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SURGERY FOR ANAL FISSURE
DOGMA:
Anal stretch is less traumatic to the
sphincter and as effective as sphincterotomy for anal
fissure.
COCHRANE REVIEW 1st AUTHOR: Nelson
STATUS: Published Review
RESULTS: Sphincterotomy was significantly more
effective than stretch and less likely to result in
incontinence.
NUMBER RCTs: 6
Operations for Anal Fissure
Anal Stretch
Open Lateral Internal Sphincterotomy
Closed Lateral Internal Sphincterotomy
Fissurectomy/Posterior Internal
Sphincterotomy
Fissurectomy/Dermal Advancement Flap
HOW DO YOU READ MEDICAL
RESEARCH?
Abstract
Tables
Last Paragraph
Analysis of Heterogeneity changes the way
you read, as in the following example in
which significant heterogeneity lead to a reassessment of two studies.
Quality Assessment: Most
Common Methodological Errors
Randomization method unspecified
Observers unblinded
Intention to treat analyses not done: what to
do with Drop-outs
To short follow-up
No crude data or specific analyses
Do the right statistical analysis – ask for
help.
All randomization methods are not the same.
e;.g. Hospital numbers or birth dates allow
you to predict group allocation and selectively
eliminate cases you might deem unsuitable.
Blinding? What you see is how a
participant is scored. Is that fissure
really healed?
Intention to Treat:
Why randomize?
“Statistical analysis was based upon intention to
treat (ITT). The ITT population was defined as
those individuals who had applied their assigned
treatment at least once and returned for assessment
of the primary end point. Patient who failed to
present for
assessment
……..were excluded from analysis.”
QUALITY ASSESSMENT
Why Marby Fails ( and maybe Weaver too)
Drop out rate > 10% (24% in Marby)
Follow-up time skewed and less than protocol for 125/156
27% had no pain
Post-operative manometry documents inadequate
sphincterotomy –14/17 non healers had higher pressures.
Different anesthetics (local vs. general)
In a follow-up study drop out rate was still 14% compared
to 0-1% in all other RCTs.
For those who still believe in cutting:
Open versus “Closed” Sphincterotomy
Anal Incontinence after Open versus
“Closed” Sphincterotomy
SO, WHAT PART OF THE PAPERS
DO I READ NOW?
Methods
Results
Until authors can be trusted to base their
conclusions upon their data and analyses,
and to review previous publications
systematically, the CONCLUSIONS should
be avoided
What’s wrong with Surgery?
Expensive
Incontinence -- Largely an unsolved
conundrum, in that rates as high as 30%
have been reported, but few if any sphincter
repairs are done after LIS. Why not? 10%
prevalence of incontinence in the metaanalysis. No published reports on therapy.
So -- Medical therapies have been sought.
OLD MEDICAL THERAPIES
Fiber
Warm water
Lubricants
Anesthetics
WRINKLE RELAXING INJECTION
Deep wrinkles such as crows feet and frown lines are caused by overactive muscle movement which
gradually wear away the collagen in the skin, causing the skin to sink and wrinkles to appear.
The Treatment
A muscle relaxant is injected directly into the wrinkles, which temporarily relaxes the nerves of the facial muscles, preventing the formation of wrinkles whilst softening existing
lines. This treatment has been used on over 1 million patients worldwide for more than 11 years.
How long will it last?
The treatment generally takes 5-8 days to work and last between 3-4 months. However, to prolong the benefits an extended course of treatments is recommended.
BOYCOTT BOTOX!
Cosmetic scandal exposed
Thousands of animals are being poisoned to death in brutal and scientifically unreliable 'safety tests' of botox 'anti-wrinkle' preparations. This is
despite the government having declared a total ban on animal tests for cosmetic products. The breach is all the more serious because the animal
victims are being subjected to the crude and widely-discredited LD50 toxicity test.
Animal Aid presented a dossier of information to Daily Mail consumer affairs correspondent, Sean Poulter, who discovered the shocking fact that the
government is directly profiting from the sale of animal-tested botulinum toxin, by manufacturing a botox-type product, Dysport, at its Health Protection Agency
facilities at Porton Down, Wiltshire.
Differentiation Between Nitroglycerin Explosive and Nitroglycerin Medication Using an IMS Detector
Jehuda Yinon1,2, Angelica Acevedo2, D. Charles Clark2 and Sheldon Brunk3
1. Weizmann Institute of Science, Dept. of Environmental Science, Rehovot 76100, Israel.
2. National Center for Forensic Science, University of Central Florida, Orlando, FL 32816, USA.
