Rob Vaughn, MD
Important Update April 2012:
A recent development must be considered in evaluating data for perioperative
beta blockade. Last Fall, Dr. Don Poldermans was dismissed by Erasmus Medical Center for violations of academic integrity.
This calls into question the data presented in the sidebar to the left entitled, "Poldermans Decrease Trial..."
or "Decrease IV." The "Poldermans Decrease Trial" is a cornerstone of data showing the benefit of perioperative
beta blockade. It's results, in my opinion, cannot be considered valid, given both the dismissal, and the lack of any
other trial that has approximated that trial's findings.
One report of the dismissal:
Another link to a story on the dismissal:
second link describes the dismissal and its consequences in a dramatic fashion. I include the reference here to highlight
how this treatment has been championed and villified over the last decade, often with less attention to dispassionate evaluation
of available data.
Times have changed in the issue
of perioperative beta blockade.
From the AHRQ Website (the link
has been taken down; it was: http://www.ahrq.gov/Clinic/ptsafety/summrpt.htm):
Clear Opportunities for Safety
The following 11 patient safety practices were the most highly rated (of the 79 practices reviewed in detail) in terms
of strength of the evidence supporting more widespread implementation. Practices appear in descending order, with the most
highly rated practices listed first. Because of the imprecision of the ratings, the editors did not further divide the practices,
nor indicate where there were ties.
- Appropriate use of prophylaxis to prevent venous thromboembolism in patients at risk.
- Use of perioperative beta-blockers
in appropriate patients to prevent perioperative morbidity and mortality.
- (followed by 9 more practices. - RV)
From the ACCF/AHA Perioperative
Guidelines: "In light of the POISE results, routine administration of perioperative beta blockers, particularly in higher fixed-dose
regimens begun on the day of surgery, cannot be advocated. "
Introduction and Most Recent Developments
Perioperative beta blockade has been advocated for nearly fifteen years,
with varying enthusiasm. Until several years ago, the advocacy had been based on several small studies that suggested
enormous benefit. In 2008, the largest RCT was published: the POISE paper appeared in the 5/12/08 issue of Lancet. Unfortunately, the full-text is not
available for free, but would be available through the "lonesome doc" feature through Pubmed.
Overall, POISE did not show benefit
for patients at reasonably high risk who got an aggressive protocol of perioperative metoprolol. Some measures (stroke)
were higher in the treatment group than placebo, although fewer patients in the metoprolol group had a myocardial infarction (4.2% vs. 5.7% p=.0017.) Overall mortality was significantly
higher in the beta-blocked group (3.1% vs. 2.3%; p=.03.)
The POISE trial has drawn significant criticism regarding the high dosing
of metoprolol in the perioperative period. The protocol for metoprolol administration was as follows:
- 2-4 hours before surgery 100mg
metoprolol XL oral if HR>50 and SBP>100.
- during the first 6 hours after surgery, additional beta blockade was added if HR>80 and SBP>100
(100mg metoprolol XL.)
- if no dose was given up to hour 6, at hour 6 the patients were given metoprolol
100mg XL if HR >45 and SBP>100.
- 12 hours after the first postoperative dose (so 14-22
hours after the first preoperative dose, patients were given 200mg metoprolol XL. This dose was continued daily for
30 days. This
daily dose was held if HR<45 or SBP<100. When restarting the daily dose, the HR had to be over 45, and SBP>100.
The restarting dose was 100mg metoprolol XL.
-patients whose HR was consistently 45-49 and SBP >100 had their daily
dose of 200mg metoprolol XL held for 12 hours.
-Patients who were unable to take medications orally were
given metoprolol IV - either a rapid or slow infusion. The rapid infusion was 5mg over 2 minutes every five minutes
to 15mg, as long as HR>50 and SBP>100. The slow infusion was 15 mg metoprolol over 60 min with HR and SBP checked 10, 30, and 60
minutes into the infusion. If the HR were <50 or SBP dropped below 100, then the infusion was stopped and subsequent
infusions had 10mg metoprolol.
