Clinical Chemistry 51: 2124-2130, 2005.
First published September 15, 2005; 10.1373/clinchem.2005.048082
(Clinical Chemistry. 2005;51:2124-2130.)
© 2005 American Association for Clinical Chemistry, Inc.
Response of Serum C-Reactive Protein to Percutaneous Coronary Intervention Has Prognostic Value
Nawsad Saleh1,a,
Bertil Svane4,
Lars-Olof Hansson3,
Jens Jensen1,
Tage Nilsson4,
Olle Danielsson2 and
Per Tornvall1
Departments of1
Cardiology,2
Clinical Chemistry, and4
Physiology and Thoracic Radiology, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
3 Department of Clinical Chemistry and Pharmacology, Uppsala University Hospital, Uppsala, Sweden.
aAddress correspondence to this author at: Department of Cardiology, Karolinska University Hospital, SE-171 76, Stockholm, Sweden. Fax 46-8-32-45-97; e-mail nawzad.saleh{at}karolinska.se.
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Abstract
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Background: Data are sparse regarding the association between C-reactive protein (CRP) and percutaneous coronary intervention (PCI) in long-term prognosis. Previous studies have shown that PCI evokes an inflammatory response. We tested the hypothesis that the CRP response to PCI has a prognostic value.
Methods: We investigated 891 consecutive patients presenting with stable or unstable angina pectoris, with serum concentrations of cardiac troponin T 
0.03 µg/L, who were undergoing a variety of PCIs. Serum concentrations of CRP and cardiac troponin T were determined before and the day after PCI. The mean follow-up time after PCI was 2.6 years, and the endpoint was death or nonfatal myocardial infarction.
Results: Seventy-six patients reached the endpoint (4.6% death, 3.9% nonfatal myocardial infarction), whereas 21% developed myocardial infarction during the procedure. CRP increased more than 2-fold after the procedure. Patients in the third tertile of the CRP response to PCI had an increased risk for death or nonfatal myocardial infarction in multivariate analysis.
Conclusions: Increased serum CRP in response to PCI is an independent predictor of death or nonfatal myocardial infarction independent of myocardial injury during the procedure. CRP determinations might be of value in risk stratification after PCI.
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Introduction
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Numerous studies have suggested that increased concentrations of preprocedural (baseline) circulating C-reactive protein (CRP)1
in patients undergoing percutaneous coronary intervention (PCI) is associated with short- (1)(2), intermediate-(3)(4)(5), and long-term(1)(6)(7)(8)(9)(10)(11) outcome. Many of these studies have included patients with myocardial injury, a possible confounding factor in assessing the role of increases in CRP before PCI. The procedure itself provokes an inflammatory reaction, as shown by increased concentrations of plasma CRP after PCI(12). Only 2 small studies have investigated the association between the CRP response to PCI and prognosis(13)(14).
PCI is associated with a risk of myocardial infarction with varying rates of incidence, depending on the method of detection and reference values. Although many patients with periprocedural myocardial infarction are asymptomatic and the myocardial injury is small, these patients have impaired prognosis (15).
The aim of the present study was to evaluate CRP determinations before and after PCI to predict the risks for death or nonfatal myocardial infarction. Our hypothesis was that, taking into account PCI-related myocardial injury, the CRP response to PCI would have a prognostic value.
