The Munich Myocardial Infarction Registry: impact of C-reactive protein and kidney function on hospital mortality in diabetic patients

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1 Original article The Munich Myocardial Infarction Registry: impact of C-reactive protein and kidney function on hospital mortality in diabetic patients Diabetes & Vascular Disease Research 7(3) The Author(s) 2010 Reprints and permission: sagepub. co.uk/journalspermissions.nav DOI: / dvr.sagepub.com Oliver Schnell 1, Karl Friedrich Braun 1, Martin Müller 1, Eberhard Standl 1 and Wolfgang Otter 2 Abstract Introduction: The aim of this study was to analyse hospital mortality with regards to the presence of diabetes, elevation of C-reactive protein (CRP) levels and impaired kidney function (IKF) on admission. Methods: All patients in the Munich Myocardial Infarction Registry ( , n = 2,015) were assessed. In both the diabetic (n = 770, 38%) and non-diabetic (n = 1,245, 61.2%) groups, CRP and kidney function on admission were analysed with regards to hospital outcome. Results: In diabetic patients, both a CRP level >7 mg/l and a glomerular filtration rate (GFR) < 60 ml/min were independent risk factors for mortality (odds ratio [OR] 3.5, 95% confidence interval [CI] and OR 4.4, 95% CI , respectively). In non-diabetic patients with CRP levels equal or below the median and absence of IKF, hospital mortality was 0.7% whereas the presence of the triad of diabetes, CRP levels above the median and IKF increased hospital mortality to 23.5%. Conclusion: The registry demonstrates that the presence of the triad of diabetes, elevated CRP levels and reduced GFR on admission is associated with an excessive hospital mortality. Optimised early interventions are to be initiated to potentially overcome the unfavourable prognosis. Keywords coronary artery disease, C-reactive protein, creatinine, diabetes, heart, impaired kidney function, myocardial infarction, mortality, prognosis Introduction Diabetes mellitus is associated with a high risk 1-3 for atherosclerosis and coronary artery disease. 4 Mortality of diabetic patients after an acute myocardial event is substantially enhanced compared with patients without diabetes. 5 A twoto three-fold higher in-hospital mortality has been reported in diabetic patients. 6,7 In diabetic patients, a cardiac mortality of 20% over 7 years has been reported, which is comparable with that of non-diabetic patients after myocardial infarction. 8 Furthermore, cardiovascular mortality in diabetic patients with acute myocardial infarction (AMI) has been observed to be 45% over a time period of 7 years. 8 Low-grade chronic inflammation of the vascular structure and the endothelial cells is related with the occurrence of atherosclerosis C-reactive protein (CRP) is a marker for inflammation and is enhanced in atherosclerosis and coronary artery disease It has also been shown that CRP plasma levels above a cut-off of 3 mg/l, as assessed with high-sensitivity immunoassays, are an indicator for increased cardiovascular risk. 16 Diabetes is considered as a state of low-grade inflammation, evidence of which is also provided by an increase in CRP levels compared with non-diabetic subjects Impairment of kidney function is an independent risk factor for cardiovascular mortality. 20,21 In diabetes with a duration of 25 years, up to 60% of patients present with abnormalities of kidney function. 22 The UK Prospective Diabetes Study 1 Diabetes Research Institute, Munich, Neuherberg, Germany 2 Center of Internal Medicine, Unterschleissheim, Munich, Germany Corresponding author: Oliver Schnell, Munich Diabetes Research Institute, Helmholtz Center, Ingolstädter Landstrasse 1, Neuherberg, Germany. oliver.schnell@sciarc.de

2 226 Diabetes and Vascular Disease Research 7(3) (UKPDS) demonstrated that elevated creatinine levels are a 2, 23 risk factor for cardiovascular complications. The aim of the present study was to analyse hospital mortality in the Munich Myocardial Infarction Registry with regards to the presence of diabetes, elevation of CRP levels and creatinine levels on admission, and to compare the results between diabetic and non-diabetic patients. Methods The data of the Munich Myocardial Infarction Registry ( ) was analysed with regards to hospital mortality. All patients (n = 2,015) who were admitted to the hospital with the diagnosis of an AMI were included: 49 patients who presented with incomplete data or in whom a myocardial infarction was not confirmed were not enrolled; 770 patients (38.2%) were classified as diabetic patients and 1,245 patients (61.8%) were classified as non-diabetic patients. Diagnosis of diabetes in the registry was based on the following criteria: the presence of diabetes mellitus was defined if the patient had been informed of this diagnosis or was on prescribed antidiabetic treatment (diet, tablets, or insulin). Patients without the diagnosis but with a blood glucose of 11,1 mmol/l (hexokinase reaction) were also classified as having diabetes mellitus. 