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Preoperative Statin Therapy and Troponin T Predict Early Complications of Coronary Artery Surgery
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Preoperative Statin Therapy and Troponin T Predict Early Complications of Coronary Artery Surgery Domingo A. Pascual, MD, PhD, Jose M. Arribas, MD, Pedro L. Tornel, MD, PhD, Francisco Marín, MD, PhD, Clara Oliver, MD, Miguel Ahumada, MD, Jesus Gomez-Plana, MD, Pedro Martínez, MD, PhD, Ramón Arcas, MD, PhD, and Mariano Valdes, MD, PhD Departments of Cardiology, Cardiovascular Surgery, and Clinical Chemistry, Hospital Universitario Arrixaca, Murcia, and Departments of Cardiology and Cardiovascular Surgery, Hospital General Universitario, Alicante, Spain
Background. Pretreatment with statins reduces early ischemic events after percutaneous coronary interventions, primarily in patients with a high level of inflammation markers. We sought to examine the association between preoperative statin therapy, systemic inflammation, and myocardial ischemia with the occurrence of early cardiac complications after coronary artery bypass grafting surgery. Methods. One hundred forty-one consecutive patients who underwent coronary artery bypass grafting surgery from two university tertiary hospitals were stratified according to their preoperative status of statin therapy (87 treated and 54 nontreated). Preoperative blood samples were collected for measurement of lipid parameters, C-reactive protein, interleukin-6, and troponin T. The evaluated primary endpoint was a composite of death and myocardial infarction at 30 days. Results. Patients undergoing preoperative statin therapy showed a reduced incidence of death (2.3% versus 13.0%, p ⴝ 0.012), myocardial infarction (5.7% versus
18.5%, p ⴝ 0.017), and primary combined endpoint (8.0% versus 22.2%, p ⴝ 0.017). In the multivariate model, preoperative troponin T greater than 0.01 ng/mL (odds ratio 6.85, p ⴝ 0.001) and nonstatin therapy (odds ratio 4.2, p ⴝ 0.01) predicted a higher risk of primary endpoint. Statins showed a significant interaction with troponin T status and benefited primarily those patients with positive troponin T. Among 19 patients with troponin T greater than 0.01 ng/mL, the primary endpoint occurred in all 6 nonstatin-treated patients, but it occurred in only 1 of 13 statin-treated patients (p < 0.001). Neither C-reactive protein nor interleukin-6 predicted early complications, nor did they interact with statin therapy (p ⴝ not significant). Conclusions. Preoperative statin therapy reduces early complications and offers additional protection in patients with positive troponin T status, regardless of inflammatory markers. (Ann Thorac Surg 2006;81:78 – 84) © 2006 by The Society of Thoracic Surgeons
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procedure is associated with widespread inflammatory response and ischemic injury [10 –12]. Aggressive lipidlowering therapy after CABG is associated with longterm reduction of ischemic events [13–15]. However, it has not been established if preoperative statin therapy is associated with an early clinical benefit after CABG. This study aimed to examine the association between preoperative statin therapy, systemic inflammation and myocardial ischemia with the occurrence of early cardiac complications after CABG.
econdary prevention trials of HMG-CoA reductase inhibitors (or statins) have shown a 25% to 30% reduction in ischemic cardiovascular events at long-term follow-up [1, 2]. In patients with acute vascular injury, such as those with acute coronary syndromes (ACS) or percutaneous coronary interventions (PCI), previous studies have consistently suggested an early reduction of deaths and ischemic events that appears to be maximal when patients are receiving statins before the ACS or PCI [3–7]. This early benefit has been related to nonlipidlowering mechanisms, including antithrombotic and anti-inflammatory effects, and the reduction of adverse cardiac events occurs primarily in patients with a high level of inflammation markers, as detected by increased C-reactive protein (CRP) serum levels [7–9]. Coronary revascularization by means of coronary artery bypass grafting (CABG) is performed in a selected population at high risk for cardiac complications, and this Accepted for publication July 13, 2005. Address correspondence to Dr Pascual, Cardiology Department, Hospital Universitario Arrixaca, Universidad de Murcia, Ctra. Madrid-Cartagena s/n, Murcia 30120, Spain; e-mail: [email protected].
© 2006 by The Society of Thoracic Surgeons Published by Elsevier Inc
Patients and Methods Patient Population and Study Design We prospectively studied 141 consecutive patients between February 2002 and July 2003. All patients underwent CABG surgery without valve repair or replacement at two university tertiary hospitals. Patients undergoing steroidal treatment, dialysis, or with systemic inflammatory conditions were excluded. Additionally, those who underwent emergency surgery (within 24 hours) were excluded. All baseline characteristics, medication use, 0003-4975/06/$32.00 doi:10.1016/j.athoracsur.2005.07.038
Abbreviations and Acronyms ACS ⫽ acute coronary syndrome CABG ⫽ coronary artery bypass graft surgery CK-MG ⫽ creatine kinase MB isoenzyme CRP ⫽ C-reactive proteinl IL-6 ⫽ interleukin⫽6 IQR ⫽ interquartile range MI ⫽ myocardial infarction OR ⫽ odds ratio PCI ⫽ percutaneous coronary intervention
procedural details, and results were electronically recorded prospectively and included in our analysis. Patients were stratified according to the status of preoperative statin medication. The statin doses and the preoperative treatment period were recorded. Before surgery, a blood sample was collected for measurement of lipid parameters, CRP, and interleukin 6 (IL-6) as inflammation biomarkers, and troponin T as a myocardial ischemia biomarker. The occurrence of death and myocardial infarction (MI) during the postoperative period was recorded at 30 days. The primary endpoint was a composite of death and MI. All recruited subjects gave their written informed consent to be part of the study, which had been approved by the local Research Committee and was performed in accordance with the Declaration of Helsinki.
