Arq. Bras. Cardiol. Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia f45JS3DtyYRfNMLhTkPMW4y S0066-782X2014001900010 S0066-782X2014005040086 00010 10.5935/abc.20140086 Original Articles High-Sensitivity C-Reactive Protein as a Predictor of Cardiovascular Events after ST-Elevation Myocardial Infarction Ribeiro Daniel Rios Pinto Ramos Adriane Monserrat Vieira Pedro Lima Menti Eduardo Bordin Odemir Luiz Jr. Souza Priscilla Azambuja Lopes de Quadros Alexandre Schaan de Portal Vera Lúcia Fundação Universitária de Cardiologia Instituto de Cardiologia Porto Alegre RS Brazil Programa de Pós-Graduação em Ciências da Saúde: Cardiologia - Instituto de Cardiologia/Fundação Universitária de Cardiologia, Porto Alegre, RS - Brazil Mailing address: Vera Lúcia Portal, Avenida Princesa Isabel, 370, Santana. Postal Code 90620-000, Porto Alegre, RS - Brazil. E-mail: veraportal.pesquisa@gmail.com

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 27 06 2014 07 2014 103 1 69 75 16 10 2013 29 01 2014 31 01 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Background:

The association between high-sensitivity C-reactive protein and recurrent major adverse cardiovascular events (MACE) in patients with ST-elevation myocardial infarction who undergo primary percutaneous coronary intervention remains controversial.

 Objective:

To investigate the potential association between high-sensitivity C-reactive protein and an increased risk of MACE such as death, heart failure, reinfarction, and new revascularization in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention.

 Methods:

This prospective cohort study included 300 individuals aged >18 years who were diagnosed with ST-elevation myocardial infarction and underwent primary percutaneous coronary intervention at a tertiary health center. An instrument evaluating clinical variables and the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores was used. High-sensitivity C-reactive protein was determined by nephelometry. The patients were followed-up during hospitalization and up to 30 days after infarction for the occurrence of MACE. Student's t, Mann-Whitney, chi-square, and logistic regression tests were used for statistical analyses. P values of ≤0.05 were considered statistically significant.

 Results:

The mean age was 59.76 years, and 69.3% of patients were male. No statistically significant association was observed between high-sensitivity C-reactive protein and recurrent MACE (p = 0.11). However, high-sensitivity C-reactive protein was independently associated with 30-day mortality when adjusted for TIMI [odds ratio (OR), 1.27; 95% confidence interval (CI), 1.07-1.51; p = 0.005] and GRACE (OR, 1.26; 95% CI, 1.06-1.49; p = 0.007) risk scores.

 Conclusion:

Although high-sensitivity C-reactive protein was not predictive of combined major cardiovascular events within 30 days after ST-elevation myocardial infarction in patients who underwent primary angioplasty and stent implantation, it was an independent predictor of 30-day mortality.

 Protein C Myocardial Infarction / mortality Electrocardiography Diagnosis Prognosis Introduction

Coronary artery disease (CAD) is a major cause of mortality worldwide. It accounted for 7 million deaths in the year of 2011, which corresponds to 11.2% of the overall mortality during that period1. Within the clinical spectrum of CAD, ST-elevation myocardial infarction (STEMI) accounts for 29%-47% cases of acute coronary syndrome (ACS)2 , 3. STEMI results from the rupture of an atherosclerotic plaque with superimposed coronary thrombosis in approximately 75% patients4 , 5.

Inflammatory responses play a key role in plaque rupture6 , 7. The usefulness of inflammatory markers as indicators of hidden atherosclerosis, in the improvement of risk algorithms8 - 12, and as predictors of the risk of recurrent events and death during ACS13 - 20 has been investigated. Among these markers, high-sensitivity C-reactive protein (hs-CRP) is the most extensively studied21.

When it comes to the prognosis of STEMI, there is a series of conflicting results with regard to hs-CRP22 - 27. Selection biases and heterogeneity of the reperfusion modalities are some of the limitations of the different studies. In the setting of primary percutaneous coronary intervention (pPCI), the data available are controversial and scarce, particularly with regard to short-term events28. Moreover, risk scores with a strong prognostic ability, particularly Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) scores, have been broadly used with the aim of early risk stratification29 , 30. However, these scores do not include inflammatory markers. This study aimed to assess the association of hs-CRP with a composite endpoint including death, reinfarction, new revascularization, and heart failure, that occurred within 30 days of the index event in patients with STEMI who underwent pPCI and stenting.

 Material and Methods Sample

The study sample was selected from patients diagnosed with STEMI according to the World Health Organization criteria who were admitted to a tertiary care hospital of interventional cardiology between 2002 and 2010. The inclusion criteria were as follows: age ≥ 18 years, both sexes, indication of pPCI and stenting, and ability to fast for at least 12 h. The exclusion criteria were as follows: history of malignancy, presence of human immunodeficiency virus (HIV) infection, presence of inflammatory disease, duration of >24 h between infarction and hospital admission, use of corticosteroid therapy, and current or recent use of nonsteroidal anti-inflammatory drugs (NSAIDs; within the last month).

 Methods

This was a prospective cohort study in which each patient was first approached right after admission to the emergency room. Patients meeting the inclusion criteria, but not the exclusion criteria, were invited to participate in the study and were asked for written informed consent. After receiving consent, a complete history was taken, followed by physical examination. Patients were assessed with respect to population data (age, sex, race), the presence of risk factors for ischemic heart disease (hypertension, diabetes mellitus, dyslipidemia, cigarette smoking, family history of CAD, and obesity), and medications used. Patients with systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, those using anti-hypertensive medication, and those with a previous diagnosis of hypertension were considered hypertensive. Patients with diabetes were defined as those with a previous diagnosis of diabetes mellitus, those consuming hypoglycemic drugs, or those with fasting blood glucose ≥ 126 mg/dL before admission. Dyslipidemia was defined as serum low-density lipoprotein cholesterol (LDL-C) > 130 mg/dL, high-density lipoprotein cholestrol (HDL-C) < 40 mg/dL, triglycerides > 150 mg/dL, or a combination of these. Smokers were considered as those who currently smoked on a regular basis or those who had quit for <1 year. A positive family history was defined as a diagnosis of CAD or other atherosclerotic disease in a male first-degree relative aged < 55 years or a female first-degree relative aged < 65 years. Obesity was diagnosed on the basis of a body mass index of ≥30 kg/m2. Clinical and electrocardiographic characteristics of the infarct, TIMI and GRACE risk scores, and type of hospital care were recorded. Then, a blood sample was drawn for hs-CRP determination. The sample was collected after a 12-h fast, but no later than within the first 24 h of infarct onset. Hs-CRP was determined using the nephelometry method (Dade Behring BNTM II, Liederbach, Germany). From hospital admission to discharge, all patients were followed-up by the research team, and the occurrence of clinical complications such as arrhythmias, heart failure, reinfarction, percutaneous reintervention, coronary artery bypass grafting, and death were recorded.

The primary endpoint of the study was the combination of major adverse cardiovascular events (MACE) including death, heart failure, reinfarction, or new revascularization (whether percutaneous or surgical) within the first 30 days after the index event. Death was considered as that from all causes. The heart failure endpoint was investigated on the basis of clinical parameters suggestive of pulmonary congestion and/or signs of low cardiac output. Reinfarction was defined as angina or anginal equivalent accompanied by a new ST-segment elevation in leads consistent with those of the territory of the artery affected in the index event. New revascularization was characterized by the need for percutaneous or surgical intervention motivated by instability of the clinical picture (elective revascularization were not considered endpoints).

