Perioperative myocardial infarction—aetiology and prevention

H.-J. Priebe*

University Hospital/Department of Anaesthesia, Hugstetter Strasse 55, D-79106 Freiburg, Germany

* E-mail: priebe{at}ana1.ukl.uni-freiburg.de


    Abstract
 Top
 Abstract
 Introduction
 Aetiology of PMI
 Prevention of perioperative MI
 Conclusions
 Addendum
 References
 
Perioperative myocardial infarction (PMI) is one of the most important predictors of short- and long-term morbidity and mortality associated with non-cardiac surgery. Prevention of a PMI is thus a prerequisite for an improvement in overall postoperative outcome. The aetiology of PMI is multifactorial. The perioperative period induces large, unpredictable and unphysiological alterations in coronary plaque morphology, function and progression, and may trigger a mismatch of myocardial oxygen supply and demand. With many diverse factors involved, it is unlikely that one single intervention will successfully improve cardiac outcome following non-cardiac surgery. A multifactorial, step-wise approach is indicated. Based on increasing knowledge of the nature of atherosclerotic coronary artery disease, and in view of the poor positive predictive value of non-invasive cardiac stress tests, and the considerable risk of coronary angiography and coronary revascularization in high-risk patients, the paradigm is shifting from an emphasis on extensive non-invasive preoperative risk stratification to a combination of selective non-invasive testing and aggressive pharmacological perioperative therapy. Perioperative plaque stabilization by pharmacological means may be as important in the prevention of PMI as an increase in myocardial oxygen supply or a reduction in myocardial oxygen demand.

Keywords: complications, cardiac ; recovery


    Introduction
 Top
 Abstract
 Introduction
 Aetiology of PMI
 Prevention of perioperative MI
 Conclusions
 Addendum
 References
 
Perioperative myocardial infarction (PMI) is one of the most important predictors of short- and long-term morbidity and mortality associated with non-cardiac surgery.80 97 98 132 Prevention of a PMI is thus a prerequisite for the improvement in overall postoperative outcome. The design of effective preventive measures requires basic knowledge of the aetiology of PMI. Unfortunately, the exact nature of PMI remains an area of uncertainty and the subject of continued debate and controversy.80 97 132 Accordingly, the first part of this article will address the aetiology of PMI, with consideration of the aetiology and pathophysiology of acute coronary syndromes, and of the diagnosis of MI (recently reviewed in detail in reference132). The second part will address strategies and means of preventing a PMI.


    Aetiology of PMI
 Top
 Abstract
 Introduction
 Aetiology of PMI
 Prevention of perioperative MI
 Conclusions
 Addendum
 References
 
Acute coronary syndrome
Aetiology
Acute coronary syndromes (ACS) are associated with structurally as well as functionally complex plaques and coronary artery stenoses, coronary endothelial lesions, and plaque inflammation.19 24 42 47 75 103 Structural morphology, cellular composition, and biological activity of coronary plaques appear to be closely linked.96 Plaque instability correlated more with biological activity and cellular composition than with angiographical findings.90 The interaction between morphological and functional factors is unpredictable. Exogenous factors (e.g. mechanical stress, vasomotor tone, infection, blood viscosity, coagulability) further modify such interaction, making the final outcome even less predictable. Systemic or multi-focal arterial inflammation may be independent risk factors for acute coronary events,19 103 supporting the broader concept of the ‘vulnerable patient’.115

Pathophysiology
Plaque progression is frequently abrupt, mostly unpredictable,19 and often related to episodes of thrombosis (which, in turn, are triggered by plaque rupture, erosion, endothelial activation, or inflammation). In the absence of a hypercoagulable state, thrombi may remain mural rather than become occlusive, and may thus produce few if any symptoms (unless they embolize).102 If subsequent lysis is incomplete and is followed by re-endothelialization, the plaque will grow. The unpredictability of plaque progression is probably related to fluctuations in risk factors and triggers, for example physical activity, mental stress, environmental temperature, smoking, infection, hydration, and arterial pressure; to heterogeneity of plaque histology; and to differences in the physical forces to which plaques are exposed.18 41 43 56 103

It is impossible to predict the time it will take the vulnerable plaque to become unstable, or the trigger that causes the plaque to rupture (i.e. mechanical stress, coronary vasospasm, widespread acute inflammatory endothelial activation, or the chronic inflammatory component of atherosclerosis). In a substantial percentage of culprit lesions, thrombosed plaques without detectable fissures were observed.29 In such cases, plaque vulnerability is probably caused by thrombogenic or high-risk blood and/or local pro-inflammatory cytokines that trigger thrombosis, sometimes even in the absence of inflammatory cell infiltration and a lipid core.

Rupture of the intimal surface of a plaque is the result of a combination of cellular processes that promote plaque instability, and of physical (haemodynamic) processes that influence the magnitude and distribution of stress on the plaque. The size of the thrombus that forms at the site of plaque rupture and the clinical consequences will depend on several key factors: the degree of plaque disruption (ulceration, fissure, or erosion) and substrate exposure as a major determinant of thrombogenicity at the local coronary artery site; the composition of the plaque; the magnitude of the stenosis; and the extent of platelet activation and intrinsic fibrinolytic activity.47

Plaque rupture is more common during various kinds of strenuous physical activity and emotional stress.111 Activation of the sympathetic nervous system in these situations leads to increased plasma concentrations of catecholamines, blood viscosity, and of arterial pressure and heart rate, which are accompanied by detectable increases in platelet aggregation and decreases in fibrinolytic activity that both tend to favour thrombosis.60 This combination of increased prothrombotic and reduced fibrinolytic activity could initiate propagation and total occlusion of the coronary artery by a mural thrombus overlying a small plaque erosion that might otherwise have been harmless. The perioperative period is characterized by comparable adrenergic stimulation, and increased prothrombotic and reduced fibrinolytic activity.

In the event of plaque rupture, thrombus growth depends not only on the size and thrombogenicity of the fissured plaque, but also on the number and activation of exposed inflammatory cells.54 Inflammatory activation of the endothelium can turn its physiological vasodilatory and antithrombotic properties into pathological vasoconstrictor and prothrombotic properties. In addition, the inflammatory response of the circulating blood may activate coagulation.138 These many variables explain why coronary lesions that are angiographically fairly small may progress acutely to severe stenosis or total occlusion.

When intraluminal thrombi attach to a ruptured plaque, total occlusion of an epicardial coronary artery may occur resulting in total interruption of nutrient blood flow to the myocardium. The situation may be worsened by distal embolization of microthrombi and by coronary vasoconstriction caused by local mediator release or systemic sympathetic activation. If coronary blood flow is interrupted for longer than 30 min, a MI may result. Persistent coronary artery occlusion will cause a progressive increase in infarct size. Loss of functional myocardium results in impaired left ventricular function, which may impair quality of life, and usually leads to premature death.13

Any discussion of the aetiology of PMI must take into account the extreme variations in clinical presentation of ACS in general. At one end of the spectrum are those patients who suffer a sudden cardiac death or an MI without any preceding episode of angina, and not followed by recurrent instability. At the other end of the spectrum are those patients who develop an MI after episodes of unstable angina over a period of days to weeks, and who often develop post-infarction angina and/or re-infarction. It is conceivable that the triggers of instability differ between such groups of patients.

Perioperative MI
Aetiology
There is pathological and angiographic evidence that the aetiology of PMI resembles that in the non-surgical setting.21 30 In PMI, acute plaque disruption and haemorrhage in the infarct-related coronary artery seems to be common,21 30 106 but the severity of underlying coronary artery stenosis does not necessarily predict the infarct territory.30 The high incidence of histologically confirmed transmural infarctions21 seems to be in contradiction to the ECG finding of almost exclusively non-Q-wave PMIs. On the other hand, the presence of circumferential PMIs21 is consistent with a myocardial oxygen supply/demand mismatch being the main trigger of myocardial injury. However, myocardial oxygen supply/demand mismatch and plaque rupture are not mutually exclusive mechanisms, and MIs may develop by different mechanisms at different locations in the same patient.

Patients who experience a PMI have angiographic evidence of extensive coronary artery disease (CAD).39 Various angiographic findings were consistent with perioperative plaque rupture at sites other than critically narrowed coronary artery stenoses, as well as with the possibility that in some patients with severe but stable CAD, PMI might have developed primarily on the basis of prolonged myocardial ischaemia.39 85

Most (>80%) PMIs occur early after surgery, are asymptomatic,10 of the non-Q-wave type (60–100%),10 46 81 83 and are most commonly preceded by ST-segment depression rather than ST-segment elevation.80 82 95 107 124 127 Long-duration (single duration >20–30 min or cumulative duration >1–2 h) rather than merely the presence of postoperative ST-segment depression, seems to be the important factor associated with adverse cardiac outcome.81 107 126 ECG evidence of myocardial ischaemia was strongly associated with an initial postoperative low troponin level and conventional subsequent increases in serum troponin concentration.82 The frequent combination of increases in heart rate preceding the ischaemic episodes, ST-segment depression rather than elevation during all ischaemic episodes; non-Q-wave rather than Q-wave MIs in almost all cases; the lack of angiographically visible thrombus or ruptured plaques in some patients who underwent coronary angiography following PMI; and complete reversal of ECG changes to baseline in all but one of the patients with ischaemia (including those with infarction),85 are highly suggestive that prolonged stress-induced myocardial ischaemia is the likely primary cause of PMI. Repeated brief ischaemic episodes may well have a cumulative effect and ultimately cause myocardial necrosis.55

Although ST-segment depression usually reflects subendocardial ischaemia and is often regarded as reversible injury, it is not inconsistent with an MI. During the early evolution of an MI, significant ST-segment elevation may be lacking.74 For that reason, in current clinical practice, acute MI is divided into ST-segment and non-ST-segment elevation MI (which ultimately develop with little cross-over into Q-wave and non-Q-wave MI, respectively).74 In most studies on perioperative cardiac ischaemic events, the populations consisted largely of elderly patients. Thus, prolonged ST-segment depression may reflect ongoing myocardial ischaemia (ultimately leading to MI), or it may reflect the beginning of an evolving MI.

Not all investigations found an association between postoperative cardiac complications and long-duration ST-segment depression, or between changes in heart rate and postoperative ST-segment changes or troponin release. Such findings would suggest either non-ischaemic causes of ST-segment depression in the perioperative period (e.g. hyperventilation, electrolyte changes, drug effects, positional changes), compensatory mechanisms in response to myocardial ischaemia (e.g. preconditioning as a result of multiple brief episodes of myocardial ischaemia and coronary reperfusion), or functional collateral perfusion.46 137

The preponderance of non-Q-wave infarctions is clearly different from the non-surgical setting. This again might suggest that PMIs are more often the result of prolonged ischaemia than of thrombotic occlusion, similar to the presumed pathophysiology of silent ischaemia.141 However, presence or absence of a Q-wave are not determined primarily by presence or absence of an MI or by the transmural nature of the underlying MI but rather by the total size of the MI.7 112 The probability of a Q-wave infarction increases with MI size and the number of transmural segments. Transmural infarctions were of the non-Q-wave type in 29% of 100 consecutive patients with documented previous MI.112 In addition, the Q-wave takes time to develop and, accordingly, does not figure strongly in present acute-management decisions.

In the presence of severe but stable CAD, coronary thrombosis may result from a decrease in coronary blood flow and stasis.52 53 Some patients with stenotic atherosclerotic lesions may develop acute MI without evidence of plaque rupture and superimposed thrombus formation. This may happen if there is a marked decrease in myocardial oxygen supply (e.g. prolonged severe coronary vasospasm), or a marked increase in myocardial oxygen demand (e.g. tachycardia). It is thus conceivable that coronary thrombosis in the postoperative setting can be the consequence rather than the cause of prolonged myocardial ischaemia and PMI.