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Materials and Methods
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study group
The study group consisted of 1061 consecutive patients presenting with stable or unstable angina pectoris, undergoing PCI at Karolinska University Hospital between May 1999 and June 2003, with inclusion breaks during weekends, Christmas, and summer holidays. We excluded 170 patients with a serum cardiac troponin T >0.03 µg/L before PCI. Unstable angina was defined as angina at rest, recent onset, or crescendo angina (<4 weeks) with a last attack of chest pain within 48 h of admission (Braunwald class I–IIIB) (16). All patients included in the study had undergone successful procedures, defined as a percentage diameter of residual stenosis of <50% in the worse of 2 orthogonal views. Complications during PCI were defined as side-branch occlusion, intimal dissection, coronary spasm, or a distal embolization. None of the patients received clopidogrel or ticlopidine, but most had received acetylsalicylic acid (ASA) before the procedure. Patients received 5000–15 000 IU of unfractionated heparin as a bolus (aimed at achieving an activated clotting time >300 s), or enoxaparin (0.5 mg/kg of bodyweight) intravenously or intraarterially at the start of the procedure, or enoxaparin (1 mg/kg of bodyweight) subcutaneously within the last 6 h before the procedure. Glycoprotein IIb/IIIa inhibitors were administrated only if a visible thrombus was encountered during the procedure. After the procedure, patients received clopidogrel (75 mg) once or ticlopidine (250 mg) twice daily for 4 weeks if stent implantation was done.
All patients gave informed consent to participate in this study, which was approved by the local ethics committee.
laboratory analyses
For laboratory analyses, 5 mL of venous blood was collected immediately before PCI and at 0600 the morning after PCI for analyses of creatine kinase-MB, CRP, and cardiac troponin T.
The CRP concentration was measured in serum by a high-sensitivity particle-enhanced immunonephelometry method, according to the instructions of the manufacturer (N High Sensitivity CRP on a BN II analyzer; Dade Behring GmbH). The lower detection limit was 0.16 mg/L. The analytical imprecision (CV) of the CRP method was 1.4% at both 1.23 and 5.49 mg/L. Serum concentrations of creatine kinase-MB and cardiac troponin T were measured on an Elecsys® 2010 (Roche). Periprocedural myocardial infarction was defined as an increase in serum cardiac troponin T to >0.05 µg/L the day after PCI.
endpoints and follow-up
The endpoint was death or nonfatal myocardial infarction. Periprocedural myocardial infarction was not included in this endpoint. The mean follow-up time after PCI was 2.6 years (6 months to 4.6 years). Information about death and hospitalization was obtained from a registry kept by the Stockholm County Council. Information about myocardial infarction was obtained by reviewing hospital records. The diagnosis of myocardial infarction was made on the basis of a combination of symptoms and increased cardiac troponin I or T concentrations according to national criteria. Twenty patients moved from Stockholm County during follow-up; therefore, information about their outcomes was obtained by telephone interview. Follow-up data were available for all patients.
statistical analyses
Continuous data are reported as the mean (SD) when gaussian-distributed or as the median (interquartile range) when skewed, and group differences were compared by Mann–Whitney U- or Kruskal–Wallis tests. Categorical variables are reported as the frequency (percentage), and differences between groups were tested by 
2 test. The CRP response to PCI was defined as the difference between baseline CRP concentrations and CRP concentrations after the procedure. CRP data were categorized into tertiles, whereas cardiac troponin T data were divided into 3 categories: no myocardial infarction, small myocardial infarctions, and large myocardial infarctions with a cutoff value of 0.3 µg/L, obtained by use of the third tertile of the cardiac troponin T value the day after PCI. A Cox proportional hazard regression model was used to evaluate the effect of CRP on the endpoint. The assumption of time-independent hazard ratios was investigated by including covariates as a function of time. A backward selection procedure was used for assessing which factors to include in the models.
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Results
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Baseline and procedural characteristics are shown in Table 1
. By the end of follow-up, 76 patients (8.5%) had reached the endpoint (4.6% death and 3.9% nonfatal myocardial infarction). Twenty-one percent of the patients developed myocardial infarction during the procedure according to cardiac troponin T, compared with 10% according to creatine kinase-MB (>10 µg/L). Periprocedural myocardial infarction, based on cardiac troponin T, was associated with the number of dilated vessels (P <0.001), lesional characteristics (P <0.001), and complications during PCI (P <0.001).