3. TSA, Transportation Security R & D, Wm. J. Hughes Technical Ctr, Atlantic City Airport, NJ 08405, USA.
In order to avoid “nuisance alarms” resulting from nitroglycerin based medications on IMS explosive detectors, a method has been developed to
identify these medications.
Since most explosives are detected in the negative-ion mode, differentiation between nitroglycerin explosive and nitroglycerin medications is
being carried out by identifying the non-explosives components of the medications in the positive-ion mode.
An Ionscan 400B (Smiths Detection) Ion Mobility Spectrometer with dual negative- and positive-ion mode has been used to detect non-explosive
components in nitroglycerin-based medications. The positive-ion mode was used to obtain typical profiles of these components.
Solvents used to dissolve the medications included methanol, isopropanol, acetonitrile and/or acetone. These solvents did not produce ion profiles
in the range of interest.
NEW MEDICAL THERAPIES
Nitroglycerin ointment
Botox injection
Calcium channel blockers -- delivered .
.
either topically or by mouth
MEDICAL THERAPY FOR ANAL FISSURE
DOGMA:
Pharmacologic means of relaxing the
internal sphincter are as effective as surgery in healing anal
fissure.
COCHRANE REVIEW 1st AUTHOR: Nelson
STATUS: Published Review
RESULTS: Nitroglycerin ointment was not significantly
better than placebo in healing fissure and far less effective
than operative sphincterotomy.
NUMBER RCTs: 32
SUMMARY
Placebo response rate 35%
GTN response rate about 55%
Botox and Calcium channel blockers no
better
Adverse events common but reversible
Already ready for an update
MORE SUMMARY
Surgery > 95% effective: LIS, open or closed
But with 10% incontinence rate
…Which nobody fixes - how bad is it
really?
Medical therapies only marginally more
effective than placebo
But may be offered at first, though most
patients with chronic fissure get surgery.
QUALITY ASSESSMENT OF GTN TRIALS
The usual quality issues investigated relate to
method of randomization, blinding, dropouts and
statistical methods.
In all placebo groups the placebo response rate for
healing was 35%.
In studies where the healing rate was more than 2
standard deviations below this, quality of endpoint
assessment is considered.
Sensitivity analyses done excluding those trials.
The Cochrane Library is a Living Journal,
each review (in theory) updated every 2 years
Surgery for Anal Fissure already updated
twice
Medical therapy due for an update this year.
Initial Screen: 61 eligible studies!!!!!!!!!
32 probably finally eligible, though I need
some work translating Flemish, Dutch,
Hebrew, Turkish and Chinese.
Patch or Slime: which would
you use?
Calcium Channel Blockers (mostly
nifedipine) vs. GTN
Quality Assessment: Most
Common Methodological Errors
Randomization method unspecified
Observers unblinded
Intention to treat analyses not done: what to
do with Drop-outs
To short follow-up
No crude data or specific analyses
Do the right statistical analysis – ask for
help.
CCB vs GTN including the recurrences
that developed at 18 weeks
Recurrence of Fissure with Prolonged
Follow-up
Most Studies only had 4 – 6 week follow-up
Jonas:
51% at 1-18 months after GTN
Graziano: 67% up to 1 year after GTN
Minguez: 41.5% after 4 years using Botox
Rotholz: 0% 2 years after LIS.
Botox vs. Placebo
Unresolved issues - Research you can
do
What is it with Incontinence after LIS? How come nobody
gets treated for it?
Why does surgical sphincterotomy work so much better,
early and late, than any type of chemical sphincterotomy?
Why is there such disparity in clinical results in different
studies of chemical sphincterotomy?
How much sphincterotomy? To the apex of the fissure,
dentate line, to a specific size?
Why not do it in the midline?
Is anterior fissure really the same disease as posterior
midline fissure?
Unresolved issues #2
Where do you inject the Botox and how much?
How valid are our definitions of acute and chronic
fissure.
Future Possibilities
Minoxidil Indoramine
Arginine
Lacidipine
Sildenafil
Gonyautoxin
Hyperbaric Oxygen
hair?
alpha blocker
amino acid
calcium channel blocker
cGMP PDE5 inhibitor
shell fish toxin
improve sphincter oxygen
Future Possibilities
Minoxidil Indoramine
Arginine
Lacidipine
Sildenafil
Gonyautoxin
Hyperbaric Oxygen
hair?
alpha blocker
amino acid
calcium channel blocker
cGMP PDE5 inhibitor
shell fish toxin
improve sphincter oxygen
Quality Assessment: Most
Common Methodological Errors
Randomization method unspecified
Observers unblinded
Intention to treat analyses not done: what to
do with Drop-outs
To short follow-up
No crude data or specific analyses
Do the right statistical analysis – ask for
help.
HEPATIC ARTERY CHEMOTHERAPY
 DOGMA:




Hepatic artery chemotherapy after resection of
liver for colorectal cancer metastases improves survival
COCHRANE REVIEW 1st AUTHOR: Nelson
STATUS: Published Review
RESULTS: No survival advantage was seen with post
hepatectomy arterial chemotherapy. Adverse events were
commmon with therapy, some lethal.
NUMBER RCTs: 7
CHARACTERISTICS OF STUDIES
STUDY
Chemo in
Controls
Chemo
Duration
Months
Post Rand.
Exclusions
Op.
Mortality
Liver
Recurren.
HAI
Liver
Recurren
Control
Wagman
11
No
FUdR
12
No
0
1
NS
Lygidakis
40
No
5FU, etc
36
No
2
0
8
Loreenz
226
No
5FU,
Folinic
6
Yes
11
23
22
Rudroff
30
No
5FU
Mito. C
5
No
1
3
7
NKemeny
156
Yes
Floxuridin
4.5
No
5
7
30
MKemeny
109
No
FUdR
+
Systemic
4*
Yes
2
8
24
5FU
1.5
No
0
1
6
N=
Tono
19
Yes
8
THERE IS TRULY A PLACE IN
HEAVEN FOR EVERY AUTHOR
THAT PUTS THEIR CRUDE DATA
IN THEIR PUBLICATIONS
FOR IT GIVES LIFE EVERLASTING
TO THEIR RESEARCH
REVERSAL OF PUBLICATION BIAS BY REANALYSIS OF THE CRUDE DATA
• As in this paper, in which an inappropriate statistic is
chosen in order to obtain a statistically significant result.
Reanalysis of the crude data, which is available in this
study in the survival curve (using the technique of
Parmar, Stat.s in Med.1998;17:2815-34. in which the
hazard ration can be determined from the curve), the
appropriate statistical analysis can be done – and an
insignificant result obtained from the intervention (see
below).
OR, RR, RD, or NNT
OR
RR
RD
NNT
Deeks & Altman 2001
Odds ratio or relative risk?
Egger & Smith 2001
HEPATIC ARTERY CHEMOTHERAPY AFTER HEPATIC
RESECTION FOR COLORECTAL METS:
Primary and sensitivity analyses
Meta-analysis of Randomized Studies of Hepatic Artery
Chemotherapy After Hepatic Resection for Metastatic
Colorectal Cancer
1.0
No Therapy
Hepatic Artery Chemo (6 Studies)
Hepatic Artery Chemo (7 studies)
Survival Probability
0.8
0.6
0.4
0.2
0.0
0
1
2
3
4
5
Years after Hepatic Resection
6
7
8
SO, WHAT PART OF THE PAPERS
DO I READ NOW?
• Methods
• Results
• Until authors can be trusted to base their
conclusions upon their data and analyses,
and to review previous publications
systematically, the CONCLUSIONS should
be avoided
WHAT IS THE BIGGEST CHANGE IN SURGICAL
PRACTICE IN YOUR CAREER?
 Antibiotics
 ICUs
 Post op Pain Relief
 Gizmos: Laparoscopy, Robots
 Malpractice
 EBM
The Cochrane
Collaboration
An international network of professionals,
preparing, maintaining, and disseminating
systematic reviews of the effects of health care
Archie Cochrane (1979)
 ”It is surely a great criticism
of our profession that we
have not organised a critical
summary, by speciality and
subspeciality, adapted
periodically, of all relevant
randomised trials”
Cochrane Collaboration
Collaborative
Review
Groups
Fields
Steering
Group
Consumer
Network
Centres
Methods
Working
Groups
COCHRANE IS ……
RESEARCH ON RESEARCH
NAME SOME RESEARCH THAT ISN’T…
Achievements, March, 2006
 471,139 titles in the Cochrane Controlled
Trials Register (Central) – all RCT or CCT
 4200 Published Cochrane Systematic
Reviews and Protocols.




