EDITORIAL COMMENT
Any Need for Preoperative Cardiac Testing in Intermediate-Risk Patients With Tight Beta-Adrenergic Blockade?*
Kim A. Eagle, MD, FACC2,* and
Wei C. Lau, MD
Cardiovascular Center, Division of Cardiovascular Medicine, Department of Internal Medicine, and the Department of Adult Cardiovascular Anesthesiology, University of Michigan Health System, Ann Arbor, Michigan.
* Reprint requests and correspondence: Dr. Kim A. Eagle, University of Michigan, Cardiovascular Center, 300 North Ingalls, 8B02, Ann Arbor, Michigan 48109-0477. (Email: keagle{at}umich.edu).
Emerging evidence-based care dictates the importance of accurate preoperative cardiac risk assessment, risk stratification, and modification of risk parameters that guide the framework for optimum perioperative risk reduction strategies. Contemporary approaches to the preoperative cardiac risk assessment use the guidelines published by the American College of Cardiology/American Heart Association (ACC/AHA) (1). However, these guidelines did not incorporate the most recent perioperative risk-stratification approach in the selection of noninvasive cardiac testing and medical treatment in the intermediate-risk patients. There is a general consensus that intermediate-risk preoperative patients should be identified and risk stratified with a clinical tool such as the revised cardiac risk index (2). Preoperative noninvasive cardiac testing should be reserved for those patients with multiple clinical predictors of risk or other modifying factors. The paradigm is shifting for supporting perioperative medical preventive therapy in the intermediate- to high-risk patients with revised cardiac risk index  2 without documented severe myocardial ischemia (3–5). Optimal medical preventive therapy with agents such as perioperative beta blockers (and possibly statins) is not yet fully delineated, because there are very few large adequately powered randomized controlled trials (RCTs) to provide definitive evidence for benefits and risks of perioperative beta blockers.
In this issue of the Journal, Poldermans et al. (6) report results from a large study that challenge the preoperative guidelines of the ACC/AHA (1) surrounding the use of noninvasive cardiac testing for stable intermediate-risk patients. By using excellent beta-blocker therapy with tight heart rate (HR) control of 60 to 65 beats/min, there was protection against major cardiac events after vascular surgery, and noninvasive cardiac testing added little prognostic value among intermediate-risk patients in this setting. A total of 770 intermediate-risk preoperative patients receiving perioperative beta-blocker with targeted HR 60 to 65 beats/min who were undergoing major vascular surgery were randomized to noninvasive cardiac testing or no testing. The group that received preoperative noninvasive cardiac testing was stratified into no ischemia, limited ischemia, and extensive ischemia on the basis of dobutamine stress echocardiography findings. Prophylactic preoperative coronary revascularization was dictated by study protocol and offered only to the group with extensive stress-induced ischemia. The decision for coronary revascularization was at the discretion of the treating physician on the basis of subjective evaluation of coronary angiography and the perceived risks of a potential delay in the index vascular surgical procedure.
There was no significant difference in the primary end point (composite postoperative cardiac death and/or nonfatal myocardial infarction [MI]) between preoperative cardiac testing and no-testing. The incidence of the 30-day composite end point of cardiac death and nonfatal MI was low (2.2%), regardless of cardiac testing or no-testing. Patients that were able to achieve a preoperative HR <65 beats/min with beta-blocker had a lower incidence of the primary end point at 30 days and on long-term follow-up.
Despite these findings and other studies highlighting the protective benefit of tight beta blockade, uncertainty remains: 1) what degree of abnormality seen on preoperative noninvasive cardiac testing should result in consideration for invasive cardiac testing and potential coronary revascularization?; 2) although the incidence of the primary end point, 2.2%, is apparently low enough to dissuade testing in the intermediate-risk patients, this study and others have not been adequately powered to establish with confidence a 25% risk reduction by tight beta-blockade therapy (7); and 3) is the observed protective effect of beta blocker solely a mechanism of "tight" HR and/or blood pressure control below the ischemic threshold, or is it a combined effect with perioperative statin therapy?
