CLINICAL STUDIES and Coronary Events Following Percutaneous Coronary Angioplasty Robbert J. de Winter, MD, PhD, Karel T. Koch, MD, PhD, Jan P. van Straalen, Gerlind Heyde, MD, Matthijs Bax, MD, Carl E. Schotborgh, MD, Karla J. Mulder, Gerard T. Sanders, PhD, Johan Fischer, PhD, Jan G. P. Tijssen, PhD, Jan J. Piek, MD, PhD PURPOSE: We investigated the associations between baseline C-reactive protein levels in patients undergoing percutaneous coronary angioplasty and death, nonfatal myocardial infarction, and repeat revascularization during 14 months of followup. METHODS: In a single-center, prospective, cohort study, plasma levels of C-reactive protein were measured in 1458 consecutive patients undergoing elective or urgent coronary angioplasty. Patients were followed at 12 to 14 months for the occurrence of death, nonfatal myocardial infarction, and repeat revascularization. RESULTS: The incidence of death or myocardial infarction was 6.1% (44/716) in patients with an increased C-reactive protein level () and 1.5% (11/742) in patients with a normal level (relative risk [RR] 4.4; 95% confidence interval [CI]: 2.2 to 8.5; P 0.0001). In a multivariate logistic regression model, an increased C-reactive protein level was an independent predictor of death or nonfatal myocardial infarction (RR 3.6; 95% CI: 1.8 to 7.2; P 0.0001). The incidence of repeat revascularization was similar in patients with or without an increased C-reactive protein level (23% [168/716] vs. 22% [163/ 742], P 0.54). Statin therapy at the time of the procedure was associated with a lower mean ( SD) C-reactive protein level (5.8 9.7 mg/l vs. 7.2 12.1 mg/l, P 0.02), but was not associated with the risk of death, nonfatal myocardial infarction, and repeat revascularization during follow-up. CONCLUSION: An increased C-reactive protein level is an independent prognostic indicator for the occurrence of death or nonfatal myocardial infarction following coronary angioplasty, but is not associated with the need for repeat revascularization. Am J Med. 2003;115:85 90. 2003 by Excerpta Medica Inc. C-reactive protein is an acute phase reactant synthesized by hepatocytes in response to proinflammatory cytokines, predominantly interleukin 6 (1,2). An elevated serum level of C-reactive protein, signifying activation of systemic inflammation, is associated with an adverse prognosis in patients with stable (3 6) or unstable angina (7 12) and following acute myocardial infarction (13,14). Levels of C-reactive protein may be a marker of the extent of atherosclerosis (15), or they may be associated with vulnerable plaques (16,17). In addition, an elevated C-reactive protein level may lead to cardiac events through its ability to bind complement (18,19). C-reactive protein also induces the expression of adhesion molecules on endothelial cells in serum (20) and is associated with endothelial dysfunction (21). From the Departments of Cardiology (RJDW, KTK, GH, MB, CES, KJM, JGPT, JJP) and Clinical Chemistry (JPVS, GTS, JF), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Requests for reprints should be addressed to Robbert J. de Winter, MD, PhD, Department of Cardiology, B2-137, Academic Medical Center, Meibergdreef 9, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands, or r.j.dewinter@amc.uva.nl. Manuscript submitted June 18, 2002, and accepted in revised form February 28, 2003. Recently, it was shown that an elevated C-reactive protein level was associated with early complications following coronary angioplasty (22). Several studies have suggested that an elevated level is associated with restenosis and the need for repeat revascularization (23 27), but another study failed to confirm this association (28). The aim of our study was to assess the long-term association of C-reactive protein levels with the risk of death, nonfatal myocardial infarction, and repeat revascularization after coronary angioplasty. METHODS Patients Consecutive patients undergoing percutaneous transluminal coronary angioplasty at the catheterization laboratory at our institution were eligible. Patients undergoing elective angioplasty for stable angina (including Braunwald class I) and patients presenting with non ST-elevation acute coronary syndrome (Braunwald class II/III) were included, but patients undergoing primary angioplasty for ST-elevation myocardial infarction were excluded. All patients routinely received 5000 IU of unfractionated heparin. Before the procedure, patients were treated with aspirin (100 to 300 mg). After the procedure, 2003 by Excerpta Medica Inc. 0002-9343/03/$ see front matter 85 All rights reserved. doi:10.1016/s0002-9343(03)00238-9
