Cardiac Events in Patients Undergoing Noncardiac Surgery: Shifting
the Paradigm from Noninvasive Risk Stratification to Therapy
Paul A. Grayburn, MD, and L. David Hillis, MD
Internists and cardiologists are often asked to estimate the risk for perioperative myocardial infarction or cardiac death in patients being considered for noncardiac surgery. Estimating this risk in an individual patient is difficult and complex. Although noninvasive imaging tests are often used for this purpose, a review of the literature reveals that the positive predictive value of noninvasive imaging tests is uniformly low and that they do not provide information beyond that obtained by assessing simple clinical risk variables. Moreover, no evidence exists that noninvasive imaging tests lead to a therapeutic strategy that reduces the risk for peri-operative myocardial infarction or cardiac death. Since the publi-cation of guidelines for preoperative risk stratifipubli-cation by the
American College of Cardiology/American Heart Association in 1996 and the American College of Physicians in 1997, three clinical trials have shown that-blocker therapy reduces the risk for perioperative cardiac events. This paper focuses on the rela-tionship between risk stratification and subsequent therapy to minimize or eliminate risk. In short, the paradigm is shifting from predicting which patient is at high risk for having a perioperative cardiac event to minimizing the likelihood of such an event with specific perioperative pharmacologic therapy.
Ann Intern Med.2003;138:506-511. www.annals.org For author affiliations, see end of text.
I
nternists and cardiologists are often asked to estimate the risk for perioperative myocardial infarction or cardiac death in patients for whom noncardiac surgery is planned. Estimating this risk in an individual patient is difficult and complex. Although two position papers on this topic have been published (by the American College of Cardiology/ American Heart Association [ACC/AHA] in 1996 [1] and by the American College of Physicians [ACP] in 1997 [2, 3]), new data have emerged that prompt reconsideration of this issue, particularly from the standpoint of perioperative therapy. We review the issues on perioperative risk strati-fication, as well as therapies to prevent myocardial infarc-tion and cardiac death.MAGNITUDE OF THE
PROBLEM
Almost 30 million patients undergo noncardiac sur-gery annually in the United States (4); about one third have known coronary artery disease or risk factors for ath-erosclerosis. The 500 000 patients who undergo peripheral vascular procedures each year are thought to have a par-ticularly high risk for perioperative cardiac events (5). However, recent data suggest that perioperative mortality is declining, particularly for carotid endarterectomy (6 – 8). Of 68 631 major operations performed in the Veterans Administration system from 1991 to 1997, 30-day mortal-ity was only 3.2% and most deaths were noncardiac (6). Mortality was 4.7% for abdominal aortic aneurysm repair and 1.2% for carotid endarterectomy. Among 45 744 ca-rotid endarterectomies performed in Florida under Medi-care from 1992 to 1996, mortality was only 0.8% (8). Technical advances in vascular surgery, such as endolumi-nal stenting, may further reduce perioperative risk in se-lected patients (9, 10).
PATHOPHYSIOLOGY OF
PERIOPERATIVE
CARDIAC
COMPLICATIONS
The pathophysiology of perioperative myocardial in-farction differs somewhat from that of myocardial infarc-tion occurring in the usual setting. In the latter, rupture of a coronary arterial atherosclerotic plaque leads to platelet aggregation and thrombus formation (11). In contrast, plaque rupture occurs in only about half of perioperative myocardial infarctions (12, 13); the remainder are due to a prolonged imbalance between myocardial oxygen supply and demand in the setting of coronary artery disease. Myo-cardial oxygen supply may be diminished by anemia or hypotension, whereas oxygen demand may be increased by tachycardia and hypertension resulting from postoperative pain, withdrawal of anesthesia, or shifts in intravascular volume. Perioperative myocardial infarction usually occurs 1 to 4 days after surgery (14 –16), when the effects of anesthesia have dissipated and perioperative pain and fluid shifts are occurring.