Thirty days after infarction, the patients were assessed in the ambulatory care section of the Institute of Cardiology so that the occurrence of any endpoint of interest could be identified.

 Ethical considerations

The research project was approved by the Research Ethics Committee of the Institute of Cardiology/University Foundation of Cardiology, under protocol number 4406.09. All patients provided written informed consent.

 Statistical analysis

Sample size calculation: Assuming a MACE prevalence rate of 23% (checked in a preliminary analysis of the database), with an error margin of 5% and a 95% confidence interval (95% CI), the required sample size was calculated to be at least 273 patients. Categorical variables were described as proportions, while quantitative variables were described as means and standard deviations or medians and interquartile ranges. For quantitative variables, Student's t-test or the Mann-Whitney test was used to evaluate comparisons between groups. The chi-square test was used to evaluate comparisons between categorical variables. Multiple logistic regression multivariate analysis was conducted with MACE as a dependent variable. The results of multivariate analyses were expressed as odds ratios (ORs). The significance level was set at p ≤ 0.05, and analyses were conducted using Statistical Package for the Social Sciences (SPSS) software version 19.

 Results

A total of 300 patients with a mean age of 59 ± 11 years were evaluated. Most patients were male (69.3%) and Caucasian (89.8%). The most prevalent risk factor for ischemic heart disease was systemic hypertension, found in 62.2% patients. Previous conditions and procedures, as well as the medications used prior to hospitalization, are shown in Table 1.

Baseline patient characteristics
Mean age (years) 59.76 (± 11)
Male sex (%) 69.3
Caucasian race (%) 89.8
Risk factors (%)  
SAH 62.2
Cigarette smoking 48.0
FH 44.3
Dyslipidemia 39.9
Diabetes mellitus 21.6
Obesity 18.2
Most frequent previous conditions and procedures (%)  
AMI 14.5
Peripheral vascular disease 7.4
Gastrointestinal disease 6.8
Ischemic stroke 5.7
COPD 3.4
PCI 11.8
CABG 3.4
Medications more frequently used before the index AMI (%)  
ACEI 27.0
Antiplatelet drugs 25.0
Beta-blockers 22.0
Diuretics 16.0
Statins 11.0

SAH: systemic arterial hypertension, FH: family history of cardiovascular disease, AMI: acute myocardial infarction, COPD: chronic obstructive pulmonary disease, PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; ACEI, angiotensin converting-enzyme inhibitors

The mean TIMI and GRACE risk scores in the sample cohort were 3.57 (standard deviation, 2.40) and 143.07 (standard deviation, 35.35), respectively. The percentage of patients assigned to Killip classification groups I, II, III, and IV were 83, 12.3, 2, and 2.7%, respectively.

The patients were divided into two groups on the basis of the year of enrollment: group 1 (137 individuals hospitalized between 2002 and 2006) and group 2 (163 patients hospitalized between 2007 and 2010). No significant difference was observed in the in-hospital use of acetylsalicylic acid, thienopyridine, angiotensin-converting enzyme inhibitors (ACEI), beta-blockers, or statins between groups.

During the first 30 days of post-infarction follow-up, 16 deaths occurred, corresponding to an overall mortality of 5.3%. In addition, 96 patients with heart failure (32.2%), one PCI procedure (0.4%), three coronary artery bypass graftings (1.1%), and ten patients with new AMI (3.3%) were identified. Recurrent MACE were observed in 104 patients (34.7%; Table 2).

Incidence of the most frequent endpoints 30 days after ST-elevation AMI
Endpoints N Incidence (%)
Heart failure 96 32.2
Death 16 5.3
New AMI 10 3.3
CABG 3 1.1
New PCI 1 0.4
MACE 104 34.7

AMI: acute myocardial infarction; CABG: coronary artery bypass grafting; PCI: percutaneous coronary intervention; MACE: major adverse cardiovascular events (death + heart failure + new PCI + CABG + new AMI).

When the patients were compared with respect to the occurrence of MACE within the first 30 days after the index event, we observed a median hs-CRP of 8.0 mg/L (range, 3.7-23.5 mg/L) in the group presenting with the endpoint and 6.4 mg/L (range, 3.1-17.2 mg/L) in the remaining (p = 0.11; Table 3). Among those who developed heart failure, the median hs-CRP was 8.0 mg/L (range, 3.7-26.0 mg/L), while the median hs-CRP was 6.4 mg/L (range, 3.1-15.5 mg/L) in the group without heart failure (p = 0.057). When hs-CRP was assessed in relation to death, there was a significant association (p = 0.05; Figure 1). The causes of death and the respective hs-CRPs in each patient are shown in Table 4.

High-sensitivity C-reactive protein (Hs-CRP) levels and major adverse cardiovascular events (MACE) 30 days after ST-elevation acute myocardial infarction
MACE* hs-CRP** (mg/L) p value
Yes 8.0 (3.7-23.5) 0.112
No 6.4(3.1-17.2) 0.112

Deaths + heart failure + new percutaneous coronary intervention + coronary artery bypass grafting + new acute myocardial infarction

values expressed as medians and interquartile ranges

 Causes of death and respective hs-CRP levels
Cases Death cause(s) hs-CRP (mg/L)
1 Cardiogenic and septic shock 4.1
2 Cardiogenic shock 7.6
3 Cardiogenic shock 191.6
4 Cardiogenic shock 38.2
5 Cardiogenic shock 26.7
6 Cardiogenic shock 17.6
7 Cardiogenic shock 33.7
8 CHF and pneumonia 48.8
9 Cardiogenic shock 5.7
10 Cardiogenic shock; contrast-induced AKI 3.4
11 CHF 49.9
12 Cardiogenic shock 54.1
13 Cardiogenic shock 3.2
14 Cardiogenic shock 2.3
15 Ventricular fibrillation 22
16 Undetermined 4.2

Hs-CRP: high-sensitivity C-reactive protein; CHF: congestive heart failure; AKI: acute kidney injury

 Bivariate analysis of high-sensitivity C-reactive protein (hs-CRP) in relation to 30-day mortality after ST-elevation acute myocardial infarction (p = 0.05)

Multivariate analysis of hs-CRP in relation to all-cause mortality, after adjusting the markers for TIMI risk score (Table 5), showed an OR of 1.28 (95% CI, 1.08-1.52; p = 0.005). The OR of the TIMI score extracted from the logistic regression equation was 1.32 (95% CI, 1.09-1.59; p = 0.004) in relation to the same endpoint. On the other hand, when hs-CRP and GRACE risk scores were included in logistic regression, an independent association was found between hs-CRP and 30-day mortality (OR, 1.26; 95% CI, 1.07-1.50; p = 0.007). The OR corresponding to the GRACE score obtained from the same analysis was 1.02 (95% CI, 1.01-1.03; p = 0.002).

Predictors of death within 30 days after ST-elevation AMI (multivariate analysis)
  Odds ratio (95%CI) p value
hsCRP adjusted for TIMI score 1.28 (1.08-1.52) 0.005
hsCRP adjusted for GRACE score 1.26 (1.07-1.50) 0.007

AMI: acute myocardial infarction; 95% CI: 95% confidence interval; hs-CRP: high-sensitivity C-reactive protein; TIMI: Thrombolysis in Myocardial Infarction; GRACE: Global Registry of Acute Coronary Events.

