The document summarizes a systematic review on the use of beta-blockers in patients undergoing non-cardiac surgery. The systematic review included randomized trials investigating beta-blockers and searched medical literature databases without restrictions. Individual studies were assessed for validity and either individual patient data or aggregate data were used in the analysis. The results found beta-blockers decreased non-fatal heart attacks but increased the risk of stroke, with inconsistent effects on mortality. The magnitude of effects was described. The conclusion indicated uncertainty around some outcomes and need for more evidence.

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EBM ON SYSTEMATIC REVIEW
Prof. dr. Mohammad Hakimi, SpOG(K), PhD.

2. The best evidence for different types of question
Level Treatment Prognosis Diagnosis
I Systematic
Review of …
Systematic
Review of …
Systematic
Review of …
II Randomised
trial
Inception
Cohort
Cross
sectional
III
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3. Pyramid of Evidence
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4. Introduction
• A systematic review (SR) is a summary of the clinical
literature that uses explicit methods to systematically
search, critically appraise, and synthesize the world
literature on a specific issue.
• Its goal is to minimize both bias (usually by not only
restricting itself to randomized trials, but also
seeking published and unpublished reports in every
language) and random error (by amassing very large
numbers of individuals).
• SRs may, but need not, include some statistical
method for combining the results of individual
studies (and we’ll call this subset “meta-analyses”).
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5. Introduction
• In contrast, traditional literature reviews
usually don’t include an exhaustive literature
search or synthesis of studies.
• The guides that we consider when appraising
a SR follow. Not surprisingly, many of them
(especially around importance and
applicability) are the same as those for
individual reports, but those for validity are
different.
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6. Meta-analysis is an optional part of a
systematic review
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7. Clinical Scenario
• We see a patient in the preoperative
assessment clinic. He is a 72-year-old man
with a history of hypertension and stroke who
is on a diuretic, a statin and ASA. He is
awaiting an elective hip replacement. The
resident in our clinic wonders whether this
patient should receive a beta-blocker
medication in the perioperative period.
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8. Clinical Question
Patient
or Problem
Intervention Comparison Outcomes
Patient undergoing
elective hip
replacement
Beta-blocker Standard
treatment
Death,
stroke and
cardiac
events
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9. Clinical Question
• Together we formulate the question:
in a patient undergoing elective hip
replacement, does treatment with a beta-
blocker decrease his risk of death, stroke
and cardiac events?
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10. Searching for Evidence
• We search PubMed Clinical Queries using the
terms “beta blockers” and “non-cardiac
surgery” and we retrieve a systematic review
by Bangalore and colleagues, published in
2008.
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11. The search strategy
• Pubmed database:
– (https://pubmed.ncbi.nlm.nih.gov)
• Using the Clinical Queries function of PubMed:
– Key words:
• “beta blockers” AND
• “non-cardiac surgery”
– Clinical Study Categories: “Therapy”
– Scope: “Broad”

