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The Story Behind the Study

Beta Blockers and Noncardiac Surgery: Why the POISE Study Alone Should Not Change Your Practice



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Am Fam Physician. 2010 Mar 15;81(6):717-719.

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From left: Dr. Mark Graber, Dr. Andrea Darby-Stewart, and Dr. Robert Dachs

Purpose

Each month, three presenters review an interesting journal article in a conversational manner. These articles involve “hot topics” that affect family physicians or “bust” commonly held medical myths. The presenters give their opinions about the clinical value of the individual study discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP.

This Month's Article

Devereaux PJ, Yang H, Yusuf S, et al., for the POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008; 371(9627):1839–1847.

Should we abandon the practice of using beta blockers to prevent myocardial infarction (MI) in persons undergoing noncardiac surgery?

Mark: There have been a number of positive studies on the use of beta blockers in persons undergoing noncardiac surgery.1,2 One article on the POISE study is published, and all of a sudden using beta blockers preoperatively has become verboten. The question is—is this a rational response?

What does this article say?

Mark: In a study of 8,351 persons older than 45 years who were beta blocker naïve and who were undergoing noncardiac surgery, 4,174 were randomized to extended-release metoprolol (Toprol XL), 200 mg per day, and 4,177 were randomized to placebo. The first 100-mg dose of metoprolol was given two to four hours before surgery. Twelve hours after surgery, patients were given an additional 100 mg of metoprolol if they had a heart rate of at least 80 bpm or a systolic blood pressure of at least 100 mm Hg. Twelve hours after the first postoperative dose, the patients were started on 200 mg of metoprolol per day. They were treated for a total of 30 days.

Any patient meeting the inclusion criteria (Table 1) who had a heart rate of at least 50 bpm and a systolic blood pressure of at least 100 mm Hg was eligible. Exclusion criteria included a known contraindication to beta blockers. Interestingly, a history of congestive heart failure was not an exclusion criterion. The reason that this is important will be discussed later.

Table 1.

Inclusion Criteria for the POISE Study

Coronary artery disease

Peripheral vascular disease

Hospitalization for congestive heart failure in

the previous three years

History of major vascular surgery

Any three of the following:

  • Undergoing intrathoracic or intraperitoneal surgery

  • History of congestive heart failure

  • Transient ischemic attack

  • Diabetes mellitus

  • Serum creatinine > 1.98 mg per dL (175 μmol per L)

  • Older than 70 years

  • Undergoing emergent or urgent surgery

  • History or risk of atherosclerotic disease

Table 1.   Inclusion Criteria for the POISE Study

View Table

Table 1.

Inclusion Criteria for the POISE Study

Coronary artery disease

Peripheral vascular disease

Hospitalization for congestive heart failure in

the previous three years

History of major vascular surgery

Any three of the following:

  • Undergoing intrathoracic or intraperitoneal surgery

  • History of congestive heart failure

  • Transient ischemic attack

  • Diabetes mellitus

  • Serum creatinine > 1.98 mg per dL (175 μmol per L)

  • Older than 70 years

  • Undergoing emergent or urgent surgery

  • History or risk of atherosclerotic disease

Outcome measures included a composite of cardiovascular death, nonfatal MI, and nonfatal cardiac arrest at 30 days after randomization. Data were analyzed as intention to treat. The drug was withheld from patients with a heart rate of less than 50 bpm or a systolic blood pressure of less than 100 mm Hg.

Here's what they found: there were fewer MIs in the metoprolol group (4.2 versus 5.7 percent; P < .05; number needed to treat = 67), but more deaths (3.1 versus 2.3 percent; P < .05; number needed to harm [NNH] = 125) and more strokes (1.0 versus 0.5 percent; P < .05; NNH = 200).

Should we believe this study?

Mark: Sort of—we can't dismiss this information, but it needs to be tempered a bit. Who in their right mind is going to give a patient who is beta blocker naïve, with a systolic blood pressure of 100 mm Hg and a heart rate of 50 bpm, a 100-mg dose of metoprolol two hours before surgery? And who is going to use 100 mg as a starting dose for someone with a history of congestive heart failure? This study seems like a setup for causing low-flow states and, as a result, more strokes (and falls, orthostatic hypotension, etc.).

In fact, there were more hypotension and bradycardia in the treatment group (P < .0001 for both outcomes) and more strokes in the group with perioperative hypotension. Could the protocol have been the cause of the additional strokes and deaths? We can't answer this question based on this study, but the choice of the protocol seems like a setup for finding adverse events with metoprolol.

Andrea: It would have been a more powerful study if it had involved a real-world scenario. Start the beta blocker approximately a week ahead of time, and shoot for a systolic blood pressure of 110 mm Hg and a heart rate of 60 bpm. Other studies that have used a lower dose of beta blockers have shown a cardiovascular benefit without any additional strokes.1,2

Mark: Another thing that is somewhat questionable is that, based on the inclusion criteria, the study authors would give a beta blocker to a 45-year-old male smoker who is hypertensive and undergoing urgent intra-abdominal surgery. Maybe this patient is a trauma patient. It certainly doesn't make intuitive sense to give him a beta blocker.

Andrea: It is good that the authors used an intention-to-treat analysis. This means that all of the patients were analyzed in the group to which they were assigned. For example, those who couldn't tolerate the beta blocker were still analyzed as part of the beta-blocker group. Often you will see a per-protocol analysis. Anytime you see this, head the other way. That means that the researchers can exclude any patient that didn't do well on the study drug.

