Application of the Sequential Organ Failure Assessment score for predicting mortality in patients with acute myocardial infarction

Resuscitation 83 (2012) 591–595

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Clinical paper

Application of the Sequential Organ Failure Assessment score for predicting mortality in patients with acute myocardial infarction夽 Shao-Sung Huang a,e , Ying-Hwa Chen a,e , Tse-Min Lu a,e , Lung-Ching Chen b,∗ , Jaw-Wen Chen c,d , Shing-Jong Lin c,e a

Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan c Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan d Institute and Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan e Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan b

a r t i c l e

i n f o

Article history: Received 28 September 2011 Received in revised form 29 November 2011 Accepted 9 December 2011

Keywords: SOFA score Myocardial infarction Prognosis

a b s t r a c t Background: Thrombolysis in Myocardial Infarction (TIMI) score and Global Registry of Acute Coronary Events (GRACE) score have been validated as predictors of death in patients with acute myocardial infarction (AMI). This study was undertaken to determine whether the Sequential Organ Failure Assessment (SOFA) score had good accuracy for predicting mortality in AMI patients, and to compare the discriminatory performance of the 3 risk scores (RSs). Methods: This was a retrospective study. We calculated the TIMI RS, GRACE RS, and SOFA score for 726 consecutive AMI patients. The study endpoint was all-cause mortality. All patients were followed up for at least 3 years or until the occurrence of death. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive ability of each score at different time points. Results: For in-hospital death, the AUC were 0.67 for TIMI RS, 0.73 for GRACE RS, and 0.79 for SOFA score (P < 0.001, respectively). However, the SOFA score and GRACE RS were significantly better for predicting the 1-year (P < 0.001, respectively) and 3-year (P < 0.001, respectively) mortality than the TIMI RS was. Multivariate Cox regression analysis revealed that the SOFA score was an independent predictor of longterm mortality in AMI patients [hazard ratio (HR), 1.313; 95% CI, 1.191–1.447]. Conclusions: The SOFA score provides potentially valuable prognostic information on clinical outcome when applied to patients with AMI. Compared with TIMI RS, both SOFA score and GRACE RS provide better discrimination for long-term mortality in patients presenting with AMI. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Despite advances in treatment of acute coronary syndrome (ACS), it continues to be associated with significant mortality and morbidity.1 Therefore, identification of high-risk patients, and selection of those who would benefit the most from more aggressive treatments forms an integral approach for optimizing ACS management and outcomes. Furthermore, stratification of ACS risk, which is recommended by practice guidelines, with tools such as risk scores (RSs), is perceived to be beneficial.1,2

夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.12.014. ∗ Corresponding author at: Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, No. 95, Wen-Chang Road, Taipei, Taiwan. Tel.: +866 2 28332211; fax: +886 2 28369133. E-mail address: [email protected] (L.-C. Chen). 0300-9572/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2011.12.014

Various scores based on initial clinical history, electrocardiogram (ECG) findings, and laboratory tests are now available that enable early risk stratification on admission. The Thrombolysis in Myocardial Infarction (TIMI)3 score was developed using databases of large clinical trials of non-ST elevation acute coronary syndromes (NSTE-ACS). The more recent Global Registry of Acute Coronary Events (GRACE)4 score was developed from a registry with a population of patients across the entire spectrum of ACS. Compared with TIMI RS, GRACE RS allows better discrimination for in-hospital and 1-year mortality in patients presenting with ACS.5 The Sequential Organ Failure Assessment (SOFA)6 score is a simple and objective score that allows for the calculation of both the number and the severity of organ dysfunction in 6 organ systems (the respiratory, coagulatory, hepatic, cardiovascular, renal, and neurologic systems), which can measure individual or aggregate organ dysfunction (Table 1). The SOFA score provides the clinician with important information on the degree and progression

