Author + information
- Received June 21, 2016
- Revision received August 5, 2016
- Accepted August 31, 2016
- Published online November 29, 2016.
- Gjin Ndrepepa, MDa,∗ (, )
- Roisin Colleran, MB, BCha,
- Siegmund Braun, MDb,
- Salvatore Cassese, MDa,
- Julia Hieber, MDa,
- Massimiliano Fusaro, MDa,
- Sebastian Kufner, MDa,
- Ilka Ott, MDa,
- Robert A. Byrne, MB, BCh, PhDa,
- Oliver Husser, MDa,
- Christian Hengstenberg, MDa,
- Karl-Ludwig Laugwitz, MDc,d,
- Heribert Schunkert, MDa,d and
- Adnan Kastrati, MDa,d
- aDepartment of Adult Cardiology, Deutsches Herzzentrum München, Technische Universität, Munich, Germany
- bDepartment of Laboratory Medicine, Deutsches Herzzentrum München, Technische Universität, Munich, Germany
- c1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany
- dDZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
- ↵∗Reprint requests and correspondence:
Dr. Gjin Ndrepepa, Deutsches Herzzentrum, Lazarettstrasse 36, 80636 München, Germany.
Background The prognostic value of high-sensitivity troponin T (hs-TnT) elevation after elective percutaneous coronary intervention (PCI) in patients with or without raised baseline hs-TnT levels is unclear.
Objectives The goal of this study was to assess whether the prognostic value of post-procedural hs-TnT level after elective PCI depends on the baseline hs-TnT level.
Methods This study included 5,626 patients undergoing elective PCI who had baseline and peak post-procedural hs-TnT measurements available. The primary outcome was 3-year mortality (with risk estimates calculated per SD increase of the log hs-TnT scale).
Results Patients were divided into 4 groups: nonelevated baseline and post-procedural hs-TnT levels (hs-TnT ≤0.014 μg/l; n = 742); nonelevated baseline but elevated post-procedural hs-TnT levels (peak post-procedural hs-TnT >0.014 μg/l; n = 2,721); elevated baseline hs-TnT levels (hs-TnT >0.014 μg/l) with no further rise post-procedure (n = 516); and elevated baseline hs-TnT levels with a further rise post-procedure (n = 1,647). A total of 265 deaths occurred: 6 (1.6%) in patients with nonelevated baseline and post-procedural hs-TnT levels; 54 (3.8%) in patients with nonelevated baseline but elevated post-procedural hs-TnT levels; 50 (16.0%) in patients with elevated baseline hs-TnT levels with no further rise post-procedure; and 155 (18.2%) in patients with elevated baseline hs-TnT levels with a further rise post-procedure (p < 0.001). After adjustment, baseline hs-TnT levels (hazard ratio [HR]: 1.22; 95% confidence interval [CI]: 1.09 to 1.38; p < 0.001) but not peak post-procedural hs-TnT levels (HR: 1.04; 95% CI: 0.85 to 1.28; p = 0.679) were associated with an increased risk of mortality. Peak post-procedural hs-TnT findings were not associated with mortality in patients with nonelevated (HR: 0.93; 95% CI: 0.69 to 1.25; p = 0.653) or elevated (HR: 1.24; 95% CI: 0.91 to 1.69; p = 0.165) baseline hs-TnT levels.
Conclusions In patients with coronary artery disease undergoing elective PCI, an increase in post-procedural hs-TnT level did not offer prognostic information beyond that provided by the baseline level of the biomarker.
Cardiac troponins are the most commonly used biomarkers for the diagnosis of myocardial damage. High-sensitivity troponin T (hs-TnT) assays enable the detection of even minor myocardial damage occurring spontaneously or after percutaneous coronary intervention (PCI) (1,2). Although elevation of cardiac troponin levels after elective PCI is common (3–5), the clinical significance of this finding remains unclear. A rise in hs-TnT level above the 99th percentile upper reference limit (URL) after elective PCI was recently reported in up to 80% of patients who had baseline hs-TnT levels within normal limits (6). Raised levels of baseline circulating troponin in patients with stable coronary artery disease (CAD) are also commonly found (7).
