- Email: [email protected]
Prognostic Usefulness of Serial C-Reactive Protein Measurements in ST-Elevation Acute Myocardial Infarction
Prognostic Usefulness of Serial C-Reactive Protein Measurements in ST-Elevation Acute Myocardial Infarction Stamatis S. Makrygiannis, MDa,*, Olga S. Ampartzidou, MDa, Michael N. Zairis, MD, PhDa, Nikolaos G. Patsourakos, MDa, Christos Pitsavos, MD, PhDb, Dimitris Tousoulis, MD, PhDb, Athanasios A. Prekates, MD, PhDc, Stefanos G. Foussas, MD, PhDa, and Dennis V. Cokkinos, MDd It has been reported that increased levels of C-reactive protein are related to adverse longterm prognosis in the setting of ST-segment elevation acute myocardial infarction (MI). In previous studies, the timing of C-reactive protein determination has varied widely. In the present study, serial high-sensitivity C-reactive protein (hsCRP) measurements were performed to investigate if any of the measurements is superior regarding long-term prognosis. A total of 861 consecutive patients admitted for ST-segment elevation MI and treated with intravenous thrombolysis within the first 6 hours from the index pain were included. HsCRP levels were determined at presentation and at 24, 48, and 72 hours. The median follow-up time was 3.5 years. New nonfatal MI and cardiac death were the study end points. By the end of follow-up, cardiac death was observed in 22.4% and nonfatal MI in 16.1% of the patients. HsCRP levels were found to be increasing during the first 72 hours. Multivariate Cox regression analysis demonstrated that hsCRP levels at presentation were an independent predictor of the 2 end points (relative risk [RR] 2.8, p [ 0.002, and RR 2.1, p [ 0.03, for MI and cardiac death, respectively), while hsCRP levels at 24 hours did not yield statistically significant results (RR 1.4, p [ 0.40, and RR 1.1, p [ 0.80, for MI and cardiac death, respectively). The corresponding RRs at 48 hours were 1.2 (p [ 0.5) for MI and 3.2 (p [ 0.007) for cardiac death and at 72 hours were 1.6 (p [ 0.30) for MI and 3.9 (p <0.001) for cardiac death. In conclusion, hsCRP levels at presentation represent an independent predictor for fatal and nonfatal events during long-term follow-up. HsCRP levels at 48 and 72 hours, which are close to peak hsCRP levels, independently predict only cardiac death. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;111:26e30) It seems that elevated levels of circulating inflammatory markers, especially C-reactive protein (CRP), bear prognostic information and may contribute to the long-term risk stratification of patients with acute coronary syndromes (ACS).1,2 However, there is now considerable evidence suggesting that it may not be possible to address ACS collectively. Because they constitute a heterogenous group, they also may demonstrate different CRP kinetics.3e6 This observation appears reasonable, as CRP might represent 2 different inflammatory components that vary within the spectrum of acute ischemia: the preexisting low-grade vascular inflammation and the acute phase response to myocardial injury and/or necrosis.7 The former is measurable at the beginning and the latter builds up as ischemic injury evolves, while interventions such as reperfusion may also alter the course of CRP.7e10 In this context, we attempted in the present study to investigate CRP kinetics as well as to prospectively evaluate the long-term prognostic significance of high-sensitivity CRP (hsCRP) measured at a Cardiology Department, “Tzanio” Hospital of Piraeus, Piraeus, Greece; University of Athens Medical School, 1st Cardiology Clinic, Hippokration Hospital, Athens, Greece; cICU, “Tzanio” Hospital of Piraeus, Piraeus, Greece; dBiomedical Research Foundation, Academy of Athens, Athens, Greece. Manuscript received June 23, 2012; revised manuscript received and accepted August 21, 2012. *Corresponding author: Tel: 30-6937418080; fax: 30-2104257482. E-mail address: [email protected] (S.S. Makrygiannis). b
0002-9149/12/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.08.041
different prespecified time points through the course of ST-segment elevation acute myocardial infarction (STEMI) in a relatively large and homogenous cohort of patients treated with thrombolysis. Methods Consecutive eligible patients admitted to our hospital for STEMI and treated with thrombolytic therapy from September 2000 to December 2003 were included in the present study. Eligible patients required to have (1) continuous chest pain upon presentation, refractory to nitrates, lasting 30 minutes, (2) ST-segment elevation 0.2 mV in 2 contiguous precordial leads or 0.1 mV in 2 contiguous limb leads or new (or presumably new) left bundle branch block on admission electrocardiography, and (3) presentation and thrombolytic regimen administration within the first 6 hours of index pain. Patients with (1) angina of secondary origin, (2) active infection or chronic inflammatory diseases, (3) significant hepatic or renal dysfunction, (4) malignancy, and (5) history of myocardial infarction (MI), coronary revascularization, or major surgery within the previous month were excluded. The study complied with the Declaration of Helsinki, the ethics committee of the hospital approved the research protocol, and informed consent was obtained from all participants. Either streptokinase or a fibrin-specific fibrinolytic agent (alteplase, reteplase, or tenecteplase) was used. All patients www.ajconline.org
Coronary Artery Disease/CRP in STEMI
