Does perioperative beta
Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes
MR; POBBLE trial investigators. Perioperative beta-blockade
(POBBLE) for patients undergoing infrarenal vascular surgery:
results of a randomized double-blind controlled trial. J
Vasc Surg. 2005 Apr;41(4):602-9.
Brady et. al. J Vasc Surg. 2005 Apr;41(4):602-9 didn't
see the effect in a 103 patient study.
This is a negative study. They found that beta blockers
had no effect. What was the chance of seeing a difference
in the groups in a 103 patient study? I calculated it
at 0.29. So they have a 1 in 3 chance of seeing a 50% reduction
in their event rate of 34%. It is not good design to assume
a 50% reduction in such trials, 20% or 30% would be more
reasonable. Designing it with a power of 0.29 is not a good
idea. When the study comes up negative, the result is
non contributory to the argument. It is just a study
without a result. It has no meaning or value to the discussion.
It is a non result.
The original Mangano study had 100 patients per group (twice
the size of the Brady et. al. study and used a surrogate
marker with a 40% event rate.) If perioperative beta blockers
reduced the risk of their combined end point 90%, the Brady
et. al. study would only have a power of 0.78. Poldermans
study was similar in size to Brady et. al. but he had a
30% event rate on a hard outcome (death), and a 90% reduction.
He had a very high risk study group with a huge effect size.
Neither of these effects are good to rely on or assume in
Mangano's study is interesting for several reasons. First
it was quite small (200 patients) and it followed patients
out for a number of years (5 were collected). The primary
outcome variable was myocardial ischemia detected by Holter.
Beta blockers reduced the risk of myocardial ischemia by
50%. We were stunned to see the differences in death rates
in long term follow-up. We followed them out to 4 years
before publishing to make sure there wasn't some problem
with randomization or postoperative medication use. How
would Mangano's study look if we included the MI's? The
study would look very similar because you have half as many
deaths in the atenolol group. When you pile up the death
certificates on a table, the pile is half as tall. It is
How can we be certain that the dramatic Polderman results
applying to patients with significant wall motion abnormalities
undergoing major vascular surgery (Lee RCRI score of at least
2) would also apply to RCRI score 0 patients? I don't think
you can be certain of anything in medicine. Does aspirin prevent
myocardial infarctions? Strokes? Death? In Men? In Women?
When you analyze studies on a given drug you find lots of
variety in the results. I also think you can get the wrong
result in studies.
Does perioperative beta
blockade increase risk ?
Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez
B, Benjamin EM: Perioperative beta-blocker therapy and mortality
after major noncardiac surgery. N Engl J Med 2005; 353:
The first result of Lindenauer is that the number needed
to treat to prevent one death is 33 in the high risk group.
That is exactly the same NNT as Mangano et. al. Lindenauer
found results that strongly support Mangano et. al. and
Poldermans et. al. A NNT of 33 is really impressive. The
drugs clearly work and clearly reduce the risk of death.
Now let's discuss the lack of a demonstrated outcome in
the RCRI 0 and 1 patients. When you look at patients who
are on preoperative medications, it is very common for medications
to be removed in the perioperative period. We reviewed 5000
patients having CABG surgery and 85% had at least one anti-ischemic
agent withdrawn. There were significant side effects of
drug withdrawal. What fraction of Lindenauer's patients
who were "on beta blockers" actually had them
withdrawn in the perioperative period? He could not tell
what day patients were operated on and did not follow drug
use after day 2 or on discharge. From our previous work
the number of patients withdrawn from beta blockers may
be as high as 50%. Why are they withdrawn? It is hard to
tell in epidemiologic trials. The most common reason seems
to be failure to continue preoperative medications into
the postoperative period.
So how does this effect Lindenauer's result? He found that
low risk patients who are admitted to the hospital on a
beta blocker do worse when compared to matched patients
who are not on the drug. The event rate in this group is
low, but withdrawal phenomena can occur in the 50% who discontinue
the drug. It may be that the risks of beta blocker withdrawal
overwhelm any benefit in the RCRI 0 groups.
