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1.
Browner WS, Li J, Mangano DT. In-hospital and long-term mortality in male veterans following noncardiac surgery: the Study of Perioperative Ischemia Research Group.  JAMA.1992;268:228-232.
2.
Ashton CM, Petersen NJ, Wray NP.  et al.  The incidence of perioperative myocardial infarction in men undergoing noncardiac surgery.  Ann Intern Med.1993;118:504-510.
3.
Gilbert K, Larocque BJ, Patrick LT. Prospective evaluation of cardiac risk indices for patients undergoing noncardiac surgery.  Ann Intern Med.2000;133:356-359.
4.
Khuri SF, Daley J, Henderson W.  et al.  The National Veterans Administration Surgical Risk Study: risk adjustment for the comparative assessment of the quality of surgical care.  J Am Coll Surg.1995;180:519-531.
5.
Lee TH, Marcantonio ER, Mangione CM.  et al.  Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery.  Circulation.1999;100:1043-1049.
6.
Lawrence VA, Hilsenbeck SG, Mulrow CD, Dhanda R, Sapp J, Page CP. Incidence and hospital stay for cardiac and pulmonary complications after abdominal surgery.  J Gen Intern Med.1995;10:671-678.
7.
Goldman L. Multifactorial index of cardiac risk in noncardiac surgery: ten-year status report.  J Cardiothorac Anesth.1987;1:237-244.
8.
Lee TH. Reducing cardiac risk in noncardiac surgery.  N Engl J Med.1999;341:1838-1840.
9.
Collins TC, Daley J, Henderson WH, Khuri SF. Risk factors for prolonged length of stay after major elective surgery.  Ann Surg.1999;230:251-259.
10.
Belzberg H, Rivkind AI. Preoperative cardiac preparation.  Chest.1999;115:82S-95S.
11.
Merli GJ, Weitz HH. The medical consultant.  Med Clin North Am.1987;71:353-355.
12.
Merli GJ, Weitz HH. Approaching the surgical patient: role of the medical consultant.  Clin Chest Med.1993;14:205-210.
13.
American College of Physicians.  Guidelines for assessing and managing the perioperative risk from coronary artery disease associated with major noncardiac surgery: American College of Physicians.  Ann Intern Med.1997;127:309-312.
14.
Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery: Multicenter Study of Perioperative Ischemia Research Group.  N Engl J Med.1996;335:1713-1720.
15.
Boersma E, Poldermans D, Bax JJ.  et al.  Predictors of cardiac events after major vascular surgery: role of clinical characteristics, dobutamine echocardiography, and β-blocker therapy.  JAMA.2001;285:1865-1873.
16.
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;341:1789-1794.
17.
Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L. Myocardial ischemia in untreated hypertensive patients: effect of a single small oral dose of a beta-adrenergic blocking agent.  Anesthesiology.1988;68:495-500.
18.
Raby KE, Brull SJ, Timimi F.  et al.  The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery.  Anesth Analg.1999;88:477-482.
19.
Urban MK, Markowitz SM, Gordon MA, Urquhart BL, Kligfield P. Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia.  Anesth Analg.2000;90:1257-1261.
20.
Shojania KG, Duncan BW, McDonald KM, Wachter RM. Making Health Care Safer: A Critical Analysis of Patient Safety Practices: Evidence Report/Technology Assessment No. 43. Rockville, Md: Agency for Healthcare Research and Quality; 2001. Publication 01-E058.
21.
Eagle KA, Berger PB, Calkins H.  et al.  ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [American College of Cardiology Web site]. Available at: http://www.acc.org/clinical/guidelines/perio/update/pdf/perio_update.pdf. Accessibility verified February 19, 2002.
22.
Detsky AS, Abrams HB, Forbath N, Scott JG, Hilliard JR. Cardiac assessment for patients undergoing noncardiac surgery: a multifactorial clinical risk index.  Arch Intern Med.1986;146:2131-2134.
23.
Goldman L, Caldera DL, Nussbaum SR.  et al.  Multifactorial index of cardiac risk in noncardiac surgical procedures.  N Engl J Med.1977;297:845-850.
24.
Mangano DT, Goldman L. Preoperative assessment of patients with known or suspected coronary disease.  N Engl J Med.1995;333:1750-1756.
25.
Mangano DT. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery.  N Engl J Med.1997;336:1452.
26.
Foster ED, Davis KB, Carpenter JA, Abele S, Fray D. Risk of noncardiac operation in patients with defined coronary disease: the Coronary Artery Surgery Study (CASS) registry experience.  Ann Thorac Surg.1986;41:42-50.
27.
Hassan SA, Hlatky MA, Boothroyd DB.  et al.  Outcomes of noncardiac surgery after coronary bypass surgery or coronary angioplasty in the Bypass Angioplasty Revascularization Investigation (BARI).  Am J Med.2001;110:260-266.
28.
Krumholz HM, Radford MJ, Wang Y, Chen J, Marciniak TA. Early beta-blocker therapy for acute myocardial infarction in elderly patients.  Ann Intern Med.1999;131:648-654.
29.
Krumholz HM, Radford MJ, Wang Y, Chen J, Heiat A, Marciniak TA. National use and effectiveness of β-blockers for the treatment of elderly patients after acute myocardial infarction: National Cooperative Cardiovascular Project.  JAMA.1998;280:623-629.
30.
White CM. Prevention of suboptimal beta-blocker treatment in patients with myocardial infarction.  Ann Pharmacother.1999;33:1063-1072.
31.
Soumerai SB, McLaughlin TJ, Spiegelman D, Hertzmark E, Thibault G, Goldman L. Adverse outcomes of underuse of β-blockers in elderly survivors of acute myocardial infarction.  JAMA.1997;277:115-121.
32.
Radford MJ, Krumholz HM. Beta-blockers after myocardial infarction—for few patients, or many?  N Engl J Med.1998;339:551-553.
33.
Gurwitz JH, Goldberg RJ, Chen Z, Gore JM, Alpert JS. Beta-blocker therapy in acute myocardial infarction: evidence for underutilization in the elderly.  Am J Med.1992;93:605-610.
Scientific Review and Clinical Applications
March 20, 2002