Several previous studies have shown that baseline, but not post-procedural, troponin elevation was associated with a poor outcome after PCI (7,8). Thus, elevated baseline troponin is a great confounder that may modulate the association between post-procedural troponin rise and outcome after PCI. Notably, whether the prognostic value of post-procedural troponin is dependent on the baseline troponin level remains unknown. Moreover, the magnitude of change and factors predisposing to elevated post-procedural levels after elective PCI in patients with or without elevated baseline troponin are unclear.
The aim of the present study was 2-fold: first, to investigate whether the prognostic value of post-procedural hs-TnT level after elective PCI depends on the baseline hs-TnT level; and second, to determine the factors that predispose to post-procedural hs-TnT elevation in patients with and without elevated baseline hs-TnT levels.
Patients and Methods
The present study was a retrospective analysis of 5,626 patients with stable CAD who underwent elective PCI in our hospitals between October 2009 and January 2015, with the last day of follow-up at the end of May 2016. The indication for the index intervention was stable CAD (if significant coronary stenosis was found on diagnostic angiography in patients presenting with symptoms) or restenosis diagnosed in the setting of scheduled angiography after previous stent implantation. All patients had baseline (pre-procedural) and peak post-procedural hs-TnT measurements available for analysis. Each patient was included in the analysis only once (i.e., at his or her first PCI procedure). Patients with acute coronary syndromes, acute infections, pregnancy, advanced impairment of renal function (serum creatinine ≥2.0 mg/dl), or a known malignancy were excluded. The study was performed in accordance with the Declaration of Helsinki.
Diagnostic criteria and PCI
Patients with stable angina, defined as chest pain that had not changed in intensity, character, frequency, or threshold over the preceding 2 months, underwent elective PCI if significant stenoses (≥70% lumen obstruction) were documented on diagnostic coronary angiography. Patients undergoing PCI in the setting of a scheduled examination after stent implantation underwent PCI if a significant restenosis in the stented coronary segment or a significant stenosis in a nonstented segment was documented on coronary angiography. Personnel blinded to patient clinical or follow-up data performed angiographic analysis in the core laboratory using an automated edge detection system (CMS, Medis Medical Imaging Systems, Neuen, the Netherlands).
Cardiovascular risk factors, including diabetes, arterial hypertension, hypercholesterolemia, and current smoking, were defined according to accepted criteria. Epicardial blood flow pre- and post-PCI was graded by using the Thrombolysis In Myocardial Infarction (TIMI) group angiographic criteria. Left ventricular ejection fraction was calculated by using the area–length method on left ventricular angiography. Body mass index was calculated by using patient weight and height measured during the index hospitalization, and glomerular filtration rate was calculated according to the Cockcroft-Gault formula.
Coronary angiography and PCI were performed according to standard practices. Before PCI, patients received aspirin (325 to 500 mg) and clopidogrel (loading dose of 600 mg) and anticoagulation therapy in the form of unfractionated heparin or bivalirudin. After PCI, patients received clopidogrel 150 mg/day until hospital discharge, followed by 75 mg/day for at least 1 month after bare-metal stent implantation or at least 6 months after drug-eluting stent implantation, in addition to aspirin 200 mg/day indefinitely. Other drugs (comprising predominantly statins, angiotensin-converting enzyme inhibitors, or beta-blockers) were prescribed at the discretion of the treating physician.
Blood samples were collected in tubes containing a lithium-heparin anticoagulant. Blood samples for hs-TnT measurements were obtained before the procedure (on admission), 6 h after PCI, and on a daily basis thereafter during the hospital stay (usually 48 h). Two or more post-procedural hs-TnT measurements were performed in 98.7% of patients. The peak level was defined as the highest post-procedural hs-TnT concentration. Troponin T was measured by a high-sensitivity assay in a cobas e 411 immunoanalyzer using electrochemiluminescence technology (Roche Diagnostics, Risch-Rotkreuz, Switzerland). The limit of blank for this assay (the concentration below which analyte-free samples are found with 95% probability) is ≤0.003 μg/l. The functional sensitivity (the lowest analyte concentration that can be reproducibly measured with a coefficient of variation ≤10%) is ≤0.013 μg/l. The 99th percentile URL is 0.014 μg/l. Baseline and peak post-procedural hs-TnT values were used for analysis. Creatinine was measured with a kinetic colorimetric assay using the compensated Jaffe method. Laboratory personnel unaware of patient clinical or follow-up data measured other biochemical parameters using standard laboratory methods.