Laboratory Assays Immediately before CABG, peripheral blood samples were collected for measurement of CRP, IL-6, troponin T, and plasma lipid levels. Plasma samples were stored at – 80°C and analyzed in a single batch at the end of study. Plasma levels of CRP were measured using particle enhanced turbidimetric immunoassay on a Dimension analyzer (Dade-Behring, Newark, New Jersey). Plasma lipid levels (total cholesterol, triglycerides, and highdensity lipoprotein and low-density lipoprotein cholesterol) were measured on a Hitachi Modular D-P analyzer with reagents from Roche Diagnostics (Roche Diagnostics GmbH, Mannheim, Germany). Plasma levels of IL-6 were measured by a “sandwich type” enzyme immunoassay (CLB, Amsterdam, Netherlands). Plasma levels of cardiac troponin T were measured by an electrochemiluminiscence immunoassay on an Elecsys System 1010 (Roche Diagnostics GmbH). The analytical sensitivity (lower detection limit) was 0.010 ng/mL. For data analysis, high levels of troponin T were defined as those above 0.010 ng/mL. The CRP and IL-6 levels were evaluated as categorical variables according to the median value. Blood samples were collected for creatine kinase MB isoenzyme (CK-MB) measurements at 6, 12, 18, and 24 hours after the CABG. If enzymes were found to be high, CK-MB levels were followed up for a longer period to determine the actual peak value. Plasma levels of CK-MB were measured by an electrochemiluminiscence immunoassay (Roche Diagnostics). The detection limit was
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0.100 to 500.0 ng/mL, and the normal value was 3.2 ng/mL in men and women. Perioperative MI was defined as an increase of CK-MB five times or more above the upper limit of normal value (3.2 ng/mL), representing greater than 4% of total CK. This enzymatic criteria takes into account the presence of a significant myocardial damage, irrespectively of the development of Q waves in the postoperative electrocardiogram [16].
Statistical Analysis Continuous variables with normal distribution are expressed as mean and standard deviation (SD) and compared by t test; variables not normally distributed are presented as median and interquartile range (IQR) and compared by Mann-Whitney U test. Categorical variables were displayed as frequencies and percentages and were compared by Fisher exact test or X2 statistics, as indicated. Univariate logistic regression analysis was performed to determine predictors of the combined primary endpoint for each potential risk factor (age, sex, hypercholesterolemia, diabetes mellitus, hypertension, body mass index, statin therapy, -blocker therapy, renal insufficiency, ejection fraction less than 40%, recent ACS (30 days), three-vessel disease, off-pump surgery, left main disease, internal mammary artery, complete revascularization, troponin T positive, CRP, IL-6, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol). Multiple logistic regression analysis (forward stepwise analysis) was used to assess independent associations with the occurrence of the primary combined endpoint. In this analysis, adjustment was performed for all potential risk factors. The statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS 10.0 for Windows; SPSS, Chicago, Illinois). A p value less than 0.05 was considered statistically significant.
Results Patient Characteristics The statin pretreated group included 87 (62%) patients receiving statin (41% atorvastatin, 31% pravastatin, 28% simvastatin) during a median of 36 days (IQR 61, minimum 16 days, maximum 420 days). Most of them received an intermediate statin dose, and less than 5% were treated with a low or a high statin dose. The rate of previous diagnosis of hypercholesterolemia was higher among statin-treated patients, whereas nonstatin-treated patients had a higher rate of previous hypertension. All other clinical and procedural variables did not differ significantly between the two groups (Table 1). The lipid profile in terms of total cholesterol and low-density lipoprotein cholesterol was significantly lower among statin-treated patients, whereas CRP, IL-6, and troponin T levels were similar (Table 2).
Statin Therapy Nonstatin-treated patients had a significant higher rate of early cardiac complications at 30 days (Table 3). The
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Table 1. Clinical Baseline Characteristics
Age (years) Male Diabetes mellitus Hypertension Hypercholesterolemia Current smoking Body mass index (kg/m2) NYHA/CCS class LVEF ⬍40% Previous heart failure Recent ACS (⬍1 month) Previous MI Renal insufficiency EuroSCORE Beta-blockers Aspirin Off-pump surgery CPB time (min) Cross-clamp time (min) Vessels disease per patient Grafts per patient Three-vessel disease Internal thoracic artery
Table 2. Biochemical Measurements
No Statins (n ⫽ 54)
Statins (n ⫽ 87)
p Value
No Statins
65.8 ⫾ 9.1 40 (74%) 25 (46%) 42 (78%) 16 (30%) 15 (28%) 27.5 ⫾ 3.5 1.4 ⫾ 0.8 7 (13%) 10 (18%) 29 (54%) 19 (35%) 6 (11%) 4.9 ⫾ 3.5 38 (71%) 47 (88%) 24 (40%) 100 ⫾ 37 58 ⫾ 17 2.6 ⫾ 0.6 2.2 ⫾ 0.8 31 (57%) 42 (78%)
64.1 ⫾ 8.9 65 (75%) 36 (41%) 53 (61%) 68 (78%) 25 (29%) 27.8 ⫾ 3.4 1.4 ⫾ 0.8 15 (17%) 14 (16%) 42 (48%) 35 (40%) 7 (8%) 4.7 ⫾ 3.0 69 (79%) 76 (87%) 35 (44%) 97 ⫾ 39 53 ⫾ 22 2.6 ⫾ 0.6 2.2 ⫾ 0.9 54 (62%) 71 (82%)
0.27 0.93 0.57 0.038 ⬍ 0.001 0.90 0.78 0.99 0.50 0.71 0.50 0.55 0.44 0.58 0.36 0.89 0.62 0.77 0.36 0.71 0.86 0.79 0.62
Values are mean ⫾ SD or n (%). ACS ⫽ acute coronary syndrome; CCS ⫽ Canadian Cardiovascular Society; CPB ⫽ cardiopulmonary bypass; EuroSCORE ⫽ European System for Cardiac Operative Risk Evaluation; LVEF ⫽ left ventricular ejection fraction; MI ⫽ myocardial infarction; NYHA ⫽ New York Heart Association.
