- Email: [email protected]
What predicts successful nonoperative management with botulinum toxin for anal fissure?
The American Journal of Surgery xxx (xxxx) xxx
Contents lists available at ScienceDirect
The American Journal of Surgery journal homepage: www.americanjournalofsurgery.com
What predicts successful nonoperative management with botulinum toxin for anal fissure? Roxanne Kyriakakis, Kathrine Kelly-Schuette, Rebecca Hoedema, Martin Luchtefeld, James Ogilvie* Spectrum Health, 4100 Lake Dr, Suite 201, United States
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 June 2019 Received in revised form 9 October 2019 Accepted 9 October 2019
Background: Botulinum toxin has been established as a non-surgical alternative for chronic anal fissures. There is a paucity of data regarding which patients benefit most from this intervention. Methods: We retrospectively collected data from all cases of chronic anal fissures treated with botulinum toxin over seven years to identify predictors of success. Non-responders were defined as any subsequent surgery or reporting satisfaction as poor or fair. Results: Of 91 patients, 60% (n ¼ 55) were responders and 26% (n ¼ 25) underwent subsequent surgery. There were significantly more females among responders (78% vs. 55%, p ¼ 0.02). A higher body mass index tended towards significance among non-responders (30 ± 7 vs. 27 ± 6, p ¼ 0.08). High satisfaction at the first visit was associated with no subsequent surgery (18% vs. 45%, p ¼ 0.002). Conclusions: Botulinum toxin can be successfully used to treat anal fissures in a majority of patients. Primary predictors of success were female sex, satisfaction at the first postprocedure visit and there was a tendency towards a lower body mass index. © 2019 Published by Elsevier Inc.
Keywords: Botulinum toxin Anal fissure Lateral internal sphincterotomy
Introduction While the true epidemiology of anal fissures is unknown, multiple series have demonstrated that among those presenting with anorectal complaints to either primary care physicians or specialists, its frequency is secondary only to hemorrhoidal disease and pruritus ani.1e3 By definition, anal fissures are ulcerations of the anoderm within the anal canal. These may be caused by, or result in, sphincter spasm and hypertonicity which in certain patients leads to relative ischemia and ulceration.4,5 Regardless of exact etiology all first line treatments are geared at relaxation of the underlying internal anal sphincter muscle. Randomized controlled trials have demonstrated that surgical relaxation via a lateral internal sphincterotomy, compared to chemical paralysis with botulinum toxin, result in improved healing and less recurrence.6 However, this is not without a cost, as the incidence of fecal incontinence, a known complication can be as high as 66%.6 As a result, some groups have advocated botulinum toxin in older patients or those at high risk for fecal incontinence.7 However, few studies exist regarding predictors of success in order
* Corresponding author. E-mail address: [email protected] (J. Ogilvie).
to best understand who benefits most from botulinum toxin. One retrospective series found that ongoing pain reported at the first post-procedure visit to be predicative of long-term success.8 However, their use of low doses of toxin limit generalizability to many practices.9,10 Other investigators identified high resting anal sphincter pressures with concomitant fibrillation as a manometric finding that may be more likely to respond to botulinum toxin11, but the use of manometry prior to toxin use limits the practicality of this marker. Our aim, therefore, was to identify all those who underwent treatment of chronic anal fissure with botulinum toxin and identify predictors of response among those who had resolution of symptoms versus those that ultimately underwent a lateral internal sphincterotomy. Based on anecdotal experience our hypothesis was that patients with an increased chronicity of symptoms would have a decreased rate of healing and less symptom relief. Methods We performed a retrospective review of all cases of chronic anal fissure treated with botulinum toxin over a 7-year time frame at a single, at a community-based training institution comprising seven surgeons affiliated with Michigan State University. Chronic anal fissure was defined as fissures that failed a minimum of 6 weeks
https://doi.org/10.1016/j.amjsurg.2019.10.012 0002-9610/© 2019 Published by Elsevier Inc.
