The experts debate: Perioperative beta-blockade for noncardiac surgery—proven safe or not?

Rebuttals and discussion

POLDERMANS REBUTTAL: MORE TRANSPARENCY NEEDED IN POISE DOSING DATA

Dr. Poldermans: The initial paper describing the POISE trial design did indeed indicate that it was possible for a patient to receive 400 mg of metoprolol on the first day of treatment. We need to see the actual doses of metoprolol given to all patients in POISE who had a perioperative stroke. If you show me these data, the issue will be much easier to discuss.

Our data from randomized trials are consistent in showing that a titrated dosing regimen using bisoprolol reduces the incidence of postoperative cardiac events with no increase in the number of strokes.

My take-home message is that if you want to use beta-blockers, use them sensibly, use them carefully, and act during surgery. If many of your patients are developing hypotension, then you are doing something wrong.

DEVEREAUX REBUTTAL: A SHIFT IN THINKING IS REQUIRED

Dr. Devereaux: The data from POISE are fully available, and I take issue with Dr. Poldermans’ contention that a patient could have received as much as 400 mg of metoprolol CR on the day of surgery; this was not an option according to protocol. I believe his statement is misleading in the same way that it is misleading to indicate that in the DECREASE trial patients may have received 20 mg of bisoprolol within 24 hours of surgery. It is possible that a patient in DECREASE could have gone to surgery at 2:00 pm and may have taken his or her bisoprolol at 10:00 am that morning. The following morning (in the hospital), it is possible that the patient would have received his or her bisoprolol 10 mg at 7:00 or 8:00 am (ie, 20 mg within 24 hours of surgery). Although this is possible and something similar could have happened within POISE, it does not reflect a patient receiving an effective dose of metoprolol CR 400 mg or bisoprolol 20 mg over a 24-hour period.

I worry about the distortion of reality in perioperative medicine that leads so many of us to believe that randomization is magical despite small sample sizes. Small randomized trials are at profound risk of imbalance between the randomized groups, whether we see it or not, and the results are therefore simply not reliable.

Unless we shift our thinking, we make ourselves susceptible to overconfidence in the benefits of a certain intervention before the data from large clinical trials become available. In the meantime, as we have seen from POISE, an intervention may have negative consequences that are not apparent from small clinical trials.

The reality of excess stroke with perioperative beta-blockers is consistent across all the trials. It does not mean that we cannot find another way to give beta-blockers safely, but if we want to establish safety, we need a large trial that unequivocally demonstrates safety, as opposed to simply using observational data, retrospective cohorts, or comparisons between two nonrandomized trials. Until we have large data sets, it is very difficult to say that we can give beta-blockers safely.

DISCUSSION WITH THE AUDIENCE

Moderator^*: Dr. Devereaux, was the hypotension in POISE related to the long-acting beta-blocker itself or to the large dose of if that was used? Similarly, were the strokes a result of the drug itself or of the hypotension?

Dr. Devereaux: I must take issue with your premise that the dose of metoprolol used in POISE was “large.” As I noted, Mangano’s study used its beta-blocker (atenolol) at 50% of its maximum daily therapeutic dose,¹ the same proportion used in POISE, and Dr. Poldermans’ own DECREASE trial allowed titration of bisoprolol up to 50% of the maximum daily therapeutic dose.³ The DIPOM trial used half the dose of metoprolol that we used, yet it too yielded a trend toward more death and stroke in the beta-blocker group.⁴ So it’s not that the dose we used was at some excessive level. At the same time, that does not mean that a smaller dose may not have achieved a similarly significant benefit in cardiac outcomes.

We can’t explain most of the strokes. Because most strokes were ischemic, I suspect that the explanation may lie in the threshold used to define clinically significant hypotension. We used an SBP cutoff of less than 90 mm Hg, but we did not classify large drops in SBP, such as from 180 to 95 mm Hg, as clinically significant hypotension. The high incidence of clinically significant hypotension in the placebo group—about 10%—suggests that hypotension was likely the driving factor for stroke. The beta-blocker exacerbated the hypotension, but its more important effect may have been that it made it harder for the body to overcome the hypotension. That is the exact same signal observed in the COMMIT trial in the setting of acute MI.²²

Dr. Poldermans: I’d like to see the intraoperative blood pressure data for the 60 patients who suffered strokes in POISE. We could then find out exactly when the hypotension occurred, what kind of hypotension it was, what the patient’s initial blood pressure reading was, and so on. If we had access to this information, we could determine which occurred first—the hypotension or the stroke.

Dr. Devereaux: Although trials can indicate a signal, they can’t explain with certainty the pathway through which the outcome occurred. For example, we know that beta-blockers prevent MI, but we don’t know how. What’s most impressive about the stroke issue is the consistency across all the perioperative beta-blocker trials: every one shows a direction of excess stroke with beta-blockers.

Question from the audience: The patient groups studied in DECREASE and POISE were different. DECREASE studied a very high-risk vascular surgery group with known coronary artery disease on the basis of echocardiography. POISE included patients undergoing emergency surgery and patients with sepsis. Can you describe the outcomes in POISE solely among the patients who underwent elective vascular surgery, similar to the patients studied in DECREASE?

Dr. Devereaux: In terms of the benefit to bisoprolol in very high-risk patients in DECREASE, remember that it was a study of 112 patients. That’s far too small a trial to establish safety or efficacy. The benefit of perioperative beta-blockade in preventing MI is unequivocal because it’s consistent across all trials. But the real issue is, was it safe?

Interestingly, in POISE, the groups at highest risk looked like they benefited the least, not the most. The notion of targeting high-risk people is not supported by POISE; if anything, the POISE results went in the direction of harm with beta-blockade in high-risk patients. That being said, the P value for interaction is not statistically significant, but it’s heading in the direction of harm. So I wouldn’t take comfort in believing that if we simply target high-risk patients, beta-blockers become safe.

Question from the audience: I believe that the seven or eight studies that showed higher stroke rates with beta-blockers all gave beta-blockade within 24 hours of surgery. Only in DECREASE was it given days and weeks in advance of surgery. Can you comment?

Dr. Poldermans: There’s clearly a relation between the time of beta-blocker initiation and the incidence of stroke. If you look at the randomized trials, you see an increased incidence of stroke in patients in whom beta-blockers are started just prior to surgery but not in patients who are on chronic beta-blockers. In our case-control study,¹⁸ we screened more than 185,000 patients for stroke and could not detect an increased incidence of stroke in those on chronic beta-blocker therapy. So stroke indeed has something to do with starting beta-blockers just before surgery.

Dr. Devereaux: In DECREASE IV, bisoprolol was started up to 1 month before surgery, yet there were 4 strokes in the bisoprolol group versus 3 in the control group.¹⁷

Dr. Poldermans: Yes, but that difference is not statistically meaningful.