Elevated troponin T and C-reactive protein predict impaired outcome for 4 years in patients with refractory unstable angina, and troponin T predicts benefit of treatment with abciximab in combination with PTCA

T Lenderinka, E Boersmaa, C Heeschenb, A Vahaniand, M.-J de Boere, V Umansf, M.J.B.M van den Branda, C.W Hammc and M.L Simoonsa,* for the CAPTURE investigators

a Department of Cardiology, Thoraxcentre, Erasmus Medical Centre Rotterdam, Rotterdam,The Netherlands
b Stanford University School of Medicine, California, USA
c Kerckhoff Heart Center, Bad-Neuheim, Germany
d The Tenon Hospital, Paris, France
e Hospital De Weezenlanden, Zwolle, The Netherlands
f Medical Centre Alkmaar, Alkmaar, The Netherlands

Received April 29, 2003; accepted May 1, 2003 * Correspondence: Prof. Dr Maarten L. Simoons, Thoraxcentre, Department of Cardiology, Erasmus Medical Centre Rotterdam: room H560: Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Aims Treatment with the glycoprotein IIb/IIIa receptor antagonist abciximab before and during coronary intervention in refractory unstable angina improves early outcome. We collected 4-year follow-up data to assess whether this benefit is sustained. Additionally, we investigated the predictive value of baseline troponin T and CRP for long-term cardiovascular events.

Methods and Results Of 1265 patients enrolled in the CAPTURE trial follow-up was available in 94% of the patients alive after 6 months (median 48 months). Survival was similar in both groups. Both elevated troponin T and CRP were associated with impaired outcome, independently of other established risk factors, but with a different time course. Elevated troponin was associated with increased procedure related risk, and elevated CRP with increased risk for subsequent events. Lower rates of the composite end-point of death or myocardial infarction with abciximab vs. placebo were sustained during long-term follow up: 15.7% vs 17.2% at 4 years (P=ns), particularly in patients with elevated troponin T: 16.9% with abciximab vs 28.4% with placebo: P=0.015. Elevated CRP was not associated with specific benefit of abciximab.

Conclusion Troponin T as a marker of thrombosis and CRP as a marker of inflammation are independent predictors of impaired outcome at 4 years follow-up. The initial benefit from abciximab with regard to death and myocardial infarction was preserved at 4 years. No specific benefit with abciximab was observed for patients with elevated CRP, suggesting that a chronic inflammatory process is not affected by abciximab. In contrast the benefit of treatment in patients with elevated troponin T implies that the acute thrombotic process in refractory unstable angina is treated effectively.

Key Words: Glycoprotein IIb/IIIa receptor antagonist • unstable angina pectoris • troponin T • C-reactive protein • long-term follow-up


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Acute coronary syndromes have been associated with inflammation and thrombosis. Markers forinflammation, such as C-reactive protein (CRP)1,2 or interleukin-63 are associated with impairedoutcome in patients with coronary heart disease. Cardiac troponin T (TnT) and troponin I are very sensitive and specific markers of myocardial necrosis in patients with acute coronary syndromes and identify patients at high risk for subsequent events.4–6 Small amounts of necrosis detected by elevated troponin levels are probably caused by micro-emboli from thrombus at the site of unstable plaques. Accordingly elevated cardiac troponinlevels may be considered markers of activethrombosis.

In the CAPTURE trial7 of patients with refractory unstable angina, undergoing percutaneous coronary intervention (PCI), elevated CRP and TnT were both associated with impaired outcome at6 months. Treatment with the glycoprotein IIb/IIIa receptor antagonist abciximab in CAPTURE didreduce the risk of early thrombotic complications (death or MI) particularly in patients with elevated troponin.8 Also in several other studies treatment with abciximab and other glycoprotein IIb/IIIareceptor antagonists resulted in improved outcome in patients with acute coronary syndromes without persistent ST-segment elevation.9,10 However, to date only one trial has reported long-term resultsof treatment with a glycoprotein IIb/IIIa receptor antagonist,11 while another study reported long-term predictive value of baseline troponin T and CRP for cardiovascular events.12 In the latter study, however, no relationship of these markers to the treatment was reported. We collected follow-up data of patients enrolled in the CAPTURE studywith a median follow-up of 4 years, and studiedthe effect of treatment with abciximab and theassociation with high troponin T and CRP levels.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Patients and treatment
The CAPTURE protocol has been described indetail.7 Briefly, patients were eligible if they had refractory unstable angina, defined as chest painat rest with concomitant ECG abnormalities compatible with myocardial ischemia (ST-depression, ST-elevation or T-wave inversion), and one or more episodes of typical chest pain or ECG abnormalities during at least 2h treatment with i.v. heparin and nitrates. The most recent ischemic episode should have occurred within 48h before enrolment,corresponding to Braunwald class III unstableangina. All patients had undergone coronary angiography, and percutaneous coronary intervention (PCI) was scheduled within 18–24 h after the startof the study medication. After informed consent, patients were randomly assigned to abciximab (ReoPro, Centocor B.V., Leiden, The Netherlands; 0.25mg.kg–1bolus plus 10µg.min–1continuous infusion) or placebo. Study medication wasstarted within 2 h of randomization and continued until 1 h after the procedure. All patients received aspirin, heparin and nitrates, whereas ß-blockers, calcium channel antagonists, and other cardiovascular drugs were given at the discretion of the investigator.