Please cite this article as: Kyriakakis R et al., What predicts successful nonoperative management with botulinum toxin for anal fissure?, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.10.012
2
R. Kyriakakis et al. / The American Journal of Surgery xxx (xxxx) xxx
of medical management. After receiving approval from the Spectrum Health institutional review board, we identified cases from an administrative billing database of a multi-surgeon colorectal practice using Current Procedure Terminology code 46505. Individual review of the electronic medical record was performed on each case to identify demographic data, indications, and previous treatments, as well as any post-procedure treatments. Botulinum toxin placement was performed either in the office setting without sedation, in the operating room, or in the endoscopy suite and was based on surgeon and patient preference. Likewise, location of the injection (into the internal anal sphincter muscle or in the intersphincteric groove) was not standardized and based on surgeon’s practice. No fissurectomies were performed in addition to the toxin injection. High-dose botulinum toxin (100 units in total) was used in each case. A positive clinical response was defined as patients reporting resolution of pain or bleeding after treatment and clinical documentation of good, better or excellent quality of life by physician. Negative clinical response was defined as patients reporting fair or poor quality of life. Summary statistics were calculated for the data. Quantitative data are described as the mean±standard deviation, while nominal data are reported as a percentage. Differences between those with a positive clinical response and those with a negative clinical response were determined using the two-tailed t-test, while differences involving nominal data were analyzed using the chisquare or Fisher’s Exact test, as appropriate. The comparison of clinical response between the pre-operative assessment and the first follow-up visit was performed using the McNemar test. Significance was assessed at p < 0.05. Analyses were performed using Stata v.15.1 (StataCorp, College Station, TX). Results We identified 106 patients (72 females, 34 males) over the course of a 7-year period (2011e2017), who each received 100 units of botulinum toxin. The mean age was 44 þ 14 years and the mean body mass index was 28 þ 7 kg/m2. In terms of smoking status, 11 (10%) were current smokers and 27 (25%) were former smokers. All patients had undergone conservative measures (fiber supplementation and/or bowel regimen) in addition to a course of topical 2% diltiazem gel prior to consideration of botulinum toxin. The most common indication was recalcitrant anal fissure (n ¼ 95, 90%) and in terms of prior anal surgery, 19 (18%) had a prior sphincterotomy and 24 (23%) had undergone a previous hemorrhoidectomy. Of the procedures, 53 were performed in the operating room, 47 in the
clinic, and 5 in the endoscopy suite. Injection into the intersphincteric groove was performed 62% of the time, the other 38% being placed into the internal anal sphincter muscle. Prior to the initial procedure, 96% of subjects rated their quality of life related to their anorectal disease as either poor or fair. Postprocedure, 15 patients (14%) did not return to the office for any follow-up. The remaining 91 patients had clinical response data available at the time of their first follow-up appointment (median 6.8 weeks). Overall, 67% (60/91) were classified as responders at the first post-procedure visit, which was a statistically significant improvement compared to the reported pre-intervention quality of life (p < 0.001). Of these 60, 48 patients (53% overall) underwent no further interventions and remained responders for a mean follow up of 7.7 months. After an initial response, 12 patients had procedures performed for recurrent or worsening symptoms, including sphincterotomy (n ¼ 8), repeat botulinum toxin injection (n ¼ 3, mean of 11 months after first injection) and fissurectomy (n ¼ 1). Of the 31 patients considered initial non-responders, 13 went on to have a lateral internal sphincterotomy and 1 a diamond anoplasty at a median of 6.2 months after the initial injection. Among the 17 initial non-responders who did not have surgery, 4 improved at a later follow-up and 13 continued to rate their quality as either fair or poor. Therefore, overall 42 of 91 patients (46%) were responders at last subsequent visit and 24 of 91 (26%) ultimately underwent surgery at a median time of 10.3 months after the initial injection. Sixteen of the 24 patients who went on to require surgery had received their botox injection in the clinic. After surgery, 92% reported an excellent or good response (22 of 24). In order to identify predictors of response and avoidance of surgery, we compared the 55 patients overall (initial responders plus those that received repeat toxin injection) to 36 nonresponders (those that underwent surgery or stated poor/fair quality of life at last encounter). There were no differences between the groups in terms of age, ASA classification, smoking status or symptom duration (Table 1). There were significantly more females among the responders (78% vs. 55%, p ¼ 0.02). Higher BMI tended towards a decreased response (30 ± 7 vs. 27 ± 6, p ¼ 0.08), although this did not reach statistical significance (see Table 1). Prior sphincterotomy was not found to affect the outcomes of botulinum toxin as only 23% of patients with prior sphincterotomy went on to require a repeat sphincterotomy. Patients who rated their response as better or excellent during their first follow up visit were far less likely to have any additional surgeries compared to those that did not (18% vs. 45%, p ¼ 0.002).
