Influence of leukocytes and glycemia on the prognosis of patients with acute myocardial infarction

Pesaro, Antonio Eduardo P.; Nicolau, Jose Carlos; Serrano Jr., Carlos V.; Truffa, Rodrigo; Gaz, Marcus Vinicius B.; Karbstein, Ralf; Giraldez, Roberto R.; Kalil Filho, Roberto; Ramires, José A.

doi:10.1590/S0066-782X2009000200003

Abstracts

BACKGROUND: Previous studies have demonstrated that leukocytosis and hyperglycemia verified at the admission of patients with acute myocardial infarction (AMI) are associated with intrahospital mortality. However, little is known on the long-term impact of these markers. OBJECTIVE: To evaluate the short-and long-term influence of the levels of glucose and leukocytes on the prognosis of patients with AMI. METHODS: A total of 809 patients with AMI were retrospectively assessed (mean age: 63.2 ± 12.87 yrs) and prospectively and consecutively included in a specific database. RESULTS: a) At the intrahospital phase, the mean values were compared between patients that died and those who survived: Leukocytosis: 12156±5977 vs 10337±3528 (p=0.004, 95%CI = 976-2663); Glucose 176±105 mg/dl vs 140±72 mg/dl (p<0.001, 95%CI = 19.4 - 52.6), respectively. b) With the adjusted mode, the same pattern was observed [p values: 0.002 (t-ratio 3.05), 0.04 (t-ratio 2.06), respectively]. c) Long-term follow-up: the univariate analysis showed P values of 0.001 (t-ratio 3.3), <0.001 (t-ratio 4.16), respectively. The multivariate analysis showed P=0.001 (t-ratio 3.35), 0.08 (t-ratio 1.75), respectively. (d) After the exclusion of the intrahospital deaths, the leukocyte (P=0.989) and glucose levels (P=0.144) did not remain significantly correlated with mortality. The same result was observed at the multivariate analysis. CONCLUSION: The levels of glucose and leukocytes at the hospital admission of patients with AMI are excellent predictors of intrahospital mortality and poor predictors of long-term death.

Leukocytosis; glucose; myocardial infarction

FUNDAMENTO: Estudos prévios demonstraram que a leucocitose e a hiperglicemia verificadas à admissão de pacientes com IAM (infarto agudo do miocárdio), estão correlacionadas com a mortalidade intra-hospitalar. Entretanto, pouco é sabido sobre o impacto desses marcadores a longo prazo. OBJETIVO: Avaliar a curto e longo prazos, a influência dos níveis de glicose e leucócitos no prognóstico de pacientes com IAM. MÉTODOS: Foram analisados, retrospectivamente, 809 pacientes (idade média 63,2 ± 12,87 anos) com IAM, incluídos de forma prospectiva e consecutiva em banco de dados específico. RESULTADOS: a) Na fase intra-hospitalar os valores médios aferidos foram comparados entre pacientes que morreram ou sobreviveram: Leucocitose 12156±5977 vs 10337±3528 (p=0.004, 95% IC= 976-2663); Glicose 176±105 mg/dl vs 140±72 mg/dl (p<0.001, 95% IC= 19.4 - 52.6), respectivamente. b) No modo ajustado, o mesmo padrão foi verificado [valores de p: 0.002 (t-ratio 3.05), 0.04 (t-ratio 2.06), respectivamente]. c) Seguimento a longo prazo: a análise univariada revelou valores de P de 0.001 (t-ratio 3.3), <0.001 (t-ratio 4.16), respectivamente. Pela análise multivariada; P=0.001 (t-ratio 3,35), 0.08 (t-ratio 1,75), respectivamente. d) Após exclusão das mortes intra-hospitalares, os níveis leucocitários (P=0.989) e a glicemia (P=0.144) não permaneceram correlacionadas significativamente com mortalidade. O mesmo resultado foi verificado na análise multivariada. CONCLUSÃO: Níveis de leucócitos e glicemia à admissão de pacientes com IAM são excelentes preditores de mortalidade intra-hospitalar, e pobres preditores de óbitos a longo prazo.