Outcome and follow-up
The primary outcome measure was all-cause mortality up to 3 years after PCI. Follow-up was performed by telephone interview at 1, 6, and 12 months after PCI in the first year and yearly thereafter. Data on mortality were obtained from hospital charts, death certificates, telephone contact with relatives of the patient or family physicians, insurance companies, or the registration of address office. Medical personnel unaware of patient clinical or laboratory data performed follow-up and adjudication of events.
Data are presented as medians with 25th to 75th percentiles, proportions (%), or Kaplan-Meier estimates (%). The distribution of continuous data was tested by using the 1-sample Kolmogorov-Smirnov test. Because all continuous data exhibited a non-Gaussian distribution pattern, the Kruskal-Wallis rank sum test was used for intergroup comparisons. Categorical data were compared by using the chi-square test. The correlates of increased hs-TnT after PCI were assessed by using the multiple linear regression model. All variables in Tables 1 and 2, except for left ventricular ejection fraction (due to incomplete data) and therapy at discharge, were entered into the model. Due to the skewed distribution of the hs-TnT levels, baseline and post-procedural hs-TnT measurements were entered into the model after logarithmic transformation.
Survival analysis was performed by using the Kaplan-Meier method, and differences in survival rates were assessed according to the univariable Cox proportional hazards model. Independent correlates of all-cause mortality were assessed by using the multivariable Cox proportional hazards model. All variables in Tables 1 and 2 were tested in the univariable analysis, and those exhibiting a significant association with mortality were entered into the model to assess factors associated with mortality. The baseline and post-procedural hs-TnT measurements were entered into the model after logarithmic transformation. The generalized estimating equation method was applied in all analyses (including multivariable analyses) that involved lesion characteristics to account for clustering of the data in the same patient. Statistical analysis was performed by using the R 2.15.1 Statistical Package (R Foundation for Statistical Computing, Vienna, Austria). A 2-sided p value <0.05 was considered to indicate statistical significance.
Patient classification and baseline data
Overall, the study included 5,626 patients. Using the 99th percentile URL of baseline hs-TnT (0.014 μg/l) as the cutoff, patients were divided into a group with baseline hs-TnT level within normal limits (hs-TnT ≤0.014 μg/l [n = 3,463]) and a group with elevated baseline hs-TnT level (hs-TnT >0.014 μg/l [n = 2,163]). Using the peak post-procedural hs-TnT level, patients with normal baseline hs-TnT were divided into a group with elevated post-procedural hs-TnT level (hs-TnT >0.014 μg/l [n = 2,721]) and another group with normal post-procedural hs-TnT level (hs-TnT ≤0.014 μg/l [n = 742]). Patients with elevated baseline hs-TnT levels were also divided into 2 groups: 1 with a further post-procedural rise in hs-TnT (peak post-procedural hs-TnT level higher than baseline hs-TnT level [n = 1,647]) and another group with no further rise in post-procedural hs-TnT (peak post-procedural hs-TnT equal to or lower than the baseline hs-TnT level [n = 516]). Baseline data are shown in Table 1, and procedural characteristics are displayed in Table 2.
Correlates of post-procedural hs-TnT
Baseline and peak post-PCI hs-TnT levels in the whole group of patients are shown in the Central Illustration. In patients with nonelevated baseline hs-TnT levels, the mean baseline and post-procedural hs-TnT values were 0.0095 μg/l and 0.098 μg/l. In patients with elevated baseline hs-TnT levels, mean baseline and post-procedural hs-TnT values were 0.113 μg/l and 0.244 μg/l. The mean change in hs-TnT (peak post-procedural value − baseline value) was 0.088 μg/l in patients with nonelevated baseline hs-TnT levels (median [25th to 75th percentiles]: 0.020 [0.010 to 0.060] μg/l), and 0.131 μg/l (median: 0.023 [0.004 to 0.080] μg/l) in those with elevated baseline hs-TnT levels. The multiple linear regression model with the generalized estimating equation method was used to assess independent correlates of peak post-procedural hs-TnT in patients with and without elevated baseline hs-TnT levels (2 separate models). Independent correlates of post-procedural hs-TnT are shown in Table 3. The elevated baseline hs-TnT level and increased CAD severity and/or procedure complexity were independently associated with elevated hs-TnT levels after PCI. Notably, restenotic lesions were associated with reduced odds of an elevation in hs-TnT after PCI in patients from both groups.