primary endpoint of death or MI occurred in 7 (8.0%) statin-pretreated patients versus 12 (22.2%) nonstatinpretreated patients (p ⫽ 0.017). In the univariate analysis, preoperative troponin T greater than 0.01 ng/mL (odds ratio [OR] 3.4, p ⫽ 0.025) and nonstatin therapy (OR 3.7, p ⫽ 0.023) significantly predicted the occurrence of MI. The presence of left ventricular systolic dysfunction (OR 5.1, p ⫽ 0.024), renal insufficiency (OR 12.3, p ⫽ 0.001), preoperative troponin T greater than 0.01 ng/mL (OR 18.2, p ⬍ 0.001), preoperative nonstatin therapy (OR 6.3, p ⫽ 0.025), and non–blocker therapy (OR 5.6, p ⫽ 0.018) were significantly associated with higher risk of death. The lipid variables and inflammatory biomarkers IL-6 and CRP did not show any significant association with the development of early complications. When we considered the primary endpoint (Table 4), nonstatin preoperative therapy, baseline troponin T greater than 0.01 ng/mL, and renal insufficiency were significantly associated with a higher risk of death or MI. In a multivariate model, nonstatin therapy and troponin T greater than 0.01 ng/mL were the only independent predictors (Table 4). Patients with an ACS within a 30-day period before CABG (71 patients, 50%) had higher levels of CRP (p ⬍
Statins
Cholesterol, mg/dL Total 193.8 ⫾ 52.7 171.2 ⫾ 49.7 Low-density lipoprotein 124.9 ⫾ 42.9 104.4 ⫾ 44.1 High-density lipoprotein 34.7 ⫾ 7.3 37.9 ⫾ 13.6 Triglycerides, mg/dL 179.3 ⫾ 126.2 148.2 ⫾ 93.7 Troponin T ⬎0.01 ng/mL 6 (11.1%) 13 (14.9%) Interleukin-6 4.77 (1.9–11.5) 3.17 (1.07–8.20) C-reactive protein 0.23 (0.12–0.78) 0.18 (0.10–0.50)
p Value 0.015 0.011 0.070 0.109 0.417 0.337 0.222
Values are mean ⫾ SD or median (25th, 75th percentiles).
0.001), IL-6 (p ⫽ 0.006), and had a higher rate of positive troponin T (21% versus 6%, p ⫽ 0.007). However, a recent ACS was not significantly associated with the primary combined endpoint (17% versus 10%, p ⫽ 0.23). Interestingly, there was a significant interaction between statin therapy and troponin T status. As shown in Table 5, baseline troponin T was greater than 0.01 ng/mL in 19 patients, 6 nonstatin pretreated and 13 statin pretreated: the primary endpoint developed in all 6 patients not receiving statins, whereas only one event occurred among 13 statin-pretreated ones. In contrast, no interactions were found between statin therapy and the inflammatory status, as measured by CRP and IL-6.
Comment As statin therapy has been shown to have an early beneficial effect in patients with ACS and in patients undergoing percutaneous coronary interventions, we investigated the role of preoperative statin therapy in patients undergoing CABG. Our study shows that preoperative statin therapy is associated with a significant reduction of death or acute MI at 30 days. It is important to note that this benefit is contained primarily in those patients with positive troponin T, but not in those with higher levels of vascular inflammation markers. Preoperative troponin T was a prognostic marker associated with higher risk for subsequent cardiac complications at 30 days. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, an early initiation of statin therapy directly after an ACS was associated Table 3. Early Events at 30 Days
Death or myocardial infarction Death Myocardial infarction Values are number (%).
No Statins (n ⫽ 54)
Statins (n ⫽ 87)
p Value
12 (22.2%) 7 (13.0%) 10 (18.5%)
7 (8.0%) 2 (2.3%) 5 (5.7%)
0.017 0.012 0.017
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Table 4. Logistic Regression Analysis for Primary Endpoint Univariate
Age Male Sex Hypercholesterolemia Diabetes mellitus Hypertension Body mass index No statin pretreatment No -blocker Renal insufficiency LVEF ⬍ 40% Recent ACS (30 days) Three-vessel disease Off-pump surgery Left main disease Internal mammary artery Complete revascularization Troponin T positive C-Reactive protein Interleukin-6 LDL cholesterol HDL cholesterol
Mutivariate
OR (95% CI)
p Value
OR (95% CI)
p Value
1.00 (0.94–1.05) 1.05 (0.35–3.20) 0.44 (0.16–1.17) 1.79 (0.63–5.0) 1.49 (0.45–3.45) 1.04 (0.88–1.24) 3.27 (1.20–8.93) 2.52 (0.89–7.14) 3.80 (1.02–14.08) 1.54 (0.46–5.17) 1.83 (0.67–4.96) 1.61 (0.63–4.16) 0.79 (0.29–2.13) 2.06 (0.77–5.5) 0.97 (0.25–3.83) 0.94 (0.31–2.89) 5.35 (1.78–16.13) 1.19 (0.29–3.1) 1.14 (0.38–3.44) 1.0 (0.99–1.01) 0.98 (0.94–1.03)
0.81 0.93 0.10 0.27 0.81 0.63 0.02 0.08 0.04 0.48 0.23 0.32 0.63 0.15 0.97 0.92 0.003 0.73 0.81 0.78 0.43
— — — — — — 3.68 (1.20–11.25) — — — — — — — — — 6.65 (1.97–22.50) — — — —
0.28 0.92 0.85 0.15 0.52 0.74 0.022 0.43 0.65 0.89 0.88 0.28 0.95 0.93 0.94 0.80 0.002 0.22 0.78 0.37 0.64
ACS ⫽ acute coronary syndrome; CI ⫽ confidence interval; ventricular ejection fraction; OR ⫽ odds ratio.