Evidence increasingly discourages the need for routine preoperative noninvasive cardiac testing strategy for most intermediate-risk preoperative patients. The selection of noninvasive cardiac stress tests for the occasional patient should anticipate that the patient will meet guidelines for coronary revascularization after coronary angiography, and no testing is recommended when it might delay surgical intervention for urgent or emergent conditions. It is important to realize that dobutamine echocardiography and nuclear perfusion stress testing for perioperative MI or death have excellent negative predictive values (near 100%) but poor positive predictive values (<20%) (1). A negative study is reassuring in that the probability of a perioperative cardiac event is very small, but a positive study is still a relatively weak predictor of a perioperative cardiac event. The study by Poldermans et al. (6) did not address this issue, and the study is underpowered to detect any potential benefit of preoperative cardiac testing with "the intent to treat" (revascularization) to reduce perioperative cardiac risk and/or long-term risk. To study the positive predictive value of noninvasive cardiac testing, randomization would need to be at the level of revascularization in an adequately sampled population with a positive stress test. The CARP (Coronary Artery Revascularization Prophylaxis) trial (8) comes closest to this criteria but was also probably underpowered.
Consensus guidelines recommend that aggressive medical management to provide myocardial protection in the perioperative state be a central element in reducing the cardiac risk. Two historical RCTs (9,10) that demonstrated that perioperative beta-blocker therapy was associated with improved outcome in surgical patients at risk for coronary artery disease are currently challenged by recent data (11,12). Today, there is still debate to precisely define the optimal use of perioperative beta blockers. Poldermans et al. (6) reported that the incidence of the 30-day end point in intermediate-risk patients with tight beta blockade was 2.2% or 17 events of 770 intermediate-risk patients. Tight HR control was also associated with a reduction in perioperative ischemia by 85%. However, the certainty with which one can trust this clinical strategy is tempered by the fact that there have been very few events among all patients enrolled in perioperative beta-blocker RCTs (13,14). The findings reported by Poldermans et al. (6) in this issue of the Journal establish a realistic (25%) risk reduction by tight beta-blockade, but the confidence limits surrounding this point estimate are broad.
Poldermans et al. (6) had previously reported that an effective beta-adrenergic blockade regimen that kept the HR to 60 to 65 beats/min could be used to prevent the HR from exceeding an "ischemic threshold" detected by preoperative electrocardiography monitoring (15). The potential mechanisms of benefit for beta-blockers include prolongation of the coronary diastolic filling time, reduction in risk of ischemic ventricular arrhythmias, and prevention of disruption of previously quiescent atheromatous plaques from unopposed sympathetic stimulation that might complicate major noncardiac surgery (16). The mechanism of a cardioprotective effect of beta-blockers could also be due to anti-inflammatory effects or a blunting of proinflammatory effects (17). Although plausible in theory, there is currently insufficient information to recommend the routine incorporation of tight HR control with beta blocker in all preoperative patients at intermediate risk. More definitive indications for perioperative beta-blocker prophylaxis await the results of the ongoing POISE (Perioperative Ischemia Evaluation) trial.
A recent expedited update on the ACC/AHA guideline focusing on perioperative beta-blocker therapy has been published (18) for the purpose of clarifying the current recommendations for national quality initiatives like the Physicians Consortium for Performance Improvement and the Surgical Care Improvement Project with regard to use of beta-blockers. The updated ACC/AHA guidelines (18) reflect the fact that preoperative beta-blocker treatment recommendations for noncardiac surgery to prevent perioperative cardiac complications are based on very few RCTs with which to answer several critical questions. What are the beneficial effects of different beta-blocker agents? How should the medications be titrated? What is an optimal dosing regimen? What route of administration is optimal? What are the risks?