 Discussion

The present study evaluated the prognostic role of hs-CRP with regard to the occurrence of 30-day recurrent MACE in patients with AMI treated with pPCI. No statistically significant association between this marker and the composite endpoint was observed. However, hs-CRP was significantly higher in patients who died within 30 days of the index event, and this association remained even after adjustment for TIMI and GRACE risk scores.

The nature of our findings is based on the hypothesis that, in individuals with AMI, the elevation of this biomarker is more attributable to the inflammatory response resulting from myocardial lesions than to vascular inflammation, unlike in individuals with unstable angina, in whom the elevation of CRP levels is associated with plaque instability and recurrent infarctions. Therefore, in patients with ACS and ST-elevation, elevated CRP levels have been related to mortality and heart failure, but not to recurrent infarctions24.

There is controversy surrounding the prognostic role of CRP in patients with STEMI. In an analysis of approximately 1000 patients with a mean follow-up of 23 months, Suleiman et al.22 verified an association between CRP and higher rates of overall mortality and heart failure after hospital discharge. Foussas et al23 found higher mortality rates within 30 days after STEMI in patients with CRP levels ≥ 5 mg/L, while the TIMI scores were the same in both groups. However, this study was initiated before the use of clopidrogel was widespread, and it did not provide information on the percentage of patients undergoing mechanical reperfusion23.

Whether the results of studies point to an association between CRP and relevant clinical endpoints24 or oppose that hypothesis25 , 27 , 31, most available evidence is based on patients receiving thrombolytic drugs. The retrospective design and failure to use the high-sensitivity method for determining CRP are also important limitations25.

In the context of STEMI treated with pPCI, the role of CRP as a prognostic marker has remained unclear. This is attributed to the paucity of evidence in this field and the disparity of information and methodological flaws present in the different publications. Tomoda and Aoki32 evaluated 234 patients with STEMI who underwent pPCI plus stenting and showed that a CRP level of ≥0.3 mg/dL was an independent predictor of a composite endpoint comprising in-hospital coronary reocclusion, reinfarction, target-vessel revascularization, and death. Limitations of this study were a retrospective design, failure to use contemporary technologies of percutaneous intervention, failure to use the high-sensitivity method to determine CRP, and failure to exclude individuals with inflammatory diseases or using antiinflamatory drugs.

In an Italian cohort comprising 758 patients, hs-CRP was associated with short-term mortality, long-term death, AMI and target-vessel revascularization33. This was also a retrospective study and was associated with a high rate of patient exclusion from the cohort (22% of the initial sample) because of the lack of CRP data on admission .

Two other studies showed an association between CRP and short-term MACE34 , 35. However, these studies were limited by a small sample size of 230 and 146 patients, respectively, and failure to explicitly list potential exclusion criteria, such as the use of NSAIDs and presence of inflammatory diseases. Kruk et al28 also reported that hs-CRP was predictive of in-hospital death without mentioning the exclusion criteria in their article.

Unlike the studies previously mentioned, and still in the context of PCI, Ohlmann et al36 did not show a prognostic relationship among CRP, infarct size, and mortality in a multivariate analysis. A small sample size (87 patients) and the fact that CRP was not determined using the high-sensitivity method may have influenced the results36. In turn, Damman et al37 did not include CRP in the score for the prediction of mortality in a very recent study with a significant number of patients (n = 1034) because the marker was not proven to be associated with mortality when adjusted for TIMI score variables. We should point out that, once again, concomitant inflammatory conditions were not considered and individuals in cardiogenic shock were excluded.

Our study plays an important role in the debate regarding prognosis and patient stratification because it shows an independent association between hs-CRP and a hard endpoint such as mortality. As previously mentioned, the association of CRP with clinically relevant endpoints in the setting of acute ischemic syndromes with ST-elevation has not yet reached a consensus in the literature. This was a prospective study that excluded clinical situations accompanied by an inflammatory response and the use of medications that interfere in this response, and it was conducted with all the contemporary therapeutic armamentarium38. The adjustment of hs-CRP to TIMI and GRACE risk scores29 , 30 provides our results with even greater consistency.

This study also has some limitations. First was its observational design. Second, it failed to establish a cut-off point for CRP level in relation to mortality. Third, it failed to use the C statistic to evaluate the prognostic accuracy of CRP in the context of STEMI because of the low frequency of this endpoint. Another limitation was the lack of hemodynamic data corresponding to coronary anatomy, which is justified by the fact that this was a fundamentally clinical study.

 Conclusions

Although hs-CRP was not predictive of composite MACE within the first 30 days after acute ST-elevation myocardial infarction in patients who underwent primary angioplasty and stenting, this marker proved to be an independent predictor of all-cause mortality.

Author contributions

Conception and design of the research: Ribeiro DRP, Ramos AM, Quadros AS, Portal VL; Acquisition of data: Ribeiro DRP, Ramos AM, Vieira PL, Menti E, Bordin Jr. OL, Souza PAL; Analysis and interpretation of the data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Ribeiro DRP, Quadros AS, Portal VL; Statistical analysis: Ribeiro DRP, Portal VL.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of master submitted by Daniel Rios Pinto Ribeiro, from Programa de pós-graduação de Ciências da Saúde - Cardiologia da Fundação Universitária de Cardiologia.