Poldermans and Boersma agree. "Pending the availability
of data from these trials (expected within four years),
we believe it is appropriate to continue beta-blocker therapy
in patients at low or intermediate risk, given the potential
cardiac risks associated with the sudden interruption of
beta-blocker therapy," they wrote.
It is hard to develop a hypothesis that explains why a
drug that is beneficial in heart attacks, heart failure,
hypertension, and in high risk surgical patients would be
harmful in lower risk patients unless there is some other
mechanism. Like, accidental withdrawal phenomena, or severe
bradycardia. We have not seen the severe bradycardia phenomena
but we clearly have demonstrated the adverse effects of
withdrawal of beta blockers and alpha-2 agonists. Perioperative
withdrawal of these agents is a bad idea.
If the issue is really clear cut, how did the IRB approve
the POISE trial involving 10,000 patients in multiple countries?
I have spoken to several of the investigators in the POISE
trial. I have learned a lot from doing medical research,
and from trying to change physician behavior. The first
thing I learned was that it is really, really hard to change
physicians behavior. If you have a therapy that clearly
prevents death in several studies and has been adopted by
the major medical parties involved as a standard of care,
it takes on average 17 years to change physicians behavior.
Why does it take so long? There are different types of physicians.
Some take one good study that shows an effect and change
practice (these physicians are in the minority). Others
look at a series of studies and discuss changing practice.
Others, take a series of studies and don't believe it no
matter if the NNT to prevent a death is 33. Still others
don't pay attention to the literature despite what it says.
Why is POISE doing a 10,000 patient study to see if perioperative
beta blockers are beneficial? Well, they were not convinced
by two studies with a total population of slightly over
300 patients. AHA and ACC weren't fully convinced either.
They made the guidelines very restrictive. The POISE investigators
were also interested in questions we didn't consider, such
as "is perioperative beta blockade safe in patients
with epidurals? Mangano et. al. was prior to the use of
local anesthetics in postoperative epidurals. When I spoke
at the CECANZ meeting the POISE investigators were very
focused on the interaction of epidurals and beta blockers,
an issue we had never even considered or thought about.
¾ of the questions I got at CECANZ were on the interaction
of epidurals and beta blockers. I had never had such a question
in 50 U.S. lectures on the topic. The POISE investigators
view the issues differently from the average U.S. physician.
Let's look at RCRI for a second.
1. High-risk type of surgery (intraperitoneal, intrathoracic,
or suprainguinal vascular procedures)
2. Ischemic heart disease (history of myocardial infarction,
history of a positive exercise test, current complaint of
chest pain considered to be secondary to myocardial ischemia,
use of nitrate therapy, or ECG with pathologic Q waves.
3. History of congestive heart failure (history of congestive
heart failure, pulmonary edema, or paroxysmal noctural dyspnea,
bilateral rales or S3 gallop, or chest radiography showing
pulmonary vascular redistribution.
4. History of cerebral vascular disease. (History of transient
ischemic attack or stroke).
5. Insulin therapy for diabetes.
6. Preoperative serum creatinin > 2.0 mg/dl.
The event rate in the RCRI 1 group is 1.4% in Lee's original
paper. An event rate for RCRI 0 it is not listed but is
likely to be still lower. To see a 50% reduction in a study
with a 1.4% event rate you would need 4448 patients per
group or 8896 total for two. So if the POISE trial were
100% RCRI 1 patients, you could see a 50% reduction with
beta blockers. The likely real effect is most likely lower
like 30%. With a 30% reduction in risk, which is what is
seen in RCRI 3 and 4 patients, you need 13,993 patients
per group or 27,986 patients. So, POISE has a high likelihood
of not seeing any benefit in RCRI 0 or 1 patients. If there
are withdrawal phenomena from inadvertent withdrawal of
the drug, you may see adverse events in RCRI 0 and 1 patients.