Role of cardiac troponin T in the long-term risk stratification of patients undergoing percutaneous coronary intervention

Jorge R. Kizera, Manoj R. Muttrejb, William H. Matthaib, Joseph McConnellc, Heather Nardoneb, Ali F. Soneld, Martin G. Keaneb and Robert L. Wilenskyb,*

a Division of Cardiology, Department of Medicine and Public Health, Weill Medical College of Cornell University, New York, NY, USA
b Cardiovascular Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
c Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
d Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pitsburgh, PA, USA

* Correspondence to: Robert L. Wilensky, MD, Cardiovascular Division, Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Gates, Philadelphia, PA 19104. Tel: (215) 615-3060; fax: (215) 615-3073
E-mail address: robert.wilensky{at}uphs.upenn.edu

Received 26 November 2002; revised 5 March 2003; accepted 18 April 2003


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aims To investigate the long-term prognostic significance of pre- and post-procedure troponin T (TnT) elevations in patients undergoing percutaneous coronary intervention (PCI).

Methods and results TnT and CK-MB were measured pre- and post-procedure in 212 patients undergoing PCI. Major adverse events (composite of death, myocardial infarction and revascularization) were ascertained 6 years later. Pre-procedural TnT was a significant independent predictor of time to major events (hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.16–2.64) and death or myocardial infarction. Post-procedural TnT elevation above normal was the only independent predictor of the primary end-point at 1 year (HR 2.39, 95% CI 1.09–5.26) but was not significantly related to event-free survival throughout follow-up. Post-PCI elevation of TnT 5x above normal, however, did significantly predict time to events during the entirety of follow-up. By contrast, CK-MB was not an independent predictor in any of the analyses.

Conclusions Our study confirms the long-term prognostic value of pre-procedural TnT elevation in patients undergoing PCI, and demonstrates the superior predictive ability of a post-procedural increase in TnT 5x normal for long-term adverse events. Whether the prognostic significance of smaller post-procedural TnT elevations extends beyond the intermediate-term awaits further investigation.

Key Words: Angioplasty • Creatine kinase • Myocardial infarction


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Closer scrutiny of myocardial damage during percutaneous coronary interventions (PCI) has revealed elevations in the serum creatine kinase (CK) level and its subfraction CK-MB in up to 26% of patients undergoing these procedures.1–6Although substantial elevations post-procedure are recognized to increase the risk of future ischaemic events, the prognostic importance of small enzyme elevations has been a matter of controversy.7–9

Cardiac troponins are more specific and sensitive markers of myocardial damage than either CK or CK-MB.10In patients with acute coronary syndromes, elevated troponins confer a heightened risk of death and (re)infarction.11–14For cardiac troponin T (TnT), long-term prognostic ability has been shown in patients with unstable coronary artery disease treated conservatively.13Among patients undergoing PCI, however, the predictive value of an increased pre-procedural TnT for ischaemic complications has been demonstrated for a shorter time frame of 6 months;15the long-term predictive power of pre-procedural TnT elevations in the context of revascularization has not been documented. While troponins outperform CK and CK-MB in prognostic ability in the foregoing contexts, the significance of post-procedural elevations of these highly sensitive biomarkers in patients undergoing PCI remains poorly defined. Accordingly, the purpose of the current study was twofold: (1) To evaluate the relationship between pre-procedure troponin T elevations in patients undergoing PCI and long-term prognosis; and (2) To assess the significance of PCI-related TnT elevations in predicting long-term incidence of adverse events.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patient cohort
Plasma samples were obtained from consecutive patients with stable angina pectoris or acute coronary syndromes who underwent PCI between May and December 1994. Patients presenting to the cardiac catheterization laboratory were enrolled regardless of procedural circumstances; however, only patients who had a successful PCI were included. Patients with cardiogenic shock or haemodynamic compromise were not enrolled.

The attending interventional cardiologist determined the chosen interventional approach (balloon [PTCA], stent, laser angioplasty or atherectomy). Stent implantation was undertaken only for patients with threatened closure or an inadequate angioplasty result (6.5% PTCA/stent vs 91% PTCA only). All patients were pretreated with either aspirin or ticlopidine and heparin was administered to achieve an activated clotting time of >300s. No patient received a glycoprotein IIb/IIIa inhibitor.

2.2. Study comparisons
We conducted separate analyses to examine the prognostic value of both pre-procedural and procedure-related TnT elevation above normal. First, we compared the time to clinical events in patients with elevated baseline TnT levels (Group I) versus patients without baseline TnT elevation (Group II). Second, we examined Group II to compare the time to events in patients in whom an elevated TnT was noted after the procedure (Group IIA) versus those in whom TnT remained normal (Group IIB). The latter analyses were repeated using larger partition values for TnT level (3x and 5x normal) to investigate the prognostic significance of higher degrees of elevation.

