The experts debate: Perioperative beta-blockade for noncardiac surgery—proven safe or not?
ABSTRACT
Guidelines on perioperative management of patients undergoing noncardiac surgery recommend the use of prophylactic perioperative beta-blockers in high-risk patients who are not already taking them, and their continuance in patients on chronic beta-blockade prior to surgery. These recommendations were challenged recently by results of the Perioperative Ischemic Evaluation (POISE), a large randomized trial of extended-release metoprolol succinate started immediately before noncardiac surgery in patients at high risk for atherosclerotic disease. While metoprolol significantly reduced myocardial infarctions relative to placebo in POISE, it also was associated with significant excesses of both stroke and mortality. The merits and limitations of POISE and its applicability in light of other trials of perioperative beta-blockade are debated here by two experts in the field—Dr. Don Poldermans and Dr. P.J. Devereaux (co-principal investigator of POISE).
Comment from the audience: I’m uncomfortable with the way Dr. Devereaux stresses the importance of significant findings from large randomized trials but then quibbles about a stroke rate of 4 versus 3, which is not statistically significant. Keep it scientific: either there is or there isn’t a P value that achieves significance.
Though I congratulate you on a great trial, any resident in my program would be fired for pursuing your strategy of perioperative care in POISE, which included using an SBP of 100 mm Hg as the threshold for stopping the beta-blocker regardless of preoperative blood pressure. An SBP of 100 mm Hg is not the definition of hypotension. Most anesthesiologists and perioperative physicians peg the beta-blockade to a reasonable level based on the preoperative blood pressure. They titrate in fluids and titrate in the beta-blocker. Certainly the timing is an issue—we don’t recommend giving it right before the operation.
Dr. Devereaux: I referred to the stroke rates in DECREASE IV because Dr. Poldermans has claimed that the excess in strokes has occurred in all trials but his, yet DECREASE IV was one of his trials and also one in which bisoprolol was started early. I’m not claiming statistical significance between the 3 versus 4 strokes in DECREASE IV, but the stroke trend is in the same direction as in the other trials, so it tells us nothing with regard to safety. My point is, has anyone proven safety? As much as we’d like to imagine that beta-blockers are safe perioperatively—and maybe they are—it has not been proven. The largest trials at present are consistent with a signal toward harm.
It’s easy to criticize the methodology after a trial is done. A number of us came together and thought we had a reasonable protocol for POISE. We found a reduction in the incidence of MI but more strokes and higher mortality with perioperative metoprolol. Does this mean there is not a safe way to give a beta-blocker and derive the benefit? Of course not. But at the moment the evidence does not support a way to give a beta-blocker safely. Do we need to find a way to give it safely? Of course we do.
For example, the design of POISE II is factorial, looking at aspirin versus placebo as well as clonidine versus placebo. There are a number of factors about clonidine that suggest we might be able to achieve the benefits we saw in POISE and avoid the risk, but until we do a large trial, we’re not going to know.
Comment from the audience: It’s important that we clearly understand the conclusion from POISE. It’s not that the administration of beta-blockers is not safe. It’s that the administration of a beta-blocker, as your methodology applied it, was not totally safe. Those are two very different conclusions.
Dr. Devereaux: I would say the conclusion is that the way that beta-blockers are being given has not been proven to be safe. The result is consistent. It’s even consistent with DECREASE IV.
Moderator: I believe in large clinical trials, but they must apply to real-life practice. POISE did not address the practices of many people in this room, particularly regarding the doses of metoprolol used. So it is hard for us to apply the findings in clinical practice. Those of you who design large trials need to think through your trial design very thoroughly, considering the millions of dollars that go into these trials. It’s not fair to clinicians to do a study that may have little clinical relevance.
Dr. Devereaux: Investigators from 190 centers in 23 countries were involved in POISE, and all of them thought we had a reasonable approach and methodology. That doesn’t mean it was perfect, yet the criticisms we are hearing now did not surface while the trial was ongoing.
Comment from the audience: My hospital in Australia contributed to the POISE study. When it started 6 or 7 years ago, the cardiologists were using beta-blockers liberally and haphazardly. It was a huge challenge to convince them that conducting the trial was justifiable—that the case for perioperative beta-blockers had not been absolutely and overwhelmingly proved. They wanted to put beta-blockers in the water supply at the doses we’re talking about.
It would be interesting to do separate analyses of the data from the various countries involved in POISE. In Australia, the percentage of the population on chronic beta-blockers—who therefore would have been ineligible for the trial—is now quite high. Most patients who need to be on beta-blockers long term are on them, whereas that was not the case 15 years ago. The population is changing even while we’re doing the trials. Australian cardiologists are no longer putting every patient on perioperative beta-blockers; they’re thinking about it first.
Dr. Devereaux: A compelling feature of POISE as an international trial is its consistency of outcomes across the planet. No matter where we looked, the outcomes were consistent: in Asia, Europe, North America, and Australia.
Moderator: Would each of you summarize your take-home message for clinicians?
Dr. Devereaux: I urge clinicians to actually read the trials themselves rather than just relying on the advice of guideline writers. It’s important not to allow ourselves to become entrenched in a practice without evidence, just because we’ve done it for so long. If you told your patients the number of MIs prevented and the potential number of excess strokes and deaths, I suspect the average patient would conclude it’s not a great trade-off.
Remember that two-thirds of MIs in the perioperative setting are clinically silent. That doesn’t mean they’re not important, but the strokes, in contrast, are profoundly devastating. One-third of patients with stroke in POISE were dead within 30 days, and of those who survived, 60% were incapacitated, needing help with everyday activities.
I encourage clinicians to read the POISE manuscript with a fresh perspective, regardless of how you’ve practiced until now. Then ask yourself whether you really are comfortable with the safety of perioperative beta-blockers at this time. Of course, that doesn’t mean the evidence won’t change in the future.
Dr. Poldermans: The main imperative is to improve postoperative care. We strongly believe that perioperative beta-blockers work in the general population. If you have a patient who needs to be on a beta-blocker after surgery, why not start it preoperatively? I believe that dosing and timing of initiation are important. If you have the opportunity to start the beta-blocker prior to surgery, do so at a reasonable dose and start early. Patients in whom beta-blockers are started immediately prior to surgery may be worse off, with a higher incidence of stroke.
*Amir K. Jaffer, MD, University of Miami Miller School of Medicine, served as moderator of the debate and the discussion period.
