The advent of endoscopic clips has resulted in a new era in colonic endoscopic resection.
Clips provide an easily applicable, durable and robust method of closure of resection
defects [1]. This has allowed endoscopists to push the boundaries of techniques with greater
control over the risks of perforation and bleeding. Adverse events (AEs) that once
may have required surgical salvage can now be managed safely, and provided that a
patient’s clinical disposition post-endoscopy is unaltered, they are now regarded
as procedural events.
In the case of per-oral endoscopic myotomy (POEM) and natural orifice transluminal
endoscopic surgery (NOTES), clips allow the closure of an iatrogenic full-thickness
injury, a concept which was once anathema to endoscopists. There is no question that
application of clips is effective in the setting of perforation, mural injury and
active bleeding. The ubiquitous availability and ease of use of these devices, however,
now may have resulted in the pendulum swinging towards their use in settings where
there may be marginal benefit. Endoscopists may use clips to guarantee their peace
of mind, rather than according to any evidence-based cost/benefit strategy.
In this edition of Endoscopy International Open, Akimoto et al. describe a novel technique
for closure of large colonic endoscopic submucosal dissection (ESD) defects. Repositionable
clips are used to grasp the mucosa at the distal defect edge, then drag this into
apposition with the proximal defect edge. The clip is then gently opened, allowing
capture of the proximal margin while holding the distal margin with one clip arm.
The clip is then deployed, holding the defect together so that standard clips may
be adjacently applied to the now more closely apposed mucosal edges.
The study was a single-center, retrospective cohort of 32 patients undergoing colonic
ESD. Clip closure was attempted in 19 patients. Closure was not attempted for rectal
lesions (n = 9) due to the relative fixation of the colon wall in the pelvis, and
was also not attempted where lesions involved the ileocecal valve (n = 3) or had evidence
of submucosal invasion (n = 1). Complete closure was effected in 18 /19 patients with
1 failure due to a mobile sigmoid colon. Mean defect size was 40.2 ± 12.0 mm and it
took a mean 10.7 ± 7.2 minutes to complete the clipping procedure. No adverse events
were reported in the clipped group. The authors did not report the frequency of AEs
in the unclipped group. The defects do not appear to have been objectively examined
prior to clipping to determine if there had been deep injury or perforation. The authors
rightly point out that this is a demonstration of concept study, and that it is inadequately
powered to determine any effect on adverse outcomes.
In essence, Akimoto et al. have shown us a neat technique with a specialized clip
to close large ESD defects. Many who use clips will be familiar with a version of
this method using standard clips whereby one arm of an open clip is embedded in a
defect edge and dragged by traction to a more favorable position, however, the Akimoto
technique allows greater tension and control to be applied. Alternative methods of
closure including endoscopic suturing or over-the-scope clips have been described,
however, they typically are cumbersome or technically challenging, and require withdrawal
and reinsertion of the endoscope. The wider question surrounding these technical tricks
is whether we should be closing these resection defects at all.
The benefits of partial or complete closure of EMR or ESD defects are far from certain.
There are well-established data showing that the rate of clinically significant delayed
bleeding is 6 % to 7 % following EMR and 1 % to 2 % following ESD [2]
[3]. Perforation is a rare event for either procedure, occurring in 0.9 % to 2.0 % following
EMR and 4 % to 6 % following ESD [3]
[4]. Delayed perforation is even less common, seen in only 0.2 % following EMR [5[.
With low event rates, studies examining the efficacy of clips have to be very large
and well designed to demonstrate an effect and exclude bias. Liaquat et al.[6] described delayed bleeding outcomes in a cohort comparing complete clipping of EMR
defects to a historical unclipped control group. Defects that could not be clipped
were also analyzed together with the historical group. The delayed hemorrhage rate
was 9.7 % in the unclipped group versus 1.8 % in the fully clipped group. Multivariate
analysis showed that not clipping (odds ratio [OR] 6.0; 95 % CI, 2.0 – 18.5), location
proximal to the splenic flexure (OR 2.9; 95 % CI, 1.05 – 8.1), and polyp size (OR
1.3; 95 % CI, 1.1 – 1.7 for each 10-mm increase in size) were associated with delayed
bleeding. Although this study produced an impressive reduction in bleeding rates,
the authors acknowledge that it was observational, retrospective and a single-operator
study. Methodological issues may have also overestimated the clipping effect [7]
[8].
Randomized controlled trials to date have been underpowered or contained flaws limiting
their applicability to clinical practice [9]
[10]
[11]. A cost-effectiveness analysis showed that treatment was only potentially viable
for lesions > 10 mm in patients receiving antiplatelet or anticoagulant agents [12] The difficulty justifying the costs of clips comes down to the fact that post – polypectomy
bleeding is relatively uncommon, typically self-limited, and the majority can be managed
conservatively without expensive and invasive investigations [2]. An economic model simulating several clipping strategies applied to an actual prospective
cohort of 1717 lesions undergoing EMR showed that clipping was not cost effective,
and in fact, clip prices would have to fall to € 10.35 each in order to offset the
cost of delayed bleeding [13]. Selection of cases at highest risk for bleeding may be a feasible way of reducing
the numbers needed to treat [14], however, no study has prospectively demonstrated the efficacy of a targeted clipping
strategy.
Prophylactic clipping to prevent delayed perforation is devoid of evidence, as the
incidence of this often serious AE is thankfully very low. Any randomized study designed
to demonstrate perfect prevention of delayed perforation (ie. risk reduction from
an estimate of 0.5 % to 0 %) would still require at least 1500 patients in each arm.
No existing study or research network has approached this size.
Although prophylactic clipping is questionable, the situation is completely different
when there is objective evidence of perforation or muscularis propria (MP) injury.
The “target sign” is a well-recognized endoscopic marker of MP injury prompting focal
clip placement over the area of concern [15]. This only represents part of the spectrum of colonic mural injury, which may range
from simple exposure of the MP, to full-thickness perforation. A classification system
describing this range of injuries after EMR has been described along with management
strategies based on the appearance of the resection defect [5]. Although there is no objective evidence that this reduces late sequelae, this proactive
management approach was associated with a delayed perforation rate of only 0.2 % in
802 patients undergoing EMR of large laterally spreading lesions in a tertiary referral
setting, mean size 37 mm (range 20 – 120 mm).
The risks of clip placement in the colon are few, as the majority of the colon is
mobile, tethered only by a mesentery, and the colon walls are pliable. Caution should
be exercised in situations in the gastrointestinal tract where these conditions do
not apply, for example, the relatively fixed descending duodenum where clips may potentially
tear the thin comparatively immobile muscle layer [16]. Clips may also complicate assessment of post-resection scars by creating artefactual
mucosal nodules that must be carefully examined to distinguish them from recurrent
adenoma. Usually the distinction is clear based on the morphology and surface pattern
[17]. It is also possible (but unreported) that clips may “bury” small areas of residual
or recurrent adenoma, preventing detection and resection at surveillance colonoscopy
and creating a theoretical risk of subsequent delayed adenomatous recurrence or post-colonoscopy
cancer.
When clips were first introduced, their extensive impact on endoscopic practice was
impossible to fully appreciate. Incremental advances in clip techniques and technology
may deliver further evolutions in endoscopy beyond our current expectations. In their
current form, clips have revolutionized endoscopy, but we may be expecting more of
them than they can deliver. Prophylactic closure of all defects is expensive and not
proven. Rather than asking how to close defects, we must first ask the question: Should
we?
