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)
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Abstract |
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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=2.6010.43; P<0.0001) in group 1 and 2.58 (95% CI=1.274.38; 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=2.927.65; P<0.0001) and at 30 days (adjusted HR=5.52, 95%CI=3.239.42; 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
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Introduction |
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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.
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Methods |
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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.
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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 1824 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 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 KruskalWallis non-parametric test. Survival analyses were performed by KaplanMeier 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).
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Results |
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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. 1216 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=1.836.00; P<0.0001) and those in group 2 had a risk of cTnI elevation seven times higher (unadjusted relative risk=7.73, 95%CI=3.2818.21; 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=1.89123.26; P=0.011) for group 1, 7.19 (95%CI=2.9517.52; P<0.0001) for group 2, and 61.8 (95%CI=7.42514.8; 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=1.3319.42; P=0.018) for group 1, HR=4.09 (95%CI=2.147.82; P<0.0001) for group 2, and HR=8.20 (95%CI=3.0921.74; P<0.0001) for group 3 (Table 6).
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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=2.927.65; P<0.0001) (Table 3), at 30 days (adjusted HR=10.97, 95%CI=5.0124.01; P<0.0001), and among 30-day survivors (adjusted HR=5.52, 95%CI=3.239.42; 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=2.637.10; P<0.0001) (Table 3).
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Discussion |
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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.
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Limitations and strengths |
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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.
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Conclusion |
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Acknowledgements |
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References |
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