Serum samples drawn at the time of randomization were available for determination of troponin T and CRP. Troponin T was measured using a one-step enzyme immunoassay based on electrochemiluminescence technology (Elecsys 2010, Boehringer Mannheim, Germany). The lowerdetection limit of this assay was 0.01mg.l–1, and the diagnostic threshold level was 0.10mg.l–1(i.e. patients with troponin T>0.1 µg . l–1were considered troponin-positive). Patients with postinfarction angina were not included in the troponin T analysis. C-reactive protein was measured by N Latex CRP Mono tests, performed on a Behring BN II Nephelometer (Dade Behring Inc., Deerfield, Illinois, USA) using polystyrene microbeads coated with monoclonal mouse antibodies. The detection limit of the assay was 0.2mg.l–1. Patients with CRP levels >10mg.l–1wereconsidered as CRP positive.

End-points
The primary end-point of CAPTURE was a composite of 30-day all-cause mortality, myocardial infarction (MI) or an urgent intervention for treatment of recurrent ischaemia. Follow-up at 6 months was part of the study protocol. MI during the index hospitalization was defined by CK-MB or CK levels exceeding three times the upper limit of normal in two samples and increased by 50% over the previous value, or an ECG with new significant Q wavesin two or more contiguous leads. Myocardial infarction after discharge was defined by CK-MBor CK levels exceeding twice the upper limit of normal, or new significant Q waves in two or more contiguous ECG leads. A clinical end-point committee adjudicated these events. Survival status and information on myocardial infarction and coronary revascularization procedures were collected for all 1234 patients who were alive 6 months after randomization. Follow-up was obtained from the treating physician, the patient or municipal registries and was not adjudicated.

Data analysis
Data were analysed according to the intention to treat principle. Continuous variables were summarized by median values with corresponding 25th and 75th percentiles. Discrete variables were summarized in terms of frequencies and percentages. Differences between abciximab and placebo were evaluated by Fisher’s exact or Wilcoxon tests. Kaplan–Meier analyses were performed to evaluate the occurrence of events over time (obviously the 6% of patients without information beyond the6 month period contribute to the time-to-event analysis only up to 6 months). Log-rank tests were applied to evaluate differences between abciximab and placebo. Multivariable Cox proportionalhazards regression analyses were applied toevaluate the relation between troponin T, CRP and long-term outcome, adjusted for known clinical determinants of adverse outcome in acute coronary syndromes. P values were two-sided, with P≤0.05 being considered significant.


    Results
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 Methods
 Results
 Discussion
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Baseline characteristics and clinical outcome
A total of 1265 patients were enrolled in theCAPTURE trial. Mortality during the first 6 months of follow-up was 2.5%. Of the remaining 1234patients, follow-up information was obtained in 1157 patients (94%) (Table 1). Sixty-four patients did not respond on (repeated) requests for information; one patient withdrew his informed consent, while no information of their current address was available in 12 patients. The numbers of patients without follow-up were equally distributed over the two treatment arms (6.0% in both the placebo group and the abciximab group). Median follow-up since randomization was 48 months (inter-quartile range: 38 to 55 months). Patients with extended follow-up, were 4 years older (62 vs 58 years; P<0.05,Table 1), but there were no other major differences between patients with and withoutextended follow-up. The rate of death or myocardial infarction was consistently lower over 4 years in patients randomized to abciximab (Table 2), although statistical significance was not maintained (Fig. 1). Four-year mortality rates weresimilar: 6.4% in patients randomized to abciximab and 6.0% for placebo.


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Table 1 Baseline characteristics of 1234 patients alive at 6 months

 

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Table 2 Cardiac events during follow-up of all patients randomized at baseline

 


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Fig. 1 Kaplan–Meier curves of death or myocardial infarction during 4-year follow-up for all patients enrolled treated with abciximab or placebo (P=0.36).

