Vascular surgery patients: perioperative and long-term risk according to the ACC/AHA guidelines, the additive role of post-operative troponin elevation

Francesca Bursi1, Luciano Babuin2, Andrea Barbieri1, Luigi Politi1, Mauro Zennaro1, Teresa Grimaldi1, Antonio Rumolo3, Mauro Gargiulo3, Andrea Stella3, Maria Grazia Modena1 and Allan S. Jaffe2,*

1Institute of Cardiology, Policlinico Hospital, Modena and Reggio Emilia University School of Medicine, Italy
2Cardiovascular Diseases and Department of Laboratory Medicine and Pathology, Gonda 5, 200 First Street SW, Mayo Clinic, Rochester, MN, USA
3Institute of Vascular Surgery, Policlinico Hospital, Modena and Reggio Emilia University School of Medicine, Italy

Received 10 April 2005; revised 6 June 2005; accepted 30 June 2005; online publish-ahead-of-print 29 July 2005.

* Corresponding author. Tel: +1 507 284 3680; fax: +1 507 266 0228. E-mail address: jaffe.allan{at}mayo.edu

See page 2358 for the editorial comment on this article (doi:10.1093/eurheartj/ehi510)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations and strengths
 Conclusion
 Acknowledgements
 References
 
Aims The objectives of this study are to evaluate the prognostic role of pre-operative stratification in patients undergoing elective major vascular surgery, the timing of adverse outcomes, and the predictive role of troponin (cTn).

Methods and results Consecutive vascular surgery candidates (n=391) were prospectively stratified and treated according to the ACC/AHA guidelines. The patients were categorized into three groups: (1) with coronary revascularization in the past 5 years, (2) with intermediate clinical risk predictors, and (3) with minor or no clinical risk predictors. cTnI was measured post-operatively. By 18 months, 18.7% of subjects had experienced death or acute myocardial infarction (MI) (by the ACC/ESC criteria). The hazard ratio (HR) was 5.21 (95% CI=2.60–10.43; P<0.0001) in group 1 and 2.58 (95% CI=1.27–4.38; P=0.004) in group 2 when compared with group 3. Most events occurred within 30 days. Elevations of cTnI were associated with adverse outcomes even after multivariable adjustment at long-term (adjusted overall HR=4.73, 95% CI=2.92–7.65; P<0.0001) and at 30 days (adjusted HR=5.52, 95%CI=3.23–9.42; P<0.0001).

Conclusion After pre-operative stratification, patients undergoing elective major vascular surgery remain at high risk of MI and death. Events occur mainly early after surgery. cTnI elevations are frequent and independently associated with increased risk. These findings suggest the need for a major re-evaluation of our approach to these patients.

Key Words: Troponin • Vascular surgery • Risk stratification


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations and strengths
 Conclusion
 Acknowledgements
 References
 
Patients referred for major vascular surgery are a population known to be at high risk for perioperative1,2 and late-cardiac events35 because of the high prevalence of underlying coronary artery disease.6,7 Often, the manifestations of ischaemia are not overt and thus considered ‘silent’.6,8 The known morbidity and mortality associated with underlying cardiovascular disease in patients who undergo non-cardiac surgery is generally well known and has resulted in guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) for pre-operative evaluation of cardiac risk in this group.9,10 These guidelines are used worldwide because no other set of guidelines exists in the area. However, reports of the use of these guidelines in vascular surgery patients have been rare11 and, to the best of our knowledge, no data on the outcomes of patients stratified according to these recommendations have been published.

Recent data have indicated that cardiac troponin (cTn) elevations occur frequently post-operatively in these patients, and even minor elevations are strongly related to perioperative ischaemia and define an adverse short- and long-term prognosis.12 These data reinforce prior studies indicative of a worse mid-13,14 and long-term2,4 survival, leading to the suggestion that in vascular surgery patients, cTn elevations should be considered from the prognostic standpoint similar to elevations in patients with acute coronary syndromes.15 The optimal strategy to prevent these events will depend on when they occur post-operatively. To date, no study has investigated the timing of these adverse events to determine whether they occur soon after vascular surgery or are predominantly late events.

Accordingly, the aims of this study are (1) to investigate whether patients undergoing elective major vascular surgery, prospectively risk stratified, according to the ACC/AHA guidelines for non-cardiac surgery are at risk of developing elevations of cTn, (2) to determine whether such elevations in this population are associated with subsequent death and/or myocardial infarction (MI), (3) if so, to determine the timing of adverse outcomes (within the first 30 days or long-term), and (4) to investigate whether post-operative cTn elevations augment the risk stratification strategy provided by the ACC/AHA guidelines.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations and strengths
 Conclusion
 Acknowledgements
 References
 