Most ischaemic episodes tend to start at the end of surgery and during emergence from anaesthesia.85 This period is characterized by increases in heart rate, arterial pressure, sympathetic tone, and procoagulant activity.16 Increased sympathetic tone can result in increases in arterial pressure, heart rate, contractility, coronary vasomotor tone, and coronary vascular shear stress. This, in turn, may trigger coronary vasospasm, plaque disruption, and coronary thrombosis. Increases in arterial pressure, heart rate, and cardiac contractility lead to subendocardial ischaemia by increasing myocardial oxygen demands in the presence of limited or absent coronary vasodilator reserve as a result of underlying CAD. Surgery-induced simultaneous procoagulant and anti-fibrinolytic activity may trigger coronary artery thrombosis during low-flow conditions in the presence of underlying stable CAD even in the absence of acute plaque disruption.

The ultimate fate of the thrombus and, thus, the extent of jeopardized myocardium will depend on the duration and degree of coronary occlusion. If the plaque disruption is major with extensive exposure of thrombogenic core material to the blood stream, acute total coronary occlusion with subsequent MI, or sudden death may develop. If the disruption is minor, the forming thrombus can be non-occlusive and the patient may stay asymptomatic or develop unstable angina or a non-Q-wave infarction. A concomitant increase in coagulability and coronary vasoconstriction (as is common in the perioperative setting) may, however, transform a non-occlusive thrombus to an occlusive thrombus. Ultimately, the balance between thrombosis and thrombolysis, and the flow conditions (affected by coronary vasomotor tone, perfusion pressure, and rheological properties) are the decisive factors in determining whether the clinical outcome will be myocardial ischaemia or an MI.

Diagnosis
A satisfactory explanation of the aetiology of PMI depends greatly on reliable data on the association between various variables and the occurrence of PMI. Such data can only be obtained if the detection of PMI is quantitatively and qualitatively reliable. However, fundamental questions remain regarding the definition and diagnostic criteria of MI in general,5 and perioperatively in particular.97 According to the definition of the World Health Organization (WHO), at least two of three criteria must be fulfilled to diagnose MI: (i) typical ischaemic chest pain; (ii) increased serum concentration of creatine kinase (CK)-MB isoenzyme; and (iii) typical electrocardiographic findings, including development of pathological Q-waves.152 160 Perioperative MI is mostly silent, and the electrocardiogram (ECG) is often difficult to interpret and frequently does not exhibit characteristic ST-segment elevation or Q-waves.17 85 Therefore, if the diagnosis of MI is based solely on the classical triad, considerable under-reporting of the true incidence of PMI is to be expected, possibly obscuring the aetiology of PMI.

The development of assays for the cardiac troponins T (cTnT) and I (cTnI) that are highly specific and sensitive for myocardial injury formed the basis of a revised definition of MI as proposed by the European Society of Cardiology and the American College of Cardiology.4 150 Either of the two following criteria satisfy the diagnosis of an acute, evolving, or a recent MI: (1) typical rise and gradual fall in cardiac troponin concentrations or more rapid rise and fall of CK-MB concentration in combination with at least one of the following: (a) typical ischaemic symptoms, (b) development of pathological Q-waves in the ECG, (c) ECG changes indicative of myocardial ischaemia (ST-segment elevation or depression), or (d) coronary artery intervention; and (2) pathological findings of an acute MI.

Debate continues as to the appropriate cut-off values of troponin concentrations for defining a clinically relevant MI. Initial cut-off values (cTnI >1.5 ng ml–1 and cTnT >0.1 ng ml–1 for certain assays) were derived from titration of troponin concentrations to a population of patients with clinically diagnosed MI. However, even small increases in serum concentrations of cardiac troponins are associated with adverse cardiac outcome in patients with or without ST-segment elevation ACS.73 92 Considering the high specificity of cardiac troponins for myocardial cell injury, the recent consensus document of the European Society of Cardiology and the American College of Cardiology Committe on the re-definition of MI states that in the presence of documented myocardial ischaemia, even minor increases in troponin serum concentration to greater than the 99th percentile of the normal population should be regarded as MI. As most troponin assays still lack adequate precision at such low concentrations, slightly higher cut-off values based on <10% imprecision are recommended.4 150

In the frequent absence of typical symptoms and ECG signs of acute MI, the diagnosis of PMI has to rest heavily on changes in biochemical markers. Cardiac troponins appear to be better suited to identify PMI than the CK-MB isoenzyme.1 85 88 110 The first study using cTnT in the diagnosis of PMI utilized a cut-off value for cTnT serum concentration of 3.1 ng ml–1.1 Subsequent studies utilized cut-off values of 0.2 and 0.1 ng ml–1,88 95 and as low as cTnI >0.6 and/or cTnT >0.03 ng ml–1.82 The following example will demonstrate the dilemma of defining the ‘correct’ incidence of PMI. In the same study,82 depending on the biochemical marker and the cut-off values, the overall incidence of PMI varied between 2.8% (CK-MB >10%), 9% (conventional cut-off values of cTnI >1.5 ng ml–1 and/orcTnT >0.1 ng ml–1), and 23% (low level cut-off values of cTnI >0.6 and/or cTnT >0.03 ng ml–1). Only 5.6% of patients fulfilled the revised definition of MI (presence of at least two of three criteria: prolonged chest pain, elevated CK-MB of cTn, ischaemic ECG changes). However, without routine measurements of serum concentrations of biochemical markers and continuous ECG monitoring for 3 postoperative days, MI would have been diagnosed in only those 3.6% of patients who experienced prolonged chest pain or symptoms of congestive heart failure. Similarly, whereas 12% of patients had increased cTnT concentrations during routine postoperative monitoring, only 3% had a PMI by the WHO definition.78

The question remains whether a reported incidence of perioperative myocardial injury based on traditional definition underestimates the true incidence of clinically relevant myocardial injury, or whether a reported incidence based on serum concentrations of cardiac troponins overestimates it. When using exclusively biochemical markers, specificity may be sacrificed for sensitivity.5 117 Another question is whether biochemical marker-defined myocardial injury carries the same predictive value as traditionally defined infarctions, and whether mechanisms and triggers are identical in both cases. Irrespective of whether one refers to small increases in serum concentrations of troponin as ‘myocardial infarction’ or ‘subclinical myocardial injury’ or ‘at risk’, even minor increases in serum concentrations of troponins (cTnI >0.6 and/or cTnT >0.03 ng ml–1) and CK-MB (CK>170 iu and CK-MB/total CK >5%) during the first 3 postoperative days were associated with approximately 50–100% increases in long-term mortality following major vascular surgery (follow-up period 1–5 years, mean 32 months).86 Larger, conventional increases in troponin concentration (cTnI >1.5 and/or cTnT >0.1 ng ml–1) and CK-MB (CK >170 iu and CK-MB/total CK >10%) were associated with 2-fold and almost 4-fold higher long-term mortality, respectively.86 Postoperative increases in cTnT >0.1 ng ml–1 correlated with postoperative cardiac events (admission for unstable angina, non-fatal MI, cardiac death) within the first 6 months following non-cardiac surgery;95 postoperative increases in cTnT more than 0.02 ng ml–1 conferred a 15-fold increase in 1-yr mortality in elderly patients undergoing non-cardiac surgery;123 and routine cTnI measurements during the first 3 postoperative days enabled prediction of all cause mortality within the first 6 months following vascular surgery.78 Furthermore, prolonged postoperative myocardial ischaemia and increases in postoperative cardiac troponin concentrations correlated strongly.85 86 Postoperative myocardial ischaemic episodes of more than 30 min and more than 60 min were, in turn, associated with 2.6- and 3.7-fold increases in long-term mortality, respectively.86 Taken together, existing evidence clearly suggests that even small increases in serum concentrations of cardiac troponins in the perioperative period reflect clinically relevant myocardial injury with short- and long-term consequences on outcome. Perioperative measurements in high-risk patients enable prompt initiation of appropriate diagnostic and therapeutic measures, which may affect long-term cardiac outcome.

Summary
Thus, the aetiology of PMI remains poorly understood.80 98 132 Existing data are inconclusive and do not allow a definitive decision on whether long-duration subendocardial myocardial ischaemia or acute coronary occlusion as a result of plaque disruption or thrombosis is the primary mechanism of perioperative MI in the individual patient. This uncertainty is to be expected considering the enormous structural and functional diversity of coronary atherosclerosis, the unpredictability of plaque progression and vulnerability, and the outstanding methodological problems of reliably detecting and diagnosing perioperative myocardial ischaemia and infarction. Plaque transformation from the stable to the vulnerable state can be acute. Widespread waxing and waning of coronary inflammation and/or of systemic blood thrombogenicity may contribute to the development of plaque vulnerability, in the absence or presence of underlying structurally vulnerable plaques. Some patients may remain vulnerable for a period of weeks to months. In such (chronically) inflamed patients it is possible that plaques will suddenly flare up and become unstable, even in the absence of inflammatory cell infiltration and a central lipid core. Plaque rupture may occur without clinical manifestations (silent plaque rupture).


    Prevention of perioperative MI
 Top
 Abstract
 Introduction
 Aetiology of PMI
 Prevention of perioperative MI
 Conclusions
 Addendum
 References
 
Two principal strategies have been used in an attempt to reduce the incidence of PMIs and other cardiac events and complications: preoperative coronary revascularization, and pharmacological treatment.

Preoperative coronary revascularization
Controversy remains as to the appropriate management of patients identified preoperatively as having relevant but correctable CAD. The effectiveness of preoperative coronary revascularization in this population continues to be debated. Proponents of ‘prophylactic’ coronary revascularization in selected patients argue that it improves both perioperative as well as long-term outcome.25 37 48 64 82 118 134 Opponents of this approach point out that morbidity and mortality of percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) in high-risk elderly vascular patients are substantial and outweigh any benefit; that recovery from such major morbidity substantially delays and even prevents the surgery for which the intervention was undertaken; that it does not differentiate between young and old age and between patients with symptomatic CAD and those with CAD discovered by cardiac stress testing only; that only survivors of coronary revascularization are included in the various reports; and, most importantly, that no prospective randomized trial exists to date that demonstrates the effectiveness of preoperative coronary revascularization in improving short- and long-term cardiac outcome and mortality in high-risk patients undergoing high-risk surgery.27 58 67 104 109 146

Preoperative coronary angiography
Coronary angiography in approximately 25% of patients with positive dipyridamole-thallium scintigraphy (DTS) followed by coronary revascularization in roughly a third of those undergoing coronary angiography was associated with improved perioperative cardiac outcome following vascular surgery compared with patients not subjected to such invasive preoperative cardiac evaluation and treatment.105 However, this benefit was entirely offset by two MIs and three deaths occurring during invasive cardiac evaluation. As a result, there was no statistically significant difference between patients who did and those who did not undergo extensive preoperative cardiac evaluation and coronary intervention in overall early and late non-fatal and fatal MI and cardiac death. These and similar findings suggest that in many patients with positive DTS undergoing high-risk surgery, coronary angiography does not necessarily confer additional useful information or benefit.

Preoperative percutaneous intervention
Data from randomized controlled trials on the effectiveness of PCI on postoperative cardiac outcome are lacking. All we have are data from retrospective analyses.

