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Isolated Elevation in Troponin T After Percutaneous Coronary Intervention Is Associated With Higher Long-Term Mortality
Journal of the American College of Cardiology © 2006 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 48, No. 9, 2006 ISSN 0735-1097/06/$32.00 doi:10.1016/j.jacc.2006.04.102
Isolated Elevation in Troponin T After Percutaneous Coronary Intervention Is Associated With Higher Long-Term Mortality Abhiram Prasad, MD, FRCP, FACC,* Mandeep Singh, MD, FACC,* Amir Lerman, MD, FACC,* Ryan J. Lennon, MS,† David R. Holmes, JR, MD, FACC,* Charanjit S. Rihal, MD, FACC* Rochester, Minnesota The aim of this study was to evaluate whether, in patients with normal post-procedure CK-MB, an isolated elevation in cardiac troponin T (cTnT) predicts long-term survival. BACKGROUND Cardiac troponin T is a sensitive and specific marker of myonecrosis. There is little known about the incidence and prognostic significance of an isolated elevation of cTnT without a rise in creatine kinase (CK)-MB following PCI. METHODS We evaluated the outcomes of 1,949 patients from the Mayo Clinic registry who had normal pre-procedure cTnT and CK-MB, required nonemergency percutaneous coronary intervention (PCI), and had normal CK-MB after the procedure. RESULTS An elevation in cTnT (cTnT⫹) was observed in 383 patients (19.6%) (median 0.04 ng/ml, interquartile range 0.03 to 0.06 ng/ml). The TnT⫹ status was associated with adverse clinical and angiographic characteristics, and multivessel PCI. Over the median follow-up duration of 26 months, mortality (p ⬍ 0.001) and the combined rate of death and myocardial infarction (p ⫽ 0.004) were significantly higher in cTnT⫹ patients. Estimated 3-year survival for those with and without cTnT elevation was 86.9% and 93.2%, respectively. By multivariate analysis, an elevation in cTnT after PCI was an independent predictor of increased long-term mortality. A doubling in the post-PCI cTnT was associated with a partial hazard ratio of 1.20 (95% confidence interval 1.02 to 1.40; p ⫽ 0.023). CONCLUSIONS An isolated minor elevation in cTnT after PCI provides long-term prognostic information regarding mortality and myocardial infarction. (J Am Coll Cardiol 2006;48:1765–70) © 2006 by the American College of Cardiology Foundation OBJECTIVES
In the era of stents and glycoprotein IIb/IIIa inhibitors, minor and often asymptomatic elevation in creatine kinase-MB fraction (CK-MB) occurs in approximately 20% of patients after percutaneous coronary intervention (PCI) (1,2). The preponderance of evidence supports the observation that greater than 5-fold rise in CK-MB above normal is associated with in-hospital adverse cardiac events and merits prolonging the hospitalization after elective procedures (1– 4), whereas an elevation of CK-MB that is 1 to 5 times normal does not appear to significantly influence in-hospital outcomes. See page 1771 The data for a relationship between CK-MB elevation and long-term survival is less consistent. Several studies suggest that any elevation of CK-MB is associated with reduced long-term survival, and that there is direct correlation between the magnitude of myonecrosis and mortality (1,5,6). In contrast, others have reported a threshold of CK-MB 5 to 8 times normal to be predictive of long-term survival (2,4,7). The differentiation of a continuous versus a threshold relationship between post-procedural myonecrosis From the *Division of Cardiovascular Diseases, Department of Internal Medicine, and the †Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Manuscript received January 13, 2006; revised manuscript received April 20, 2006, accepted April 23, 2006.
and long-term survival is important to establish, because it provides insight into the pathophysiologic mechanisms for the association (8). A threshold of 5 to 8 times normal would support a direct effect of myocardial injury on survival, whereas a continuous relationship would be consistent with the CK-MB elevation being a marker of atherosclerotic burden and disease activity. We hypothesized that the relationship is continuous, even at very low levels of myonecrosis. The aim of this study was to evaluate whether, in patients with normal postprocedure CK-MB, an isolated elevation in cardiac troponin T (cTnT) predicts long-term survival.
METHODS Since 1979, all patients undergoing percutaneous revascularization at the Mayo Clinic in Rochester, Minnesota, are prospectively followed in a registry. The registry includes demographic, clinical, angiographic, and procedural data. Immediate and in-hospital events are recorded, and each patient is surveyed by telephone using a standardized questionnaire at 6 months, 1 year, and then annually after the procedure. All adverse events are confirmed by reviewing the medical records of the patients followed at our institution and by contacting the patients’ physicians and reviewing the hospital records of patients followed elsewhere. The current study included all consecutive patients from the database for the period of August 1, 2000, when routine
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JACC Vol. 48, No. 9, 2006 November 7, 2006:1765–70 Table 1. Baseline Clinical Characteristics
Abbreviations and Acronyms CABG ⫽ coronary artery bypass graft CK-MB ⫽ creatine kinase-MB CRP ⫽ C-reactive protein cTnT ⫽ cardiac troponin T MI ⫽ myocardial infarction PCI ⫽ percutaneous coronary intervention
measurements of cTnT were initiated for our PCI patients, through October 31, 2003. Inclusion criteria were a normal preprocedure cTnT (below the 10% coefficient of variation [CV] value) and CK-MB. Patients were excluded if they suffered myocardial infarction (MI) in the week before PCI or had a post-procedure elevation in CK-MB. Hospital charts of each patient were reviewed to verify the data, and the study was approved by the Institutional Review Board. There were 5,505 PCIs performed on 4,760 unique patients. One hundred seventeen patients refused use of their records for research, yielding a sample size of 5,368 PCIs. Of these, 1,997 had elevated baseline cTnT, 52 had elevated baseline CK-MB, 733 had elevated post-PCI CK-MB, and 357 had missing values for at least 1 of these 3 measures. Fifty-two PCIs were excluded for pre-procedural shock or recent myocardial infarction (within 7 days before PCI). Of the remaining 2,177 qualifying PCIs, the first for each of the 1,949 patients was included. Blood samples for cardiac biomarkers were collected before and at 8 and 16 h after PCI. The analysis was performed using a highly sensitive and precise third-generation assay (Elecsys; Roche Diagnostics, Indianapolis, Indiana). The upper limit of normal for the assay is ⬍0.03 ng/ml. The following definitions were used for the database. Myocardial infarction during follow-up was defined by the presence of 2 of 3 criteria: chest pain lasting 20 min or longer, new ST/Twave changes or Q waves on the electrocardiogram, and increased cardiac biomarker (CK or CK-MB) levels at least twice the upper limit of the normal range. The number of diseased coronary arteries was defined by the number of major coronary arteries with luminal diameter stenosis ⱖ70%. Patients with ⱖ50% stenosis in the left main coronary artery were considered to have 2-vessel disease if there was right dominance and 3-vessel disease if there was left dominance. Angiographic success was defined as PCI with residual stenosis ⬍50% in at least one treatment site. Complete revascularization was achieved if there were no remaining stenoses ⱖ70%. Statistical analysis. Data are presented as the mean values ⫾ SD or as a frequency (percentage). Kaplan-Meier methods were used to estimate survival curves. Survival was analyzed in successful PCIs, with the discharge date as day 0. Comparisons between groups are made using Student t test, Pearson chi-squared statistic, Mann-Whitney rank sum test, and log rank test for continuous, nominal, ordinal (i.e., number of diseased vessels, number of vessels treated, and length of stay), and survival data, respectively.
