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explain the variability between studies based on differences in populations, inter-
ventions, outcome measurement or other methodologic issues. Subgroup and sensi-
tivity analysis may be necessary to illuminate these differences which may or may
not downgrade the evidence based on the perceived effect on the outcome of
interest.
Indirectness
There are two types of indirectness recognized within the GRADE system [12].
The first is when there is evidence comparing intervention A with intervention B
and intervention B with C but no direct evidence from a comparison of A with
C. In this case an inference can be made but the level of evidence for that outcome
is marked down one level. This type of indirectness is more common in pharmaco-
logic trials. Evidence may also be classified as indirect if there are differences
between the best available evidence with respect to the populations under study,
specific interventions, co-interventions or outcome measurements and the PICO
(population, intervention, comparator and outcome) of the initial clinical
question.
Publication Bias
Negative studies are less likely to be published resulting in publication bias [9].
These studies also suffer from lag time bias being published at a later date. Negative
studies are often relegated to lower impact journals or as a thesis or abstract in an
obscure publication such as proceedings of a meeting and in languages other than
English. Omission of negative studies may lead to an overestimation of treatment
effect.
Another form of publication bias is selective outcome reporting [9]. This should
be suspected if some of the expected outcomes for a specific clinical problem are
suspiciously absent. Selective outcome reporting may also occur when composite
or derived outcomes are reported as significant and primary outcomes are either not
significant or not discussed. It also causes an overestimation of the effects of an
intervention.
Upgrading Evidence
Occasionally outcomes from descriptive or observational studies which are nor-
mally classified as low level evidence may be upgraded one level. GRADE has
specified three situations whereby observational evidence may be upgraded usually
from very low to low level evidence (Fig. 2.2).
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Large Magnitude of Effect
Occasionally an observational study demonstrates a very large treatment effect [13].
GRADE defines a large effect as a relative risk (RR) of >2.0 and <5.0 based on
consistent evidence from at least two studies with no significant confounders. A
very large magnitude of effect is defined as a relative risk of >5.0 and <0.2. The
effect should be based on direct evidence with no other perceived forms of bias. An
example of this would be the original case series published on mesorectal excision
where the reduction in local recurrence was far greater than either accepted levels
in the literature following standard surgery at the time or the improvements obtained
by adjuvant therapy [15].
Plausible Confounders
In this situation, a confounder effect would be expected to act in opposition to the
observed effect [13]. For example, all plausible confounders would reduce the dem-
onstrated effect or increase it if no effect was observed. Thus the presence of the
confounder increases the likelihood that the observed effect is real and therefore the
evidence may be upgraded.
Dose Response Gradient
When increased exposure to an intervention is associated with a larger treatment
effect or greater harm, this may be considered a dose response gradient [13]. In this
situation, the evidence may be upgraded as we have more confidence in the observed
effect. This is not likely to occur in surgical studies as the treatment effect is usually
an all or none phenomena.
Overall Quality Rating
Once the evidence for each outcome has been identified, stratified and evaluated for
the presence of bias, an estimation of the confidence in the observed effect is deter-
mined based on the qualities in the previous section. This information is best sum-
marized in an evidence profile table (EP) [2]. Next, a quality rating of the best
available evidence is assigned for each separate outcome to one of the four catego-
ries (Table 2.1). This becomes the overall estimate of the confidence in the expressed
treatment effect for a specific outcome [16]. Prior to a recommendation, an overall
quality rating for all the evidence for all outcomes is determined. When there are
W.D. Bu ie
15
different levels of quality for each outcome, the GRADE system by convention
bases the overall quality rating on the lowest quality of available evidence for the
specified outcomes (Fig. 2.2).