Percutaneous transluminal coronary angioplasty. Following preoperative percutaneous transluminal coronary angioplasty (PTCA) in patients undergoing non-cardiac surgery, the reported incidences of non-fatal PMI and perioperative cardiac death were low.2 40 58 67 However, neither of these studies is of adequate size or design to allow any conclusion regarding the effectiveness of preoperative PTCA. None of these reports contained control groups of patients with CAD that were not subjected to preoperative PTCA. In a retrospective, case-matched study, preoperative PTCA was associated with reduced overall perioperative cardiac events when compared with patients with CAD that had not undergone PTCA.131 However, the overall reduction in cardiac events was because of a reduction in the incidence of angina pectoris and congestive heart failure but not in non-fatal PMI and mortality. Furthermore, if PTCA had been performed less than 90 days before surgery, any potential benefit was lost.

Coronary stenting. Patients who have recently been subjected to coronary stenting run a high risk of suffering a PMI and serious bleeding.72 156 162 Of 40 patients who underwent coronary stenting within 6 weeks of major non-cardiac surgery, seven suffered a PMI, 11 experienced major bleeding, and eight died.72 All PMIs, deaths, and haemorrhages occurred in patients who had undergone stenting within 14 days of surgery. Fatal cardiac events were mostly caused by stent thrombosis (likely a result of interruption of antiplatelet medication 1–2 days before surgery). In contrast, severe bleeding occurred in patients whose antiplatelet medication was continued.

Eight (4%) of 207 patients undergoing non-cardiac surgery in the 2 months following successful coronary stenting suffered major cardiac events (non-fatal PMI one, fatal PMI two, deaths six).162 All of these eight patients were among those 168 patients who underwent surgery within 6 weeks of stent placement. No major complication was observed in the 39 patients who had surgery 7–9 weeks after stent placement.

Preoperative surgical coronary revascularization
Numerous reports include a substantial number of patients who underwent high-risk vascular surgery following CABG.37 48 64 84 134 Unfortunately, no prospective, randomized trial exists on the effect of preoperative CABG on cardiac outcome. Several retrospective studies,25 37 45 48 118 and one prospective non-randomized study82 have suggested that in survivors of preoperative CABG surgery, perioperative morbidity and mortality of subsequent major non-cardiac surgery is comparable with patients without clinical evidence of CAD. In a retrospective analysis of 3368 operations in patients enrolled in the Coronary Artery Surgery Study registry, prior CABG improved outcome in major non-cardiac surgery (abdominal, thoracic, vascular, head, and neck).37 Compared with medically treated patients, the perioperative event rate was lower in patients who had previously undergone CABG (PMI 0.8 vs 2.7%, mortality 1.7 vs 3.3%). The event-lowering effect of CABG was most pronounced in patients with advanced angina and/or multi-vessel CAD. No difference in cardiac outcome was observed during minor surgery. Although these findings seem to suggest a cardioprotective effect of preoperative CABG in patients with CAD undergoing major non-cardiac surgery, the analysis did not take into account the added risks of coronary angiography and myocardial revascularization.

Timing of non-cardiac surgery following CABG may be crucial. In a retrospective, case-control study, patients who underwent high-risk vascular surgery within 1 month of CABG had a higher mortality and a trend towards a higher incidence of MI than those undergoing surgery at a later date.15 This confirms previous findings of increased mortality associated with simultaneous CABG and vascular surgery,134 or with non-cardiac surgery within 1–6 months of CABG compared with surgery performed later than 6 months following CABG.26

Risk calculation in preoperative coronary revascularization
In the individual patient, the combined risk of preoperative coronary interventions (coronary angiography, PCI, or CABG) and scheduled non-cardiac surgery may well exceed the perioperative risk of non-cardiac surgery alone in patients without prior CABG. Any potential benefit of preoperative coronary revascularization will be restricted to those patients who survived the preoperative coronary evaluation and revascularization.

In patients with peripheral vascular disease, in-hospital and long-term outcomes (MI, transient ischaemic attack, stroke, bleeding complications) following PCI were substantially worse and procedural success lower than in patients without peripheral vascular disease.142 In such a patient population, coronary angiography was associated with an incidence of MI and mortality of 0.07–0.25% and 1.0–2.5%, respectively.104 Percutaneous intervention and CABG carry a 3–10% risk of MI, and a mortality of 1–2.5% and 2–8.5% (depending on urgency of CABG), respectively.104 121 Depending on the type and extent of CAD, vascular surgery alone is associated with an incidence of PMI of 0.5–15% and a mortality of 0.8–20%.104

It is obvious from these numbers that in individual patients overall perioperative cardiac morbidity and mortality may well be lower when undergoing vascular surgery without prior coronary revascularization. Decision analysis suggested that on average, vascular surgery without preoperative coronary intervention results in better perioperative outcome.104 However, the overall long-term outcome might well be comparable because those patients who did not undergo preoperative coronary angiography and coronary revascularization will be faced at some time postoperatively with just those coronary interventions and their associated risks. In addition, there is evidence that the results of PCI in high-risk patients has improved in recent years.142 This is likely a result of more routine coronary stenting, increased use of drug-eluting stents and stents that are easier to deploy, and advances in pharmacotherapy.12 It is conceivable that such advances might shift the risk/benefit balance towards preoperative PCI.

Recommendations for preoperative coronary angiography
In general, indications for preoperative coronary angiography are similar to those in the non-operative setting. The Class I recommendations for preoperative coronary angiography are accordingly restrictive, apply only to patients with suspected or known CAD and include: (i) evidence for high risk of adverse outcome based on non-invasive test results; (ii) angina pectoris unresponsive to adequate medical therapy; (iii) unstable angina, particularly when facing intermediate or high risk non-cardiac surgery; and (iv) equivocal non-invasive test results in patients at high clinical risk undergoing high risk surgery.34 35

Recommendations for preoperative coronary intervention
In view of the considerable risk of percutaneous intervention in high-risk patients, it is highly unlikely that prophylactic PCI to merely ‘get the patient through surgery’ will reduce the incidence of PMI. PCI with or without stenting should thus be reserved for patients who have a medical indication for such intervention unrelated to surgery.

PTCA. The indications for preoperative PTCA are identical to those in the non-operative setting.144 Following balloon angioplasty without coronary stenting, surgery should be delayed for at least a week.34 35 This is beyond the time period of within hours to days of the intervention during which arterial recoil and acute thrombosis at the site of angioplasty are most likely to occur, and it allows healing of the vessel injury at the site of balloon treatment.

Coronary stenting. Stent thrombosis is a serious complication and mostly results in Q-wave infarction or death.28 In patients not undergoing surgery, stent thrombosis most commonly occurs within hours to days of stent placement.28 Dual antiplatelet medication with a thienopyridine (mostly clopidogrel) and aspirin reduces the incidence of early stent thrombosis to less than 1%.163 The risk of stent thrombosis diminishes with re-endothelialization of the initially completely denuded endothelial surface. Re-endothelialization occurs within approximately 8 weeks of placement of the stent.153 On the other hand, re-stenosis may develop by 6–8 weeks after stent placement. If, however, re-stenosis has not occurred by 8–12 months after PCI (with or without stent), it is unlikely to develop thereafter.

If a coronary stent is placed, elective non-cardiac surgery should be delayed for an absolute minimum of 2 weeks, but ideally for 4–6 weeks.34 35 162 This delay will allow completion of a course of dual antiplatelet medication (which reduces the incidence of early stent thrombosis), and allow bare metal stents to be endothelialized.

Today, however, stents eluting antiproliferative drugs, which delay endothelialization are increasingly being placed.44 As this may well increase the risk of early and late stent thrombosis, a 6–12-month period of antiplatelet treatment has been recommended.61 Thus, conclusions drawn from, and recommendations based on, previous reports72 156 162 apply to bare metal stents only. This caveat is emphasized by a recent Letter to the Editor.8 Twelve weeks after having simultaneously received a bare metal stent and two paclitaxel-eluting stents accompanied by antiplatelet therapy with clopidogrel and aspirin, antiplatelet drugs were discontinued before knee surgery. Immediately postoperatively, the patient suffered a PMI. Coronary angiography revealed total occlusion of both paclitaxel-eluting stents but an open bare metal stent. This single report would suggest that following placement of a drug-eluting stent, it might be safer to postpone elective surgery for several months rather than weeks.

The matter becomes even more complicated because there is preliminary evidence to suggest that the rate of re-endothelialization differs between drugs being eluted from the stent. Antiplatelet therapy may have to be continued for a longer period of time following placement of a paclitaxel-eluting stent (possibly for 6 months) than following placement of a sirolismus-eluting stent (possibly 2–3 months).

If patients require elective non-cardiac surgery within 2 months of PCI, there are several options. If surgery (and the surgeon) allows dual antiplatelet therapy (mostly clopidogrel and aspirin) to be continued perioperatively, a drug-eluting stent can be placed. If surgery (or the surgeon) does not allow perioperative continuation of dual antiplatelet therapy, a drug-eluting stent should probably not be used. In such a case, heparin- or phosphorylcholine-coated stents may possibly reduce the risk of stent thrombosis in the absence of clopidogrel. This possibility is, however, not supported by any data. Under certain circumstances, PTCA without stent placement may be the most appropriate option. Needless to say, the choice for the type of stent (bare metal vs drug eluting vs coated) and the type of PCI (angioplasty with or without stenting) rests entirely with the interventionalist. However, as the anaesthetist will be involved in the perioperative management of these high-risk patients, and as the perioperative period differs considerably from the non-operative setting, the interventionalist may benefit from the anaesthetist's knowledge and feedback. Close preoperative consultation between interventionalist and anaesthetist is required to minimize the risk of perioperative cardiac and overall morbidity and mortality.

Recommendation for preoperative surgical coronary revascularization
The indications for preoperative surgical coronary revascularization are essentially identical to those in the non-operative setting.36 62 They include patients with: (i) acceptable coronary revascularization risk and suitable viable myocardium with left main stenosis; (ii) three-vessel CAD in conjunction with left ventricular dysfunction; (iii) two-vessel disease involving severe proximal left anterior descending artery obstruction; and (iv) intractable coronary ischaemia despite maximal medical therapy. If major non-cardiac surgery is indicated following recent CABG, timing appears crucial. Limited data would suggest postponing elective major surgery for at least 4–6 weeks,15 134 151 possibly for even up to 6 months after CABG.26

Conclusions
Thus, prospective, randomized investigations on the effect of preoperative coronary revascularization on short- and long-term cardiac and overall outcome do not exist. Survivors of coronary revascularization tend to have a better perioperative and long-term cardiac outcome than patients with comparable CAD without preoperative coronary revascularization.

However, in this analysis the high cardiac morbidity and mortality associated with preoperative coronary angiography and coronary revascularization (PCI or CABG) in high-risk patients are not taken into account. In addition, survivors of PCI face the perioperative risk of coronary (stent) thrombosis or haemorrhage associated with discontinuation or continuation of dual antiplatelet therapy, respectively. Overall outcome may thus be comparable between preoperatively revascularized and non-revascularized patients—it may be even worse in individual revascularized patients. The decision for or against preoperative coronary revascularization, and for or against PCI or CABG, should therefore be based entirely on universally accepted medical indications for coronary revascularization and the appropriate technique. The philosophy of performing preoperative coronary revascularization merely ‘to get the patient through surgery’ is contrary to all available evidence. If the decision for preoperative coronary revascularization is made, timing with respect to the subsequent surgery appears crucial. If these caveats are being observed, it is conceivable that carefully selected patients might benefit from preoperative coronary revascularization. However, only prospective randomized trials can tell.

