Arq Bras Cardiol Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia fg8jccxVGLYGpFWL4GHSRxq S0066-782X2014002200008 00008 10.5935/abc.20140130 Original Articles Diabetes Mellitus and Glucose as Predictors of Mortality in Primary Coronary Percutaneous Intervention David Renato Budzyn Almeida Eduardo Dytz Cruz Larissa Vargas Sebben Juliana Cañedo Feijó Ivan Petry Schmidt Karine Elisa Schwarzer Avena Luísa Martins Gottschall Carlos Antonio Mascia Quadros Alexandre Schaan de Fundação Universitária de Cardiologia Instituto de Cardiologia Porto Alegre RS Brazil Instituto de Cardiologia/Fundação Universitária de Cardiologia (IC/FUC), Porto Alegre, RS - Brazil Mailing Address: Alexandre Schaan de Quadros, Avenida Princesa Isabel, 370, Santana. Postal Code 90620-000, Porto Alegre, Rio Grande do Sul, Brazil. E-mail: editoracao-pc@cardiologia.org.br; quadros.pesquisa@gmail.com

Potential Conflict of Interest

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

 12 09 2014 10 2014 103 4 323 330 12 02 2014 06 05 2014 09 05 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:

Diabetes mellitus and admission blood glucose are important risk factors for mortality in ST segment elevation myocardial infarction patients, but their relative and individual role remains on debate.

 Objective:

To analyze the influence of diabetes mellitus and admission blood glucose on the mortality of ST segment elevation myocardial infarction patients submitted to primary coronary percutaneous intervention.

 Methods:

Prospective cohort study including every ST segment elevation myocardial infarction patient submitted to primary coronary percutaneous intervention in a tertiary cardiology center from December 2010 to May 2012. We collected clinical, angiographic and laboratory data during hospital stay, and performed a clinical follow-up 30 days after the ST segment elevation myocardial infarction. We adjusted the multivariate analysis of the studied risk factors using the variables from the GRACE score.

 Results:

Among the 740 patients included, reported diabetes mellitus prevalence was 18%. On the univariate analysis, both diabetes mellitus and admission blood glucose were predictors of death in 30 days. However, after adjusting for potential confounders in the multivariate analysis, the diabetes mellitus relative risk was no longer significant (relative risk: 2.41, 95% confidence interval: 0.76 - 7.59; p-value: 0.13), whereas admission blood glucose remained and independent predictor of death in 30 days (relative risk: 1.05, 95% confidence interval: 1.02 - 1.09; p-value ≤ 0.01).

 Conclusion:

In ST segment elevation myocardial infarction patients submitted to primary coronary percutaneous intervention, the admission blood glucose was a more accurate and robust independent predictor of death than the previous diagnosis of diabetes. This reinforces the important role of inflammation on the outcomes of this group of patients.

 Diabetes Mellitus Blood Glucose Biological Markers Myocardial Infarction Percutaneous Coronary Intervention Introduction

Diabetes mellitus (DM) is an important risk factor for mortality in patients with ST-segment elevation myocardial infarction (STEMI)1-3. In addition, high blood glucose levels on admission are directly related to short-term mortality after STEMI4-9, regardless of previous diagnosis of DM10-14 or the reperfusion therapy used15. Primary percutaneous coronary intervention (PPCI) is currently the reperfusion therapy of choice in STEMI patients when performed in a timely manner and by experienced cardiologists16,17. However, previous studies on the effect of admission glucose levels on clinical outcomes after STEMI are scarce and do not reflect the current practice of interventional cardiology18-20.

The pathophysiological characteristics of hyperglycemia in STEMI patients are distinct from those observed in DM patients in stable clinical conditions21. The most recent guidelines of the European Society of Cardiology reveal some controversies in the acute management of blood glucose levels in STEMI patients and indicate the need for further assessment of this variable during contemporary medical practice22. The present study aimed to evaluate the effect of DM and admission hyperglycemia on short-term mortality in STEMI patients subjected to PPCI.

 Methods Experimental design

This unicentric prospective cohort study evaluated all STEMI patients subjected to PPCI at our institution between December 2010 and May 2012. Our hospital is a high-volume tertiary referral center for interventional cardiology. It performs approximately 2,500 percutaneous coronary interventions (PCI) per year, and PPCI is the routine reperfusion strategy for STEMI patients. The Research Ethics Committee of this institution reviewed the present study, and all patients enrolled signed a free informed consent form. The authors are solely responsible for the design and conduct of the study, including the analyses, design, manuscript revisions, and approval of the final manuscript. No external funding was provided to support this study.

 Patients

STEMI patients hospitalized in our institution and referred to PPCI by the attending physician were included in the study. For most patients, this was their first contact with our institution. STEMI was defined as chest pain at rest for > 30 min, associated with (1) ST-segment elevation of >1 mm in ≥2 contiguous electrocardiographic leads or (2) new left bundle branch block. Exclusion criteria were as follows: chest pain for >12 h, age of <18 years, and patient refusal to enroll in the study.

PPCI was performed as recommended in the literature17. Upon admission, all patients were treated with 300 mg of acetylsalicylic acid and 300-600 mg of clopidogrel. Unfractionated heparin (60-100 U/kg) was administered before PPCI. The technical aspects of the procedure, such as type and number of stents, use of adjunct devices, and administration of glycoprotein IIb/IIIa inhibitors, were decided by the cardiologist responsible for PPCI.

Blood samples were collected in the emergency room and analyzed in the hemodynamics room.

 Clinical outcomes and patient follow-up

Patients were monitored during hospitalization and by phone contact 1 month after hospital discharge. Coronary flow before and after the procedure was assessed according to the guidelines established by the Thrombolysis in Myocardial Infarction (TIMI) study group23. Myocardial perfusion was evaluated using the myocardial blush grade24. Stent thrombosis was defined according to the criteria established by the Academic Research Consortium25. Delta T was defined as the time between the onset of chest pain and hospital admission. Door-to-balloon time was defined as the time between hospital admission and the first balloon inflation procedure in the artery associated with acute myocardial infarction (AMI). The definition of DM was based on patients' information and use of hypoglycemic therapy.