Leucocitose; glucose; infarto do miocárdio

FUNDAMENTO: Estudios previos demostraron que tanto la leucocitosis como la hiperglucemia verificadas cuando de la admisión de pacientes con infarto agudo de miocardio (IAM), están correlacionadas con la mortalidad intrahospitalaria. Sin embargo, poco se sabe acerca del impacto de esos marcadores a largo plazo. OBJETIVO: Evaluar, a corto y largo plazos, la influencia de los niveles de glucosa y leucocitos en el pronóstico de pacientes con IAM. MÉTODOS: Se analizaron, retrospectivamente, a 809 pacientes (edad promedio 63,2 ± 12,87 años) con IAM, incluidos de forma prospectiva y consecutiva en banco de datos específico. RESULTADOS: a) En la fase intrahospitalaria se compararon los valores promedio obtenidos entre pacientes que murieron o supervivieron: leucocitosis 12.156±5.977 vs 10.337±3.528 (p=0.004, 95% IC= 976-2663); glucosa 176±105 mg/dl vs 140±72 mg/dl (p<0.001, 95% IC= 19.4 - 52.6), respectivamente. b) En el modo ajustado, se verificó el mismo estándar [valores de p: 0.002 (t-ratio 3.05), 0.04 (t-ratio 2.06), respectivamente]. c) Seguimiento a largo plazo: el análisis univariado reveló valores de P de 0.001 (t-ratio 3.3), <0.001 (t-ratio 4.16), respectivamente. Ya el análisis multivariado: P=0.001 (t-ratio 3,35), 0.08 (t-ratio 1,75), respectivamente. d) Tras la exclusión de las muertes intrahospitalarias, los niveles leucocitarios (P=0.989) y la glucemia (P=0.144) no permanecieron correlacionadas significativamente con la mortalidad. Igual resultado se verificó en el análisis multivariado. CONCLUSIÓN: Los niveles de leucocitos y glucemia al ingreso de pacientes con IAM resultan excelentes predictores de mortalidad intrahospitalaria, y pobres predictores de óbitos a largo plazo.

Leucocitosis; glucosa; infarto de miocardio

ORIGINAL ARTICLE

Instituto do Coração, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP - Brazil

Mailing address

SUMMARY

BACKGROUND: Previous studies have demonstrated that leukocytosis and hyperglycemia verified at the admission of patients with acute myocardial infarction (AMI) are associated with intrahospital mortality. However, little is known on the long-term impact of these markers.

OBJECTIVE: To evaluate the short-and long-term influence of the levels of glucose and leukocytes on the prognosis of patients with AMI.

METHODS: A total of 809 patients with AMI were retrospectively assessed (mean age: 63.2 ± 12.87 yrs) and prospectively and consecutively included in a specific database.

RESULTS: a) At the intrahospital phase, the mean values were compared between patients that died and those who survived: Leukocytosis: 12156±5977 vs 10337±3528 (p=0.004, 95%CI = 976-2663); Glucose 176±105 mg/dl vs 140±72 mg/dl (p<0.001, 95%CI = 19.4 52.6), respectively. b) With the adjusted mode, the same pattern was observed [p values: 0.002 (t-ratio 3.05), 0.04 (t-ratio 2.06), respectively]. c) Long-term follow-up: the univariate analysis showed P values of 0.001 (t-ratio 3.3), <0.001 (t-ratio 4.16), respectively. The multivariate analysis showed P=0.001 (t-ratio 3.35), 0.08 (t-ratio 1.75), respectively. (d) After the exclusion of the intrahospital deaths, the leukocyte (P=0.989) and glucose levels (P=0.144) did not remain significantly correlated with mortality. The same result was observed at the multivariate analysis.

CONCLUSION: The levels of glucose and leukocytes at the hospital admission of patients with AMI are excellent predictors of intrahospital mortality and poor predictors of long-term death.

Key words: Leukocytosis; glucose; myocardial infarction.

Introduction

Patients with unstable myocardial ischemic syndromes (UMIS) must be routinely submitted to risk stratification when admitted at the hospital. The objective of this early stratification is to determine the risk and prognosis of these patients, which allows establishing a more adequate therapeutic management and clinical follow-up of the patients. In this sense, the classification by Braunwaldª and the risk scores published by the TIMI group (Thrombolysis In Myocardial Infarction)^b,c, for UMIS without ST-elevation as well as for acute myocardial infarction (AMI) with ST-elevation, have been largely used for early stratification. However, other risk markers have been investigated in an attempt to make the short- and long-term prognostic assessments more accurate. Previous studies demonstrated that leukocytosis and hyperglycemia verified at the hospital admission of patients with AMI are correlated with intrahospital mortality^d-7. However, little is known about the long-term impact of these markers.

Thus, the main purpose of this study was to evaluate the short- and long-term influence of the levels of glucose and leukocytes on the prognosis of patients with AMI and compare the impact of these "new" markers with that of the "traditional" ones, such as left ventricular (LV) ejection fraction (EF) and age.

Methods

This is a unicentric study, in which all patients were selected from an Intensive Care Coronary Unit. A total of 809 patients with AMI were retrospectively assessed (mean age: 63.2 ± 12.87 yrs) and prospectively and consecutively included in a specific database, between February 1998 and July 2005. The criteria used for the AMI diagnosis were: troponin curve or fraction of creatine kinase (CK-MB) associated to at least of the following: ischemic symptoms, development of pathological Q waves at the electrocardiogram (ECG), electrocardiographic alterations indicative of ischemia (ST elevation or depression) or post-coronary intervention.