Pharmacological treatment
Beta-blockers
Perioperative ß-blocker therapy has been listed as a ‘top-tier’ patient safety practice by the Institute of Medicine.140 Several prospective and retrospective studies suggest that perioperative ß-blockade improves cardiac outcome in patients with or at risk CAD,100 157 and in patients with documented inducible myocardial ischaemia undergoing non-cardiac surgery.14 129 130 It has been suggested that ß-adrenoceptor-antagonists (‘ß-blockers’) should be administered to almost all patients with one or more factors that are known to be associated with a higher perioperative cardiac risk.76

Rationale for the use of perioperative ß-blocker therapy. Numerous cardiovascular and other effects (anti-arrhythmic, anti-inflammatory, altered gene expression and receptor activity, protection against apoptosis) of ß-blockers may account for their cardioprotective effect in the operative and non-operative setting.6 70 94 All ß-blockers, except those with intrinsic sympathetic activity, reduce mortality in both MI,51 57 143 and heart failure patients.68 149 Randomized clinical trials involving more than 24 000 patients have shown that ß-adrenoceptor-antagonism (‘ß-blockade’) reduces post-myocardial infarction mortality, probably by a reduction in infarct size and ventricular arrhythmias.147 On the basis of such data it seems logical that perioperative ß-blocker therapy should be beneficial during the period of perioperative stress.

Activation of the hypothalamus–pituitary–adrenal axis persists for at least 1 week following surgery. Adrenal cortical stimulation is accompanied by sympathetic nervous system-induced adrenal medullary activation, resulting in the release of catecholamines with subsequent stimulation of adrenergic receptors. Adrenergic receptors are located in virtually every organ. In the human heart, they mediate numerous biological responses, including inotropy, chronotropy, myocyte apoptosis, and direct myocyte toxicity.

Catecholamines increase each of the four determinants of myocardial oxygen consumption (i.e. heart rate, preload, afterload, and contractility). ß-Blockers have the potential of reducing myocardial O2 consumption (thus improving the myocardial O2 supply/demand balance) by decreasing sympathetic tone and myocardial contractility, in turn resulting in decreases in heart rate and arterial pressure. Furthermore, they decrease ß2-adrenoceptor-mediated release of intracardiac norepinephrine during ischaemia (reducing cardiac toxicity); they attenuate exercise-induced coronary vasoconstriction (improving exercise capacity); and they have antiarrhythmic properties (increasing the threshold for ventricular fibrillation during myocardial ischaemia).

Effect on perioperative cardiac mortality. The effect of perioperative ß-blocker therapy on cardiac outcome has been assessed in two, much discussed studies.100 130 In a randomized, double-blind, placebo-controlled study, the benefit of perioperative atenolol in patients with or at risk for CAD undergoing major non-cardiac surgery under general anaesthesia was examined.100 Atenolol (n=99) or placebo (n=101) were started intravenously approximately 30 min before induction of anaesthesia and continued until hospital discharge or for up to 7 days postoperatively. Outcome variables included cardiac death (death because of MI, dysrhythmia, or congestive heart failure), and cardiac events (non-fatal MI, unstable angina and/or congestive heart failure requiring admission and treatment, myocardial revascularization) during the 2 yr following hospital discharge (i.e. in-hospital cardiac morbidity and mortality were not included in the analysis). Over the 2-yr follow-up period, overall mortality after hospital discharge was significantly lower in the atenolol (10%) than in the placebo group (21%, P=0.019). This amounts to a relative risk reduction of 55%. The main reason for this difference was a reduction in cardiac deaths during the first 6 months in the atenolol-treated patients. The combined cardiovascular outcomes were similarly reduced in the atenolol group.

The study has been criticized on numerous grounds. (i) Only those adverse events were included in the analysis that occurred after hospital discharge when patients had stopped taking ß-blockers. However, four patients in the atenolol, and two patients in the control group died during hospitalization. It is inappropriate to exclude these in-hospital events from the overall analysis. If they are included, the difference in deaths between the atenolol (n=13) and the placebo group (n=23) loses statistical significance (P=0.1). (ii) The potential for acute ß-withdrawal symptoms in the control group cannot be excluded. Eight patients on chronic ß-blocker medication were acutely taken off their ß-blockers when they were randomized to the control group. Thus, acute ß-withdrawal symptoms could possibly have contributed to the less favourable outcome in the placebo group. (iii) Approximately 40% of patients did not tolerate the full dose, and roughly 15% did not tolerate atenolol at all. (iv) Female gender was under-represented. (v) The exact number of patients with intermediate rather than high risk for adverse perioperative cardiac outcome was not specified. (vi) There was a trend towards a more severe cardiac history (previous MI, angina, diabetes, coronary revascularizations, advanced age) in the placebo group, and a trend towards more effective cardiac therapy (i.e. ß-blockers, angiotensin-converting enzyme inhibitors) at hospital discharge in the atenolol group. Given the many study limitations (mainly the overall small number of events, the unrealistically high treatment effect of 55% and no statistically significant difference between groups when in-hospital deaths are included), one has to question the appropriateness of the recommendation for perioperative ß-blocker therapy by the American College of Physicians that was based on this study.125

A subsequent study looked at the benefit of perioperative bisoprolol in patients with documented CAD (diagnosed by new wall motion abnormalities on dobutamine stress echocardiography) undergoing major vascular surgery.130 1351 patients undergoing elective major vascular surgery were screened for cardiac risk factors (age over 70 yr, angina, prior MI, compensated or a history of congestive heart failure, current treatment for ventricular arrhythmias, current treatment for diabetes mellitus, limited exercise capacity). 846 of the 1352 patients had at least one of these cardiac risk factors and were, in turn, screened for a positive dobutamine stress echocardiogram (DSE). Of the 846 patients, 173 had a positive DSE. Of these, 61 were excluded from further study because of either extensive wall motion abnormalities on DSE, strong evidence on DSE for left main or severe three-vessel CAD, or because they were already taking ß-blockers. The remaining 112 patients were randomized to receive either bisoprolol (n=59) or ‘standard care’ (n=53). Bisoprolol was started on average 37 (range 7–89) days before surgery and was continued for 30 days postoperatively. Outcome variables included cardiac death and non-fatal MI during the first 30 days following surgery. The authors reported a 10-fold lower rate of perioperative cardiac events in the bisoprolol group compared with the ‘standard care’ group (3.4 vs 34%; P=0.001).

Although the results strongly suggest that patients with documented CAD disease undergoing high-risk surgery benefit from perioperative ß-blockade, this investigation also has several limitations: (i) the study included only 112 patients and a total of merely 20 events. In view of the small sample size, the possibility cannot be ruled out that the observed 90% relative reduction in 30-day adverse outcome occurred by chance alone. The number of 3.2 needed to treat for prevention of PMI and mortality is 10-fold lower than a meta-analysis-derived number of 42 for secondary prevention after MI in the medical setting.9 51 (ii) The trial was terminated early because the interim analysis had suggested a large treatment effect. However, unexpectedly large beneficial effects suggested by studies that are terminated early are cause for scepticism.159 (iii) Treatment was not blinded. (iv) Standard care (given to the control group) was not defined. (v) The study population was highly selective: of the 1351 initially screened patients, only 112 (8%) were eventually included in the actual study. Thus, the results are not necessarily representative of a broader patient population. (vi) Patients with severe CAD were excluded. (vii) Finally, the 34% complication rate in the standard care group (nine cardiac deaths, nine MIs) is rather high. A high complication rate in the control group generally tends to favour the treatment group. Despite the various limitations, the accompanying editorial87 stated that ‘... In the absence of major contraindications therapeutic doses of beta-adrenergic antagonists should be given to patients with an intermediate or high risk of cardiac complications’.

Unanswered questions
The repeated recommendations for perioperative ß-blockade in patients with suspected or documented CAD71 87 125 is mainly based on the findings of those two prospective, randomized controlled trials in a little over 300 patients. Several unanswered questions remain.

Should ß-blockers be administered together with other sympatholytic therapies? The safety of simultaneously administering ß-blockers in patients receiving thoracic epidural anaesthesia or {alpha}2-adrenergic agonists has not been established. It is conceivable that the interaction between treatments causes an unacceptably high incidence of bradycardia and hypotension, counteracting any potential cardioprotective effect of ß-blocker therapy. At present, it remains unknown whether it is necessary to add ß-blockers to treatments like {alpha}2-adrenergic agonists that have themselves demonstrated cardioprotection in the perioperative period.158 161

Is there a ß-blocker of choice for perioperative ß-blocker therapy? Blocking or blunting the perioperative adrenergic stress response is most likely the key pathophysiological intervention that associates perioperative ß-blocker therapy with improved cardiac outcome. Therefore, although not proven yet, it is rather unlikely that pharmacological differences between ß-blockers (e.g. in receptor selectivity and affinity, lipophilicity, intrinsic sympathomimetic activity) have any impact on efficacy and safety of treatment. Choice of the ß-blocker should be based on those, admittedly very few, controlled randomized trials that have demonstrated effectiveness of perioperative ß-blocker therapy.100 130 Any cardioselective ß-blocker (such as atenolol, bisoprolol, or metoprolol) is probably an acceptable choice.

When should perioperative ß-blockade be started? Perioperative cardioprotection was demonstrated when the medication had been initiated either weeks before the scheduled surgery,130 or as late as during premedication148 and induction of anaesthesia.100 The recently revised ACC/AHA guidelines on perioperative cardiovascular evaluation for non-cardiac surgery34 recommend that in patients with Class I indications for perioperative ß-blocker therapy (see below), ß-blockers be started days or weeks before elective surgery. This makes sense as it will allow titration of theß-blocker to the targeted heart rate.

What should be the therapeutic goal? It is assumed that cardiovascular and sympathetic suppression is required to produce cardiac protection. The extent of such suppression is difficult to assess clinically. Basically all studies on the perioperative use of ß-blockers have, therefore, taken heart rate as a physiological surrogate of sympathetic tone.100 130 Preoperatively, ß-blockers were titrated to achieve heart rates between 50 and 60 beats min–1.130 Postoperatively, heart rates of less than 80 beats min–1100 130 154 or 20% below the preoperative ischaemic threshold133 were aimed at. The revised ACC/AHA Guidelines recommend that the preoperative dose is titrated to achieve a resting heart rate between 50 and 60 beats min–1.34

For how long should ß-blocker therapy be continued postoperatively? In the two main controlled, randomized trials on the effectiveness of perioperative ß-blocker therapy, ß-blockers were continued for up to a week100 and up to a month130 following surgery. In the latter study, following the initial study period of 30 postoperative days, the 101 survivors continued to receive either bisoprolol therapy (n=57) or standard care (n=44) according to their initial randomization.129 In the bisoprolol group, the dose was adjusted to achieve a heart rate between 50 and 60 beats min–1. Patients were followed for 11–30 months after surgery (median 22 months). Cardiac events (cardiac death and non-fatal MI) occurred in seven (12%) patients in the bisoprolol group and in 14 (32%) patients in the standard care group (P=0.025). These results suggest that long-term postoperative ß-blockade reduces the incidence of late cardiac events, certainly among survivors of major vascular surgery who had received perioperative ß-blockade.

It appears obvious that those patients with objective indications for the use of ß-blockers should continue ß-blocker therapy after hospital discharge. In patients without clear indications for long-term ß-blocker therapy, ß-blockers should probably be continued for at least the time of hospitalization, and preferably for up to 1 month postoperatively. In those patients in whom ß-blocker therapy is going to be discontinued after discharge, the dose should be tapered slowly to avoid acute withdrawal symptoms. In those patients in whom ß-blocker therapy is going to be continued after discharge, the dose should be adjusted as indicated.

