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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1209_Библиотеки_им_академика_М_И_Перельмана.pdf
1© Springer International Publishing Switzerland 2016
J.M. Millis, J.B. Matthews (eds.), Diffi cult Decisions in Hepatobiliary
and Pancreatic Surgery, Diffi cult Decisions in Surgery: An Evidence-Based
Approach, DOI 10.1007/978-3-319-27365-5_1
Chapter 1
Finding and Appraising the Evidence: EBM
and GRADE
Sadeesh K. Srinathan
Abstract This chapter provides an overview of the principles of evidence based
medicine (EBM) which will assist in making diffi cult decisions in the face of incomplete and inadequate evidence. The steps of searching for the evidence using the
PICO format and an overview of the study design types which make up the body
evidence will be discussed. A more detailed treatment of the GRADE system to
make explicit the decisions on the quality of evidence and the nature of recommendations for interventions will be provided.
Keywords Evidence based medicine • EBM • GRADE • PICO
Introduction
Surgeons routinely make diffi cult decisions. In many cases, the diffi culty lies in the
need to make these decisions in the face of incomplete or unreliable information. An
example of this in an individual patient is deciding to perform an exploratory laparotomy for an acute abdomen where the evidence from diagnostic studies may be
incomplete or contradictory. Another example, in terms of policy, would be to
decide on the appropriateness of screening for occult malignancies where the evidence for early detection may be closely matched by evidence for undesirable
events such as overtreatment.
In this book, diffi cult scenarios commonly encountered by the hepatobiliary surgeon are presented. The authors lay out the available evidence and make a recommendation as to the appropriate responses in these scenarios. They have followed
the principles of evidence based medicine in order to come to their recommendations
S. K. Srinathan (*)
Department of Surgery , University of Manitoba ,
GE 604 – 820 Sherbrook Street, Health Sciences Centre ,
Winnipeg , Manitoba R3A 1R9 , Canada
e-mail:
ssrinathan@ex63change.hsc.mb.ca
2
and the purpose of this introductory chapter is to present an overview of the process
which led their recommendations.
The phrase Evidence Based Medicine ( EBM ) came into widespread use after
1992 following a publication by Guyatt et al. [ 5 ], and is now commonly agreed to
mean: ‘…the conscientious, explicit, and judicious use of current best evidence in
making decisions about the care of individual patients. The practice of evidence
based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research” it also means that “…
thoughtful identifi cation and compassionate use of individual patients’ predicaments, rights, and preferences in making clinical decision…” [ 13 ].
The practice of EBM can be carried out by using the following principles: (1) ask
a clinical question, (2) locate the evidence, (3) appraise and synthesize the evidence,
and (4) apply the evidence [ 12 ].
Ask the Clinical Question
On the face of it, asking the clinical question is straightforward. A patient problem
is presented and a question arises. For example, Mrs. Smith is presenting with painless jaundice and a diagnosis of periampullary carcinoma. In considering the surgical options, you consider whether a pylorus preserving pancreaticoduodenectomy
rather than a standard Whipple procedure should be performed.
Going directly to Google with the key words “pylorus preserving pancreaticoduodenectomy ”, we obtain 47,900 hits, while Wikipedia results in 2 hits. Clearly,
neither of these extremes is satisfactory in determining a surgical approach. A useful step is to convert this specifi c clinical question about Mrs. Smith to a form that
will allow us to search for the relevant evidence. The PICO format, which is used
throughout this book, is a useful tool for this purpose.
The P stands for Patient or Population and specifi es the patient group to which
the question refers, in this case it may be: (a) all patients undergoing a pancreaticoduodenectomy , (b) women over the age of 50, (c) Caucasian women over 50, or (d)
Caucasian women over 50 who have previously undergone a cholecystectomy . It is
apparent that each iteration of the defi nition of the population is more and more specifi c. These details are important, but we may limit the information available to us
if we defi ne our population of interest too narrowly.
The I is for the Intervention or exposure of interest, and specifi es what has happened to a group of patients such as an operation, or a diagnostic test. In our example the intervention we are considering is a pylorus preserving
pancreaticoduodenectomy . However, there could also be specifi c issues that are
considered important such as the specifi c method of reconstruction used or the use
of drains.
The C refers to the comparator that we are interested in. In this case it is a standard Whipple procedure, but again we should be mindful of specifi c details of the
standard procedure that may be important for our specifi c question.