received chewed aspirin in a dose of 500 mg on presentation, and it was continued orally in a dose of 100 to 325 mg/day indefinitely. Heparin was given in a bolus dose of 5,000 U on admission in all patients, followed by intravenous infusion titrated to a therapeutic activated partial thromboplastin time. Heparin was continued in uncomplicated cases for 48 hours, followed by subcutaneous administration of enoxaparin (1 mg/kg/12 hours). Clopidogrel was not routinely administered at the time the study began. Further medical therapy, including b blockers, nitrates, angiotensin-converting enzyme inhibitors, glycoprotein IIb/IIIa inhibitors, and statins, was left at the discretion of the attending physician, who was unaware of the study protocol. Before discharge, all patients were advised for smoking cessation, body weight reduction, regular exercise, and lipid monitoring. The Eagle 4,000 monitor (GE Marquette Medical Systems, Milwaukee, Wisconsin) was connected to each patient immediately after admission to the coronary care unit. ST-segment recording was started with the first acquired electrocardiogram and continued for 24 hours using the ST Guard system (GE Marquette Medical Systems). The operation of this system has been described previously.11,12 In the present study, the absence of abrupt and sustained >50% ST-segment recovery from the last updated reference electrocardiogram in the first 90 minutes after the start of intravenous thrombolysis was used to define failed reperfusion.13 All ST-segment trends were analyzed off-line by a welltrained investigator blinded to the patients’ clinical and biochemical data. In-hospital and postdischarge follow-up data were prospectively collected on predesigned case report forms. After discharge, patients were followed up at 30 days and subsequently every 6 months for a period of 3 years, on an outpatient basis or by telephone interview. The prespecified end points of the present study were new nonfatal MI and cardiac death within the follow-up period. New nonfatal MI was defined as a new episode of chest pain 30 minutes in duration, resulting in rehospitalization, with new electrocardiographic changes (ST-T changes or new Q waves, or both, in 2 contiguous leads) and an increase in plasma levels of either creatine kinase-MB (2 times normal) or cardiac troponin I or T (>99th percentile of normal). Cardiac death was defined as sudden unexplained death, death due to fatal MI, or death after rehospitalization because of heart failure or possible acute myocardial ischemia. The diagnosis of clinical outcomes was verified by review of death certificates, discharge medical reports, hospital records, or contact with the attending physicians. Events were adjudicated by a committee blinded to other patient information. Venous blood samples were obtained at prespecified time points: at presentation and at 24, 48, and 72 hours from presentation. Coded serum samples were stored at 80 C until batch analysis at the end of the study. Hs-CRP was measured using a highly sensitive nephelometric method (BNII; Dade Behring, Inc., Marburg, Germany) with a lower detection limit of 0.1 mg/L. Normally distributed continuous variables are expressed as mean SD and categorical variables as percentages. Normal distribution was evaluated using the KolmogorovSmirnov test. Continuous variables were compared using
27
Student’s t test or the Mann-Whitney U test as appropriate. Associations of dichotomous variables were tested using chi-square or Fisher’s exact tests as appropriate. The predictive effect of hsCRP was evaluated with univariate and multivariate Cox regression models. All hsCRP values were log transformed. All tests were 2 tailed, and p values <0.05 were considered significant. Statistical analysis was performed using SPSS release 17.0 (SPSS, Inc., Chicago, Illinois). Results A total of 902 patients with STEMIs were treated during the period of enrollment, and 872 received intravenous thrombolysis. Eleven were excluded (4 patients with active infection, 4 with known chronic inflammatory disease, 2 with renal failure under hemodialysis, and 1 with diagnosed malignancy). Thus, 861 patients with STEMI treated with thrombolysis were included in the present analysis. Baseline characteristics by means of medical history and status on presentation are listed in Table 1. Therapeutic interventions during the follow-up period are listed in Table 2. Hs-CRP was found to increase, as expected, at a lower rate for the first 24 hours and then in a steeper way for the next day. The levels of hs-CRP continued increasing until at least the 72-hour measurement (Figure 1). The median follow-up duration was 3.5 years. Data regarding clinical outcomes were obtained for all patients. By the end of the follow-up period, nonfatal MI was observed in 16.1% of the study patients, and cardiac death was reached by 22.4%. Univariate analysis was performed for all baseline variables, therapeutic interventions, and the different measurements of hsCRP levels to investigate their significance as univariate predictors. Variables that reached statistical significance in univariate analysis were included in the multivariate model. Thus, age, gender, hypertension, diabetes mellitus, previous MI, previous revascularization, delay until fibrinolysis >4 h, anterior wall MI, Killip class II to IV, heart rate >100 beats/min, and systolic blood pressure <100 mm Hg were the adjusting variables. Multivariate Cox regression analysis demonstrated that hsCRP level at presentation was an independent predictor of the 2 end points, while CRP level at 24 hours did not yield statistically significant results. HsCRP levels at 48 and 72 hours were found to be an independent predictor only of cardiac death (Table 3). Discussion The first finding of the present study refers to hsCRP kinetics. As shown, hsCRP continues increasing for the first 72 hours in patients with STEMIs treated with thrombolysis <6 hours after symptom onset. This observation corroborates and furthers the results of previous studies based on smaller numbers of patients. In early studies lacking hsCRP assays, Kushner et al,14 studying a sample of 19 patients with MIs and a wide range of time from index pain to admission, reported a time to peak CRP of 62.8 19.8 hours, while de Beer et al,15 observing 33 patients with MIs, reported 50.5 23.3 hours.