TnT TnT <0.03 ng/ml >0.03 ng/ml (n ⴝ 1,566) (n ⴝ 383) p Value Age, yrs Male gender Diabetes Hypertension History of cholesterol ⱖ240 mg/dl Current smoker Current/former smoker Canadian Heart Class III/IV CHF on presentation History of CHF LV ejection fraction ⱕ40% Prior MI Prior PTCA Prior CABG Peripheral vascular disease CVA/TIA Moderate/severe renal disease Body mass index, kg/m2 In-hospital medications Aspirin, no Beta-blockers Lipid-lowering drugs ACE inhibitors
65.8 ⫾ 11.1 69.7 ⫾ 11.1 ⬍0.001 1,120 (72%) 264 (69%) 0.32 423 (27%) 109 (29%) 0.54 1,131 (75%) 280 (77%) 0.66 1,307 (88%) 302 (87%) 0.43 202 (13%) 34 (9%) 0.031 1,003 (65%) 241 (64%) 0.71 911 (58%) 247 (64%) 0.024 87 (6%) 39 (10%) ⬍0.001 151 (11%) 65 (20%) ⬍0.001 133 (8%) 50 (13%) 0.006 544 (36%) 148 (40%) 0.16 630 (40%) 147 (38%) 0.51 382 (24%) 96 (25%) 0.79 147 (10%) 52 (14%) 0.013 172 (11%) 55 (15%) 0.06 28 (2%) 13 (3%) 0.050 30.1 ⫾ 5.7 29.5 ⫾ 5.3 0.048 1,547 (99%) 1,234 (79%) 1,179 (75%) 722 (46%)
378 (99%) 296 (77%) 271 (71%) 197 (51%)
0.88 0.52 0.07 0.07
Values expressed as n (%). ACE ⫽ angiotensin-converting enzyme; CABG ⫽ coronary artery bypass grafting; CHF ⫽ congestive heart failure; CVA ⫽ cerebrovascular accident; LV ⫽ left ventricular; MI ⫽ myocardial infarction; PTCA ⫽ percutaneous transluminal coronary angioplasty; TIA ⫽ transient ischemic attack; TnT ⫽ troponin T.
Cox proportional hazards models were used to estimate partial hazards ratios. Covariate models for each follow-up end point were constructed in the following manner: simple associations with the end point were estimated for covariates with sufficient data (⬍10% missing values); covariates significant at the 0.15 level were incorporated into a full covariate model; a backward selection procedure was used (with 0.05 significance threshold) to produce the final covariate model. Cardiac troponin (base 2 logarithmic transformation) was then added to the covariate-only model. Ejection fraction was dichotomized at 40%, and the hazard ratio for age is based on a 10-year increment in age. All analyses presented here were performed using SAS software (SAS Institute, Cary, North Carolina).
RESULTS Baseline characteristics. There were 383 (19.6%) patients with elevated cTnT (cTnT⫹) (median 0.04 ng/ml; interquartile range 0.03 to 0.06 ng/ml) and normal CK-MB after PCI among the 1,949 patients enrolled in the study. The clinical characteristics of patients with and without cTnT elevation are summarized in Table 1. Patients with a rise in cTnT had more adverse clinical characteristics; they were older, more likely to have moderate to severe angina, a history of congestive heart failure (CHF), an ejection fraction ⱕ40%, and peripheral vascular disease and less likely to be current
Prasad et al. Troponin T and PCI
JACC Vol. 48, No. 9, 2006 November 7, 2006:1765–70 Table 2. Angiographic Characteristics
Number of diseased vessels Single Double Three Type C lesion Thrombus present Calcified lesion Eccentric lesion Bifurcation lesion Ostial lesion Severe angulation Minor branches (any lesion) Major branches (any lesion)
TnT <0.03 ng/ml (n ⴝ 1,566)
TnT >0.03 ng/ml (n ⴝ 383)
528 (36%) 577 (40%) 342 (24%) 492 (32%) 112 (8%) 469 (33%) 1,097 (82%) 180 (12%) 239 (23%) 32 (2%) 548 (38%) 281 (19%)
111 (29%) 133 (38%) 108 (31%) 163 (44%) 41 (12%) 143 (41%) 273 (85%) 47 (13%) 53 (20%) 11 (3%) 138 (39%) 79 (22%)
p Value 0.011
⬍0.001 0.020 0.003 0.17 0.61 0.39 0.34 0.72 0.20
Values expressed as n (%). TnT ⫽ troponin T.