The patients were followed for up to 6.4 years (mean survival time of 5.15 years), with annual prospective assessments in relation to mortality. The follow-up of the study population was carried out annually by phone or personal interview. The patients (or their family members) were contacted by phone, visits to the office or active personal search (personal search at the workplace, residence, neighbors' houses, etc).

The values of the first leukocyte and glycemia measurements were analyzed in relation to the intrahospital and long-term prognosis. The blood collection for glycemia and leukocytosis measurement was carried out at the moment of the hospital admission.

In the adjusted models, the following variables were considered: history of angioplasty, myocardial revascularization surgery, myocardial infarction, diabetes, smoking, history of heart failure (HF), age, sex, heart rate (HR), systolic arterial pressure (SAP), ST-segment elevation, glycemia, leukocytes, EF (first echocardiogram; Simpson's method), presence of fibrinolysis and primary angioplasty.

For the intrahospital phase, the Student's t test or Kruskal-Wallis test (univariate analysis) and logistic regression (multivariate analysis) were used. For the long-term analysis, Cox proportional hazards estimation was used. The stepwise method⁸ (with an entry of 0.10 and removal of 0.10), was used for the logistic regression analysis.

Results

A. Study population

The data regarding the studied population are shown in Table 1.

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B. Intra-hospital phase

At the intrahospital phase, 92 patients (11.37%) died. The mean time until death was 94 hours (95%CI; 60.90-127.0). The mean values measured for the variables were compared between patients that died and those who survived: Leukocytosis 12156±5977 vs 10337±3528 (p=0.004, 95% CI = 976-2663); Glucose 176±105 mg/dl vs 140±72 mg/dl (p<0.001, 95% CI = 19.40-52.60), respectively. As it can be observed, the two analyzed variables significantly correlated with the worst prognosis.

Table 2 demonstrates the results of the multivariate model. After the logistic regression analysis of 16 variables, through the stepwise model (with an entry of 0.10 and removal of 0.10), it was observed that only 5 variables significantly and independently correlated with the intrahospital mortality: glycemia, leukocytes, age, EF and SAP.

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C. Late follow-up

C.1. General population

During the extra-hospital phase, there were 94 additional deaths. The probability of global survival was 77% (Kaplan-Mayer). Regarding the long-term follow-up, considering the totality of patients, significant correlations were observed between glycemia/leukocytes and mortality, as shown in Table 3. Table 4 shows that, in the multivariate model, six analyzed variables remained as prognostic factors for the long-term evolution in the global population. However, glycemia showed only a tendency to correlate with mortality.

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C.2. Patients that survived the intrahospital phase

As shown in Table 5, when the intrahospital deaths were excluded, leukocytes and glycemia levels no longer correlated with the long-term evolution. In other words, the prognostic value of leukocytes and glycemia levels is restricted to the intrahospital phase, presenting no impact after hospital discharge. This behavior does not present alterations in the adjusted models, as shown in Table 6, where only the history of HF, age and EF correlate with mortality.

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Discussion

In the last three decades, the treatment of AMI showed significant advancement, which resulted in the decrease of the morbimortality related to the disease⁹. That occurred mainly due to new pharmacological and mechanical primary reperfusion strategies, multiple anti-aggregation, in addition to the broad use of invasive stratification and the possibility of revascularization with angioplasty and stents¹⁰.

However, patients with UMIS have different characteristics, which determine their risk and prognosis variability. Some of these patients benefit from aggressive therapeutic measures, such as percutaneous invasive approach and strict glycemia control^11,12.

In this sense, to identify patients at higher risk has been a constant concern in literature. In addition to the studies to validate risk scores and the variables that are traditionally associated with a poor prognosis, such as age and left ventricular dysfunction, investigators have recently worked on the identification of new prognostic variables, such as inflammatory markers, natriuretic peptide, leukocytosis and hyperglycemia, among others^12-15.

Diabetic patients are recognized as being high-risk patients and having worse short- and long-term prognosis after AMI. The MONICA report showed that the mortality for diabetic and non-diabetic infarcted patients, after 28 days of evolution, was 12.6% and 7.3%, respectively¹⁶. Therefore, the inclusion of diabetes mellitus in the early risk stratification is justified.