β-Blockers and Reduction of Cardiac Events in Noncardiac SurgeryClinical Applications

Author Affiliations

Author Affiliations: Department of Medicine, University of California, San Francisco.

JAMA. 2002;287(11):1445-1447. doi:10.1001/jama.287.11.1445
Abstract

Recent studies suggest that β-blockers administered perioperatively may reduce the risk of adverse cardiac events and mortality in patients who have cardiac risk factors and undergo major noncardiac surgery. The objective of this article is to provide practicing physicians with examples of perioperative β-blocker use in practice by using several hypothetical cases. Although current evidence describing the effectiveness of perioperative β-blockade may not address all possible clinical situations, it is possible to formulate an evidence-based approach that will maximize benefit to patients. We describe how information from several sources can be used to guide management of patients with limited exercise tolerance, those at highest risk for perioperative cardiac events, patients who are taking β-blockers long-term, and those with relative contraindications to β-blockade. Even though fine points of their use remain to be elucidated, perioperative β-blocker use is important and can be easily applied in practice by any physician involved with the care of patients perioperatively.

Cardiac events such as myocardial infarction or cardiac death are a common complication of noncardiac surgery,16 increase mortality,7,8 result in higher costs,6,9 and are the most common reason for preoperative evaluations.1012

Until recently, methods to reduce the incidence of these complications depended on preoperative clinical assessment followed by additional tests or procedures, if indicated.13 Newer information suggests that a substantial proportion of cardiac complications may be prevented with use of β-blockers perioperatively.1419 In fact, such a use has recently been endorsed as a key process to improve patient safety20 and has been included in published guidelines of perioperative cardiac risk management.13,21 Unfortunately, use of β-blockers has not been explicitly incorporated into published guidelines regarding preoperative cardiac evaluation,13,21 and physicians seeking to use β-blockers for their patients in an evidence-based manner must amalgamate their approach according to several sources of information.

Patient 1

Patient 1 is a 70-year-old man who is to undergo a right hemicolectomy for removal of a recently discovered cecal carcinoma. He has hypertension that is well controlled by an angiotensin-converting enzyme (ACE) inhibitor and has smoked 1 pack of cigarettes daily for 50 years. He is able to rake his yard and walk at length without difficulty. Electrocardiogram and physical examination results are normal.