smokers. There was no difference in the use of beta-blocker, angiotensin-converting enzyme inhibitors, and lipidlowering therapy between the groups. Angiographic and procedural characteristics. Table 2 summarizes the angiographic characteristics. Patients with
cTnT⫹ had more extensive disease with multivessel coronary artery disease, type C lesions, and lesions associated with thrombus, and calcification. Procedural characteristics are presented in Table 3. Procedural success (98%) and post-procedure TIMI (Thrombolysis In Myocardial Infarction) grade 3 flow (97%) were equally high in both groups. There was no difference in the use of glycoprotein IIb/IIIa inhibitors, stents, and atherectomy devices between the groups. In concert with more extensive disease and adverse baseline clinical characteristics, cTnT⫹ patients underwent more urgent procedures, had more multivessel PCI, and had more complicated procedural outcomes with more dissection and branch vessel occlusion. Outcomes. The length of hospitalization was longer among cTnT⫹ patients (Table 4). There was 1 in-hospital death among cTnT⫹ patients and none in those with normal cTnT levels. The 1,916 patients with successful PCI were followed for a median of 26 months; 92% had at least 1 year of follow-up. Mortality and the combined rate of death and MI were significantly higher in cTnT⫹ patients (Figs. 1 and 2). Estimated 1, 2, and 3-year survival rates for those with and without cTnT elevation were 97% and
Table 3. Procedural Characteristics
Nature procedure Elective Urgent Total vessels treated 1 2 3 Total stents placed Device used Balloon only Stent Cutting balloon Atherectomy GP IIb/IIIa administration Vessel treated Left main Left anterior descending Circumflex Right Vein graft intervention Successful procedure Post-procedure TIMI 3 flow in all lesions Post-procedure TIMI 2 or 3 flow in all lesions Branch occlusion Intimal tear In-lab coronary occlusion—reopened In-lab coronary occlusion—remained Coronary occlusion within 24 h Coronary occlusion after 24 h Coronary embolization Maximum balloon length (mm) Maximum device size (mm)
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TnT <0.03 ng/ml (n ⴝ 1,566)
TnT >0.03 ng/ml (n ⴝ 383)
853 (54%) 713 (46%)
163 (43%) 220 (57%)
1,339 (86%) 212 (14%) 15 (1%) 1.3 ⫾ 1.0
305 (80%) 73 (19%) 5 (1%) 1.5 ⫾ 1.1
⬍0.001
118 (8%) 1,352 (86%) 158 (10%) 29 (2%) 750 (48%)
26 (7%) 339 (89%) 36 (9%) 11 (3%) 198 (52%)
0.62 0.26 0.69 0.21 0.19
34 (2%) 687 (44%) 386 (25%) 562 (36%) 121 (8%) 1,540 (98%) 1,420 (97%) 1,449 (99%) 18 (1%) 203 (13%) 4 (0.3%) 4 (0.3%) 6 (0.4%) 0 0 16.0 ⫾ 6.8 3.3 ⫾ 0.7
5 (1%) 188 (49%) 111 (29%) 124 (32%) 39 (10%) 376 (98%) 352 (97%) 357 (99%) 10 (3%) 67 (18%) 2 (0.5%) 1 (0.2%) 2 (0.5%) 0 0 16.1 ⫾ 5.2 3.4 ⫾ 0.6
0.28 0.07 0.08 0.20 0.12 0.82 0.87 0.73 0.031 0.022 0.40 0.98 0.70
p Value ⬍0.001
0.005
Values expressed as n (%). GP ⫽ glycoprotein; TIMI ⫽ Thrombolysis In Myocardial Infarction; TnT ⫽ troponin T.
0.79 0.20
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Table 4. In-Hospital Outcomes TnT <0.03 ng/ml (n ⴝ 1,566)
TnT >0.03 ng/ml (n ⴝ 383)
1,391 (89%) 120 (8%) 55 (4%) 0
307 (80%) 55 (14%) 21 (5%) 1 (0.3%)
Length of stay 1–2 days 3–4 days 5⫹ days Death
p Value ⬍0.001
0.20
Values expressed as n (%).
98.1%, 90.2% and 95.9%, and 86.9% and 93.2%, respectively. By multivariate analysis an elevation in post-PCI cTnT, age, diabetes, peripheral vascular disease, ejection fraction ⬍40%, calcified lesion, and saphenous vein graft PCI were independent predictors of increased long-term mortality (Table 5). There was no evidence of a nonlinear or threshold effect for the association between post-PCI cTnT and the time to mortality. A doubling in the post-PCI cTnT measure was associated with a partial hazard ratio of 1.20 (95% confidence interval 1.02 to 1.4; p ⫽ 0.023).
DISCUSSION The major findings of the present study are that following PCI in patients with normal baseline cTnT: 1) isolated minor elevation in cTnT, with normal CK-MB, occurs in about 20% of patients; 2) the rise in cTnT is independently associated with increased long-term mortality; but 3) these patients represent a low-risk group for in-hospital mortality. The present study analyzes the prognostic significance of an isolated rise in cTnT after successful nonemergency PCI procedures. The findings are representative of contemporary practice, because the majority of patients were treated with stents (⬎86%), atherectomy devices were used infrequently (⬍3%), and glycoprotein IIb/IIIa inhibitors were used in approximately 50% of interventions. In-hospital event rates were extremely low regardless of cTnT status, but follow-up death and the combined end point of death/MI were
Figure 2. Kaplan-Meier estimates for survival free of death or myocardial infarction for those with (TnT ⱖ0.03) and without (TnT ⬍0.03) elevated troponin. The composite end point consisted of 19 myocardial infarctions (MI) and 35 deaths for those with elevated troponin and 68 MI and 75 deaths for those without. cTnT ⫽ cardiac troponin T.
significantly higher in cTnT⫹ patients. Elevation in cTnT was an independent predictor of mortality over a median follow-up period of 2.2 years. Comparison with previous studies. Earlier studies have evaluated the relationship between cardiac troponin I (9 –14) and troponin T (14) with long-term mortality. However, unlike the present investigation, all except one (11) did not exclude patients who had elevated CK-MB after the revascularization procedure. Several (10,13,14) did not exclude patients with MI who would have had abnormal cardiac biomarker levels at baseline. For these reasons, the reported frequency for post-procedure troponin elevation ranged from 17% to 48%, and although some found elevated troponin to be an independent predictor of survival (10,12,14), others did not (9,11,13). The inconsistent findings may relate to heterogeneity in the inclusion criteria, the sensitivity and specificity of the assay used to measure troponin, and the duration of follow-up. The study by Natarajan et al. (11) analyzed the impact of troponin I and excluded patients with elevated CK-MB and pre-procedure MI. The incidence of isolated troponin elevation was similar (17%) to the present study, but troponin I was not found to be a predictor of mortality. However, their study had a Table 5. Multiple Cox Model for Long-Term Mortality
Figure 1. Kaplan-Meier survival estimates for those with (TnT ⱖ0.03) and without (TnT ⬍0.03) elevated troponin. There were 40 and 80 deaths, respectively, observed on follow-up. cTnT ⫽ cardiac troponin T.