Is there a risk of discontinuing perioperative ß-blockade? It is conceivable that acute withdrawal symptoms could develop when ß-blockade is abruptly discontinued in patients at increased cardiac risk who were started preoperatively on ß-blockers. Although neither of the controlled randomized trials reported such adverse effects of discontinuation ofß-blockers,100 130 results of a retrospective analysis in a small number of patients would suggest that discontinuation of ß-blockers in vascular surgery patients may be associated with an increased risk of postoperative morbidity and mortality.139 It thus seems advisable to discontinue ß-blocker therapy gradually (and only after a period of preferably 30 days postoperatively) in those patients considered not to have a clear indication for long-term therapy.

Is ‘routine’ chronic ß-blocker therapy continued perioperatively as effective as acutely initiated, closely monitored, heart rate-targeted perioperative ß-blocker therapy? Those 53 patients who were excluded from the bisoprolol study130 because they were already taking ß-blockers, subsequently underwent planned vascular surgery under continued but not specified ß-blocker therapy. In this subpopulation, the 30-day perioperative cardiac mortality was 7.5%, which is twice as high as that reported in the randomized part of the trial. These findings would suggest that perioperative ß-blocker therapy might be less effective when not closely monitored and strictly heart rate-targeted.

The total cohort of 1351 consecutive patients initially screened in the randomized trial on bisoprolol130 was retrospectively re-analyzed.14 360 (27%) patients received ß-blockers perioperatively, whereas 991 (73%) did not. Except for those 59 patients who were part of the randomized trial, ß-blocker management was not specified in those 360 patients. The perioperative cardiac event rate (non-fatal MI, cardiac death) was 2.2% (n=8) in the ß-blocker-treated patients (which is comparable with the 3.4% event rate reported in the randomized part of the trial), and 3.7% (n=37) in the non-ß-blocked patients (which is almost 10-fold lower than the 34% event rate reported in the randomized part of the trial). The finding of a comparably low perioperative cardiac event rate in this larger population of ß-blocked patients (who, presumably, were less intensively monitored than those patients who participated in the prospective, controlled trial) could be interpreted as suggestive evidence that ‘routine’ chronic ß-blocker therapy continued perioperatively is, in fact, as effective as acute, closely monitored, heart rate-targeted perioperative ß-blocker therapy.

Who should receive perioperative ß-blocker therapy? Of the 1351 patients initially screened in the randomized trial on bisoprolol, 1118 (83%) had at most one or two clinical risk factors (defined as age ≥70 yr, current angina, prior MI, congestive heart failure, prior cerebrovascular event, diabetes mellitus, renal failure).14 Among this subgroup of patients with relatively low cardiac risk, those receiving ß-blockers perioperatively had a significantly lower cardiac event rate (2/263 patients, 0.8%) than those not receiving ß-blockers (20/855 patients, 2.3%). Amongst a further subset of 375 patients with no clinical risk factor at all, cardiac event rates were comparably low between those receiving (0/48 patients, 0%) and those not receiving ß-blockers (4/327 patients, 1.2%).

In contrast, in the subgroup of 233 (17%) patients with more than/equal to three clinical risk factors, those receiving ß-blockers had a cardiac event rate of 6.2% (6/97 patients) compared with a cardiac event rate of 12.5% (17/136 patients) in those not receiving ß-blockers. Within this subgroup of patients with more than/equal to three clinical risk factors, 207 patients had four or fewer new wall motion abnormalities on dobutamine stress echocardiography. Those receiving ß-blockers perioperatively had a lower cardiac event rate (2/86 patients, 2.3%) than those not receiving ß-blockers (12/121 patients, 10.6%). However, in a further subgroup of 26 patients with more than/equal to three clinical risk factors and five or more new wall motion abnormalities on dobutamine stress echocardiography, there was no difference in the cardiac event rates between those receiving ß-blockers perioperatively (4/11 patients, 36%) and those not receiving ß-blockers (5/15 patients, 33%).

These data are based on retrospective analysis, treatments were neither controlled nor randomized or blinded, and the number of patients in some of the subgroups was too small to allow valid statistical analysis. Taking these limitations into due consideration, the results would suggest that in patients undergoing vascular surgery, perioperative ß-blocker therapy may possibly be beneficial in all but subsets of very low or very high risk patients. The findings would further suggest indirectly that aggressive ß-blockade in high-risk patients undergoing high-risk surgery may reduce the need for additional preoperative non-invasive cardiac testing, and coronary angiography and revascularization. It is likely that the combined morbidity and mortality from the three sequential procedures, coronary angiography, coronary revascularization and subsequent major vascular surgery, is higher than the 3.4% incidence of major cardiac complications in patients receiving perioperative bisoprolol.130 Only in a subset of patients with extensive myocardial ischaemia, may perioperative ß-blocker therapy not be sufficiently protective.14

Based on the results of various studies, the revised ACC/AHA Guidelines34 list several conditions as Class I indications for perioperative ß-blocker therapy (i.e. conditions for which there is evidence for and/or general agreement that the therapy is useful and effective): (i) the need for ß-blockers in the recent past to control symptoms of angina; (ii) patients with symptomatic arrhythmias or hypertension; and (iii) patients at high risk for a perioperative cardiac event based on the finding of myocardial ischaemia on perioperative testing who are undergoing vascular surgery. Class IIa indications for perioperative ß-blocker therapy (i.e. conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the performed therapy, with the weight of evidence/opinion in favour of usefulness/efficacy of the performed therapy) include preoperative identification of untreated hypertension, known CAD, or major risk factors for CAD.

When it comes to defining the contraindications for the use of ß-blockers, it is helpful to remember that the 2001 AHA/ACC Guidelines for secondary prevention of MI and death recommend to initiate ß-blockade in all post-MI patients and to continue such therapy indefinitely.143 They list as absolute contraindications for the use of ß-blockers symptomatic bradycardia (usually a heart rate <50–60 beats min–1), symptomatic hypotension (usually a systolic arterial pressure <90–100 mm Hg), severe heart failure requiring i.v. diuretics or inotropes, cardiogenic shock, asthma or reactive airway disease requiring bronchodilator and/or steroids, and 2° or 3° AV block.

Proposed algorithm for the use of perioperative ß-blocker therapy
An algorithm for the use of perioperative ß-blocker therapy based on various studies on perioperative ß-blocker therapy and preoperative risk stratification has been suggested.9 In high-risk patients with more than/equal to three major clinical risk factors (high-risk surgical procedure, CAD, cerebrovascular disease, insulin-dependent diabetes mellitus, chronic renal insufficiency) and a positive non-invasive cardiac stress test (DTS, DSE), additional coronary angiography and coronary revascularization should be considered because the perioperative cardiac event rate will remain in the 6.5–16% range even with perioperative ß-blocker therapy. In high-risk patients with negative non-invasive test results, and in clinically intermediate risk patients[1–2 major clinical risk factors or any of two minor risk factors100 such as age ≥65 yr, hypertension, current smoker, serum cholesterol ≥6.18 mmol litre–1 (≥240 mg dl–1), non-insulin-requiring diabetes mellitus] with good functional capacity and without evidence of angina or peripheral vascular disease, ß-blocker therapy is started preoperatively and surgery is performed as planned.

In clinically intermediate-risk patients with poor functional capacity and with evidence of angina or peripheral vascular disease, additional therapies and/or interventions (coronary angiography and revascularization) should be considered. Finally, in low-risk patients without clinical risk factors, the perioperative cardiac event rate is low with (0.4%) or without (0.4–1.0%) perioperative ß-blockade, so that perioperative ß-blockade is deemed unnecessary.

In conclusion, although perioperative ß-blocker therapy has been designated as one of 11 specific practices with sufficient clinical-based evidence for patient safety to justify immediate and widespread implementation,140 before a final recommendation for a liberal use of perioperative ß-blockade can be made safely, several caveats have to be kept in mind. All studies that support use of perioperative ß-blocker therapy have included rather small numbers of patients (as few as 26154). Often, recruitment of patients was highly selective and consecutive (recruitment rate as low as 8%130), excluding application of the results to an unselected surgical population. Furthermore, the beneficial effects were probably not only because of a rather aggressive therapy (targeted heart rates maximally 80 beats min–1), but also (and perhaps even more importantly) because of continuous close monitoring of the patient. This will ensure both optimal cardioprotection and patient safety. More uncontrolled but equally aggressive postoperative administration of ß-blockers on ordinary surgical wards might well result in more adverse side-effects, possibly negating any beneficial effects. Although current evidence suggests that selected patients are likely to benefit from perioperative ß-blocker therapy, we have to acknowledge that data on risks and benefits of such therapy are still few and inconclusive.32 A large definitive trial on perioperative ß-blocker therapy is needed.31 Until the results of such a trial are available, it seems fair to conclude: ‘Peri-operative ß-blockade: a useful treatment that should be greeted with cautious enthusiasm’.66

Alpha-2 adrenoceptor agonists
Alpha-2 adrenoceptor agonists improve cardiovascular morbidity and mortality following non-cardiac and cardiac surgery.33 108 119 122 158 161 In a prospective, randomized, double-blinded study in 190 patients undergoing non-cardiac surgery, prophylactic clonidine (0.2 mg orally and as dermal patch for 4 days) reduced perioperative myocardial ischaemia and improved 30-day and 2-yr mortality but had no effect on PMI.158 The long-term beneficial effect could have been a result of the reduction in perioperative myocardial ischaemia.

The mechanism of the protective effect is likely to be manifold. Alpha-2 adrenoceptor agonists attenuate perioperative haemodynamic instability,108 inhibit central sympathetic discharge,114 reduce peripheral norepinephrine release,38 and dilate post-stenotic coronary vessels.65

Aspirin
Early postoperative administration of aspirin improved outcome following coronary artery bypass surgery.99 Aspirin is known to reduce cardiac events in patients with ACS and in patients not known to have CAD.23 It eliminates the diurnal variation in plaque rupture.136 Compared with controls, patients with unstable angina had more than twice the blood concentrations of interleukin-6, CRP, and macrophage colony-stimulating factor.69 Those concentrations decreased after 6 weeks of aspirin treatment. Aspirin will, of course, reduce platelet aggregability, but its ability to reduce future MI appears greatest in individuals with serological evidence of increased inflammation.135 Thus, the anti-inflammatory effect of aspirin may be additive to its antithrombotic effect in patients with plaque instability. This effect may be of particular relevance in the perioperative setting.

Statins
Perioperative use of statins may be associated with reduced perioperative mortality in patients undergoing major vascular surgery.77 128 In a multicentre observational study including over 780 000 individuals, lipid-lowering therapy (primarily statins) during the first two days of hospitalization was associated with decreased mortality in patients undergoing non-cardiac surgery (2.13 vs 3.05% in non-treated patients).93 These findings are consistent with results of a cohort study in almost 20 000 patients with ACS.145 Patients who were taking statins when experiencing ACS had fewer MIs than patients not taking statins. Institution of aggressive statin therapy in patients with acute coronary syndrome resulted in reduced plaque volume at 6-month follow-up.120 It thus appears that statin therapy may modulate early pathophysiological processes during ischaemic cardiac events.

‘Pleiotropic’ effects of statins independent of their lipid-lowering action have been proposed as the mechanisms of their beneficial effects. These pleiotropic effects include reversal of endothelial dysfunction,91 155 modulation of macrophage activation,3 immunological effects,3 andanti-inflammatory,3 antithrombotic,155 and antiproliferative actions (possibly mediated by the induction of heme oxygenase-1).89 The direct effect of statins on vascular function may result in coronary plaque stabilization.