ISSUES IN
RISK
STRATIFICATION
The goal of risk stratification is to reduce risk (17). First, any test used for preoperative risk stratification must be accurate. It should have a high positive and negative predictive value and should result in a change in risk from the pretest likelihood. Since predictive values depend on event rate, likelihood ratios should be calculated. The like-lihood ratio of a positive or negative test result should be greater than 10 or less than 0.2, respectively, because these values indicate a substantial change in risk from the pretest level (2). The test should provide information that adds or is complementary to known risk variables. Second, risk stratification is most helpful when it influences outcome. For example, would a test lead to cancellation of surgery or alternative treatment? Would it mandate therapy to reduce perioperative risk, such as prophylactic coronary
revascu-larization? Finally, the harms– benefit tradeoff of risk strat-ification must be favorable. For example, routine preoper-ative imaging tests may lead to an adverse outcome by delaying needed surgery. Each clinical risk index or diag-nostic test should be evaluated with these critical elements in mind (Table 1).
RISK
STRATIFICATION BY
CLINICAL
VARIABLES
Cardiac Risk Index
The original cardiac risk index (18) was described in 1001 patients undergoing general, orthopedic, or urologic procedures. Subsequently, this index was modified and then tested in another clinical setting in blinded fashion in patients undergoing vascular or general surgery (19). Eagle and colleagues (20) proposed a simple clinical risk index that, although widely used, has not been tested prospec-tively in another clinical setting. Lee and colleagues (21) described the largest and most current scheme of clinical risk assessment, the revised cardiac risk index. After iden-tifying the following six variables in 2893 patients, they tested them in another clinical setting in 1422 patients: high-risk surgical procedure, history of ischemic heart dis-ease (excluding previous coronary revascularization), his-tory of heart failure, hishis-tory of stroke or transient ischemic attack, preoperative insulin therapy, and preoperative se-rum creatinine levels greater than 152.5 mol/L (⬎2.0 mg/dL). By receiver-operating characteristic curve analysis, the revised cardiac risk index was superior to the original and modified cardiac risk indices. We recommend the re-vised cardiac risk index (Table 2)for clinical risk evalua-tion because of its simplicity, strength of study design, and superior receiver-operating characteristic curve analysis. Does Clinical Risk Stratification Satisfy the Critical Elements?
1. Is it accurate? Yes. The receiver-operating character-istic curve area greater than 0.8 indicates that the revised cardiac risk index is accurate in segregating patient risk groups.
2. Does it add to pretest knowledge? Yes.
3. Is the harms– benefit tradeoff favorable? Yes. The revised cardiac risk index is derived inexpensively from the history, physical examination, and serum creatinine level.
RISK
STRATIFICATION BY
DIAGNOSTIC
TESTING
For diagnostic testing to be useful in risk stratification, it should provide information that adds or is complemen-tary to that provided by the revised cardiac risk index. Furthermore, diagnostic testing should not lead to unnec-essary additional testing or harmful delays in surgery (22–25). Finally, diagnostic testing ideally should lead to proven therapy to reduce risk.
Myocardial Perfusion Imaging
Myocardial perfusion imaging, performed at rest and during vasodilator stress, is widely used. Since many pa-tients referred for vascular surgery cannot ambulate effec-tively because of claudication, their histories may not pro-vide an accurate assessment of symptoms or functional class. Patients with reversible or fixed perfusion defects probably have coronary artery disease, the main risk factor for perioperative cardiac events. Most patients do not de-velop chest pain or ST-segment depression during vasodi-lator stress (26). However, they have impaired vasodivasodi-lator reserve in areas subtended by a stenosed coronary artery, leading to heterogeneity in radionuclide activity in differ-ent segmdiffer-ents of myocardium. Thus, perfusion imaging is sensitive for detecting coronary artery disease, not ischemia (27). Table 3 lists large studies of myocardial perfusion imaging in which likelihood ratios could be calculated from the published data (20, 28 –37).
Does This Test Satisfy the Critical Elements?
1. Is it accurate? No. The positive likelihood ratio is low. The negative likelihood ratio is good in some studies but poor in others. Two large prospective, blinded studies showed that myocardial perfusion imaging did not provide independent prognostic value beyond clinical risk stratifi-cation (34, 39).