Bob: There was a meta-analysis of beta blockers in noncardiac surgery published within a month of this study.3 If you dissect the meta-analysis and exclude the POISE study, there is no change in cardiovascular mortality (odds ratio [OR] = 0.78; 95% confidence interval [CI], 0.41 to 1.46), but there is a reduction in nonfatal MI (OR = 0.47; 95% CI, 0.30 to 0.74). This seems like a worthy goal. That said, the authors of the meta-analysis caution that the American College of Cardiology and American Heart Association guidelines committee “should soften their advocacy for this intervention until conclusive evidence is available.”

What should the family physician do?

Mark: I think the bottom line is that patients who need to be on a beta blocker (e.g., those with congestive heart failure or coronary artery disease) should start well before surgery and should have the dose stabilized before surgery. We know that patients with an indication for beta blockers benefit if we continue their beta blocker through the surgical period.4 In fact, the trials that were most positive were those that studied beta blockers in high-risk patients.3

Andrea: I agree. It doesn't seem as though this study should change our practice in toto. However, we should be a bit more circumspect and plan ahead for our patients who might need surgery.

Bob: For now, we should try to limit the use of perioperative beta blockers to high-risk patients, and we should use a reasonable dose. Start at least a week ahead and titrate to a reasonable heart rate and blood pressure.

addendum: We are prescient. The American Heart Association came out with a position paper after this was written suggesting that beta blockers should be continued in patients who are already on them, and that beta blockers titrated to heart rate and blood pressure are reasonable in patients in whom preoperative assessment identifies coronary artery disease or high cardiac risk (defined by the presence of more than one clinical risk factor) who are undergoing intermediate-risk surgery.5

Main Points

• The data on the use of beta blockers during noncardiac surgery remain inconclusive.

• Although the POISE study is an important contribution to the literature, it uses a protocol that is unrealistic. It should not change our practice on beta blockers wholesale.

• For now, we should try to limit the use of perioperative beta blockers to high-risk patients, and we should use a reasonable dose. Consider using the protocol in one of the Dutch studies and titrate the dose up slowly until you reach a reasonable heart rate and blood pressure.1,2

• Plan ahead. Get your patients with an indication for beta-blocker therapy on a stable, tolerable dose.

EBM Points

• Make sure that a study protocol makes sense. Don't assume that a study uses an appropriate dose or schedule of a drug.

• Look for an intention-to-treat analysis. This type of analysis evaluates all patients in the group to which they were assigned. Thus, persons who didn't tolerate the treatment (for example) are still analyzed in their original group. This reflects our real-world experience. Some of our patients are going to do badly or stop a medication. They still need to be included in our equation when we decide whether or not to use a drug.

• Avoid articles with a per-protocol analysis. This allows the researcher to throw out any data from patients who don't tolerate a drug (for example). So, a per-protocol analysis may not reflect the kind of results we will see in our practice and typically overestimates the net benefit of an intervention.

Main Points

• The data on the use of beta blockers during noncardiac surgery remain inconclusive.

• Although the POISE study is an important contribution to the literature, it uses a protocol that is unrealistic. It should not change our practice on beta blockers wholesale.

• For now, we should try to limit the use of perioperative beta blockers to high-risk patients, and we should use a reasonable dose. Consider using the protocol in one of the Dutch studies and titrate the dose up slowly until you reach a reasonable heart rate and blood pressure.1,2

• Plan ahead. Get your patients with an indication for beta-blocker therapy on a stable, tolerable dose.

EBM Points

• Make sure that a study protocol makes sense. Don't assume that a study uses an appropriate dose or schedule of a drug.

• Look for an intention-to-treat analysis. This type of analysis evaluates all patients in the group to which they were assigned. Thus, persons who didn't tolerate the treatment (for example) are still analyzed in their original group. This reflects our real-world experience. Some of our patients are going to do badly or stop a medication. They still need to be included in our equation when we decide whether or not to use a drug.

• Avoid articles with a per-protocol analysis. This allows the researcher to throw out any data from patients who don't tolerate a drug (for example). So, a per-protocol analysis may not reflect the kind of results we will see in our practice and typically overestimates the net benefit of an intervention.

Address correspondence to Mark A. Graber, MD, FACEP, at mark-graber@uiowa.edu. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999;341(24):1789–1794.

2. Poldermans D, Bax JJ, Schouten O, et al., for the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo Study Group. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control? J Am Coll Cardiol. 2006;48(5):964–969.

3. Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH. Perioperative beta blockers in patients having non-cardiac surgery: a meta-analysis [published correction appears in Lancet. 2009;373(9677):1764]. Lancet. 2008;372(9654):1962–1976.

4. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 2002 guidelines on perioperative cardiovascular evaluation for noncardiac surgery) developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery [published correction appears in J Am Coll Cardiol. 2008;52(9):794–797]. J Am Coll Cardiol. 2007;50(17):1707–1732.

5. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine, Society for Vascular Surgery. 2009 ACCF/AHA focused update on perioperative beta blockade. J Am Coll Cardiol. 2009;54(22):2102–2128.

For more information on EBM terms, see the EBM Toolkit at http://www.aafp.org/afp/ebmtoolkit.



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