Post-procedural hs-TnT and mortality
Overall, there were 265 deaths during the follow-up period: 6 deaths (1.6%) in patients with normal baseline and post-procedural hs-TnT levels; 54 deaths (3.8%) in patients with normal baseline and raised post-procedural hs-TnT levels; 50 deaths (16.0%) in patients with raised baseline levels but no further elevation in post-procedural hs-TnT; and 155 deaths (18.2%) among patients with elevated baseline hs-TnT levels and further elevation in post-procedural hs-TnT (overall log-rank test p < 0.001) (Figure 1). In patients with normal baseline hs-TnT levels, elevated post-procedural hs-TnT measurements were associated with increased risk of mortality compared with patients with a post-procedural hs-TnT level within normal limits (univariable hazard ratio [HR]: 2.38; 95% confidence interval [CI]: 1.03 to 5.54; p = 0.043). In patients with elevated baseline hs-TnT levels, further elevation in post-procedural hs-TnT was not associated with increased risk of mortality compared with patients with no further elevation in post-procedural hs-TnT (univariable HR: 1.09; 95% CI: 0.79 to 1.51; p = 0.575).
In the univariable analysis, age (p < 0.001), female sex (p = 0.002), diabetes (p = 0.009), arterial hypertension (p < 0.001), body mass index (p = 0.019), hypercholesterolemia (p = 0.005), multivessel disease (p < 0.001), previous coronary artery bypass surgery (p < 0.001), baseline hs-TnT level (p < 0.001), peak post-procedural hs-TnT level (p < 0.001), glomerular filtration rate (p < 0.001), left ventricular ejection fraction (p < 0.001), vessel treated (p = 0.004), restenotic lesions (p < 0.001), baseline TIMI flow grade (p = 0.014), balloon diameter (p = 0.003), maximal balloon pressure (p = 0.007), and post-procedural TIMI flow grade (p = 0.042) were independently associated with mortality risk. All of these variables, except for post-procedural TIMI flow (due to strong correlation with post-procedural hs-TnT), were entered into the Cox proportional hazards model with the generalized estimating equation method. When the post-procedural hs-TnT-mortality association was tested in the model in the entire group of patients and adjusted for the factors associated with mortality risk listed previously (excluding baseline hs-TnT), there was a trend for an association between post-procedural hs-TnT level and the risk of mortality (adjusted HR: 1.22; 95% CI: 0.98 to 1.41; p = 0.082 for each SD increase in the logarithmic scale of post-procedural hs-TnT). When baseline hs-TnT level was entered into the model, the baseline hs-TnT level (HR: 1.22; 95% CI: 1.09 to 1.38; p < 0.001), but not peak post-procedural hs-TnT level (HR: 1.04; 95% CI: 0.85 to 1.28; p = 0.679), was associated with increased risk of mortality (both risk estimates calculated per SD increase in the logarithmic scale of hs-TnT) (Table 4). The association between peak post-procedural hs-TnT and mortality was not significant in the group with normal baseline hs-TnT level (HR: 0.93; 95% CI: 0.69 to 1.25; p = 0.653) or in the group with elevated baseline hs-TnT level (HR: 1.24; 95% CI: 0.91 to 1.69; p = 0.165), with both risk estimates calculated per SD increase in the logarithmic scale of peak post-procedural hs-TnT.
Mortality according to various cutoffs of post-procedural hs-TnT
The association between post-procedural hs-TnT level and mortality was assessed over several multiples of 99th percentile URL cutoffs in patients with and without elevations in baseline hs-TnT. The results of this analysis are shown in Table 5. Notably, the hs-TnT elevation >70 × the 99th percentile URL cutoff, compared with post-procedural hs-TnT ≤70 × the 99th percentile URL, was associated with increased risk of mortality in patients with elevated baseline hs-TnT level (45.1% vs. 17.1%; univariable HR: 4.20; 95% CI: 1.98 to 8.44; p < 0.001) but not in those with nonelevated levels of the biomarker (5.3% vs. 3.3%; HR: 1.42; 95% CI: 0.03 to 8.72; p = 0.772). In patients with elevated baseline hs-TnT, the association between the >70 × the 99th percentile URL cutoff and mortality was tested in the multivariable Cox model, with hs-TnT entered as a categorical variable (dichotomized at the 70 × the 99th percentile cutoff). The analysis showed a trend toward an independent association between hs-TnT >70 × the 99th percentile URL and mortality (p = 0.093), and a trend toward an interaction between post-procedural hs-TnT >70 × the 99th percentile URL and baseline level of the biomarker with regard to the prediction of mortality (p for interaction = 0.073).