This was a prospectively designed study using the ACC/AHA guidelines for perioperative cardiovascular evaluation in non-cardiac surgery.9 Between September 2000 and July 2002, all subjects referred for elective major vascular surgery at the ‘Policlinico University Hospital’ of Modena (Italy) were prospectively screened according to the guidelines for pre-operative evaluation of cardiac risk in non-cardiac surgery. In addition, an evaluation of renal function was included. This assessment was added to the guidelines in 2002.10 cTnI was measured post-operatively at prospectively determined pre-specified time points. Samples for measurement of cTnI were obtained on post-operative days 1, 2, and 3. These time points were chosen because patients are at greatest risk for cardiac complications during the first 72 h after vascular surgery.16 The outcome data were analysed to investigate the relationship between the events and the risk stratification algorithm proposed by the ACC/AHA. The paradigm divides patients into three clinical risk groups:

  1. Group 1 included subjects with history of coronary revascularization in the past 5 years and no recurrent symptoms.
  2. Group 2 included patients with intermediate clinical cardiovascular risk predictors.
  3. Group 3 included patients with minor or no clinical cardiovascular risk predictors.

Subsequently, each of these groups was divided into subgroups, on the basis of the presence of an elevated cTnI post-operatively.

The study complies with the Declaration of Helsinki, the Ethics Committee has approved the research protocol, and the informed consent has been obtained from the subjects.

Perioperative cardiovascular stratification
The ACC/AHA guidelines for pre-operative evaluation of cardiac risk in non-cardiac surgery are based on a step-wise Bayesian approach intended to identify patients that are candidates for cardiac testing and subsequent specific management. The clinician must consider the following variables step-by-step: urgency level of non-cardiac surgery (emergency, urgency, or elective), history of coronary revascularization in the past 5 years, recent coronary evaluation in the past 2 years, and clinical predictors of increased perioperative cardiovascular risk. The clinical predictors of pre-operative cardiovascular risk are classified into three categories: major, intermediate, and low risk predictors (Table 1). According to the guidelines, patients with history of coronary revascularization in the past 5 years, who have remained stable without recurrent signs or symptoms of ischaemia until the time of surgery (group 1), are sent to the operation without further cardiac testing, as the likelihood of perioperative cardiac death or MI had been previously reported to be low.9,10,17 Similarly, the subgroup which has undergone an invasive or non-invasive coronary evaluation in the past 2 years, in the absence of an unfavourable stress test result or changes of symptoms, can also undergo surgery without further evaluation. For the purpose of the analysis and because detailed information on risk factors was collected for all patients in this group, this group was evaluated more rigorously than mandated, in a manner similar to intermediate risk patients (group 2), i.e. on the basis of the presence of clinical cardiovascular risk predictors.


View this table:
[in this window]
[in a new window]
 
Table 1 Clinical predictors of cardiovascular risk
 
We did not have patients with major clinical cardiovascular risk predictors, because our study was in a population referred for elective surgery. For patients with intermediate, minor, or no clinical cardiovascular risk predictors, consideration of functional capacity [metabolic equivalents (METs) as determined by history of daily activity] and level of surgery-specific risk (high risk: aortic or infrainguinal major vascular surgery; intermediate risk: carotid endarterectomy) allows an approach to identify patients that may most benefit from further non-invasive testing. Patients with intermediate cardiovascular risk predictors (group 2) underwent non-invasive testing and eventually coronary angiography in the presence of poor functional capacity (METs <4) or high surgical risk and, finally, patients with minor or no clinical cardiovascular risk predictors (group 3) underwent non-invasive testing and eventually coronary angiography in presence of poor functional capacity (METs <4) and high surgical risk.

This step-wise approach was applied independently to each patient by two cardiologists. The conclusion drawn by each investigator for each file was similar in all cases.

Troponin assay
cTnI was measured with the Stratus CS STAT fluorimetric analyzer (Dade Behring Inc., Newark, DE, USA), which is a high level of analytic precision two-site sandwich immunoassay based on solid phase radial partition immunoassay technology. The minimum detectable concentration is 0.03 ng/mL and the upper reference limit (99th percentile of the reference range) is 0.07 ng/mL. At the time of this study in our institute, the lowest concentration with coefficient of variation <10% was 0.10 ng/mL. Values ≥10% coefficient of variation, i.e. 0.10 ng/mL, were used to define cTnI elevations. This is the criterion used by Landesberg et al.4

Follow-up
The main dependent variable was the combined endpoint death or MI after the index surgery. The planned follow-up took place at 18–24 months after the surgery and incorporated review of hospital charts, death certificates, autopsy reports (if available), and telephone interview by two independent investigators unaware of the patients' history, laboratory exams, and aim of the study. MI was clinically and independently diagnosed by pre-specified criteria using the new American College of Cardiology/European Society of Cardiology (ACC/ESC) definition, which requires a typical rise and gradual fall of troponin values when either the setting, clinical, or ECG findings suggest the presence of acute ischaemia.18 To be included, the reviewers had to agree. After adjudication, this was the situation for all cases.

