Vascular Surgery Patients: Perioperative and Long-Term Risk According to the ACC/AHA Guidelines, the Additive Role of Post-Operative Troponin Elevation

European Heart Journal (2005) 26, 2448–2456 Clinical research doi:10.1093/eurheartj/ehi430

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, 1 3 3 3 1

Teresa Grimaldi , Antonio Rumolo , Mauro Gargiulo , Andrea Stella , Maria Grazia Modena , Downloaded from https://academic.oup.com/eurheartj/article/26/22/2448/507655 by guest on 27 September 2021 and Allan S. Jaffe2*

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

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

KEYWORDS Aims The objectives of this study are to evaluate the prognostic role of pre-operative stratification in Troponin; patients undergoing elective major vascular surgery, the timing of adverse outcomes, and the predictive Vascular surgery; role of troponin (cTn). Risk stratification Methods and results Consecutive vascular surgery candidates (n ¼ 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 ¼ 2.60–10.43; P , 0.0001) in group 1 and 2.58 (95% CI ¼ 1.27–4.38; P ¼ 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 ¼ 4.73, 95% CI ¼ 2.92–7.65; P , 0.0001) and at 30 days (adjusted HR ¼ 5.52, 95%CI ¼ 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.

Introduction patients stratified according to these recommendations have been published. Patients referred for major vascular surgery are a population Recent data have indicated that cardiac troponin (cTn) known to be at high risk for perioperative1,2 and late-cardiac 3–5 elevations occur frequently post-operatively in these events because of the high prevalence of underlying coro- patients, and even minor elevations are strongly related to nary artery disease.6,7 Often, the manifestations of ischae- 6,8 perioperative ischaemia and define an adverse short- and mia are not overt and thus considered ‘silent’. The long-term prognosis.12 These data reinforce prior studies known morbidity and mortality associated with underlying indicative of a worse mid-13,14 and long-term2,4 survival, cardiovascular disease in patients who undergo non-cardiac leading to the suggestion that in vascular surgery patients, surgery is generally well known and has resulted in guide- cTn elevations should be considered from the prognostic lines from the American College of Cardiology/American standpoint similar to elevations in patients with acute coro- Heart Association (ACC/AHA) for pre-operative evaluation of 15 9,10 nary syndromes. The optimal strategy to prevent these cardiac risk in this group. These guidelines are used events will depend on when they occur post-operatively. worldwide because no other set of guidelines exists in To date, no study has investigated the timing of these the area. However, reports of the use of these guidelines 11 adverse events to determine whether they occur soon in vascular surgery patients have been rare and, to after vascular surgery or are predominantly late events. the best of our knowledge, no data on the outcomes of Accordingly, the aims of this study are (1) to investigate whether patients undergoing elective major vascular * Corresponding author. Tel: þ1 507 284 3680; fax: þ1 507 266 0228. surgery, prospectively risk stratified, according to the E-mail address: [email protected] ACC/AHA guidelines for non-cardiac surgery are at risk of

& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: [email protected] Vascular surgery patients 2449 developing elevations of cTn, (2) to determine whether such Table 1 Clinical predictors of cardiovascular risk elevations in this population are associated with subsequent death and/or myocardial infarction (MI), (3) if so, to deter- Major mine the timing of adverse outcomes (within the first 30 Unstable coronary syndromes: acute or recent MI; unstable or days or long-term), and (4) to investigate whether post- severe angina (Canadian class III or IV) operative cTn elevations augment the risk stratification Decompensated heart failure strategy provided by the ACC/AHA guidelines. Significant arrhythmias Severe valvular disease Intermediate Mild angina pectoris (Canadian class I or II) Methods Previous MI by history or pathological Q-wave Compensated or prior heart failure This was a prospectively designed study using the ACC/AHA guide- Diabetes mellitus lines for perioperative cardiovascular evaluation in non-cardiac