Table 1 Comparison between overall respondersa and Non-responders.
Age BMI Sex (% female) ASA ASA 1 ASA 2 ASA 3 Smoking status Active Former Never Symptom Duration (3 months) Prior Sphincterotomy Location OR/endoscopy Clinic a
Non-Responder (N ¼ 36)
Responder (N ¼ 55)
p-value
43 ± 13 30 ± 7 56%
45 ± 15 27 ± 6 78%
0.54 0.08 0.02 0.68
22% 75% 3%
27% 67% 5%
3% 28% 69% 19% 19%
11% 27% 62% 15% 22%
39% 61%
47% 53%
0.35
0.56 0.79 0.43
Overall responders include initial responders (n ¼ 48), later responders (N ¼ 4), and patients requiring early repeat botox treatments (n ¼ 3).
Please cite this article as: Kyriakakis R et al., What predicts successful nonoperative management with botulinum toxin for anal fissure?, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.10.012
R. Kyriakakis et al. / The American Journal of Surgery xxx (xxxx) xxx
Discussion The first line treatment for an anal fissure is medical management with stool modification, high fiber supplementation and involuntary smooth muscle relaxation (topical nitroglycerine or topical/oral calcium channel blockers). While topical therapies may prove effective in up to 70% of cases, locally injected botulinum toxin has been suggested to demonstrate superior rates of healing prior to considering sphincterotomy. Although a meta-analysis examining the efficacy of botulinum toxin reported on healing rates ranging from 33 to 98%, treatment success averaged between 60 and 70%.12 Our results mirror these findings as we found 60% of our cohort exhibited a favorable response, although 14% did not return for follow-up after injection. Similar to previous reports8 we also identified that quality of life ratings at the first post-operative visit were associated with not undergoing future surgical procedures. In addition, we also found that male sex was associated with decreased success with botulinum toxin. While doses higher than 100 units were not used in this study and given the controversy surrounding a dose-related response, it is unclear from existing studies whether there would be any benefit from escalated doses in male patients.9,10,12 We also found that two thirds of patients requiring a surgical procedure had botulinum toxin injected in the clinic. This raises the question about whether injection in the operating room may improve outcomes. Interestingly, we also noted a higher BMI tended towards an increased likelihood of being a nonresponder. The trend towards significance with a higher BMI may be due to the increased baseline anal resting and squeeze pressures. Given the lack of a significant difference between male and female BMI in our study (29 vs. 28 kg/m2, p ¼ 0.49), we doubt confounding, but postulate that increased sphincter length and hypertonicity may be a factor. However, there are no published studies suggesting a link with anal sphincter pressures and BMI. Given the retrospective design of the study we are inherently limited by the nature of the data. Our endpoint of response was left to the individual surgeon and subject to their documentation and perceived patient benefit. Patient reported and validated quality of life and incontinence data were available for <25% of patients as these data points were routinely administered were begun in the last years of the study and were therefore not reported. Nevertheless, with a crude measure of satisfaction coupled with an only 14% loss to follow-up we were able to track the clinically relevant endpoint of whether or not additional surgeries were performed. This becomes critical when discussing treatment options and the long-term success with patients. We were also limited by knowing the exact duration of symptoms prior to treatment with botulinum toxin. The natural history of anal fissures is often a waxing and waning phenomenon, as they may heal themselves for long periods of time prior to a patient presenting for definitive treatment. As a result, patient records may not reflect the exact duration of symptoms as this data point was were not explicitly targeted a priori. While our initial hypothesis was not proven in this case, prospectively designed research will be
