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Clinical Chemistry 50: 1589-1596, 2004. First published June 17, 2004; 10.1373/clinchem.2004.032656
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(Clinical Chemistry. 2004;50:1589-1596.)
© 2004 American Association for Clinical Chemistry, Inc.


Proteomics and Protein Markers

Preprocedural C-Reactive Protein Is Not Associated with Angiographic Restenosis or Target Lesion Revascularization after Coronary Artery Stent Placement

Saskia Z.H. Rittersma1, Robbert J. de Winter1,a, Karel T. Koch1, Carl E. Schotborgh1, Matthijs Bax1, Gerlind S. Heyde1, Jan P. van Straalen2, Karla J. Mulder1, Jan G.P. Tijssen1, Gerard T. Sanders2 and Jan J. Piek1

Departments of1 Cardiology and 2 Clinical Chemistry, Academic Medical Center, University of Amsterdam, The Netherlands.

aAddress correspondence to this author at: Department of Cardiology, B2-137, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Fax 31-20-6962609; e-mail r.j.dewinter{at}amc.uva.nl.


   Abstract
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
Background: We assessed the predictive value of preprocedural plasma C-reactive protein (CRP) concentrations and statin therapy on 6 months angiographic and 1-year clinical outcome after nonurgent coronary stent placement.

Methods and Results: Baseline plasma high-sensitivity CRP concentrations were prospectively measured in 345 patients undergoing elective stent placement in a native coronary artery. The binary angiographic in-stent restenosis (ISR; stenosis ≥50% of vessel diameter) rate was 19% in patients with CRP values within the reference interval (≤3 mg/L) and 22% in patients with CRP >3 mg/L [odds ratio (OR) = 1.2; 95% confidence interval (CI), 0.73–2.09]. Statin therapy in a univariate analysis significantly reduced both angiographic and clinical ISR rates. Multivariate logistic regression analysis identified unstable angina, smoking, and stent length, but neither CRP concentration nor statin therapy as independent predictors for angiographic ISR. Patients with an abnormal CRP value showed a trend toward a higher risk of nonfatal myocardial infarction (3.8% vs 0.5%; OR = 7.43; 95% CI, 0.87–61.65). Target lesion revascularization rates did not differ between the two groups (9.6% vs 10.6%; OR = 1.13; 95% CI, 0.56–2.28). In multivariate analysis, male sex (OR = 0.44, 95% CI, 0.19–0.97) and statin therapy (OR = 0.26; 95% CI, 0.09–0.68) were independent predictors for the occurrence of target lesion revascularization.

Conclusions: This study demonstrated a lack of association between preprocedural plasma CRP concentrations and angiographic coronary ISR or clinically driven target lesion revascularization. Patients with an abnormal CRP concentration showed a trend toward higher risk of nonfatal myocardial infarction during 1 year of follow-up. Statin therapy was independently associated with decreased clinically driven target lesion revascularization, underlining the beneficial effects of statins on clinical outcome.


   Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
The major long-term complication of percutaneous transluminal coronary angioplasty (PTCA)1 remains restenosis, which occurs 3–6 months after bare stent placement in 15–30% of patients(1)(2). The arterial wall injury induced by balloon inflation and stent placement is followed by a cascade of events, including sustained leukocyte infiltration in the arterial wall and smooth muscle cell migration and proliferation(3)(4). The concept of a substantial inflammatory role in the pathogenesis of restenosis has been supported by several clinical investigations(5)(6). An increased plasma concentration of the acute-phase reactant C-reactive protein (CRP) reflects activation of systemic inflammation, and recent data suggest that the CRP concentration predicts the risk of recurrent coronary events in patients with stable angina(7)(8) or unstable angina(9)(10) and after acute myocardial infarction(11)(12). Data concerning the prognostic value of baseline CRP concentration for both restenosis and clinical outcome after PTCA are conflicting(13)(14)(15)(16). In addition, the beneficial effect of statin therapy on angiographic and clinical outcome has been a subject of debate. The treatment of in-stent restenosis (ISR) remains difficult; therefore, adequate risk stratification before stent placement is important to identify patients who might benefit from additional treatment or from drug-eluting stent placement. The aim of this study was to assess the long-term prognostic value of plasma CRP concentration at baseline and during statin therapy for the occurrence of angiographic coronary ISR, death, nonfatal myocardial infarction, or target lesion revascularization (TLR).