Statistic analysis
Summary statistics are presented as frequencies (percentages) or as mean±SD. Categorical variables were compared by a {chi}2 test or Fisher's exact test, when appropriate, and continuous variables by ANOVA. For skewed distributions, variables are presented as median and first and third quartiles (Q1 and Q3) and groups were compared by Kruskal–Wallis non-parametric test. Survival analyses were performed by Kaplan–Meier curves and the groups were compared by the log-rank test. Unadjusted and adjusted hazard ratios (HRs) for the combined endpoint death and MI were analysed by Cox regression analysis. To investigate the acute hazard, patients who did not experience death or MI were censored at 30 days. The individuals who died within 30 days were excluded from the analysis to evaluate the HR for the combined endpoint in 30-day survivors. Only one endpoint event was included for each patient.

The variables for the multivariable Cox regression model were selected among the variables with P<0.10 at univariate analysis and age and gender were forced into the model. As the definition of the three groups was based on the clinical predictors of cardiovascular risk, which included most of cardiovascular risk factors and cardiac co-morbidity, to avoid collinearity and to keep the model as parsimonious as possible, these variables were treated in two ways. They were not entered individually but as summary variable (clinical risk group) initially. Subsequently, they were entered separately in place of the summary variable as well. We statistically evaluated the Cox proportional hazards model assumptions by plotting the scaled Schoenfeld residuals against time and by testing the correlation between these two variables, and there were no major violations of these assumptions. The only continuous co-variable was age, which was tested by including the quadratic term for age in the model. It was not significant. Logistic regression analysis was used to evaluate the unadjusted relative risk of post-operative cTnI elevation in the three groups. All tests were two-sided, and for all analyses, P<0.05 was considered statistically significant. For some cells with very small numbers, multivariable adjustment could not be applied.

All P-values were reported to allow for evaluation of any type I error that could occur.

All statistical analyses were performed with the software SPSS® 10.0 for Windows (SPSS Institute Inc., Chicago, IL, USA) and STATA® 8.0 (College Station, TX, USA).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations and strengths
 Conclusion
 Acknowledgements
 References
 
Baseline characteristics
During the study period, 391 candidates referred for elective major vascular surgery at our institution were risk stratified and treated according to the ACC/AHA guidelines for pre-operative evaluation of cardiac risk in non-cardiac surgery (Figure 1). All 391 patients who were screened eventually underwent surgery. In the overall population, there were 32 patients with history of coronary revascularization in the past 5 years (mean 3.3±1.6 years) and asymptomatic in the interim (group 1) who, according to the guidelines, went directly to surgery. There were 193 patients with intermediate clinical cardiovascular risk predictors (group 2) and 166 patients with minor or no clinical cardiovascular risk predictors (group 3). None of the patients had major clinical cardiovascular risk predictors. Among the 147 (37.6%) patients who underwent stress testing before the vascular procedure, 87 (59.2%) had the stress test >6 months before the surgery and 18 (12.2%) had inducible ischaemia. Pre-operative myocardial revascularization was considered to be the best therapeutic option after coronary angiography in eight patients of these patients (six coronary artery bypass grafts and two percutaneous transluminal coronary angioplasties), a mean time of 84±15 days before operation; these subjects represent the 5.4% of subjects who underwent non-invasive stress testing. The remaining patients were treated pre-operatively with an intensified medical regimen including high dose beta-blockers titrated to heart rate, nitrates, and statins. The baseline characteristics of these three groups are shown in Table 2.



View larger version (37K):
[in this window]
[in a new window]
 
Figure 1 Step-wise approach to perioperative cardiac assessment adapted from the ACC/AHA guidelines. Intermediate clinical predictors are mild angina pectoris, previous MI, compensated or a prior history of heart failure, diabetes mellitus, and renal insufficiency. Minor clinical predictors included advanced age, an abnormal ECG, a rhythm other than sinus rhythm, a low functional capacity, a history of stroke, and/or controlled systemic hypertension. PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.

 

View this table:
[in this window]
[in a new window]
 
Table 2 Baseline characteristics of the three groups
 
Follow-up
The mean follow-up was 18.9±6.2 months. During the entire follow-up, 83 subjects experienced at least one endpoint event: 46 subjects had died and 52 experienced an acute MI. At 18 months, overall event-free survival was 81.3%, 55.1% in group 1, 77.4% in group 2, and 90.7% in group 3 (P<0.0001; Figure 2). At 18 months, death occurred in 20.0% in group 1, 13.7% in group 2, and 4.4% in group 3 (P=0.0036); the incidence of MI was 39.6% in group 1, 12.0% in group 2, and 7.4% in group 3 (P<0.0001). Considering group 3 as referent, the HR of the combined endpoint was 5.21 (95%CI=2.60–10.43; P<0.0001) in group 1 and 2.58 (95%CI=1.52–4.38; P=0.004) in group 2 (Table 3).