Renal insufficiency Downloaded from https://academic.oup.com/eurheartj/article/26/22/2448/507655 by guest on 27 September 2021 surgery.9 Between September 2000 and July 2002, all subjects Minor referred for elective major vascular surgery at the ‘Policlinico Advanced age University Hospital’ of Modena (Italy) were prospectively screened Abnormal ECG (left ventricular hypertrophy, left bundle branch according to the guidelines for pre-operative evaluation of cardiac block, ST-T abnormalities) risk in non-cardiac surgery. In addition, an evaluation of renal func- Rhythm other than sinus (e.g. atrial fibrillation) tion was included. This assessment was added to the guidelines Low functional capacity (e.g. inability to climb one flight of in 2002.10 cTnI was measured post-operatively at prospectively stairs with a bag of groceries) determined pre-specified time points. Samples for measurement History of stroke of cTnI were obtained on post-operative days 1, 2, and 3. These Uncontrolled systemic hypertension 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 We did not have patients with major clinical cardiovascular risk risk groups: predictors, because our study was in a population referred for elective surgery. For patients with intermediate, minor, or no clinical (i) Group 1 included subjects with history of coronary revascula- cardiovascular risk predictors, consideration of functional capacity rization in the past 5 years and no recurrent symptoms. [metabolic equivalents (METs) as determined by history of daily (ii) Group 2 included patients with intermediate clinical cardio- activity] and level of surgery-specific risk (high risk: aortic or infra- vascular risk predictors. inguinal major vascular surgery; intermediate risk: carotid endar- (iii) Group 3 included patients with minor or no clinical cardiovas- terectomy) allows an approach to identify patients that may most cular risk predictors. benefit from further non-invasive testing. Patients with intermedi- Subsequently, each of these groups was divided into subgroups, on ate cardiovascular risk predictors (group 2) underwent non-invasive the basis of the presence of an elevated cTnI post-operatively. testing and eventually coronary angiography in the presence of poor The study complies with the Declaration of Helsinki, the Ethics functional capacity (METs ,4) or high surgical risk and, finally, Committee has approved the research protocol, and the informed patients with minor or no clinical cardiovascular risk predictors consent has been obtained from the subjects. (group 3) underwent non-invasive testing and eventually coronary angiography in presence of poor functional capacity (METs ,4) and high surgical risk. Perioperative cardiovascular stratification This step-wise approach was applied independently to each patient by two cardiologists. The conclusion drawn by each investi- The ACC/AHA guidelines for pre-operative evaluation of cardiac risk gator for each file was similar in all cases. 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 Troponin assay consider the following variables step-by-step: urgency level of cTnI was measured with the Stratus CS STAT fluorimetric analyzer non-cardiac surgery (emergency, urgency, or elective), history of (Dade Behring Inc., Newark, DE, USA), which is a high level of ana- coronary revascularization in the past 5 years, recent coronary lytic precision two-site sandwich immunoassay based on solid phase evaluation in the past 2 years, and clinical predictors of increased radial partition immunoassay technology. The minimum detectable perioperative cardiovascular risk. The clinical predictors of pre- concentration is 0.03 ng/mL and the upper reference limit (99th operative cardiovascular risk are classified into three categories: percentile of the reference range) is 0.07 ng/mL. At the time of major, intermediate, and low risk predictors (Table 1 ). According this study in our institute, the lowest concentration with coefficient to the guidelines, patients with history of coronary revascularization of variation ,10% was 0.10 ng/mL. Values 10% coefficient of vari- in the past 5 years, who have remained stable without recurrent ation, i.e. 0.10 ng/mL, were used to define cTnI elevations. This is signs or symptoms of ischaemia until the time of surgery (group the criterion used by Landesberg et al.4 1), are sent to the operation without further cardiac testing, as the likelihood of perioperative cardiac death or MI had been pre- Follow-up viously reported to be low.9,10,17 Similarly, the subgroup which has undergone an invasive or non-invasive coronary evaluation in the The main dependent variable was the combined endpoint death or past 2 years, in the absence of an unfavourable stress test result MI after the index surgery. The planned follow-up took place at or changes of symptoms, can also undergo surgery without further 18–24 months after the surgery and incorporated review of hospital evaluation. For the purpose of the analysis and because detailed charts, death certificates, autopsy reports (if available), and tele- information on risk factors was collected for all patients in this phone interview by two independent investigators unaware of the group, this group was evaluated more rigorously than mandated, patients’ history, laboratory exams, and aim of the study. MI was in a manner similar to intermediate risk patients (group 2), i.e. on clinically and independently diagnosed by pre-specified criteria the basis of the presence of clinical cardiovascular risk predictors. using the new American College of Cardiology/European Society of 2450 F. Bursi et al.