2. Does it influence outcome? No published prospec-tive trials have addressed this question.
3. Is the harms– benefit tradeoff favorable? No. Pa-tients with positive test results often are subjected to fur-Table 1. Critical Elements for Risk Stratification in Patients
Undergoing Noncardiac Surgery Risk-assessment tool must be accurate
Predicts perioperative events (positive likelihood ratio⬎10)
Predicts absence of perioperative events (negative likelihood ratio⬍0.2) Risk-assessment tool must influence outcome
Identifies subgroups in which surgery should be cancelled or treatment changed
Identifies subgroups that do or do not benefit from proven therapy to reduce risk
Risk-assessment tool must have a favorable harms–benefit tradeoff
Table 2. Major Cardiac Event Rates by the Revised Cardiac Risk Index*
Class Events/Patients,n/n Event Rate (95% CI),%
I (0 risk factors) 2/488 0.4 (0.05–1.5)
II (1 risk factor) 5/567 0.9 (0.3–2.1)
III (2 risk factors) 17/258 6.6 (3.9–10.3) IV (ⱖ3 risk factors) 12/109 11.0 (5.8–18.4)
ROC curve area 0.806†
*Adapted from Lee et al. (21). ROC⫽receiver-operating characteristic. †P⫽0.034 versus original cardiac risk index (ROC curve area, 0.701), modified cardiac risk index (ROC curve area, 0.582), and American Society of Anesthesia Classification (ROC curve area, 0.697). Major cardiac events include myocardial infarction, cardiac arrest, pulmonary edema, and complete heart block. Risk factors are high-risk surgical procedure (intraperitoneal, intrathoracic, or suprainguinal vascular reconstruction), history of ischemic heart disease (excluding previous re-vascularization), history of congestive heart failure, history of stroke or transient ischemic attack, preoperative insulin therapy, and preoperative serum creatinine levels⬎152.5mol/L (⬎2.0 mg/dL).
ther evaluation, such as coronary angiography. Such a strategy is costly and may delay surgery unnecessarily.
Dobutamine Stress Echocardiography
Dobutamine stress echocardiography (DSE) allows a physician to evaluate left ventricular regional wall motion at rest and during dobutamine stress. It provides an adren-ergic stimulus that is more similar physiologically to the stress of the perioperative period than that provided by vasodilators. Dobutamine stress echocardiography is widely available and portable and does not involve radiation ex-posure. Since an adequate cardiac workload is not always achieved with dobutamine alone, atropine or handgrip ex-ercise may be used with dobutamine to ensure an adequate increase in heart rate and systemic arterial pressure (38, 39).Table 4lists large studies that have evaluated the use of DSE for risk stratification for patients undergoing non-cardiac surgery (40 – 43).
Does This Test Satisfy the Critical Elements?
1. Is it accurate? No. The likelihood ratio of a positive test result is poor. The negative likelihood ratio is good in all but one study. A recent large study (43) showed that
DSE did not add incremental value in low- or medium-risk patients (score of 0 to 2 on the revised cardiac medium-risk index). 2. Does it influence outcome? No studies have ad-dressed this prospectively.
3. Is the harms– benefit tradeoff favorable? No. Do-butamine stress echocardiography has a low positive pre-dictive value. Patients with positive test results are often
subjected to further evaluation, which may cause an unnec-essary delay in noncardiac surgery.
Coronary Angiography
Coronary angiography is not recommended for risk stratification in patients undergoing noncardiac surgery (1– 3). However, patients considered for noncardiac surgery who have an indication for angiography independent of the planned surgery should undergo angiography, such as those with acute coronary syndromes or angina refractory to medical therapy. The ACC/AHA guidelines also recom-mend coronary angiography for patients with high-risk re-sults on noninvasive testing.