2.3. Troponin T and CK-MBmassdetermination
Blood samples were drawn at four time-points: immediately prior to and after the procedure, 8–12h thereafter and 24h later if the patient was still hospitalized. Plasma samples were stored at –80°C until analysed. For analysis the samples were sent overnight on dry ice to the Mayo Clinic. TnT and CK-MBmasssampling was performed using an Elecsys 2010 automated immunochemistry analyser (Roche Diagnostics Corp., Indianapolis, IN) following manufacturers’ recommended procedures. Both methods utilize sandwich electrochemiluminescence immunoassays, each employing two monoclonal antibodies. TnT levels ≥0.1ng/ml and CK-MBmasslevels ≥6.2ng/ml were considered abnormal.

2.4. Follow-up and definition of end-points
Clinical follow-up was obtained in 212 of the 215 patients enrolled. Incidence of clinical events was assessed 6 years after the index procedure by investigators blinded to TnT status. Events were ascertained by direct contact with the patient or, in the event of death, the next of kin. All hospital and out-patient records were reviewed. The primary end-point, major adverse events, was defined as the composite of death of any cause, myocardial infarction (MI) and angina pectoris requiring revascularization. Secondary analyses were performed for the composite end-point of death and MI. MI was established by the presence of any of the following: new electrocardiographic changes (ST-segment deviation ≥2mm in contiguous leads, or appearance of new Q waves); CK elevation ≥2x upper limit of normal with an accompanying relative index for CK-MB ≥5%; or demonstration of a new focal wall motion abnormality by echocardiography or angiocardiography. Revascularizationincluded repeat PCI for restenosis of the target lesion as well as PCI of another significant lesion, or coronary artery bypass grafting (CABG).

2.5. Statistical analysis
All analyses were performed using SAS, v.8.1. Categorical variables are presented as percents and continuous variables as medians (ranges). Comparisons between groups employed the chi-square, Fisher’s exact test, or Wilcoxon rank-sum test as appropriate. Concordance between TnT and CK-MB positivity was evaluated with the kappa statistic. Life table analysis based on the product-limit method was used to estimate rates of freedom from morbid events. The log-rank test was employed to assess the unadjusted relationship between TnT level and event-free survival. Explanatory Cox proportional hazard models were developed to determine the independent predictors of freedom from major adverse events. Thirteen candidate variables with the potential to influence the rate of morbid events were pre-specified and included age, sex, diabetes mellitus, indication for catheterization, prior PCI, prior CABG, reduced left ventricular (LV) ejection fraction (<50%), 3-vessel disease, leftanterior descending lesion, PCI at multiple sites, AHA/ACC type C lesion and pre- or post-procedural CK-MBmassand TnT levels. When higher cutoffs of TnT (3x and 5x normal) were examined, the partition value for CK-MBmasswas increased to 3x normal. These covariates were all considered in building multivariable explanatory models of event-free survival. This was accomplished by using the ‘score’ function in SAS, which selects the 1-variable, 2-variable, 3-variable, and so on, models that yield the highest score chi-square. The number of variables in the final model was then determined by selecting the largest model leading to a decrease in Akaike’s information criterion ({alpha}=3).16


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Patient characteristics are shown in Table 1. Of the 212 patients in the entire cohort 84% underwent PCI for an acute coronary syndrome and 84 (40%) had a positive TnT prior to the procedure (Group I).Median pre-procedure TnT in these patients was 0.54ng/ml (0.10–18.91), with a corresponding median CK-MB of 2.4ng/ml (0.6–421.5). Group I patients were comparable to baseline-negative subjects (Group II) in age, gender and traditional coronary risk factors. All Group I patients were referred for acute coronary syndromes, which contrasted with Group II patients in whom 27% had stable angina pectoris. While a greater percentage of patients in Group I had suffered a prior MI, fewer had previous bypass surgery. More patients in Group II were taking calcium-channel blockers, but use of other medications was similar.


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Table 1 Demographic, clinical and angiographic characteristics of study cohort and subgroups

 
The majority of patients in the total cohort had single-vessel disease and AHA/ACC type B2 lesions (each 55%). There were no significant differences between Groups I and II in the prevalence of type C lesions, three-vessel disease or multi-vessel interventions (Table 1). Patients with baseline-negative TnT more often had critical lesions in the territory of the left anterior descending artery, but they exhibited a higher median LV ejection fraction than their baseline-positive counterparts.

In the subset with a baseline-negative TnT, of the 125 patients with analysable post-procedure blood specimens, 23 (18%) exhibited a rise in TnT following the intervention (Group IIa). Median post-procedure TnT in this subgroup was 1.16ng/ml (0.13–12.94), while median CK-MB was 2.8ng/ml (0–411.7). These patients were less frequently hypertensive compared to those whose TnT remained negative after the intervention (Group IIb). Otherwise, there were no significant differences between Groups IIa and IIb with regard to clinical or angiographic characteristics.