With regard to follow-up, major adverse cardiac events (MACE) were defined as the combination of death from all causes, new AMI, or stroke. New AMI was defined as recurrent chest pain with an elevation of serum biomarkers, following an initial decline in the natural curve, with ST-segment elevation or new Q waves. Urgent revascularization was defined as both an unplanned revascularization procedure within 30 days after STEMI, and PCI or a coronary artery bypass grafting procedure for the treatment of recurrent ischemia.

 Statistical analysis

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software version 16.0 (SPSS, Inc., Chicago, Illinois). The study power was calculated using the comparison of proportions. Considering the sample size, the power to detect a difference in the 30-day outcome of death between patients with and without DM was 82% using Fisher's exact test. Categorical variables were reported as frequency and percentage. Continuous data were presented as the mean and standard deviation. Variables were considered normal on the basis of the values of central tendency, kurtosis, and skewness in the frequency histograms, in addition to statistical analysis used in previous studies. The chi-square or Fisher's exact test was used for comparisons between categorical variables. The t test was used for comparisons between continuous variables. A p value of <0.05 was considered significant.

Multivariate analysis with stepwise and backward logistic regression models was used to identify independent predictors of cardiovascular mortality 30 days after hospital discharge. Initially, a model including only DM and the GRACE score was adopted to assess the contribution of DM in the rate of events, corrected by a robust score and including comorbidities and clinical variables. Subsequently, a second multivariate analysis was performed, including DM, GRACE score26,27, and other variables with statistical significance. The dependent variables included in this model were as follows: GRACE score, post-PCI TIMI flow grade 3, DM, delta T, blood glucose, and cholesterol.

 Results

During the study period, 740 patients underwent PPCI within the first 12 h after STEMI. DM was present in 134 patients (18%). Table 1 compares the basic characteristics of patients with and without DM. DM patients were older, predominantly women, with a higher frequency of hypertension, dyslipidemia, and previous angina. In DM Patients, smoking was less common, whereas chronic use of aspirin was more frequent. Approximately 40% infarctions occurred on anterior artery walls, with no significant difference between the groups with and without DM. Patients with DM had an increased body mass index and waist circumference compared with those without.

Clinical profile of patients (n = 740) according to the presence or absence of diabetes mellitus
Characteristic DM Absence of DM p value
(N = 134) (N = 606)
Age (years) 63 ± 11 60 ± 12 < 0.01
Female (%) 38 29 0.04
Caucasian (%) 90 87 0.43
Hypertension (%) 80 61 < 0.01
Dyslipidemia (%) 47 30 < 0.01
Current smoking (%) 28 45 < 0.01
Family history (%) 26 33 0.13
Medical history
AMI (%) 27 20 0.06
CABG (%) 5 2 0.19
CRF (%) 3 2 0.63
Angina (%) 48 36 0.01
Daily use of ASA (%) 41 23 < 0.01
ECC, mL/min/1.73 m2 86 ± 37 87 ± 31 0.81
Total cholesterol (mg/dL) 192 ± 52 204 ± 57 0.02
BMI, (kg/m2) 27.6 ± 4.3 26.8 ± 4.1 0.05
AC (cm) 96 ± 14 93 ± 15 0.05
SBP (mmHg) 136 ± 32 135 ± 29 0.86
Delta T (hours) 5.2 ± 5.3 4.6 ± 4.3 0.12
DBT (hours) 1.7 ± 1.3 1.56 ± 1.3 0.30
Admission glucose levels (mg/dL) 253 ± 124 143 ± 51 < 0.01

AMI: acute myocardial infarction; CABG: coronary artery bypass grafting procedure; CRF: chronic renal failure; ASA: acetylsalicylic acid; ECC: endogenous creatinine clearance; BMI: body mass index; AC: abdominal circumference; SBP: systolic blood pressure; DBT: door-to-balloon time; DM: diabetes mellitus.

DM patients had higher glucose levels on admission and lower plasma cholesterol levels.

In general, the angiographic profile of patients with and without DM was similar. However, DM patients exhibited a lower Blush 3 score after the procedure (57% vs. 69%; p < 0.01). Most of the stents implanted (99.3%) were of the conventional type.

During hospital follow-up, the rates of severe arrhythmia or cardiac arrest (11.5% vs. 7.7%; p = 0.15) and stent thrombosis (3.1% vs. 3%; p = 0.96) in patients with DM were similar to those in patients without DM. However, the occurrence of acute renal failure (8.5% vs. 2.5%; p < 0.01), the need for mechanical ventilation (11.5% vs. 6.5%; p = 0.04), and the development of congestive heart failure (13.7% vs. 6.5%; p = 0.01) were more frequent in DM patients. Figure 1 shows a 30-day follow-up as a function of DM. The incidence of MACE (20.1 vs. 11.6; p < 0.01) and death (16.4% vs. 7.3%; p < 0.01) were higher in patients with DM than in those without.

Clinical outcomes during a 30-day follow-up (n = 740) as a function of DM. MACE:major adverse cardiac events; new AMI: acute myocardial infarction; Revasc: new revascularization.

The multivariate analysis for the 30-day outcome of death was initially performed using DM and GRACE score variables, both of which proved to be predictors of this outcome: GRACE risk score [relative risk (RR): 1.048, 95% confidence interval (CI): 1.037-1.059; p < 0.01] and DM (RR: 1.926, 95% CI: 1.016-3.650; p = 0.04). The complete model, including other variables and admission glucose levels, is shown in Table 2. We observed that when considering the variables representing the baseline risk of the patient as a result of PPCI and admission glucose levels, DM lost statistical significance. Nevertheless, admission glucose levels were an important predictor of the 30-day outcome of death because an increase of 10 mg/dL in the glucose levels was observed for every 5% increase in RR events (RR: 1.05, 95% CI: 1.02-1.09; p < 0.01). The cutoff glucose level for the optimal prediction of the primary outcome was evaluated using the receiver operating characteristic curve, which yielded a glucose level of 159 mg/dL, a sensitivity of 63%, a specificity of 68%, and an area under the curve of 0.65 (95% CI: 0.61-0.69).