THERAPIES
TO
REDUCE THE
RISK FOR
PERIOPERATIVE
CARDIAC
COMPLICATIONS
Coronary Artery Bypass Grafting
No randomized, controlled trials have assessed the benefit of coronary artery bypass grafting (CABG) before noncardiac surgery, but patients with previous CABG have low rates of cardiac complications with noncardiac surgery (44 – 47). Using the Coronary Artery Surgery Study (CASS) registry data, Eagle and colleagues (47) found that patients who underwent major vascular, abdominal, tho-racic, or head and neck surgery after previous CABG had fewer perioperative deaths and myocardial infarctions than patients receiving medical therapy. Based on these data, the ACC/AHA and ACP guidelines do not recommend non-Table 3. Studies of Vasodilator Stress Nuclear Perfusion Imaging for Risk Stratification
Study (Reference) Surgery Patients Death or Myocardial Infarction
Predictive Values Likelihood Ratios
Positive Negative Positive Negative
n 4OOOOOOOOO%OOOOOOOOO3
Eagle et al. (20) Vascular 200 8 16 98 2.32 0.21
Cutler and Leppo (28) Abdominal aortic 116 10 20 100 2.44 0
Younis et al. (29) Vascular 111 7 15 100 2.27 0.37
Hendel et al. (30) Vascular 327 9 14 99 1.49 0.16
Lette et al. (31) Mixed 355 8 17 99 2.27 0.12
Brown and Rowen (32) Vascular 231 5 13 99 2.04 0.11
Vanzetto et al. (33) Abdominal aortic 134 9 13 98 3.02 0.12
Baron et al. (34) Abdominal aortic 457 5 4 96 0.91 1.05
Bry et al. (35) Vascular 237 7 11 100 1.82 0.16
Younis et al. (36) General 161 9 18 98 2.18 0.22
Roghi et al. (37) Vascular 320 4 5 98 1.86 0.52
Table 4. Studies of Dobutamine Stress Echocardiography for Risk Stratification
Study (Reference) Surgery Patients Death or Myocardial Infarction
Predictive Values Likelihood Ratios Positive Negative Positive Negative
n 4OOOOOOOOOO%OOOOOOOOOO3
Poldermans et al. (40) Vascular 131 4 14 100 5.88 0
Poldermans et al. (41) Vascular 300 6 24 100 5.26 0
Das et al. (42) General 530 6 15 100 2.70 0
invasive testing for risk stratification in symptom-free pa-tients who have had CABG within 5 years (1, 2).
Coronary artery bypass grafting does not protect an asymptomatic patient from complications of noncardiac surgery. Coronary artery bypass grafting itself confers a risk for death, nonfatal myocardial infarction, stroke, and cog-nitive dysfunction. Peri-CABG mortality in more than 180 000 Medicare patients (1996 data) was 5.4% (48). The recovery period after CABG causes an obligate delay in planned noncardiac surgery. In two studies of patients with abnormal dipyridamole thallium scans (49, 50), a strategy of coronary angiography and subsequent CABG led to worse outcomes than did noncardiac surgery without preoperative imaging. In short, prophylactic CABG is more likely to harm than benefit most patients undergoing noncardiac surgery. However, if the patient has symptoms or coronary anatomy that mandate CABG independently of planned noncardiac surgery, CABG is indicated.
Percutaneous Coronary Intervention
No randomized, controlled trials have shown that per-cutaneous coronary intervention is beneficial as prophylac-tic therapy in patients undergoing noncardiac surgery, and a recent report by Kaluza and colleagues (51) suggests cau-tion in performing noncardiac surgery soon after coronary arterial stenting. Among patients who had noncardiac sur-gery within 6 weeks of successful stent placement, 20% died, 18% had nonfatal myocardial infarction, and 28% had major bleeding. Percutaneous coronary intervention should be reserved for patients with an acute coronary syn-drome or stable angina refractory to medical therapy. If coronary stenting is performed, elective noncardiac surgery should be deferred for 6 weeks or longer.
-Adrenergic Blockade
Since publication of the ACC/AHA and ACP guide-lines on risk stratification for noncardiac surgery, two ran-domized, controlled trials and one large nonrandomized report have shown that -blocker therapy reduces periop-erative cardiac complications. Mangano and colleagues (52) performed a randomized, double-blind, placebo-controlled trial of atenolol in 200 patients with known coronary artery disease or risk factors for atherosclerosis who underwent noncardiac surgery. No perioperative deaths occurred in patients given atenolol, and only one death was reported in patients receiving placebo. However, by 6 months, eight deaths had occurred in patients given placebo and none in patients given atenolol (P⬍ 0.001). This difference was sustained for the 2-year follow-up period. In Poldermans and colleagues’ study (53), 112 patients with one or more clinical risk factors and ischemia by DSE scheduled to undergo abdominal aortic aneurysm repair or infrainguinal arterial reconstruction were randomly as-signed to placebo or bisoprolol. The study was terminated early when the investigators noted that bisoprolol markedly reduced perioperative mortality (17% vs. 3.4%;P⫽0.02) and myocardial infarction (17% vs. 0%;P⬍0.001).