The mean (SD) CRP concentration was 1.82 (0.88–4.36) mg/L at baseline and 3.98 (1.90–8.84) mg/L after PCI, respectively. The cardiac troponin T concentration was 0.01 (0.01–0.01) µg/L before and 0.01 (0.01–0.05) µg/L after PCI, respectively. There was no difference in baseline CRP concentrations between patients with or without periprocedural myocardial infarction [1.76 (0.88–4.44) vs 1.83 (0.91–4.35) mg/L], whereas the CRP response to PCI was higher in patients with periprocedural myocardial infarction [1.85 (0.46–5.62) vs 1.34 (0.35–3.29) mg/L; P <0.01]. Associations between baseline CRP and CRP response to PCI and between baseline and procedural characteristics are shown in Table 2
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Patients with death or nonfatal myocardial infarction had increased baseline CRP concentrations [3.08 (1.21–7.07) vs 1.76 (0.85–4.12) mg/L; P <0.001] and CRP response to PCI [2.69 (0.53–9.66) vs 1.4 (0.37–3.29) mg/L; P <0.0001] compared with those without such events (Fig. 1
). Patients with periprocedural myocardial infarction, as determined by cardiac troponin T, had an increased risk for death (8%) or nonfatal myocardial infarction (5%) during follow-up compared with those without PCI-related myocardial injury (in total, 13% vs 7%; P <0.01). For patients who died or suffered nonfatal myocardial infarctions during follow-up, CRP response was increased in response to PCI in both patients with stable or unstable angina pectoris compared with those without such events [stable, 2.77 mg/L vs 1.33 mg/L (P <0.001); unstable, 1.54 mg/L vs 1.44 mg/L (P <0.001)]. There was no statistical difference in preprocedural CRP concentrations between patients with or without events or in patients with stable or unstable angina pectoris (stable, 2.24 mg/L vs 1.51 mg/L; unstable, 3.9 mg/L vs 2.6 mg/L). Associations between baseline values, procedural characteristics, and outcome are shown in Table 3
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Figure 1. Box plots of CRP concentrations before ( ) and in response to PCI ( ) according to death or nonfatal myocardial infarction.
The symbols inside the boxes indicate the medians; the boxes represent the 25th–75 percentiles; the whiskers represent the non-outlier (10th–90th percentile) range.
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Table 3. Baseline and procedural characteristics in patients without or with death or nonfatal myocardial infarction.1
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The CRP response to PCI was associated with an increased risk for death or nonfatal myocardial infarction in multivariate analyses including age, sex, presence of diabetes mellitus or unstable angina pectoris, severity of coronary artery disease (CAD), creatinine, cardiac troponin T, baseline CRP, and CRP response to PCI (Table 4
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ROC curves demonstrating the ability of baseline CRP and CRP response to PCI to predict death or nonfatal myocardial infarction during follow-up are shown in Fig. 2
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Figure 2. ROC curves showing the ability of CRP, before (solid line) and in response to PCI (dashed line), to predict death or nonfatal myocardial infarction after PCI.
The diagonal line is the line of identity.
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Discussion
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The results of our study showed that a CRP measurement the day after PCI contained considerable prognostic information. The CRP response to PCI added prognostic information to a baseline CRP measurement. Furthermore, the increased risk associated with the CRP response was independent of measurement of cardiac troponin T, a sensitive marker of myocardial injury. To assess the potential clinical utility of testing for circulating CRP concentrations among patients with CAD, it is necessary to evaluate the predictive value of CRP in relation to biochemical markers of myocardial ischemia because myocardial injury might cause an inflammatory response. Data from the CAPTURE, FRISC, and TIMI trial investigations suggest that both CRP and cardiac troponin T are independent predictors of risk in patients with acute coronary syndrome and that their predictive values are additive (3)(17)(18).