Multiple logistic regression analysis for 30-day mortality
Predictor Relative risk 95% CI p value
GRACE score 1.04 1.03 - 1.06 < 0.01
Post-PCI TIMI flow grade 3 0.30 0.12 - 0.71 < 0.01
DM 2.41 0.77 - 7.60 0.13
Delta T 1.08 1.02 - 1.15 < 0.01
Admission blood glucose levels* 1.05 1.02 - 1.09 < 0.01
Total cholesterol 0.99 0.98 - 1.00 0.05

Admission glucose levels were included in the model in increments of 10 mg/dL.

PCI: percutaneous coronary intervention; Diabetes mellitus: DM

 Discussion

The present study confirms the increased risk of adverse events for diabetic patients with STEMI subjected to PPCI. Furthermore, it showed that DM is a predictor of short-term events when corrected for the multiple comorbidities represented in the GRACE risk score26,27. However, DM lost its statistical significance when other variables, e.g., admission glucose levels, were added to the multivariate model used for predicting 30-day mortality. These results demonstrate the importance of hyperglycemia on admission as a risk factor for short-term events in this context, and suggest that a significant proportion of the risk represented by DM is mediated by admission hyperglycemia, which is more frequent and pronounced in patients with DM compared with those without DM.

Hyperglycemia in DM patients is caused by resistance to insulin and decreased insulin production in pancreatic cells, whereas stress hyperglycemia during AMI and in other serious acute diseases is caused by a complex mechanism of secretion of hormones, including adrenaline, glucagon, growth hormone, and cytokines. In addition to being a marker of the severity of clinical conditions, myocardial damage from stress hyperglycemia may be due to adverse effects including increased oxidative stress, platelet activation, and endothelial dysfunction, leading to increased infarct size21. Previous studies have shown that hyperglycemia induces an inflammatory response during AMI28 and that its resolution can restore this response29. Two cohort studies of AMI patients (with and without ST-segment elevation) demonstrated that admission hyperglycemia was an independent predictor of in-hospital mortality30,31 but was not significant for long-term mortality30. In addition, admission hyperglycemia had distinct effects on mortality when patients were subdivided into age groups31. The analysis of the CARDINAL study indicated that the decreased blood glucose levels in the first 24 h after infarction was associated with decreased 30-day mortality in patients without DM32.

DM patients have impaired microvascular structure and diffuse endothelial dysfunction, which contributes to decreased blood perfusion, particularly in the context of acute hypoperfusion, such as STEMI33. In the present study, the percentage of patients who achieved a Blush 3 score after the procedure was lower in the group with DM, corroborating the results of previous studies34. Even with a TIMI flow grade 3 after PPCI, DM patients exhibit less complete resolution of the ST segment after stent implantation, which also indicates impaired microvascular flow35. These results corroborate the worse cardiovascular outcomes that DM patients exhibit after STEMI.

Recent studies have suggested that DM is primarily associated with worse long-term outcomes in STEMI patients, whereas the increased cardiovascular risk was primarily due to hyperglycemia. Ishihara et al18 and Hoebers et al19 demonstrated that hyperglycemia, but not DM, is associated with short-term adverse events in STEMI patients subjected to PCI. Ergelen et al20 analyzed the clinical outcome of STEMI patients as a function of DM and blood glucose levels: DM with admission hyperglycemia, DM without admission hyperglycemia, absence of DM with admission hyperglycemia, and absence of DM without admission hyperglycemia. It was observed that patients without DM and with admission hyperglycemia had a higher risk of in-hospital mortality, whereas DM patients with admission hyperglycemia had the worst long-term outcomes. These results agree with those of Kosiborod et al7 who, in a large study of AMI patients, showed that the risk of mortality of patients with admission hyperglycemia was higher for those without a DM history, compared with DM patients. This effect is not restricted to STEMI cases because patients admitted to intensive care units with severe acute illnesses and admission hyperglycemia had worse clinical outcomes compared with those having lower glucose levels36.

Our study reinforces the results reported above and demonstrates that the unfavorable prognostic role of hyperglycemia in short-term adverse events is more relevant and independent than the role of DM18. An important advantage of the present study is the inclusion of unselected and consecutive patients, representative of real-world clinical practice. The percentage of DM patients was 18%, which was similar to that reported in other studies (17-21%)2,34,37.

Limitations

One limitation of the present study involves the lack of data on glycosylated hemoglobin (HbA1c). Approximately 50% of STEMI patients experience changes in glucose metabolism38, and HbA1c can be a diagnostic criterion of DM39. Moreover, it was demonstrated that the prognostic role of admission hyperglycemia is more important than increased HbA1c levels40, and that HbA1c assumes greater significance in predicting long-term events instead of predicting short-term events9,11. The criteria used for the diagnosis of DM (reported by the patient) may have underestimated the number of DM patients. However, it is important to highlight that the percentage of DM patients found herein was similar to that in previous studies, and the blood glucose levels was significantly higher in patients with DM than in those without. Moreover, the assessment of ventricular function during hospitalization was performed by the medical staff, and the study protocol did not include the routine and prospective collection of such data. The large amount of missing data on ventricular function (>25%) prevented the accurate analysis of this variable, and this limitation has occurred in other observational studies on AMI patients subjected to PPCI.