3
required to truly answer the question of whether an association between symptom duration and response truly exist. In conclusion, as one of the largest North American series of botulinum toxin for chronic anal fissures we have demonstrated that 60% of patients have responded to injection and 26% ultimately underwent subsequent surgery. We have shown that male sex is associated with a decreased response to injection and higher likelihood of future surgery. Similar to previous studies patient satisfaction at the first follow up procedure was a good predictor of future success. Future prospective evaluation of patients with detailed pre-procedure symptomatology and perhaps manometry will be required to better understand which patients ultimately derived the most benefit from botulinum toxin. Acknowledgments We would like to thank Alan T. Davis, PhD and Tracy J. Kohler PhD for their statistical expertise and assistance preparing the manuscript. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.amjsurg.2019.10.012. References nan C. The 1. Abramowitz L, Benabderrahmane M, Pospait D, Philip J, Laoue prevalence of proctological symptoms amongst patients who see general practitioners in France. Eur J Gen Pract. 2014 Dec;20(4):301e306. 2. Kuehn HG, Gebbensleben O, Hilger Y, Rohde H. Relationship between anal symptoms and anal findings. Int J Med Sci. 2009;6(2):77e84. 3. Idrees JJ, Clapp M, Brady JT, Stein SL, Reynolds HL, Steinhagen E. Evaluating the accuracy of hemorrhoids: comparison among specialties and symptoms. Dis Colon Rectum. 2019 Jul;62(7):867e871. 4. Gibbons CP, Read NW. Anal hypertonia in fissures: cause or effect? Br J Surg. 1986 Jun;73(6):443e445. 5. Keck JO, Staniunas RJ, Coller JA, Barrett RC, Oster ME. Computer-generated profiles of the anal canal in patients with anal fissure. Dis Colon Rectum. 1995 Jan;38(1):72e79. 6. Chen H-L, Woo X-B, Wang H-S, et al. Botulinum toxin injection versus lateral internal sphincterotomy for chronic anal fissure: a meta-analysis of randomized control trials. Tech Coloproctol. 2014 Aug;18(8):693e698. rez F, Serrano P, Candela F, Lacueva J, Calpena R. Surgical versus 7. Arroyo A, Pe chemical (botulinum toxin) sphincterotomy for chronic anal fissure: long-term results of a prospective randomized clinical and manometric study. Am J Surg. 2005 Apr;189(4):429e434. 8. Dat A, Chin M, Skinner S, et al. Botulinum toxin therapy for chronic anal fissures: where are we at currently? ANZ J Surg. 2017 Sep;87(9):E70eE73. 9. Glover PH, Tang S, Whatley JZ, et al. High-dose circumferential chemodenervation of the internal anal sphincter: a new treatment modality for uncomplicated chronic anal fissure: a retrospective cohort study (with video). Int J Surg Lond Engl. 2015 Nov;23(Pt A):1e4. 10. Ravindran P, Chan DL, Ciampa C, George R, Punch G, White SI. High-dose versus low- dose botulinum toxin in anal fissure disease. Tech Coloproctol. 2017 Oct;21(10):803e808. 11. Moon A, Chitsabesan P, Plusa S. Anal sphincter fibrillation: is this a new finding that identifies resistant chronic anal fissures that respond to botulinum toxin? Colorectal Dis Off J Assoc Coloproctol G B Irel. 2013 Aug;15(8):1007e1010. 12. Bobkiewicz A, Francuzik W, Krokowicz L, et al. Botulinum toxin injection for treatment of chronic anal fissure: is there any dose-dependent efficiency? A meta-analysis. World J Surg. 2016 Dec;40(12):3064e3072.