Table 1. Baseline Clinical, Angiographic, and Procedural Characteristics Characteristic (n 716) (n 742) P Value Number (%), Mean SD, or Median (Range) Age (years) 63 11 60 11 0.0001 Male sex 488 (68) 568 (77) 0.0001 Body weight (kg) 81 13 80 12 0.31 Hypertension 303 (42) 242 (33) 0.0001 Diabetes mellitus 120 (17) 88 (12) 0.01 Statin therapy at time of procedure 264 (37) 315 (43) 0.03 Cigarette smoking 286 (40) 252 (34) 0.021 Braunwald class I vs. II/III 502 (70) 637 (86) 0.0001 Restenotic lesion 66 (9) 101 (14) 0.01 Stents 300 (42) 336 (45) 0.21 Percent diameter stenosis preangioplasty 91 10 91 12 0.18 Lesion length (mm) 12 6 12 7 0.48 Percent diameter stenosis postangioplasty 15 20 13 14 0.17 C-reactive protein (mg/l) 11.9 (3.1 148) 1.40 (0.2 3.0) patients received aspirin 100 mg/d indefinitely and ticlopidine 250 mg twice daily or clopidogrel 75 mg/d for 4 weeks after stent placement. Stents were used electively in patients with chronic total occlusions, restenotic lesions, ostial lesions, or severe saphenous vein graft disease. Provisional stenting was performed as bailout or for unsatisfactory balloon result. Serial sampling of serum creatine kinase and creatine kinase MB levels was performed at the discretion of the operator. The institutional committee on human research approved the protocol. Blood was collected in heparin-coated tubes through the arterial sheath at the start of the procedure. C-reactive protein was measured with a nephelometric assay (Dade Behring Diagnostics, Marburg, Germany). For the present analysis, we defined a cutoff of 3.0 mg/l (the 90th percentile of the normal distribution) as abnormal (10,29,30). Clinical Follow-up Follow-up was obtained by sending a questionnaire to the patients 12 to 14 months after the procedure. If there was no reply or if an event was reported, review of medical records and telephone contact with the patients, their relatives, referring cardiologists, and general practitioners were used to complete follow-up information. Patients with residual or recurrent anginal symptoms requiring repeat revascularization procedures were all referred to our institution, and data about these procedures were collected. Use of medical treatment including statin therapy was recorded at the time of the procedure. Most patients were referred from other centers, and although statin treatment was advised for all patients, its prescription was at the discretion of the referring cardiologists. The primary endpoint was defined as death from all causes or nonfatal myocardial infarction. The definition of myocardial infarction included elevation of cardiac markers or the development of new Q waves on the electrocardiogram; we also included periprocedural myocardial infarctions with a creatine kinase MB peak greater than two times the upper limit of normal. Statistical Analysis Continuous variables with normal distributions were expressed as means ( SD) and compared with the unpaired Student t test. Categorical baseline variables were compared with the Fisher exact test or the chi-squared statistic, as appropriate. Multivariate logistic regression analysis was performed to establish the independent predictive value of an elevated C-reactive protein level; other variables (Table 1) were forced into the model. Kaplan- Meier survival analysis and life tables were constructed; the cumulative probabilities of death, nonfatal myocardial infarction, or repeat revascularization were compared with the log-rank test. We also investigated whether there was a relation between the level of C-reactive protein and the incidence of death, nonfatal myocardial infarction, and repeat revascularization by quartiles of C-reactive protein, using the first quartile ( 1.3 mg/l) as the comparison group. Statistical analyses were performed using the Statistical Package for Social Sciences software (SPSS 10.1 for Windows; SPSS Inc., Chicago, Illinois). P values 0.05 were considered statistically significant. 86 August 1, 2003 THE AMERICAN JOURNAL OF MEDICINE Volume 115