The overall quality rating is the basis for the strength of any recommendations
that follows (Fig. 2.1). Strength of recommendation is defined as “the extent to
which we can be … confident that desirable consequences of an intervention out-
weigh undesirable consequences” [16]. GRADE classifies recommendations into
two categories based on how strongly the evidence supports the recommendation. A
strong recommendation indicates that a specific course of action would be appropri-
ate for most patients in most situations. A weak recommendation on the other hand
indicates that although the recommended course of action would be appropriate for
most patients in this situation, for many patients it would not [17]. Occasionally
evidence for a specific outcome is so inadequate that no evidence based recommen-
dation can be made.
Conclusion
Clinical decisions must be based on best evidence. High quality structured reviews
or CPGs with transparent evaluation of quality of the evidence using a system such
as GRADE are invaluable. While the clinician may not have the time or training to
perform a structured review, they must be able to evaluate studies for quality when
information on a desired outcome is not part of a CPG.
While evidence is essential for good clinical decision-making, it cannot be
applied in isolation. A clinician must consider the risks versus benefits and the bur-
dens and costs of each management strategy. In addition, the goals, values and
expectations of the patient as well as the experience of the clinician in similar situ-
ations must be considered. It is the responsibility of the clinician to assess and
interpret the evidence as it applies to each individual patient’s situation and guide
the patient in the quest for optimal, safe, patient centered care.
References
1. Guyatt G, Drummond R, Meade MO, Cook DJ, Glossary. In: Users’ Guides to the Medical
Literature: a manual for evidence based clinical practice. 3rd ed. New York: McGraw-Hill
Professional; 2015. p. 655.
2. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction – GRADE evidence
profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383–94.
3. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of
evidence and strength of recommendations. BMJ. 2008;336:924–6.
4. Guyatt GH, Oxman AD, Kunz R, et al. What is “quality of evidence” and why is it important
to clinicians? BMJ. 2008;336:995–8.
2 Evaluating Evidence
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5. Guyatt GH, Oxman AD, Kunz R, et al. Going from evidence to recommendations. BMJ.
2008;336:1049–51.
6. Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, et al. GRADE guidelines: 2. Framing
the question and deciding on important outcomes. J Clin Epidemiol. 2011;64:395–400.
7. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the quality of
evidence. J Clin Epidemiol. 2011;64:401–6.
8. Guyatt G, Oxman AD, Kunz R, et al. GRADE guidelines: 4. Rating the quality of evidence
study limitations (risk of bias). J Clin Epidemiol. 2011;64:407–15.
9. Guyatt GH, Oxman AD, Montori V, et al. GRADE guidelines: 5. Rating the quality of
evidence- publication bias. J Clin Epidemiol. 2011;64:1277–82.
10. Guyatt GH, Oxman AD, Kunz R, Broxzek J, et al. GRADE guidelines: 6. Rating the quality of
evidence – imprecision. J Clin Epidemiol. 2011;64:1283–93.
11. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7. Rating the quality of evidence-
inconsistancy. J Clin Epidemiol. 2011;64:1294–302.
12. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 8. Rating the quality of evidence-
indirectness. J Clin Epidemiol. 2011;64:1303–10.
13. Guyatt GH, Oxman AD, Sultan S, et al. GRADE guidelines: 9. Rating up the quality of evi-
dence. J Clin Epidemiol. 2011;64:1211–6.
14. Guyatt G, Meade MO, Agoritsas T, et al. What is the question. In: Guyatt G, Drummond R,
Meade MO, Cook DJ, editors. Users’ guides to the medical literature: a manual for evidence
based clinical practice. 3rd ed. New York: McGraw-Hill Professional; 2015. p. 22.
15. MacFarlane JK, Heald RJ. Mesorectal excision for rectal cancer. Lancet. 1993;341:457–60.
16. Brozek JL, Aki EA, Alonson-Coello P, et al. Grading quality of evidence and strength of rec-
ommendations in clinical practice guidelines: part 1 of 3 an overview of the GRADE approach
and grading quality of evidence about interventions. Allergy. 2009;64:669–77.