Please cite this article as: Kyriakakis R et al., What predicts successful nonoperative management with botulinum toxin for anal fissure?, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.10.012
Contents lists available at ScienceDirect
The American Journal of Surgery journal homepage: www.americanjournalofsurgery.com
What predicts successful nonoperative management with botulinum toxin for anal fissure? Roxanne Kyriakakis, Kathrine Kelly-Schuette, Rebecca Hoedema, Martin Luchtefeld, James Ogilvie* Spectrum Health, 4100 Lake Dr, Suite 201, United States
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 June 2019 Received in revised form 9 October 2019 Accepted 9 October 2019
Background: Botulinum toxin has been established as a non-surgical alternative for chronic anal fissures. There is a paucity of data regarding which patients benefit most from this intervention. Methods: We retrospectively collected data from all cases of chronic anal fissures treated with botulinum toxin over seven years to identify predictors of success. Non-responders were defined as any subsequent surgery or reporting satisfaction as poor or fair. Results: Of 91 patients, 60% (n ¼ 55) were responders and 26% (n ¼ 25) underwent subsequent surgery. There were significantly more females among responders (78% vs. 55%, p ¼ 0.02). A higher body mass index tended towards significance among non-responders (30 ± 7 vs. 27 ± 6, p ¼ 0.08). High satisfaction at the first visit was associated with no subsequent surgery (18% vs. 45%, p ¼ 0.002). Conclusions: Botulinum toxin can be successfully used to treat anal fissures in a majority of patients. Primary predictors of success were female sex, satisfaction at the first postprocedure visit and there was a tendency towards a lower body mass index. © 2019 Published by Elsevier Inc.
Keywords: Botulinum toxin Anal fissure Lateral internal sphincterotomy
Introduction While the true epidemiology of anal fissures is unknown, multiple series have demonstrated that among those presenting with anorectal complaints to either primary care physicians or specialists, its frequency is secondary only to hemorrhoidal disease and pruritus ani.1e3 By definition, anal fissures are ulcerations of the anoderm within the anal canal. These may be caused by, or result in, sphincter spasm and hypertonicity which in certain patients leads to relative ischemia and ulceration.4,5 Regardless of exact etiology all first line treatments are geared at relaxation of the underlying internal anal sphincter muscle. Randomized controlled trials have demonstrated that surgical relaxation via a lateral internal sphincterotomy, compared to chemical paralysis with botulinum toxin, result in improved healing and less recurrence.6 However, this is not without a cost, as the incidence of fecal incontinence, a known complication can be as high as 66%.6 As a result, some groups have advocated botulinum toxin in older patients or those at high risk for fecal incontinence.7 However, few studies exist regarding predictors of success in order
* Corresponding author. E-mail address: [email protected] (J. Ogilvie).
to best understand who benefits most from botulinum toxin. One retrospective series found that ongoing pain reported at the first post-procedure visit to be predicative of long-term success.8 However, their use of low doses of toxin limit generalizability to many practices.9,10 Other investigators identified high resting anal sphincter pressures with concomitant fibrillation as a manometric finding that may be more likely to respond to botulinum toxin11, but the use of manometry prior to toxin use limits the practicality of this marker. Our aim, therefore, was to identify all those who underwent treatment of chronic anal fissure with botulinum toxin and identify predictors of response among those who had resolution of symptoms versus those that ultimately underwent a lateral internal sphincterotomy. Based on anecdotal experience our hypothesis was that patients with an increased chronicity of symptoms would have a decreased rate of healing and less symptom relief. Methods We performed a retrospective review of all cases of chronic anal fissure treated with botulinum toxin over a 7-year time frame at a single, at a community-based training institution comprising seven surgeons affiliated with Michigan State University. Chronic anal fissure was defined as fissures that failed a minimum of 6 weeks
https://doi.org/10.1016/j.amjsurg.2019.10.012 0002-9610/© 2019 Published by Elsevier Inc.