   Materials and Methods
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
patients
For this study, we recruited 345 consecutive patients into a single-center, prospective observational cohort. All patients had successful single stent placement in a native coronary artery (ACS Multilink; Guidant Inc.). Indications for stent placement were bail-out or unsatisfactory result after balloon angioplasty alone, chronic total occlusions, ostial disease, and restenosis after balloon angioplasty. Exclusion criteria were ISR, saphenous vein graft lesions, bifurcated lesions, lesions longer than 25 mm, reference vessel diameter <2.5 mm, and primary PTCA for myocardial infarction. Statin therapy was recorded at the time of the procedure and at follow-up. Patients were treated with 100 mg of aspirin and 250 mg of Ticlopidine or 75 mg of Clopidogrel daily for 1 month after PTCA and 100 mg of aspirin thereafter. The study complied with the Declaration of Helsinki, and the local research and ethics committee approved the protocol.

crp
Blood was collected in 10-mL heparin-coated tubes through the arterial sheath at the start of the procedure. CRP was measured with a high-sensitivity nephelometric assay (Dade Behring Diagnostics). For the present analysis, we used a cutoff value of 3.0 mg/L as reported previously(17)(18)(19) and as recommended for use for clinical health practice recently(20), taking into account that CRP concentrations >3 mg/L (considered as high risk) correspond to approximately the highest tertile of CRP in the adult population. ROC analysis identified no specific threshold concentration of CRP for maximized predictive value in our study population (area under the curve, 0.53; Fig. 1 ). The attending physician was blinded to plasma CRP values.



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Figure 1. ROC curve showing the absence of a specific threshold preprocedural CRP concentration for maximized predictive value for the occurrence of ISR.

Area under the curve, 0.53 (95% CI, 0.46–0.61); P = 0.39.

follow-up
Patients returned for follow-up angiography between 6 and 10 months after stent placement. Clinical follow-up at 1 year was obtained through written questionnaires that were sent to the patients, review of hospital records, chart review, and telephone contact with the patient, with the referring cardiologists, the patient’s general practitioner, or the patient’s relatives. TLR was defined as revascularization of the stented segment or within 5-mm margins proximal or distal to the stent by either repeat PTCA or coronary artery bypass grafting.

quantitative coronary analysis
Quantitative coronary analysis was performed off-line on images obtained before stent placement, immediately after stent placement, and at 6–10 months of follow-up, with use of a computerized system (QCA-CMS, Ver. 5.0; MEDIS)(21). All angiograms were analyzed by a local core laboratory. The angiography was performed in at least two projections after intracoronary injection of isosorbide dinitrate (0.2 mg). The tip of the 6- or 7-French catheter, filled with contrast, was used for calibration. The minimum diameter of the lumen was measured at the narrowest point of the lesion or within the stent. Minimum lumen diameter, reference diameter of the vessel, and the degree of stenosis, expressed as a percentage of the diameter of the vessel, were calculated as mean values of two orthogonal views, using end-diastolic frames. Acute luminal gain was defined as the difference between minimum lumen diameter post-PTCA and minimum lumen diameter before PTCA (mm), late luminal loss as the difference between minimum lumen diameter at follow-up, and minimum lumen diameter immediately after PTCA (mm). Binary ISR was defined as stenosis ≥50% of vessel diameter at follow-up angiography. The same views and calibration techniques were used at follow-up angiography.

endpoints
The primary endpoint of this study was angiographic ISR and late luminal loss in the minimum lumen diameter at 6–10 months of follow-up. The secondary endpoint was the occurrence of major adverse cardiac events (death, nonfatal myocardial infarction, repeat PTCA, or TLR) during the 1-year follow-up period.