S.K. Srinathan
3
O stands for the Outcome of interest. It is very important to be specifi c about the
outcome of interest as it is likely that various studies may have used different outcomes in the study design than the one you are interested in. One study may have
been focused on gastric emptying, whereas another may have been focused on blood
loss during the procedure. It is worthwhile to identify each outcome of interest in the
specifi c clinical scenario and to order them in order of importance to the patient and
surgeon so that an overall assessment of the utility of an intervention can be made.
Taking these features of the clinical question into account, we can frame the
scenario for Mrs. Smith in the following PICO question:
In patients with periampullary carcinoma or carcinoma of the pancreatic head, does a pylo-
rus preserving pancreaticoduodenectomy result in 1) less blood loss 2) lower incidence of
delayed gastric emptying 3) lower operative mortality than a standard Whipple procedure?
P: Patients with a periampullary carcinoma or carcinoma of the pancreatic head
I: pylorus preserving pancreaticoduodenectomy with the use of drains
C: standard Whipple operation with the use of drains
O: (1) operative mortality , (2) delayed emptying, (3) blood loss
It is worth considering when reviewing the chapters in this book, whether the
PICO questions chosen by the authors are suffi ciently similar to your own formulation of the question for their fi ndings and recommendations to apply to your specifi c
case.
Find the Evidence
Often the fi rst step in a literature search is to go to PubMed, the interface to access
the Medline database of citations in the National Library of Medicine in the United
States. However, a search of “pylorus preserving pancreaticoduodenectomy ” produces 781 citations. This is more than we can reasonably go through for the purposes of answering a specifi c question for a patient. But, if we use the Clinical
Queries page in PubMed which uses an algorithm to deliver focused studies relevant
to clinical practice, [ 10 ] we obtain citations for 35 systematic reviews and 45 clini-
cal studies, much better. Alternative search engines include TRIPdatabase ( http://
www.tripdatabase.com/ ) and SUMsearch ( http://sumsearch.org/ ), which use multi-
ple databases including Medline, EMBASE, and databases of guidelines and technology may also be used. Last, but certainly not least is the expertise available
through your local medical librarian who will be well versed in the methods of
constructing a PICO question and fi nding the relevant information from the medical
literature.
1 Finding and Appraising the Evidence: EBM and GRADE
4
Appraise the Studies
Once we have found the studies of interest, the next step is to identify the “best evidence”. The concept of “best evidence” assumes a hierarchy of evidence. But in
order to apply a hierarchy, it is important to understand the types of study designs
and their use in answering specifi c types of clinical questions. Grimes et al. [ 7 ] pro-
vide a useful taxonomy of study designs (Fig.
1.1 ). In general, questions related to
the superiority of one intervention over another (or no intervention) are best
answered by experimental studies where one group of patients are assigned to the
intervention by a bias free method, while another receive a comparison intervention.
The gold standard for the experimental study is a well-designed randomized trial.
Other types of clinical questions such as that of prognosis are appropriately answered
using cohort studies, while questions of diagnosis rely on comparing the performance of a diagnostic test to a gold standard.
All study types have the potential for any number of biases which may lead to a
fi nding which deviates from the “truth” [
8 ]. The tools of critical appraisal are used
Fig. 1.1 Algorithm for classifi cation of types of clinical research (Grimes and Schulz [ 7 ],
Reprinted with permission from Elsevier)
S.K. Srinathan
5
determine the type and extent of these biases in the design and conduct of the study,
and make a judgment of how it may have affected the fi ndings of the study and the
extent to which it undermines our confi dence in the validity of the fi ndings.
There are many excellent resources and tools to guide us in the specifi cs of
appraising the medical literature and practicing EBM and these are listed in the
recommended readings.
What happens when despite the best formulation of a question and literature
search we are unable to fi nd the high quality systematic review or randomized trial
to guide us? Do we abandon the principles of EBM ? Again from Sackett: “Evidence
based medicine is not restricted to randomized trials and meta-analyses. It involves
tracking down the best external evidence with which to answer our clinical questions…. However, some questions about therapy do not require randomized trials
(successful interventions for otherwise fatal conditions) or cannot wait for the trials
to be conducted. And if no randomized trial has been carried out for our patient's
predicament, we must follow the trail to the next best external evidence and work
from there” [ 13 ].