24 AMI was diagnosed in the presence of at least two of the following criteria: 25 persistent angina pectoris for 20 minutes, ST segment elevation in at least two continuous standard leads of 1 mm and of 2 mm in precordial leads respectively, and elevation of serum creatine kinase (CK) above the normal range of 70 U/L or an elevation of Troponin I or T. Patients were classified according to the recommendations of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC). 26 Patients with AMI were treated according to the guidelines of the ACC and the American Heart Association. 27 Early percutaneous transluminal coronary angioplasty (PTCA) was defined as performing PTCA within 6 hours of admission. Treatment of diabetes with insulin was performed as described previously. 24 Patients with a renal impairment were defined as patients with a creatinine level of 105,6 mmol/l on admission or with a previously known impairment of kidney function. Discharge from the intensive care unit was determined by the decline of serum CK to the near-normal range and was succeeded by admittance to the general ward of the Department of Cardiology. Estimated glomerular filtration rate (egfr) was assessed with the Cockroft Gault formula. 24 GFR was grouped according to the following cut-points: GFR 90 ml/min, GFR ml/min, GFR <60 ml/min. Plasma glucose, glycated haemoglobin (HbA1c, normal range < 6.2%), CK, electrolytes, blood count, lipids, CRP and creatinine were analysed on admission. CRP was analysed with high-sensitivity immunoassays. Hypertension was defined according to World Health Organization (WHO) criteria, which include multiple measurements of blood pressure of 140/90 mmhg. 28 History of hypertension or being treated with anti-hypertensive medications was also considered as prevalent hypertension. The history of peripheral artery disease was assessed in all patients. Resuscitation was defined as a cardiopulmonary resuscitation, which included cardiac massage, use of a heart defibrillator and/or artificial respiration. If not otherwise specified, results are reported as mean ± standard deviation (SD). Group comparisons were performed by Mann Whitney U-test for continuous variables and chi-squared test for categorical variables. Multivariate analysis was performed to identify the influence of clinical variables. Crude odds ratios (ORs) and confidence intervals (CIs) were calculated. They were adjusted for age, sex and clinical variables (adjusted ORs). The statistical analyses were performed with the SAS software program. Results Clinical characteristics on admission and laboratory values of the entire group of patients with AMI (n = 2,015) who were admitted between 1999 and 2004 are displayed in Table 1. In the entire group of patients with a myocardial infarction, the mean CRP levels were 30.4 ± 57.1 mg/l with a median CRP level of 7 mg/l. The mean creatinine levels were 105 ± 70 mmol/l; 432 patients (33%) presented with a creatinine level of >1.2 mg/dl. In the entire group of patients, 117 patients (6%) died within the first 24 hours after admission. Subsequent hospital mortality was 10% (n = 205). This resulted in a total hospital mortality of 16% (n = 322). A total of 770 patients presented with diabetes (38%) and 1,245 patients were classified as non-diabetic patients (62%). On admission, diabetic patients were older, morefrequently female and less-frequently smokers than nondiabetic patients (Table 1). The body mass index (BMI) and the heart rate were higher in diabetic patients compared with non-diabetic patients. Diabetic patients presented with higher HbA1c, blood glucose, creatinine levels, CRP values and lower GFR on admission as compared with the non-diabetic group (Table 1). CK and peak CK did not differ significantly different between the two groups. History of coronary artery disease and symptoms of myocardial infarction were different between diabetic and non-diabetic patients: 321 diabetic patients (n = 43%) presented with previously known coronary artery disease compared with 330 non-diabetic patients (27%; p ); 517 diabetic patients (68%) reported chest pain compared with 1,024 non-diabetic patients (83.3%, p ). Mortality rates were higher in diabetic patients than in non-diabetic patients. In diabetic patients, total hospital