Cardiology (ACC/ESC) definition, which requires a typical rise and testing before the vascular procedure, 87 (59.2%) had the gradual fall of troponin values when either the setting, clinical, or stress test .6 months before the surgery and 18 (12.2%) 18 ECG findings suggest the presence of acute ischaemia. To be had inducible ischaemia. Pre-operative myocardial revascu- included, the reviewers had to agree. After adjudication, this was larization was considered to be the best therapeutic option the situation for all cases. after coronary angiography in eight patients of these patients (six coronary artery bypass grafts and two percuta- Statistic analysis neous transluminal coronary angioplasties), a mean time of Summary statistics are presented as frequencies (percentages) or as 84 + 15 days before operation; these subjects represent mean + SD. Categorical variables were compared by a x2 test or the 5.4% of subjects who underwent non-invasive stress Fisher’s exact test, when appropriate, and continuous variables by testing. The remaining patients were treated pre- ANOVA. For skewed distributions, variables are presented as operatively with an intensified medical regimen including median and first and third quartiles (Q1 and Q3) and groups were com- high dose beta-blockers titrated to heart rate, nitrates, pared by Kruskal–Wallis non-parametric test. Survival analyses were and statins. The baseline characteristics of these three Downloaded from https://academic.oup.com/eurheartj/article/26/22/2448/507655 by guest on 27 September 2021 performed by Kaplan–Meier curves and the groups were compared by groups are shown in Table 2. 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 Follow-up experience death or MI were censored at 30 days. The individuals who died within 30 days were excluded from the analysis to evaluate The mean follow-up was 18.9 + 6.2 months. During the the HR for the combined endpoint in 30-day survivors. Only one end- entire follow-up, 83 subjects experienced at least one endpoint event was included for each patient. point event: 46 subjects had died and 52 experienced an The variables for the multivariable Cox regression model were acute MI. At 18 months, overall event-free survival was selected among the variables with P , 0.10 at univariate analysis 81.3%, 55.1% in group 1, 77.4% in group 2, and 90.7% in and age and gender were forced into the model. As the definition group 3 (P , 0.0001; Figure 2 ). At 18 months, death of the three groups was based on the clinical predictors of cardiovascular risk, which included most of cardiovascular risk factors occurred in 20.0% in group 1, 13.7% in group 2, and 4.4% in and cardiac co-morbidity, to avoid collinearity and to keep the group 3 (P ¼ 0.0036); the incidence of MI was 39.6% in model as parsimonious as possible, these variables were treated in group 1, 12.0% in group 2, and 7.4% in group 3 two ways. They were not entered individually but as summary vari- (P , 0.0001). Considering group 3 as referent, the HR of able (clinical risk group) initially. Subsequently, they were entered the combined endpoint was 5.21 (95%CI ¼ 2.60–10.43; separately in place of the summary variable as well. We statistically P , 0.0001) in group 1 and 2.58 (95%CI ¼ 1.52–4.38; evaluated the Cox proportional hazards model assumptions by plot- P ¼ 0.004) in group 2 (Table 3 ). ting the scaled Schoenfeld residuals against time and by testing the There was a steep decline in event-free survival early correlation between these two variables, and there were no major after surgery, which persisted during the follow-up. At 30 violations of these assumptions. The only continuous co-variable days, 40 (10.2%) subjects had died and/or experienced an was age, which was tested by including the quadratic term for age in the model. It was not significant. Logistic regression analysis acute MI (18 died and 32 had acute MI). Event-free survival was used to evaluate the unadjusted relative risk of post-operative at 30 days was 72% in group 1, 88% in group 2, and 96% in cTnI elevation in the three groups. All tests were two-sided, and for group 3 (P , 0.0001) (Figure 2 ). The HR of the combined all analyses, P , 0.05 was considered statistically significant. For endpoint was 7.84 (95%CI ¼ 2.92–21.08; P , 0.0001) in some cells with very small numbers, multivariable adjustment group 1 and 2.96 (95%CI ¼ 1.27–6.91; P ¼ 0.012) in group 2 could not be applied. when compared with group 3 (Table 4 ). All P-values were reported to allow for evaluation of any type I Among 373 patients who survived after 30 days, 65 (17.4%) error that could occur. subjects subsequently died or experienced an acute MI (28 w All statistical analyses were performed with the software SPSS died and 46 had acute MI). Event-free survival at 18 10.0 for Windows (SPSS Institute Inc., Chicago, IL, USA) and months was 60.8% in group 1, 82.1% in group 2, and 93.2% STATAw 8.0 (College Station, TX, USA). in group 3 (P , 0.0001). The HR of the combined endpoint was 4.81 (95%CI ¼ 2.24–10.32; P , 0.0001) in group 1 and Results 2.21 (95%CI ¼ 1.24–3.93; P ¼ 0.007) in group 2 (Table 4 ). Post-operative cTnI was elevated in 85 patients (21.7%): Baseline characteristics 15 (46.9%) patients in group 1, 53 (27.5%) in group 2, and During the study period, 391 candidates referred for elec- 17 (10.2%) in group 3 (P , 0.0001). Peak values of cTnI tive major vascular surgery at our institution were risk stra- were observed on the first post-operative day, i.e. 12–16 h tified and treated according to the ACC/AHA guidelines for after the surgery. Considering group 3 as referent, patients pre-operative evaluation of cardiac risk in non-cardiac in group 1 had a risk of cTnI elevation three times surgery (Figure 1 ). All 391 patients who were screened higher (unadjusted relative risk ¼ 3.32, 95%CI ¼ 1.83–6.00; eventually underwent surgery. In the overall population, P , 0.0001) and those in group 2 had a risk of cTnI elevation there were 32 patients with history of coronary revascula- seven times higher (unadjusted relative risk ¼ 7.73, rization in the past 5 years (mean 3.3 + 1.6 years) and 95%CI ¼ 3.28–18.21; P , 0.0001). asymptomatic in the interim (group 1) who, according to When each group was divided into two subgroups on the the guidelines, went directly to surgery. There were 193 basis of the presence of cTnI 0.10 ng/mL, patients with patients with intermediate clinical cardiovascular risk pre- elevated cTnI had a significantly higher risk of both com- dictors (group 2) and 166 patients with minor or no clinical bined endpoint and MI alone, which was consistent among cardiovascular risk predictors (group 3). None of the the three clinical risk groups (Table 5 ). Post-operative cTnI patients had major clinical cardiovascular risk predictors. was strongly associated with the combined endpoint in all Among the 147 (37.6%) patients who underwent stress clinical risk groups, the HR for death or MI at 30 days was Vascular surgery patients 2451 Downloaded from https://academic.oup.com/eurheartj/article/26/22/2448/507655 by guest on 27 September 2021