Please cite this article as: Kyriakakis R et al., What predicts successful nonoperative management with botulinum toxin for anal fissure?, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.10.012
2
R. Kyriakakis et al. / The American Journal of Surgery xxx (xxxx) xxx
of medical management. After receiving approval from the Spectrum Health institutional review board, we identified cases from an administrative billing database of a multi-surgeon colorectal practice using Current Procedure Terminology code 46505. Individual review of the electronic medical record was performed on each case to identify demographic data, indications, and previous treatments, as well as any post-procedure treatments. Botulinum toxin placement was performed either in the office setting without sedation, in the operating room, or in the endoscopy suite and was based on surgeon and patient preference. Likewise, location of the injection (into the internal anal sphincter muscle or in the intersphincteric groove) was not standardized and based on surgeon’s practice. No fissurectomies were performed in addition to the toxin injection. High-dose botulinum toxin (100 units in total) was used in each case. A positive clinical response was defined as patients reporting resolution of pain or bleeding after treatment and clinical documentation of good, better or excellent quality of life by physician. Negative clinical response was defined as patients reporting fair or poor quality of life. Summary statistics were calculated for the data. Quantitative data are described as the mean±standard deviation, while nominal data are reported as a percentage. Differences between those with a positive clinical response and those with a negative clinical response were determined using the two-tailed t-test, while differences involving nominal data were analyzed using the chisquare or Fisher’s Exact test, as appropriate. The comparison of clinical response between the pre-operative assessment and the first follow-up visit was performed using the McNemar test. Significance was assessed at p < 0.05. Analyses were performed using Stata v.15.1 (StataCorp, College Station, TX). Results We identified 106 patients (72 females, 34 males) over the course of a 7-year period (2011e2017), who each received 100 units of botulinum toxin. The mean age was 44 þ 14 years and the mean body mass index was 28 þ 7 kg/m2. In terms of smoking status, 11 (10%) were current smokers and 27 (25%) were former smokers. All patients had undergone conservative measures (fiber supplementation and/or bowel regimen) in addition to a course of topical 2% diltiazem gel prior to consideration of botulinum toxin. The most common indication was recalcitrant anal fissure (n ¼ 95, 90%) and in terms of prior anal surgery, 19 (18%) had a prior sphincterotomy and 24 (23%) had undergone a previous hemorrhoidectomy. Of the procedures, 53 were performed in the operating room, 47 in the
clinic, and 5 in the endoscopy suite. Injection into the intersphincteric groove was performed 62% of the time, the other 38% being placed into the internal anal sphincter muscle. Prior to the initial procedure, 96% of subjects rated their quality of life related to their anorectal disease as either poor or fair. Postprocedure, 15 patients (14%) did not return to the office for any follow-up. The remaining 91 patients had clinical response data available at the time of their first follow-up appointment (median 6.8 weeks). Overall, 67% (60/91) were classified as responders at the first post-procedure visit, which was a statistically significant improvement compared to the reported pre-intervention quality of life (p < 0.001). Of these 60, 48 patients (53% overall) underwent no further interventions and remained responders for a mean follow up of 7.7 months. After an initial response, 12 patients had procedures performed for recurrent or worsening symptoms, including sphincterotomy (n ¼ 8), repeat botulinum toxin injection (n ¼ 3, mean of 11 months after first injection) and fissurectomy (n ¼ 1). Of the 31 patients considered initial non-responders, 13 went on to have a lateral internal sphincterotomy and 1 a diamond anoplasty at a median of 6.2 months after the initial injection. Among the 17 initial non-responders who did not have surgery, 4 improved at a later follow-up and 13 continued to rate their quality as either fair or poor. Therefore, overall 42 of 91 patients (46%) were responders at last subsequent visit and 24 of 91 (26%) ultimately underwent surgery at a median time of 10.3 months after the initial injection. Sixteen of the 24 patients who went on to require surgery had received their botox injection in the clinic. After surgery, 92% reported an excellent or good response (22 of 24). In order to identify predictors of response and avoidance of surgery, we compared the 55 patients overall (initial responders plus those that received repeat toxin injection) to 36 nonresponders (those that underwent surgery or stated poor/fair quality of life at last encounter). There were no differences between the groups in terms of age, ASA classification, smoking status or symptom duration (Table 1). There were significantly more females among the responders (78% vs. 55%, p ¼ 0.02). Higher BMI tended towards a decreased response (30 ± 7 vs. 27 ± 6, p ¼ 0.08), although this did not reach statistical significance (see Table 1). Prior sphincterotomy was not found to affect the outcomes of botulinum toxin as only 23% of patients with prior sphincterotomy went on to require a repeat sphincterotomy. Patients who rated their response as better or excellent during their first follow up visit were far less likely to have any additional surgeries compared to those that did not (18% vs. 45%, p ¼ 0.002).