statistical analysis
Data are given as the mean (SD) or as the number (proportion). Continuous variables with gaussian distributions were compared by Student unpaired t-test; categorical variables were compared by the {chi}2 or Fisher exact test where appropriate. Continuous variables with a nongaussian distribution were compared by Mann–Whitney test or by Kruskal–Wallis test. Multivariate logistic regression analyses were performed to determine the association between CRP concentration, statin therapy, and angiographic binary ISR and TLR; univariate variables with significant impact (P <0.05) and known predictive variables were entered in the model (control of confounding). The incidences of ISR and TLR were compared between groups according to quartiles of CRP concentrations. CRP values were logarithmically transformed for univariate linear regression analysis with late luminal loss as the dependent variable. The statistical analysis was performed with the Statistical Package for Social Sciences software (SPSS 11.0 for Windows; SPSS Inc.). A P value <0.05 was considered statistically significant.


   Results
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
baseline variables
The clinical characteristics of the patient population are summarized in Table 1 . The baseline CRP concentration was abnormal (>3.0 mg/L) in 158 of 345 patients (46%). Patients with an abnormal CRP value were significantly more often females and more often had unstable angina. In addition, these patients tended to more often have hypertension and diabetes mellitus, although these differences did not reach statistical significance. The angiographic and lesion characteristics at the time of stent placement are listed in Table 2 ; these variables were equally distributed between the two groups.


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Table 1. Baseline clinical characteristics.


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Table 2. Angiographic and lesion characteristics.

angiographic outcomes
All 345 patients underwent follow-up angiography after 6–10 months. The angiographic data are summarized in Table 3 . Binary angiographic ISR was found in 70 of 345 patients (20%) and was not associated with an abnormal CRP value [median (range) CRP, 3.1 (0.2–52.50) mg/L vs 2.6 (0.20–79.20) mg/L; P = 0.38]. Moreover, the stenosis as a percentage of diameter, the minimal lumen diameter, and late luminal loss (Fig. 2 ) were comparable between the two groups, and log CRP values showed no relationship with late luminal loss (Fig. 3 ; R2 = 0.003). The risk of binary ISR was significantly lower in patients with statin treatment [15% vs 25%; odds ratio (OR) = 0.53; 95% confidence interval (CI) 0.31–0.91; P = 0.020], most notably in patients with abnormal CRP values (14% vs 29%; OR = 0.38; 95% CI, 0.17–0.86; P = 0.018; Fig. 4 ). The median CRP concentration was lower in patients treated with statin than in those not treated with statin, although this difference was not significant (4.6 vs 6.3 mg/L; P = 0.73). All patients initially treated with statin at inclusion (n = 166) continued this treatment during follow-up; 83 started during follow-up, and 96 never used a statin. Binary ISR rates were 15%, 19%, and 30% in these patient groups, respectively ({chi}2 = 8.69; P = 0.013). Multivariate logistic regression analysis including the predictive variables by univariate analysis and well-known predictive variables identified smoking, unstable angina, and stent length as independent prognostic factors for angiographic ISR (Table 4 ). However, the association between CRP concentration or statin therapy and restenosis was lost in multivariate analysis. In addition, the introduction of an interaction term of statin therapy and CRP did not affect the regression coefficients of the variables included in the multivariate model.


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Table 3. Results at angiographic follow-up.



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Figure 2. Cumulative frequency distribution of late luminal loss (in mm) in patients with preprocedural plasma CRP ≤3 mg/L or >3 mg/L.



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Figure 3. Scatter plot showing the relationship between log CRP (in mg/L) and late luminal loss (in mm).

R2 = 0.003 (linear regression analysis).



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Figure 4. Bar graph showing the risk of angiographic ISR (stenosis ≥50% of vessel diameter) in relation to statin therapy and plasma CRP concentrations (cutoff, 3.0 mg/L).

{blacksquare}, CRP ≤3 mg/L; {cjs2108}, CRP >3 mg/L. Numbers in columns indicate the incidence for each group.