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.

15.24 (95%CI ¼ 1.89–123.26; P ¼ 0.011) for group 1, 7.19 clinical risk group, age, gender, low exercise tolerance in (95%CI ¼ 2.95–17.52; P , 0.0001) for group 2, and 61.8 METS, surgical risk, and beta-blockers (adjusted (95%CI ¼ 7.42–514.8; P , 0.0001) for group 3 (Table 6 ). HR ¼ 4.73, 95%CI ¼ 2.92–7.65; P , 0.0001) (Table 3 ), at The association between post-operative elevations of cTnI 30 days (adjusted HR ¼ 10.97, 95%CI ¼ 5.01–24.01; and death or MI was less strong, but remained significant P , 0.0001), and among 30-day survivors (adjusted among 30-day survivors, HR ¼ 5.08 (95%CI ¼ 1.33–19.42; HR ¼ 5.52, 95%CI ¼ 3.23–9.42; P , 0.0001) (Table 4 ). The P ¼ 0.018) for group 1, HR ¼ 4.09 (95%CI ¼ 2.14–7.82; addition of beta-blockers, perioperatively (P ¼ 0.259) and P , 0.0001) for group 2, and HR ¼ 8.20 (95%CI ¼ post-discharge (P ¼ 0.861), did not affect the outcomes. 3.09–21.74; P , 0.0001) for group 3 (Table 6 ). However, patients receiving beta-blockers chronically pre- Among the patients who underwent myocardial revascu- operatively did worse with HRs from 2.1 to 3.2, depending larization, a time to the vascular procedure longer than on the follow-up period. When elevations of cTnI are included 1 year was not related to cTnI elevation (unadjusted relative in the model, the differences in the HRs between groups 2 risk ¼ 0.89, 95%CI ¼ 0.13–1.81; P ¼ 0.286) or to the com- and 3 were eliminated. bined endpoint (HR ¼ 0.82, 95%CI ¼ 0.31–2.2; P ¼ 0.686). Further adjustment for significant individual components (chronic renal insufficiency, diabetes, history of coronary artery disease, and heart failure) rather than use of the Multivariable analysis summary variable did not change the strong independent The strong association of cTnI with the combined endpoint association between cTnI and MI and death (HR ¼ 4.32, persisted unchanged during follow-up after adjusting for 95%CI ¼ 2.63–7.10; P , 0.0001) (Table 3 ). 2452 F. Bursi et al.

Table 2 Baseline characteristics of the three groups

Group 1 Group 2 Group 3 P-value

Age (n ¼ 391), mean + SD 69.0 + 9.4 70.4 + 8.5 69.3 + 8.6 0.411 Women (n ¼ 391) 8 (25) 51 (26.4) 39 (23.5) 0.815 High surgery risk (n ¼ 391) 17 (53.1) 135 (69.9) 91 (54.8) 0.007 Diabetes (n ¼ 391) 15 (46.9) 126 (65.3) 0 (0) 0.0001 Smoking (n ¼ 390) 20 (62.5) 108 (56.0) 98 (59.4) 0.695 Hypertension (n ¼ 391) 27 (84.4) 161 (83.4) 108 (65.1) 0.0001 Dyslipidaemia (n ¼ 391) 12 (37.5) 35 (18.1) 31 (18.7) 0.034 Previous coronary artery disease (n ¼ 391) 32 (100) 51 (26.4) 0 (0) 0.0001 Previous heart failure (n ¼ 391) 18 (56.3) 64 (33.2) 0 (0) 0.0001