 Conclusion

This contemporary analysis with consecutive patients, representative of the clinical practice in a tertiary interventional cardiology hospital, corroborates the increased risk for DM patients subjected to primary angioplasty. It demonstrates the important prognostic role of admission hyperglycemia in predicting short-term adverse cardiovascular events. Furthermore, the latter variable does not depend on other comorbidities or clinical diagnoses, including the diagnosis of DM, and is more important than DM.

Author contributions

Conception and design of the research: David RB, Sebben JC, Gottschall CAM, Quadros AS; Acquisition of data: David RB, Almeida ED, Sebben JC, Feijó IP, Schmidt KES, Avena LM; Analysis and interpretation of the data AND Writing of the manuscript: David RB, Almeida ED, Cruz LV, Quadros AS; Statistical analysis: David RB, Quadros AS; Critical revision of the manuscript for intellectual content: David RB, Almeida ED, Cruz LV, Sebben JC, Feijó IP, Schmidt KES, Avena LM, Gottschall CAM, Quadros AS.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

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Marfella R Siniscalchi M Esposito K Sellitto A De Fanis U Romano C et al Effects of stress hyperglycemia on acute myocardial infarction: role of inflammatory immune process in functional cardiac outcome Diabetes Care 2003 26 11 3129 3135 Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes. 2004;53(8):2079-86. Stentz FB Umpierrez GE Cuervo R Kitabchi AE Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises Diabetes 2004 53 8 2079 2086 Pesaro AE, Nicolau JC, Serrano Jr CV, Truffa R, Gaz MV, Karbstein R, et al. Influence of leukocytes and glycemia on the prognosis of patients with acute myocardial infarction. Arq Bras Cardiol. 2009;92(2):84-8. Pesaro AE Nicolau JC Serrano CV Jr Truffa R Gaz MV Karbstein R et al Influence of leukocytes and glycemia on the prognosis of patients with acute myocardial infarction Arq Bras Cardiol 2009 92 2 84 88 Nicolau JC, Serrano CV Jr, Giraldez RR, Baracioli LM, Moreira HG, Lima F, et al. In patients with acute myocardial infarction, the impact of hyperglycemia as a risk factor for mortality is not homogeneous across age-groups. Diabetes Care. 2012;35(1):150-2. Nicolau JC Serrano CV Jr Giraldez RR Baracioli LM Moreira HG Lima F et al In patients with acute myocardial infarction, the impact of hyperglycemia as a risk factor for mortality is not homogeneous across age-groups Diabetes Care 2012 35 1 150 152 Goyal A, Mahaffey KW, Garg J, Nicolau JC, Hochman JS, Weaver WD, et al. Prognostic significance of the change in glucose level in the first 24 h after acute myocardial infarction: results from the CARDINAL study. Eur Heart J. 2006;27(11):1289-97. Goyal A Mahaffey KW Garg J Nicolau JC Hochman JS Weaver WD et al Prognostic significance of the change in glucose level in the first 24 h after acute myocardial infarction: results from the CARDINAL study Eur Heart J 2006 27 11 1289 1297 Kawaguchi M, Techigawara M, Ishihata T, Asakura T, Saito F, Maehara K, et al. A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension. Heart Vessels. 1997;12(6):267-74. Kawaguchi M Techigawara M Ishihata T Asakura T Saito F Maehara K et al A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension Heart Vessels 1997 12 6 267 274 Timmer JR, van der Horst IC, de Luca G, Ottervanger JP, Hoorntje JC, de Boer MJ, et al. Comparison of myocardial perfusion after successful primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction with versus without diabetes mellitus. Am J Cardiol. 2005;95(11):1375-7. Timmer JR van der Horst IC de Luca G Ottervanger JP Hoorntje JC de Boer MJ et al Comparison of myocardial perfusion after successful primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction with versus without diabetes mellitus Am J Cardiol 2005 95 11 1375 1377 Angeja BG, de Lemos J, Murphy SA, Marble SJ, Antman EM, Cannon CP, et al. Impact of diabetes mellitus on epicardial and microvascular flow after fibrinolytic therapy. Am Heart J. 2002;144(4):649-56. Angeja BG de Lemos J Murphy SA Marble SJ Antman EM Cannon CP et al Impact of diabetes mellitus on epicardial and microvascular flow after fibrinolytic therapy Am Heart J 2002 144 4 649 656 Evans NR, Dhatariya KK. Assessing the relationship between admission glucose levels, subsequent length of hospital stay, readmission and mortality. Clin Med. 2012;12(2):137-9. Evans NR Dhatariya KK Assessing the relationship between admission glucose levels, subsequent length of hospital stay, readmission and mortality Clin Med 2012 12 2 137 139 Lavi S, Kapeliovich M, Gruberg L, Roguin A, Boulos M, Grenadier E, et al. Hyperglycemia during acute myocardial infarction in patients who are treated by primary percutaneous coronary intervention: impact on long-term prognosis. Int J Cardiol. 2008;123(2):117-22. Lavi S Kapeliovich M Gruberg L Roguin A Boulos M Grenadier E et al Hyperglycemia during acute myocardial infarction in patients who are treated by primary percutaneous coronary intervention: impact on long-term prognosis Int J Cardiol 2008 123 2 117 122 Collet JP, Montalescot G. The acute reperfusion management of STEMI in patients with impaired glucose tolerance and type 2 diabetes. Diab Vasc Dis Res. 2005;2(3):136-43. Collet JP Montalescot G The acute reperfusion management of STEMI in patients with impaired glucose tolerance and type 2 diabetes Diab Vasc Dis Res 2005 2 3 136 143 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26 Suppl 1:S5-20. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Report of the expert committee on the diagnosis and classification of diabetes mellitus Diabetes Care 2003 26 Suppl 1 S5 S20 Hadjadj S, Coisne D, Mauco G, Ragot S, Duengler F, Sosner P, et al. Prognostic value of admission plasma glucose and HbA in acute myocardial infarction. Diabet Med. 2004;21(4):305-10. Hadjadj S Coisne D Mauco G Ragot S Duengler F Sosner P et al Prognostic value of admission plasma glucose and HbA in acute myocardial infarction Diabet Med 2004 21 4 305 310 Liu Y, Yang YM, Zhu J, Tan HQ, Liang Y, Li JD. Haemoglobin A(1c), acute hyperglycaemia and short-term prognosis in patients without diabetes following acute ST-segment elevation myocardial infarction. Diabet Med. 2012;29(12):1493-500. Liu Y Yang YM Zhu J Tan HQ Liang Y Li JD Haemoglobin A(1c), acute hyperglycaemia and short-term prognosis in patients without diabetes following acute ST-segment elevation myocardial infarction Diabet Med 2012 29 12 1493 1500 Diabetes Mellitus e Glicemia como Preditores de Mortalidade na Intervenção Coronariana Primária David Renato Budzyn Almeida Eduardo Dytz Cruz Larissa Vargas Sebben Juliana Cañedo Feijó Ivan Petry Schmidt Karine Elisa Schwarzer Avena Luísa Martins Gottschall Carlos Antonio Mascia Quadros Alexandre Schaan de Fundação Universitária de Cardiologia Instituto de Cardiologia Porto Alegre RS Brasil Instituto de Cardiologia/Fundação Universitária de Cardiologia (IC/FUC), Porto Alegre, RS - Brasil Correspondência: Alexandre Schaan de Quadros, Avenida Princesa Isabel, 370, Santana. CEP 90620-000, Porto Alegre, RS - Brasil. E-mail: editoracao-pc@cardiologia.org.br; quadros.pesquisa@gmail.com Fundamento:

Diabetes Mellitus e glicemia de admissão são importantes fatores de risco para mortalidade em pacientes com infarto agudo do miocárdio com elevação do segmento ST, mas a contribuição relativa e independente de cada um deles permanece em debate na literatura.

 Objetivo:

Analisar a influência de diabetes mellitus e da glicemia de admissão na mortalidade de pacientes com infarto agudo do miocárdio com elevação do segmento ST submetidos à intervenção coronariana percutânea primária.

 Métodos:

Estudo de coorte prospectivo incluindo todos os pacientes com infarto agudo do miocárdio com elevação do segmento ST submetidos à intervenção coronariana percutânea primária em um centro terciário de cardiologia no período de dezembro de 2010 a maio de 2012. Foram coletados dados clínicos, laboratoriais e angiográficos, com seguimento clínico de 30 dias após o evento. A análise multivariada dos fatores de risco estudados foi ajustada para as variáveis do escore GRACE.

 Resultados:

Dentre os 740 pacientes incluídos, a prevalência de diabetes mellitus relatada foi de 18%. Na análise simples, tanto diabetes mellitus quanto glicemia de admissão foram preditores de mortalidade em 30 dias. Entretanto, após ajuste de potenciais confundidores na análise multivariada, o risco proporcionado pelo diabetes mellitus deixou de ser significativo (risco relativo: 2,41, intervalo de confiança de 95%: 0,76 - 7,59; p = 0,13) enquanto a glicemia de admissão permaneceu como preditor independente de mortalidade em 30 dias (risco relativo: 1,05, intervalo de confiança de 95%: 1,02 - 1,09; p ≤ 0,01)

 Conclusão:

Em pacientes com infarto agudo do miocárdio com elevação do segmento ST submetidos à intervenção coronariana percutânea primária, a glicemia de admissão foi um preditor independente de mortalidade mais robusto e acurado do que o diagnóstico prévio de diabetes, reforçando o papel importante da resposta inflamatória no desfecho desse grupo de pacientes.

 Diabetes Mellitus Glicemia Marcadores Biológicos Infarto do Miocárdio Intervenção Coronária Percutânea Introdução

O Diabetes Mellitus (DM) é um estabelecido fator de risco para mortalidade em pacientes que apresentam Infarto Agudo do Miocárdio com Supradesnivelamento do Segmento ST (IAMCSST)1-3. A glicemia da admissão, quando elevada, também está diretamente relacionada com mortalidade a curto prazo após IAMCSST4-9, independentemente do diagnóstico prévio de DM10-14 e da terapia de reperfusão utilizada15. A Intervenção Coronariana Percutânea Primária (ICPp), atualmente, é a terapia de reperfusão de escolha em pacientes com IAMCSST quando realizada em tempo hábil e por hemodinamicistas experientes16,17, mas estudos prévios, que analisaram a influência da glicemia de admissão em desfechos após IAMCSST, são escassos ou não representativos da atual prática de cardiologia intervencionista18-20.

A hiperglicemia que ocorre em pacientes com IAMCSST tem fisiopatologia diferente daquela presente em pacientes com DM em condição clínica estável21. As diretrizes mais recentes da Sociedade Europeia de Cardiologia frisam as controvérsias no manejo agudo da glicemia dos pacientes com IAMCSST e apontam para a necessidade de análises mais aprofundadas dessa questão na prática médica contemporânea22. O objetivo deste estudo foi avaliar a influência do DM e da hiperglicemia de admissão na mortalidade a curto prazo em pacientes com IAMCSST submetidos à ICPp.

 Métodos Delineamento

Estudo unicêntrico de coorte prospectivo que incluiu todos os pacientes com IAMCSST submetidos à ICPp em nossa instituição no período de dezembro de 2010 a maio de 2012. Nosso hospital é um centro de referência terciário de alto volume para cardiologia intervencionista, com realização de aproximadamente 2.500 ICP por ano, sendo a ICPp a estratégia de reperfusão de rotina em pacientes com IAMCSST. Todos os pacientes incluídos assinaram o termo livre de consentimento, e o estudo foi avaliado pelo comitê de ética da instituição. Os autores são os únicos responsáveis pelo desenho e pela condução do estudo, incluindo todas as análises, elaboração, edição do manuscrito e a aprovação de seu conteúdo final. Nenhum financiamento externo foi usado para apoiar este estudo.