Table 1 Comparison between overall respondersa and Non-responders.
Age BMI Sex (% female) ASA ASA 1 ASA 2 ASA 3 Smoking status Active Former Never Symptom Duration (3 months) Prior Sphincterotomy Location OR/endoscopy Clinic a
Non-Responder (N ¼ 36)
Responder (N ¼ 55)
p-value
43 ± 13 30 ± 7 56%
45 ± 15 27 ± 6 78%
0.54 0.08 0.02 0.68
22% 75% 3%
27% 67% 5%
3% 28% 69% 19% 19%
11% 27% 62% 15% 22%
39% 61%
47% 53%
0.35
0.56 0.79 0.43
Overall responders include initial responders (n ¼ 48), later responders (N ¼ 4), and patients requiring early repeat botox treatments (n ¼ 3).
Please cite this article as: Kyriakakis R et al., What predicts successful nonoperative management with botulinum toxin for anal fissure?, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.10.012
R. Kyriakakis et al. / The American Journal of Surgery xxx (xxxx) xxx
Discussion The first line treatment for an anal fissure is medical management with stool modification, high fiber supplementation and involuntary smooth muscle relaxation (topical nitroglycerine or topical/oral calcium channel blockers). While topical therapies may prove effective in up to 70% of cases, locally injected botulinum toxin has been suggested to demonstrate superior rates of healing prior to considering sphincterotomy. Although a meta-analysis examining the efficacy of botulinum toxin reported on healing rates ranging from 33 to 98%, treatment success averaged between 60 and 70%.12 Our results mirror these findings as we found 60% of our cohort exhibited a favorable response, although 14% did not return for follow-up after injection. Similar to previous reports8 we also identified that quality of life ratings at the first post-operative visit were associated with not undergoing future surgical procedures. In addition, we also found that male sex was associated with decreased success with botulinum toxin. While doses higher than 100 units were not used in this study and given the controversy surrounding a dose-related response, it is unclear from existing studies whether there would be any benefit from escalated doses in male patients.9,10,12 We also found that two thirds of patients requiring a surgical procedure had botulinum toxin injected in the clinic. This raises the question about whether injection in the operating room may improve outcomes. Interestingly, we also noted a higher BMI tended towards an increased likelihood of being a nonresponder. The trend towards significance with a higher BMI may be due to the increased baseline anal resting and squeeze pressures. Given the lack of a significant difference between male and female BMI in our study (29 vs. 28 kg/m2, p ¼ 0.49), we doubt confounding, but postulate that increased sphincter length and hypertonicity may be a factor. However, there are no published studies suggesting a link with anal sphincter pressures and BMI. Given the retrospective design of the study we are inherently limited by the nature of the data. Our endpoint of response was left to the individual surgeon and subject to their documentation and perceived patient benefit. Patient reported and validated quality of life and incontinence data were available for <25% of patients as these data points were routinely administered were begun in the last years of the study and were therefore not reported. Nevertheless, with a crude measure of satisfaction coupled with an only 14% loss to follow-up we were able to track the clinically relevant endpoint of whether or not additional surgeries were performed. This becomes critical when discussing treatment options and the long-term success with patients. We were also limited by knowing the exact duration of symptoms prior to treatment with botulinum toxin. The natural history of anal fissures is often a waxing and waning phenomenon, as they may heal themselves for long periods of time prior to a patient presenting for definitive treatment. As a result, patient records may not reflect the exact duration of symptoms as this data point was were not explicitly targeted a priori. While our initial hypothesis was not proven in this case, prospectively designed research will be