 References 1. World Health Organization. (WHO). The 10 leading causes of death by broad income group. Geneva; 2011 [Access 2013 Out 10]. Available from: http://www.who.int/mediacentre/factsheets/fs310/en/index.html World Health Organization. (WHO) The 10 leading causes of death by broad income group Geneva 2011 Access 2013 Out 10 Available from: http://www.who.int/mediacentre/factsheets/fs310/en/index.html 2. Roe MT, Parsons LS, Pollack CV Jr, Canto JG, Barron HV, Every NR, et al; National Registry of Myocardial Infarction Investigators. Quality of care by classification of myocardial infarction: treatment patterns for ST-segment elevation vs non-ST- segment elevation myocardial infarction. Arch Intern Med. 2005;165(14):1630-6. Roe MT Parsons LS Pollack CV Jr Canto JG Barron HV Every NR et al National Registry of Myocardial Infarction Investigators Quality of care by classification of myocardial infarction: treatment patterns for ST-segment elevation vs non-ST- segment elevation myocardial infarction Arch Intern Med 2005 165 14 1630 1636 3. Mandelzweig L, Battler A, Boyko V, Bueno H, Danchin N, Filippatos G, et al. The Euro Heart Survey Investigators. The second Euro Heart Survey on acute coronary syndromes: characteristics, treatment, and outcome of patients with ACS in Europe and the Mediterranean Basin in 2004. Eur Heart J. 2006;27(19):2285-93. Mandelzweig L Battler A Boyko V Bueno H Danchin N Filippatos G et al The Euro Heart Survey Investigators The second Euro Heart Survey on acute coronary syndromes: characteristics, treatment, and outcome of patients with ACS in Europe and the Mediterranean Basin in 2004 Eur Heart J 2006 27 19 2285 2293 4. Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol. 2006;47(8 Suppl.):C7-12. Falk E Pathogenesis of atherosclerosis J Am Coll Cardiol 2006 47 8 Suppl C7 12 5. Kubo T, Imanishi T, Takarada S, Kuroi A, Ueno S, Yamano T, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol. 2007;50(10):933-9. Kubo T Imanishi T Takarada S Kuroi A Ueno S Yamano T et al Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy J Am Coll Cardiol 2007 50 10 933 939 6. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340(2):115-26. Ross R Atherosclerosis: an inflammatory disease N Engl J Med 1999 340 2 115 126 7. Weintraub HS. Identifying the vulnerable patient with rupture-prone plaque. Am J Cardiol. 2008;101(12A):3F-10F. Weintraub HS Identifying the vulnerable patient with rupture-prone plaque Am J Cardiol 2008 101 12A 3F 10F 8. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297(6):611-9. Erratum in JAMA. 2007;297(13):1433. Ridker PM Buring JE Rifai N Cook NR Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score JAMA 2007 297 6 611 619 Erratum in JAMA. 2007;297(13):1433. 9. Zethelius B, Berglund L, Sundström J, Ingelsson E, Basu S, Larsson A, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med. 2008;358(20):2107-16. Zethelius B Berglund L Sundström J Ingelsson E Basu S Larsson A et al Use of multiple biomarkers to improve the prediction of death from cardiovascular causes N Engl J Med 2008 358 20 2107 2116 10. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, et al; Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344(26):1959-65. Ridker PM Rifai N Clearfield M Downs JR Weis SE Miles JS et al Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events N Engl J Med 2001 344 26 1959 1965 11. Blake GJ, Ridker PM, Kuntz KM. Projected life-expectancy gains with statin therapy for individuals with elevated C-reactive protein levels. J Am Coll Cardiol. 2002;40(1):49-55. Blake GJ Ridker PM Kuntz KM Projected life-expectancy gains with statin therapy for individuals with elevated C-reactive protein levels J Am Coll Cardiol 2002 40 1 49 55 12. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195207. Ridker PM Danielson E Fonseca FA Genest J Gotto AM Jr Kastelein JJ et al JUPITER Study Group Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein N Engl J Med 2008 359 21 2195207 2195207 13. Morrow DA, de Lemos JA, Sabatine MS, Wiviott SD, Blazing MA, Shui A, et al. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation. 2006;114(4):281-8. Morrow DA de Lemos JA Sabatine MS Wiviott SD Blazing MA Shui A et al Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial Circulation 2006 114 4 281 288 14. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med. 1994;331(7):417-24. Liuzzo G Biasucci LM Gallimore JR Grillo RL Rebuzzi AG Pepys MB et al The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina N Engl J Med 1994 331 7 417 424 15. Morrow DA, Rifai N, Antman EM, Weiner DL, McCabe CH, Cannon CP, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. 1998;31(7):1460-5. Morrow DA Rifai N Antman EM Weiner DL McCabe CH Cannon CP et al C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction J Am Coll Cardiol 1998 31 7 1460 1465 16. Toss H, Lindahl B, Siegbahn A, Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. Circulation. 1997;96(12):4204-10. Toss H Lindahl B Siegbahn A Wallentin L Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease Circulation 1997 96 12 4204 4210 17. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. 2000;343(16):1139-47. Lindahl B Toss H Siegbahn A Venge P Wallentin L Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease N Engl J Med 2000 343 16 1139 1147 18. Heeschen C, Hamm CW, Bruemmer J, Simoons ML. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE Investigators. Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial. J Am Coll Cardiol. 2000;35(6):1535-42. Heeschen C Hamm CW Bruemmer J Simoons ML Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE Investigators. Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial J Am Coll Cardiol 2000 35 6 1535 1542 19. Biasucci LM, Liuzzo G, Grillo RL, Caligiuri G, Rebuzzi AG, Buffon A, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation. 1999;99(7):855-60. Biasucci LM Liuzzo G Grillo RL Caligiuri G Rebuzzi AG Buffon A et al Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability Circulation 1999 99 7 855 860 20. James SK, Armstrong P, Barnathan E, Califf R, Lindahl B, Siegbahn A, et al; GUSTO-IV-ACS Investigators. Troponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: a GUSTO-IV substudy. J Am Coll Cardiol. 2003;41(6):916-24. James SK Armstrong P Barnathan E Califf R Lindahl B Siegbahn A et al GUSTO-IV-ACS Investigators Troponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: a GUSTO-IV substudy J Am Coll Cardiol 2003 41 6 916 924 21. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111(12):1805-12. Pepys MB Hirschfield GM C-reactive protein: a critical update J Clin Invest 2003 111 12 1805 1812 22. Suleiman M, Khatib R, Agmon Y, Mahamid R, Boulos M, Kapeliovich M, et al. Early Inflammation and Risk of Long-Term Development of Heart Failure and Mortality in Survivors of Acute Myocardial Infarction: Predictive Role of C-Reactive Protein. J Am Coll Cardiol. 2006;47(5):962-8. Suleiman M Khatib R Agmon Y Mahamid R Boulos M Kapeliovich M et al Early Inflammation and Risk of Long-Term Development of Heart Failure and Mortality in Survivors of Acute Myocardial Infarction: Predictive Role of C-Reactive Protein J Am Coll Cardiol 2006 47 5 962 968 23. Foussas SG, Zairis MN, Lyras AG, Patsourakos NG, Tsirimpis VG, Katsaros K, et al. Early prognostic usefulness of C-reactive protein added to the Thrombolysis In Myocardial Infarction Risk Score in acute coronary syndromes. Am J Cardiol. 2005;96(4):533-7. Foussas SG Zairis MN Lyras AG Patsourakos NG Tsirimpis VG Katsaros K et al Early prognostic usefulness of C-reactive protein added to the Thrombolysis In Myocardial Infarction Risk Score in acute coronary syndromes Am J Cardiol 2005 96 4 533 537 24. Suleiman M, Aronson D, Reisner SA, Kapeliovich MR, Markiewicz W, Levy Y, et al. Admission C-reactive protein levels and 30-day mortality in patients with acute myocardial infarction. Am J Med. 2003;115(9):695-701. Suleiman M Aronson D Reisner SA Kapeliovich MR Markiewicz W Levy Y et al Admission C-reactive protein levels and 30-day mortality in patients with acute myocardial infarction Am J Med 2003 115 9 695 701 25. Nikfardjam M, Müllner M, Schreiber W, Oschatz E, Exner M, Domanovits H, et al. The association between C-reactive protein on admission and mortality in patients with acute myocardial infarction. J Intern Med. 2000; 247(3):341-5. Nikfardjam M Müllner M Schreiber W Oschatz E Exner M Domanovits H et al The association between C-reactive protein on admission and mortality in patients with acute myocardial infarction J Intern Med 2000 247 3 341 345 26. Zebrack JS, Anderson JL, Maycock CA, Horne BD, Bair TL, Muhlestein JB, et al; Intermountain Heart Collaborative (IHC) Study Group. Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction. Am J Cardiol. 2002;89(2):145-9. Zebrack JS Anderson JL Maycock CA Horne BD Bair TL Muhlestein JB et al Intermountain Heart Collaborative Study Group Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction Am J Cardiol 2002 89 2 145 149 27. Mega JL, Morrow DA, De Lemos JA, Sabatine MS, Murphy SA, Rifai N, et al. B-type natriuretic peptide at presentation and prognosis in patients with ST-segment elevation myocardial infarction: An ENTIRE-TIMI-23 substudy. J Am Coll Cardiol. 2004;44(2):335-9. Mega JL Morrow DA De Lemos JA Sabatine MS Murphy SA Rifai N et al B-type natriuretic peptide at presentation and prognosis in patients with ST-segment elevation myocardial infarction: An ENTIRE-TIMI-23 substudy J Am Coll Cardiol 2004 44 2 335 339 28. Kruk M, Przyluski J, Kalinczuk L, Pregowski J, Deptuch T, Kadziela J, et al; ANIN Myocardial Infarction Registry Group. Association of Non-Specific Inflammatory Activation With Early Mortality in Patients With ST-Elevation Acute Coronary Syndrome Treated With Primary Angioplasty. Circ J. 2008;72(2):205-11. Kruk M Przyluski J Kalinczuk L Pregowski J Deptuch T Kadziela J et al ANIN Myocardial Infarction Registry Group Association of Non-Specific Inflammatory Activation With Early Mortality in Patients With ST-Elevation Acute Coronary Syndrome Treated With Primary Angioplasty Circ J 2008 72 2 205 211 29. Morrow DA, Antman EM, Charlesworth A, Cairns R, Murphy SA, de Lemos JA, et al. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an In TIME trial substudy. Circulation. 2000;102(17):2031-7. Morrow DA Antman EM Charlesworth A Cairns R Murphy SA de Lemos JA et al TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an In TIME trial substudy Circulation 2000 102 17 2031 2037 30. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, et al; Global Registry of Acute Coronary Events Investigators. Predictors of Hospital Mortality in the global registry of acute coronary events. Arch Intern Med. 2003;163(19):2345-53. Granger CB Goldberg RJ Dabbous O Pieper KS Eagle KA Cannon CP et al Global Registry of Acute Coronary Events Investigators Predictors of Hospital Mortality in the global registry of acute coronary events Arch Intern Med 2003 163 19 2345 2353 31. Steg PG, Ravaud P, Tedgui A, Puel J, Moyse D, Curaudeau E, et al; ELISCOR Investigators. Predischarge C-reactive protein and 1-year outcome after acute coronary syndromes. Am J Med. 2006;119(8):684-92. Steg PG Ravaud P Tedgui A Puel J Moyse D Curaudeau E et al ELISCOR Investigators Predischarge C-reactive protein and 1-year outcome after acute coronary syndromes Am J Med 2006 119 8 684 692 32. Tomoda H, Aoki N. Prognostic value of C-reactive protein levels within six hours after the onset of acute myocardial infarction. Am Heart J. 2000;140(2):324-8. Tomoda H Aoki N Prognostic value of C-reactive protein levels within six hours after the onset of acute myocardial infarction Am Heart J 2000 140 2 324 328 33. Ortolani P, Marzocchi A, Marrozzini C, Palmerini T, Saia F, Taglieri N, et al. 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(10):1241-9. Ortolani P Marzocchi A Marrozzini C Palmerini T Saia F Taglieri N et al 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 10 1241 1249 34. Magadle R, Hertz I, Merlon H, Weiner P, Mohammedi I, Robert D. The relation between preprocedural C-reactive protein levels and early and late complications in patients with acute myocardial infarction undergoing interventional coronary angioplasty. Clin Cardiol. 2004;27(3):163-8. Magadle R Hertz I Merlon H Weiner P Mohammedi I Robert D The relation between preprocedural C-reactive protein levels and early and late complications in patients with acute myocardial infarction undergoing interventional coronary angioplasty Clin Cardiol 2004 27 3 163 168 35. Yip HK, Hang CL, Fang CY, Hsieh YK, Yang CH, Hung WC, et al. Level of high-sensitivity C-reactive protein is predictive of 30-day outcomes in patients with acute myocardial infarction undergoing primary coronary intervention. Chest. 2005;127(3):803-8. Yip HK Hang CL Fang CY Hsieh YK Yang CH Hung WC et al Level of high-sensitivity C-reactive protein is predictive of 30-day outcomes in patients with acute myocardial infarction undergoing primary coronary intervention Chest 2005 127 3 803 808 36. Ohlmann P, Jaquemin L, Morel O, El Behlgiti R, Faure A, Michotey MO, et al. Prognostic value of C-reactive protein and cardiac troponin I in primary percutaneous interventions for ST-elevation myocardial infarction. Am Heart J. 2006;152(6):1161-7. Ohlmann P Jaquemin L Morel O El Behlgiti R Faure A Michotey MO et al Prognostic value of C-reactive protein and cardiac troponin I in primary percutaneous interventions for ST-elevation myocardial infarction Am Heart J 2006 152 6 1161 1167 37. Damman P, Beijk MA, Kuijt WJ, Verouden NJ, van Geloven N, Henriques JP, et al. Multiple biomarkers at admission significantly improve the prediction of mortality in patients undergoing primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2011;57(1):29-36. Damman P Beijk MA Kuijt WJ Verouden NJ van Geloven N Henriques JP et al Multiple biomarkers at admission significantly improve the prediction of mortality in patients undergoing primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction J Am Coll Cardiol 2011 57 1 29 36 38. Boden WE, Eagle K, Granger CB. Reperfusion strategies in acute ST-segment elevation myocardial infarction: a comprehensive review of contemporary management options. J Am Coll Cardiol. 2007;50(10):917-29. Boden WE Eagle K Granger CB Reperfusion strategies in acute ST-segment elevation myocardial infarction: a comprehensive review of contemporary management options J Am Coll Cardiol 2007 50 10 917 929 Proteína C-Reativa Prediz Eventos Cardiovasculares Após Infarto do Miocárdio com Elevação do ST? Ribeiro Daniel Rios Pinto Ramos Adriane Monserrat Vieira Pedro Lima Menti Eduardo Bordin Odemir Luiz Jr. Souza Priscilla Azambuja Lopes de Quadros Alexandre Schaan de Portal Vera Lúcia Fundação Universitária de Cardiologia Instituto de Cardiologia Programa de Pós-Graduação em Ciências da Saúde: Cardiologia Porto Alegre RS Brasil Programa de Pós-Graduação em Ciências da Saúde: Cardiologia - Instituto de Cardiologia/Fundação Universitária de Cardiologia, Porto Alegre, RS - Brasil Correspondência: Vera Lúcia Portal, Avenida Princesa Isabel, 370, Santana. CEP 90620-000, Porto Alegre, RS − Brasil. E-mail: veraportal.pesquisa@gmail.com