Previous stroke/TIA (n ¼ 378) 8 (28.6) 36 (19.1) 32 (19.8) 0.504 Downloaded from https://academic.oup.com/eurheartj/article/26/22/2448/507655 by guest on 27 September 2021 Chronic obstructive pulmonary disease (n ¼ 391) 10 (31.3) 61 (31.6) 41 (24.7) 0.333 Renal failure (n ¼ 389) 12 (37.5) 61 (31.6) 0 (0) 0.0001 Permanent atrial ﬁbrillation (n ¼ 371) 3 (10.7) 13 (7.1) 9 (5.7) 0.598 METS,4(n ¼ 391) 10 (31.3) 50 (25.9) 7 (4.2) 0.0001 Previous beta-blockers (n ¼ 387) 10 (31.3) 24 (12.6) 15 (9.1) 0.003 Perioperative beta-blockersa (n ¼ 284) 19 (73.1) 91 (62.3) 83 (74.1) 0.112 Post-discharge beta-blockers (n ¼ 373) 18 (60.0) 91 (50.8) 89 (54.3) 0.597 Delta haemoglobin pre-post (n ¼ 370), median (Q1–Q3) 1.15 (0.07–2) 1.45 (0.6–2.4) 1.5 (0.62–2.2) 0.309 Type of surgery (n ¼ 391) 0.2 Carotid endoarterectomy 15 (46.9) 58 (30.1) 75 (45.2) Low-extremity bypass surgery 15 (46.9) 115 (59.6) 72 (43.4) Aortic repair 2 (6.3) 20 (6.3) 19 (11.4)

Groups as in Figure 1. Values are number (%) unless indicated otherwise. TIA, transient ischaemic attack; NB, according to the stratiﬁcation algorithm, there are several cells with no patients in group 3. a Morning of surgery, during surgery, and/or ﬁrst 48 h after surgery.

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 Figure 2 Survival free from MI among the three groups of patients. Top improve immediate periprocedural and long-term clinical panel: survival during the entire follow-up. Bottom panel: survival over 30 9 days. Note that most events occurred early. outcomes of 30 million patients who undergo noncardiac surgery every year in the United States.5 They have been predicated on an extensive body of literature Discussion attempting to identify individuals at higher risk on the basis of clinical variable19–21 or diagnostic tests22,23 and to The present study indicates that despite pre-operative risk improve outcomes.24–26 Although patients undergoing elec- stratification, according to the ACC/AHA guidelines, tive major vascular surgery are a very high risk group, patients undergoing elective major vascular surgery because of the diffuse nature of the atherosclerotic remain at high risk of death and acute MI. Patients who disease,15 these guidelines have not been extensively evalu- had revascularization in the past 5 years and patients with ated in this type of surgery. Perhaps, this also implies that intermediate clinical risk predictors had a higher risk than they are not followed universally.27 In our study, we prospec- patients with minor or no clinical risk predictors, but even tively stratified elective major vascular surgery candidates within this group, the event rate at 18 months was substan- according to the available ACC/AHA guidelines. When the tial (9.3%). The frequency of post-operative troponin 2002 update guidelines were published, our database was elevations we observed (21.7%) is similar to that reported sufficiently robust and included in most instances the data Vascular surgery patients 2453

Table 3 Unadjusted and adjusted HR for the combined endpoint death and MI during the follow-up

Death or MI HR P-value Model 1 adjusted HR P-value Model 2 adjusted HR P-value (95% CI) (95% CI) (95% CI)

Group 3 (reference) 1.00 1.00 Group 1 vs. group 3 5.21 (2.60–10.43) ,0.0001 2.50 (1.18–5.28) 0.016 Group 2 vs. group 3 2.58 (1.52–4.38) 0.004 1.43 (0.81–2.51) 0.215 Age (n ¼ 391) 1.04 (1.01–1.07) 0.010 1.05 (1.02–1.08) 0.0003 1.05 (1.02–1.08) 0.0003 Women (n ¼ 391) 1.31 (0.82–2.09) 0.262 1.59 (0.98–2.57) 0.060 1.64 (1.01–2.66) 0.046 METS , 4(n ¼ 391) 3.48 (2.22–5.47) ,0.0001 1.82 (1.08–3.07) 0.024 1.63 (1.96–2.75) 0.068 High surgical risk (n ¼ 391) 1.21 (1.03–1.42) 0.022 1.15 (0.97–1.37) 0.109 1.14 (0.96–1.37) 0.147 Previous beta-blockers (n ¼ 387) 2.08 (1.22–3.55) 0.007 2.12 (1.20–3.74) 0.009 1.94 (1.11–3.41) 0.020