Median follow-up for the entire cohort was 5.6 years. The cumulative incidence of major adverse events was not significantly different between Groups I and II (Table 2). There was a difference in time to such events (Fig. 1a). In multivariable analyses, baseline TnT emerged as a significant independent predictor of event-free survival, in conjunction with history of previous PCI or CABG (Table 3). When analyses were limited to death or MI, baseline TnT again showed a significant univariable relationship to event-free survival (Fig. 1b). In multivariable analyses, pre-procedure TnT remained a significant independent predictor, along with previous CABG and female gender, in the explanatory model (Table 3). By contrast, pre-procedure CK-MBmasswas not an independent predictor of event-free survival for the primary or secondary end-points.


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Table 2 Cumulative eventsain relation to baseline troponin T elevation in entire cohort undergoing percutaneous coronary intervention

 


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Fig. 1 (a) Kaplan–Meier plot comparing event-free survival (death, myocardial infarction or revascularization) in patients with pre-procedural TnT elevations versus patients with normal levels. (b) Kaplan–Meier plot of event-free survival for death or myocardial infarction in the same groups.

 

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Table 3 Multivariable analysis for major adverse events following percutaneous coronary intervention in entire cohort (n=212)

 
In the subset with baseline-negative TnT, there was no significant difference in cumulative incidence of major adverse events in relation to post-procedure TnT elevation (Table 4). This was true regardless of the partition value selected for TnT level, although the 5x cutoff neared the threshold for significance. Analysis of the univariable relationship between TnT and time to death, MI or revascularization similarly did not show a significant difference when 1x normal was used as the cutoff (Fig. 2a). When the cutoff was increased to 3x normal, however, the difference in event free-survival approached significance (P=0.077), becoming significant at the 5x partition value (P=0.002, Fig. 2b).


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Table 4 Cumulative eventsain relation to post-procedural troponin t elevation in subgroup with baseline negative troponin T

 


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Fig. 2 (a) Kaplan–Meier plot for the triple composite end-point in baseline TnT negative patients with increased post-procedural TnT (1x normal) vs persistently negative TnT patients. (b) Kaplan–Meier plot for the triple composite end-point for baseline TnT-negative patients with post-procedural TnT elevations 5x normal versus those with TnT levels below this cutoff.

 
In multivariable analyses, post-procedure TnT was not a significant independent predictor of time to the primary end-point when the 1x and 3x partition values were used; reduced LV ejection fraction, three-vessel coronary artery disease and ACC/AHA lesion type emerged as the only significant factors in the explanatory models (Table 5). Forcing both 1x and 3x cutoffs of TnT into the latter explanatory models yielded HR’s of 1.50 (95% CI 0.72–3.12, P=0.274) and 1.83 (95% CI 0.88–3.80, P=0.105), respectively. Use of the 5x partition value, however, showed TnT to be the strongest independent predictor of event-free survival(Table 5).


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Table 5 Multivariable analysis for major adverse eventsain patients with a negative troponin T prior to percutaneous coronary intervention (n=125)

 
Although post-PCI elevation of TnT above normal was not significantly related to event-free survival (triple composite end-point) during the entire follow-up period, separate analyses showed it to be significantly predictive of time to events at the 1-year time point (log-rank, P=0.025). In fact, TnT emerged as the only independent predictor of freedom from major adverse events at 1-year of follow-up (HR 2.39, 95% CI 1.09–5.26, P=0.030).

Respecting the double composite end-point, the smaller number of events in the subset did not allow performance of multivariable analyses. In univariable analyses, none of the cutoff values for TnT was significantly related to event-free survival.

Post-procedural CK-MB elevation, whether 1x or 3x normal, was not a significant univariable predictor of event-free survival for the primary or secondary end-points. This marker was also not a significant prognostic factor for major adverse events whether or not TnT was considered inselecting the optimal explanatory model.

There was considerable discordance between positive and negative values for TnT and CK-MBmass. Using the upper reference limit for these markers, kappa statistics at baseline and post-procedure were 0.28 and 0.40, respectively.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
This study represents one of the longest-term assessments to date of the role of TnT in risk-stratification of patients undergoing PCI. Pre-procedural TnT elevation was significantly related to event-free survival during a follow-up approaching 6 years. Among patients who were initially TnT negative, post-procedural TnT elevation was the only significant predictor of event-free survival at 1-year. At 6-year follow-up post-procedural elevation of TnT was no longer a significant prognostic factor, giving way to reduced ejection fraction, three-vessel coronary disease and lesion severity. However, at 6-years use of a larger partition value of 5x normal made TnT elevation the strongest identified predictor of long-term freedom frommajor adverse events. Neither pre- nor post-procedure CK-MBmassproved to be an independent predictor of event-free survival, irrespective of concomitant consideration of TnT, attesting to the superiority of the latter marker for prognostication in these settings.