HDL ⫽ high-density lipoprotein;
with an early reduction of recurrent ischemic events [4]. However, initiation of statins after onset of ACS appears to be less effective compared with pretreatment before the onset of symptoms [4]. Heeschen and associates [5] found that statin pretreatment before the onset of ACS significantly reduced death and MI rate at 30 days, discontinuation of statin therapy abrogated its beneficial effect, and initiation of statin therapy during hospitalization failed to reduce early cardiac events. Statin therapy among PCI patients seems to be associated with a significant benefit, to an extent comparable with that reported in patients with ACS [6, 17, 18]. The initiation of statins after CABG has shown a significant long-term benefit [13–15]. In post-CABG trial, aggressive lipid-lowering therapy slowed down the progression of obstructive changes in saphenous vein grafts as well as the need for new revascularization procedures [13, 14]. In postinfarction patients with average cholesterol levels, statin therapy after CABG reduced coronary death and MI in the long term [15]. Patients undergoing CABG are a selected population with high prevalence of multivessel disease, diabetes mellitus, depressed left ventricular ejection fraction, and severe inducible ischemia, and consequently are at high risk for early cardiac complications. However, few data exist about the potential short-term benefit of statin therapy. In our study, similar to ACS and PCI, pretreatment with statins was independently associated with a significant reduction of adverse cardiac events at 30 days,
LDL ⫽ low-density lipoprotein;
LVEF ⫽ left
death and MI. Previously, Dotani and coworkers [19] found a significant reduction at 60 days in the composite endpoint of death, MI, and unstable angina among patients receiving statin therapy. Recently, preoperative statin therapy has been identified as an independent predictor of death or stroke after CABG, but not postoperative MI [20]. These two retrospective analyses did not take into account the influence of ischemic and inflammatory status. On the other hand, Florens and associates [21] randomized patients undergoing elective CABG to receive atorvastatin 24 hours before the operation, but this study failed to find a benefit in clinical outcome or inflammation response after surgery. This absence of effect might have been due to the short duration of Table 5. Primary Endpoint According With Troponin T (TnT) and Statin Status
TnT ⫹ (n ⫽ 19) Statin No statin TnT ⫺ (n ⫽ 122) Statin No statin
Death/MI (⫹)
Death/MI (⫺)
1 (7.7%) 6 (100%)
12 —
⬍ 0.001
6 (8.1%) 6 (12.5%)
68 42
NS
Values are number and % statin status. MI ⫽ myocardial infarction; NS ⫽ not significant.
p Value
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therapy. The length of statin pretreatment required to produce a clinical benefit remains unknown. Experimental studies have shown a significant benefit on inflammation and endothelial function as early as 14 days [22]. In our study, preoperative statin therapy was longer than 14 days in all cases (16 days minimum). In patients undergoing PCI, baseline CRP has shown an incremental prognostic value for early adverse coronary events, death and MI [23, 24]. The benefit of statin pretreatment seems to be dependent on the baseline inflammatory status, as statins significantly attenuate the increased risk for adverse cardiac events in patients with high CRP levels [7, 8]. In patients undergoing CABG, clinical risk models have been developed to anticipate postoperative complications, but the role of new markers of inflammation and ischemia have not been defined in this setting. In a retrospective analysis of 86 patients, baseline CRP showed a predictive value for long-term ischemic complications but not for early events [11]. In contrast, Gaudino and coworkers [12] did not find an association between markers of inflammatory activation (CRP, IL-6) and in-hospital postoperative complications. Similarly, in our study CRP and IL-6 did not achieve a significant association with early cardiac events. Contrary to what happens with PCI, these results suggest that baseline CRP levels do not have early prognostic value in CABG. Our study identified the troponin T at baseline as a predictive variable for death or MI. Troponins have become a consistent prognostic marker in ACS and a positive value, even with a cut-off value as low as 0.010 pg/mL, identifies patients with increased risk of death from cardiac causes [25–27]. After revascularization procedures, PCI or CABG, the subsequent increase of troponins is associated with higher risk for cardiac complications [28, 29]. Carrier and colleagues [30] identified troponin T level before CABG as the strongest variable correlated with postoperative MI, and no other studies have evaluated the value of preoperative troponin levels. In our study, although a significant correlation was found between a recent ACS and baseline troponin T and CRP levels, only a baseline positive troponin T achieved prognostic value. Troponins appear be more useful than CRP in predicting short-term prognosis, as they generally indicate the presence of complex thrombotic coronary arteriosclerotic lesions associated with a high risk of early ischemic events. Conversely, CRP is a marker of underlying ongoing destabilizing stimuli and therefore might be a better marker of longer term prognosis. In our opinion, these findings suggest that myocardial ischemia plays the main role in CABG, in contrast with PCI where inflammation is the cornerstone. It has become readily apparent through experimental and clinical studies that beneficial effects of statins may be independent from cholesterol reduction [31–33]. Myocardial ischemia followed by reperfusion results in cardiomyocite injury and contractile dysfunction. In experimental models of ischemia and reperfusion, pretreatment with statins exerts cardioprotective effects, reduces significantly myocardial infarction size, and preserves cardiac contractile
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function and coronary perfusion, despite unaltered serum cholesterol levels [33–37]. In a model of acutely ischemic myocardium and surgical revascularization, Lazar and colleagues [36] found that pretreatment with statins during 21 days improved coronary artery relaxation. The cardioprotective effects of statins are unrelated to the cholesterollowering action and appear to be mediated through enhancement of endothelial NO release, which therefore overcomes the hypoxia-mediated inhibition of NO synthesis activity, leading to the preservation of endothelial function and the inhibition of neutrophil-mediated tissue injury [33, 34, 38, 39]. In patients undergoing CABG, Chello and associates [40] found that pretreatment with simvastatin reduced adhesion of activated neutrophils to vascular endothelium, suggesting that the benefits of statin therapy may also occur in the immediate postoperative period. Our clinical findings confirm that preoperative statin therapy exerts additional cardiac protection during CABG and the early postoperative period, mainly in patients at high risk of ischemic events, such as those with baseline positive troponin T levels.
Limitations This study is limited by its nonrandomized design, and certainly we can only explore associations, and no causality is implied. Only a randomized controlled trial does allow one to conclude that statins protect against death and MI. Another major limitation of the present study is the small size. Death and perioperative MI rates are high for the cohort of patients and the number of grafts is low. This raises the question as to whether or not other variables may account for these results. Nevertheless, the two study groups were comparable in terms of clinical and procedural characteristics. Statin therapy was initiated based on high cholesterol levels and the need for CABG was not known to the physician in charge of initiation of statin. Thus, it is unlikely that a selection bias might have contributed to the observed outcome. However, despite careful use of regression models to adjust for potential confounders, unmeasurable factors may still exist and surgeon or patient bias may also affect our findings. This clinical benefit and the presence of a potential dose or time-dependent effect need further confirmation through a large-scale randomized clinical trial. In conclusion, for patients undergoing CABG, baseline troponin T status predicts a significant higher risk of early complications. Preoperative statin therapy reduces early complications and offers additional protection during CABG in patients with positive troponin T levels, regardless of inflammatory markers.