Perioperative beta-blockers (n ¼ 284) 0.74 (0.44–1.25) 0.259 Downloaded from https://academic.oup.com/eurheartj/article/26/22/2448/507655 by guest on 27 September 2021 Previous heart failure (n ¼ 391) 3.60 (2.31–5.60) ,0.0001 1.142 (0.62–2.09) 0.666 Previous coronary artery 2.67 (1.71–4.19) ,0.0001 1.74 (0.99–3.06) 0.053 disease (n ¼ 391) Renal failure (n ¼ 389) 3.16 (2.01–4.97) ,0.0001 2.05 (1.23–3.41) 0.006 Diabetes (n ¼ 391) 1.30 (0.84–2.01) 0.233 cTnl positive (n ¼ 391) 5.62 (3.64–8.67) ,0.0001 4.73 (2.92–7.65) ,0.000 4.32 (2.63–7.10) ,0.0001

Table 4 Unadjusted and adjusted HR for the combined endpoint death and MI at 30 days and among 30 day survivors

Death or MI HR (95% CI) P-value Adjusted HR (95% CI) P-value

At 30 days Group 3 (reference) 1.00 1.00 Group 1 vs. group 3 7.84 (2.92–21.08) ,0.0001 2.48 (0.89–6.91) 0.083 Group 2 vs. group 3 2.96 (1.27–6.91) 0.012 1.34 (0.55–3.25) 0.513 Age (n ¼ 391) 1.03 (0.99–1.07) 0.0164 1.04 (1.00–1.09) 0.039 Women (n ¼ 391) 1.69 (0.88–3.25) 0.115 2.19 (1.11–4.33) 0.024 METS , 4(n ¼ 391) 4.46 (2.38–8.38) ,0.0001 2.15 (1.09–4.13) 0.027 High surgical risk (n ¼ 391) 1.22 (0.96–1.54) 0.110 Previous beta-blockers (n ¼ 387) 3.16 (1.57–6.37) 0.001 2.85 (1.35–6.07) 0.006 Perioperative beta-blockers (n ¼ 284) 1.17 (0.54–2.54) 0.694 cTnl positive (n ¼ 391) 15.20 (7.20–32.07) ,0.0001 10.97 (5.01–24.01) ,0.0001 Among 30-day survivors Group 3 (reference) 1.00 1.00 Group 1 vs. group 3 4.81 (2.24–10.32) ,0.0001 2.73 (1.21–6.14) 0.015 Group 2 vs. group 3 2.21 (1.24–3.93) 0.007 1.37 (0.74–2.54) 0.315 Age (n ¼ 373) 1.02 (0.97–1.06) 0.119 1.04 (1.01–1.07) 0.012 Women (n ¼ 373) 0.94 (0.52–1.67) 0.825 1.19 (0.66–2.15) 0.562 METS , 4(n ¼ 373) 2.59 (1.50–4.48) 0.001 1.41 (0.79–2.52) 0.251 High surgical risk (n ¼ 373) 1.11 (0.93–1.32) 0.234 Post-discharge beta-blockers (n ¼ 368) 1.05 (0.63–1.73) 0.850 cTnl positive (n–373) 6.00 (3.67–9.79) ,0.0001 5.52 (3.23–9.42) ,0.0001

necessary to re-subset these patients into more contempo- coronary artery bypass among patients undergoing major vas- rary groups. In the present study, the proportion of patients cular surgery when compared with those receiving medical who underwent myocardial revascularization before the therapy. Recent data have challenged those findings in vascular procedure was 10.2%, as that reported by other patients who like ours appeared to have stable cardiac symp- authors investigating a similar vascular surgery population toms. In that setting, revascularization before elective vascu- that underwent different risk stratification.12 Nonetheless, lar surgery did not seem to be of benefit.30 It is apparent that the application of the current ACC/AHA guidelines was not accepting revascularization during the prior 5 years without sufficient to provide protection from death and acute MI, further evaluation is not sufficient to prevent adverse out- according to a recent report by Monahan et al.28 However, comes. Whether the concept is flawed or this is an issue of it did provide for a gradient of risk. Those who had under- timing will require much larger data sets to ascertain. gone myocardial revascularization in the past 5 years Equally concerning and a harder finding given the larger consist of a relatively small number of individuals, but this numbers is the group of patients with ‘intermediate’ clinical group of patients had a 44% incidence of death or MI. This cardiovascular risk predictors. They also showed a signifi- is in contrast to the data from the Coronary Artery Surgery cantly increased risk of the combined endpoint, despite Study,29 which showed a survival benefit associated with careful evaluation. Following the ACC/AHA algorithm did 2454 F. Bursi et al.

