10 %) in the former group [24].

A recent paper by Lewis et al. on novel biologic strategies in the management of anal fistulas is a compilation of 23 studies reviewing the use of biologics in fistula surgery warrants mentioning, even though none have results comparing to anal fistulotomy to the long-term eradication rate [6].

The following is a summary of the “biologics” and relevant studies in the above paper.