According to American Heart Association/American College of Cardiology (AHA/ACC) criteria, this patient has a low to intermediate risk for coronary artery disease and good exercise tolerance and is to undergo a procedure that is generally associated with an intermediate (<5%) risk of perioperative cardiac events.21 American College of Physicians (ACP) guidelines, which endorse use of the Modified Cardiac Risk index22 to assess perioperative risk, also suggest that this patient is at low risk because he meets none of the clinical criteria included in this risk index.13 Similarly, he meets none of the criteria included in the original Risk Index23 or in the Revised Cardiac Risk Index.5 Thus, he has a low predicted risk for perioperative cardiac events and would require no additional testing or risk stratification before surgery, according to recommendations from several sources.13,21,24

Despite low predicted risk for perioperative cardiac events, the patient has clear risk factors for coronary artery disease and is a candidate for perioperative atenolol according to criteria used by Mangano.25 In addition to including patients with known coronary disease, this study included patients at risk, defined as those who met at least 2 of the following criteria: older than 65 years, hypertension, current smoker, a serum cholesterol concentration of at least 240 mg/dL (6.21 mmol/L), or diabetes mellitus. Although they observed no difference in in-hospital mortality caused by β-blockade, a relative reduction in all-cause mortality of nearly 55% became evident at 2 years. This difference, which appeared within the first 8 months of follow-up, was ascribed to a marked relative reduction in cardiac events in the first year of therapy (67% reduction at year 1 and 48% at year 2).

Broader use of β-blockade was subsequently endorsed by the ACP,22 which suggested that physicians consider using atenolol for all patients meeting the criteria of Mangano et al. This recommendation was made according to the results of the study and the concordance of these findings with earlier nonrandomized trials. Given this patient's substantial risk for coronary disease, current evidence suggests he may benefit from perioperative β-blockade, begun preoperatively and continued at least through hospitalization.

Patient 2

This patient is a 75-year-old man who is to undergo resection of an abdominal aortic aneurysm. He smokes, has diabetes mellitus, and had a myocardial infarction 5 years ago. He reports no anginal symptoms, but his physical activity is limited by leg claudication. He is receiving aspirin, digoxin, an ACE inhibitor, and insulin twice daily. On examination, he has a prominent abdominal bruit and absent distal pulses; his cardiac and lung examination and electrocardiogram results are normal. He has a baseline serum creatinine level of 2.0 mg/dL (177 µmol/L).

According to Revised Cardiac Risk Index criteria (4 points), this patient is predicted to have a perioperative cardiac event rate well above 10% without β-blockade; his risk may be as high as 7% even if β-blockers are prescribed appropriately. Thus, β-blockade alone may not be adequate to reduce cardiac risk in patients at the highest risk for perioperative cardiac events. This level of risk would prompt additional risk stratification according to ACP and AHA/ACC guidelines.13,21

In high-risk patients such as patient 2, noninvasive tests of myocardial perfusion (ie, stress scintigraphy or dobutamine echocardiography) are recommended initially.13,21,24 Stress scintigraphy and dobutamine echocardiography have negative predictive values generally higher than 98%,21 and if this patient were to have a normal noninvasive test result, he could receive β-blockers and proceed to surgery without additional testing. Evidence from Boersma et al15 suggests that this approach effectively identifies high-risk patients who can proceed to surgery safely while receiving β-blockers, with an estimated adverse event rate of 1.2% or less.

If a noninvasive test result is positive, evidence to support this patient's care is limited by a lack of data from prospective trials. As a result, neither the AHA/ACC nor the ACP recommends preoperative revascularization unless the patient has indications (ie, unstable coronary symptoms or multivessel disease with depressed ejection fraction) in the absence of the planned surgical procedure.13,21 These recommendations were made according to studies suggesting that the risk of preoperative coronary artery bypass surgery offset its benefit.26 Recent studies of patients who underwent noncardiac surgery following angioplasty suggest that this modality may have benefit, but care strategies that include preoperative angioplasty remain to be evaluated prospectively.27

Despite a history of coronary artery disease and myocardial infarction, patient 2 was not taking a β-blocker preoperatively. Strong evidence exists to suggest that β-blockers are underused in appropriate patients such as this one.2833 Thus, this case represents an example in which the perioperative period is an opportunity to initiate long-term β-blocker use not only to reduce perioperative risk, but also to provide secondary prevention of cardiac events following the patient's myocardial infarction. Unless he has a clear contraindication for these medications, this patient's perioperative β-blocker use should be continued indefinitely.