 
Troponin T
The initial large and significant difference in death or MI favouring abciximab among patients with troponin T>0.1µg.l–1at randomisation was maintained throughout follow-up. At 4 years, death or myocardial infarction in patients with a positive troponin T occurred in 16.9% for those receiving abciximab and in 28.4% for those receiving placebo (P=0.015). Four-year mortality rates were 8.7% and 11.7% (P=ns) in troponin T-positive patients randomized to abciximab and placebo, respectively (Table 3). Initially abciximab reduced event rates after randomization as compared to placebo in both troponin-positive and troponin-negative patients, while the absolute event reduction was most pronounced in the troponin-positive cohort. However, during follow-up the initial (modest) benefit of abciximab was further reduced in the troponin negative patients. In fact, the long-term incidence of death or MI among troponin-positive patients randomized to abciximab was similar to the troponin-negative patients, regardless of the treatment allocation in this latter group (Fig. 2). With regard to the composite end-point (death, myocardial infarction or any revascularization–PTCA, CABG) some evidence of a differential treatment effect between troponin T-positive and negative patients was found (P=0.065). In the troponin T-positive patients an event occurred in 42.7% with abciximab and in 50.5% with placebo (P=0.094). In the troponin T-negative patients these event rates were 48.7% and 43.6% (P=0.44), respectively.


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Table 3 Cardiac events during follow-up according to troponin T status

 


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Fig. 2 Kaplan–Meier curves of death and/or myocardial infarction according to troponin T status and treatment received. Significantly (P=0.015) more events occurred in patients with positive troponin T and receiving placebo.

 
C-reactive protein
CRP upon admission was also a determinant of long-term outcome, as patients with a high CRP (>10mg.l–1) had a significantly higher incidence of death or MI than those with normal CRP (23.0% vs 15.3%; P=0.011) (Fig. 3). Mortality at 4 years was 9.2% for patients with high CRP and 3.9% for patients with low CRP (P=0.001). However, in contrast to troponin, the risk reduction by abciximab was not related to CRP status (differential treatment effect: P=0.56). Death or a myocardialinfarction at 4 years occurred in 18.9% of thepatients with high CRP receiving abciximab and in 23.0% (P=0.29) for patients having a high CRP receiving placebo. For a low CRP it was 11.4% and 15.3% (P=0.16) respectively (Table 4). In theCRP-positive patients at 4 year death, myocardial infarction or revascularization occurred in 57.6% with abciximab and in 50.0% with placebo (P=0.56). In the CRP-negative patients this was 47.0% and 42.7% (P=0.79) respectively.



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Fig. 3 Kaplan–Meier curves of death and/or myocardial infarction according to CRP status and treatment received. There was no significant difference between the groups.

 

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Table 4 Cardiac events during follow-up of according to CRP status

 
Troponin T and C-reactive protein
Troponin T and CRP had independent prognostic value (Fig. 4). Patients with both elevated troponin T and CRP had the highest 4-year event rate (death or MI: 16.8%), whereas patients with a low CRPand negative troponin had the lowest event rate (3.9%; P<0.001). Both troponin T (hazard ratio 1.7 (1.1–2.5), P=0.009) and elevated CRP (hazardratio 1.6 (1.1–2.4), P=0.013) remained independently significant determinants of long-term cardiac outcome after correction by multivariable analysis for other established risk factors: age, sex, diabetes, hypertension, smoking, hypercholesterolemia, previous cardiovascular disease i.e. myocardial infarction, heart failure, PTCA, CABG or stroke- and peripheral vascular disease. The long-term riskreduction with abciximab was most pronounced in troponin T-positive patients regardless of CRP value (hazard ratio 0.44 vs 0.92, abciximab vs placebo respectively; P=0.073).



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Fig. 4 Kaplan–Meier curves of death and/or myocardial infarction according to CRP and troponin T status and treatment received.

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Abciximab was the first glycoprotein IIb/IIIa receptor blocker to demonstrate improved outcome at 30-days in patients with acute coronary syndromes scheduled to undergo percutaneous coronary intervention (PCI). These findings from CAPTURE7 are consistent with those from all other trials with abciximab in patients undergoing PCI, for stableor unstable angina or myocardial infarction, with balloon angioplasty, stent or other devices.11,13–16A combined analysis of all studies revealed asignificant reduction of mortality at follow-up in patients receiving abciximab at the time of PCI, in addition to the reduction in death and myocardial infarction and urgent reintervention.17

Patients in CAPTURE with a high troponin T value at enrolment, and patients having an elevated CRP were at increased risk for death or myocardial infarction during follow-up. A positive CRP became predictive as of 6 months follow-up. These results confirm those of the FRISC II study,12 in which the prognostic value of troponin T and CRP was studied in unstable angina patients treated with dalteparin. In both studies elevated levels of troponin T and CRP were strongly and independently related to the long-term risk of death from cardiac causes. A unique finding in CAPTURE is the marked acute and long-term treatment benefit with abciximab inpatients with elevated troponin T irrespective of the CRP level (Fig. 4).