Three points should be made about the POISE treatment protocol:
The dosing was aggressive. The product
insert for metoprolol XL recommends a starting dose of 25-100 mg qd for HTN, 100mg qd for angina and 25mg for CHF. However,
metoprolol XL has a greater "first pass" effect pharmacokinetically, and 200mg metoprolol XL is equivalent to 65mg
metoprolol q12 hours (from Yang in Can J Anesth.) 200mg qd is about the same as atenolol 50mg qd (from Rossner, S. Eur
J Clin Pharm.)
The aggressive dosing yeilded a HR on average that was about the same as the other RCTs that showed benefit. The heart rate after beta blocking
is measured at different times during the major trials, but with these results: Poldermans (see sidebar) postop HR was
71; DECREASE IV postop HR was 64, MVas postop HR was 69; DiPOM postop HR was 70; POISE HR at discharge was 72.
At present, it is still reasonable
to continue to advocate perioperative beta blockade to prevent cardiovascular events, assuming cardiovascular compromise would
be very carefully avoided -best achieved by starting weeks before surgery with oral beta blockers. It is not - in this
author's opinion - reasonable to mandate any protocol for perioperative beta blockade as "best practice." No protocol
has been demonstrated in a large RCT to reduce overall mortality, and the largest three RCTs demonstrated either no benefit
or minimal - but defined - harm.
This website details some of the history of this clinical
question. The history should serve as a cautionary tale to practitioners who do not evaluate data from publications
in light of their own clinical experience. Perioperative beta blockade was advocated by non-anesthesiologists and non-surgeons
as a standard of care. It was never widely adopted in the same dosing or timing as the protocols of experiments that
showed benefit. Practitioners who did not routinely push atenolol before induction, and who did not generalize DECREASE
to less sick patients should be congratulated for their prudence in light of POISE's results.
At present, the most authoritative
statement on perioperative beta blockade is the American College of Cardiology Foundation/ American Heart Association
Focused Update published November, 2009. The document is 108 pages long, including broader perioperative management,
and is available on the American Heart Association website. Importantly, the chair of the task force is Dr. Lee Fleisher,
an anesthesiologist. The link is: http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.109.192690
The relevant questions in 2010
1. Should my 65 year-old smoker with diabetes and known CAD having a colectomy be beta blocked. If so,
to what HR and for how long?
2. More importantly, in a time of increasing mandates in perioperative medicine including thromboprophylaxis
and antibiotic administration - should perioperative beta blockade be mandated?
The Focused Update answers both questions with
reasonable clarity, though two physicians could read probably read the same text and arrive at different answers to the questions
stated above. The task force evaluates all evidence, then presents recommendations that vary in their certainty on the
issue. The exact choice of words used to convey their certainty may carry different meanings to different authors. Physicians
should read the text of the "Update" before they arrive at the conclusion that the ACC/AHA "recommends"
perioperative beta blockade. One example would be the terms "it is reasonable to perform" and the "procedure/treatment
should be perfomed." Some authors have clearly translated "it is reasonable" to "the ACC/AHA recommends."
Below are excerpts from the Update
pertaining to these questions.
The diagram on page e180 suggests that a patient with poor functional status, a history of CAD, and
diabetes having a colectomy should "proceed with planned surgery with HR control or consider non-invasive testing if
it will change management." That would suggest an endorsement of HR control with beta blockers. However, a footnote at the bottom
of the page states: "consider perioperative beta blockade (see table 11 for populations in which this has been shown
to reduce cardiac morbidity/mortality. ) That would suggest an endorsement of careful weighing of risks and benefits before
pursuing HR control. Table 11 details the individual studies of beta blockers.
"Recomendations for treatment" appear
later on page e213:
The single class I recommendation
"treatment should be performed" - the only candidate for mandates, and already included in SCIP mandates - is
the continuation of beta blockers for those already taking them.