 Pacientes

Foram considerados para inclusão no estudo os pacientes com IAMCSST hospitalizados em nossa instituição e encaminhados para ICPp pelo médico assistente. Na maioria dos pacientes, este foi o primeiro contato com nossa instituição. IAMCSST foi definido como dor torácica em repouso com duração de mais de 30 minutos associada com (1) elevação do segmento ST > 1 mm em ≥ 2 derivações contíguas do eletrocardiograma, ou (2) novo bloqueio de ramo esquerdo. Os critérios de exclusão foram: dor torácica com mais de 12 horas de duração, idade inferior a 18 anos e recusa do paciente em participar do estudo.

A ICPp foi realizada conforme preconizado na literatura17. Todos os pacientes foram medicados na admissão com 300 mg de ácido acetilsalicílico e 300 a 600 mg de clopidogrel. Heparina não fracionada (60 a 100 U/kg) foi administrada antes da ICPp. Aspectos técnicos do procedimento, como o tipo e número de stents, o uso de dispositivos adjuntos e o uso de glicoproteína IIb/IIIa, ficaram a critério do médico hemodinamicista responsável pela ICPp.

A coleta de sangue para análise laboratorial foi realizada na sala de emergência, antes de seu encaminhamento para a sala de hemodinâmica.

 Resultados clínicos e seguimentos

Os pacientes foram acompanhados durante a internação hospitalar e por contato telefônico 1 mês após a alta hospitalar. O fluxo coronário antes e após os procedimentos foi avaliado e descrito conforme o critério Thrombolysis In Myocardial Infarction (TIMI)23. A perfusão miocárdica foi avaliada pelo Blush miocárdico24. Trombose de stent foi definida de acordo com os critérios da Academic Research Consortium (ARC)25. Delta T foi definido como o tempo entre o início da dor torácica e a apresentação no hospital. Tempo porta-balão foi considerado aquele entre a chegada ao hospital até a primeira inflação do balão dentro da artéria relacionada com o Infarto Agudo do Miocárdio (IAM). A definição de DM foi baseada na informação do paciente e no uso de medicações hipoglicemiantes.

Em relação ao seguimento, Eventos Cardiovasculares Maiores (ECVM) foram definidos como a combinação de óbito por todas as causas, novo IAM ou Acidente Vascular Cerebral (AVC). Novo IAM foi definido por dor torácica recorrente com nova elevação de biomarcadores séricos, após a queda inicial da curva natural, com elevação do segmento ST ou novas ondas Q. Revascularização de urgência foi definida tanto como um procedimento de revascularização não planejado nos primeiros 30 dias após o IAMCSST, quanto por ICP ou cirurgia de revascularização do miocárdio para tratamento de isquemia recorrente.

 Análise estatística

Análise estatística foi realizada com o programa Statistical Package for the Social Science (SPSS), versão 16.0 (SPSS, Inc., Chicago, Illinois). O poder do estudo foi calculado utilizando cálculo de comparação de proporções. Para o tamanho amostral de nosso estudo, o poder para detecção de diferença no desfecho de óbito em 30 dias entre pacientes diabéticos e não diabéticos foi de 82% (teste de Fisher). Variáveis categóricas foram relatadas como frequência e porcentagem. Dados contínuos foram apresentados como média e desvio padrão. As variáveis foram consideradas normais, de acordo com a observação de suas medidas de tendência central, curtose e assimetria nos histogramas de frequência, sendo também considerado o tratamento estatístico utilizado em estudos prévios. Foram utilizados os testes qui-quadrado ou exato de Fisher para comparações entre variáveis categóricas. O teste t foi usado para comparações entre variáveis contínuas. Valor de p < 0,05 foi considerado estatisticamente significativo.

Análise multivariada com modelos de regressão logística stepwise backwards foi utilizada para identificar preditores independentes de mortalidade cardiovascular 30 dias após alta hospitalar. Inicialmente, foi realizado um modelo incluindo somente DM e o escore GRACE, para avaliar a contribuição do DM na taxa de eventos, corrigido por um escore robusto e que incluiu comorbidades e variáveis clínicas. Após, foi realizada uma segunda análise multivariada, incluindo-se DM, o escore GRACE26,27 e outras variáveis com significância estatística no presente estudo. As variáveis dependentes incluídas neste modelo foram escore GRACE, fluxo TIMI 3 pós-ICP, DM, delta T, glicemia e colesterol.

 Resultados

Durante o período do estudo, 740 pacientes foram submetidos à ICPp durante as primeiras 12 horas após IAMCSST. DM esteve presente em 134 pacientes (18%), e a Tabela 1 compara características de base dos pacientes com e sem DM. Os pacientes com DM eram mais velhos, mais frequentemente mulheres e tinham mais hipertensão, dislipidemia e angina prévia. Tabagismo foi menos comum em diabéticos, mas o uso crônico de aspirina foi mais frequente. Aproximadamente 40% dos infartos foram em parede anterior, não havendo diferença estatisticamente significativa entre os grupos com e sem DM. Os pacientes com DM apresentaram maior Índice de Massa Corporal (IMC) e circunferência abdominal.