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Preoperative Statin Therapy and Troponin T Predict Early Complications of Coronary Artery Surgery Domingo A. Pascual, MD, PhD, Jose M. Arribas, MD, Pedro L. Tornel, MD, PhD, Francisco Marín, MD, PhD, Clara Oliver, MD, Miguel Ahumada, MD, Jesus Gomez-Plana, MD, Pedro Martínez, MD, PhD, Ramón Arcas, MD, PhD, and Mariano Valdes, MD, PhD Departments of Cardiology, Cardiovascular Surgery, and Clinical Chemistry, Hospital Universitario Arrixaca, Murcia, and Departments of Cardiology and Cardiovascular Surgery, Hospital General Universitario, Alicante, Spain
Background. Pretreatment with statins reduces early ischemic events after percutaneous coronary interventions, primarily in patients with a high level of inflammation markers. We sought to examine the association between preoperative statin therapy, systemic inflammation, and myocardial ischemia with the occurrence of early cardiac complications after coronary artery bypass grafting surgery. Methods. One hundred forty-one consecutive patients who underwent coronary artery bypass grafting surgery from two university tertiary hospitals were stratified according to their preoperative status of statin therapy (87 treated and 54 nontreated). Preoperative blood samples were collected for measurement of lipid parameters, C-reactive protein, interleukin-6, and troponin T. The evaluated primary endpoint was a composite of death and myocardial infarction at 30 days. Results. Patients undergoing preoperative statin therapy showed a reduced incidence of death (2.3% versus 13.0%, p ⴝ 0.012), myocardial infarction (5.7% versus
18.5%, p ⴝ 0.017), and primary combined endpoint (8.0% versus 22.2%, p ⴝ 0.017). In the multivariate model, preoperative troponin T greater than 0.01 ng/mL (odds ratio 6.85, p ⴝ 0.001) and nonstatin therapy (odds ratio 4.2, p ⴝ 0.01) predicted a higher risk of primary endpoint. Statins showed a significant interaction with troponin T status and benefited primarily those patients with positive troponin T. Among 19 patients with troponin T greater than 0.01 ng/mL, the primary endpoint occurred in all 6 nonstatin-treated patients, but it occurred in only 1 of 13 statin-treated patients (p < 0.001). Neither C-reactive protein nor interleukin-6 predicted early complications, nor did they interact with statin therapy (p ⴝ not significant). Conclusions. Preoperative statin therapy reduces early complications and offers additional protection in patients with positive troponin T status, regardless of inflammatory markers. (Ann Thorac Surg 2006;81:78 – 84) © 2006 by The Society of Thoracic Surgeons
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procedure is associated with widespread inflammatory response and ischemic injury [10 –12]. Aggressive lipidlowering therapy after CABG is associated with longterm reduction of ischemic events [13–15]. However, it has not been established if preoperative statin therapy is associated with an early clinical benefit after CABG. This study aimed to examine the association between preoperative statin therapy, systemic inflammation and myocardial ischemia with the occurrence of early cardiac complications after CABG.
econdary prevention trials of HMG-CoA reductase inhibitors (or statins) have shown a 25% to 30% reduction in ischemic cardiovascular events at long-term follow-up [1, 2]. In patients with acute vascular injury, such as those with acute coronary syndromes (ACS) or percutaneous coronary interventions (PCI), previous studies have consistently suggested an early reduction of deaths and ischemic events that appears to be maximal when patients are receiving statins before the ACS or PCI [3–7]. This early benefit has been related to nonlipidlowering mechanisms, including antithrombotic and anti-inflammatory effects, and the reduction of adverse cardiac events occurs primarily in patients with a high level of inflammation markers, as detected by increased C-reactive protein (CRP) serum levels [7–9]. Coronary revascularization by means of coronary artery bypass grafting (CABG) is performed in a selected population at high risk for cardiac complications, and this Accepted for publication July 13, 2005. Address correspondence to Dr Pascual, Cardiology Department, Hospital Universitario Arrixaca, Universidad de Murcia, Ctra. Madrid-Cartagena s/n, Murcia 30120, Spain; e-mail: [email protected].
© 2006 by The Society of Thoracic Surgeons Published by Elsevier Inc
Patients and Methods Patient Population and Study Design We prospectively studied 141 consecutive patients between February 2002 and July 2003. All patients underwent CABG surgery without valve repair or replacement at two university tertiary hospitals. Patients undergoing steroidal treatment, dialysis, or with systemic inflammatory conditions were excluded. Additionally, those who underwent emergency surgery (within 24 hours) were excluded. All baseline characteristics, medication use, 0003-4975/06/$32.00 doi:10.1016/j.athoracsur.2005.07.038
Abbreviations and Acronyms ACS ⫽ acute coronary syndrome CABG ⫽ coronary artery bypass graft surgery CK-MG ⫽ creatine kinase MB isoenzyme CRP ⫽ C-reactive proteinl IL-6 ⫽ interleukin⫽6 IQR ⫽ interquartile range MI ⫽ myocardial infarction OR ⫽ odds ratio PCI ⫽ percutaneous coronary intervention
procedural details, and results were electronically recorded prospectively and included in our analysis. Patients were stratified according to the status of preoperative statin medication. The statin doses and the preoperative treatment period were recorded. Before surgery, a blood sample was collected for measurement of lipid parameters, CRP, and interleukin 6 (IL-6) as inflammation biomarkers, and troponin T as a myocardial ischemia biomarker. The occurrence of death and myocardial infarction (MI) during the postoperative period was recorded at 30 days. The primary endpoint was a composite of death and MI. All recruited subjects gave their written informed consent to be part of the study, which had been approved by the local Research Committee and was performed in accordance with the Declaration of Helsinki.