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Table 1 Baseline characteristics (n ¼ 861) Variable Age (yrs), mean SD Men Arterial hypertension Current smoking Diabetes mellitus Hypercholesterolemia Familial coronary artery disease Previous stable angina pectoris Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary bypass Time from symptom onset to fibrinolysis >4 h Anterior wall myocardial infarction Killip class IIeIV Heart rate >100 beats/min Systolic blood pressure <100 mm Hg Body weight <67 kg
Value 60.3 9.7 663 (77.0%) 394 (45.8%) 513 (59.6%) 255 (29.6%) 549 (63.8%) 383 (44.5%) 119 (13.8%) 143 (16.6%) 108 (12.5%) 87 (10.1%) 313 (36.4%) 451 (52.4%) 126 (14.6%) 97 (11.3%) 38 (4.4%) 76 (8.8%)
Coronary revascularization Aspirin Statins b blockers Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers
Table 3 Predictive effect of the different high-sensitivity C-reactive protein measurements for the study end points hsCRP Measurement Presentation 24 h 48 h 72 h
Table 2 Revascularization and drug therapy during follow-up (n ¼ 861) Therapy
Figure 1. Trend line of median hsCRP values in the course of STEMI.
Cardiac Death, RR (p Value) 2.1 1.1 3.2 3.9
(0.03) (0.8) (0.007) (<0.001)
New Nonfatal MI, RR (p Value) 2.8 1.4 1.2 1.6
(0.002) (0.4) (0.5) (0.3)
n (%) 623 840 638 743 732
(72.4%) (97.6%) (74.1%) (86.3%) (85.0%)
Pietilä et al,16 studying 188 patients with MIs treated with thrombolysis, found that peak CRP values were observed between the second and fourth days, whereas in another cohort of 220 patients with first Q-wave MIs, Anzai et al17 found that peak CRP occurred 3 2 days from MI onset. Accordingly, in more recent studies, Dedobbeleer et al7 retrospectively demonstrated that peak CRP was noted on the third day after STEMI mostly treated with thrombolysis, Sánchez et al5 reported that hsCRP reached its peak from 44 to 53 hours, Ziakas et al18 reported 72 hours in a similar cohort, and Dimitrijevic et al19 reported 24 to 72 hours from symptom onset. The present results also demonstrate that serum hsCRP levels on presentation are an independent predictor of longterm cardiac death and new nonfatal MI in patients with STEMIs submitted to thrombolysis. Serum hsCRP levels at 48 and 72 hours, approximating the actual peak hsCRP value, are independent predictors only for long-term cardiac death. The intermediate measurement of hsCRP, at 24 hours, was not found to be prognostic. A possible explanation is that the ongoing hsCRP increase triggered by acute myocardial damage at this point might cover the much lower levels of a preexisting vascular inflammation while not yet delineating the full extent of the acute-phase response. This explanation might also be the reason behind the controversial results reported in previous studies with wider times from symptom onset to presentation or blood sampling.3,19,20
As far as hsCRP levels on presentation are concerned, our observation is constant in all our studies21,22 and consistent with previous work by other investigators. Ortolani et al,23 in a cohort of 758 patients with STEMIs treated with mechanical reperfusion in the first 12 hours, retrospectively showed that hsCRP on admission seems to be an independent predictor of long-term mortality and reinfarction. Smit et al24 in a subanalysis of data from the Ongoing Tirofiban in Myocardial Infarction Evaluation (ON-TIME) trial reported that higher early hsCRP was associated with nonfatal MI or death in the following year. Similarly Canale et al25 observed that early hsCRP levels were independent risk predictors of major adverse cardiovascular events and death in 26-month follow-up after STEMI. Because CRP during the acute-phase reaction is synthesized and secreted mainly in the liver, in response to interleukin-6, it takes some hours to increase.14 Therefore, early hsCRP values seem to represent the preexisting low-grade inflammation, in contrast to myocardial tissue damage and necrosis, which ought to be depicted in later measurements and ultimately determine peak hsCRP values in MI. Early hsCRP values seem to bear significant long-term prognostic information also in cohorts with STEMI and non-STEMI26e28 as well as the whole spectrum of ACS,29 possibly independently from the potential consequent necrosis, because they are still unaffected by such a stimulus. In contrast, different kinetics and peak hsCRP values have been reported within the spectrum of ACS, implying that at least MI should be addressed separately, while differences have also been observed among non-STEMI, STEMI, and even reperfusion-treated STEMI.3e6,8 Therefore, it seems that results deriving from composite samples with patients with MIs should be interpreted with caution and ideally reported according to index diagnosis. In this
