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Editorial

-blockade to prevent perioperative


death in non-cardiac surgery: questions,
controversy, and not enough answers
Prashant Vaishnava, Kim A Eagle
The use of perioperative -blockade in
patients undergoing non-cardiac surgery
are informed, in part, by the Dutch
Echocardiographic Cardiac Risk Evaluation
Applying
Stress
Echocardiography
(DECREASE) family of studies.1 Allegations
of research fraud have discredited the
DECREASE studies and diluted the evidence
supporting the cardiovascular benet of
perioperative blockade.24 All studies
investigated in the DECREASE family were
found to be insecure because of aws
ranging from ctitious methods to fabrication of data to no evidence of written
informed consent.3 4 Current European and
American guidelines continue to offer Class
I recommendations for continuation of preexisting -blockade,5 6 and initiation of
-blockade in those patients known to have
ischaemic heart disease or myocardial ischaemia according to preoperative testing,5 and
those undergoing high-risk (primarily vascular) surgery.5
Recognising the limitations of the awed
DECREASE data, Bouri et al3 performed a
meta-analysis of secure intention-to-treat
randomised controlled trial (RCT) data of
-blockade on perioperative mortality, nonfatal myocardial infarction, stroke and hypotension in patients undergoing non-cardiac
surgery. Studies from the DECREASE family
of studies were excluded; the meta-analysis
included 10 529 patients from nine secure
trials. Initiation of a course of -blockade
before surgery was associated with a signicant 27% increase in mortality (relative risk
(RR) 1.27, 95% CI 1.01 to 1.60, p=0.04).
-blockade reduced non-fatal myocardial
infarction (RR 0.73, 95% CI 0.61 to 0.88,
p=0.001) but increased stroke (RR 1.73,
95% CI 1.00 to 2.99, p=0.05) and hypotension (RR 1.51, 95% CI 1.37 to 1.67,
p<0.00 001). The magnitude and clinical
impact of the increase in mortality and
stroke may be questionable, given the
reported CIs.

The Department of Internal Medicine, The Division of


Cardiovascular Medicine, The University of Michigan
Health System, Ann Arbor, Michigan, USA
Correspondence to Dr Prashant Vaishnava, 1500
East Medical Center Drive, Cardiovascular Center,
Ofce 2706-SPC 5853, Ann Arbor, MI 48109, USA;
pvaishna@umich.edu
Vaishnava P, et al. Heart March 2014 Vol 100 No 6

The meta-analysis by Bouri et al, while


a meaningful appraisal of credible data
and a step forward in discrediting and
excluding awed data, is largely dominated by results from the POISE
(PeriOperative ISchemic Evaluation) trial.7
POISE was a randomised, double-blind,
placebo-controlled trial in which 100 mg
oral extended-release metoprolol or
matching placebo was administered 24 h
prior to non-cardiac surgery in 8351
patients with, or at risk of, atherosclerotic
vascular disease. Six hours following
surgery, patients received another dose of
100 mg of oral extended-release metoprolol or matching placebo (this dose could
have been given earlier to any patient
with a heart rate of 80 bpm or more and
systolic blood pressure of 100 mm Hg or
higher). Twelve hours following the 6 h
postoperative dose, participants started
taking metoprolol succinate 200 mg once
daily or matching placebo for 30 days.7
Fewer patients in the metoprolol group
(compared to those receiving placebo)
experienced the primary composite cardiovascular endpoint (244 (5.8%) patients
in the metoprolol group vs 290 (6.9%) in
the placebo group; HR 0.84, 95% CI
0.70 to 0.99; p=0.0399). However, there
were more deaths (129 (3.1%) vs 97
(2.3%) patients; HR 1.33, 95% CI 1.03
to 1.74; p=0.0317) and strokes (41
(1.0%) vs 19 (0.5%) patients; HR 2.17,
95% CI 1.26 to 3.74; p=0.0053) in the
metoprolol group. Even though POISE
drew attention to the risks associated with
perioperative -blockade, the practice of
initiating a relatively large dose of
-blockade in the hours preceding surgery
may be inconsistent with clinical practice,
and limits the signicance of the ndings.
As highlighted in the European perioperative guidelines, the total dose of metoprolol succinate in the 24 h [was] 400 mg, at
least in a number of patients, highlighting
the intensity of perioperative -blockade
in POISE. Bouri et al address the issue of
POISE-like regimens being underrepresentative of clinical practice, but highlight
that such a perception is not borne out by
practice surveys of Canadian anaesthesiologists in 2003 (60% of anaesthesiologists
who actually initiated therapy did so with

a single dose of -blocker before surgery;