Table 5 Events during the follow-up, based on the presence of cTnl positive

cTnl positive cTnl negative HR (95% CI) P-value

Group 1 (n ¼ 32) 15 17 Death or MI 10 4 4.8 (1.48–15.57) 0.009 Death 3 4 0.86 (0.19–3.87) 0.850 MI 9 3 5.42 (1.44–20.37) 0.012 Group 2 (n ¼ 193) 53 140 Death or MI 25 25 3.66 (2.09–6.39) ,0.0001 Death 10 19 1.50 (0.70–3.22) 0.301 MI 19 8 8.61 (3.74–19.8) ,0.0001 Group 3 (n ¼ 166) 17 149

Death or MI 8 11 8.44 (3.37–21.15) ,0.0001 Downloaded from https://academic.oup.com/eurheartj/article/26/22/2448/507655 by guest on 27 September 2021 Death 3 7 3.47 (0.88–13.63) 0.074 MI 5 8 7.31 (2.38–22.45) 0.001 Total (n ¼ 391) 85 306 Death or MI 43 40 5.62 (3.64–8.67) ,0.0001 Death 16 30 2.04 (1.11–3.74) 0.02 MI 33 19 8.81 (4.99–15.58) ,0.0001

not prevent the risk of future events, despite stress testing guidelines work well for other surgeries, which potentially in 73.6% of patients of group 2. This strong association with involve lower risk patient groups. adverse events was true also in patients with minor or no A second major finding of our study was that after surgery, clinical cardiovascular risk predictors, who had a lower but even minor elevations of cTnI were the most important pre- not trivial risk of death and acute MI. One possibility for dictor of subsequent death and MI. The association between these results is that many of the stress tests (59%) were cTnI and the combined endpoint death and MI was significant done .6 months before the surgical procedure. Perhaps, in all clinical subsets and was independent of other clinical stress testing closer to the time of surgery would be more variables. There was a positive association between mor- efficacious, although in our patients, a stress test .6 tality alone and cTnI elevations as well. These elevations months before the surgery was not associated with a also seem to predict predominantly, although not exclu- worse outcome.31 It is also possible that the absence of indu- sively, early risk (30 days). Thus, our study confirms and cible ischaemia is a weak predictor of event-free survival, at expands the findings of Landersberg et al.4 that elevations least for patients with underlying coronary heart disease of cTnI above the lowest level of analytic sensitivity achiev- undergoing major vascular surgery. able without inducing analytic false positives identify If this is the case, there are several possible reasons for patients at risk of death or major cardiac event even after the lack of efficacy of stress testing. One possibility is risk stratification. that our patients may have been more likely to have If indeed most of the events had occurred over the long- diffuse distal vessel disease given the high prevalence of term, one could argue that once identified, patients at diabetes, hypertension, and chronic renal insufficiency. In risk could be evaluated and treated. Unfortunately, a large this setting, regional inducible ischaemia may be more dif- proportion of the events occurred early, i.e. within 30 ficult to detect with stress testing because of global days. This finding was more clearly evident for groups 1 reduced coronary flow reserve rather than regional and 2. To the best of our knowledge, this is the first study reduction of perfusion related to the presence of a severe to demonstrate this association. It suggests that better risk underlying plaque.32 Furthermore, in these patients, a stratification a priori and an aggressive early response to prothrombotic milieu and autonomic dysfunction with troponin elevations, as in patients with acute coronary syn- abnormal coronary vasoconstriction may be present inde- dromes, are indicated. The exact therapeutic strategies pendently of the severity of coronary artery disease.31 that might be optimal are unclear, and our data do not Therefore, a negative pre-operative stress test before test a given strategy. It is known from the data of major vascular surgery may have a relatively low Landesberg that most troponin elevations in these patients negative predictive value.33 From the data of Sicari are associated with ischaemic appearing ST-segment et al.,34 it appears that this may be particularly the case changes, in keeping with the known high incidence of coron- in patients who are on anti-ischaemic therapy during ary artery disease in these patients.2,6 However, neither stress testing.34 the new institution of perioperative (P ¼ 0.259) nor post- Our data in aggregate underscore the potential difficulty discharge beta-blockers (P ¼ 0.861) made a difference in of identifying vascular patients who are at risk for cardiac any of the groups. Indeed, patients previously on beta- ischaemic events using the presently recommended algo- blockers did worse, perhaps because they were identified rithm. Indeed, the algorithm proposed in the guidelines by the use of that agent as at greater risk; this finding is had to rely predominantly on observational data and similar to previous studies as reported in the meta-analysis expert opinion because there were no randomized trials to by Giles et al.35 Beyond beta-blockade, other myocardial help define the process.9,10 These findings may or may not protective or vascular stabilizing drugs may be helpful.36 be unique to vascular surgery patients. It may be that the However, given the complexity of implementing invasive Vascular surgery patients 2455