Coronary Artery Disease/CRP in STEMI
context, Pietilä et al16 reported that peak CRP predicted increased mortality up to 6 months after STEMI treated with thrombolytic drugs. Dimitrijevic et al,19 in a small cohort of 31 patients mostly treated with thrombolysis, found that peak CRP was a significant prognostic marker of 1-year outcomes and remained so after multivariate analysis with established risk factors. In an earlier study, Anzai et al17 also have reported peak CRP to be an independent predictor of 1-year cardiac death. Being observational in nature, the presented work is subject to the corresponding limitations. Also, the facts that the study begun before the widespread use of new antiplatelet drugs, including clopidogrel and glycoprotein IIb/IIIa inhibitors, and only pharmacologic reperfusion was used might indicate some distance from current medical practice. HsCRP determinations were obtained up to 72 hours from presentation, and because serum hsCRP levels were found to be still increasing by that time, at least another measurement and possibly a postdischarge measurement might have been useful, although optimal timing for the latter is also unknown. Significant strengths of the present study are its prospective design, lengthy follow-up period, and sample. This was a large, representative STEMI cohort comprising only patients treated with thrombolysis in the first 6 hours from symptom onset, offering the advantage of homogeneity, which is particularly important in view of the evidence suggesting different hsCRP kinetics within the spectrum of ACS. Moreover, the proximity of presentation time to index pain has certain advantages, including more accurate determination of symptom onset, early serum hsCRP determination, and a similar impact of time until treatment on clinical outcomes for the whole cohort. 1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685e1695. 2. He LP, Tang XY, Ling WH, Chen WQ, Chen YM. Early C-reactive protein in the prediction of long-term outcomes after acute coronary syndromes: a meta-analysis of longitudinal studies. Heart 2010;96: 339e346. 3. Scirica BM, Morrow DA, Cannon CP, de Lemos JA, Murphy S, Sabatine MS, Wiviott SD, Rifai N, McCabe CH, Braunwald E; Thrombolysis In Myocardial Infarction (TIMI) Study Group. Clinical application of C-reactive protein across the spectrum of acute coronary syndromes. Clin Chem 2007;53:1800e1807. 4. Brunetti ND, Troccoli R, Correale M, Pellegrino PL, Di Biase M. C-reactive protein in patients with acute coronary syndrome: correlation with diagnosis, myocardial damage, ejection fraction and angiographic findings. Int J Cardiol 2006;109:248e256. 5. Sánchez PL, Rodríguez MV, Villacorta E, Albarrán C, Cruz I, Moreiras JM, Martín F, Pabón P, Fernández-Avilés F, Martín-Luengo C. Kinetics of C-reactive protein release in different forms of acute coronary syndrome [article in Spanish]. Rev Esp Cardiol 2006;59: 441e447. 6. Zebrack JS, Anderson JL, Maycock CA, Horne BD, Bair TL, Muhlestein JB; Intermountain Heart Collaborative (IHC) Study Group. Usefulness of high-sensitivity C-reactive protein in predicting longterm risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction. Am J Cardiol 2002;89:145e149. 7. Dedobbeleer C, Melot C, Renard M. C-reactive protein increase in acute myocardial infarction. Acta Cardiol 2004;59:291e296. 8. Tsakiris AK, Marnelos PG, Nearchou NS, Papadakis JE, Karatzis EN, Skoufas PD. The influence of thrombolytic therapy on C-reactive protein in ST-segment elevation acute myocardial infarction. Hellenic J Cardiol 2006;47:218e222. 9. Pietila K, Harmoinen A, Hermens W, Simoons ML, Van de Werf F, Verstraete M. Serum C-reactive protein and infarct size in myocardial
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infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy. Eur Heart J 1993;14:915e919. De Servi S, Mariani M, Mariani G, Mazzone A. C-reactive protein increase in unstable coronary disease cause or effect? J Am Coll Cardiol 2005;46:1496e1502. Shah A, Wagner GS, Granger CB, O’Connor CM, Green CL, Trollinger KM, Califf RM, Krucoff MW. Prognostic implications of TIMI flow grade in the infarct related artery compared with continuous 12-lead ST-segment resolution analysis. J Am Coll Cardiol 2000;35: 666e672. Krucoff MW, Croll MA, Pope JE, Granger CB, O’Connor CM, Sigmon KN, Wagner BL, Ryan JA, Lee KL, Kereiakes DJ. Continuous 12-lead ST-segment recovery analysis in the TAMI 7 study. Performance of a non-invasive method for real-time detection of failed myocardial reperfusion. Circulation 1993;88:437e446. Langer A, Krucoff MW, Klootwijk P, Veldkamp R, Simoons ML, Granger C, Califf RM, Armstrong PW. Noninvasive assessment of speed and stability of infarct-related artery reperfusion: results of the GUSTO ST segment monitoring study. J Am Coll Cardiol 1995;25:1552e1557. Kushner I, Broder ML, Karp D. Control of the acute phase response. Serum C-reactive protein kinetics after acute myocardial infarction. J Clin Invest 1978;61:235e242. de Beer FC, Hind CR, Fox KM, Allan RM, Maseri A, Pepys MB. Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction. Br Heart J 1982;47:239e243. Pietilä KO, Harmoinen AP, Jokiniitty J, Pasternack AI. Serum C-reactive protein concentration in acute myocardial infarction and its relationship to mortality during 24 months of follow-up in patients under thrombolytic treatment. Eur Heart J 1996;17:1345e1349. Anzai T, Yoshikawa T, Shiraki H, Asakura Y, Akaishi M, Mitamura H, Ogawa S. C-reactive protein as a predictor of infarct expansion and cardiac rupture after a first Q-wave acute myocardial infarction. Circulation 1997;96:778e784. Ziakas A, Gavrilidis S, Giannoglou G, Souliou E, Gemitzis K, Kalampalika D, Vayona MA, Pidonia I, Parharidis G, Louridas G. In-hospital and long-term prognostic value of fibrinogen, CRP, and IL-6 levels in patients with acute myocardial infarction treated with thrombolysis. Angiology 2006;57:283e293. Dimitrijevic O, Stojcevski BD, Ignjatovic S, Singh NM. Serial measurements of C-reactive protein after acute myocardial infarction in predicting one-year outcome. Int Heart J 2006;47:833e842. Nikfardjam M, Müllner M, Schreiber W, Oschatz E, Exner M, Domanovits H, Laggner AN, Huber K. The association between C-reactive protein on admission and mortality in patients with acute myocardial infarction. J Intern Med 2000;247:341e345. Zairis MN, Manousakis SJ, Stefanidis AS, Papadaki OA, Andrikopoulos GK, Olympios CD, Hadjissavas JJ, Argyrakis SK, Foussas SG. C-reactive protein levels on admission are associated with response to thrombolysis and prognosis after ST-segment elevation acute myocardial infarction. Am Heart J 2002;144:782e789. Zairis MN, Adamopoulou EN, Manousakis SJ, Lyras AG, Bibis GP, Ampartzidou OS, Apostolatos CS, Anastassiadis FA, Hatzisavvas JJ, Argyrakis SK, Foussas SG, Biomarkers of Inflammation and Outcome in Acute Coronary Syndromes (BIAS) Investigators. The impact of hs C-reactive protein and other inflammatory biomarkers on long-term cardiovascular mortality in patients with acute coronary syndromes. Atherosclerosis 2007;194:397e402. Ortolani P, Marzocchi A, Marrozzini C, Palmerini T, Saia F, Taglieri N, Baldazzi F, Silenzi S, Bacchi-Reggiani ML, Guastaroba P, Grilli R, Branzi A. Predictive value of high sensitivity C-reactive protein in patients with ST-elevation myocardial infarction treated with percutaneous coronary intervention. Eur Heart J 2008;29:1241e1249. Smit JJ, Ottervanger JP, Slingerland RJ, Kolkman JJ, Suryapranata H, Hoorntje JC, Dambrink JH, Gosselink AT, de Boer MJ, Zijlstra F, van ’t Hof AW; ON-TIME Study Group. Comparison of usefulness of C-reactive protein versus white blood cell count to predict outcome after primary percutaneous coronary intervention for ST elevation myocardial infarction. Am J Cardiol 2008;101:446e451. Canale ML, Stroppa S, Caravelli P, Petronio AS, Mariotti R, Mariani M, Balbarini A, Barsotti A. Admission C-reactive protein serum levels and survival in patients with acute myocardial infarction with persistent ST elevation. Coron Artery Dis 2006;17:693e698. Tommasi S, Carluccio E, Bentivoglio M, Buccolieri M, Mariotti M, Politano M, Corea L. C-reactive protein as a marker for cardiac
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ischemic events in the year after a first, uncomplicated myocardial infarction. Am J Cardiol 1999;83:1595e1599. 27. Bursi F, Weston SA, Killian JM, Gabriel SE, Jacobsen SJ, Roger VL. C-reactive protein and heart failure after myocardial infarction in the community. Am J Med 2007;120:616e622. 28. Akkus MN, Polat G, Yurtdas M, Akcay B, Ercetin N, Cicek D, Doven O, Sucu N. Admission levels of C-reactive protein and plasminogen
activator inhibitor-1 in patients with acute myocardial infarction with and without cardiogenic shock or heart failure on admission. Int Heart J 2009;50:33e45. 29. Kim H, Yang DH, Park Y, Han J, Lee H, Kang H, Park HS, Cho Y, Chae SC, Jun JE, Park WH. Incremental prognostic value of C-reactive protein and N-terminal proB-type natriuretic peptide in acute coronary syndrome. Circ J 2006;70:1379e1384.