Miscellaneous preventive measures
Postoperative myocardial ischaemia has been shown to be associated with postoperative anaemia,116 hypothermia,49 50 and pain.11 101 All of them activate sympathetic tone with adverse effects on cardiovascular function and coagulation. The result will be an increase in myocardial oxygen consumption in the presence of a decrease in delivery. As perioperative myocardial ischaemia is a predictor of adverse short- and long-term cardiac outcome, maintenance of an appropriate haemoglobin concentration, normothermia, and adequate pain control are essential preventive measures.


    Conclusions
 Top
 Abstract
 Introduction
 Aetiology of PMI
 Prevention of perioperative MI
 Conclusions
 Addendum
 References
 
The aetiology of PMI is multifactorial. The perioperative period induces large, unpredictable and unphysiological changes in sympathetic tone, cardiovascular performance, coagulation and inflammatory response (to name just a few). These changes induce, in turn, unpredictable alterations in plaque morphology, function and progression. Simultaneous perioperative alterations in homeostasis and coronary plaque characteristics may trigger a mismatch of myocardial oxygen supply and demand by numerous mechanisms. If not alleviated in time, it will ultimately result in MI, irrespective of its aetiology (morphologically, haemodynamically, inflammatory, or coagulation induced). With these many and diverse factors involved, it is highly unlikely that one single intervention will successfully improve cardiac outcome following non-cardiac surgery. A multifactorial, step-wise approach is indicated.20 22 59 79 113

Based on increasing knowledge of the nature of atherosclerotic CAD, and in view of the poor positive predictive value of non-invasive cardiac stress tests and the considerable risk of coronary angiography and coronary revascularization in high-risk patients, the paradigm is shifting from an emphasis on extensive non-invasive preoperative risk stratification to an emphasis on a combination of selective non-invasive testing (to reliably identify those patients who truly benefit from preoperative intervention, such as cancellation of surgery, preoperative coronary revascularization, initiation or optimization of cardioprotective medication), and aggressive perioperative pharmacological therapy.59 63 Perioperative plaque stabilization by pharmacological means (statins, aspirin, ß-blockers) may be as important in the prevention of PMI as an increase in myocardial oxygen supply (by coronary revascularization), or a reduction in myocardial oxygen demand (by ß-blockers or {alpha}2-agonists).


    Addendum
 Top
 Abstract
 Introduction
 Aetiology of PMI
 Prevention of perioperative MI
 Conclusions
 Addendum
 References
 
Since preparation of the manuscript, the results of a randomized study were published which investigated the effect of preoperative coronary revascularization (by either percutaneous coronary intervention or bypass surgery) on long-term outcome in 510 patients undergoing vascular surgery.1 Patients with severe coronary artery disease, poor left ventricular function or severe aortic stenosis were excluded from randomization. At a median follow-up time of 2.7 yr, there was no difference in mortality between the revascularized and non-revascularized groups (22% and 23%, respectively). Twenty-four months after randomization, the vast majority of patients were taking beta-blockers (approx. 80%), statins (approx. 70%), aspirin (approx. 85%) and angiotensin-converting-enzyme inhibitors (approx. 55%). The results suggest that in patients with stable coronary artery disease and unimpaired left ventricular function who receive excellent perioperative medical therapy, coronary revascularization before vascular surgery does not improve long-term outcome.

1 McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004; 351: 2795–804[Abstract/Free Full Text]


    References
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 Abstract
 Introduction
 Aetiology of PMI
 Prevention of perioperative MI
 Conclusions
 Addendum
 References
 
1 Adams JE III, Sicard GA, Allen BT, et al. Diagnosis of perioperative myocardial infarction with measurement of cardiac troponin I. N Engl J Med 1994; 330: 670–4[Abstract/Free Full Text]

2 Allen JR, Helling TS, Hartzler GO. Operative procedures not involving the heart after percutaneous transluminal coronary angioplasty. Surg Gynecol Obstet 1991; 173: 285–8[ISI][Medline]

3 Almog Y, Shefer A, Novack V, et al. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 2004; 110: 880–5[Abstract/Free Full Text]

4 Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; 36: 959–69[CrossRef][ISI][Medline]

5 Alpert JS. Defining myocardial infarction: ‘Will the real myocardial infarction please stand up?’ (Editorial). Am Heart J 2003; 146: 377–9[CrossRef][ISI][Medline]

6 Anzai T, Yoshikawa T, Takahashi T, et al. Early use of beta-blockers is associated with attenuation of serum C-reactive protein elevation and favorable short-term prognosis after acute myocardial infarction. Cardiology 2003; 99: 47–53[CrossRef][ISI][Medline]

7 Arai AE, Hirsch GA. Q-wave and non-Q-wave myocardial infarctions through the eyes of cardiac magnetic resonance imaging (Editorial Comment). J Am Coll Cardiol 2004: 44: 561–3[CrossRef][ISI][Medline]

8 Auer J, Berent R, Weber T, Eber B. Risk of noncardiac surgery in the months following placement of a drug-eluting coronary stent (Letter to the Editor). J Am Coll Cardiol 2004; 43: 713

9 Auerbach DA, Goldman L. ß-blockers and reduction of cardiac events in noncardiac surgery. Scientific review. JAMA 2002; 287: 1435–44[Abstract/Free Full Text]

10 Badner NH, Knill RL, Brown JE, et al. Myocardial infarction after noncardiac surgery. Anesthesiology 1998; 88: 572–8[CrossRef][ISI][Medline]

11 Beattie WS, Buckley DN, Forrest JB. Epidural morphine reduces the risk of postoperative myocardial ischaemia in patients with cardiac risk factors. Can J Anaesth 1993; 40: 532–41[Abstract]

12 Bhatt DL. Peripheral arterial disease in the catheterization laboratory: an underdetected and undertreated risk factor. Mayo Clin Proc 2004; 79: 1107–9[ISI][Medline]

13 Boersma E, Mercado N, Poldermans D, Gardien M, Vos J, Simoons ML. Acute myocardial infarction. Lancet 2003; 361: 847–58[CrossRef][ISI][Medline]

14 Boersma E, Poldermans D, Bax JJ, et al., for the DECREASE Study Group. Predictors of cardiac events after major vascular surgery: role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy. JAMA 2001; 285: 1865–73[Abstract/Free Full Text]

15 Breen P, Lee J-W, Pomposelli F, Park KW. Timing of high-risk vascular surgery following coronary artery bypass surgery: a 10-year experience from an academic centre. Anaesthesia 2004; 59: 422–7[CrossRef][ISI][Medline]

16 Breslow MJ, Parker SD, Frank SM, et al. Determinants of catecholamine and cortisol responses to lower extremity revascularization: the PIRAT study group. Anesthesiology 1993; 79: 1202–9[ISI][Medline]

17 Browner WS, Li J, Mangano DT, for the Study of Perioperative Ischemia Research Group. In-hospital and long-term mortality in male veterans following noncardiac surgery. JAMA 1992; 268: 228–32[Abstract]

18 Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation 1994; 89: 503–5[ISI][Medline]

19 Casscells W, Naghavi M, Willerson JT. Vulnerable atherosclerotic plaque. A multifocal disease. Circulation 2003; 107: 2072–5[Free Full Text]

20 Chassot PG, Delabays A, Spahn DR. Preoperative evaluation of patients with, or at risk of, coronary artery disease undergoing non-cardiac surgery. Br J Anaesth 2002; 89: 747–59[Abstract/Free Full Text]

21 Cohen MC, Aretz TH. Histological analysis of coronary artery lesions in fatal postoperative myocardial infarction. Cardiovasc Pathol 1999; 8: 133–9[CrossRef][ISI][Medline]

22 Cohn SL, Goldman L. Preoperative risk evaluation and perioperative management of patients with coronary artery disease. Med Clin N Am 2003; 87: 111–36[CrossRef][ISI][Medline]

23 Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet 2001; 357: 89–95[CrossRef][ISI][Medline]

24 Corti R, Fuster V, Badimon JJ. Pathogenic concepts of acute coronary syndromes. J Am Coll Cardiol 2003; 41: 7S–14S[CrossRef][ISI][Medline]

25 Crawford ES, Morris GC jr, Howell JF, Flynn WF, Moorhead DT. Operative risk in patients with previous coronary artery bypass. Ann Thorac Surg 1978; 26: 215–21[Abstract]

26 Cruchley PM, Kaplan JA, Hug CC jr, Nagle D, Sumpter R, Finucane D. Non-cardiac surgery in patients with prior myocardial revascularization. Can Anaesth Soc J 1983; 30: 629–34[ISI][Medline]

27 Cutler BS, Leppo JA. Dipyridamole thallium 201 scintigraphy to detect coronary artery disease before abdominal surgery. J Vasc Surg 1987; 5: 91–100[CrossRef][ISI][Medline]

28 Cutlip DE, Baim DS, Ho KKL, et al. Thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001; 103: 1967–71[Abstract/Free Full Text]

29 Davies MJ. Stability and instability: two faces of coronary atherosclerosis. Circulation 1996; 94: 2013–20[Free Full Text]

30 Dawood MA, Gutpa DK, Southern J, Walia A, Atkinson JB, Eagle KA. Pathology of fatal perioperative myocardial infarction: implications regarding pathophysiology and prevention. Int J Cardiol 1996; 57: 37–44[CrossRef][ISI][Medline]

31 Devereaux PJ, Leslie K, Yang H. The effect of perioperative beta-blockers on patients undergoing noncardiac surgery—is the answer in? Can J Anesth 2004; 51: 749–55[Free Full Text]

32 Devereaux PJ, Yusuf S, Yang H, Choi PTL, Guyatt GH. Are the recommendations to use perioperative ß-blocker therapy in patients undergoing noncardiac surgery based on reliable evidence? CMAJ 2004; 171: 245–7[Free Full Text]

33 Dorman BH, Zucker JR, Verrier ED, Gartman DM, Slachman FN. Clonidine improves perioperative myocardial ischemia, reduces anesthetic requirement, and alters hemodynamic parameters in patients undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth 1993; 7: 386–95[CrossRef][Medline]

34 Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). 2002. American College of Cardiology Web site. Available at: www.acc.org/clinical/guidelines/perio/dirIindex.htm

35 Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—Executive Summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 2002; 105: 1257–67[Free Full Text]

36 Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to update the 1999 Guidelines on Coronary Artery Bypass Graft Surgery). J Am Coll Cardiol 2004; 44: 1146–54[CrossRef][ISI][Medline]

37 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. Circulation 1997; 96: 1882–7[Abstract/Free Full Text]

38 Ellis JE, Drijvers G, Pedlow S, et al. Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis. Anesth Analg 1994; 79: 1133–40[Abstract]

39 Ellis SG, Hertzer NR, Young JR, Brener S. Angiographic correlates of cardiac death and myocardial infarction complicating major nonthoracic vascular surgery. Am J Cardiol 1996; 77: 1126–8[CrossRef][ISI][Medline]

40 Elmore JR, Hallett JW jr, Gibbons RJ, et al. Myocardial revascularization before abdominal aortic aneurysmorrhaphy: effect of coronary angioplasty. Mayo Clin Proc 1993; 68: 637–41[ISI][Medline]

41 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657–71[Free Full Text]

42 Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996; 93: 1354–63[Abstract/Free Full Text]

43 Feldman CL, Stone PH. Intravascular hemodynamic factors responsible for progression of coronary atherosclerosis and development of vulnerable plaque. Curr Opin Cardiol 2000; 15: 430–40[CrossRef][ISI][Medline]