3 Schnell et al. 227 Table 1. Diabetic and non-diabetic patients with acute myocardial infarction ( ): clinical characteristics and laboratory values (mean ± standard deviation; median). Entire group of patients (n = 2,015) Diabetic patients (n = 770) Non-diabetic patients (n = 1,245) p-value (diabetic versus nondiabetic patients) Age [years] 68 ± ± ± Female [n (%)] 691 (34%) 319 (41%) 372 (30%) Smoker [n (%)] 767 (42%) 219 (32%) 548 (47%) Body mass index [kg/m 2 ] 26.6 ± Heart rate [/min] 82 ± ± ± ± ± Hypertension [n (%)] 1227 (62%) 531 (71 %) 696 (57 %) Blood glucose [mmol/l] 9.3 ± ± ± HbA1c [%] 6.6 ± Total cholesterol [mmol/l] 4.9 ± HDL [mmol/l] 1.1 ± LDL [mmol/l] 3.3 ± Triglycerides [mmol/l] 1.6 ± Creatinine [mmol/l] 105 ± Est GFR [ml/min] 75.7 ± CRP [mg/l] 30 ± 57 7 CRP max [mg/l] 76 ± CK [U/I] 183 ± CK max [U/I] 597 ± ± ± ± ± ± ± ± ± ± ± ± 1, ± ± ± ± ± ± ± ± ± ± ± ns < 0.05 < 0.05 HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; egfr, estimated glomerular filtration rate; CRP, C-reactive protein; CK, creatine kinase; ns, not significant. ns ns mortality was increased more than two-fold compared with non-diabetic patients (24%, n = 182 versus 11%, n = 140; p ). Hospital mortality within 24 hours of admission was doubled in diabetic patients compared with nondiabetic patients (8%, n = 65 versus 4%, n = 117; p ). CRP levels on admission differed between diabetic patients who died in the hospital compared with those who survived: 53.3 ± 73 mg/l versus 32.7 ± 59.3 mg/l (p = 0.001). In diabetic patients, a CRP level of >7 mg/l was an independent risk factor for mortality (corrected for age, sex, BMI, smoking; OR 3.5, 95% CI ). Diabetic patients who died in the hospital presented with higher creatinine levels on admission compared with those who survived (167 ± 123 mmol/l versus 114 ± 53 mmol/l; p ). In diabetic patients, a GFR level <60 ml/min was an independent risk factor for mortality (corrected for age, sex, BMI, smoking; OR 4.4, 95% CI ). In non-diabetic patients, a CRP level of >7 mg/l did not present an independent risk factor for mortality (corrected for age, sex, BMI, smoking; OR 1.4, 95% CI ). In the

4 228 Diabetes and Vascular Disease Research 7(3) Table 2. Adjusted and unadjusted mortality rates of non-diabetic and diabetic patients with regards to different cut-off levels. Cut-off Non-diabetic patients Diabetic patients Unadjusted adjusted OR (95% CI) p-value OR (95% CI) p-value CRP >7 mg/l GFR <60 ml/min Age (Cat.) BMI 30 (kg/m2) ns ns Sex (men versus women) < ns Smoking < 0.05 Adjusted for age, BMI, sex, smoking OR (95% CI) p-value OR (95% CI) p-value CRP >7 mg/l ns GFR <60 ml/min OR, odds ratio; CI, confidence interval; GFR, glomerular filtration rate; CRP, C-reactive protein; ns, not significant no diabetes diabetes no IKF, CRP 7 mg/l no IKF, CRP > 7 mg/l IKF, CRP 7 mg/l IKF, CRP > 7 mg/l Figure 1. Impact of diabetes, elevated C-reactive protein and impaired kidney function on hospital mortality in patients with acute myocardial infarction. IKF, impaired kidney function (glomerular filtration rate <60 ml/min); CRP, C-reactive protein. group, creatinine levels were respectively 141 ± 88 mmol/l versus 97 ± 53 mmol/l (p ). In non-diabetic patients, a GFR level <60 ml/min was an independent risk factor for mortality (corrected for age, sex, BMI, smoking; OR 3.9, 95% CI ). Unadjusted and adjusted ORs of mortality rates of diabetic and non-diabetic subjects are presented in Table 2. In diabetic and non-diabetic patients, mortality rates with regards to GFR were as follows: GFR 90 ml/min 5.6% versus 1.6% (p = 0.01), GFR ml/min 7.5% versus 4.1% (ns), GFR <60 ml/min 19.7% versus 13.2% (p < 0.05). Figure 1 displays the risks for hospital mortality with regards to the presence of diabetes, CRP level >7 mg/l on admission and the presence of impaired kidney function