View larger version (19K):
[in this window]
[in a new window]
 
Figure 2 Survival free from MI among the three groups of patients. Top panel: survival during the entire follow-up. Bottom panel: survival over 30 days. Note that most events occurred early.

 

View this table:
[in this window]
[in a new window]
 
Table 3 Unadjusted and adjusted HR for the combined endpoint death and MI during the follow-up
 
There was a steep decline in event-free survival early after surgery, which persisted during the follow-up. At 30 days, 40 (10.2%) subjects had died and/or experienced an acute MI (18 died and 32 had acute MI). Event-free survival at 30 days was 72% in group 1, 88% in group 2, and 96% in group 3 (P<0.0001) (Figure 2). The HR of the combined endpoint was 7.84 (95%CI=2.92–21.08; P<0.0001) in group 1 and 2.96 (95%CI=1.27–6.91; P=0.012) in group 2 when compared with group 3 (Table 4).


View this table:
[in this window]
[in a new window]
 
Table 4 Unadjusted and adjusted HR for the combined endpoint death and MI at 30 days and among 30 day survivors
 
Among 373 patients who survived after 30 days, 65 (17.4%) subjects subsequently died or experienced an acute MI (28 died and 46 had acute MI). Event-free survival at 18 months was 60.8% in group 1, 82.1% in group 2, and 93.2% in group 3 (P<0.0001). The HR of the combined endpoint was 4.81 (95%CI=2.24–10.32; P<0.0001) in group 1 and 2.21 (95%CI=1.24–3.93; P=0.007) in group 2 (Table 4).

Post-operative cTnI was elevated in 85 patients (21.7%): 15 (46.9%) patients in group 1, 53 (27.5%) in group 2, and 17 (10.2%) in group 3 (P<0.0001). Peak values of cTnI were observed on the first post-operative day, i.e. 12–16 h after the surgery. Considering group 3 as referent, patients in group 1 had a risk of cTnI elevation three times higher (unadjusted relative risk=3.32, 95%CI=1.83–6.00; P<0.0001) and those in group 2 had a risk of cTnI elevation seven times higher (unadjusted relative risk=7.73, 95%CI=3.28–18.21; P<0.0001).

When each group was divided into two subgroups on the basis of the presence of cTnI ≥0.10 ng/mL, patients with elevated cTnI had a significantly higher risk of both combined endpoint and MI alone, which was consistent among the three clinical risk groups (Table 5). Post-operative cTnI was strongly associated with the combined endpoint in all clinical risk groups, the HR for death or MI at 30 days was 15.24 (95%CI=1.89–123.26; P=0.011) for group 1, 7.19 (95%CI=2.95–17.52; P<0.0001) for group 2, and 61.8 (95%CI=7.42–514.8; P<0.0001) for group 3 (Table 6). The association between post-operative elevations of cTnI and death or MI was less strong, but remained significant among 30-day survivors, HR=5.08 (95%CI=1.33–19.42; P=0.018) for group 1, HR=4.09 (95%CI=2.14–7.82; P<0.0001) for group 2, and HR=8.20 (95%CI=3.09–21.74; P<0.0001) for group 3 (Table 6).


View this table:
[in this window]
[in a new window]
 
Table 5 Events during the follow-up, based on the presence of cTnl positive
 

View this table:
[in this window]
[in a new window]
 
Table 6 Events at 30 days and among 30-day survivors in the subgroups based on the presence of cTnl positive
 
Among the patients who underwent myocardial revascularization, a time to the vascular procedure longer than 1 year was not related to cTnI elevation (unadjusted relative risk=0.89, 95%CI=0.13–1.81; P=0.286) or to the combined endpoint (HR=0.82, 95%CI=0.31–2.2; P=0.686).

Multivariable analysis
The strong association of cTnI with the combined endpoint persisted unchanged during follow-up after adjusting for clinical risk group, age, gender, low exercise tolerance in METS, surgical risk, and beta-blockers (adjusted HR=4.73, 95%CI=2.92–7.65; P<0.0001) (Table 3), at 30 days (adjusted HR=10.97, 95%CI=5.01–24.01; P<0.0001), and among 30-day survivors (adjusted HR=5.52, 95%CI=3.23–9.42; P<0.0001) (Table 4). The addition of beta-blockers, perioperatively (P=0.259) and post-discharge (P=0.861), did not affect the outcomes. However, patients receiving beta-blockers chronically pre-operatively did worse with HRs from 2.1 to 3.2, depending on the follow-up period. When elevations of cTnI are included in the model, the differences in the HRs between groups 2 and 3 were eliminated.