Subsequently, Boersma and colleagues (43) calculated the odds ratios for perioperative death and myocardial farction using clinical variables, the revised cardiac risk in-dex, DSE, and-blocker therapy in 1351 patients screened by Poldermans and colleagues (53). Dobutamine stress echocardiography was performed in 1097 patients, and -blockers were given to 360 patients. The incidence of nonfatal myocardial infarction or death was 3.3%. Among the 83% of patients found to be at low or intermediate risk by the revised cardiac risk index (0 to 2 risk factors), car-diac complications occurred in fewer than 2% of patients taking-blockers, irrespective of DSE results. In contrast, DSE provided additional, complementary information in patients with 3 or more risk factors: Among patients re-ceiving-blockers, the event rate was 2% in those without ischemia by DSE and 11% if DSE showed ischemia.
In summary,-blockade reduces the incidence of peri-operative cardiac complications in patients at low, interme-diate, and high risk, as defined by the revised cardiac risk index. It is effective even in patients with inducible isch-emia by DSE. Finally,-blockers are inexpensive. Questions remain about-blockade in patients having noncardiac sur-gery. First, patients with severe left ventricular systolic dys-function were excluded from previous studies. It is unclear how these patients should be managed. Second, the optional duration of-blocker therapy is uncertain. Third, it is unclear whether the observed benefit of atenolol or bisoprolol is unique to these agents or similar for all-blockers.
Other Medical Therapies
A few studies have examined nitroglycerin or calcium-channel blockers in patients undergoing noncardiac sur-gery. The results are inconclusive. Aspirin reduces morbid-ity and mortalmorbid-ity in patients with acute coronary syndromes (54), but no data exist on its use periopera-tively. Its potential benefits must be balanced against the increased risk for bleeding. Similarly, no studies have as-sessed the effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or angiotensin-converting enzyme inhibitors on the incidence of perioperative cardiac events.
PROPOSED
CLINICAL
ALGORITHM FOR
PREOPERATIVE
RISK
STRATIFICATION
On the basis of the above considerations, preoperative risk stratification can be simplified so that the following questions are addressed (Figure). First, has the patient had coronary revascularization within 5 years without recurrent symptoms? If “yes,” the patient may have surgery, since risk for perioperative myocardial infarction or death is very low. Second, would cardiac catheterization and revascular-ization be chosen irrespective of the proposed noncardiac surgery? If “yes,” the urgency of the noncardiac surgery must be weighed against the urgency of coronary angiog-raphy and revascularization. If the surgery is elective and the need for revascularization is pressing, angiography or revascularization should be done and noncardiac surgery
should be deferred. If “no,” and the patient has none of the revised cardiac risk index variables, noncardiac surgery can be done without delay. If the patient has one or two risk variables,-blockade should be initiated perioperatively. If -blockade is contraindicated, surgery can be done without it, since the risk in these patients is only minimally in-creased. If the patient has three or more risk variables, -blockade should be initiated perioperatively. If -block-ade is contraindicated or the surgical risk is deemed excessive, canceling or deferring the surgery should be considered. In such patients, DSE may be helpful since perioperative risk is low in patients without ischemia and high in patients with ischemia (43).
CONCLUSIONS
Risk stratification in patients scheduled for noncardiac surgery remains an important issue. The era of routine non-invasive testing has ended; myocardial perfusion imaging and DSE add little to the clinically defined risk index in most patients. Coronary angiography and revasculariza-tion should be performed in patients who require these procedures independently of planned noncardiac surgery. Patients considered at risk for myocardial infarction or car-diac death during noncarcar-diac surgery should receive a -blocker to reduce the risk for perioperative cardiac events. From the University of Texas Southwestern Medical Center and Veter-ans Affairs Medical Center, Dallas, Texas.
Grant Support:Dr. Grayburn is supported by a Mid-Career Investigator in Patient-Oriented Research Award (K24-HL03980) from the National Heart, Lung, and Blood Institute.