0002-9149/12/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.08.041
different prespecified time points through the course of ST-segment elevation acute myocardial infarction (STEMI) in a relatively large and homogenous cohort of patients treated with thrombolysis. Methods Consecutive eligible patients admitted to our hospital for STEMI and treated with thrombolytic therapy from September 2000 to December 2003 were included in the present study. Eligible patients required to have (1) continuous chest pain upon presentation, refractory to nitrates, lasting 30 minutes, (2) ST-segment elevation 0.2 mV in 2 contiguous precordial leads or 0.1 mV in 2 contiguous limb leads or new (or presumably new) left bundle branch block on admission electrocardiography, and (3) presentation and thrombolytic regimen administration within the first 6 hours of index pain. Patients with (1) angina of secondary origin, (2) active infection or chronic inflammatory diseases, (3) significant hepatic or renal dysfunction, (4) malignancy, and (5) history of myocardial infarction (MI), coronary revascularization, or major surgery within the previous month were excluded. The study complied with the Declaration of Helsinki, the ethics committee of the hospital approved the research protocol, and informed consent was obtained from all participants. Either streptokinase or a fibrin-specific fibrinolytic agent (alteplase, reteplase, or tenecteplase) was used. All patients www.ajconline.org
Coronary Artery Disease/CRP in STEMI
received chewed aspirin in a dose of 500 mg on presentation, and it was continued orally in a dose of 100 to 325 mg/day indefinitely. Heparin was given in a bolus dose of 5,000 U on admission in all patients, followed by intravenous infusion titrated to a therapeutic activated partial thromboplastin time. Heparin was continued in uncomplicated cases for 48 hours, followed by subcutaneous administration of enoxaparin (1 mg/kg/12 hours). Clopidogrel was not routinely administered at the time the study began. Further medical therapy, including b blockers, nitrates, angiotensin-converting enzyme inhibitors, glycoprotein IIb/IIIa inhibitors, and statins, was left at the discretion of the attending physician, who was unaware of the study protocol. Before discharge, all patients were advised for smoking cessation, body weight reduction, regular exercise, and lipid monitoring. The Eagle 4,000 monitor (GE Marquette Medical Systems, Milwaukee, Wisconsin) was connected to each patient immediately after admission to the coronary care unit. ST-segment recording was started with the first acquired electrocardiogram and continued for 24 hours using the ST Guard system (GE Marquette Medical Systems). The operation of this system has been described previously.11,12 In the present study, the absence of abrupt and sustained >50% ST-segment recovery from the last updated reference electrocardiogram in the first 90 minutes after the start of intravenous thrombolysis was used to define failed reperfusion.13 All ST-segment trends were analyzed off-line by a welltrained investigator blinded to the patients’ clinical and biochemical data. In-hospital and postdischarge follow-up data were prospectively collected on predesigned case report forms. After discharge, patients were followed up at 30 days and subsequently every 6 months for a period of 3 years, on an outpatient basis or by telephone interview. The prespecified end points of the present study were new nonfatal MI and cardiac death within the follow-up period. New nonfatal MI was defined as a new episode of chest pain 30 minutes in duration, resulting in rehospitalization, with new electrocardiographic changes (ST-T changes or new Q waves, or both, in 2 contiguous leads) and an increase in plasma levels of either creatine kinase-MB (2 times normal) or cardiac troponin I or T (>99th percentile of normal). Cardiac death was defined as sudden unexplained death, death due to fatal MI, or death after rehospitalization because of heart failure or possible acute myocardial ischemia. The diagnosis of clinical outcomes was verified by review of death certificates, discharge medical reports, hospital records, or contact with the attending physicians. Events were adjudicated by a committee blinded to other patient information. Venous blood samples were obtained at prespecified time points: at presentation and at 24, 48, and 72 hours from presentation. Coded serum samples were stored at 80 C until batch analysis at the end of the study. Hs-CRP was measured using a highly sensitive nephelometric method (BNII; Dade Behring, Inc., Marburg, Germany) with a lower detection limit of 0.1 mg/L. Normally distributed continuous variables are expressed as mean SD and categorical variables as percentages. Normal distribution was evaluated using the KolmogorovSmirnov test. Continuous variables were compared using
27