Further adjustment for significant individual components (chronic renal insufficiency, diabetes, history of coronary artery disease, and heart failure) rather than use of the summary variable did not change the strong independent association between cTnI and MI and death (HR=4.32, 95%CI=2.63–7.10; P<0.0001) (Table 3).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations and strengths
 Conclusion
 Acknowledgements
 References
 
The present study indicates that despite pre-operative risk stratification, according to the ACC/AHA guidelines, patients undergoing elective major vascular surgery remain at high risk of death and acute MI. Patients who had revascularization in the past 5 years and patients with intermediate clinical risk predictors had a higher risk than patients with minor or no clinical risk predictors, but even within this group, the event rate at 18 months was substantial (9.3%). The frequency of post-operative troponin elevations we observed (21.7%) is similar to that reported by Landesberg et al.4 when sensitive cut-offs for troponin are used. They are in contrast to what was reported previously using higher cut-off values.13,14 The fact that even minor troponin elevations were so highly predictive of subsequent events in our study, as the Landesberg study, suggests the importance of using these more contemporary cut-off values.4,15 Most of the subsequent events occurred within the first 30 days after surgery. In addition, cTnI elevations were frequent and were strongly associated with the risk of subsequent death and/or MI among all clinical risk groups. This association of cTnI and adverse events was independent of several clinical variables including renal insufficiency as shown by Kertai et al.2 These findings suggest the need for a major re-evaluation of our approach to these patients.

The ACC/AHA guidelines for pre-operative evaluation of cardiac risk in non-cardiac surgery were created to improve immediate periprocedural and long-term clinical outcomes 9 of ~30 million patients who undergo non-cardiac surgery every year in the United States.5 They have been predicated on an extensive body of literature attempting to identify individuals at higher risk on the basis of clinical variable1921 or diagnostic tests22,23 and to improve outcomes.2426 Although patients undergoing elective major vascular surgery are a very high risk group, because of the diffuse nature of the atherosclerotic disease,15 these guidelines have not been extensively evaluated in this type of surgery. Perhaps, this also implies that they are not followed universally.27 In our study, we prospectively stratified elective major vascular surgery candidates according to the available ACC/AHA guidelines. When the 2002 update guidelines were published, our database was sufficiently robust and included in most instances the data necessary to re-subset these patients into more contemporary groups. In the present study, the proportion of patients who underwent myocardial revascularization before the vascular procedure was 10.2%, as that reported by other authors investigating a similar vascular surgery population that underwent different risk stratification.12 Nonetheless, the application of the current ACC/AHA guidelines was not sufficient to provide protection from death and acute MI, according to a recent report by Monahan et al.28 However, it did provide for a gradient of risk. Those who had undergone myocardial revascularization in the past 5 years consist of a relatively small number of individuals, but this group of patients had a 44% incidence of death or MI. This is in contrast to the data from the Coronary Artery Surgery Study,29 which showed a survival benefit associated with coronary artery bypass among patients undergoing major vascular surgery when compared with those receiving medical therapy. Recent data have challenged those findings in patients who like ours appeared to have stable cardiac symptoms. In that setting, revascularization before elective vascular surgery did not seem to be of benefit.30 It is apparent that accepting revascularization during the prior 5 years without further evaluation is not sufficient to prevent adverse outcomes. Whether the concept is flawed or this is an issue of timing will require much larger data sets to ascertain.

Equally concerning and a harder finding given the larger numbers is the group of patients with ‘intermediate’ clinical cardiovascular risk predictors. They also showed a significantly increased risk of the combined endpoint, despite careful evaluation. Following the ACC/AHA algorithm did not prevent the risk of future events, despite stress testing in 73.6% of patients of group 2. This strong association with adverse events was true also in patients with minor or no clinical cardiovascular risk predictors, who had a lower but not trivial risk of death and acute MI. One possibility for these results is that many of the stress tests (59%) were done >6 months before the surgical procedure. Perhaps, stress testing closer to the time of surgery would be more efficacious, although in our patients, a stress test >6 months before the surgery was not associated with a worse outcome.31 It is also possible that the absence of inducible ischaemia is a weak predictor of event-free survival, at least for patients with underlying coronary heart disease undergoing major vascular surgery.

If this is the case, there are several possible reasons for the lack of efficacy of stress testing. One possibility is that our patients may have been more likely to have diffuse distal vessel disease given the high prevalence of diabetes, hypertension, and chronic renal insufficiency. In this setting, regional inducible ischaemia may be more difficult to detect with stress testing because of global reduced coronary flow reserve rather than regional reduction of perfusion related to the presence of a severe underlying plaque.32 Furthermore, in these patients, a prothrombotic milieu and autonomic dysfunction with abnormal coronary vasoconstriction may be present independently of the severity of coronary artery disease.31 Therefore, a negative pre-operative stress test before major vascular surgery may have a relatively low negative predictive value.33 From the data of Sicari et al.,34 it appears that this may be particularly the case in patients who are on anti-ischaemic therapy during stress testing.34

Our data in aggregate underscore the potential difficulty of identifying vascular patients who are at risk for cardiac ischaemic events using the presently recommended algorithm. Indeed, the algorithm proposed in the guidelines had to rely predominantly on observational data and expert opinion because there were no randomized trials to help define the process.9,10 These findings may or may not be unique to vascular surgery patients. It may be that the guidelines work well for other surgeries, which potentially involve lower risk patient groups.