Table 6 Events at 30 days and among 30-day survivors in the subgroups based on the presence of cTnl positive

cTnl positive cTnl negative HR (95% CI) P-value

Events at 30 days Group 1 (n ¼ 32) 15 17 Death or MI 8 2 15.24 (1.89–123.26) 0.011 Death 2 1 5.50 (0.50–60.93) 0.164 MI 8 1 15.42 (1.89–123.26) 0.011 Group 2 (n ¼ 193) 53 140 Death or MI 18 7 7.19 (2.95–17.52) ,0.0001 Death 6 7 2.87 (0.96–8.57) 0.058 MI 15 4 10.84 (3.56–32.98) ,0.0001

Group 3 (n ¼ 166) 17 149 Downloaded from https://academic.oup.com/eurheartj/article/26/22/2448/507655 by guest on 27 September 2021 Death or MI 6 1 61.8 (7.42–514.8) ,0.0001 Death 1 1 12.37 (0.77–197.84) 0.075 MI 4 0 NA NA Events among 30-day survivors Group 1 (n ¼ 29) 13 16 Death or MI 8 3 5.08 (1.33–19.42) 0.018 Group 2 (n ¼ 180) 47 133 Death or MI 19 18 4.09 (2.14–7.82) ,0.0001 Group 3 (n ¼ 164) 16 148 Death or MI 7 10 8.20 (3.09–21.74) ,0.001

cardiac interventions post-operatively, the better approach Finally, because of its prolonged elevation in the blood (up would be better a priori risk stratification. Certainly, an to 10 days), cTnI could reflect pre-operative events, which aggressive approach to patients with post-operative were clinically unapparent, in a small subset of patients. elevations of troponin is advised. Focusing on the short-term morbidity should not be inter- preted as indicating that for patients who do well initially, Conclusion the risk is obviated. Late events were still predicted by After pre-operative risk stratification according to the ACC/ elevations of cTnI, suggesting that even if patients do well AHA guidelines, patients undergoing elective major vascular initially, they may require evaluation and perhaps additional surgery have a high risk of death and acute MI and most of therapy. the events occur within the first 30 days after surgery. cTnI elevations were frequent and were strongly and inde- Limitations and strengths pendently associated with the risk of subsequent death and/or MI. Our data suggest the need for a re-evaluation Treating physicians were not blinded to the results of labora- of the approach to risk stratification in patients undergoing tory tests, but it is unlikely that the knowledge of the results vascular surgery. Furthermore, given the significant early of cTnI influenced the management of the patients because hazard, additional strategies for post-operative treatment the clinical interpretation of minor elevations of cTnI with must be developed and tested. 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 revasculariza- Acknowledgements tion. However, because the benefit of prophylactic coronary- artery revascularization before elective major vascular The study was supported by a grant from the Ministero dell’ surgery was and still is unclear,30,35 only patients with a high Universita e della Ricerca Scientifica e Tecnologica (MURST). We risk stress testing result underwent coronary angiography. thank Diane Grill, MS, from Health Science Research Department of Mayo Clinic for the statistical support. 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, References even when beta-blocker therapy has been universally applied in clinical trials, cardiac morbidity and mortality 1. Raby KE, Barry J, Creager MA, Cook EF, Weisberg MC, Goldman L. have not been eliminated.37 Detection and significance of intraoperative and postoperative myocardial ischemia in peripheral vascular surgery. JAMA 1992;268:222–227. The surgical details of the procedure itself and/or the 2. Kertai MD, Boersma E, Klein J, Van Urk H, Bax JJ, Poldermans D. Long- details of the stress testing and/or other patient character- term prognostic value of asymptomatic cardiac troponin T elevations in istics may be of importance but the focus of the study was patients after major vascular surgery. Eur J Vasc Endovasc Surg 2004; towards the initial risk stratification with the AHA/ACC 28:59–66. guidelines. For similar reasons, neither we prospectively 3. Landesberg G, Mosseri M, Wolf YG, Bocher M, Basevitch A, Rudis E, Izhar U, Anner H, Weissman C, Berlatzky Y. Preoperative thallium scan- collect the information on the success of revascularization ning, selective coronary revascularization, and long-term survival after nor the extent of CAD. major vascular surgery. Circulation 2003;108:177–183. 2456 F. Bursi et al.

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