Our results regarding a univariate association between baseline CRP concentrations and long-term mortality or morbidity are in agreement with previous studies (3)(6)(7)(8)(9)(10)(11). Whereas several investigators have studied the prognostic value of a CRP determination before PCI, there is a paucity of studies of the prognostic role of the CRP response to PCI. Only 2 studies have investigated the role of the CRP response to PCI on prognosis. Gaspardone et al.(14) showed, in 81 patients with stable angina pectoris, that lack of normalization of plasma CRP concentrations 72 h after PCI with stent implantation was associated with a combined endpoint consisting of coronary death, nonfatal myocardial infarction, and recurrence of angina pectoris. Recently, Liu et al.(13) showed that plasma concentrations of secretory type II phospholipase A2, which is involved in the production of various proinflammatory lipids, had a more rapid response than CRP to PCI. Although CRP and secretory type II phospholipase A2 were highly correlated, only increased concentrations of secretory type II phospholipase A2 after PCI were associated with a combined endpoint consisting of coronary death, nonfatal myocardial infarction, and recurrence of angina pectoris in 247 patients. Our prospective study is the first to investigate the combined prognostic value of baseline CRP, CRP response to PCI, and periprocedural myocardial infarction based on cardiac troponin T measurements in a large consecutive group of patients undergoing PCI without increased preprocedural cardiac troponin T concentrations. The results show that the CRP response to PCI, in addition to that of baseline CRP and periprocedural myocardial injury, has prognostic value for predicting the risk for death or nonfatal myocardial infarction.
The results of our study highlight the interest in finding a therapy that could lower CRP concentrations and thereby possibly decrease the risk of future coronary events. Although ASA is indisputably effective in both primary and secondary prevention of CAD (19), and ASA therapy appears to have its greatest effect among men with CRP concentrations in the highest quartile(20), controversy exists as to whether such therapy is associated with an effect on circulating CRP concentrations(21)(22)(23). Accordingly, in the present nonrandomized study, medication with ASA was associated with a lower baseline CRP and with a decreased incidence of death or nonfatal myocardial infarction during follow-up. Statins have antiinflammatory effects, thus decreasing plasma CRP concentrations(24). Furthermore, observational studies have suggested that statin therapy decreases the risk for major adverse cardiac events in patients with increased plasma CRP concentrations undergoing PCI with stent implantation(5)(25). Our nonrandomized study could not confirm that statin therapy was associated with either baseline CRP or CRP response to PCI, or the outcome after PCI. The conflicting results of different CRP-lowering therapies in CAD have led us to conclude that there is a need for large randomized studies, in particular in the setting of PCI.
Interestingly, an increase in cardiac troponin T to >0.3 µg/L after PCI was associated with an independent risk for death or nonfatal myocardial infarction. This information adds to previous conflicting results of studies regarding the role of an increase in cardiac troponins after PCI (15). Exploration of the results of the multivariate analysis shows that patients with a cardiac troponin T >0.3 µg/L the day after PCI and a CRP response to PCI in the third tertile have a more than 5-fold increase in risk for death or nonfatal myocardial infarction during the first 2 years after PCI.
One limitation of our study is that the timing of blood sampling after PCI was not optimal regarding the peak CRP concentration, which occurs 
48 h after the procedure (12). The prognostic value of a CRP determination at this time-point can only be speculated, but it would most likely have produced a larger difference between patients with or without events. However, from a practical point of view, blood sampling the day of discharge is preferable. Another limitation is that the results cannot be extrapolated to patients treated with clopidogrel in addition to ASA. Interestingly, one recent, nonrandomized study(26) has suggested that treatment with clopidogrel before the procedure attenuates the CRP response to PCI. A third limitation is that the results cannot be extrapolated to patients with increased cardiac troponins before the procedure. Finally, the heterogeneity in follow-up time might be considered as a limitation.
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Acknowledgments
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This study was supported by grants from the Swedish Heart and Lung Foundation.
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Footnotes
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1 Nonstandard abbreviations: CRP, C-reactive protein; PCI, percutaneous coronary intervention; ASA, acetylsalicylic acid; and CAD, coronary artery disease. 
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Abstract
Introduction