Student’s t test or the Mann-Whitney U test as appropriate. Associations of dichotomous variables were tested using chi-square or Fisher’s exact tests as appropriate. The predictive effect of hsCRP was evaluated with univariate and multivariate Cox regression models. All hsCRP values were log transformed. All tests were 2 tailed, and p values <0.05 were considered significant. Statistical analysis was performed using SPSS release 17.0 (SPSS, Inc., Chicago, Illinois). Results A total of 902 patients with STEMIs were treated during the period of enrollment, and 872 received intravenous thrombolysis. Eleven were excluded (4 patients with active infection, 4 with known chronic inflammatory disease, 2 with renal failure under hemodialysis, and 1 with diagnosed malignancy). Thus, 861 patients with STEMI treated with thrombolysis were included in the present analysis. Baseline characteristics by means of medical history and status on presentation are listed in Table 1. Therapeutic interventions during the follow-up period are listed in Table 2. Hs-CRP was found to increase, as expected, at a lower rate for the first 24 hours and then in a steeper way for the next day. The levels of hs-CRP continued increasing until at least the 72-hour measurement (Figure 1). The median follow-up duration was 3.5 years. Data regarding clinical outcomes were obtained for all patients. By the end of the follow-up period, nonfatal MI was observed in 16.1% of the study patients, and cardiac death was reached by 22.4%. Univariate analysis was performed for all baseline variables, therapeutic interventions, and the different measurements of hsCRP levels to investigate their significance as univariate predictors. Variables that reached statistical significance in univariate analysis were included in the multivariate model. Thus, age, gender, hypertension, diabetes mellitus, previous MI, previous revascularization, delay until fibrinolysis >4 h, anterior wall MI, Killip class II to IV, heart rate >100 beats/min, and systolic blood pressure <100 mm Hg were the adjusting variables. Multivariate Cox regression analysis demonstrated that hsCRP level at presentation was an independent predictor of the 2 end points, while CRP level at 24 hours did not yield statistically significant results. HsCRP levels at 48 and 72 hours were found to be an independent predictor only of cardiac death (Table 3). Discussion The first finding of the present study refers to hsCRP kinetics. As shown, hsCRP continues increasing for the first 72 hours in patients with STEMIs treated with thrombolysis <6 hours after symptom onset. This observation corroborates and furthers the results of previous studies based on smaller numbers of patients. In early studies lacking hsCRP assays, Kushner et al,14 studying a sample of 19 patients with MIs and a wide range of time from index pain to admission, reported a time to peak CRP of 62.8 19.8 hours, while de Beer et al,15 observing 33 patients with MIs, reported 50.5 23.3 hours.
28
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Table 1 Baseline characteristics (n ¼ 861) Variable Age (yrs), mean SD Men Arterial hypertension Current smoking Diabetes mellitus Hypercholesterolemia Familial coronary artery disease Previous stable angina pectoris Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary bypass Time from symptom onset to fibrinolysis >4 h Anterior wall myocardial infarction Killip class IIeIV Heart rate >100 beats/min Systolic blood pressure <100 mm Hg Body weight <67 kg
Value 60.3 9.7 663 (77.0%) 394 (45.8%) 513 (59.6%) 255 (29.6%) 549 (63.8%) 383 (44.5%) 119 (13.8%) 143 (16.6%) 108 (12.5%) 87 (10.1%) 313 (36.4%) 451 (52.4%) 126 (14.6%) 97 (11.3%) 38 (4.4%) 76 (8.8%)
Coronary revascularization Aspirin Statins b blockers Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers
Table 3 Predictive effect of the different high-sensitivity C-reactive protein measurements for the study end points hsCRP Measurement Presentation 24 h 48 h 72 h
Table 2 Revascularization and drug therapy during follow-up (n ¼ 861) Therapy
Figure 1. Trend line of median hsCRP values in the course of STEMI.
Cardiac Death, RR (p Value) 2.1 1.1 3.2 3.9
(0.03) (0.8) (0.007) (<0.001)
New Nonfatal MI, RR (p Value) 2.8 1.4 1.2 1.6
(0.002) (0.4) (0.5) (0.3)
n (%) 623 840 638 743 732
(72.4%) (97.6%) (74.1%) (86.3%) (85.0%)
Pietilä et al,16 studying 188 patients with MIs treated with thrombolysis, found that peak CRP values were observed between the second and fourth days, whereas in another cohort of 220 patients with first Q-wave MIs, Anzai et al17 found that peak CRP occurred 3 2 days from MI onset. Accordingly, in more recent studies, Dedobbeleer et al7 retrospectively demonstrated that peak CRP was noted on the third day after STEMI mostly treated with thrombolysis, Sánchez et al5 reported that hsCRP reached its peak from 44 to 53 hours, Ziakas et al18 reported 72 hours in a similar cohort, and Dimitrijevic et al19 reported 24 to 72 hours from symptom onset. The present results also demonstrate that serum hsCRP levels on presentation are an independent predictor of longterm cardiac death and new nonfatal MI in patients with STEMIs submitted to thrombolysis. Serum hsCRP levels at 48 and 72 hours, approximating the actual peak hsCRP value, are independent predictors only for long-term cardiac death. The intermediate measurement of hsCRP, at 24 hours, was not found to be prognostic. A possible explanation is that the ongoing hsCRP increase triggered by acute myocardial damage at this point might cover the much lower levels of a preexisting vascular inflammation while not yet delineating the full extent of the acute-phase response. This explanation might also be the reason behind the controversial results reported in previous studies with wider times from symptom onset to presentation or blood sampling.3,19,20