Laboratory Assays Immediately before CABG, peripheral blood samples were collected for measurement of CRP, IL-6, troponin T, and plasma lipid levels. Plasma samples were stored at – 80°C and analyzed in a single batch at the end of study. Plasma levels of CRP were measured using particle enhanced turbidimetric immunoassay on a Dimension analyzer (Dade-Behring, Newark, New Jersey). Plasma lipid levels (total cholesterol, triglycerides, and highdensity lipoprotein and low-density lipoprotein cholesterol) were measured on a Hitachi Modular D-P analyzer with reagents from Roche Diagnostics (Roche Diagnostics GmbH, Mannheim, Germany). Plasma levels of IL-6 were measured by a “sandwich type” enzyme immunoassay (CLB, Amsterdam, Netherlands). Plasma levels of cardiac troponin T were measured by an electrochemiluminiscence immunoassay on an Elecsys System 1010 (Roche Diagnostics GmbH). The analytical sensitivity (lower detection limit) was 0.010 ng/mL. For data analysis, high levels of troponin T were defined as those above 0.010 ng/mL. The CRP and IL-6 levels were evaluated as categorical variables according to the median value. Blood samples were collected for creatine kinase MB isoenzyme (CK-MB) measurements at 6, 12, 18, and 24 hours after the CABG. If enzymes were found to be high, CK-MB levels were followed up for a longer period to determine the actual peak value. Plasma levels of CK-MB were measured by an electrochemiluminiscence immunoassay (Roche Diagnostics). The detection limit was
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0.100 to 500.0 ng/mL, and the normal value was 3.2 ng/mL in men and women. Perioperative MI was defined as an increase of CK-MB five times or more above the upper limit of normal value (3.2 ng/mL), representing greater than 4% of total CK. This enzymatic criteria takes into account the presence of a significant myocardial damage, irrespectively of the development of Q waves in the postoperative electrocardiogram [16].
Statistical Analysis Continuous variables with normal distribution are expressed as mean and standard deviation (SD) and compared by t test; variables not normally distributed are presented as median and interquartile range (IQR) and compared by Mann-Whitney U test. Categorical variables were displayed as frequencies and percentages and were compared by Fisher exact test or X2 statistics, as indicated. Univariate logistic regression analysis was performed to determine predictors of the combined primary endpoint for each potential risk factor (age, sex, hypercholesterolemia, diabetes mellitus, hypertension, body mass index, statin therapy, -blocker therapy, renal insufficiency, ejection fraction less than 40%, recent ACS (30 days), three-vessel disease, off-pump surgery, left main disease, internal mammary artery, complete revascularization, troponin T positive, CRP, IL-6, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol). Multiple logistic regression analysis (forward stepwise analysis) was used to assess independent associations with the occurrence of the primary combined endpoint. In this analysis, adjustment was performed for all potential risk factors. The statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS 10.0 for Windows; SPSS, Chicago, Illinois). A p value less than 0.05 was considered statistically significant.
Results Patient Characteristics The statin pretreated group included 87 (62%) patients receiving statin (41% atorvastatin, 31% pravastatin, 28% simvastatin) during a median of 36 days (IQR 61, minimum 16 days, maximum 420 days). Most of them received an intermediate statin dose, and less than 5% were treated with a low or a high statin dose. The rate of previous diagnosis of hypercholesterolemia was higher among statin-treated patients, whereas nonstatin-treated patients had a higher rate of previous hypertension. All other clinical and procedural variables did not differ significantly between the two groups (Table 1). The lipid profile in terms of total cholesterol and low-density lipoprotein cholesterol was significantly lower among statin-treated patients, whereas CRP, IL-6, and troponin T levels were similar (Table 2).
Statin Therapy Nonstatin-treated patients had a significant higher rate of early cardiac complications at 30 days (Table 3). The
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Table 1. Clinical Baseline Characteristics
Age (years) Male Diabetes mellitus Hypertension Hypercholesterolemia Current smoking Body mass index (kg/m2) NYHA/CCS class LVEF ⬍40% Previous heart failure Recent ACS (⬍1 month) Previous MI Renal insufficiency EuroSCORE Beta-blockers Aspirin Off-pump surgery CPB time (min) Cross-clamp time (min) Vessels disease per patient Grafts per patient Three-vessel disease Internal thoracic artery
Table 2. Biochemical Measurements
No Statins (n ⫽ 54)
Statins (n ⫽ 87)
p Value
No Statins
65.8 ⫾ 9.1 40 (74%) 25 (46%) 42 (78%) 16 (30%) 15 (28%) 27.5 ⫾ 3.5 1.4 ⫾ 0.8 7 (13%) 10 (18%) 29 (54%) 19 (35%) 6 (11%) 4.9 ⫾ 3.5 38 (71%) 47 (88%) 24 (40%) 100 ⫾ 37 58 ⫾ 17 2.6 ⫾ 0.6 2.2 ⫾ 0.8 31 (57%) 42 (78%)
64.1 ⫾ 8.9 65 (75%) 36 (41%) 53 (61%) 68 (78%) 25 (29%) 27.8 ⫾ 3.4 1.4 ⫾ 0.8 15 (17%) 14 (16%) 42 (48%) 35 (40%) 7 (8%) 4.7 ⫾ 3.0 69 (79%) 76 (87%) 35 (44%) 97 ⫾ 39 53 ⫾ 22 2.6 ⫾ 0.6 2.2 ⫾ 0.9 54 (62%) 71 (82%)
0.27 0.93 0.57 0.038 ⬍ 0.001 0.90 0.78 0.99 0.50 0.71 0.50 0.55 0.44 0.58 0.36 0.89 0.62 0.77 0.36 0.71 0.86 0.79 0.62
Values are mean ⫾ SD or n (%). ACS ⫽ acute coronary syndrome; CCS ⫽ Canadian Cardiovascular Society; CPB ⫽ cardiopulmonary bypass; EuroSCORE ⫽ European System for Cardiac Operative Risk Evaluation; LVEF ⫽ left ventricular ejection fraction; MI ⫽ myocardial infarction; NYHA ⫽ New York Heart Association.