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19. The Evidence
• Bangalore S, Wetterslev J, Pranesh S, et al.
Perioperative beta blockers in patients having
non-cardiac surgery: a meta-analysis. Lancet.
2008;372(9654):1962–1976.
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21. Are the results of this systematic
review valid?
1. Is this a systematic review of
randomized trials?
Our review includes randomized trials
investigating the use of beta-blockers in
patients undergoing non-cardiac surgery.
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22. Are the results of this systematic
review valid?
2. Does it describe a comprehensive and
detailed search for relevant trials?
The authors of our review searched
PubMed, EMBASE, and the Cochrane
Library from 1966 to May 2008. They also
searched references of retrieved articles.
There is no mention of language
restrictions.
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23. Flow diagram for a
systematic review
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24. Are the results of this systematic
review valid?
3. Were the individual studies assessed for
validity?
In the review we found, the authors used the quality
assessment methods recommended by the Cochrane
Collaboration and included consideration of the
sequence generation of allocation, allocation
concealment, masking of participants, personnel and
outcomes assessors, incomplete outcome data,
selective outcome reporting, and other sources of
bias. Three people independently assessed quality and
completed data abstraction.
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25. Are the results of this systematic
review valid?
4. Were individual patient data (or aggregate
data) used for the analysis?
A less frequent point to consider is whether the
authors used individual patient data (rather than
summary tables or published reports) for their
analysis.
We’d feel more confident about the conclusions of
the study, especially as it related to subgroups, if
individual patient data were used, because they
provide the opportunity to test promising subgroups
from one trial in an identical subgroup from other
trials.
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26. Are the results of this systematic
review valid?
4. Were individual patient data (or aggregate data)
used for the analysis? (cont’d)
Individual patient data allow more reliable analyses
of patients’ time to specific clinical events.
Individual patient data analysis also allows for more
accurate subgroup analysis and ensures
appropriateness of follow-up and analysis.
Analysis of published, aggregate data can give
different answers to an individual patient data meta-
analysis because of exclusion of trials, of patients,
and differences in length of follow-up, among other
factors.
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27. Standardized Reporting
• Moher D, Liberati A, Tetzlaff J, Altman DG, The
PRISMA Group. Preferred Reporting Items for
Systematic Reviews and Meta-Analyses: The
PRISMA Statement. PLoS Medicine
6(7):e1000097, 2009.
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29. Are the valid results of this systematic
review important?
1. Are the results consistent across studies?
In the study we found, heterogeneity was assessed by
the I2 statistic.
This refers to the proportion of total variation
observed between the trials that is attributable to
differences between trials rather than sampling error.
The authors regarded an I2 of 25% as low and 75% or
more as high.
Clinical heterogeneity was present across trials with
differences in patient characteristics, beta-blocker
used, and dose, timing and duration of drug use.
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30. Are the valid results of this systematic
review important?
1. Are the results consistent across studies?
(cont’d)
Sensitivity analyses were completed to determine the
impact of heterogeneity on the results.
Some 80% of deaths, MIs and strokes came from a
single trial which used a relatively high dose of
metoprolol.
However, the risk of stroke was increased regardless
of whether or not this study was included in the
meta-analysis.
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36. Are the valid results of this systematic
review important?
2. What is the magnitude of the treatment
effect?
In the beta-blocker example, the risk of non-fatal MI
was decreased [NNT 64 (49 to 107)] with use of beta-
blockers as was the risk of myocardial ischemia [NNT
17 (14 to 22)].
However, there was a trend for increased all-cause
mortality and cardiovascular mortality in patients
who received beta-blockers.
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37. Are the valid results of this systematic
review important?
2. What is the magnitude of the treatment
effect? (cont’d)
And, non-fatal stroke was increased in those who
received beta blockers [NNH 282 (123 to 1208)].
Overall, this evidence suggests that there is no clear
benefit to providing beta blockers to patients
undergoing non-cardiac surgery.
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39. Clinical Bottom Line
• The high surgical risk subgroup had a 63%
reduction in odds of all cause mortality and a
44% reduction in odds of non-fatal MI.
• However, there were too few events to
provide definitive evidence of benefit for this
subgroup of patients.
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40. Searching for Evidence
https://www.cochranelibrary.com
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45. Author’s Conclusion
• The evidence for early all-cause mortality with perioperative
beta-blockers was uncertain. We found no evidence of a
difference in cerebrovascular events or ventricular
arrhythmias, and the certainty of the evidence for these
outcomes was low and very low. We found low-certainty
evidence that beta-blockers may reduce atrial fibrillation and
myocardial infarctions. However, beta-blockers may increase
bradycardia (low-certainty evidence) and probably increase
hypotension (moderate-certainty evidence). Further evidence
from large placebo-controlled trials is likely to increase the
certainty of these findings, and we recommend the
assessment of impact on quality of life. We found 18 studies
awaiting classification; inclusion of these studies in future
updates may also increase the certainty of the evidence.
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