44 Finkelstein A, McClean D, Kar S, et al. Local drug delivery via a coronary stent with programmable release pharmacokinetics. Circulation 2003; 107: 777–84[Abstract/Free Full Text]

45 Fleisher LA, Eagle KA, Shaffer T, Anderson GF. Perioperative and long-term mortality rates after major vascular surgery: the relationship to preoperative testing in the Medicare population. Anesth Analg 1999; 89: 849–55[Abstract/Free Full Text]

46 Fleisher LA, Nelson AH, Rosenbaum SH. Postoperative myocardial ischemia: aetiology of cardiac morbidity or manifestation of underlying disease? J Clin Anesth 1995; 7: 1–6[CrossRef][ISI][Medline]

47 Forrester JS. Role of plaque rupture in acute coronary syndromes. Am J Cardiol 2000; 86 (Suppl): J15–23[ISI][Medline]

48 Foster ED, Davis KB, Carpenter JA, Abele S, Fray D. Risk of noncardiac operations in patients with defined coronary disease: The Coronary Artery Surgery Study (CASS) registry experience. Ann Thorac Surg 1986; 41: 42–50[Abstract]

49 Frank S, Beattie C, Christopherson R, et al. Unintentional hypothermia is associated with postoperative myocardial ischemia. The Perioperative Ischemia Randomized Anesthesia Trial Study Group. Anesthesiology 1993; 78: 468–76[ISI][Medline]

50 Frank S, Fleisher L, Breslow M, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. JAMA 1997; 277: 1127–34[Abstract]

51 Freemantle N, Cleland J, Young P, Mason J, Harrison J. ß-Blockade after myocardial infarction: systematic review and meta regression analysis. Br Med J (Clin Res Ed) 1999; 318: 1730–7

52 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathophysiology of coronary artery disease and the acute syndromes (I). N Engl J Med 1992; 326: 242–50[ISI][Medline]

53 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathophysiology of coronary artery disease and the acute syndromes (II). N Engl J Med 1992; 326: 310–8[ISI][Medline]

54 Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: biology. Lancet 1999; 353: (Suppl 2): S115–9

55 Geft IL, Fishbein MC, Ninomyia K, et al. Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation 1982; 66: 1150–3[Abstract]

56 Gertz SD, Roberts WC. Hemodynamic shear force in rupture of coronary arterial atherosclerotic plaques. Am J Cardiol 1990; 66: 1368–72[CrossRef][ISI][Medline]

57 Gheorghiade M, Goldstein S. ß-Blockers in the post-myocardial infarction patient. Circulation 2002; 106: 394–8[Free Full Text]

58 Gottlieb A, Banoub M, Sprung J, Levy PJ, Beven M, Mascha EJ. Perioperative cardiovascular morbidity in patients with coronary artery disease undergoing vascular surgery after percutaneous transluminal coronary angioplasty. J Cardiothorac Vasc Anesth 1998; 12: 501–6[CrossRef][ISI][Medline]

59 Grayburn PA, Hillis LD. Cardiac events in patients undergoing noncardiac surgery: shifting the paradigm from noninvasive risk stratification to therapy. Ann Intern Med 2003; 138: 506–11[Abstract/Free Full Text]

60 Grignani G, Soffiantino F, Zuchella M, et al. Platelet activation by emotional stress in patients with coronary artery disease. Circulation 1991; 83 (Suppl II): 128–36[ISI]

61 Grube E, Silber S, Hauptmann KE, et al. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003; 107: 38–42[Abstract/Free Full Text]

62 Guidelines and indications for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Coronary Artery Bypass Graft Surgery). J Am Coll Cardiol 1991; 17: 543–89[ISI][Medline]

63 Henke PK, Blackburn S, Proctor MC, et al. Patients undergoing infrainguinal bypass to treat atherosclerotic vascular disease are under-prescribed cardioprotective medications: effect on graft patency, limb salvage, and mortality. J Vasc Surg 2004; 39: 357–65[CrossRef][ISI][Medline]

64 Hertzer NR, Beven EG, Young JR, 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[ISI][Medline]

65 Heusch G, Schipke J, Thamer V. Clonidine prevents the sympathetic initiation and aggravation of poststenotic myocardial ischemia. J Cardiovasc Pharmacol 1985; 7: 1176–82[ISI][Medline]

66 Howell SJ, Sear JW, Foex P. Peri-operative ß-blockade: a useful treatment that should be greeted with cautious enthusiasm (Editorial). Br J Anaesth 2001; 86: 161–4[Free Full Text]

67 Huber KC, Evans MA, Bresnahan JF, Gibbons RJ, Holmes DR jr. Outcome of noncardiac operations in patients with severe coronary artery disease successfully treated preoperatively with coronary angioplasty. Mayo Clin Proc 1992; 67: 15–21[ISI][Medline]

68 Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). Available at: http://www.acc.org/clinical/guidelines/failure/hf_index.htm

69 Ikonomidis I, Andreotti F, Economou E, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999; 100: 793–8[Abstract/Free Full Text]

70 Jenkins NP, Keevil BG, Hutchinson IV, Brooks NH. Beta-blockers are associated with lower C-reactive protein concentration in patients with coronary artery disease. Am J Med 2002; 112: 269–74[CrossRef][ISI][Medline]

71 Jones KG, Powell JT. Slowing the heart saves lives: advantages of perioperative ß-blockade. Br J Surg 2000; 87: 689–90[CrossRef][ISI][Medline]

72 Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000; 35: 1288–94[CrossRef][ISI][Medline]

73 Kaul P, Newby LK, Fu Y, et al. Troponin T and quantitative ST-segment depression offer complimentary prognostic information in the risk stratification of acute coronary syndrome patients. J Am Coll Cardiol 2003; 41: 371–80[CrossRef][ISI][Medline]

74 Keith A, Fox A. Management of acute coronary syndromes: an update. Heart 2004; 90: 698–706[Free Full Text]

75 Kereiakes DJ. The emperor's clothes. In search of the vulnerable plaque. Circulation 2003; 107: 2076–7[Free Full Text]

76 Kertai MD, Bax JJ, Klein J, Poldermans D. Is there any reason to withhold ß blockers from high-risk patients with coronary artery disease during surgery? Anesthesiology 2004; 100: 4–7[CrossRef][ISI][Medline]

77 Kertai MD, Boersma E, Westerhout CM, et al. Association between long-term statin use and mortality after successful abdominal aortic aneurysm surgery. Am J Med 2004; 116: 96–103[CrossRef][ISI][Medline]

78 Kim LJ, Martinez EA, Faraday N, et al. Cardiac troponin I predicts short-term mortality in vascular surgery patients. Circulation 2002; 106: 2366–71[Abstract/Free Full Text]

79 Krupski WC. Update on perioperative evaluation and management of cardiac disease in vascular surgery patients. J Vasc Surg 2002; 36: 1292–308[CrossRef][ISI][Medline]

80 Landesberg G. The pathophysiology of perioperative myocardial infarction: facts and perspectives. J Cardiothorac Vasc Anesth 2003; 17: 90–100[CrossRef][ISI][Medline]

81 Landesberg G, Luria MH, Cotev S, et al. Importance of long-duration postoperative ST-segment depression in cardiac morbidity after vascular surgery. Lancet 1993; 341: 715–9[CrossRef][ISI][Medline]

82 Landesberg G, Mosseri M, Shatz V, et al. Cardiac troponin after major vascular surgery. The role of perioperative ischemia, preoperative thallium scanning, and coronary revascularization. J Am Coll Cardiol 2004; 44: 569–75[CrossRef][ISI][Medline]

83 Landesberg G, Mosseri M, Wolf Y, et al. Perioperative myocardial ischemia and infarction. Identification by continuous 12-lead electrocardiogram with online ST-segment monitoring. Anesthesiology 2002; 96: 262–70

84 Landesberg G, Mosseri M, Wolf YG, et al. Preoperative thallium scanning, selective coronary revascularization, and long-term survival after major vascular surgery. Circulation 2003; 108: 177–83[Abstract/Free Full Text]

85 Landesberg G, Mosseri M, Zahger D, et al. Myocardial infarction following vascular surgery: the role of prolonged, stress-induced, ST-depression-type ischemia. J Am Coll Cardiol 2001; 37: 1858–63[CrossRef][ISI][Medline]

86 Landesberg G, Shatz V, Akopnik I, et al. Association of cardiac troponin, CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery. J Am Coll Cardiol 2003; 42: 1547–54[CrossRef][ISI][Medline]

87 Lee TH. Reducing cardiac risk (Editorial). N Engl J Med 1999; 341: 1838–40[Free Full Text]

88 Lee TH, Thomas EJ, Ludwig LE, et al. Troponin T as a marker for myocardial ischemia in patients undergoing major noncardiac surgery. Am J Cardiol 1996; 77: 1031–6[CrossRef][ISI][Medline]

89 Lee T-S, Chang C-C, Zhu Y, Shyy JYJ. Simvastatin induces heme oxygenase-1. A novel mechanism of vessel protection. Circulation 2004; 110: 1296–301[Abstract/Free Full Text]

90 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001; 104: 365–72[Free Full Text]

91 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135–43[Abstract/Free Full Text]

92 Lindahl B, Toss H, Siegbahn A, et al., the Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. N Engl J Med 2000; 343: 1139–47[Abstract/Free Full Text]

93 Lindenauer PK, Pekow P, Wang K, Gutierrez B, Benjamin EM. Lipid-lowering therapy and in-hospital mortality following major noncardiac surgery. JAMA 2004; 291: 2092–9[Abstract/Free Full Text]

94 London MJ, Zaugg M, Schaub MC, Spahn DR. Perioperative ß-adrenergic receptor blockade. Physiologic foundations and clinical controversies. Anesthesiology 2004; 100: 170–5[CrossRef][ISI][Medline]

95 Lopez-Jimenez F, Goldman L, Sacks DB, et al. Prognostic value of cardiac troponin T after noncardiac surgery: 6-month follow-up data. J Am Coll Cardiol 1997; 29: 1241–5[CrossRef][ISI][Medline]

96 MacNeill BD, Jang I-K, Bouma BE, et al. Focal and multi-focal plaque macrophage distributions in patients with acute and stable presentations of coronary artery disease. J Am Coll Cardiol 2004; 44: 972–9[CrossRef][ISI][Medline]

97 Mangano DT. Adverse outcomes after surgery in the year 2001—a continuing odyssey (Editorial). Anesthesiology 1998; 88: 561–4[CrossRef][ISI][Medline]

98 Mangano DT. Perioperative cardiac morbidity. Anesthesiology 1990; 72: 153–84[ISI][Medline]

99 Mangano DT, for the Multicenter Study of Perioperative Ischemia Research Group. Aspirin and mortality from coronary bypass surgery. N Engl J Med 2002; 347: 1309–17[Abstract/Free Full Text]

100 Mangano DT, Layug EL, Wallace A, Tateo I, for the Multicenter Study of Perioperative Ischemia Research Group. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery: Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996; 335: 1713–20[Abstract/Free Full Text]

101 Mangano DT, Siliciano D, Hollenberg M, et al. Postoperative myocardial ischemia therapeutic trials using intensive analgesia following surgery. Anesthesiology 1992; 76: 343–53

102 Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart 1999; 82: 265–8[Abstract/Free Full Text]

103 Maseri A, Fuster V. Is there a vulnerable plaque? Circulation 2003; 107: 2068–71[Free Full Text]

104 Mason JJ, Owens DK, Harris RA, Cooke JP, Hlatky MA. The role of coronary angiography and coronary revascularization before noncardiac surgery. JAMA 1995; 273: 1919–25[Abstract]