primary endpoint of death or MI occurred in 7 (8.0%) statin-pretreated patients versus 12 (22.2%) nonstatinpretreated patients (p ⫽ 0.017). In the univariate analysis, preoperative troponin T greater than 0.01 ng/mL (odds ratio [OR] 3.4, p ⫽ 0.025) and nonstatin therapy (OR 3.7, p ⫽ 0.023) significantly predicted the occurrence of MI. The presence of left ventricular systolic dysfunction (OR 5.1, p ⫽ 0.024), renal insufficiency (OR 12.3, p ⫽ 0.001), preoperative troponin T greater than 0.01 ng/mL (OR 18.2, p ⬍ 0.001), preoperative nonstatin therapy (OR 6.3, p ⫽ 0.025), and non–blocker therapy (OR 5.6, p ⫽ 0.018) were significantly associated with higher risk of death. The lipid variables and inflammatory biomarkers IL-6 and CRP did not show any significant association with the development of early complications. When we considered the primary endpoint (Table 4), nonstatin preoperative therapy, baseline troponin T greater than 0.01 ng/mL, and renal insufficiency were significantly associated with a higher risk of death or MI. In a multivariate model, nonstatin therapy and troponin T greater than 0.01 ng/mL were the only independent predictors (Table 4). Patients with an ACS within a 30-day period before CABG (71 patients, 50%) had higher levels of CRP (p ⬍
Statins
Cholesterol, mg/dL Total 193.8 ⫾ 52.7 171.2 ⫾ 49.7 Low-density lipoprotein 124.9 ⫾ 42.9 104.4 ⫾ 44.1 High-density lipoprotein 34.7 ⫾ 7.3 37.9 ⫾ 13.6 Triglycerides, mg/dL 179.3 ⫾ 126.2 148.2 ⫾ 93.7 Troponin T ⬎0.01 ng/mL 6 (11.1%) 13 (14.9%) Interleukin-6 4.77 (1.9–11.5) 3.17 (1.07–8.20) C-reactive protein 0.23 (0.12–0.78) 0.18 (0.10–0.50)
p Value 0.015 0.011 0.070 0.109 0.417 0.337 0.222
Values are mean ⫾ SD or median (25th, 75th percentiles).
0.001), IL-6 (p ⫽ 0.006), and had a higher rate of positive troponin T (21% versus 6%, p ⫽ 0.007). However, a recent ACS was not significantly associated with the primary combined endpoint (17% versus 10%, p ⫽ 0.23). Interestingly, there was a significant interaction between statin therapy and troponin T status. As shown in Table 5, baseline troponin T was greater than 0.01 ng/mL in 19 patients, 6 nonstatin pretreated and 13 statin pretreated: the primary endpoint developed in all 6 patients not receiving statins, whereas only one event occurred among 13 statin-pretreated ones. In contrast, no interactions were found between statin therapy and the inflammatory status, as measured by CRP and IL-6.
Comment As statin therapy has been shown to have an early beneficial effect in patients with ACS and in patients undergoing percutaneous coronary interventions, we investigated the role of preoperative statin therapy in patients undergoing CABG. Our study shows that preoperative statin therapy is associated with a significant reduction of death or acute MI at 30 days. It is important to note that this benefit is contained primarily in those patients with positive troponin T, but not in those with higher levels of vascular inflammation markers. Preoperative troponin T was a prognostic marker associated with higher risk for subsequent cardiac complications at 30 days. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, an early initiation of statin therapy directly after an ACS was associated Table 3. Early Events at 30 Days
Death or myocardial infarction Death Myocardial infarction Values are number (%).
No Statins (n ⫽ 54)
Statins (n ⫽ 87)
p Value
12 (22.2%) 7 (13.0%) 10 (18.5%)
7 (8.0%) 2 (2.3%) 5 (5.7%)
0.017 0.012 0.017
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Table 4. Logistic Regression Analysis for Primary Endpoint Univariate
Age Male Sex Hypercholesterolemia Diabetes mellitus Hypertension Body mass index No statin pretreatment No -blocker Renal insufficiency LVEF ⬍ 40% Recent ACS (30 days) Three-vessel disease Off-pump surgery Left main disease Internal mammary artery Complete revascularization Troponin T positive C-Reactive protein Interleukin-6 LDL cholesterol HDL cholesterol
Mutivariate
OR (95% CI)
p Value
OR (95% CI)
p Value
1.00 (0.94–1.05) 1.05 (0.35–3.20) 0.44 (0.16–1.17) 1.79 (0.63–5.0) 1.49 (0.45–3.45) 1.04 (0.88–1.24) 3.27 (1.20–8.93) 2.52 (0.89–7.14) 3.80 (1.02–14.08) 1.54 (0.46–5.17) 1.83 (0.67–4.96) 1.61 (0.63–4.16) 0.79 (0.29–2.13) 2.06 (0.77–5.5) 0.97 (0.25–3.83) 0.94 (0.31–2.89) 5.35 (1.78–16.13) 1.19 (0.29–3.1) 1.14 (0.38–3.44) 1.0 (0.99–1.01) 0.98 (0.94–1.03)
0.81 0.93 0.10 0.27 0.81 0.63 0.02 0.08 0.04 0.48 0.23 0.32 0.63 0.15 0.97 0.92 0.003 0.73 0.81 0.78 0.43
— — — — — — 3.68 (1.20–11.25) — — — — — — — — — 6.65 (1.97–22.50) — — — —
0.28 0.92 0.85 0.15 0.52 0.74 0.022 0.43 0.65 0.89 0.88 0.28 0.95 0.93 0.94 0.80 0.002 0.22 0.78 0.37 0.64
ACS ⫽ acute coronary syndrome; CI ⫽ confidence interval; ventricular ejection fraction; OR ⫽ odds ratio.