Ejection fraction Calcified lesion Age Glycoprotein IIb/IIIa use Saphenous vein graft PCI Diabetes Peripheral vascular disease Post-PCI troponin (log2) Ever smoked
Chi-Square Test
Hazard Ratio (95% CI)
p Value
17.7 12.8 11.2 7.7 7.5 7.5 5.4 5.2 4.5
2.5 (1.6–3.8) 2.03 (1.4–3.0) 1.39 (1.2–1.7) 0.58 (0.4–0.8) 1.99 (1.2–3.2) 1.69 (1.2–2.5) 1.72 (1.1–2.7) 1.20 (1.02–1.4) 1.58 (1.0–2.4)
⬍0.0001 ⬍0.001 ⬍0.001 0.004 0.006 0.006 0.021 0.023 0.034
CI ⫽ confidence interval; PCI ⫽ percntaneous coronary intervention.
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smaller sample size and a follow-up of only 1 year. Consistent with this fact is the finding in the present investigation that the Kaplan-Meier curves for survival and survival free of MI diverged after 1 year. To our knowledge, our study is the first to report that an isolated elevation in troponin is a predictor of outcomes. Mechanisms for the adverse clinical outcomes. The relationship between long-term survival and very low levels of cTnT elevation following PCI is remarkable. This suggests that there may be a continuous, rather than a threshold relationship between the magnitude of rise in the biomarkers of myocardial injury and long-term outcomes. Two potential mechanisms may explain this observation. First, studies with magnetic resonance imaging have confirmed that an elevation in troponin after PCI is related to myocardial necrosis, and that there is a positive correlation between the magnitude of injury and the extent of troponin release (15). Thus, myocardial injury may impair left ventricular function and predispose to arrhythmias, which would influence survival. Alternatively, cTnT and CK-MB elevation may be a marker for severe atherosclerosis, increased plaque burden (16), presence of vulnerable plaques, endothelial dysfunction, microvascular injury, and inflammation. Inflammation, as measured by elevated C-reactive protein (CRP), is an independent predictor of adverse long-term outcomes after PCI (1). The present study supports the latter mechanism, because the patients with elevated cTnT were older and had more severe angina, multivessel disease, complex lesion morphology, coronary thrombus, left ventricular systolic dysfunction, peripheral vascular disease, and urgent procedures, all consistent with advanced or unstable coronary artery disease. Moreover, pharmacologic interventions that have antiinflammatory and antithrombotic effects, such as statins and glycoprotein IIb/IIIa inhibitors have been shown to reduce the incidence and magnitude of myonecrosis (17,18). It seems unlikely that the very low level of myonecrosis observed in the present study would have been adequate to impact left ventricular function. One can speculate that both mechanisms may be at play, with minor myonecrosis serving as a marker of advanced and active atherosclerosis and large increases in biomarkers diagnosing periprocedural MI that would directly impact prognosis. Mechanisms for the troponin elevation. Patients with cTnT elevation had greater atherosclerotic burden, as suggested by a higher prevalence of multivessel disease and type C lesions and a greater number of stents used per patient. Despite these differences, procedural success and TIMI grade 3 flow was achieved in nearly all patients. However, cTnT⫹ patients had a higher incidence of branch vessel occlusion and coronary dissection. Abrupt closure was not different between the groups, and angiographic embolization was not detected in any patient. These observations are consistent with earlier studies that have implicated branch vessel occlusion, dissection, and embolization as the mechanisms for the ischemic injury and myonecrosis (11,12,19).
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However, angiographic complications were absent in approximately three-quarters of the patients with elevated cTnT. Impaired microvascular perfusion, due to plaque and thrombus embolization, and vasoconstriction may be underlying mechanisms in a significant proportion of patients (20 –22). This would be either undetectable by routine angiographic evaluation in the catheterization laboratory or present as slow reflow. Study limitations. Although the data was collected prospectively, this is a retrospective single-center analysis and is subject to the limitations of such analyses. Furthermore, multiple regression models are unable to account for unobserved covariates that may be confounded with troponin. Independent core angiographic laboratory analysis to investigate myocardial perfusion was not performed and may have provided insight into the mechanism for the cTnT release in patients without angiographic complications. Markers of inflammation such as CRP were not routinely measured. Emerging data indicate that TnT values between the 10% CV value, which we used, and the 99th percentile value of 0.01 ng/ml have prognostic significance. This fact and the recent data concerning the potential significance of pre-PCI TnT levels for evaluating post-PCI myonecrosis (23) highlights the need for additional studies. Conclusions and clinical implications. Patients with an isolated elevation in cTnT following nonemergency PCI represent a very low-risk group for in-hospital major adverse cardiac events, and their hospitalization need not be prolonged. However, an isolated elevation in cTnT is associated with higher rates of death and MI on follow-up, provides long-term prognostic information, and appears to identify, independent of well recognized markers of atherosclerotic burden and ventricular function, high-risk patients who may benefit from more intensive secondary prevention. Further studies using multiple biomarkers together with imaging techniques such as intravascular ultrasound and core angiographic laboratory analysis are required to improve our understanding of the mechanisms responsible for the myonecrosis, with the goal of improving risk stratification and ultimately developing novel treatment strategies. Reprint requests and correspondence: Dr. Abhiram Prasad, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: [email protected].