Requests for Single Reprints: Paul A. Grayburn, MD, Baylor Heart and Vascular Institute, 3500 Gaston Avenue, Dallas, TX 75246. Current author addresses are available at www.annals.org. References
1.Eagle KA, Brundage BH, Chaitman BR, Ewy GA, Fleisher LA, Hertzer NR, et al.Guidelines for perioperative cardiovascular evaluation for noncardiac sur-gery. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol. 1996;27:910-48. [PMID: 8613622]
2. 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;127:309-12. [PMID: 9265433]
3.Palda VA, Detsky AS.Perioperative assessment and management of risk from coronary artery disease. Ann Intern Med. 1997;127:313-28. [PMID: 9265434] 4.Mangano DT, Goldman L.Preoperative assessment of patients with known or suspected coronary disease. N Engl J Med. 1995;333:1750-6. [PMID: 7491140]
5.Hertzer NR, Beven EG, Young JR, O’Hara PJ, Ruschhaupt WF 3rd, Graor RA, et al.Coronary artery disease in peripheral vascular patients. A classification of 1000 coronary angiograms and results of surgical management. Ann Surg. 1984;199:223-33. [PMID: 6696538]
6.Khuri SF, Daley J, Henderson W, Hur K, Hossain M, Soybel D, et al. Relation of surgical volume to outcome in eight common operations: results from the VA National Surgical Quality Improvement Program. Ann Surg. 1999;230: 414-29; discussion 429-32. [PMID: 10493488]
7.Brittenden J, Murie JA, Jenkins AM, Ruckley CV, Bradbury AW.Carotid endarterectomy before and after publication of randomized controlled trials. Br J Surg. 1999;86:206-10. [PMID: 10100788]
8.Pearce WH, Parker MA, Feinglass J, Ujiki M, Manheim LM.The impor-tance of surgeon volume and training in outcomes for vascular surgical proce-dures. J Vasc Surg. 1999;29:768-76; discussion 777-8. [PMID: 10231626] 9.Zarins CK, White RA, Schwarten D, Kinney E, Diethrich EB, Hodgson KJ, et al.AneuRx stent graft versus open surgical repair of abdominal aortic aneu-rysms: multicenter prospective clinical trial. J Vasc Surg. 1999;29:292-305; dis-cussion 306-8. [PMID: 9950987]
10.Moore WS, Kashyap VS, Vescera CL, Quin˜ones-Baldrich WJ.Abdominal aortic aneurysm: a 6-year comparison of endovascular versus transabdominal re-pair. Ann Surg. 1999;230:298-306; discussion 306-8. [PMID: 10493477] 11.Fuster V, Badimon L, Badimon JJ, Chesebro JH.The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med. 1992;326:242-50. [PMID: 1727977]
12.Cohen MC, Aretz TH.Histological analysis of coronary artery lesions in fatal postoperative myocardial infarction. Cardiovasc Pathol. 1999;8:133-9. [PMID: 10722235]
13.Dawood MM, Gutpa DK, Southern J, Walia A, Atkinson JB, Eagle KA. Pathology of fatal perioperative myocardial infarction: implications regard-ing pathophysiology and prevention. Int J Cardiol. 1996;57:37-44. [PMID: 8960941]
14.Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM.Association of perioperative myocardial ischemia with cardiac mor-bidity and mortality in men undergoing noncardiac surgery. The Study of Perioperative Ischemia Research Group. N Engl J Med. 1990;323:1781-8. [PMID: 2247116]
15.Raby KE, Goldman L, Creager MA, Cook EF, Weisberg MC, Whittemore AD, et al.Correlation between preoperative ischemia and major cardiac events after peripheral vascular surgery. N Engl J Med. 1989;321:1296-300. [PMID: 2797102]
16.Raby KE, Barry J, Creager MA, Cook EF, Weisberg MC, Goldman L. Detection and significance of intraoperative and postoperative myocardial Figure. Proposed clinical algorithm for risk stratification.