4.1. Pre-procedural troponins and events
Troponins (T and I) have emerged as important markers of increased risk of death and (re)infarction in patients with acute coronary syndromes, whether managed conservatively or with PCI.12–15,17The current study extends these observations by demonstrating that a positive pre-procedural TnT identifies a patient subgroup with increased risk of major adverse events during follow-up exceeding 5years.

Elevated TnT levels may be associated with more ‘active’ lesions, which in turn are associated with increased long-term coronary instability. Angiographic studies have demonstrated anassociation of increased troponin levels and coronary thrombi, complex lesions, more severe coronary artery disease, decreased coronary blood flow and greater activation of the coagulation system compared to patients with normal troponin levels.12,18–21The presence of thrombus or complex lesion morphology at index PCI has been associated with increased short-term events.22Hence, the persistence of increased risk over time may reflect more severe disease with greater likelihood of continued coronary instability. This is supported in part by the observation that prior history of CABG, indicating more extensive disease, was also related to the primary and secondary end-points in the multivariable explanatory models.

4.2. Post-procedural creatine kinase and events
The clinical significance of CK and CK-MB elevations following otherwise uncomplicated PCI has been the subject of considerable debate.8Several studies have failed to demonstrate an association between CK-MB elevation and major adverse events unless higher magnitudes were considered (>5x normal).1,5–7Others have reported that small CK-MB elevations (1–2x normal) do confer a higher risk of major ischaemic events.2–4,9,23,24The extent to which CK-MB elevation (myocardial damage) is directly related to increased events, or represents a marker of greater plaque burden, is not well defined.5,8,9,25Although we did not demonstrate an association between CK-MBmassand major adverse events, this finding may reflect lack of statistical power given the low number of patients with an elevated CK-MBmass.

4.3. Post-procedural troponin T and events
The prognostic significance of troponin elevations following PCI, which may occur in as many as 44% of patients,25has been less well studied. Some investigators have failed to document an association between post-procedural cardiac troponin I (TnI) elevation and adverse ischaemic events, but their studies have been limited by small sample size.26,27Others have reported worse clinical outcomes in association with post-procedural TnI elevations at 90 days28and 44.5 months.29During the longest-term follow-up to date (mean 77 months), Wu and colleagues did not detect an increased risk of major ischaemic events in relation to post-procedural TnT increase,30but the patient cohort was of modest size. The current study offers supporting evidence that may elucidate some of the controversy. A TnT elevation was an important predictor of major adverse events 1-year following the intervention with greater accuracy than CK-MB. An elevation ≥5x normal was the strongest long-term predictor of major adverse events at 6-years, lending support to the premise that TnT at some multiple of the upper reference limit is helpful in risk-stratification.

4.4. Limitations
The relatively modest number of patients evaluated in this study precluded assessing the effect of post-procedural TnT elevation on a composite end-point of death and MI in multivariable analyses. Future studies will need to evaluate the significance of procedural increases in troponins for mortality and MI end-points separately. Because event ascertainment at follow-up was based on review of medical records, which may be incomplete, we prospectively applied more liberal criteria for MI adjudication than those of the World Health Organization (WHO).31However, a large majority of MIs satisfied WHO criteria and since end-point ascertainment was blinded to marker status these criteria would not be responsible for the observed differences between groups. Using troponin for the diagnosis of MI during the follow-up period was not possible as these markers were not in general use when the patients underwent their procedure. Lastly, the majority of patients underwent PTCA without stenting, reflecting the prevailing PCI approach of the period rather than the current interventional approach. To the extent that the adverse effects of TnT elevations relate to underlying myocardial damage, elevations of this marker might similarly be expected to carry an unfavourable prognosis in modern interventional practice. Nevertheless, extrapolating our results to modern practice is complicated by the opposite effects of coronary stenting, which leads to more frequent marker elevation,5and glycoprotein IIb/IIIa inhibition, which may reduce embolic platelet aggregates following an intervention.32The precise relationship between stent-related troponinelevation and adverse events will require further investigation in order to determine the degree to which its prognostic implications are dependent on the method of revascularization and adjunctive pharmacotherapies.


    5. Conclusions
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
PCI in the setting of an increased TnT level is associated with diminished event-free survival at5-year follow-up. Revascularization-associated increases in TnT carry a heightened risk of major adverse events for at least 1-year. The strongest independent predictor of event-free survival was a post-procedural TnT elevation ≥5x normal.


    Acknowledgments
 
Presented in part at the 2001 Annual Scientific Sessions of the American College of Cardiology, Orlando, FL.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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