Potencial conflito de interesse

Declaro não haver conflito de interesses pertinentes.

 Fundamento:

A associação entre proteína C-reativa ultrassensível e eventos cardiovasculares maiores recorrentes em pacientes com infarto agudo do miocárdio com supradesnivelamento do segmento ST submetidos à intervenção coronariana percutânea primária é controversa.

 Objetivo:

Verificar se a proteína C-reativa ultrassensível está associada a risco aumentado de eventos cardiovasculares maiores, como morte, insuficiência cardíaca, reinfarto e nova revascularização, em pacientes com infarto agudo do miocárdio com supradesnivelamento do segmento ST tratados com intervenção coronariana percutânea primária.

 Métodos:

Coorte prospectiva, incluindo 300 indivíduos maiores de 18 anos admitidos em um centro terciário com diagnóstico de infarto agudo do miocárdio com supradesnivelamento do segmento ST submetidos à intervenção coronariana percutânea primária. Utilizou-se instrumento contendo variáveis clínicas e escores de risco TIMI e GRACE, além da proteína C-reativa ultrassensível analisada por nefelometria. Os pacientes foram acompanhados na internação e até 30 dias após o infarto para a ocorrência de eventos cardiovasculares maiores recorrentes. Na análise estatística, foram utilizados os testes t de Student, Mann-Whitney, qui-quadrado e regressão logística. O valor de p ≤ 0,05 foi considerado significativo.