17. Andrews JC, Schunemann HJ, Oxman AD, et al. GRADE Guidelines: 15. Going from evi-
dence to recommendations-determinant of a recommendations direction and strength. J Clin
Epidemiol. 2013;66:726–35.
W.D. Bu ie
Part I
IBD
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19© Springer International Publishing Switzerland 2017
N. Hyman, K. Umanskiy (eds.), Difficult Decisions in Colorectal Surgery,
Difficult Decisions in Surgery: An Evidence-Based Approach,
DOI 10.1007/978-3-319-40223-9_3
Chapter 3
IBD: Management of Symptomatic Anal
Fistulas in Patients with Crohn’s Disease
Lisa S. Poritz
Introduction
Approximately 30 % of patients with Crohn’s disease (CD) will have or develop
perianal fistulas (PF) during the course of their disease. Not only do symptomatic
PF cause pain and drainage, they may also lead to sepsis, incontinence, restriction
of activities, and decreased quality of life. Ultimately, some patients may end up
with permanent fecal diversion either due to progression of disease or in some cases
owing to complications from aggressive treatment.
The optimal treatment of these fistulas is controversial. The purpose of this chap-
ter is to compare the results of medical and surgical treatment for symptomatic PF
in CD patients. While there are numerous studies looking at the results of either
medical or surgical treatment, little high quality comparative data exists and evi-
dence based comparisons are challenging at best.
Not all fistulas in patients with CD are the same and both fistula characteristics
and patient factors are integral in determining the best therapy. It is important to
know whether there is active mucosal disease in the rectum, whether or not the
patient is concurrently receiving medical therapy for luminal disease, the history of
medication use and any adverse reactions, previous surgical treatment, and level of
continence.
For the purposes of this chapter we will divide patients into three categories and
assume that patients are not on medications for luminal CD. The literature and rec-
ommendations will be discussed as they pertain to the following patient scenarios:
L.S. Poritz
The Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine,
Hershey, PA, USA
e-mail: lporitz@outlook.com
20
Scenario 1: The patient with a simple fistula and no macroscopic rectal disease
Scenario 2: The patient with either a simple or a complex fistula and macroscopic
rectal disease
Scenario 3: The patient with a complex fistula and no macroscopic rectal disease
Search Strategy
A systematic review of the literature using PubMed was performed for the period:
1995–2015. Search terms included: CD, PF, fistula plug, ligation of internal fistula
tract (LIFT) procedure, and mucosal advancement flap. Articles were limited to
peer reviewed reports in English. Additional studies were identified from the refer-
ences of the initial articles retrieved as appropriate.
The studies discussed will be primarily randomized controlled trials and large
observational studies. In the case where neither exists for a given treatment modal-
ity, the best available data will be discussed. The quality of evidence and recom-
mendations were made according to modified GRADE system (Tables 3.1 and 3.2).
Results
Patients who present with fistulizing perianal CD typically require examination
under anesthesia (EUA), assessment of the rectal mucosa for disease activity, drain-
age of any abscesses and placement of setons as the initial step. The primary pur-
pose of seton placement is control of anorectal sepsis; setons allow for continued
drainage from the fistula tract and usually prevent abscess formation. Antibiotics
are often prescribed simultaneously (primarily ciprofloxacin or metronidazole) until
the perianal sepsis has resolved. Further therapy depends on the disease activity of
the rectal mucosa and complexity of the fistula.
Scenario 1: The Patient with a Simple Fistula and No
Macroscopic Rectal Disease
Patients with a simple superficial fistulas and no macroscopic rectal disease can
often be treated by surgery alone without the need for medical therapy beyond ini-
tial antibiotics. If the fistula does not traverse any sphincter muscle, these patients
Table 3.1 PICO table
Patient population Intervention Comparator Outcomes studied
Crohn’s patients with symptomatic anal
fistulas
Surgery Medical Therapy
Remission rate
Cure rate
Adverse event
L.S. Poritz
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Table 3.2 Quality of evidence
Study Patients Treatment Comparator Response rate Remission rate Type of study
Quality of
evidence
van Koperen
et al. [2]
61 Fistulotomy/Seton/or
advancement flap
None NA 44–82 % Retrospective Low
Pearson et al.