Poldermans et al. (6) reported that 42% to 43% of the intermediate-risk patients received statins preoperatively in combination with tight beta-blockade in both the testing and no testing group. Two retrospective trials have shown an association between perioperative statin therapy and decreased perioperative cardiac complications (19,20). In addition a small prospective randomized trial that compared atorvastatin versus placebo for patients undergoing major vascular surgery (21) demonstrated an 18% reduction (8% vs. 26%, respectively) in cardiac death, nonfatal MI, and ischemic stroke in the group that received atorvastatin. Thus, whether the observed beneficial perioperative risk prevention effect demonstrated by Poldermans et al. (6) can be explained by the tight beta-blocker therapy alone or in combination with pleiotropic and anti-inflammatory effects of statins and beta-blockade is not known. Definitive indications for a perioperative combination therapy with statin and beta-blocker prophylaxis awaits the efficacy result of the ongoing DECREASE-IV (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo-IV) trial.
The current ACC/AHA guideline recommendations for perioperative beta-blocker therapy (18) suggest using beta blockers for the following situations: 1) should be continued in all high-risk patients previously receiving beta-blocker therapy undergoing vascular surgery; 2) should be administered to all high-risk patients identified by myocardial ischemia on preoperative assessment undergoing vascular surgery; 3) probably recommended for high-risk patients defined by multiple clinical predictors undergoing intermediate- or high-risk procedures; 4) might be considered for intermediate-risk patients defined by a single clinical predictor undergoing intermediate- or high-risk procedures; 5) might be considered in low-risk patients defined by clinical predictors not receiving beta-blocker therapy undergoing vascular surgery; and 6) should not be administered in preoperative patients with absolute contraindications to beta-blocker.
Finally, the real message here is that patients with stable coronary artery disease, receiving effective medical therapy, have low risk. In contrast, these data do not apply to unstable patients, where increasingly the evidence suggests that aggressive medical and interventional treatment provides optimal coronary outcomes.
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Footnotes
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* Editorials published in the Journal of American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
2 Dr. Eagle has received grant and/or research support from Biosite, Bristol-Myers Squibb, Cardiac Sciences, Blue Cross Blue Shield of Michigan, Hewlett Foundation, Mardigian Fund, Pfizer, SanofiAventis, and the Varbedian Fund. He has served as a consultant for the National Institutes of Health National Heart, Lung, and Blood Institute, Pfizer, SanofiAventis, and the Robert Wood Johnson Foundation.
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References
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Perioperative beta-blocker therapy and mortality after major noncardiac surgery N Engl J Med 2005;353:349-361.[CrossRef][Web of Science][Medline] 5. Auerbach AD, Goldman L. Beta-blockers and reduction of cardiac events in noncardiac surgeryclinical applications. JAMA 2002;287:1445-1447.[Abstract/Free Full Text] 6. Poldermans D, Bax JJ, Schouten O, et al. 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;48:964-969.[Abstract/Free Full Text] 7. Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med 1984;3:409-422.[Web of Science][Medline] 8. McFalls EO, Ward HB, Moritz TE, et al. Coronary artery revascularization before elective major vascular surgery N Engl J Med 2004;351:2795-2804.[CrossRef][Web of Science][Medline] 9. Mangano DT, Layug EL, Wallace A, et al. 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Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2006 guideline update for perioperative cardiovascular evaluation for noncardiac surgeryfocused update on perioperative beta-blocker therapy—a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 2006;47:2343-2355.[Free Full Text] 19. Kertai MD, Boersma E, Westerhout CM, et al. A combination of statins and beta-blockers is independently associated with a reduction in the incidence of perioperative mortality and nonfatal myocardial infarction in patients undergoing abdominal aortic aneurysm surgery Eur J Vasc Endovasc Surg 2004;28:343-352.[CrossRef][Web of Science][Medline] 20. Poldermans D, Bax JJ, Kertai, MD, et al. 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