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Vol. 48, No. 9, 2006 ISSN 0735-1097/06/$32.00 doi:10.1016/j.jacc.2006.04.102
Isolated Elevation in Troponin T After Percutaneous Coronary Intervention Is Associated With Higher Long-Term Mortality Abhiram Prasad, MD, FRCP, FACC,* Mandeep Singh, MD, FACC,* Amir Lerman, MD, FACC,* Ryan J. Lennon, MS,† David R. Holmes, JR, MD, FACC,* Charanjit S. Rihal, MD, FACC* Rochester, Minnesota The aim of this study was to evaluate whether, in patients with normal post-procedure CK-MB, an isolated elevation in cardiac troponin T (cTnT) predicts long-term survival. BACKGROUND Cardiac troponin T is a sensitive and specific marker of myonecrosis. There is little known about the incidence and prognostic significance of an isolated elevation of cTnT without a rise in creatine kinase (CK)-MB following PCI. METHODS We evaluated the outcomes of 1,949 patients from the Mayo Clinic registry who had normal pre-procedure cTnT and CK-MB, required nonemergency percutaneous coronary intervention (PCI), and had normal CK-MB after the procedure. RESULTS An elevation in cTnT (cTnT⫹) was observed in 383 patients (19.6%) (median 0.04 ng/ml, interquartile range 0.03 to 0.06 ng/ml). The TnT⫹ status was associated with adverse clinical and angiographic characteristics, and multivessel PCI. Over the median follow-up duration of 26 months, mortality (p ⬍ 0.001) and the combined rate of death and myocardial infarction (p ⫽ 0.004) were significantly higher in cTnT⫹ patients. Estimated 3-year survival for those with and without cTnT elevation was 86.9% and 93.2%, respectively. By multivariate analysis, an elevation in cTnT after PCI was an independent predictor of increased long-term mortality. A doubling in the post-PCI cTnT was associated with a partial hazard ratio of 1.20 (95% confidence interval 1.02 to 1.40; p ⫽ 0.023). CONCLUSIONS An isolated minor elevation in cTnT after PCI provides long-term prognostic information regarding mortality and myocardial infarction. (J Am Coll Cardiol 2006;48:1765–70) © 2006 by the American College of Cardiology Foundation OBJECTIVES
In the era of stents and glycoprotein IIb/IIIa inhibitors, minor and often asymptomatic elevation in creatine kinase-MB fraction (CK-MB) occurs in approximately 20% of patients after percutaneous coronary intervention (PCI) (1,2). The preponderance of evidence supports the observation that greater than 5-fold rise in CK-MB above normal is associated with in-hospital adverse cardiac events and merits prolonging the hospitalization after elective procedures (1– 4), whereas an elevation of CK-MB that is 1 to 5 times normal does not appear to significantly influence in-hospital outcomes. See page 1771 The data for a relationship between CK-MB elevation and long-term survival is less consistent. Several studies suggest that any elevation of CK-MB is associated with reduced long-term survival, and that there is direct correlation between the magnitude of myonecrosis and mortality (1,5,6). In contrast, others have reported a threshold of CK-MB 5 to 8 times normal to be predictive of long-term survival (2,4,7). The differentiation of a continuous versus a threshold relationship between post-procedural myonecrosis From the *Division of Cardiovascular Diseases, Department of Internal Medicine, and the †Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Manuscript received January 13, 2006; revised manuscript received April 20, 2006, accepted April 23, 2006.
and long-term survival is important to establish, because it provides insight into the pathophysiologic mechanisms for the association (8). A threshold of 5 to 8 times normal would support a direct effect of myocardial injury on survival, whereas a continuous relationship would be consistent with the CK-MB elevation being a marker of atherosclerotic burden and disease activity. We hypothesized that the relationship is continuous, even at very low levels of myonecrosis. The aim of this study was to evaluate whether, in patients with normal postprocedure CK-MB, an isolated elevation in cardiac troponin T (cTnT) predicts long-term survival.
METHODS Since 1979, all patients undergoing percutaneous revascularization at the Mayo Clinic in Rochester, Minnesota, are prospectively followed in a registry. The registry includes demographic, clinical, angiographic, and procedural data. Immediate and in-hospital events are recorded, and each patient is surveyed by telephone using a standardized questionnaire at 6 months, 1 year, and then annually after the procedure. All adverse events are confirmed by reviewing the medical records of the patients followed at our institution and by contacting the patients’ physicians and reviewing the hospital records of patients followed elsewhere. The current study included all consecutive patients from the database for the period of August 1, 2000, when routine
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JACC Vol. 48, No. 9, 2006 November 7, 2006:1765–70 Table 1. Baseline Clinical Characteristics
Abbreviations and Acronyms CABG ⫽ coronary artery bypass graft CK-MB ⫽ creatine kinase-MB CRP ⫽ C-reactive protein cTnT ⫽ cardiac troponin T MI ⫽ myocardial infarction PCI ⫽ percutaneous coronary intervention
measurements of cTnT were initiated for our PCI patients, through October 31, 2003. Inclusion criteria were a normal preprocedure cTnT (below the 10% coefficient of variation [CV] value) and CK-MB. Patients were excluded if they suffered myocardial infarction (MI) in the week before PCI or had a post-procedure elevation in CK-MB. Hospital charts of each patient were reviewed to verify the data, and the study was approved by the Institutional Review Board. There were 5,505 PCIs performed on 4,760 unique patients. One hundred seventeen patients refused use of their records for research, yielding a sample size of 5,368 PCIs. Of these, 1,997 had elevated baseline cTnT, 52 had elevated baseline CK-MB, 733 had elevated post-PCI CK-MB, and 357 had missing values for at least 1 of these 3 measures. Fifty-two PCIs were excluded for pre-procedural shock or recent myocardial infarction (within 7 days before PCI). Of the remaining 2,177 qualifying PCIs, the first for each of the 1,949 patients was included. Blood samples for cardiac biomarkers were collected before and at 8 and 16 h after PCI. The analysis was performed using a highly sensitive and precise third-generation assay (Elecsys; Roche Diagnostics, Indianapolis, Indiana). The upper limit of normal for the assay is ⬍0.03 ng/ml. The following definitions were used for the database. Myocardial infarction during follow-up was defined by the presence of 2 of 3 criteria: chest pain lasting 20 min or longer, new ST/Twave changes or Q waves on the electrocardiogram, and increased cardiac biomarker (CK or CK-MB) levels at least twice the upper limit of the normal range. The number of diseased coronary arteries was defined by the number of major coronary arteries with luminal diameter stenosis ⱖ70%. Patients with ⱖ50% stenosis in the left main coronary artery were considered to have 2-vessel disease if there was right dominance and 3-vessel disease if there was left dominance. Angiographic success was defined as PCI with residual stenosis ⬍50% in at least one treatment site. Complete revascularization was achieved if there were no remaining stenoses ⱖ70%. Statistical analysis. Data are presented as the mean values ⫾ SD or as a frequency (percentage). Kaplan-Meier methods were used to estimate survival curves. Survival was analyzed in successful PCIs, with the discharge date as day 0. Comparisons between groups are made using Student t test, Pearson chi-squared statistic, Mann-Whitney rank sum test, and log rank test for continuous, nominal, ordinal (i.e., number of diseased vessels, number of vessels treated, and length of stay), and survival data, respectively.