However, the presence of hyperglycemia was also identified as a poor prognosis factor in non-diabetic infarcted patients^17-19. It was recently demonstrated that hyperglycemia is still a poor prognosis factor also in patients submitted to percutaneous coronary intervention, regardless of the presence of diabetes²⁰. It was also verified in this and in other studies^21,22 that there is an association between hyperglycemia, no-reflow phenomena and ventricular remodeling, which are known factors of severity and worse prognosis in the evolution of patients with AMI²³.

Similarly, another study demonstrated that hyperglycemia, but not diabetes, was a poor intrahospital prognostic factor²⁴. Regarding the long-term follow-up, previous studies demonstrated that hyperglycemia, regardless of the presence of diabetes, was also a risk factor for mortality in patients with AMI^25-27.

The data obtained in our study were similar to those found by other authors regarding the influence of glycemia on mortality. Glycemia levels at the hospital admission were significantly higher in patients that died during the hospital stay. During the follow-up of more than 6 years, hyperglycemia remained as a bad prognosis factor, although the adjusted model showed only a tendency to worse mortality. However, after the exclusion of the intrahospital deaths, the variables age, ejection fraction (EF) and history of HF remained significantly correlated with mortality, but not the levels of leukocytes or glycemia. This fact might be related to the hypotheses that hyperglycemia is not only a prognostic marker, but a direct cardiovascular system aggressor in the acute phase of AMI.

Experimental studies demonstrated that hyperglycemia is capable of causing platelet thrombosis, increasing the circulation of leukocyte adhesion molecules and decreasing the endothelium-dependent vasodilation, nitric oxide availability and the collateral coronary circulation^28-31. The decrease in nitric oxide and prostacyclin levels, or even the increase in vasoconstrictors such as endothelin, are enhanced by hyperglycemia through protein kinase C activation, hexosamine increase and the activation of the pro-inflammatory nuclear factor Kappa B, with the consequent formation of superoxide radicals³². A study that induced diabetes in swine demonstrated an increase in IL-6, tumor necrosis factor (TNF), macrophage chemotactic proteins and adhesion molecules in fibroblasts of the coronary adventitia³³.

Regarding the leukocytosis, some studies explored its prognostic value in AMI³⁴. One of the most relevant ones included leukocytosis as part of a risk score for infarcted patients³⁴. In this study, men with leukocyte levels > 9,000/microL presented a relative risk of death of 1.66 (1.35-2.05) during the 4-year follow-up. Recently, the leukocytosis in patients with AMI was directly associated with the infarction area size, presence of shock and death in six months³⁴. In another study, patients with leukocyte levels > 10,000 microL during AMI presented a higher incidence of TIMI 0/1 flow, adverse cardiovascular events, both intrahospital and throughout five years, in comparison with patients with leukocyte levels below this range³⁵. The increase in neutrophil levels was also associated not only to the late treatment and the presence of occluded artery, but also to the decreased reperfusion in patients with AMI³⁶. When compared to other inflammatory markers, the increase in leukocyte levels was a predictor of adverse events similar to C-reactive protein and a better predictor than the serum amyloid A, fibrinogen and interleukin-6, throughout five years after the AMI³⁷.

In our study, leukocytosis was associated to a worse intrahospital prognosis, even in adjusted models. However, as it occurred with hyperglycemia, during the long-term follow-up, when the intrahospital deaths are excluded, leukocytosis was no longer a long-term poor prognostic marker. The higher impact of this marker during the acute phase of AMI can be justified by the association of leukocytosis with increased acute inflammatory states, presence of more significant ischemia and difficulty in reperfusion, as mentioned before^36,37.

Finally, it is worth mentioning that, despite the evidence that the adequate control of glycemia in the acute phase of AMI is beneficial^11,38, the careful control of hyperglycemia is neglected in many institutions. On the other hand, attempts to control the inflammatory process have been reported with conflicting results in the literature³⁹. Although a small study had initially pointed out a possible benefit with the use of anti-inflammatory agents in UMIS⁴⁰, the excess of cardiovascular events associated to the use of non-hormonal anti-inflammatory agents in several randomized studies discouraged the use of this treatment⁴¹. The control of inflammation was also investigated considering the use of statins in UMIS. In the last years, the pleiotropic effects of these drugs have been extensively investigated, especially the anti-inflammatory action. In this sense, a recent study demonstrated the efficiency of the decrease in C-reactive protein and LDL-cholesterol in patients with UMIS, without using high doses of atorvastatin. Moreover, there was an additional cardiovascular benefit in the group of patients with higher inflammatory reduction^42-44.

In conclusion, leukocyte and glycemia levels at the hospital admission of patients with AMI are excellent predictors of intrahospital mortality and poor predictors of long-term death. A previous history of HF was an independent predictor of mortality only at long-term. On the other hand, age and EF are short- and long-term independent predictors of mortality.

Potential Conflict of Interest

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

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any post-graduation program.

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