3
required to truly answer the question of whether an association between symptom duration and response truly exist. In conclusion, as one of the largest North American series of botulinum toxin for chronic anal fissures we have demonstrated that 60% of patients have responded to injection and 26% ultimately underwent subsequent surgery. We have shown that male sex is associated with a decreased response to injection and higher likelihood of future surgery. Similar to previous studies patient satisfaction at the first follow up procedure was a good predictor of future success. Future prospective evaluation of patients with detailed pre-procedure symptomatology and perhaps manometry will be required to better understand which patients ultimately derived the most benefit from botulinum toxin. Acknowledgments We would like to thank Alan T. Davis, PhD and Tracy J. Kohler PhD for their statistical expertise and assistance preparing the manuscript. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.amjsurg.2019.10.012. References nan C. The 1. Abramowitz L, Benabderrahmane M, Pospait D, Philip J, Laoue prevalence of proctological symptoms amongst patients who see general practitioners in France. Eur J Gen Pract. 2014 Dec;20(4):301e306. 2. Kuehn HG, Gebbensleben O, Hilger Y, Rohde H. Relationship between anal symptoms and anal findings. Int J Med Sci. 2009;6(2):77e84. 3. Idrees JJ, Clapp M, Brady JT, Stein SL, Reynolds HL, Steinhagen E. Evaluating the accuracy of hemorrhoids: comparison among specialties and symptoms. Dis Colon Rectum. 2019 Jul;62(7):867e871. 4. Gibbons CP, Read NW. Anal hypertonia in fissures: cause or effect? Br J Surg. 1986 Jun;73(6):443e445. 5. Keck JO, Staniunas RJ, Coller JA, Barrett RC, Oster ME. Computer-generated profiles of the anal canal in patients with anal fissure. Dis Colon Rectum. 1995 Jan;38(1):72e79. 6. Chen H-L, Woo X-B, Wang H-S, et al. Botulinum toxin injection versus lateral internal sphincterotomy for chronic anal fissure: a meta-analysis of randomized control trials. Tech Coloproctol. 2014 Aug;18(8):693e698. rez F, Serrano P, Candela F, Lacueva J, Calpena R. Surgical versus 7. Arroyo A, Pe chemical (botulinum toxin) sphincterotomy for chronic anal fissure: long-term results of a prospective randomized clinical and manometric study. Am J Surg. 2005 Apr;189(4):429e434. 8. Dat A, Chin M, Skinner S, et al. Botulinum toxin therapy for chronic anal fissures: where are we at currently? ANZ J Surg. 2017 Sep;87(9):E70eE73. 9. Glover PH, Tang S, Whatley JZ, et al. High-dose circumferential chemodenervation of the internal anal sphincter: a new treatment modality for uncomplicated chronic anal fissure: a retrospective cohort study (with video). Int J Surg Lond Engl. 2015 Nov;23(Pt A):1e4. 10. Ravindran P, Chan DL, Ciampa C, George R, Punch G, White SI. High-dose versus low- dose botulinum toxin in anal fissure disease. Tech Coloproctol. 2017 Oct;21(10):803e808. 11. Moon A, Chitsabesan P, Plusa S. Anal sphincter fibrillation: is this a new finding that identifies resistant chronic anal fissures that respond to botulinum toxin? Colorectal Dis Off J Assoc Coloproctol G B Irel. 2013 Aug;15(8):1007e1010. 12. Bobkiewicz A, Francuzik W, Krokowicz L, et al. Botulinum toxin injection for treatment of chronic anal fissure: is there any dose-dependent efficiency? A meta-analysis. World J Surg. 2016 Dec;40(12):3064e3072.
Please cite this article as: Kyriakakis R et al., What predicts successful nonoperative management with botulinum toxin for anal fissure?, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.10.012