A second major finding of our study was that after surgery, even minor elevations of cTnI were the most important predictor of subsequent death and MI. The association between cTnI and the combined endpoint death and MI was significant in all clinical subsets and was independent of other clinical variables. There was a positive association between mortality alone and cTnI elevations as well. These elevations also seem to predict predominantly, although not exclusively, early risk (30 days). Thus, our study confirms and expands the findings of Landersberg et al.4 that elevations of cTnI above the lowest level of analytic sensitivity achievable without inducing analytic false positives identify patients at risk of death or major cardiac event even after risk stratification.

If indeed most of the events had occurred over the long-term, one could argue that once identified, patients at risk could be evaluated and treated. Unfortunately, a large proportion of the events occurred early, i.e. within 30 days. This finding was more clearly evident for groups 1 and 2. To the best of our knowledge, this is the first study to demonstrate this association. It suggests that better risk stratification a priori and an aggressive early response to troponin elevations, as in patients with acute coronary syndromes, are indicated. The exact therapeutic strategies that might be optimal are unclear, and our data do not test a given strategy. It is known from the data of Landesberg that most troponin elevations in these patients are associated with ischaemic appearing ST-segment changes, in keeping with the known high incidence of coronary artery disease in these patients.2,6 However, neither the new institution of perioperative (P=0.259) nor post-discharge beta-blockers (P=0.861) made a difference in any of the groups. Indeed, patients previously on beta-blockers did worse, perhaps because they were identified by the use of that agent as at greater risk; this finding is similar to previous studies as reported in the meta-analysis by Giles et al.35 Beyond beta-blockade, other myocardial protective or vascular stabilizing drugs may be helpful.36 However, given the complexity of implementing invasive cardiac interventions post-operatively, the better approach would be better a priori risk stratification. Certainly, an aggressive approach to patients with post-operative elevations of troponin is advised.

Focusing on the short-term morbidity should not be interpreted as indicating that for patients who do well initially, the risk is obviated. Late events were still predicted by elevations of cTnI, suggesting that even if patients do well initially, they may require evaluation and perhaps additional therapy.


    Limitations and strengths
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations and strengths
 Conclusion
 Acknowledgements
 References
 
Treating physicians were not blinded to the results of laboratory tests, but it is unlikely that the knowledge of the results of cTnI influenced the management of the patients because the clinical interpretation of minor elevations of cTnI with normal CK-MB at the time of the study was uncertain.

Only eight patients (44.4%) of the 18 with inducible ischaemia at the stress test had prophylactic revascularization. However, because the benefit of prophylactic coronary-artery revascularization before elective major vascular surgery was and still is unclear,30,35 only patients with a high risk stress testing result underwent coronary angiography.

Beta-blockers use was not universal. Thus, it is possible that some of the events and/or cTnI elevations might have been obviated by the use of beta-blockade. Nonetheless, even when beta-blocker therapy has been universally applied in clinical trials, cardiac morbidity and mortality have not been eliminated.37

The surgical details of the procedure itself and/or the details of the stress testing and/or other patient characteristics may be of importance but the focus of the study was towards the initial risk stratification with the AHA/ACC guidelines. For similar reasons, neither we prospectively collect the information on the success of revascularization nor the extent of CAD.

Finally, because of its prolonged elevation in the blood (up to 10 days), cTnI could reflect pre-operative events, which were clinically unapparent, in a small subset of patients.


    Conclusion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations and strengths
 Conclusion
 Acknowledgements
 References
 
After pre-operative risk stratification according to the ACC/AHA guidelines, patients undergoing elective major vascular surgery have a high risk of death and acute MI and most of the events occur within the first 30 days after surgery. cTnI elevations were frequent and were strongly and independently associated with the risk of subsequent death and/or MI. Our data suggest the need for a re-evaluation of the approach to risk stratification in patients undergoing vascular surgery. Furthermore, given the significant early hazard, additional strategies for post-operative treatment must be developed and tested.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations and strengths
 Conclusion
 Acknowledgements
 References
 
The study was supported by a grant from the Ministero dell' Universita e della Ricerca Scientifica e Tecnologica (MURST). We thank Diane Grill, MS, from Health Science Research Department of Mayo Clinic for the statistical support.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations and strengths
 Conclusion
 Acknowledgements
 References
 