Table 2. Outcomes by Preprocedural Level Outcome (n 716) (n 742) Odds Ratio (95% Confidence Interval)* P Value Number (%) Clinical events Death 21 (2.9) 5 (0.7) 4.5 (1.7 11.9) 0.002 Myocardial infarction 23 (3.2) 6 (0.8) 4.1 (1.7 10) 0.002 Revascularization Coronary angioplasty 149 (21) 142 (19) 1.11 (0.86 1.44) 0.46 Cardiac surgery 19 (2.7) 21 (2.8) 0.94 (0.50 1.76) 0.96 Composite endpoint Death/myocardial infarction 44 (6.1) 11 (1.5) 4.4 (2.2 8.5) 0.0001 Repeat revascularization 168 (23.5) 163 (22.0) 1.09 (0.85 1.39) 0.54 * Comparing patients with abnormal vs. normal C-reactive protein levels. RESULTS Patients with an abnormal C-reactive protein level ( 3 mg/l) were significantly older, more often women, more often smokers, more likely to have hypertension or diabetes, and more often in Braunwald class II or III than were those with normal levels (Table 1). Patients with abnormal levels were also less often taking statins at the time of the procedure but were more often taking statins at follow-up (37% [264/716] vs. 43% [315/742], P 0.03). Statin therapy was associated with a lower mean preprocedural C-reactive protein level (5.8 9.7 mg/l vs. 7.2 12.1 mg/l, P 0.02). The proportion of patients with restenotic lesions was lower in those with elevated C-reactive protein levels. According to the modified American Heart Association classification, 2% (n 28) were type A, 26% (n 381) were type B1, 46% (n 670) were type B2, and 26% (n 379) were type C. Clinical Follow-up Follow-up was completed for all patients (Table 2). All 26 deaths were due to cardiac causes. Mortality was signifi- Figure 1. Cumulative probability of death or nonfatal myocardial infarction (MI) following percutaneous coronary angioplasty, by C-reactive protein level (P 0.0001). August 1, 2003 THE AMERICAN JOURNAL OF MEDICINE Volume 115 87
Figure 2. Cumulative probability of repeat revascularization (percutaneous transluminal angioplasty [PTCA] or coronary artery bypass graft [CABG] surgery) following percutaneous coronary angioplasty, by C-reactive protein level (P 0.24). cantly greater in patients with an increased C-reactive protein level, as was the incidence of nonfatal myocardial infarction (Table 2). Thus, an abnormal C-reactive protein level was strongly associated with the risk of the combined endpoint of death or nonfatal myocardial infarction. In contrast, an abnormal C-reactive protein level was not associated with repeat revascularization (23% [168/716] vs. 22% [163/742], P 0.54). There was a significant difference in the cumulative probability of death or nonfatal myocardial infarction in patients with an abnormal C-reactive protein level as compared with those who had a normal level (Figure 1; P 0.0001). There was also a slightly lower cumulative probability of repeat revascularization in patients with an abnormal level that was not statistically significant (Figure 2; P 0.24). Multivariate Analysis In a multivariate logistic regression analysis, an increased C-reactive protein level was associated with almost a Table 3. Multivariate Associations with Death or Nonfatal Myocardial Infarction, or Repeat Revascularization Characteristic Death or Myocardial Infarction Odds Ratio (95% Confidence Interval) P Value Repeat Revascularization Odds Ratio (95% Confidence Interval) P Value Age 65 years 2.62 (1.42 4.84) 0.002 0.99 (0.75 1.30) 0.93 Male sex 0.99 (0.54 1.80) 0.97 1.09 (0.81 1.46) 0.57 Hypertension 1.50 (0.85 2.65) 0.16 0.93 (0.71 1.22) 0.93 Diabetes mellitus 1.74 (0.89 3.38) 0.10 1.39 (0.98 1.97) 0.07 Statin therapy at baseline 0.75 (0.42 1.33) 0.32 1.21 (0.93 1.58) 0.15 Cigarette smoking 1.43 (0.76 2.66) 0.27 0.84 (0.63 1.11) 0.22 Braunwald class I (vs. class II or III) 0.64 (0.32 1.30) 0.22 1.13 (0.83 1.54) 0.43 Restenotic lesion 0.45 (0.14 1.53) 0.20 1.04 (0.70 1.56) 0.84 Use of stents 1.55 (0.83 2.91) 0.17 0.99 (0.74 1.34) 0.97 Percent diameter stenosis preangioplasty 1.006 (0.98 1.04) 0.70 0.99 (0.98 1.0) 0.16 Lesion length (mm) 0.98 (0.94 1.03) 0.49 1.02 (1.0 1.04) 0.02 Percent diameter stenosis postangioplasty 1.007 (0.99 1.02) 0.32 1.01 (1.0 1.02) 0.007 C-reactive protein 3.6 (1.8 7.2) 0.0001 1.05 (0.81 1.37) 0.71 88 August 1, 2003 THE AMERICAN JOURNAL OF MEDICINE Volume 115