[6]
9 RCT AZA or 6MP Placebo 54 %: AZA or
6MP
21 %: placebo
NA Meta-analysis Moderate
Present et al.
[7]
94 Infliximab Placebo IFX: 62 %
Placebo: 26 %
IFX: 46 %
Placebo: 13 %
RCT Moderate
Sands et al.
(ACCENT II)
[8]
195 Infliximab Placebo IFX: 46 %
Placebo: 23 %
NA RCT Moderate
Dewint et al.
(ADAFI) [13]
76 ADA and Cipro ADA and
placebo
Cipro: 71 %
Placebo: 47 %
Cipro: 65 %
Placebo: 33 %
RCT Moderate
Grimaud et al.
[15]
77 Fibrin glue Observation NA 38 %: fibrin glue
16 %: observation
RCT Moderate
Makowiec
et al. [18]
32 Endorectal advancement flap None NA 50 % (initial primary
healing 89 %)
Prospective Low
Hyman [19] 14 Endorectal advancement flap None NA 50 % (initial rate 71 %) Prospective Low
Gingold et al.
[20]
15 LIFT None NA 60 % at 2 months Prospective Low
Molendijk
et al. [23]
232 Surgical therapy Medical Therapy Surgery: 97 %
Medicine:
72.2 %
Both: 93.2 %
Surgery: 91.7 %
Medicine: 64.3 %
Both: 86.6 %
Retrospective Low
Gaertner et al.
[24]
226 IFX and surgery Surgery NA 60 %: surgery
59 %: surgery and IFX
Retrospective Low
RCT randomized controlled trial, AZA Azathioprine, 6MP 6-mercaptopurine, IFX Infliximab, LIFT Ligation internal fistula tract, ADA Adalimumab
3 IBD: Management of Symptomatic Anal Fistulas in Patients with Crohn’s Disease
22
are good candidates for fistulotomy. For patients in whom the fistula traverses the
sphincter muscle, fistulotomy may still be appropriate if the amount of muscle is
small and the continence is not already compromised. Healing rates of up to 100 %
have been reported [1–3]. The risk associated with primary fistulotomy is poor
wound healing, recurrence and incontinence [2]. For patients in whom fistulotomy
is not appropriate, a seton can be considered the primary treatment and left for long
term drainage [4]. In some patients. the setons can be removed after the perianal
sepsis resolves and the fistula tracts will close [1]. Indeed, a healing rate of up to
25 % has been found in the placebo groups in the medical trials discussed below. If
the fistula recurs, the patients should be then be treated as if they have a complex
fistula (scenario 3).
Scenario 2: The Patient with Either a Simple or a Complex
Fistula and Macroscopic Rectal Disease
The presence of active disease in the rectum will significantly compromise the suc-
cess rate of surgical intervention. After drainage of sepsis and placement of a
seton(s), these patients should be evaluated for medical therapy to try and eradicate
the inflammation in the rectum. In some cases, medical therapy may also cure the
fistula. Placement of a draining seton prior to inititation of medical treatment has
been shown to improve the results with anti-TNF therapy [5]. Below is a brief sum-
mary of the major classes of drugs used to treat perianal CD.
Antibiotics are useful to help control perianal sepsis and may also decrease pain,
but there are no randomized clinical trials (RCT) that show that antibiotics alone can
result in fistula closure. Uncontrolled studies show a benefit with the use of metro-
nidazole or ciprofloxacin that is quickly lost on withdrawal of the drug.
As with antibiotics, there are no RCTs that support the use of azathioprine or its
derivatives as single therapy for the treatment of PF in patients with CD. Pearson
et al. performed a meta-analysis of RCTs using these drugs and in the subset of
patients with perianal disease, found a 54 % response with the drugs versus 21 %
with placebo [6]. However, these drugs are slow in onset and are rarely used as first
line mono drug therapy for fistulizing perianal disease.