  1. Raby KE, Barry J, Creager MA, Cook EF, Weisberg MC, Goldman L. Detection and significance of intraoperative and postoperative myocardial ischemia in peripheral vascular surgery. JAMA 1992;268:222–227.[Abstract]
  2. Kertai MD, Boersma E, Klein J, Van Urk H, Bax JJ, Poldermans D. Long-term prognostic value of asymptomatic cardiac troponin T elevations in patients after major vascular surgery. Eur J Vasc Endovasc Surg 2004;28:59–66.[CrossRef][ISI][Medline]
  3. Landesberg G, Mosseri M, Wolf YG, Bocher M, Basevitch A, Rudis E, Izhar U, Anner H, Weissman C, Berlatzky Y. Preoperative thallium scanning, selective coronary revascularization, and long-term survival after major vascular surgery. Circulation 2003;108:177–183.[Abstract/Free Full Text]
  4. Landesberg G, Shatz V, Akopnik I, Wolf YG, Mayer M, Berlatzky Y, Weissman C, Mosseri M. Association of cardiac troponin, CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery. J Am Coll Cardiol 2003;42:1547–1554.[Abstract/Free Full Text]
  5. Mangano DT, Goldman L. Preoperative assessment of patients with known or suspected coronary disease. N Engl J Med 1995;333:1750–1756.[Free Full Text]
  6. Hertzer NR, Beven EG, Young JR, O'Hara PJ, Ruschhaupt WF III, Graor RA, Dewolfe VG, Maljovec LC. Coronary artery disease in peripheral vascular patients. A classification of 1000 coronary angiograms and results of surgical management. Ann Surg 1984;199:223–233.[ISI][Medline]
  7. Belch JJ, Topol EJ, Agnelli G, Bertrand M, Califf RM, Clement DL, Creager MA, Easton JD, Gavin JR III, Greenland P, Hankey G, Hanrath P, Hirsch AT, Meyer J, Smith SC, Sullivan F, Weber MA. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med 2003;163:884–892.[Free Full Text]
  8. Fleisher LA, Rosenbaum SH, Nelson AH, Barash PG. The predictive value of preoperative silent ischemia for postoperative ischemic cardiac events in vascular and nonvascular surgery patients. Am Heart J 1991;122:980–986.[CrossRef][ISI][Medline]
  9. Eagle KA, Brundage BH, Chaitman BR, Ewy GA, Fleisher LA, Hertzer NR, Leppo JA, Ryan T, Schlant RC, Spencer WH III, Spittell JA Jr, Twiss RD, Ritchie JL, Cheitlin MD, Gardner TJ, Garson A Jr, Lewis RP, Gibbons RJ, O'Rourke RA, Ryan TJ. Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 1996;27:910–948.[CrossRef][ISI][Medline]
  10. Eagle KA, Berger PB, Calkins H, Chaitman BR, Ewy GA, Fleischmann KE, Fleisher LA, Froehlich JB, Gusberg RJ, Leppo JA, Ryan T, Schlant RC, Winters WL Jr, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Jacobs AK, Hiratzka LF, Russell RO, Smith SC Jr. 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;105:1257–1267.[Free Full Text]
  11. Samain E, Farah E, Leseche G, Marty J. Guidelines for perioperative cardiac evaluation from the American College of Cardiology/American Heart Association task force are effective for stratifying cardiac risk before aortic surgery. J Vasc Surg 2000;31:971–979.[CrossRef][ISI][Medline]
  12. Landesberg G, Mosseri M, Shatz V, Akopnik I, Bocher M, Mayer M, Anner H, Berlatzky Y, Weissman C. Cardiac troponin after major vascular surgery: the role of perioperative ischemia, preoperative thallium scanning, and coronary revascularization. J Am Coll Cardiol 2004;44:569–575.[Abstract/Free Full Text]
  13. Lopez-Jimenez F, Goldman L, Sacks DB, Thomas EJ, Johnson PA, Cook EF, Lee TH. Prognostic value of cardiac troponin T after noncardiac surgery: 6-month follow-up data. J Am Coll Cardiol 1997;29:1241–1245.[Abstract]
  14. Kim LJ, Martinez EA, Faraday N, Dorman T, Fleisher LA, Perler BA, Williams GM, Chan D, Pronovost PJ. Cardiac troponin I predicts short-term mortality in vascular surgery patients. Circulation 2002;106:2366–2371.[Abstract/Free Full Text]
  15. Jaffe AS. A small step for man, a leap forward for postoperative management. J Am Coll Cardiol 2003;42:1555–1557.[Free Full Text]
  16. Badner NH, Knill RL, Brown JE, Novick TV, Gelb AW. Myocardial infarction after noncardiac surgery. Anesthesiology 1998;88:572–578.[CrossRef][ISI][Medline]
  17. Mahar LJ, Steen PA, Tinker JH, Vlietstra RE, Smith HC, Pluth JR. Perioperative myocardial infarction in patients with coronary artery disease with and without aorta–coronary artery bypass grafts. J Thorac Cardiovasc Surg 1978;76:533–537.[Abstract]
  18. 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;36:959–969.[Free Full Text]