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Table 4. Multivariate logistic regression analysis of predictive value of CRP and other variables for the occurrence of binary ISR (stenosis ≥50% of vessel diameter).

clinical outcomes
Clinical follow-up was completed in all patients, and the results are listed in Table 5 . No patients died during follow-up, and only one underwent coronary artery bypass grafting in the first year after stent placement. The incidence of repeat PTCA (including both TLR and PTCA of lesions other than the ones treated at the time of inclusion) was similar in patients with CRP concentrations >3 mg/L and in patients with a CRP value ≤3 mg/L (24% vs 18%; OR = 0.70; 95% CI, 0.42–1.20). In addition, TLR rates did not differ between groups (9.6% vs 10.6%; OR = 1.13; 95% CI, 0.56–2.28). A CRP concentration >3 mg/L was associated with an increased incidence of nonfatal myocardial infarction, although this tendency was not statistically significant (3.8% vs 0.5%; OR = 7.43; 95% CI, 0.87–61.65). Patients who were treated with statins had a significantly reduced risk of TLR (4% vs 16%; OR = 0.24; 95% CI, 0.10–0.56), and in multivariate analysis, male sex (OR = 0.44; 95% CI, 0.19–0.97) and statin therapy (OR = 0.26; 95% CI, 0.09–0.68) were independent predictors for the occurrence of TLR.


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Table 5. Clinical outcomes at 1-year follow-up.

outcomes according to crp quartiles
The incidences of angiographic ISR and TLR according to quartiles of preprocedural CRP values are shown in Fig. 5 . Neither ISR rates nor TLR rates correlated with the CRP quartiles (P = 0.57 for ISR; P = 0.44 for TLR).



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Figure 5. Bar graph showing angiographic ISR ({blacksquare}) rates and TLR ({cjs2108}) rates according to plasma CRP quartiles.

{chi}2 = 2.0 for ISR (P = 0.58); {chi}2 = 2.7 for TLR (P = 0.44). Numbers in columns indicate the incidence for each group.


   Discussion
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
The results of the present study demonstrated that baseline CRP concentration before coronary artery stent placement was not predictive for the occurrence of angiographic ISR or TLR. Importantly, the continuous variable late luminal loss did not differ between patients with high or low CRP concentration, which confirms the binary outcome of restenosis. Our study had >80% power to detect a difference in late luminal loss of 0.2 mm; therefore, it is unlikely that a relevant association between CRP value and late luminal loss was missed. In multivariate analysis including predictive factors identified by univariate analysis for ISR, we found that smoking, unstable angina, and stent length, but not CRP concentration or statin treatment were independent predictors. In addition, quartiles of CRP concentrations were not associated with a consistent increase in ISR rates. Considering the fact that, in general, the clinically driven target revascularization rate is often ~50% of the angiographic ISR rate(22), a lack of association between CRP values and TLR was not unexpected in our study. In contrast to TLR, there was a trend toward a higher incidence of nonfatal myocardial infarction in patients with CRP concentration >3 mg/L, which is in accordance with previous reports(23)(24)(25).

Risk stratification for ISR has been a major field of interest and remains relevant for the identification of patients who could benefit from different treatment strategies, including the use of drug-eluting stents. Our results confirm and extend previous studies on risk factors for ISR(26). However, we could not find an association between diabetes and angiographic restenosis. It is important to recognize that the risk of diabetic nephropathy attributable to contrast agents, together with preferential treatment with coronary artery bypass grafting for diabetic patients with multivessel disease in the time period of the study(27), contributed to the fact that in our study only 10% of the included patients had diabetes. A lack of association between diabetes and restenosis may be explained by this low percentage of diabetic patients in our cohort.