Although we can approach each problem we face by formulating a question and
fi nding the best available evidence, individual clinicians are unlikely to have the
time or resources to do this for all possible scenarios. To illustrate: our example
PICO question generated 171 results using PubMed. There were 50 reviews, 74 relevant trials or studies, 3 guidelines and 44 other possibly relevant titles. This took
an experienced medical librarian about 2.5 h to identify these studies, and does not
include the time necessary to actually read these documents and appraise them.
The alternative to searching for each question has been standard textbooks,
which seek to distill the evidence and guide clinical practice. The authors of these
textbooks have always made decisions about which studies to consider and judgments about their confi dence in making recommendation based on this evidence.
However, these judgments and decisions have not been transparent. And although
there are many schemes in use which grade the level of evidence and have been
increasingly used in textbooks, it is not clear on what basis these decisions of grade
were specifi cally arrived at [ 2 ]. A good systematic review makes transparent the
question, the search strategy, and the rules for inclusion of studies and on what basis
the quality of the study is determined. However, the fi nal assessment of the overall
quality of evidence and the subsequent recommendation arising from this evidence
is often obscure.
In order to address this defi ciency this book has adopted the GRADE system to
make transparent the decision-making about the quality of evidence and the factors
considered in making a recommendation and a statement about the strength of this
recommendation. The reader may disagree with certain judgments made by the
authors, but the reason for disagreement will hopefully be clear with the GRADE
system and the reader can make up their own minds whether the conclusions drawn
by the authors are on the whole reasonable or valid. The key component of GRADE
is that it explicitly separates the process of evaluating the quality of the evidence
for an intervention from the process of making a recommendation for its adoption
(or not).
1 Finding and Appraising the Evidence: EBM and GRADE
6
The GRADE System
The GRADE system defi nes quality in the following way: “In the context of a systematic review, the ratings of the quality of evidence refl ect the extent of our confi dence that the estimates of the effect are correct. In the context of making
recommendations, the quality ratings refl ect the extent of our confi dence that the
estimates of an effect are adequate to support a particular decision or recommendation” [ 3 ]. It is the latter defi nition that applies in this book, and the authors have
included a discussion of their clinical experience that brings into play the necessity
of balancing confl icting factors in making a recommendation. A more thorough
discussion is provided by Andrews et al. and Brozek et al. [ 1 , 4 ].
The GRADE table used in this book lays out the justifi cation of why these decisions are made and it is instructive to describe in detail the components of the table.
This example of a GRADE table is from Karanicalos et al.: (Tables 1.1 and 1.2 ) [ 9 , 11 ]
Table 1.1 The GRADE system
Study design
Initial quality
of the body of
evidence Lower if Higher if
Quality of a body of
evidence
Randomized
trials
High → Risk of bias Large effect High ⊕⊕⊕⊕
−1 Serious +1 Large
−2 Very serious +2 Very large
Inconsistency Dose response Moderate ⊕⊕⊕
−1 Serious +1 Evidence
of a gradient
Observational
studies
Low → −2 Very serious
Indirectness All plausible
residual
confounding
Low ⊕⊕
−1 Serious +1 Would
reduce a
demonstrated
effect
−2 Very serious +2 Would
suggest a
spurious effect
if no effect was
observed
Imprecision Very low ⊕
−1 Serious
−2 Very serious
Publication bias
−1 Likely
−2 Very likely
Derived from: Balshem et al. [
3 ]
S.K. Srinathan
7
Table 1.2 GRADE profi le for systematic review comparing pylorus preserving to standard Whipple procedure by Karanicolas et al.