ischemia in peripheral vascular surgery. JAMA. 1992;268:222-7. [PMID: 1608141]
17.Wilson R, Crouch EA.Risk assessment and comparisons: an introduction. Science. 1987;236:267-70. [PMID: 3563505]
18.Goldman L, Caldera DL, Nussbaum SR, Southwick FS, Krogstad D, Mur-ray B, et al.Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med. 1977;297:845-50. [PMID: 904659]
19.Detsky AS, Abrams HB, McLaughlin JR, Drucker DJ, Sasson Z, Johnston N, et al.Predicting cardiac complications in patients undergoing non-cardiac surgery. J Gen Intern Med. 1986;1:211-9. [PMID: 3772593]
20.Eagle KA, Coley CM, Newell JB, Brewster DC, Darling RC, Strauss HW, et al.Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery. Ann Intern Med. 1989;110:859-66. [PMID: 2655519]
21.Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, et al.Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100: 1043-9. [PMID: 10477528]
22.Massie BM, Mangano DT.Assessment of perioperative risk: have we put the cart before the horse [Editorial]. J Am Coll Cardiol. 1993;21:1353-6. [PMID: 8473641]
23.Massie BM, Mangano DT.Risk stratification for noncardiac surgery. How (and why)? [Editorial] Circulation. 1993;87:1752-5. [PMID: 8491030] 24.Bodenheimer MM.Noncardiac surgery in the cardiac patient: what is the question? Ann Intern Med. 1996;124:763-6. [PMID: 8633838]
25.Lee TH.Reducing cardiac risk in noncardiac surgery [Editorial]. N Engl J Med. 1999;341:1838-40. [PMID: 10588971]
26.Iskandrian AS.Dipyridamole sesta MIBI myocardial imaging [Editorial]. Am J Cardiol. 1991;68:674-5. [PMID: 1877486]
27.Zaret BL, Wackers FJ.Nuclear cardiology (1). N Engl J Med. 1993;329: 775-83. [PMID: 8350888]
28.Cutler BS, Leppo JA.Dipyridamole thallium 201 scintigraphy to detect coronary artery disease before abdominal aortic surgery. J Vasc Surg. 1987;5:91-100. [PMID: 3795395]
29.Younis LT, Aguirre F, Byers S, Dowell S, Barth G, Walker H, et al. Perioperative and long-term prognostic value of intravenous dipyridamole thal-lium scintigraphy in patients with peripheral vascular disease. Am Heart J. 1990; 119:1287-92. [PMID: 2353615]
30.Hendel RC, Whitfield SS, Villegas BJ, Cutler BS, Leppo JA. Predic-tion of late cardiac events by dipyridamole thallium imaging in patients under-going elective vascular surgery. Am J Cardiol. 1992;70:1243-9. [PMID: 1442573]
31.Lette J, Waters D, Cerino M, Picard M, Champagne P, Lapointe J. Pre-operative coronary artery disease risk stratification based on dipyridamole imaging and a simple three-step, three-segment model for patients undergoing noncar-diac vascular surgery or major general surgery. Am J Cardiol. 1992;69:1553-8. [PMID: 1598869]
32.Brown KA, Rowen M.Extent of jeopardized viable myocardium determined by myocardial perfusion imaging best predicts perioperative cardiac events in patients undergoing noncardiac surgery. J Am Coll Cardiol. 1993;21:325-30. [PMID: 8425993]
33.Vanzetto G, Machecourt J, Blendea D, Fagret D, Borrel E, Magne JL, et al. Additive value of thallium single-photon emission computed tomography myo-cardial imaging for prediction of perioperative events in clinically selected high cardiac risk patients having abdominal aortic surgery. Am J Cardiol. 1996;77: 143-8. [PMID: 8546081]
34.Baron JF, Mundler O, Bertrand M, Vicaut E, Barre´ E, Godet G, et al. Dipyridamole-thallium scintigraphy and gated radionuclide angiography to assess cardiac risk before abdominal aortic surgery. N Engl J Med. 1994;330:663-9. [PMID: 8107716]
35.Bry JD, Belkin M, O’Donnell TF Jr, Mackey WC, Udelson JE, Schmid CH, et al.An assessment of the positive predictive value and cost-effectiveness of dipyridamole myocardial scintigraphy in patients undergoing vascular surgery. J Vasc Surg. 1994;19:112-21; discussion 121-4. [PMID: 8301724]
36.Younis L, Stratmann H, Takase B, Byers S, Chaitman BR, Miller DD. Preoperative clinical assessment and dipyridamole thallium-201 scintigraphy for prediction and prevention of cardiac events in patients having major
noncardio-vascular surgery and known or suspected coronary artery disease. Am J Cardiol. 1994;74:311-7. [PMID: 8059690]