The main findings of this study can be summarized as follows: 1) in patients with CAD undergoing elective PCI, a procedure-related hs-TnT rise occurred in the majority of patients (77.6%); 2) post-procedural hs-TnT elevation was not associated with an increased risk of mortality for up to 3 years, regardless of the pre-procedural hs-TnT level; 3) the pre-procedural hs-TnT elevation was independently associated with an increased risk of mortality; and 4) pre-procedural hs-TnT level and angiographic characteristics underlying procedure complexity were independent correlates of elevated post-procedural hs-TnT level in patients both with and without elevated baseline levels of the biomarker.
Circulating troponin after PCI consists of 2 fractions: a pre-procedural or baseline fraction and a fraction that reflects PCI-related troponin rise. Continuous microscopic loss of cardiomyocytes during normal life (9) and cardiomyocyte renewal (10) are 2 processes that contribute to physiological baseline concentrations of circulating troponin. Multiple additional factors can increase levels of circulating cardiac troponin in clinical scenarios other than acute coronary syndromes (11). Prasad et al. (7) showed that 37% of patients undergoing elective PCI have elevated pre-procedural troponin levels. The elevated circulating troponin level in these patients may be explained by a less favorable cardiovascular and metabolic risk profile (11), more extensive CAD (12), or clinically silent complicated atherosclerotic plaques (13). It is proposed that elevated baseline circulating troponin level in patients with stable CAD may be caused by cardiometabolic risk–related stress on the myocardium (14,15) or by cycles of silent atherosclerotic plaque rupture and sealing, leading to repeated myocardial ischemia (13). Both of these conditions are associated with increased cardiovascular risk, and they may explain the association between elevated baseline hs-TnT and mortality.
The principal finding of the present study was that post-procedural hs-TnT elevation was not associated with an increased risk of mortality, regardless of baseline hs-TnT level. Although elevated baseline hs-TnT in itself was strongly associated with an increased risk of mortality, it had no impact on the association between the PCI-related rise in hs-TnT and the risk of subsequent mortality up to 3 years after PCI. A PCI-related hs-TnT elevation 6 times the URL in patients with normal baseline hs-TnT and >9 times the URL in patients with elevated baseline levels of the biomarker was not associated with increased mortality risk. The striking separation of the Kaplan-Meier curves for mortality (showing mortality differences predominantly secondary to baseline hs-TnT levels), in addition to the results of the multivariable analysis, lend further support to this finding. Miller et al. (8) also showed that long-term prognosis was most often related to the baseline troponin level, rather than to the biomarker response to PCI. However, the study by Miller et al. differs from the present study in that it included not only patients with stable CAD but also those with acute coronary syndromes, a conventional troponin assay was used, and fewer deaths were reported. Notwithstanding these differences, the current study corroborates the findings of Miller et al. in a large series of patients with stable CAD by using a contemporary high-sensitivity cardiac troponin assay. Furthermore, by finding a trend toward an interaction between the post-procedural hs-TnT >70 × the 99th percentile URL and baseline hs-TnT level regarding prediction of mortality, the present study may offer support to the definition of clinically relevant myocardial infarction after coronary revascularization in the Consensus Document of the Society for Cardiovascular Angiography and Interventions (16).