5,859 abstracts of critically appraised systematic reviews
> 1,300 Journals handsearched for RCT and CCT by 2004
> 140,000 retagging of papers in the MEDLINE by 2004
>10,000 people working voluntarily within the collaboration
The Cochrane Collaboration
2 million new
articles every year
Which patients with
rectal cancer should
have preop radiotherapy ?
None –
only
postop
Everybody – no
doubt
Well – that
depends!!
GOBSATT
Meta-analysis
The use of statistical techniques in a systematic review to integrate the results of included studies.
For each study, the effect size from each trial
ˆ

i
is given weight
wi
in the analysis. The overall estimate of the pooled effect,
ˆ

MH
is given by
ˆ

MH 
 w ˆ
w
i
i
i
wi  bi ci / N i
se{ln(Oˆ RMH )}  (( PR ) / R 2  (( PS  QR ) /( R  S ))  (QS ) / S 2 ) / 2
R   ai di / Ni S  bi ci / Ni
PR  (ai  di )ai di / Ni2 PS  (ai  di )bi ci / Ni2 QR  (bi  ci )ai di / Ni2
QS  (bi  ci )bi ci / Ni2
A SYSTEMATIC REVIEW IS…
 A CLEARLY STATED OBJECTIVE UP FRONT
 CLEARLY DEFINED ELIGIBILITY CRITERIA FOR





INCLUDED STUDIES
A SEARCH STRATEGY DEFINED BEFORE ANY
STUDIES ARE CHOSEN
OBJECTIVE DATA EXTRACTION: USE A FORM!
QUALITY ASSESSMENT OF INDIVIDUAL STUDIES.
Randomization/concealment/drop-outs
(can you argue with any of the above?)
ONLY THEN: META-ANALYSIS
Metal-analysis?
What is meta-analysis?




A mathematical method for obtaining a summary statistic of
effect across all included studies - with confidence intervals
and a calculation of heterogeneity, i.e., how different are the
fruits in the tree, and should a meta-analysis be done at all?
For continuous variables, such as weight or length of stay or
survival, it is calculated roughly by using a weighted mean
average of individual study data.
For dichotomous variables, such as gender or drug versus
placebo, using a stratified Chi square.
Heterogeneity is calculated using a Mantel Haenszel chi
square.
How do I do it?