crp and restenosis
Several studies have focused on the relationship between CRP concentration and angiographic and clinical restenosis, but the results are conflicting. Walter et al.(14) described a significant increase in the incidence of binary angiographic ISR and cardiac events (although not in TLR) in patients with high CRP during 6 months of follow-up. Buffon et al.(13) found a significant difference in 1-year event-free survival from clinical restenosis in favor of patients with a CRP concentration below the 3 mg/L cutoff point. However, in a prospective study, Zairis et al.(28) found no association between CRP values and angiographic restenosis, although patients with high CRP concentrations were at higher risk of cardiac events (death, nonfatal myocardial infarction, or rehospitalization for rest-unstable angina) up to 3 years after coronary stenting. In addition, Horne et al.(15) described a lack of association between CRP concentration and clinical restenosis in a large prospective cohort of 415 patients. In our study, we investigated both angiographic and clinical restenosis rates in relation to preprocedural CRP plasma concentrations and found a consistent lack of association. We previously showed that the preprocedural CRP value was associated with an increased risk of myocardial infarction but not with repeat revascularization(24). These findings, together with a lack of association between CRP concentrations and restenosis in the present study, suggest that evidence of preprocedural inflammation is associated with lesion progression rather than with ISR. Moreover, we found that the cumulative frequency distribution of the continuous variable late luminal loss, as a reflection of neointimal tissue growth, was identical between the two groups. Although the local sustained inflammatory response after stent placement plays a role in the process of restenosis(3), this may not be reflected by an increased baseline plasma CRP concentration, which signifies activation of systemic inflammation. Interestingly, initial plaque inflammation of coronary lesions retrieved by atherectomy has been found to be associated with the incidence of restenosis(29) and plaque instability(30), but data concerning the relationship between plasma CRP concentration and plaque CRP are lacking in these studies.

statin therapy and restenosis
Our results showed that statin therapy at the time of stent placement was associated with a decreased risk of angiographic ISR and TLR, predominantly in patients with a high CRP concentration, confirming the results of Walter et al.(31) and Chan et al.(32). Importantly, the physicians were blinded to CRP values; consequently, these values did not influence clinical decision-making concerning statin therapy during follow-up. Consistent with patients who continued statin therapy during the 6–10 months of follow-up, patients who started statin use during the study had a decreased risk of ISR compared with those who never received statin therapy. Patients receiving statin therapy at inclusion had a lower plasma CRP value in our study population, although this difference was not statistically significant. However, in multivariate logistic regression analysis, neither CRP concentration nor statin therapy at inclusion predicted the occurrence of angiographic ISR. In contrast to angiographic outcome, the risk of clinically driven TLR was independently influenced by statin treatment in our study. This discrepancy may be explained by a plaque-stabilizing effect of statins rather than an antiproliferative effect, which would attenuate the clinical symptoms and reduce the need for repeat revascularization. The beneficial effects of statins include a reduction in vascular inflammation, improvement in endothelial function, and a reduction in platelet aggregation and thrombus formation; thus, statins probably influence the vascular wall process after injury(33). However, these beneficial effects remain controversial regarding the restenotic process(34)(35).

limitations
The present study was designed as a nonrandomized single-center cohort study. Nevertheless, baseline clinical and angiographic characteristics were equally distributed, except for some expected variables known to influence plasma CRP concentrations. In addition, the patients treated with statin at the time of stent placement may reflect a subset of patients with established or long-standing symptomatic coronary artery disease. This does not explain, however, why statin therapy was associated with a decreased risk of ISR in our study.

In conclusion, our study demonstrated a lack of association between preprocedural plasma CRP concentrations and angiographic or clinical coronary ISR. Thus, plasma CRP values may not be useful for identifying those patients who are candidates for novel therapies aimed at reducing restenosis. Patients with CRP >3 mg/L showed a trend toward higher risk of nonfatal myocardial infarction during 1 year of follow-up. Statin therapy was independently associated with a decreased risk of clinical ISR, underlining the beneficial role of statins in clinical outcome.


   Footnotes
 
1 Nonstandard abbreviations: PTCA, percutaneous transluminal coronary angioplasty; CRP, C-reactive protein; ISR, in-stent restenosis; TLR, target lesion revascularization; OR, odds ratio; and CI, confidence interval.


   References
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
 

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