5 Schnell et al. 229 (IKF; defined as GFR <60 ml/min): in patients with CRP levels equal or below the median, absence of diabetes and IKF, hospital mortality was 0.7% whereas in patients with CRP levels above the median, presence of diabetes and IKF, hospital mortality increased significantly to 23.5% (p ). Discussion The study of the Munich Myocardial Infarction Registry ( ) demonstrates that the triad of diabetes, increase in CRP levels on admission and IKF on admission is associated with a significant deterioration of hospital outcome in patients with myocardial infarction. The presence of the triad was accompanied by a highly increased hospital mortality compared with the absence of the triad (0.7% versus 23.5%). More than one-third of the patients Munich Myocardial Infarction Registry presented with diabetes on admission. The two-fold increase in hospital mortality in diabetic patients with AMI compared with non-diabetic patients confirms previous results of the Monica Registries of both Finland and Germany. 5,29 The Munich Myocardial Infarction Registry, which investigates patients with troponin-positive myocardial infarction with and without ST elevation, emphasizes the importance of CRP levels on admission with regards to hospital outcome of diabetic and non-diabetic patients. 30 The previously defined cut-off of 7 mg/l for CRP on admission was confirmed for patients with AMI. 30 Our study demonstrates that the presence of diabetes in patients without elevated CRP or creatinine levels on admission increases the hospital mortality from 0.7% to 6.2%. The presence of an elevated CRP in non-diabetic patients increased hospital mortality to a comparable extent (6.0%). Compared with the non-diabetic group, elevated CRP levels did not translate into a higher mortality in diabetic patients (5.3%). The standard cut-off for CRP had been reported to be 5 mg/l. 15 The use of this cut-off level, however, does not incorporate the overall CRP elevation in AMI, which is to occur as a result of the acute event. 31,32 Higher cut-offs had been suggested in other studies, which, however, only included 147 and 250 patients. 33,34 IKF had a stronger impact on hospital mortality (nondiabetic patients 9.8%, diabetic patients 12.8%). Diabetic patients with both elevated CRP levels and IKF presented with the highest mortality (23.5%). The data supports the view that IKF is a key risk factor for cardiac complications. 2 Previously it has been reported that an increase in creatinine levels of 8.8 mmol/l is associated with an increase in risk for mortality of 36% and an increase in risk for atherosclerosis to 47%. 35 The UKPDS also confirmed that creatinine is an independent risk factor for cardiovascular events in diabetes. 23 The Munich Myocardial Infarction Registry demonstrates that the assessment of the triad of diabetes, elevated CRP and IKF on admission enables the identification of patients with an excessive risk of hospital mortality. Nearly one-quarter of the patients, who presented with the triad died in the hospital. There is evidence that each of the three factors contributes to the adverse outcome in the patients, whereas the presence of IKF predominantly affects the hospital outcome. In patients with AMI, who present with the triad of diabetes, signs of inflammation and IKF, and intensified treatment approaches are required to overcome their unfavourable prognosis. References 1. Al Suwaidi J, Reddan DN, Williams K, et al. (2002) Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes. Circulation 106(8): Anavekar NS, McMurray JJ, Velazquez EJ, et al. (2004) Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 351(13): Wright RS, Reeder GS, Herzog CA, et al. (2002) Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann Intern Med 137(7): Standl E and Schnell O (2000) A new look at the heart in diabetes mellitus: from ailing to failing. Diabetologia 43(12): Lowel H, Koenig W, Engel S, Hormann A and Keil U (2000) The impact of diabetes mellitus on survival after myocardial infarction: can it be modified by drug treatment? 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6 230 Diabetes and Vascular Disease Research 7(3) of cardiovascular disease in apparently healthy men. N Engl J Med 336(14): Ross R (1999) Atherosclerosis an inflammatory disease. N Engl J Med 340(2): Blake GJ and Ridker PM (2003) C-reactive protein and other inflammatory risk markers in acute coronary syndromes. J Am Coll Cardiol 41(4 Suppl S): Pai JK, Pischon T, Ma J, et al. (2004) Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 351(25): Rowe IF, Walker LN, Bowyer DE, Soutar AK, Smith LC and Pepys MB (1985) Immunohistochemical studies of C-reactive protein and apolipoprotein B in inflammatory and arterial lesions. J Pathol 145(3): Blake GJ and Ridker PM (2002) Inflammatory bio-markers and cardiovascular risk prediction. 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