Quality assessment Summary of fi ndings
# of studies
(#of participants)
Study
limitations
a
Consistency Directness Precision
Publication
bias
Relative effect
(95 % CI)
d
Best estimate
of Whipple
group risk
Absolute effect
(95 %CI) Quality
Five year mortality:
3(229) Serious
limitations (−1)
No important
inconsistency
Direct No important
imprecision
Unlikely 0.98 (0.87–1.11) 82.50 % 20 less/1,000;120
less to 80 more
+++,
moderate
In-hospital mortality:
6(490) Serious
limitations (−1)
No important
inconsistency
Direct Imprecision
(−1)
c
Unlikely 0.40 (0.14–1.13) 4.90 % 20 less/1,000; 50
less to 10 more
++, low
Blood transfusions (units):
5(320) Serious
limitations (−1)
No important
inconsistency
Direct No important
imprecision
Unlikely – 2.45 units −0.66 (−1.06 to
−0.25); favours
pylorus
preservation)
+++,
moderate
Biliary leaks:
3(268) Serious
limitations (−1)
No important
inconsistency
Direct Imprecision
(−1)
c
Unlikely 4.77
(0.23–97.96)
0 20 more/1,000;
20 less to 50 more
++, low
Hospital stay (days):
5(446) Serious
limitations (−1)
No important
inconsistency
Direct Imprecision
(−1)
c
Unlikely – 19.17 days −1.45 (−3.28 to
0.38); favours
pylorus
preservation
++, low
(continued)
1 Finding and Appraising the Evidence: EBM and GRADE
8
Table 1.2 (continued)
Quality assessment Summary of fi ndings
# of studies
(#of participants)
Study
limitations
a
Consistency Directness Precision
Publication
bias
Relative effect
(95 % CI)
d
Best estimate
of Whipple
group risk
Absolute effect
(95 %CI) Quality
Delayed gastric emptying:
5(442) Serious
limitations (−1)
Unexplained
heterogeneity
(−1)
b
Direct Imprecision
(−1)
c
Unlikely 1.52 (0.74–3.14) 25.50 % 110 more/1,000;
80 less to 290
more
+, very
low
Derived from: Karanicolas et al. [
11 ]
a
Unclear allocation concealment in all studies, patients blinded in only one study, outcome assessors not blinded in any study, >20 % loss to follow-up in three
studies, not analysed using intention to treat in one study
b
I
2
= 72.6 %, P = 0.006
c
Confi dence interval includes possible benefi t from both surgical approaches
d
Relative risks (95 % confi dence intervals) are based on random effect models
S.K. Srinathan
9
The Header
The general title of the clinical question being considered.
Sub Heading
A question broken up into the PICO format of patient or population, the setting, the
intervention and the comparison to which the intervention is being made. The question is that which is of interest to the author of the table and may or may not refl ect
the evidence which addresses this question.
Outcomes
The key component of the GRADE process is to focus on the outcomes to which the
evidence applies. Individual studies may focus on differing outcomes that are of
interest. It is often the case that many studies address common outcomes refl ecting
benefi t, but do not reliably report on other outcomes, especially on harm. It is possible that with the same questions and same group of studies, the quality of evidence
supporting an intervention is high for one outcome such but not others. This latter
point is one of the reasons that during formulating the question it is useful to list in
order of importance the outcomes of interest.
Justifi cation for Quality Assessment
In the GRADE system, a judgment is made whether the overall quality of evidence
for each outcome is High, Moderate, Low, or Very Low. Initially evidence from
RCTs is considered to be High quality evidence while observational studies start off
as Low quality. Whether the overall body of evidence moves up or down the ranking
is determined by the extent to which the studies have features which move them up
or down and (Table
1.1 ) [ 3 ], specifi es the features which move a study up or down
the list.
Study Limitation
The fi rst judgment is related to the possible defi ciency in the study designs themselves and these are determined during the critical appraisal process, features such
as adequacy of randomization and blinding.
1 Finding and Appraising the Evidence: EBM and GRADE
10
Inconsistency
Different studies may come to different conclusions either qualitatively e.g. the
intervention works vs. it doesn’t or the degree to which a treatment works, i.e. the
effect size differs. A measure of this in systematic reviews is the degree of heterogeneity often reported as the I 2 value and this is illustrated in our example when
examining delayed gastric emptying. This heterogeneity can be due to differences
in the patient population studied, the nature of the intervention, means of measuring
outcomes or other study design features.
Directness
This is the degree to which the studies actually address the question we are interested in. The results may be indirect because the study population is different from
one we are interested in or the intervention is differs substantially from what we are
interested in. This is slightly different from the above example the indirectness
refers to the whole body of evidence in relation to our specifi c question.
Precision
Studies may report effects with wide confi dence intervals where the values at the
upper and lower bounds would suggest the different clinical actions. In our example, the mortality associated with PPP is expected to between 120 more deaths and
80 less deaths per 1000 patients. The wide confi dence intervals are most often
driven by too small a sample size in a study.
Publication Bias
We may suspect publication bias when the preponderance of the available evidence
comes from a number of small studies, most of which have been commercially
funded. This may suggest that studies which not showing an effect have not been
published which biases the evidence.
Features Increasing Quality of Observational Studies
Large Magnitude of Effect
In well designed observation studies, if a large and plausible effect is observed (relative risk of greater than 5 or less than 0.2) there is reasonable confi dence that the
effect is not due to confounding. This is the reason why one doesn’t really require a
RCT to determine if parachutes are effective.
S.K. Srinathan