TnT TnT <0.03 ng/ml >0.03 ng/ml (n ⴝ 1,566) (n ⴝ 383) p Value Age, yrs Male gender Diabetes Hypertension History of cholesterol ⱖ240 mg/dl Current smoker Current/former smoker Canadian Heart Class III/IV CHF on presentation History of CHF LV ejection fraction ⱕ40% Prior MI Prior PTCA Prior CABG Peripheral vascular disease CVA/TIA Moderate/severe renal disease Body mass index, kg/m2 In-hospital medications Aspirin, no Beta-blockers Lipid-lowering drugs ACE inhibitors
65.8 ⫾ 11.1 69.7 ⫾ 11.1 ⬍0.001 1,120 (72%) 264 (69%) 0.32 423 (27%) 109 (29%) 0.54 1,131 (75%) 280 (77%) 0.66 1,307 (88%) 302 (87%) 0.43 202 (13%) 34 (9%) 0.031 1,003 (65%) 241 (64%) 0.71 911 (58%) 247 (64%) 0.024 87 (6%) 39 (10%) ⬍0.001 151 (11%) 65 (20%) ⬍0.001 133 (8%) 50 (13%) 0.006 544 (36%) 148 (40%) 0.16 630 (40%) 147 (38%) 0.51 382 (24%) 96 (25%) 0.79 147 (10%) 52 (14%) 0.013 172 (11%) 55 (15%) 0.06 28 (2%) 13 (3%) 0.050 30.1 ⫾ 5.7 29.5 ⫾ 5.3 0.048 1,547 (99%) 1,234 (79%) 1,179 (75%) 722 (46%)
378 (99%) 296 (77%) 271 (71%) 197 (51%)
0.88 0.52 0.07 0.07
Values expressed as n (%). ACE ⫽ angiotensin-converting enzyme; CABG ⫽ coronary artery bypass grafting; CHF ⫽ congestive heart failure; CVA ⫽ cerebrovascular accident; LV ⫽ left ventricular; MI ⫽ myocardial infarction; PTCA ⫽ percutaneous transluminal coronary angioplasty; TIA ⫽ transient ischemic attack; TnT ⫽ troponin T.
Cox proportional hazards models were used to estimate partial hazards ratios. Covariate models for each follow-up end point were constructed in the following manner: simple associations with the end point were estimated for covariates with sufficient data (⬍10% missing values); covariates significant at the 0.15 level were incorporated into a full covariate model; a backward selection procedure was used (with 0.05 significance threshold) to produce the final covariate model. Cardiac troponin (base 2 logarithmic transformation) was then added to the covariate-only model. Ejection fraction was dichotomized at 40%, and the hazard ratio for age is based on a 10-year increment in age. All analyses presented here were performed using SAS software (SAS Institute, Cary, North Carolina).
RESULTS Baseline characteristics. There were 383 (19.6%) patients with elevated cTnT (cTnT⫹) (median 0.04 ng/ml; interquartile range 0.03 to 0.06 ng/ml) and normal CK-MB after PCI among the 1,949 patients enrolled in the study. The clinical characteristics of patients with and without cTnT elevation are summarized in Table 1. Patients with a rise in cTnT had more adverse clinical characteristics; they were older, more likely to have moderate to severe angina, a history of congestive heart failure (CHF), an ejection fraction ⱕ40%, and peripheral vascular disease and less likely to be current
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JACC Vol. 48, No. 9, 2006 November 7, 2006:1765–70 Table 2. Angiographic Characteristics
Number of diseased vessels Single Double Three Type C lesion Thrombus present Calcified lesion Eccentric lesion Bifurcation lesion Ostial lesion Severe angulation Minor branches (any lesion) Major branches (any lesion)
TnT <0.03 ng/ml (n ⴝ 1,566)
TnT >0.03 ng/ml (n ⴝ 383)
528 (36%) 577 (40%) 342 (24%) 492 (32%) 112 (8%) 469 (33%) 1,097 (82%) 180 (12%) 239 (23%) 32 (2%) 548 (38%) 281 (19%)
111 (29%) 133 (38%) 108 (31%) 163 (44%) 41 (12%) 143 (41%) 273 (85%) 47 (13%) 53 (20%) 11 (3%) 138 (39%) 79 (22%)
p Value 0.011
⬍0.001 0.020 0.003 0.17 0.61 0.39 0.34 0.72 0.20
Values expressed as n (%). TnT ⫽ troponin T.