37.Roghi A, Palmieri B, Crivellaro W, Sara R, Puttini M, Faletra F. Preoper-ative assessment of cardiac risk in noncardiac major vascular surgery. Am J Car-diol. 1999;83:169-74. [PMID: 10073816]
38.McNeill AJ, Fioretti PM, el-Said SM, Salustri A, Forster T, Roelandt JR. Enhanced sensitivity for detection of coronary artery disease by addition of atro-pine to dobutamine stress echocardiography. Am J Cardiol. 1992;70:41-6. [PMID: 1615868]
39.Afridi I, Main ML, Parrish DL, Kizilbash A, Levine BD, Grayburn PA. Usefulness of isometric hand grip exercise in detecting coronary artery disease during dobutamine atropine stress echocardiography in patients with either stable angina pectoris or another type of positive stress test. Am J Cardiol. 1998;82: 564-8. [PMID: 9732880]
40.Poldermans D, Fioretti PM, Forster T, Thomson IR, Boersma E, el-Said EM, et al.Dobutamine stress echocardiography for assessment of perioperative cardiac risk in patients undergoing major vascular surgery. Circulation. 1993;87: 1506-12. [PMID: 8491005]
41.Poldermans D, Arnese M, Fioretti PM, Salustri A, Boersma E, Thomson IR, et al. Improved cardiac risk stratification in major vascular surgery with dobutamine-atropine stress echocardiography. J Am Coll Cardiol. 1995;26:648-53. [PMID: 7642854]
42.Das MK, Pellikka PA, Mahoney DW, Roger VL, Oh JK, McCully RB, et al.Assessment of cardiac risk before nonvascular surgery: dobutamine stress echo-cardiography in 530 patients. J Am Coll Cardiol. 2000;35:1647-53. [PMID: 10807472]
43.Boersma E, Poldermans D, Bax JJ, Steyerberg EW, Thomson IR, Banga JD, et al.Predictors of cardiac events after major vascular surgery: role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy. JAMA. 2001;285:1865-73. [PMID: 11308400]
44.Crawford ES, Morris GC Jr, Howell JF, Flynn WF, Moorhead DT. Op-erative risk in patients with previous coronary artery bypass. Ann Thorac Surg. 1978;26:215-21. [PMID: 313187]
45.Reul GJ Jr, Cooley DA, Duncan JM, Frazier OH, Ott DA, Livesay JJ, et al. The effect of coronary bypass on the outcome of peripheral vascular operations in 1093 patients. J Vasc Surg. 1986;3:788-98. [PMID: 3486298]
46.Nielsen JL, Page CP, Mann C, Schwesinger WH, Fountain RL, Grover FL. Risk of major elective operation after myocardial revascularization. Am J Surg. 1992;164:423-6. [PMID: 1443365]
47.Eagle KA, Rihal CS, Mickel MC, Holmes DR, Foster ED, Gersh BJ. Cardiac risk of noncardiac surgery: influence of coronary disease and type of surgery in 3368 operations. CASS Investigators and University of Michigan Heart Care Program. Coronary Artery Surgery Study. Circulation. 1997;96: 1882-7. [PMID: 9323076]
48.Health Care Financing Administration.Medicare Participating Heart Bypass Center Demonstration. Accessed at http://cms.hhs.gov/researchers/reports/1998/ oregon2.pdf on 23 January 2003.
49.Mason JJ, Owens DK, Harris RA, Cooke JP, Hlatky MA.The role of coronary angiography and coronary revascularization before noncardiac vascular surgery. JAMA. 1995;273:1919-25. [PMID: 7783301]
50.Fleisher LA, Skolnick ED, Holroyd KJ, Lehmann HP.Coronary artery revascularization before abdominal aortic aneurysm surgery: a decision analytic approach. Anesth Analg. 1994;79:661-9. [PMID: 7943772]
51.Kałuza GL, Joseph J, Lee JR, Raizner ME, Raizner AE.Catastrophic out-comes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol. 2000;35:1288-94. [PMID: 10758971]
52.Mangano DT, Layug EL, Wallace A, Tateo I.Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Peri-operative Ischemia Research Group. N Engl J Med. 1996;335:1713-20. [PMID: 8929262]
53.Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blanken-steijn JD, et al.The effect of bisoprolol on perioperative mortality and myocar-dial infarction in high-risk patients undergoing vascular surgery. Dutch Echocar-diographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999;341:1789-94. [PMID: 10588963]
54.Awtry EH, Loscalzo J.Aspirin. Circulation. 2000;101:1206-18. [PMID: 10715270]