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Table 1 The Sequential Organ Failure Assessment (SOFA) score. SOFA score Respiration PaO2 /FiO2 (mmHg) Coagulation Platelets × 103 /mm3 Liver Bilirubin (mg/dl) Cardiovasculara Hypotension CNS Glasgow coma scale Renal Creatinine (mg/dL) or urine output (mL/d)

0

1

2

3

4

>400

<400

<300

<200

<100

>150

<150

<100

<50

<20

<1.2

1.2–1.9

2.0–5.9

6.0–11.9

>12.0

No hypotension

MAP < 70

Dopamine ≤ 5 or Dobutamine (any)

Dopamine > 5 or Norepinephrine ≤ 0.1

Dopamine > 15 or Norepinephrine > 0.1

15

13–14

10–12

6–9

<6

<1.2

1.2–1.9

2.0–3.4

3.5–4.9 or <500

>5.0 or <200

MAP, mean arterial pressure; CNS, central nervous system. a Vasoactive medications administered for at least 1 h (dopamine and norepinephrine ␮g/kg/min).

of organ dysfunction in cardiovascular patients.7,8 The suitability of the SOFA score for predicting in-hospital and long-term mortality in patients with acute myocardial infarction (AMI) is uncertain. The aims of this study were to determine whether the SOFA score, when applied to a cohort of patients with AMI, would show good accuracy for predicting clinical outcome, and to compare the inhospital and long-term prognostic accuracy of the TIMI RS, GRACE RS, and SOFA score.

2.3. Clinical follow-up for endpoint All patients included in the study were followed up for at least 3 years or until the occurrence of death. The study endpoint was all-cause mortality at the time of discharge, 1 year, and 3 years. All patients were contacted by telephone periodically and their medical records were followed up regularly. 2.4. Statistical analysis

2. Methods 2.1. Study population This was a retrospective study of consecutive patients with AMI admitted to a coronary care unit (CCU) between May 2002 and December 2005. AMI was classified into 2 types: ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI). STEMI was defined as having ST-segment elevation ≥1 mm in 2 contiguous ECG leads (or ≥2 mm in V1 –V3 leads) or a new left bundle branch block together with chest pain for >30 min and/or evidence of myonecrosis with elevated troponin I level ≥ 0.1 ng/mL. NSTEMI was diagnosed in patients with typical chest pain and troponin I elevation above ≥0.1 ng/mL and no ST-segment elevation detected in the ECG. Before enrollment, a detailed review of each patient’s chart was conducted to gather data on symptoms, medications, coronary risk factors, cardiac events that had occurred earlier, smoking status, and other systemic diseases. Hypertension was defined as a systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or use of antihypertensive treatment. Diabetes mellitus was defined according to World Health Organization criteria.9 Smokers were classified as former only if they had not smoked for more than 6 months. To reduce patient selection bias, there was no age limit or other specific exclusion criteria. The study was approved by the local research ethics committee.

2.2. Risk score calculation The TIMI and GRACE RSs were calculated on the basis of the initial clinical history, ECG, and laboratory values collected on admission. The SOFA score was calculated at the time of hospitalization according to the modalities described by Vincent et al.6 Although the present study was retrospective, all data were collected prospectively and entered into a computer database.