smokers. There was no difference in the use of beta-blocker, angiotensin-converting enzyme inhibitors, and lipidlowering therapy between the groups. Angiographic and procedural characteristics. Table 2 summarizes the angiographic characteristics. Patients with
cTnT⫹ had more extensive disease with multivessel coronary artery disease, type C lesions, and lesions associated with thrombus, and calcification. Procedural characteristics are presented in Table 3. Procedural success (98%) and post-procedure TIMI (Thrombolysis In Myocardial Infarction) grade 3 flow (97%) were equally high in both groups. There was no difference in the use of glycoprotein IIb/IIIa inhibitors, stents, and atherectomy devices between the groups. In concert with more extensive disease and adverse baseline clinical characteristics, cTnT⫹ patients underwent more urgent procedures, had more multivessel PCI, and had more complicated procedural outcomes with more dissection and branch vessel occlusion. Outcomes. The length of hospitalization was longer among cTnT⫹ patients (Table 4). There was 1 in-hospital death among cTnT⫹ patients and none in those with normal cTnT levels. The 1,916 patients with successful PCI were followed for a median of 26 months; 92% had at least 1 year of follow-up. Mortality and the combined rate of death and MI were significantly higher in cTnT⫹ patients (Figs. 1 and 2). Estimated 1, 2, and 3-year survival rates for those with and without cTnT elevation were 97% and
Table 3. Procedural Characteristics
Nature procedure Elective Urgent Total vessels treated 1 2 3 Total stents placed Device used Balloon only Stent Cutting balloon Atherectomy GP IIb/IIIa administration Vessel treated Left main Left anterior descending Circumflex Right Vein graft intervention Successful procedure Post-procedure TIMI 3 flow in all lesions Post-procedure TIMI 2 or 3 flow in all lesions Branch occlusion Intimal tear In-lab coronary occlusion—reopened In-lab coronary occlusion—remained Coronary occlusion within 24 h Coronary occlusion after 24 h Coronary embolization Maximum balloon length (mm) Maximum device size (mm)
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TnT <0.03 ng/ml (n ⴝ 1,566)
TnT >0.03 ng/ml (n ⴝ 383)
853 (54%) 713 (46%)
163 (43%) 220 (57%)
1,339 (86%) 212 (14%) 15 (1%) 1.3 ⫾ 1.0
305 (80%) 73 (19%) 5 (1%) 1.5 ⫾ 1.1
⬍0.001
118 (8%) 1,352 (86%) 158 (10%) 29 (2%) 750 (48%)
26 (7%) 339 (89%) 36 (9%) 11 (3%) 198 (52%)
0.62 0.26 0.69 0.21 0.19
34 (2%) 687 (44%) 386 (25%) 562 (36%) 121 (8%) 1,540 (98%) 1,420 (97%) 1,449 (99%) 18 (1%) 203 (13%) 4 (0.3%) 4 (0.3%) 6 (0.4%) 0 0 16.0 ⫾ 6.8 3.3 ⫾ 0.7
5 (1%) 188 (49%) 111 (29%) 124 (32%) 39 (10%) 376 (98%) 352 (97%) 357 (99%) 10 (3%) 67 (18%) 2 (0.5%) 1 (0.2%) 2 (0.5%) 0 0 16.1 ⫾ 5.2 3.4 ⫾ 0.6
0.28 0.07 0.08 0.20 0.12 0.82 0.87 0.73 0.031 0.022 0.40 0.98 0.70
p Value ⬍0.001
0.005
Values expressed as n (%). GP ⫽ glycoprotein; TIMI ⫽ Thrombolysis In Myocardial Infarction; TnT ⫽ troponin T.
0.79 0.20
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Table 4. In-Hospital Outcomes TnT <0.03 ng/ml (n ⴝ 1,566)
TnT >0.03 ng/ml (n ⴝ 383)
1,391 (89%) 120 (8%) 55 (4%) 0
307 (80%) 55 (14%) 21 (5%) 1 (0.3%)
Length of stay 1–2 days 3–4 days 5⫹ days Death
p Value ⬍0.001
0.20
Values expressed as n (%).
98.1%, 90.2% and 95.9%, and 86.9% and 93.2%, respectively. By multivariate analysis an elevation in post-PCI cTnT, age, diabetes, peripheral vascular disease, ejection fraction ⬍40%, calcified lesion, and saphenous vein graft PCI were independent predictors of increased long-term mortality (Table 5). There was no evidence of a nonlinear or threshold effect for the association between post-PCI cTnT and the time to mortality. A doubling in the post-PCI cTnT measure was associated with a partial hazard ratio of 1.20 (95% confidence interval 1.02 to 1.4; p ⫽ 0.023).
DISCUSSION The major findings of the present study are that following PCI in patients with normal baseline cTnT: 1) isolated minor elevation in cTnT, with normal CK-MB, occurs in about 20% of patients; 2) the rise in cTnT is independently associated with increased long-term mortality; but 3) these patients represent a low-risk group for in-hospital mortality. The present study analyzes the prognostic significance of an isolated rise in cTnT after successful nonemergency PCI procedures. The findings are representative of contemporary practice, because the majority of patients were treated with stents (⬎86%), atherectomy devices were used infrequently (⬍3%), and glycoprotein IIb/IIIa inhibitors were used in approximately 50% of interventions. In-hospital event rates were extremely low regardless of cTnT status, but follow-up death and the combined end point of death/MI were
Figure 2. Kaplan-Meier estimates for survival free of death or myocardial infarction for those with (TnT ⱖ0.03) and without (TnT ⬍0.03) elevated troponin. The composite end point consisted of 19 myocardial infarctions (MI) and 35 deaths for those with elevated troponin and 68 MI and 75 deaths for those without. cTnT ⫽ cardiac troponin T.
significantly higher in cTnT⫹ patients. Elevation in cTnT was an independent predictor of mortality over a median follow-up period of 2.2 years. Comparison with previous studies. Earlier studies have evaluated the relationship between cardiac troponin I (9 –14) and troponin T (14) with long-term mortality. However, unlike the present investigation, all except one (11) did not exclude patients who had elevated CK-MB after the revascularization procedure. Several (10,13,14) did not exclude patients with MI who would have had abnormal cardiac biomarker levels at baseline. For these reasons, the reported frequency for post-procedure troponin elevation ranged from 17% to 48%, and although some found elevated troponin to be an independent predictor of survival (10,12,14), others did not (9,11,13). The inconsistent findings may relate to heterogeneity in the inclusion criteria, the sensitivity and specificity of the assay used to measure troponin, and the duration of follow-up. The study by Natarajan et al. (11) analyzed the impact of troponin I and excluded patients with elevated CK-MB and pre-procedure MI. The incidence of isolated troponin elevation was similar (17%) to the present study, but troponin I was not found to be a predictor of mortality. However, their study had a Table 5. Multiple Cox Model for Long-Term Mortality
Figure 1. Kaplan-Meier survival estimates for those with (TnT ⱖ0.03) and without (TnT ⬍0.03) elevated troponin. There were 40 and 80 deaths, respectively, observed on follow-up. cTnT ⫽ cardiac troponin T.