25% did not prescribe -blockade beyond
this initial dose).8 A dose of 400 mg of
extended-release metoprolol perioperatively, is probably too aggressive. More
commonly
and
more
prudently,
-blockade is initiated weeks in advance
of planned surgery, and titrated carefully
to avoid hypotension and bradycardia.
Others have highlighted the potential net
hazards of early intravenous -blockade;
in the CLOpidogrel and Metoprolol in
Myocardial Infarction Trial (COMMIT),
there was an excess of cardiogenic shock
in acute MI patients randomised to early
metoprolol therapy (up to 15 mg intravenous, then 200 mg oral daily), compared to those who received placebo.9
Ultimately, the Bouri et al meta-analysis
seems to do little more than corroborate
ndings from POISE, a trial which has
already informed guideline-based care,
and which is based on a regimen of perioperative -blockade not well representative of clinical practice. Other secure
studies would suggest results that are discrepant to those reported in the
meta-analysis. In particular, a recent retrospective cohort analysis by London et al10
should be considered. In this analysis of
140 000 patients treated at 104 US
Veterans Affairs medical centres, the
authors found that the use of perioperative -blockade was associated with a
reduction in 30-day mortality (RR 0.73,
95% CI 0.65 to 0.83, p<0.001) in those
patients with two or more Revised
Cardiac Risk Factors and non-fatal
Q-wave myocardial infarction, or nonfatal cardiac arrest at 30 days (RR 0.67,
CI 0.57 to 0.79, p<0.001).9 Though
patients undergoing vascular surgery may
be at greatest risk of cardiovascular complications, the benets in this retrospective
analysis were limited to patients undergoing non-vascular surgery (the vascular
cohort was comparatively smaller in the
study).
Bouri et al suggest that guideline
bodies should retract their recommendations based on ctitious data without
further delay. Such a recommendation
may be premature. There are discrepancies in the literature about the protective
effects of -blockers, and POISE-like regimens are simply not reective of common
clinical practice. More than 2 years have
passed since the allegations of scientic
fraud in the DECREASE family of studies.
It is time to move forward in the perioperative communitytime to move
beyond the turmoil created by research
misconduct. For now, the guidelines
provide a common ground for clinical
443

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Editorial
practice. -Blockade should indeed be
used judiciously and limited to those
already on this therapy, or those with
documented ischaemia and facing highrisk surgery. The risks of -blockade that
is overly aggressive or started too late
perioperatively, cannot be overlooked; the
harms of -blocker withdrawal cannot be
overstated. When -blockade is newly
initiated perioperatively, it should be done
so in the weeks (not days) preceding
surgery and carefully titrated to appropriate blood pressure and heart rate targets.
There are many questions about outcomes
from perioperative -blockade, patient
selection, class effect, and the optimal
dosing and regimens for such therapy. We
need answers for these questions
answers that may come from randomised
clinical trials that are conducted honestly,
credibly and transparently.

To cite Vaishnava P, Eagle KA. Heart 2014;100:443


444.
Received 9 January 2014
Revised 16 January 2014
Accepted 17 January 2014

Patient consent Obtained.


Provenance and peer review Commissioned;
internally peer reviewed.

444

http://dx.doi.org/10.1136/heartjnl-2013-304262
Heart 2014;100:443444.
doi:10.1136/heartjnl-2013-305384

REFERENCES
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2
3

Contributors Both authors contributed to the


generation and review of this manuscript.
Competing interests None.

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10

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Vaishnava P, et al. Heart March 2014 Vol 100 No 6

Downloaded from http://heart.bmj.com/ on February 15, 2015 - Published by group.bmj.com

-blockade to prevent perioperative death in


non-cardiac surgery: questions, controversy,
and not enough answers
Prashant Vaishnava and Kim A Eagle
Heart 2014 100: 443-444

doi: 10.1136/heartjnl-2013-305384
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