Table 4. Quartiles of and Risk of Coronary Outcomes Outcome Quartiles of (mg/l) 1.3 (n 378) 1.3 3.0 (n 364) 3.0 7.0 (n 355) 7.0 (n 361) Number (%) Death or nonfatal myocardial infarction 7 (2) 4 (1) 16 (5) 28 (8) Repeat revascularization 79 (21) 84 (23) 81 (23) 87 (24) fourfold increase in the risk of death or myocardial infarction (Table 3). The use of statins at the time of the procedure was not associated with death or myocardial infarction. In multivariate analyses, diabetes, lesion length, and percent diameter stenosis after angioplasty were significant independent predictors of repeat revascularization, whereas an abnormal C-reactive protein level was not. Level and Outcomes When patients were categorized by quartiles of C-reactive protein level (Table 4), there was a higher risk of death or nonfatal myocardial infarction for the third and fourth quartiles compared with the first quartile (P 0.09 for the third quartile; P 0.001 for the fourth quartile). The risks of repeat revascularization were similar among quartiles of C-reactive protein level. DISCUSSION We found that C-reactive protein level was a significant independent predictor of death or nonfatal myocardial infarction following percutaneous coronary intervention. Although increased levels were associated with several patient characteristics, including age, sex, diabetes, smoking, and Braunwald class, which are known to influence C-reactive protein levels, C-reactive protein was still associated with these outcomes after multivariate adjustment. In contrast with previous reports, we failed to show an association between C-reactive protein levels and repeat revascularizations for restenosis, irrespective of stent placement. Previous studies of the association between C-reactive protein levels and restenosis have been conflicting. Buffon et al (23) described an association between C-reactive protein levels and late clinical restenosis during a 1-year follow-up in 52 patients with stable angina and 59 patients with unstable who had single-vessel disease. Another study involving 447 patients reported that a C-reactive protein level 10 mg/l was an independent predictor of repeated coronary revascularization (26). A recent report indicated that an elevated C-reactive protein level carried a more than twofold increased risk of death, myocardial infarction, or revascularization during 6 months of follow-up; the increase in risk was attenuated by statin therapy (27). However, in an atherectomy and restenosis study, Zhou et al could not demonstrate a relation between C-reactive protein levels and the occurrence of angiographic restenosis (28). Finally, a large study by Chew et al (22) showed a strong association between an elevated C-reactive protein level and 30-day complications. However, late restenosis was not reported. Several studies have shown that statins lower C-reactive protein levels independent of their effects on lowdensity lipoprotein cholesterol levels (31,32). This includes both short- and long-term effects (33 35). Indeed, a recent study found that statin therapy reduced the risk of death, myocardial infarction, or repeat revascularization following angioplasty in patients with cholesterol levels between 3.5 and 7.0 mmol/l, although the benefits (as compared with placebo) were not apparent until 1.5 years of follow-up (36). Our study has several limitations. First, it was conducted at a single center. However, the patients are representative of those undergoing percutaneous coronary angioplasty. Second, although follow-up was thorough, there were no systematic follow-up visits and no repeat electrocardiograms; thus, silent myocardial infarctions may have been missed. Finally, we could not demonstrate an association between statin treatment at the time of the procedure and prognosis during the 12 to 14 months of follow-up. Perhaps a larger study or a longer follow-up is necessary, or it may take higher doses of statins for the beneficial effects to become apparent (patients in our study were usually taking simvastatin 10 to 20 mg/d, pravastatin 20 mg/d, or atorvastatin 10 mg/d). In conclusion, our study shows that C-reactive protein levels are increased in nearly 50% of patients undergoing percutaneous coronary angioplasty. An increased level was an independent prognostic indicator for death or nonfatal myocardial infarction during follow-up, but not for repeat revascularization. ACKNOWLEDGMENT We are very grateful to the nursing staff of the catheterization laboratory of the Academic Medical Center of the University of Amsterdam and to all the cardiologists and general practitioners who kindly assisted in the follow-up. August 1, 2003 THE AMERICAN JOURNAL OF MEDICINE Volume 115 89
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