Características clínicas dos pacientes (n =740) conforme presença de diabetes mellitus
Característica DM Não DM Valor de p
(n = 134) (n = 606)
Idade, anos 63 ± 11 60 ± 12 < 0,01
Sexo feminino, % 38 29 0,04
Raça branca, % 90 87 0,43
HAS, % 80 61 < 0,01
Dislipidemia, % 47 30 < 0,01
Tabagismo atual, % 28 45 < 0,01
História familiar, % 26 33 0,13
História médica pregressa
IAM, % 27 20 0,06
CRM, % 5 2 0,19
IRC, % 3 2 0,63
Angina, % 48 36 0,01
Uso diário de AAS, % 41 23 < 0,01
DCE, mL/min/1,73m2 86 ± 37 87 ± 31 0,81
Colesterol total, mg/dL 192 ± 52 204 ± 57 0,02
IMC, kg/m2 27,6 ± 4,3 26,8 ± 4,1 0,05
CA, cm 96 ± 14 93 ± 15 0,05
PAS, mmHg 136 ± 32 135 ± 29 0,86
Delta T, horas 5,2 ± 5,3 4,6 ± 4,3 0,12
TPB, horas 1,7 ± 1,3 1,56 ± 1,3 0,30
Glicemia de admissão, mg/dL 253 ± 124 143 ± 51 < 0,01

HAS: hipertensão arterial sistêmica; IAM: infarto agudo do miocárdio; CRM: cirurgia de revascularização do miocárdio; IRC: insuficiência renal crônica; AAS: ácido acetilsalicilico; DCE: depuração de creatinina endógena; IMC: Índice de massa corporal; CA: circunferência abdominal; PAS: pressão arterial sistólica; TPB: tempo porta-balão; DM: diabetes mellitus.

Em relação às características laboratoriais, os pacientes com DM apresentaram maior glicemia de admissão e menor nível de colesterol plasmático.

As comparações entre as características angiográficas dos pacientes com ou sem DM foram geralmente similares, mas os pacientes com DM apresentaram taxas mais baixas de escore Blush 3 após o procedimento (57% vs. 69%; p < 0,01). Os stents implantados foram, em sua maioria (99,3%), os convencionais.

Durante o acompanhamento hospitalar, os pacientes com DM apresentaram taxas de arritmia grave ou parada cardíaca (11,5% vs. 7,7%; p = 0,15) e trombose de stent (3,1% vs. 3%; p = 0,96) semelhantes as dos pacientes sem DM, mas a ocorrência de insuficiência renal aguda (8,5% vs. 2,5%; p < 0,01), a necessidade de ventilação mecânica (11,5% vs. 6,5%; p = 0,04) e o desenvolvimento de insuficiência cardíaca congestiva (13,7% vs. 6,5%; p = 0,01) foram maiores nos primeiros. A Figura 1 demonstra os seguimentos de 30 dias conforme a presença de DM. Houve maior incidência de ECVM (20,1 vs. 11,6; p < 0,01) e de óbito (16,4% vs. 7,3%; p < 0,01) nos pacientes com DM.

Desfechos em seguimentos de 30 dias (n = 740) conforme presença de diabetes mellitus (DM). ECVM: eventos cardiovasculares maiores; IAM: novo infarto agudo do miocárdio; Revasc: nova revascularização.

A análise multivariada para o desfecho de mortalidade em 30 dias foi realizada inicialmente somente com as variáveis DM e GRACE, sendo que ambas se mostraram preditoras do desfecho analisado: escore de risco de GRACE (Risco Relativo - RR: 1,048, Intervalo de Confiança de 95% - IC95%: 1,037 - 1,059; p < 0,01) e DM (RR: 1,926, IC95% 1,016 - 3,650; p = 0,04). O modelo completo, com a inclusão de outras variáveis e da glicemia de admissão, está demonstrado na Tabela 2, observando-se que, em um contexto que contemplou variáveis representativas do risco basal do paciente, resultado da ICPp e glicemia de admissão, o DM perdeu a significância estatística. Não obstante, a glicemia de admissão comprovou ser um importante preditor de mortalidade em 30 dias, pois, para cada aumento de 10 mg/dL de glicose, houve um aumento de 5% no RR de eventos (RR: 1,05, IC95%: 1,02 - 1,09; p < 0,01). Avaliamos o ponto de corte da glicemia para predição ótima do desfecho primário por curva ROC (sigla do inglês Receiver Operating Characteristic), identificando o valor de 159 mg/dL com sensibilidade de 63% e especificidade de 68%, com área sob a curva de 0,65 (IC95%: 0,61 - 0,69).

Análise de regressão logística múltipla para óbito em 30 dias
Preditor Risco relativo IC95% Valor de p
GRACE 1,04 1,03 - 1,06 < 0,01
TIMI 3 pós-ICP 0,30 0,12 - 0,71 < 0,01
DM 2,41 0,77 - 7,60 0,13
Delta T 1,08 1,02 - 1,15 < 0,01
Glicemia de admissão* 1,05 1,02 - 1,09 < 0,01
Colesterol total 0,99 0,98 - 1,00 0,05

Glicemia de admissão foi incluída no modelo com incrementos de 10 mg/dL.

ICP: intervenção coronária percutânea; DM: Diabetes mellitus.

 Discussão

O presente estudo confirma que o risco de eventos em pacientes diabéticos que apresentam IAMCSST e são submetidos à ICPp é aumentado, e que o DM é um preditor de eventos a curto prazo quando corrigido para diversas comorbidades representadas no escore de risco GRACE26,27. No entanto, quando outras variáveis foram acrescentadas no modelo, principalmente a glicemia de admissão, observou-se que o DM perdeu sua significância estatística no modelo multivariado para predizer mortalidade em 30 dias. Esses resultados demonstram a importância da hiperglicemia de admissão como fator de risco para eventos a curto prazo nesse contexto e sugerem que um percentual significativo do risco proporcionado pelo DM seja mediado pela hiperglicemia de admissão, que é mais comum e mais pronunciada do que nos pacientes sem DM.