 Resultados:

A média de idade foi de 59,76 anos, sendo 69,3% do gênero masculino. Não houve associação estatisticamente significativa entre proteína C-reativa ultrassensível e eventos cardiovasculares maiores recorrentes (p = 0,11). No entanto, a proteína C-reativa ultrassensível foi associada a óbito em 30 dias, de forma independente, quando ajustada para o escore TIMI (razão de chances de 1,27; intervalo de confiança de 95% de 1,07-1,51; valor de p = 0,005) e GRACE (razão de chances de 1,26; intervalo de confiança de 95% de 1,06-1,49; valor de p = 0,007).

 Conclusão:

Embora a proteína C-reativa ultrassensível não tenha sido preditora de eventos cardiovasculares maiores combinados até o 30° dia de evolução de infarto agudo do miocárdio com elevação do segmento ST, em pacientes submetidos à angioplastia primária e implante de stent, ela foi um preditor independente de mortalidade em 30 dias.

 Proteína C-Reativa Infarto do Miocárdio / mortalidade Eletrocardiografia Diagnóstico Prognóstico Introdução

A Doença Arterial Coronariana (DAC) é a principal causa de mortalidade em nível global, tendo sido responsável por 7 milhões de óbitos no ano de 2011, correspondendo a 11,2% do total no referido período1.

Dentro do espectro clínico da DAC, o Infarto Agudo do Miocárdio com Supradesnivelamento do Segmento ST (IAMCSST) representa 29 a 47% dos casos de Síndromes Coronarianas Agudas (SCA)2 , 3 e se deve, em cerca de 75% das vezes, à ruptura de uma placa aterosclerótica com trombose coronariana superposta4 , 5. No contexto da ruptura da placa, a resposta inflamatória tem um papel decisivo6 , 7.

Marcadores inflamatórios têm sido avaliados tanto como indicadores de aterosclerose oculta e aprimoramento de algoritmos de risco8 - 12, quanto na predição de risco de eventos recorrentes e óbito na vigência de SCA13 - 20. Dentre esses marcadores, a Proteína C-Reativa Ultrassensível (PCR-us) tem sido um dos mais estudados21.

No que tange ao prognóstico do IAMCSST, há uma série de resultados conflitantes com relação à PCRus22 - 27. Vieses de seleção e heterogeneidade das modalidades de reperfusão são algumas das falhas dos diferentes estudos. No âmbito da Intervenção Coronariana Percutânea Primária (ICPp), os dados disponíveis, além de controversos, são mais escassos, especialmente em termos de eventos de curto prazo28. Também com a finalidade de estratificação de risco precoce, escores de risco, em particular os modelos TIMI (sigla do inglês Thrombolysis in Myocardial Infarction) e GRACE (de Global Registry of Acute Coronary Events), vêm sendo largamente utilizados, ambos com forte capacidade prognóstica29 , 30. Entretanto, esses escores não contemplam marcadores inflamatórios. O objetivo deste estudo foi avaliar a associação da PCR-us com o desfecho composto por morte, reinfarto, nova revascularização e insuficiência cardíaca, em pacientes com IAMCSST tratados com ICPp e implante de stent, em até 30 dias após o evento índice.

 Material e Métodos Amostra

A amostra deste estudo foi selecionada a partir de pacientes internados em um centro terciário de cardiologia intervencionista entre os anos de 2002 e 2010, com diagnóstico de IAMCSST, segundo os critérios da Organização Mundial da Saúde.

Foram considerados como critérios de inclusão: idade ≥ 18 anos, ambos os gêneros, ICPp com stente jejum de pelo menos 12 horas.

Os critérios de exclusão utilizados foram: história de neoplasia; infecção pelo Vírus da Imunodeficiência Humana (HIV); doença inflamatória; evolução do infarto (do início do quadro clínico à admissão hospitalar) superior a 24 horas; corticoterapia; uso de anti-inflamatórios não esteroidais atual ou recente (há menos de 1 mês).

 Métodos

Coorte prospectiva, em que a primeira abordagem do paciente se fez tão logo de sua admissão no setor de emergência. Se o paciente preenchesse os critérios de inclusão e não apresentasse critérios para exclusão, era convidado a participar do estudo com posterior assinatura do Termo de Consentimento Livre e Esclarecido. Após, era realizada uma anamnese completa, seguida de exame físico. Os pacientes eram avaliados quanto aos dados populacionais (idade, gênero e raça) e à presença de fatores de risco para cardiopatia isquêmica (hipertensão, diabetes melito, dislipidemia, tabagismo, história familiar para DAC e obesidade), além das medicações em uso. Pacientes com cifras sistólicas ≥ 140 mmHg e/ou cifras diastólicas ≥ 90 mmHg, ou em uso de medicação anti-hipertensiva ou diagnóstico prévio, foram considerados hipertensos. Foram definidos como diabéticos aqueles com diagnóstico prévio, ou os que já usavam hipoglicemiantes, ou portadores de glicemias de jejum anteriores à internação ≥ 126 mg/dL. Dislipidemia foi definida como Lipoproteína de Baixa Densidade (LDL, do inglês Low Density Lipoprotein) > 130 mg/dL, Lipoproteína de Alta Densidade (HDL, do inglês High Density Lipoprotein) < 40 mg/dL ou triglicerídeos > 150 mg/dL, ou combinações destes. Consideraram-se tabagistas pacientes em uso regular atual ou em abstinência há menos de 1 ano. História familiar positiva foi definida como diagnóstico de DAC ou de outra doença aterosclerótica em familiares de primeiro grau (com idade < 55 anos em homens e < 65 anos em mulheres). O diagnóstico de obesidade foi feito com base em um índice de massa corporal ≥ 30 kg/m2. Características clínicas e eletrocardiográficas do infarto, pontuação nos escores de risco TIMI (sigla do inglês Thrombolysis in Myocardial Infarction) e GRACE (de Global Registry of Acute Coronary Events), e tipo de tratamento hospitalar foram anotados. A seguir, procedeu-se à coleta de uma amostra sanguínea para posterior análise de PCRus. A coleta foi feita respeitando-se jejum de 12 horas, sem, no entanto, ultrapassar a 24ª hora de evolução do infarto. A PCRus foi analisada pelo método de nefelometria (Dade Behring BN(tm) II, Liederbach, Alemanha). Desde a admissão até a alta, todos os pacientes tiveram sua evolução acompanhada pela equipe de pesquisa, sendo registrada a ocorrência de complicações clínicas como: arritmias, insuficiência cardíaca, reinfarto, reintervenção percutânea, cirurgia de revascularização do miocárdio ou óbito.

O desfecho primário do estudo foi a combinação de Eventos Cardiovasculares Maiores (ECVM) que incluía morte, insuficiência cardíaca, reinfarto e nova revascularização (percutânea ou cirúrgica) em até 30 dias após o evento índice. Considerou-se morte como óbito por todas as causas. O desfecho "insuficiência cardíaca" foi averiguado a partir de parâmetros clínicos sugestivos de congestão pulmonar e/ou sinais de baixo débito cardíaco. Reinfarto foi definido como angina ou equivalente anginoso acompanhado de nova elevação do segmento ST, em derivações compatíveis com o território da artéria acometida no evento índice. Nova revascularização foi caracterizada como a necessidade de intervenção percutânea ou cirúrgica motivada por instabilização do quadro clínico (revascularizações eletivas não foram consideradas como desfechos).

Trinta dias após o infarto, os pacientes foram atendidos em consulta no ambulatório do Instituto de Cardiologia, a fim de identificar a ocorrência de algum desfecho de interesse.