Don’t worry, there is lots of software that will do most or all of it
for you.
You just have to read carefully and pull the data and methods
out of the tables.
The best software is free:
www/cdc.gov - Epi-info
www.cochrane.org - Revman
[email protected] - HEpiMA
Strength of randomised controlled
trials (RCT)
•
The method most capable of avoiding
potential bias (gray hair – age & gender)
•
Best evidence for identifying treatment of
choice
•
Can be combined by meta-analysis using
simple statistical techniques
We do not need a RCT to find out
whether this intervention is lethal !
Limitations of randomised
controlled trials (RCT)
•
Rarely able to answer questions on
aetiology, diagnosis, and prognosis (except
in recent publications about HRT from the WHI)
•
Limited applicability due to limited
generalisation
•
Subgroup analyses are difficult
•
Often sponsored by pharmaceutical
companies and thus potentially biased
Sniderman 1999
Meta-analysis I
Pros
•
More objective appraisal of evidence (name
something better)
•
Reduce the possibility of false negative results
•
Allows testing of a priori hypotheses regarding
treatment effects in subgroup of patients
•
Heterogeneity between studies may be explored
and sometimes explained
Egger & Smith, BMJ 1997
Meta-analysis II
Cons
•
Not allways in agreement with mega-trials
•
Represents ”the unacceptable face of
statisticism”
•
Produces a population ”average” effect,
not applicable to the individual patient
•
Sensitive to publication and language bias
Egger & Smith, BMJ 1997
DEFINE SCIENCE
 Science is the systematic elimination of bias
 DEFINE COCHRANE………
WHEN YOU DO RESEARCH, WHAT DO YOU
WANT TO GET FROM IT?
 Publication
 Grants
 Tenure
 Power
 Fame
 Travel
 Make a difference
Summary Statistics
All Study Designs
Study Design
Anal Stretch vs.
Sphincterotomy,
Randomized Studies
Anal Stretch vs.
Sphincterotomy,
Retrospective Studies
Open vs. Closed
Sphincterotomy,
Randomized Studies
Open vs. Closed
Sphincterotomy,
Retrospective Studies
Posterior vs. Lateral
Sphincterotomy,
Retrospective Studies
Odds Ratio 95% CI Odds Ratio 95% CI
1.31
0.69-2.93 8.47
2.34-38.3
2.94
1.66-4.17 1.72
0.98-3.23
1.65
0.21-15
0.79
0.29-2.13
1.12
0.61-2.05 1.36
0.86-1.72
2.18
0.88-5.73 3.16
1.39-6.84
Tests of Homogeneity
Study Design
AS vs. Sph; RCTs
AS vs. Sph; non-RCTs
O vs. C Sph; RCTs
O vs. C; non-RCTs
P vs. L Sph; non-RCTs
p=, Persistence
<0.01
0.60
0.99
0.85
0.075
p=,
0.30
0.95
0.80
0.01
0.40
Intention to Treat:
Why randomize?
“Statistical analysis was based upon intention to treat (ITT).
The ITT population was defined as those individuals who
had applied their assigned treatment at least once and
returned for assessment of the primary end point. Patient
who failed to present for assessment … were excluded
from analysis.”
©2000
AP Photo/ Newport News Daily Press, Kenneth D. Lyo
In early October, at the end of a multi-week trial that drew national media attention, a Los Angeles jury determined that BOTOX ® did not cause a Hollywood socialite's alleged
crippling migraine headaches, deflating the woman's argument that her celebrity dermatologist downplayed the product's potentially harmful side effects in order to collect large
fees to inject the drug.
The Bad News
About BOTOX®
Facts About BOTOX®
It was the first time that Allergan, the pharmaceutical
The Rise of
Allergan
MEDICAL THERAPY FOR ANAL FISSURE
 DOGMA:




Pharmacologic means of relaxing the internal
sphincter are as effective as surgery in healing anal fissure.
COCHRANE REVIEW 1st AUTHOR: Nelson
STATUS: Published Review
RESULTS: Nitroglycerin ointment was not significantly better
than placebo in healing fissure and far less effective than
operative sphincterotomy.
NUMBER RCTs: 32
SUMMARY
 Placebo response rate 35%
 GTN response rate about 55%
 Botox and Calcium channel blockers no
better
 Adverse events common but reversible
 Already ready for an update
MORE SUMMARY
 Surgery > 95% effective: LIS,
open or closed
 But with 10% incontinence rate
 …Which nobody fixes - how bad is it really?
 Medical therapies only marginally more
effective than placebo
 But may be offered at first, though most
patients with chronic fissure get surgery.
SUMMARY
 Placebo response rate 35%
 GTN response rate about 55%
 Botox and Calcium channel blockers no
better
 Adverse events common but reversible
MORE SUMMARY
 Surgery > 95% effective: LIS,
open or closed
 But with 10% incontinence rate
 That nobody fixes - how bad is it really?
 Medical therapies only marginally more
effective than placebo
 But may be offered at first, though most
patients with chronic fissure get surgery.
SO, WHAT PART OF THE PAPERS
DO I READ NOW?
 Methods
 Results
 Until authors can be trusted to base their
conclusions upon their data and analyses,
and to review previous publications
systematically, the CONCLUSIONS should be
avoided

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