A hiperglicemia nos pacientes com DM é causada por resistência à ação da insulina e por diminuição de produção nas células pancreáticas, ao passo que a hiperglicemia de estresse, que ocorre no IAM e em outras doenças agudas graves, é provocada por uma combinação complexa na secreção de hormônios como adrenalina, glucagon, hormônio do crescimento e citocinas. Além de representar um marcador da gravidade da situação clínica, a hiperglicemia de estresse também pode ocasionar dano miocárdico, devido a efeitos adversos, como aumento do estresse oxidativo, ativação plaquetária e disfunção endotelial, com aumento do tamanho do infarto21. Estudos prévios têm demonstrado que a hiperglicemia induz à resposta inflamatória no IAM28, e que sua resolução está associada com normalização desse efeito29. Dois estudos de coorte de pacientes com IAM (com e sem supradenivelamento de ST) demonstraram que a hiperglicemia da admissão foi preditor independente de mortalidade intra-hospitalar30,31, porém não atingiu significância estatística para mortalidade a longo prazo30; a hiperglicemia da admissão ainda demonstrou efeito variável no impacto de mortalidade quando os pacientes eram subdivididos por faixas etárias31. Ademais, análise do estudo CARDINAL demonstrou que o achado de redução da glicemia nas primeiras 24 horas após o infarto se associou com menor mortalidade em 30 dias em pacientes não diabéticos32.

Os pacientes portadores de DM apresentam dano estrutural microvascular e disfunção endotelial difusa, o que contribui para a diminuição da perfusão sanguínea, principalmente em um contexto de hipoperfusão aguda, como o IAMCSST33. No presente estudo, observamos que o percentual de pacientes que obtiveram Blush 3 após o procedimento foi menor no grupo com DM, corroborando esses achados e confirmando estudos prévios34. Mesmo com um escore 3 de TIMI após ICPp, pacientes com DM têm menor resolução completa do segmento ST após colocação do stent, o que também demonstra comprometimento no fluxo microvascular35. Esses achados contribuem para a pior evolução cardiovascular que os pacientes com DM apresentam após o IAMCSST.

Estudos recentes têm sugerido que o DM está associado principalmente a piores desfechos a longo prazo em pacientes com IAMCSST, enquanto que o aumento de risco cardiovascular seria mediado principalmente pela hiperglicemia. Ishihara e cols.18 e Hoebers e cols.19 demonstraram que a hiperglicemia, mas não o DM, está associada a eventos adversos a curto prazo em população com IAMCSST submetida à ICP. Ergelen e cols.20 analisaram a evolução clínica de pacientes com IAMCSST, conforme a combinação entre a presença de DM e a glicemia de admissão: DM com hiperglicemia de admissão, DM sem hiperglicemia de admissão, ausência de DM com hiperglicemia de admissão e ausência de DM sem hiperglicemia de admissão. Observou-se que os pacientes sem DM e com hiperglicemia de admissão apresentam maior risco de mortalidade intra-hospitalar, enquanto que os piores desfechos a longo prazo ficaram com pacientes diabéticos com hiperglicemia de admissão hospitalar. Esses resultados concordam com Kosiborod e cols.7, que, em grande estudo populacional de pacientes com IAM, mostraram que o risco de mortalidade em pacientes com elevada glicemia de admissão é maior em pacientes sem antecedente de DM, quando comparado com os pacientes diabéticos. Esse efeito não se restringe apenas ao contexto do IAMCSST, já que pacientes internados em unidades de terapia intensiva com doenças agudas graves e com hiperglicemia na admissão também apresentaram pior evolução clínica do que aqueles com glicemia menor36.

Nosso estudo reforça as observações descritas acima, já que demonstra que o papel prognóstico desfavorável da hiperglicemia para eventos a curto prazo é mais intenso e independente daquele do DM18. Uma característica importante do nosso estudo é que foram incluídos pacientes não selecionados, consecutivos, e representativos da prática clínica do mundo real. O percentual de paciente diabéticos foi de 18%, o que é semelhante aquele relatados em outros estudos (17 a 21%)2,34,37.

Limitações

A ausência de medidas de Hemoglobina Glicosilada (HbA1c) pode ser considerada uma limitação deste estudo. Aproximadamente 50% dos pacientes com IAMCSST apresentam alteração no metabolismo da glicose38, e o dado de HbA1c pode ser critério diagnóstico de DM39. Por outro lado, já foi demonstrado que a hiperglicemia de admissão tem um papel prognóstico mais relevante do que HBA1c elevada40, e a HbA1c tem maior significância na predição de eventos a longo prazo do que a curto prazo9,41. A definição utilizada para o diagnóstico de DM (referido pelo paciente) pode ter subestimado o número de pacientes com essa doença, mas é importante ressaltar que o percentual de pacientes com DM incluídos neste estudo foi semelhante ao de relatos anteriores, e a glicemia dos pacientes com DM foi significativamente maior do que aquela dos pacientes sem esse diagnóstico. A avaliação da função ventricular durante a internação ficou a critério da equipe médica assistente, sendo que o protocolo deste estudo não incluiu a coleta rotineira e prospectiva dessa informação. O alto percentual de dados faltantes em relação à essa variável (> 25%) não permitiu sua análise acurada, o que tem sido também uma limitação de outros estudos observacionais incluindo pacientes com IAM submetidos à ICPp.

 Conclusão

Esta análise contemporânea com pacientes consecutivos e representativos da prática clínica de um centro terciário em cardiologia intervencionista confirma o risco aumentado de pacientes com DM submetidos à angioplastia primária. Além disso, demonstra o importante papel prognóstico da hiperglicemia na admissão para predição de eventos cardiovasculares a curto prazo, que é independente de várias comorbidades, de outras características clínicas e inclusive do diagnóstico de DM, sendo mais intenso do que este.

Contribuição dos autores

Concepção e desenho da pesquisa: David RB, Sebben JC, Gottschall CAM, Quadros AS; Obtenção de dados: David RB, Sebben JC, Feijó IP, Schmidt KES, Avena LM; Análise e interpretação dos dados E Redação do manuscrito: David RB, Almeida ED, Cruz LV, Quadros AS; Análise estatística: David RB, Almeida ED, Quadros AS; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: David RB, Almeida ED, Cruz LV, Sebben JC, Feijó IP, Schmidt KES, Avena LM, Gottschall CAM, Quadros AS.

Potencial conflito de interesse

Declaro não haver conflito de interesses pertinentes.

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Vinculação acadêmica

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