 Considerações éticas

O projeto de pesquisa foi aprovado pelo Comitê de Ética em Pesquisa do Instituto de Cardiologia/Fundação Universitária de Cardiologia e protocolado sob o número 4406.09. Todos os pacientes assinaram o Termo de Consentimento Livre e Esclarecido.

 Análise estatística

Cálculo do tamanho da amostra: Assumindo uma taxa de prevalência de ECVM (verificada em análise preliminar do banco de dados) de 23%, com margem de erro de 5% e Intervalo de Confiança de 95% (IC95%), calculou-se um número amostral necessário de pelo menos 273 pacientes. As variáveis categóricas foram descritas na forma de proporções e as quantitativas por meio de média e desvio padrão ou mediana e intervalo interquartil. Foram utilizados o teste t de Student ou Mann-Whitney para comparações entre grupos nas variáveis quantitativas, e o teste qui-quadrado para comparações entre as variáveis categóricas. Análise multivariada por regressão logística múltipla foi realizada com ECVM como variável dependente. Os resultados das análises multivariadas foram expressos na forma de Razão de Chances (RC). O nível de significância adotado foi p ≤ 0,05 e as análises foram realizadas por meio do software Statistical Package for the Social Sciences (SPSS) versão 19.

 Resultados

Foram avaliados 300 pacientes, com média de idade de 59 ± 11 anos, em sua maioria do gênero masculino (69,3%) e de cor branca (89,8%). Dentre os fatores de risco para cardiopatia isquêmica, o mais prevalente foi hipertensão arterial sistêmica, presente em 62,2% dos casos. As patologias e os procedimentos prévios, bem como as medicações utilizadas antes da internação, são apresentados na Tabela 1.

Características basais da amostra
Idade (média em anos) 59,76 (± 11)
Gênero masculino (%) 69,3
Raça branca (%) 89,8
Fatores de risco (%)  
HAS 62,2
Tabagismo 48,0
HF 44,3
Dislipidemia 39,9
Diabete mellitus 21,6
Obesidade 18,2
Doenças e procedimentos prévios mais frequentes (%)  
IAM 14,5
Doença vascular periférica 7,4
Doença gastrintestinal 6,8
AVC isquêmico 5,7
DPOC 3,4
ICP 11,8
CRM 3,4
Medicamentos mais usados antes do IAM Índice (%)  
IECA 27,0
Antiplaquetários 25,0
Betabloqueadores 22,0
Diuréticos 16,0
Estatinas 11,0

HAS: hipertensão arterial sistêmica; HF: história familiar de doença cardiovascular; IAM: infarto agudo do miocárdio; AVC: acidente vascular cerebral; DPOC: doença pulmonar obstrutiva crônica; ICP: intervenção coronariana percutânea; CRM: cirurgia de revascularização do miocárdio; IECA: inibidores da enzima conversora da angiotensina.

Os valores médios, na amostra, dos escores de risco TIMI e GRACE, foram, respectivamente, 3,57 pontos (desvio padrão = 2,40) e 143,07 pontos (desvio padrão = 35,35). As frequências das classificações de Killip em grupos I, II, III e IV foram nesta ordem: 83%, 12,3%, 2% e 2,7%.

Os pacientes foram divididos em dois grupos: Grupo 1 (137 indivíduos hospitalizados entre 2002 e 2006) e Grupo 2 (163 pacientes internados entre 2007 e 2010). Não houve diferença significativa, entre ambos os grupos, com relação ao uso intra-hospitalar de ácido acetilsalicílico, tienopiridínicos, inibidores da enzima conversora da angiotensina (IECA), betabloqueadores ou estatinas.

Até o 30º dia de acompanhamento pós-infarto, foram verificados 16 óbitos, correspondendo a uma mortalidade total de 5,3%. Constataram-se, ainda, 96 casos de insuficiência cardíaca (32,2%), um procedimento de ICP (0,4%), três cirurgias de revascularização do miocárdio (1,1%) e dez casos de novo IAM (3,3%). ECVM recorrentes foram observados em 104 casos, constituindo um percentual de 34,7% (Tabela 2).

Incidência dos desfechos mais frequentes 30 dias após infarto agudo do miocárdio (IAM) com supradesnivelamento do segmento ST
Desfechos n Incidência (%)
Insuficiência cardíaca 96 32,2
Óbito 16 5,3
Novo IAM 10 3,3
CRM 3 1,1
Nova ICP 1 0,4
ECVM 104 34,7

CRM: cirurgia de revascularização do miocárdio; ICP: intervenção coronariana percutânea; ECVM: eventos adversos cardiovasculares maiores (óbitos + insuficiência cardíaca + nova ICP + CRM + novo IAM).

Ao compararmos os pacientes quanto à ocorrência de ECVM em até 30 dias do evento índice, observou-se que a mediana da PCRus foi igual a 8,0 mg/L (3,7 a 23,5 mg/L) no grupo que apresentou o desfecho versus 6,4 mg/L (3,1 a 17,2 mg/L) nos demais indivíduos (p = 0,11) (Tabela 3). Dentre aqueles que desenvolveram insuficiência cardíaca, a mediana da PCRus foi de 8,0 mg/L (3,7 a 26,0 mg/L), comparada ao valor de 6,4 mg/L (3,1 a 15,5 mg/L) no grupo sem IC (p = 0,057). Quando a PCRus foi avaliada em relação ao óbito, houve associação significativa, com p = 0,05 (Figura 1). Estão dispostas, na Tabela 4, as causas de óbito, bem como os respectivos valores de PCRus em cada caso.

Níveis de proteína C-reativa ultrassensível (PCRus) e eventos adversos cardiovasculares maiores (ECVM) 30 dias após infarto agudo do miocárdio com supradesnivelamento do segmento ST
ECVM* PCRus** (mg/L) Valor de p
Sim 8,0 (3,7-23,5) 0,112
Não 6,4 (3,1-17,2) 0,112

Óbitos + insuficiência cardíaca + nova intervenção coronária percutânea + cirurgia de revascularização do miocárdio + novo infarto agudo do miocário.

valores expressos na forma de mediana e amplitude interquartil.

 Causas de óbito e respectivos níveis de proteína C-reativa ultrassensível (PCRus)
Casos Causa (s) do óbito PCRus (mg/L)
1 Choque cardiogênico e séptico 4,1
2 Choque cardiogênico 7,6
3 Choque cardiogênico 191,6
4 Choque cardiogênico 38,2
5 Choque cardiogênico 26,7
6 Choque cardiogênico 17,6
7 Choque cardiogênico 33,7
8 ICC e pneumonia 48,8
9 Choque cardiogênico 5,7
10 Choque cardiogênico; IRA pós-contraste 3,4
11 ICC 49,9
12 Choque cardiogênico 54,1
13 Choque cardiogênico 3,2
14 Choque cardiogênico 2,3
15 Fibrilação ventricular 22
16 Indeterminada 4,2

ICC: insuficiência cardíaca congestiva; IRA: insuficiência renal aguda.

 Análise bivariada da proteína C-reativa ultrassensível (PCRus) em relação a óbito 30 dias após infarto agudo do miocárdio com supradesnivelamento do segmento ST (p = 0,05).

Fazendo-se uma análise multivariável da PCRus em relação ao óbito por todas as causas e ajustando-se o marcador pelo escore de risco TIMI (Tabela 5), foi verificada uma RC de 1,28 (IC95%: 1,08-1,52; p = 0,005). A RC do escore TIMI, em relação ao mesmo desfecho, extraída da equação de regressão logística, foi de 1,32 (IC95%: 1,09-1,59; p = 0,004). Quando incluímos, por outro lado, a PCRus e o escore de risco GRACE em uma regressão logística, obtivemos, novamente, associação independente da PCRus com o desfecho de mortalidade em 30 dias (RC = 1,26; IC95%: 1,07-1,50; p = 0,007), sendo a RC correspondente ao escore GRACE, obtida da mesma análise, de 1,02 (IC95%: 1,01-1,03; p = 0,002).