Patient 3

This patient is a 69-year-old woman who is to undergo elective total knee replacement. An avid walker, she was until recently able to exercise for 30 minutes without limitation. She has no history of knee problems and takes no medications. Her physical examination and electrocardiogram results are normal.

According to AHA/ACC and ACP criteria, patient 3 has a low risk for coronary artery disease, has good exercise tolerance, and is to undergo a procedure that is generally associated with an intermediate (<5%) risk of perioperative cardiac events.21 She meets none of the criteria included in the Revised Cardiac Risk Index5 or the original Risk Index23 and has no clinical criteria used to detect patients at risk for coronary disease.25

Given her low risk of perioperative cardiac events, it seems unlikely that she will gain any benefit, in absolute or relative terms, from use of perioperative β-blockade. In addition, this patient does not meet criteria for use of β-blockers used in any studies published to date. In fact, results from Boersma et al15 suggest that β-blockade provides little additional benefit in patients with no clinical risk factors. Patients who have no or minimal cardiac risk factors may be as likely to experience adverse effects from β-blockers as to experience a cardioprotective benefit. Thus, evidence does not support use of β-blockade in this patient's care.

Comment

The advent of perioperative β-blockade represents an important advance in the management of cardiac risk in patients undergoing noncardiac surgery. Clinicians should be aware of the limitations of the current evidence base describing the effectiveness of this therapy. In particular, the studies have enrolled fewer than 700 patients, many of whom were selected according to specific research or critical criteria. Thus, we await the results of large clinical trials for evidence that can guide decision making in specific clinical situations.

Despite limitations of the literature describing the effectiveness of perioperative β-blockade, it is possible to formulate a coherent approach based on strong evidence describing the ability to predict cardiac risk and on longstanding experience with β-blockers. In the meantime, physicians can promote effective implementation of this therapy through an evidence-based rational approach.

