The controversy about using beta
blockers in the perioperative period for non-cardiac surgery just heated up
again. Results of the POISE (Perioperative Ischemic Evaluation) trial (1) revealed
this month at the American Heart Association 2007 Scientific Sessions, showed
that perioperative beta blockers did reduce the frequency of perioperative MI
but increased frequency of stroke and actually increased
overall mortality.
Use of perioperative beta blockers
to reduce morality in high risk patients undergoing noncardiac surgery has been
in vogue for the past 10 years. A number of clinical studies had shown
beneficial effect of beta-blockers in myocardial ischemia in other
circumstances, and since most post-op cardiac events were felt to be likely
mediated by myocardial ischemia, extension of their use to the perioperative
setting was logical.
The actual clinical evidence for
use of beta-blockers in the perioperative period was based upon results of only
a few clinical trials, each having very few patients enrolled. Mangano et al.
(2) randomized 200 high-risk patients undergoing major noncardiac surgery to
either atenolol or placebo. They found a 50% reduction in perioperative
ischemia detected by Holter in the atenolol group but no difference in
in-hospital mortality or MI occurrence. Surprisingly, though, those in the
atenolol group had a significant reduction in cardiac events 6-8 months later.
The Dutch DECREASE trial
(3) looked at 112 vascular surgery patients who had evidence of ischemia
on pre-op dobutamine stress echocardiography. This was a randomized controlled
trial but was not blinded. Those randomized to bisoprolol had a 10-fold
decrease in perioperative MI and cardiac death compared to placebo.
An AHRQ evidence report
(4) in 2001 identified perioperative use of beta blockers as one of eleven
evidence-based patient safety practices that should be more widely adopted.
Many have now extended the use of periperative beta blockers to those
intermediate and high risk patients not previously on beta blockers.
The ACC/AHA
Guidelines on Perioperative Beta Blocker Therapy (5) were updated late
in 2006. They provide a class I indication for continuation of beta blockers in
patients taking them for any class I indication (eg. angina, MI, CHF,
arrhythmias, hypertension) or in any patient whose pre-op evaluation
demonstrates ischemia. They add class IIa indications (probably recommended)
for patients with known coronary artery disease or multiple risk factors and
class IIb (“may be considered”) in patients with a single risk factor
undergoing intermediate or high risk procedures. Class IIa evidence means there
is conflicting evidence, weighted in favor, and class IIb means there is
conflicting evidence, with efficacy less well established.
Several national quality improvement
programs, including SCIP (the Surgical Care Improvement Project) (6) and
the IHI’s 5 Million Lives Campaign (7), have included use of beta blockers in
attempt to reduce perioperative mortality. However, their programs have focused
only on those patients previously on beta blockers, for which there is class I
evidence of efficacy.
But not everyone has been
convinced of the benefit of perioperative beta blockers in patients not already
on them. There has been considerable evidence on the negative side as well. The
POBBLE randomized trial (8) published in 2005 showed no benefit of
beta-blockade in patients undergoing noncardiac vascular surgery. However, it
was a small study (only 100 patients total in the study). Likewise, the MaVS
study (9) published in 2006 failed to show a statistically significant
benefit of beta blockade in high risk patients undergoing vascular surgery.
A retrospective cohort study
published in 2005 by Lindenauer et al (10) showed a reduction of in-hospital
deaths on perioperative beta blockers in those patients deemed high risk but
not in those deemed low risk. Though this was not a randomized controlled
trial, it lent further impetus to the routine use of beta blockers
perioperatively in high risk patients.
A sizeable multicenter randomized
controlled trial of long-acting forms of metoprolol in diabetic patients
undergoing major noncardiac surgery (DIPOM) (11)subsequently showed no
improvement in overall mortality or cardiac morbidity in the treated group.