  19. Goldman L, Caldera DL, Nussbaum SR, Southwick FS, Krogstad D, Murray B, Burke DS, O'Malley TA, Goroll AH, Caplan CH, Nolan J, Carabello B, Slater EE. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977;297:845–850.[Abstract]
  20. Eagle KA, Boucher CA. Cardiac risk of noncardiac surgery. N Engl J Med 1989;321:1330–1332.[ISI][Medline]
  21. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, Ludwig LE, Pedan A, Goldman L. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100:1043–1049.[Abstract/Free Full Text]
  22. Sicari R, Ripoli A, Picano E, Djordjevic-Dikic A, Di Giovanbattista R, Minardi G, Matskeplishvili S, Ambatiello S, Pulignano G, Accarino M, Lusa AM, Del Rosso GF, Pedrinelli R, Buziashvili Y. Perioperative prognostic value of dipyridamole echocardiography in vascular surgery: A large-scale multicenter study in 509 patients. EPIC (Echo Persantine International Cooperative) Study Group. Circulation 1999;100:II269–II274.[Medline]
  23. Poldermans D, Fioretti PM, Forster T, Thomson IR, Boersma E, el-Said EM, du Bois NA, Roelandt JR, van Urk H. Dobutamine stress echocardiography for assessment of perioperative cardiac risk in patients undergoing major vascular surgery. Circulation 1993;87:1506–1512.[Abstract/Free Full Text]
  24. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996;335:1713–1720.[Abstract/Free Full Text]
  25. Mason JJ, Owens DK, Harris RA, Cooke JP, Hlatky MA. The role of coronary angiography and coronary revascularization before noncardiac vascular surgery. JAMA 1995;273:1919–1925.[Abstract]
  26. Grayburn PA, Hillis LD. Cardiac events in patients undergoing noncardiac surgery: shifting the paradigm from noninvasive risk stratification to therapy. Ann Intern Med 2003;138:506–511.[Abstract/Free Full Text]
  27. Pierpont GL, Moritz TE, Goldman S, Krupski WC, Littooy F, Ward HB, McFalls EO. Disparate opinions regarding indications for coronary artery revascularization before elective vascular surgery. Am J Cardiol 2004;94:1124–1128.[CrossRef][ISI][Medline]
  28. Monahan TS, Shrikhande GV, Pomposelli FB, Skillman JJ, Campbell DR, Scovell SD, Logerfo FW, Hamdan AD. Preoperative cardiac evaluation does not improve or predict perioperative or late survival in asymptomatic diabetic patients undergoing elective infrainguinal arterial reconstruction. J Vasc Surg 2005;41:38–45; discussion 45.[CrossRef][ISI][Medline]
  29. Rihal CS, Eagle KA, Mickel MC, Foster ED, Sopko G, Gersh BJ. Surgical therapy for coronary artery disease among patients with combined coronary artery and peripheral vascular disease. Circulation 1995;91:46–53.[Abstract/Free Full Text]
  30. McFalls EO, Ward HB, Moritz TE, Goldman S, Krupski WC, Littooy F, Pierpont G, Santilli S, Rapp J, Hattler B, Shunk K, Jaenicke C, Thottapurathu L, Ellis N, Reda DJ, Henderson WG. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004;351:2795–2804.[Abstract/Free Full Text]
  31. Picano E, Sicari R. Risk stratification by stress echocardiography: a whiter shade of pale? Eur J Echocardiogr 2004;5:162–164.[CrossRef][Medline]
  32. Kamalesh M, Matorin R, Sawada S. Prognostic value of a negative stress echocardiographic study in diabetic patients. Am Heart J 2002;143:163–168.[CrossRef][ISI][Medline]
  33. Di Carli MF, Hachamovitch R. Should we screen for occult coronary artery disease among asymptomatic patients with diabetes? J Am Coll Cardiol 2005;45:50–53.[Abstract/Free Full Text]
  34. Sicari R, Cortigiani L, Bigi R, Landi P, Raciti M, Picano E. Prognostic value of pharmacological stress echocardiography is affected by concomitant antiischemic therapy at the time of testing. Circulation 2004;109:2428–2431.[Abstract/Free Full Text]
  35. Giles JW, Sear JW, Foex P. Effect of chronic beta-blockade on peri-operative outcome in patients undergoing non-cardiac surgery: an analysis of observational and case control studies. Anaesthesia 2004;59:574–583.[CrossRef][ISI][Medline]
  36. Moscucci M, Eagle KA. Coronary revascularization before noncardiac surgery. N Engl J Med 2004;351:2861–2863.[Free Full Text]
  37. Auerbach AD, Goldman L. beta-Blockers and reduction of cardiac events in noncardiac surgery: scientific review. JAMA 2002;287:1435–1444.[Abstract/Free Full Text]

Related articles in EHJ:

Should the ACC/AHA guidelines be changed in patients undergoing vascular surgery?
Sanne E. Hoeks, Jeroen J. Bax, and Don Poldermans
EHJ 2005 26: 2358-2360. [Extract] [Full Text]