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Article Information
Scientific Review and Clinical Applications Section Editor: Wendy Levinson, MD, Contributing Editor.
References
1.
Browner WS, Li J, Mangano DT. In-hospital and long-term mortality in male veterans following noncardiac surgery: the Study of Perioperative Ischemia Research Group.  JAMA.1992;268:228-232.
2.
Ashton CM, Petersen NJ, Wray NP.  et al.  The incidence of perioperative myocardial infarction in men undergoing noncardiac surgery.  Ann Intern Med.1993;118:504-510.
3.
Gilbert K, Larocque BJ, Patrick LT. Prospective evaluation of cardiac risk indices for patients undergoing noncardiac surgery.  Ann Intern Med.2000;133:356-359.
4.
Khuri SF, Daley J, Henderson W.  et al.  The National Veterans Administration Surgical Risk Study: risk adjustment for the comparative assessment of the quality of surgical care.  J Am Coll Surg.1995;180:519-531.
5.
Lee TH, Marcantonio ER, Mangione CM.  et al.  Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery.  Circulation.1999;100:1043-1049.
6.
Lawrence VA, Hilsenbeck SG, Mulrow CD, Dhanda R, Sapp J, Page CP. Incidence and hospital stay for cardiac and pulmonary complications after abdominal surgery.  J Gen Intern Med.1995;10:671-678.
7.
Goldman L. Multifactorial index of cardiac risk in noncardiac surgery: ten-year status report.  J Cardiothorac Anesth.1987;1:237-244.
8.
Lee TH. Reducing cardiac risk in noncardiac surgery.  N Engl J Med.1999;341:1838-1840.
9.
Collins TC, Daley J, Henderson WH, Khuri SF. Risk factors for prolonged length of stay after major elective surgery.  Ann Surg.1999;230:251-259.
10.
Belzberg H, Rivkind AI. Preoperative cardiac preparation.  Chest.1999;115:82S-95S.
11.
Merli GJ, Weitz HH. The medical consultant.  Med Clin North Am.1987;71:353-355.
12.
Merli GJ, Weitz HH. Approaching the surgical patient: role of the medical consultant.  Clin Chest Med.1993;14:205-210.
13.
American College of Physicians.  Guidelines for assessing and managing the perioperative risk from coronary artery disease associated with major noncardiac surgery: American College of Physicians.  Ann Intern Med.1997;127:309-312.
14.
Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery: Multicenter Study of Perioperative Ischemia Research Group.  N Engl J Med.1996;335:1713-1720.
15.
Boersma E, Poldermans D, Bax JJ.  et al.  Predictors of cardiac events after major vascular surgery: role of clinical characteristics, dobutamine echocardiography, and β-blocker therapy.  JAMA.2001;285:1865-1873.
16.
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;341:1789-1794.
17.
Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L. Myocardial ischemia in untreated hypertensive patients: effect of a single small oral dose of a beta-adrenergic blocking agent.  Anesthesiology.1988;68:495-500.
18.
Raby KE, Brull SJ, Timimi F.  et al.  The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery.  Anesth Analg.1999;88:477-482.
19.
Urban MK, Markowitz SM, Gordon MA, Urquhart BL, Kligfield P. Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia.  Anesth Analg.2000;90:1257-1261.
20.
Shojania KG, Duncan BW, McDonald KM, Wachter RM. Making Health Care Safer: A Critical Analysis of Patient Safety Practices: Evidence Report/Technology Assessment No. 43. Rockville, Md: Agency for Healthcare Research and Quality; 2001. Publication 01-E058.
21.
Eagle KA, Berger PB, Calkins H.  et al.  ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [American College of Cardiology Web site]. Available at: http://www.acc.org/clinical/guidelines/perio/update/pdf/perio_update.pdf. Accessibility verified February 19, 2002.
22.
Detsky AS, Abrams HB, Forbath N, Scott JG, Hilliard JR. Cardiac assessment for patients undergoing noncardiac surgery: a multifactorial clinical risk index.  Arch Intern Med.1986;146:2131-2134.
23.
Goldman L, Caldera DL, Nussbaum SR.  et al.  Multifactorial index of cardiac risk in noncardiac surgical procedures.  N Engl J Med.1977;297:845-850.
24.
Mangano DT, Goldman L. Preoperative assessment of patients with known or suspected coronary disease.  N Engl J Med.1995;333:1750-1756.
25.
Mangano DT. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery.  N Engl J Med.1997;336:1452.
26.
Foster ED, Davis KB, Carpenter JA, Abele S, Fray D. Risk of noncardiac operation in patients with defined coronary disease: the Coronary Artery Surgery Study (CASS) registry experience.  Ann Thorac Surg.1986;41:42-50.
27.
Hassan SA, Hlatky MA, Boothroyd DB.  et al.  Outcomes of noncardiac surgery after coronary bypass surgery or coronary angioplasty in the Bypass Angioplasty Revascularization Investigation (BARI).  Am J Med.2001;110:260-266.
28.
Krumholz HM, Radford MJ, Wang Y, Chen J, Marciniak TA. Early beta-blocker therapy for acute myocardial infarction in elderly patients.  Ann Intern Med.1999;131:648-654.
29.
Krumholz HM, Radford MJ, Wang Y, Chen J, Heiat A, Marciniak TA. National use and effectiveness of β-blockers for the treatment of elderly patients after acute myocardial infarction: National Cooperative Cardiovascular Project.  JAMA.1998;280:623-629.
30.
White CM. Prevention of suboptimal beta-blocker treatment in patients with myocardial infarction.  Ann Pharmacother.1999;33:1063-1072.
31.
Soumerai SB, McLaughlin TJ, Spiegelman D, Hertzmark E, Thibault G, Goldman L. Adverse outcomes of underuse of β-blockers in elderly survivors of acute myocardial infarction.  JAMA.1997;277:115-121.
32.
Radford MJ, Krumholz HM. Beta-blockers after myocardial infarction—for few patients, or many?  N Engl J Med.1998;339:551-553.
33.
Gurwitz JH, Goldberg RJ, Chen Z, Gore JM, Alpert JS. Beta-blocker therapy in acute myocardial infarction: evidence for underutilization in the elderly.  Am J Med.1992;93:605-610.
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