As far as hsCRP levels on presentation are concerned, our observation is constant in all our studies21,22 and consistent with previous work by other investigators. Ortolani et al,23 in a cohort of 758 patients with STEMIs treated with mechanical reperfusion in the first 12 hours, retrospectively showed that hsCRP on admission seems to be an independent predictor of long-term mortality and reinfarction. Smit et al24 in a subanalysis of data from the Ongoing Tirofiban in Myocardial Infarction Evaluation (ON-TIME) trial reported that higher early hsCRP was associated with nonfatal MI or death in the following year. Similarly Canale et al25 observed that early hsCRP levels were independent risk predictors of major adverse cardiovascular events and death in 26-month follow-up after STEMI. Because CRP during the acute-phase reaction is synthesized and secreted mainly in the liver, in response to interleukin-6, it takes some hours to increase.14 Therefore, early hsCRP values seem to represent the preexisting low-grade inflammation, in contrast to myocardial tissue damage and necrosis, which ought to be depicted in later measurements and ultimately determine peak hsCRP values in MI. Early hsCRP values seem to bear significant long-term prognostic information also in cohorts with STEMI and non-STEMI26e28 as well as the whole spectrum of ACS,29 possibly independently from the potential consequent necrosis, because they are still unaffected by such a stimulus. In contrast, different kinetics and peak hsCRP values have been reported within the spectrum of ACS, implying that at least MI should be addressed separately, while differences have also been observed among non-STEMI, STEMI, and even reperfusion-treated STEMI.3e6,8 Therefore, it seems that results deriving from composite samples with patients with MIs should be interpreted with caution and ideally reported according to index diagnosis. In this
Coronary Artery Disease/CRP in STEMI
context, Pietilä et al16 reported that peak CRP predicted increased mortality up to 6 months after STEMI treated with thrombolytic drugs. Dimitrijevic et al,19 in a small cohort of 31 patients mostly treated with thrombolysis, found that peak CRP was a significant prognostic marker of 1-year outcomes and remained so after multivariate analysis with established risk factors. In an earlier study, Anzai et al17 also have reported peak CRP to be an independent predictor of 1-year cardiac death. Being observational in nature, the presented work is subject to the corresponding limitations. Also, the facts that the study begun before the widespread use of new antiplatelet drugs, including clopidogrel and glycoprotein IIb/IIIa inhibitors, and only pharmacologic reperfusion was used might indicate some distance from current medical practice. HsCRP determinations were obtained up to 72 hours from presentation, and because serum hsCRP levels were found to be still increasing by that time, at least another measurement and possibly a postdischarge measurement might have been useful, although optimal timing for the latter is also unknown. Significant strengths of the present study are its prospective design, lengthy follow-up period, and sample. This was a large, representative STEMI cohort comprising only patients treated with thrombolysis in the first 6 hours from symptom onset, offering the advantage of homogeneity, which is particularly important in view of the evidence suggesting different hsCRP kinetics within the spectrum of ACS. Moreover, the proximity of presentation time to index pain has certain advantages, including more accurate determination of symptom onset, early serum hsCRP determination, and a similar impact of time until treatment on clinical outcomes for the whole cohort. 1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685e1695. 2. He LP, Tang XY, Ling WH, Chen WQ, Chen YM. Early C-reactive protein in the prediction of long-term outcomes after acute coronary syndromes: a meta-analysis of longitudinal studies. Heart 2010;96: 339e346. 3. Scirica BM, Morrow DA, Cannon CP, de Lemos JA, Murphy S, Sabatine MS, Wiviott SD, Rifai N, McCabe CH, Braunwald E; Thrombolysis In Myocardial Infarction (TIMI) Study Group. Clinical application of C-reactive protein across the spectrum of acute coronary syndromes. Clin Chem 2007;53:1800e1807. 4. Brunetti ND, Troccoli R, Correale M, Pellegrino PL, Di Biase M. C-reactive protein in patients with acute coronary syndrome: correlation with diagnosis, myocardial damage, ejection fraction and angiographic findings. Int J Cardiol 2006;109:248e256. 5. Sánchez PL, Rodríguez MV, Villacorta E, Albarrán C, Cruz I, Moreiras JM, Martín F, Pabón P, Fernández-Avilés F, Martín-Luengo C. Kinetics of C-reactive protein release in different forms of acute coronary syndrome [article in Spanish]. Rev Esp Cardiol 2006;59: 441e447. 6. Zebrack JS, Anderson JL, Maycock CA, Horne BD, Bair TL, Muhlestein JB; Intermountain Heart Collaborative (IHC) Study Group. Usefulness of high-sensitivity C-reactive protein in predicting longterm risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction. Am J Cardiol 2002;89:145e149. 7. Dedobbeleer C, Melot C, Renard M. C-reactive protein increase in acute myocardial infarction. Acta Cardiol 2004;59:291e296. 8. Tsakiris AK, Marnelos PG, Nearchou NS, Papadakis JE, Karatzis EN, Skoufas PD. The influence of thrombolytic therapy on C-reactive protein in ST-segment elevation acute myocardial infarction. Hellenic J Cardiol 2006;47:218e222. 9. Pietila K, Harmoinen A, Hermens W, Simoons ML, Van de Werf F, Verstraete M. Serum C-reactive protein and infarct size in myocardial
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