The first randomized placebo controlled trial using anti-TNF therapy in fistuliz-
ing CD was performed by Present et al. in 1999. They studied 94 patients and com-
pared a 3 dose induction regimen with either 5 or 10 mg/kg of infliximab to placebo.
They found a significantly higher number of patients treated with infliximab had a
response and or achieved remission [7]. In this study there was no maintenance
therapy and the duration of fistula closure was about 3 months. Subsequently, a
maintenance study (ACCENT II) was performed taking patients who responded to
induction with infliximab and randomizing them to maintenance every 8 weeks with
infliximab or placebo. The infliximab maintenance group had a longer time until
loss of response as compared to the placebo group [8].
L.S. Poritz
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Initial RCTs with adalimumab included a subgroup analysis for patients with
fistulizing disease. In CLASSIC-1 and GAIN there was no benefit to adalimumab
over placebo [9, 10]. However, in CHARM there was a significant benefit to the use
of adalimumab [11].
Results in studies combining antibiotics and anti-TNF agents have been mixed.
West et al. combined infliximab with either ciprofloxacin or placebo, and observed
a nonsignificant trend toward a better response with concomitant antibiotics [12].
Dewint et al. performed a RCT adding either placebo or ciprofloxacin to adalim-
umab and found a significant increase in response and remission with combined
therapy. However, the added benefit of the antibiotic was lost when it was discontin-
ued [13].
The anti-TNF drugs have convincingly been shown to reduce fistula drainage
and induce remission, but not without high cost and risks including infections, infu-
sion reactions and malignancy. Even when fistula tracts are healed with biologic
therapy, numerous studies have demonstrated residual tracts by ultrasound suggest-
ing that the track may not be truly healed [14].
If the patient has a good response to medical therapy, drainage from the fistula
will decrease and the setons will become more snug in the fistula tract. At that point
they should be removed so as not to prevent complete healing. If the fistulas persist
but the rectal mucosal disease resolves with medical treatment, then further surgical
therapy may be considered. Simple fistulas can now be treated with fistulotomy as
discussed above. For complex fistulas the most commonly utilized options include
fibrin glue, fistula plug, endorectal advancement flap, and LIFT.
Fibrin glue has been used with inconsistent results in both patients with and
without CD. Grimaud et al. performed a RCT comparing fibrin glue to observation
and found a significantly higher response rate at 8 weeks (38 % vs. 16 %) [15].
A systematic review of the anal fistula plug was performed by O’Riordan et al.
Of the 530 patients within the studies reviewed, 42 had CD. The rate of healing in
this population was 54.8 % [16]. However, the authors felt that the population was
too small and heterogeneous to be adequately evaluated.
Most studies looking at endorectal advancement flap for PF do not specify the
disease etiology and segregating out the results for patients with CD can be difficult.
A systematic review of all endorectal advancement flaps (CD and non CD) in 2010
identified only 91 CD patients treated by flap repair [17]. The weighted success rate
was 64 % (range 33.3–92.9). Some of the best results were obtained by Makowiec
et al. who had an initial 89 % success rate with a 33 % recurrence rate, however, half
of the patients had a diverting stoma, and Hyman who had an initial 71 % healing
rate with a 50 % long term healing rate [18, 19].
Gingold et al. performed a prospective evaluation of the LIFT procedure in 15
patients with CD related PF. They had a 60 % rate of healing of both the external
opening and the surgical site at 2 months [20]. Newer surgical therapies such as
injection of stem cells into the fistula tract may hold promise, but there is not enough
data to warrant conclusions at this time.
For patients with severe complicated PF disease often coupled with inconti-
nence, temporary fecal diversion is often a necessary adjunct to medical and sur-
3 IBD: Management of Symptomatic Anal Fistulas in Patients with Crohn’s Disease