105 Massie MT, Rohrer MJ, Leppo JA, Cutler BS. Is coronary angiography necessary for vascular surgery patients who have positive results of dipyridamole thallium scans? J Vasc Surg 1997; 25: 975–82[ISI][Medline]

106 Master AM, Dack S, Jaffe H. Perioperative coronary artery occlusion. JAMA 1938; 110: 1415–8

107 McCann RL, Clements FM. Silent myocardial ischemia in patients undergoing peripheral vascular surgery: incidence and association with perioperative cardiac morbidity and mortality. J Vasc Surg 1989; 9: 583–7[CrossRef][ISI][Medline]

108 McSPI-Europe Research Group. Perioperative sympatholysis: beneficial effects of the {alpha}2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia. Anesthesiology 1997; 86: 346–63[CrossRef][ISI][Medline]

109 Mesh CL, Cmolik BL, Van Heekeren DW, et al. Coronary bypass in vascular patients: a relatively high-risk procedure. Ann Vasc Surg 1997; 11: 612–9[CrossRef][ISI][Medline]

110 Metzler H, Gries M, Rehak P, Lang T, Frühwald S, Toller W. Perioperative myocardial cell injury: the role of troponins. Br J Anaesth 1997; 78: 386–90[Abstract/Free Full Text]

111 Mittleman MA, Maclure M, Tofler GH, et al. Triggering of acute myocardial infarction by heavy physical exertion: protection against triggering by regular exercise. N Engl J Med 1993; 329: 1677–83[Abstract/Free Full Text]

112 Moon JCC, De Arenaza DP, Elkington AG, et al. The pathological basis of Q-wave and non-Q-wave myocardial infarction. J Am Coll Cardiol 2004; 44: 554–60[CrossRef][ISI][Medline]

113 Mukherjee D, Eagle KA. Perioperative cardiac assessment for noncardiac surgery: eight steps to the best possible outcome. Circulation 2003; 107: 2771–4[Free Full Text]

114 Muzi M, Goff DR, Kampine JP, et al. Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans. Anesthesiology 1992; 77: 864–71[ISI][Medline]

115 Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient. A call for new definitions and risk assessment strategies: part I. Circulation 2003; 108: 1664–72[Abstract/Free Full Text]

116 Nelson AH, Fleisher LA, Rosenbaum SH. Relationship between postoperative anaemia and cardiac morbidity in high-risk vascular patients in the intensive care unit. Crit Care Med 1993; 21: 860–6[ISI][Medline]

117 Neumayer G, Gaenzer H, Pfister R, et al. Plasma level of cardiac troponin I after prolonged strenuous exercise. Am J Cardiol 2001; 87: 369–71[CrossRef][ISI][Medline]

118 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[ISI][Medline]

119 Nishina K, Mikawa K, Uesugi T, et al. Efficacy of clonidine for prevention of perioperative myocardial ischemia: a critical appraisal and meta-analysis of the literature. Anesthesiology 2002; 96: 323–9[CrossRef][ISI][Medline]

120 Okazaki S, Yokoyama T, Miyauchi K, et al. Early statin treatment in patients with acute coronary syndrome. Demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: The ESTABLISH Study. Circulation 2004; 110: 1061–8[Abstract/Free Full Text]

121 O'Rourke DJ, Quinton HB, Piper W, et al., for the Northern New England Cardiovascular Disease Study Group. Ann Thorac Surg 2004; 78: 466–70[Abstract/Free Full Text]

122 Oliver MF, Goldman L, Julian DG, Holme I. Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease: the European Mivazerol Trial (EMIT). Anesthesiology 1999; 91: 951–61[ISI][Medline]

123 Oscarsson A, Eintrei C, Anskär S, et al. Troponin T-values provide long-term prognosis in elderly patients undergoing non-cardiac surgery. Acta Anaesthesiol Scand 2004; 48: 1071–9[CrossRef][ISI][Medline]

124 Ouyang P, Gerstenblith G, Furman WR, et al. Frequency and significance of early postoperative silent myocardial ischemia in patients having peripheral vascular surgery. Am J Cardiol 1989; 64: 1113–6[CrossRef][ISI][Medline]

125 Palda VA, Detsky AS. Perioperative assessment and management of risk from coronary artery disease. Clinical Guideline, Part II. Ann Intern Med 1997; 127: 313–28[Abstract/Free Full Text]

126 Pasternak PF, Grossi EA, Baumann G, et al. Silent myocardial ischemia monitoring predicts late as well as perioperative cardiac events in patients undergoing vascular surgery. J Vasc Surg 1992; 16: 171–80[CrossRef][ISI][Medline]

127 Pasternak PF, Grossi EA, Baumann G, et al. The value of silent myocardial ischemia monitoring in the prediction of perioperative myocardial infarction in patients undergoing peripheral vascular surgery. J Vasc Surg 1989; 10: 617–25[CrossRef][ISI][Medline]

128 Poldermans D, Bax JJ, Kertai MD, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003; 107: 1848–51[Abstract/Free Full Text]

129 Poldermans D, Boersma E, Bax JJ, et al., for the Dutch Cardiac Risk Evaluation Applying Stress Echocardiography Group. Bisoprolol reduces cardiac death and myocardial infarction in high-risk patients as long as 2 years after successful major vascular surgery. Eur Heart J 2001; 22: 1353–8[Abstract/Free Full Text]

130 Poldermans D, Boersma E, Bax JJ, et al., for the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999; 341: 1789–94[Abstract/Free Full Text]

131 Posner KL, Van Norman GA, Chan V. Adverse cardiac outcomes after noncardiac surgery in patients with prior percutaneous transluminal coronary angioplasty. Anesth Analg 1999; 89: 553–60[Abstract/Free Full Text]

132 Priebe HJ. Triggers of perioperative myocardial ischaemia and infarction. Br J Anaesth 2004; 93: 9–20[Abstract/Free Full Text]

133 Raby KE, Brull SDJ, Timimi F, et al. The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery. Anesth Analg 1999; 88: 477–82[Abstract/Free Full Text]

134 Reul GJ, Cooley DA, Duncan JM, et al. The effect of coronary bypass on the outcome on peripheral vascular operations in 1093 patients. J Vasc Surg 1986; 3: 788–98[CrossRef][ISI][Medline]

135 Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–9[Abstract/Free Full Text]

136 Ridker PM, Manson JE, Buring JE, et al. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation 1990; 82: 897–902[Abstract]

137 Sabia PJ, Powers ER, Ragosta M, et al. An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction. N Engl J Med 1992; 327: 1825–31[Abstract]

138 Sambola A, Osende J, Hathcock J, et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 2003; 107: 973–7[Abstract/Free Full Text]

139 Shammash JB, Trost JC, Gold JM, et al. Perioperative ß-blocker withdrawal and mortality in vascular surgical patients. Am Heart J 2001; 141: 148–53[CrossRef][ISI][Medline]

140 Shojania KG, Duncan BW, McDonald KM, Wachter RM. Safe but sound: patient safety meets evidence-based medicine. JAMA 2002; 288: 508–13[Free Full Text]

141 Singh N, Langer A. Current status of silent myocardial ischemia. Can J Cardiol 1995; 11: 286–9[ISI][Medline]

142 Singh M, Lennon RJ, Darbar D, Gersh B, Holmes DR, Rihal C. Effect of peripheral arterial disease in patients undergoing coronary intervention with intracoronary stents. Mayo Clin Proc 2004; 79: 1113–8[ISI][Medline]

143 Smith SC Jr, Blair SN, Bonow RO, et al. AHA/ACC Scientific Statement: AHA/ACC guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease: 2001 update. A statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 2001; 104: 1577–9[Free Full Text]

144 Smith SC jr, Dove JT, Jacobs AK, et al. ACC/AHA guidelines for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty). J Am Coll Cardiol 2001; 37: 2215–38[CrossRef][ISI][Medline]

145 Spencer FA, Allegrone J, Goldberg RJ, et al., for the Grace Investigators. Association of statin therapy with outcomes of acute coronary syndromes: the GRACE study. Ann Intern Med 2004; 140: 857–66[Abstract/Free Full Text]

146 Steinberg JB, Kresowik TF, Behrendt DM. Prophylactic myocardial revascularization based on dipyridamole-thallium scanning before peripheral vascular surgery. Cardiovasc Surg 1993; 1: 552–7[Medline]

147 Stevenson LW. Beta-blockers for stable heart failure. N Engl J Med 2002; 346: 1346–7[Free Full Text]

148 Stone JG, Foex P, Sear JW, et al. Myocardial ischemia in untreated hypertensive patients: Effects of a single small dose of a beta-adrenergic blocking agent. Anesthesiology 1988; 68: 495–500[ISI][Medline]

149 The CIBIS-II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet 1999; 353: 9–13[CrossRef][ISI][Medline]

150 The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J 2000; 21: 1502–13[Abstract/Free Full Text]

151 Thompson JP. Ideal peri-operative management of patients with cardiovascular disease: the quest continues (Editorial). Anaesthesia 2004; 59: 417–21[CrossRef][ISI][Medline]

152 Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, et al. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 1994; 90: 583–612[Abstract]

153 Ueda Y, Nanto S, Komamura K, Kodama K. Neointimal coverage of stents in human coronary arteries observed by angioscopy. J Am Coll Cardiol 1994; 23: 341–6[ISI][Medline]

154 Urban MK, Markowitz SM, Gordon MA, et al. Postoperative prophylactic administration of ß-adrenergic blockers in patients at risk of myocardial ischemia. Anesth Analg 2000; 90: 1257–61[Abstract/Free Full Text]

155 Vaughan CJ, Gotto AM jr. Update on statins: 2003. Circulation 2004; 110: 886–92[Free Full Text]

156 Vicenzi MN, Ribitsch D, Luha O, Klein W, Metzler H. Coronary artery stenting before noncardiac surgery: more threat than safety? Anesthesiology 2001; 94: 367–8[CrossRef][ISI][Medline]

157 Wallace AW, Layug B, Tateo I., et al., for the McSPI Research Group. Prophylactic atenolol reduces postoperative myocardial ischemia. Anesthesiology 1998; 88: 7–17[CrossRef][ISI][Medline]

158 Wallace AW, Galindez D, Salahieh A, et al. Effect of clonidine on cardiovascular morbidity and mortality after noncardiac surgery. Anesthesiology 2004; 101: 284–93[CrossRef][ISI][Medline]

159 Wheatley KW, Clayton D. Be skeptical about unexpected large apparent treatment effects: the case of an MRC AML 12 randomization. Control Clin Trials 2003; 24: 66–70[CrossRef][ISI][Medline]

160 WHO MONICA Project Principal Investigators. World Health Organization MONICA Project (monitoring trends and determinants of cardiovascular disease): a major international collaboration. J Clin Epidemiol 1988; 41: 105–14[CrossRef][ISI][Medline]

161 Wijeysundera DN, Naik JS, Beattie S. Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: a meta-analysis. Am J Med 2003; 114: 742–52[CrossRef][ISI][Medline]

162 Wilson HS, Fasseas P, Orford JL, et al. Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol 2003; 42: 234–40[CrossRef][ISI][Medline]

163 Wilson RH, Rihal CS, Bell MR, Velianou JL, Holmes DR jr, Berger PB. Timing of coronary stent thrombosis in patients treated with ticlopidine and aspirin. Am J Cardiol 1999; 83: 1006–11[CrossRef][ISI][Medline]