The class IIa recommendations mean that the evidence isn't clear, but the
weight of the evidence is in favor of the intervention; "the treatment is reasonable." These should NOT be candidates for mandated care:
-beta blockers titrated to HR
and BP are
probably recommended for vascular patients with known CAD or cardiac ischemia defined in preoperative testing. The vascular patients
do not patients having carotid surgery.
-beta blockers titrated to HR and BP are reasonable for vascular patients with more than one cardiac risk factors (CAD, CHF,
CVA, DM, CRI.)
-beta blockers titrated to HR and BP are reasonable for intermediate risk surgery with more than one cardiac risk factors.
Otherwise, the usefulness is uncertain.
It is noted - based on POISE's results - that routine administration of high-dose beta blockars in the abscence of dose
titration is not useful and may be harmful to patients not currently taking beta blockers who are undergoing noncardiac surgery.
In fact, the Summary states: "In light of the POISE results, routine administration of perioperative beta blockers, particularly
in higher fixed-dose regimens begun on the day of surgery, cannot be advocated."
Perioperative beta blockade was introduced in a widespread fashion in the
mid-nineties with an influential paper by Mangano in NEJM out of the VA at UCSF (n=200). The NNT to prevent
a death with a very low cost intervention was in the low double digits. (See side-menu.)
The paper was followed up by another trial
- Poldermans (DECREASE- that showed that beta blocking vascular patients with positive (reversible defect) dobutamine
stress echos yielded a NNT to prevent MI of about three. The trial was randomized but unblinded (n=100). (Also side-menu.)
Two other papers about the same
time supported beta blockade, one running an esmolol drip on total knees (Urban), and one preventing ST depression
with beta blockers on vascular patients (Raby...these two are under "early data", side-menu.)
Review articles and meta-analyses
appeared in journals from Medicine, Cardiology, Surgery, Anesthesiology, and surgical subspecialties. The AHA/ACC adressed
the issue in their 2001 recommendations for perioperative care in a careful fashion, but called the evidence for beta-blocking
patients at risk for cardiac events "Level Two A" - which is not conclusive, but the weight of the evidence or expert
opinion is in favor of the intervention.
With such impressive NNTs and such a high profile, perioperative beta blockade became an "evidence-based"
recommendation. Papers were published about the low numbers of eligible patients who were actually getting beta-blocked.
Protocols were developed.
The Agency for Healthcare Research and Quality, a part of HHS, defined perioperative
beta blockade as one of the most important best practices to reduce mortality and morbidity IN ALL OF MEDICINE:
"The use of beta-blockers
to reduce perioperative cardiac events and mortality represents a major advance in perioperative medicine for some patients
at intermediate and high risk for cardiac events during noncardiac surgery. Wider use of this therapy should be promoted and
studied, with future research focused on fine-tuning dosages and schedules and identifying populations of patients in which
its use is cost-effective. "
Perioperative beta blockade was seen as one of eleven most important (of
the seventy-nine practices reviewed in detail) best practices to push for compliance to make patients safer. Their analysis
and recommendations proved wrong, and could have resulted in increased morbidity and mortality.
(ref: http://www.ahrq.gov/Clinic/ptsafety/chap25.htm and http://www.ahrq.gov/Clinic/ptsafety/summrpt.htm)
Meanwhile, larger trials were ongoing that would drastically
erode the evidence that beta blockade had any benefit.
As well, Canadian investigators obtained funding to adress the issue with
a very large trial enrolling 10,000 patients (POISE.)
Two of the larger trials, MVas and DiPOM were published in 2006, along with a very large retrospective analysis (Lindenauer.)
None of these trials showed benefit, except the retrospective analysis showed benefit in very high risk patients.
POISE was published in 2008. In POISE, metoprolol seemed to
prevent non-fatal MI (3.6% in metop, 5.1% in placebo; p=.0008). However, more beta blocked patients had a stroke (1.0%
metop, 0.5% placebo; p=.0053). This helped to drive overall mortality higher in the beta blocked patients: 3.1% metop
to 2.3% placebo; p=.0317.
In 2009, the ACCF/AHA Perioperative Guidelines were updated as above.
Please see the sidebar for a more in-depth
discussion of select topics.