The present findings support the concept that the pathophysiology of atherosclerosis in acute coronary syndromes is multifactorial, with a chronic (inflammatory) basis18 and an acute thrombotic exacerbation.19–21 Inflammation may result in plaque instability, fissuring or rupture, with resulting local thrombosis and micro-embolization. This results in distal thrombotic occlusion and myocardial necrosis as detected by elevated cardiac troponin T. These local thrombotic events are in fact ameliorated by PCI, as is evident from the myocardial infarction event curves in CAPTURE and in other studies. Abciximab and other glycoprotein IIb/IIIa receptor antagonists inhibit platelet aggregation and thus reduce thrombotic complications associated with percutaneous coronary intervention, when started early before PCI,22 particularly in patients with elevated cardiac troponin T. In contrast, elevated CRP is a marker of a chronic inflammatory process in the coronary wall23 resulting in repetitive occurrences of cardiovascular events.2,24,25 In patients undergoing coronary angioplasty cardiac events at 1 year and beyond are predicted by high preprocedural levels of CRP.26 Short-term therapy with abciximab provides no protection against these events. Although abciximab has demonstrated antiinflammatory effects,which may ameliorate the acute inflammatory process27 and lower CRP caused by PCI28 it apparently does not control the underlying inflammatory process as a cause of elevated CRP that is associated with long-term risk. Also, prolonged treatment with an oral glycoprotein IIb/IIIa receptor antagonist provides no benefit.29 In fact mortality was increased in five studies with these latter agents, possibly as a result of a proaggregating effect of glycoprotein IIb/IIIa receptor antagonists at the low doses which were given.29

Limitations to this study
The follow-up data was obtained either from the physicians, the municipal registries or directly from the patient. The clinical event committee did not adjudicate the follow-up data, accordingly criteria for myocardial infarction might differ betweeninvestigators and some events may have been missed. Seventy-seven patients were lost to follow-up. They were significantly younger, which could explain their mobility and tendency not to reply. Yet missing data were evenly distributed and thus are unlikely to be biased. Patients with possible chronic infections of different origin resulting in elevated CRP at baseline were not specificallyrecorded and could not be removed from this analysis. However, as in most clinical trials patients with ‘significant non-cardiac disease’ were excluded.

In the analyses, arbitrarily cut-off values for troponin T (>0.1µg.l–1) and CRP (>10mg.l–1) were applied. A more detailed subgroup analysis oftroponin T and CRP revealed similar results (Fig. 5).



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Fig. 5 Incidence of death or myocardial infarction at 4 years according to CRP and troponin T status. Cut-off values used were: for troponin T: <0.01 ng . ml–1; 0.01–<0.10 ng . ml–1;0.10–<0.30 ng . ml–1and >0.30 ng . ml–1. For CRP: <5mg . 1–1,5–<10mg.l–1, 10–20mg.l–1and >20mg.l–1. The numbers are percentages per subgroup: {blacksquare}=deaths; {square}=total of death and myocardial infarcts (MI).

 

    Conclusion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
This study confirms the value of abciximab inpatients undergoing percutaneous intervention for refractory unstable angina pectoris and support the recommendations in the European and other guidelines for routine troponin T testing in patientspresenting with chest pain in an emergency department.30–32 Both troponin T and CRP are independent predictors of impaired long-term outcome. Troponin T is a powerful indicator for a treatment benefit with abciximab in patients with refractory angina undergoing PCI. If troponin T is positive and there are no contra-indications,abciximab or another glycoprotein IIb/IIIa receptor blocker should be given, and a percutaneousintervention should follow with at least 1h, but preferably 12h of infusion.17,22,33

Future studies with antiinflammatory therapy that is more potent than aspirin should assess a potential additional long-term benefit in patients with unstable angina. The baseline CRP levelmay serve as an indicator for use of such antiinflammatory therapy.


    Footnotes
 
CAPTURE was supported by Centocor B. V., Leiden,The Netherlands.


    References
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 Results
 Discussion
 Conclusion
 References
 

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