Although factors responsible for baseline hs-TnT elevation help to explain the increased mortality risk in patients with elevated baseline levels of the biomarker, the relationship between factors associated with troponin rise post-PCI and mortality is less clear. Procedure-related factors or complications increasing the risk of myocardial damage via distal embolization, side-branch occlusion, or suboptimal myocardial flow are proven risk factors for post-procedural troponin rise (3,17,18). The present study also found that increased procedural complexity was associated with elevated hs-TnT levels after PCI, regardless of the baseline hs-TnT level. However, if the troponin response to PCI was assessed by using less sensitive troponin assays, as was the case in multiple previous studies, relatively extensive myocardial damage would be needed to result in a procedure-related troponin rise. The currently used high-sensitivity troponin assays, including that used in the present study, allow detection of troponin release from minuscule damage of myocardial tissue. Thus, it is plausible that post-procedural elevation of the magnitude observed in the present study may reflect subtle PCI-related myocardial damage that is too small (or transient) to have clinical sequelae.
A study by Lim et al. (19) found that only a small minority (5 of 26 patients) fulfilling troponin criteria for PCI-related (type 4a) myocardial infarction had evidence of peri-procedural necrosis on cardiac magnetic resonance imaging. The investigators suggest that current troponins are oversensitive for the diagnosis of PCI-related myocardial injury. In the present study, despite post-procedural hs-TnT elevations in the majority of patients and identification of several indexes of procedural complexity as predisposing factors for this rise, optimal post-procedural TIMI flow (grade 3) was restored in >97% of patients. Thus, a combination of factors (including the use of a high-sensitivity troponin assay) capable of detecting troponin elevation caused by subtle PCI-related myocardial damage, adjustment for baseline hs-TnT level, and the capacity of current-day PCI to achieve optimal revascularization, even in the setting of high procedural complexity, may have attenuated the association of post-procedural troponin rise with mortality. The inverse association between restenotic lesions and post-procedural hs-TnT may offer evidence for the role of distal embolization in the elevation of post-procedural hs-TnT level. Intervention in restenotic lesions, which have a higher fibrotic/atherosclerotic content ratio compared with native atherosclerotic plaques, may be associated with less distal embolization, myocardial injury, and troponin elevation due to this factor.
First, serial testing of hs-TnT levels before PCI was not performed, resulting in a lack of data on biomarker stability at baseline. If hs-TnT levels are unstable before PCI, the ability to discriminate between a spontaneous and procedure-related hs-TnT elevation is limited. This scenario is particularly relevant in the case of patients presenting with acute coronary syndromes. Nonetheless, all patients included in the present study had clinically stable CAD at the time of the index PCI. Moreover, given that the proportion of patients with hs-TnT elevation post-PCI seems to differ little between the groups with or without elevated baseline hs-TnT levels, we believe that PCI was responsible for the biomarker increase in the vast majority of patients in both groups. The collection of blood samples after the PCI follows the common practice in our center as well as others regarding post-procedural troponin measurements. We are aware of the possibility that the precise peak value of post-procedural troponin may have been missed in a number of patients. This would have required multiple measurements in a short time interval. Finally, these data are from the hs-TnT assay and may not be extrapolated to assess the performance of other conventional or high-sensitivity troponin assays. In the present study, a 0.014-μg/l cutoff was used to define the hs-TnT elevation, which differs from the 0.03-μg/l cutoff we used previously to detect troponin elevations with conventional troponin assays.
In patients with CAD undergoing elective PCI, post-procedural hs-TnT elevation was not associated with an increased risk of mortality for up to 3 years in patients with or without elevated baseline levels of the biomarker. Although there was a strong and independent association between baseline hs-TnT and mortality, the PCI-related elevation in hs-TnT did not offer prognostic information beyond that provided by baseline hs-TnT levels.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with CAD undergoing elective PCI, the baseline level of hs-TnT was strongly and independently associated with 3-year mortality, whereas post-procedural hs-TnT elevations did not provide additional prognostic information beyond the baseline hs-TnT level.
TRANSLATIONAL OUTLOOK: Further studies in larger numbers of patients are needed to determine whether certain thresholds of post-procedural hs-TnT elevation carry independent prognostic value in patients with particular patterns of CAD undergoing PCI.
Dr. Byrne has received lecture fees from B. Braun Melsungen, Biotronik, and Boston Scientific; and research grants to the institution from Boston Scientific and HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary artery disease
- confidence interval
- hazard ratio
- high-sensitivity troponin T
- percutaneous coronary intervention
- Thrombolysis In Myocardial Infarction
- upper reference limit
- Received June 21, 2016.
- Revision received August 5, 2016.
- Accepted August 31, 2016.
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