Ejection fraction Calcified lesion Age Glycoprotein IIb/IIIa use Saphenous vein graft PCI Diabetes Peripheral vascular disease Post-PCI troponin (log2) Ever smoked
Chi-Square Test
Hazard Ratio (95% CI)
p Value
17.7 12.8 11.2 7.7 7.5 7.5 5.4 5.2 4.5
2.5 (1.6–3.8) 2.03 (1.4–3.0) 1.39 (1.2–1.7) 0.58 (0.4–0.8) 1.99 (1.2–3.2) 1.69 (1.2–2.5) 1.72 (1.1–2.7) 1.20 (1.02–1.4) 1.58 (1.0–2.4)
⬍0.0001 ⬍0.001 ⬍0.001 0.004 0.006 0.006 0.021 0.023 0.034
CI ⫽ confidence interval; PCI ⫽ percntaneous coronary intervention.
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smaller sample size and a follow-up of only 1 year. Consistent with this fact is the finding in the present investigation that the Kaplan-Meier curves for survival and survival free of MI diverged after 1 year. To our knowledge, our study is the first to report that an isolated elevation in troponin is a predictor of outcomes. Mechanisms for the adverse clinical outcomes. The relationship between long-term survival and very low levels of cTnT elevation following PCI is remarkable. This suggests that there may be a continuous, rather than a threshold relationship between the magnitude of rise in the biomarkers of myocardial injury and long-term outcomes. Two potential mechanisms may explain this observation. First, studies with magnetic resonance imaging have confirmed that an elevation in troponin after PCI is related to myocardial necrosis, and that there is a positive correlation between the magnitude of injury and the extent of troponin release (15). Thus, myocardial injury may impair left ventricular function and predispose to arrhythmias, which would influence survival. Alternatively, cTnT and CK-MB elevation may be a marker for severe atherosclerosis, increased plaque burden (16), presence of vulnerable plaques, endothelial dysfunction, microvascular injury, and inflammation. Inflammation, as measured by elevated C-reactive protein (CRP), is an independent predictor of adverse long-term outcomes after PCI (1). The present study supports the latter mechanism, because the patients with elevated cTnT were older and had more severe angina, multivessel disease, complex lesion morphology, coronary thrombus, left ventricular systolic dysfunction, peripheral vascular disease, and urgent procedures, all consistent with advanced or unstable coronary artery disease. Moreover, pharmacologic interventions that have antiinflammatory and antithrombotic effects, such as statins and glycoprotein IIb/IIIa inhibitors have been shown to reduce the incidence and magnitude of myonecrosis (17,18). It seems unlikely that the very low level of myonecrosis observed in the present study would have been adequate to impact left ventricular function. One can speculate that both mechanisms may be at play, with minor myonecrosis serving as a marker of advanced and active atherosclerosis and large increases in biomarkers diagnosing periprocedural MI that would directly impact prognosis. Mechanisms for the troponin elevation. Patients with cTnT elevation had greater atherosclerotic burden, as suggested by a higher prevalence of multivessel disease and type C lesions and a greater number of stents used per patient. Despite these differences, procedural success and TIMI grade 3 flow was achieved in nearly all patients. However, cTnT⫹ patients had a higher incidence of branch vessel occlusion and coronary dissection. Abrupt closure was not different between the groups, and angiographic embolization was not detected in any patient. These observations are consistent with earlier studies that have implicated branch vessel occlusion, dissection, and embolization as the mechanisms for the ischemic injury and myonecrosis (11,12,19).
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However, angiographic complications were absent in approximately three-quarters of the patients with elevated cTnT. Impaired microvascular perfusion, due to plaque and thrombus embolization, and vasoconstriction may be underlying mechanisms in a significant proportion of patients (20 –22). This would be either undetectable by routine angiographic evaluation in the catheterization laboratory or present as slow reflow. Study limitations. Although the data was collected prospectively, this is a retrospective single-center analysis and is subject to the limitations of such analyses. Furthermore, multiple regression models are unable to account for unobserved covariates that may be confounded with troponin. Independent core angiographic laboratory analysis to investigate myocardial perfusion was not performed and may have provided insight into the mechanism for the cTnT release in patients without angiographic complications. Markers of inflammation such as CRP were not routinely measured. Emerging data indicate that TnT values between the 10% CV value, which we used, and the 99th percentile value of 0.01 ng/ml have prognostic significance. This fact and the recent data concerning the potential significance of pre-PCI TnT levels for evaluating post-PCI myonecrosis (23) highlights the need for additional studies. Conclusions and clinical implications. Patients with an isolated elevation in cTnT following nonemergency PCI represent a very low-risk group for in-hospital major adverse cardiac events, and their hospitalization need not be prolonged. However, an isolated elevation in cTnT is associated with higher rates of death and MI on follow-up, provides long-term prognostic information, and appears to identify, independent of well recognized markers of atherosclerotic burden and ventricular function, high-risk patients who may benefit from more intensive secondary prevention. Further studies using multiple biomarkers together with imaging techniques such as intravascular ultrasound and core angiographic laboratory analysis are required to improve our understanding of the mechanisms responsible for the myonecrosis, with the goal of improving risk stratification and ultimately developing novel treatment strategies. Reprint requests and correspondence: Dr. Abhiram Prasad, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: [email protected].
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