HDL ⫽ high-density lipoprotein;
with an early reduction of recurrent ischemic events [4]. However, initiation of statins after onset of ACS appears to be less effective compared with pretreatment before the onset of symptoms [4]. Heeschen and associates [5] found that statin pretreatment before the onset of ACS significantly reduced death and MI rate at 30 days, discontinuation of statin therapy abrogated its beneficial effect, and initiation of statin therapy during hospitalization failed to reduce early cardiac events. Statin therapy among PCI patients seems to be associated with a significant benefit, to an extent comparable with that reported in patients with ACS [6, 17, 18]. The initiation of statins after CABG has shown a significant long-term benefit [13–15]. In post-CABG trial, aggressive lipid-lowering therapy slowed down the progression of obstructive changes in saphenous vein grafts as well as the need for new revascularization procedures [13, 14]. In postinfarction patients with average cholesterol levels, statin therapy after CABG reduced coronary death and MI in the long term [15]. Patients undergoing CABG are a selected population with high prevalence of multivessel disease, diabetes mellitus, depressed left ventricular ejection fraction, and severe inducible ischemia, and consequently are at high risk for early cardiac complications. However, few data exist about the potential short-term benefit of statin therapy. In our study, similar to ACS and PCI, pretreatment with statins was independently associated with a significant reduction of adverse cardiac events at 30 days,
LDL ⫽ low-density lipoprotein;
LVEF ⫽ left
death and MI. Previously, Dotani and coworkers [19] found a significant reduction at 60 days in the composite endpoint of death, MI, and unstable angina among patients receiving statin therapy. Recently, preoperative statin therapy has been identified as an independent predictor of death or stroke after CABG, but not postoperative MI [20]. These two retrospective analyses did not take into account the influence of ischemic and inflammatory status. On the other hand, Florens and associates [21] randomized patients undergoing elective CABG to receive atorvastatin 24 hours before the operation, but this study failed to find a benefit in clinical outcome or inflammation response after surgery. This absence of effect might have been due to the short duration of Table 5. Primary Endpoint According With Troponin T (TnT) and Statin Status
TnT ⫹ (n ⫽ 19) Statin No statin TnT ⫺ (n ⫽ 122) Statin No statin
Death/MI (⫹)
Death/MI (⫺)
1 (7.7%) 6 (100%)
12 —
⬍ 0.001
6 (8.1%) 6 (12.5%)
68 42
NS
Values are number and % statin status. MI ⫽ myocardial infarction; NS ⫽ not significant.
p Value
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therapy. The length of statin pretreatment required to produce a clinical benefit remains unknown. Experimental studies have shown a significant benefit on inflammation and endothelial function as early as 14 days [22]. In our study, preoperative statin therapy was longer than 14 days in all cases (16 days minimum). In patients undergoing PCI, baseline CRP has shown an incremental prognostic value for early adverse coronary events, death and MI [23, 24]. The benefit of statin pretreatment seems to be dependent on the baseline inflammatory status, as statins significantly attenuate the increased risk for adverse cardiac events in patients with high CRP levels [7, 8]. In patients undergoing CABG, clinical risk models have been developed to anticipate postoperative complications, but the role of new markers of inflammation and ischemia have not been defined in this setting. In a retrospective analysis of 86 patients, baseline CRP showed a predictive value for long-term ischemic complications but not for early events [11]. In contrast, Gaudino and coworkers [12] did not find an association between markers of inflammatory activation (CRP, IL-6) and in-hospital postoperative complications. Similarly, in our study CRP and IL-6 did not achieve a significant association with early cardiac events. Contrary to what happens with PCI, these results suggest that baseline CRP levels do not have early prognostic value in CABG. Our study identified the troponin T at baseline as a predictive variable for death or MI. Troponins have become a consistent prognostic marker in ACS and a positive value, even with a cut-off value as low as 0.010 pg/mL, identifies patients with increased risk of death from cardiac causes [25–27]. After revascularization procedures, PCI or CABG, the subsequent increase of troponins is associated with higher risk for cardiac complications [28, 29]. Carrier and colleagues [30] identified troponin T level before CABG as the strongest variable correlated with postoperative MI, and no other studies have evaluated the value of preoperative troponin levels. In our study, although a significant correlation was found between a recent ACS and baseline troponin T and CRP levels, only a baseline positive troponin T achieved prognostic value. Troponins appear be more useful than CRP in predicting short-term prognosis, as they generally indicate the presence of complex thrombotic coronary arteriosclerotic lesions associated with a high risk of early ischemic events. Conversely, CRP is a marker of underlying ongoing destabilizing stimuli and therefore might be a better marker of longer term prognosis. In our opinion, these findings suggest that myocardial ischemia plays the main role in CABG, in contrast with PCI where inflammation is the cornerstone. It has become readily apparent through experimental and clinical studies that beneficial effects of statins may be independent from cholesterol reduction [31–33]. Myocardial ischemia followed by reperfusion results in cardiomyocite injury and contractile dysfunction. In experimental models of ischemia and reperfusion, pretreatment with statins exerts cardioprotective effects, reduces significantly myocardial infarction size, and preserves cardiac contractile
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function and coronary perfusion, despite unaltered serum cholesterol levels [33–37]. In a model of acutely ischemic myocardium and surgical revascularization, Lazar and colleagues [36] found that pretreatment with statins during 21 days improved coronary artery relaxation. The cardioprotective effects of statins are unrelated to the cholesterollowering action and appear to be mediated through enhancement of endothelial NO release, which therefore overcomes the hypoxia-mediated inhibition of NO synthesis activity, leading to the preservation of endothelial function and the inhibition of neutrophil-mediated tissue injury [33, 34, 38, 39]. In patients undergoing CABG, Chello and associates [40] found that pretreatment with simvastatin reduced adhesion of activated neutrophils to vascular endothelium, suggesting that the benefits of statin therapy may also occur in the immediate postoperative period. Our clinical findings confirm that preoperative statin therapy exerts additional cardiac protection during CABG and the early postoperative period, mainly in patients at high risk of ischemic events, such as those with baseline positive troponin T levels.
Limitations This study is limited by its nonrandomized design, and certainly we can only explore associations, and no causality is implied. Only a randomized controlled trial does allow one to conclude that statins protect against death and MI. Another major limitation of the present study is the small size. Death and perioperative MI rates are high for the cohort of patients and the number of grafts is low. This raises the question as to whether or not other variables may account for these results. Nevertheless, the two study groups were comparable in terms of clinical and procedural characteristics. Statin therapy was initiated based on high cholesterol levels and the need for CABG was not known to the physician in charge of initiation of statin. Thus, it is unlikely that a selection bias might have contributed to the observed outcome. However, despite careful use of regression models to adjust for potential confounders, unmeasurable factors may still exist and surgeon or patient bias may also affect our findings. This clinical benefit and the presence of a potential dose or time-dependent effect need further confirmation through a large-scale randomized clinical trial. In conclusion, for patients undergoing CABG, baseline troponin T status predicts a significant higher risk of early complications. Preoperative statin therapy reduces early complications and offers additional protection during CABG in patients with positive troponin T levels, regardless of inflammatory markers.
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