Preditores de óbito em 30 dias após infarto agudo do miocárdio com supradesnivelamento do segmento ST (análise multivariável)
  Razão de chances (IC95%) Valor de p
PCRus ajustada ao escore TIMI 1,28 (1,08-1,52) 0,005
PCRus ajustada ao escore GRACE 1,26 (1,07-1,50) 0,007

IC95%: intervalo de confiança de 95%; PCRus: proteína C-reativa ultrassensível; TIMI: Thrombolysis i n Myocardial Infarction; GRACE: Global Registry of Acute Coronary Events.

 Discussão

O presente estudo avaliou o papel prognóstico da PCRus quanto à ocorrência de ECVM recorrentes em 30 dias em pacientes com IAM tratados com ICPp, sendo que não foi observada associação estatisticamente significativa entre este marcador e o desfecho composto. Entretanto, a PCRus foi significativamente maior nos casos com óbito em 30 dias, e tal associação foi mantida mesmo após ajuste com os escores de risco TIMI e GRACE.

A natureza dos nossos achados pode se basear na hipótese de que, ao contrário dos indivíduos com angina instável, nos quais a elevação do biomarcador está associada à instabilização da placa e a infartos recorrentes, no caso do IAM, a elevação da PCR é mais atribuível à resposta inflamatória decorrente da lesão miocárdica do que à inflamação vascular. Assim, em SCA com supradesnivelamento de ST, a PCR tem sido relacionada com mortalidade e insuficiência cardíaca, mas não com infartos recorrentes24.

Existe controvérsia sobre o papel prognóstico da PCR, em pacientes com IAMCSST. Em uma análise de aproximadamente mil pacientes com seguimento médio de 23 meses, Suleiman e cols.22 verificaram associação entre a PCR e maiores taxas de mortalidade geral e insuficiência cardíaca após a alta hospitalar. Foussas e cols.23 encontraram maiores índices de mortalidade em 30 dias pós-IAMCSST naqueles em que a PCR era ≥ 5 mg/L, sendo a pontuação no escore TIMI igual nos dois grupos de comparação. Esse trabalho, no entanto, iniciou antes da disseminação do uso do clopidogrel, além de não informar a porcentagem de pacientes submetidos à reperfusão mecânica23.

Sejam os resultados dos trabalhos indicativos de associação da PCR com desfechos clínicos relevantes24, ou contrários a essa hipótese25 , 27 , 31, grande parte da evidência disponível se faz às custas de pacientes submetidos ao uso de trombolítico. O delineamento retrospectivo e o não uso de método ultrassensível para a mensuração da PCR também são limitações importantes25.

No cenário do IAMCSST tratado com ICPp, o papel da PCR como marcador prognóstico também não é claro. Atribui-se tal fato à escassez de evidências nesse terreno, bem como à divergência das informações e às falhas metodológicas presentes nas diferentes publicações. Tomoda e Aoki32, avaliando 234 pacientes com IAMCSST submetidos à ICPp + stent, demonstraram que a PCR ≥ 0,3 mg/dL foi preditora independente de desfecho composto constituído por reoclusão coronariana, reinfarto, revascularização do vaso alvo e mortalidade intra-hospitalares. Limitações desse estudo foram desenho retrospectivo, não uso de tecnologias contemporâneas de intervenção percutânea, PCR dosada por método sem alta sensibilidade e não exclusão de indivíduos usuários de anti inflamatórios e portadores de doenças inflamatórias.

Já em uma coorte italiana composta por 758 pacientes, a PCRus foi associada tanto à mortalidade em curto prazo, como à morte, ao IAM e à revascularização de vaso alvo em longo prazo33. Esse estudo também teve delineamento retrospectivo, bem como alto índice de exclusão de pacientes da coorte (22% da amostra inicial) por ausência de PCR admissional.

Outros dois trabalhos evidenciaram associação do marcador com ECVM em curto prazo, sendo comprometidos, entretanto, por número amostral reduzido, respectivamente 230 e 146 pacientes, e por falta de explicitação de critérios de exclusão em potencial, como uso de AINES e as doenças inflamatórias34 , 35. Kruk e cols.28 também demonstraram predição da PCRus com relação a óbitos hospitalares, sem mencionar, no artigo, os critérios de exclusão.

Contrariando as associações acima, ainda no contexto da ICP, Ohlmann e cols.36 não obtiveram relação prognóstica da PCR com tamanho do infarto e mortalidade, na análise multivariada. Amostra pequena (87 pacientes) e o fato de a PCR não ser ultrassensível podem ter influenciado os resultados36. Já Damman e cols.37, em estudo bastante recente e com número expressivo de pacientes (1.034 pacientes), não incluíram a PCR em escore para predição de mortalidade, pois o marcador não se associou à mortalidade ao ser ajustado pelas variáveis do escore TIMI. Note-se, mais uma vez, que condições inflamatórias intercorrentes não foram consideradas; além disso, indivíduos em choque cardiogênico foram excluídos.

Com relação a prognóstico e estratificação de pacientes, nosso estudo tem um lugar importante nesse debate, ao demonstrar a associação independente da PCRus com um desfecho duro, como mortalidade. Como dito anteriormente, a associação da PCR com desfechos clinicamente relevantes, no cenário das síndromes isquêmicas agudas com elevação do segmento ST, ainda não é consenso na literatura. Este foi um estudo prospectivo, que excluiu situações clínicas que transcorrem com resposta inflamatória e o uso de medicamentos que interferem nessa resposta, realizado à luz de todo arsenal terapêutico contemporâneo38. O ajuste da PCRus aos escores de risco TIMI e GRACE29 , 30 confere ainda maior consistência aos nossos resultados.

Por outro lado, o estudo apresenta algumas limitações: delineamento observacional; não foi possível estabelecer um ponto de corte para a PCR com relação à mortalidade e nem o uso da estatística C (para avaliar a acurácia prognóstica da PCR no contexto do IAMCSST), devido à baixa ocorrência desse desfecho.

Outra limitação foi não dispormos de dados hemodinâmicos a respeito da anatomia coronariana, fato este justificado por se tratar de um estudo eminentemente clínico.

 Conclusão

Embora a proteína C-reativa ultrassensível não seja preditora de eventos cardiovasculares maiores combinados, até o 30° dia de evolução de infarto agudo do miocárdio com elevação do segmento ST, em pacientes submetidos à angioplastia primária e implante de stent, o marcador foi preditor independente de mortalidade por todas as causas.

Contribuição dos autores

Concepção e desenho da pesquisa: Ribeiro DRP, Ramos AM, Quadros AS, Portal VL; Obtenção de dados: Ribeiro DRP, Ramos AM, Vieira PL, Menti E, Bordin Jr. OL, Souza PAL; Análise e interpretação dos dados, Redação do manuscrito e v: Ribeiro DRP, Quadros AS, Portal VL; Análise estatística: Ribeiro DRP, Portal VL.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Este artigo é parte de Dissertação de Mestrado de Daniel Rios Pinto Ribeiro pelo Programa de pós-graduação de Ciências da Saúde - Cardiologia da Fundação Universitária de Cardiologia.