Several meta-analyses have
subsequently been done. Devereaux et al. (12) analyzed data from 22 RCT’s (2437
patients) and concluded that beta blockers produced no statistically
significant improvement in any single outcome measure but did produce a
nominally significant improvement in a composite measure. Wiesbauer et al. (13)
found no reduction in perioperative MI or mortality in patients on beta
blockers.
Now the POISE trial seems to
answer many of the controversial issues. POISE was a randomized, controlled
multicenter trial in high-risk patients undergoing major noncardiac surgery who
were not on beta blockers prior to their planned surgery. They were randomized
to receive either the long-acting beta blocker metoprolol-CR or placebo before
surgery and throughout the perioperative period. The primary outcome measure
was a composite of cardiovascular death, nonfatal MI, and cardiac arrest at 30
days after randomization. There was a statistically significant reduction in
the primary outcome in the metoprolol CR group, driven primarily by a reduction
in nonfatal MI. However, overall mortality and frequency of stroke were
increased in the metoprolol CR group. For every 1000 patients treated, 15 MI’s
were prevented but there was an excess of 8 deaths in the metropolol group.
Some have criticized the POISE
protocol for a number of reasons, including the dosage used and the lack of a
titration period. The metoprolol group did have a higher incidence of
significant hypotension and bradycardia. Others have criticized the degree of
hypotension tolerated by the investigators before intervention. And the study
has only been presented in abstract form so far. But the bottom line is that
this is the highest level of evidence to date and it strongly suggests that we
need to change our current approach.
So where does this all leave us?
There is still general agreement that those patients previously on beta
blockers should have them continued through the perioperative period. In fact,
there is likely a detrimental effect from beta blocker withdrawal in such
patients. It seems to us that this is the only group currently for which we can
comfortably recommend perioperative beta blockers. For those not previously on
beta blockers there is currently no clearcut answer at this time. The POISE
trial certainly casts doubt on the benefit and safety of prophylactic beta
blockers in the perioperative period. Undoubtedly, there will be analysis of
subgroups in the POISE trial attempting to identify characteristics of those
patients who might benefit. However, those will be post-hoc analyses and they
serve only to raise hypotheses for further testing. Only randomized controlled
trials are likely to provide the answer to this dilemma.
One very difficult issue is what
to do with patients who were not previously on beta blockers but have a
condition for which beta blockers are indicated long-term (eg. prior MI, CHF,
etc.). This group would have been started on beta blockers in the perioperative
period according to ACC/AHA guidelines. However, even though POISE excluded
patients in whom physicians planned to start beta blockers within 30 days, we
think that the results of the POISE trial even raise the question as to whether
those patients would be better off having beta blockers started electively at a
time well after the perioperative period. Some physicians will probably
continue to consider use of perioperative beta blockers in patients in whom
preoperative evaluation shows evidence of ischemia. But they will probably
begin the beta blockers well prior to surgery and titrate the dosage gradually
and be very careful to avoid hypotension. The results of future studies, such
as the DECREASE V study currently being undertaken in the Netherlands, may
clarify some of the remaining issues. But for now POISE should significantly
reduce the number of patients receiving perioperative beta blockers.
Hospitals and ambulatory surgery
facilities still need protocols and procedures in place to ensure that patients
who should receive perioperative beta blockers do, in fact, receive them.
Obviously, good medication reconciliation is required in ensuring those who
have been on beta blockers are identified and appropriately continued on them
through the perioperative period.
Sometimes things that make a lot
of sense turn out to be wrong when subjected to the type of scientific scrutiny
we need to apply to patient safety practices as well as therapeutic or
diagnostic practices.
Update: See
our November 4, 2008 Patient Safety Tip of the Week “Beta
Blockers Take More Hits” and our November 2010 What’s New in the Patient
Safety World column “More
Perioperative Beta Blocker Controversy”
References:
Update: See
our November 4, 2008 Patient Safety Tip of the Week “Beta
Blockers Take More Hits”
http://www.patientsafetysolutions.com Patient
Safety Tip of the Week Archive What’s New in
the Patient Safety World Archive