Data were expressed in terms of mean and standard deviation (SD) for numeric variables and as the number (percent) for categorical variables. Comparisons of continuous variables between groups were performed by Student’s t-test. Subgroup comparisons of categorical variables were assessed by a chi-square or Fisher’s exact test. For each of the 3 RSs, receiver operating characteristic (ROC) curves were used to relate the calculated scores to the rate of adverse clinical events at discharge, 1 year, and 3 years. The area under the ROC curve (AUC), or C-statistic, was used as a measure of the predictive accuracy of the RS. The relative performance of each test was evaluated with a 95% confidence interval (CI) for the difference between 2 AUCs. Multivariable Cox regression analysis was performed to determine the independent predictors of all-cause mortality. Variables significantly associated with survival were adjusted for in the multivariable model. Data were analyzed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA) and MedCalc version 4.2 (MedCalc Software, Mariakerke, Belgium). A P-value < 0.05 was considered to indicate statistical significance. 3. Results 3.1. Patient characteristics A total of 726 consecutive patients (598 males, 82%) were enrolled in this study. Among them, 404 (56%) had STEMI and 322 (44%) had NSTEMI. All patients were followed up until May 2010. The baseline characteristics of all patients are shown in Table 2. The mean age of our cohort was 67 (SD 12) years. The TIMI RS, GRACE RS, and SOFA score were significantly higher in non-survivors compared with that in survivors (P < 0.001, respectively). 3.2. Prognostic accuracy of the risk scores The all-cause mortality was 6.9% during index admission, 17.1% at 1 year, and 27.1% at 3 years. Table 3 lists the AUC for the 3 RSs in predicting in-hospital, 1 year, and 3 years death, respectively. TIMI RS, GRACE RS, and SOFA score were able to discriminate patients of

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Table 2 Baseline characteristics in survivors and non-survivors.

Age (years) Male Current smoker Hypertension Diabetes mellitus Hypercholesterolemia Previous MI Previous stroke/TIA Prior PCI/CABG SBP (mmHg) DBP (mmHg) Lipid profiles (mg/dl) Triglycerides Total cholesterol High-density lipoprotein Low-density lipoprotein Fasting glucose (mg/dl) Creatinine (mg/dl) Killip classification Killip = 1 Killip > 1 Previous medication Antiplatelet ␤-Blocker ACE inhibitor/ARB Statin In-hospital revascularization TIMI score GRACE score SOFA score

Total (n = 726)

Survivors (n = 477)

Non-survivors (n = 249)

P

67 (12) 598 (82%) 317 (44%) 466 (64%) 262 (36%) 129 (18%) 81 (11%) 86 (12%) 98 (14%) 131 (31) 74 (18)

64 (13) 396 (83%) 229 (48%) 281 (59%) 150 (31%) 88 (18%) 43 (9%) 32 (7%) 53 (11%) 131 (30) 74 (18)

73 (9) 202 (81%) 88 (36%) 185 (74%) 112 (45%) 41 (17%) 38 (15%) 54 (22%) 45 (18%) 130 (34) 73 (18)

<0.001 0.525 0.001 <0.001 <0.001 0.507 0.011 <0.001 0.009 0.714 0.362

137.4 (101.7) 180.7 (45.6) 40.1 (11.6) 115.7 (36.8) 146.2 (86.6) 1.76 (1.77)

147.4 (111.7) 185.3 (45.5) 40.2 (10.7) 118.6 (35.6) 139.7 (76.1) 1.47 (1.39)

117.7 (74.8) 171.6 (44.3) 39.7 (13.1) 109.8 (38.6) 158.4 (102.5) 2.34 (2.23)

<0.001 <0.001 0.607 0.005 0.013 <0.001 <0.001

409 (56%) 317 (44%)

315 (66%) 162 (34%)

94 (38%) 155 (62%)

128 (18%) 201 (28%) 256 (35%) 103 (14%) 465 (64%) 4.4 (2.3) 167.4 (46.7) 2.5 (2.3)

76 (16%) 124 (26%) 154 (32%) 63 (13%) 352 (74%) 4.1 (2.3) 155.7 (44.7) 1.8 (1.8)

52 (21%) 77 (31%) 102 (41%) 40 (16%) 113 (45%) 5.1 (2.3) 191.1 (41.5) 3.8 (2.5)

0.097 0.159 0.020 0.295 <0.001 <0.001 <0.001 <0.001

Values are mean (SD) or number (%). MI, myocardial infarction; TIA, transient ischemic attack; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; SBP, systolic blood pressure; DBP, diastolic blood pressure; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker.

Table 3 AUCs of the risk scores at different time points in AMI patients.

Overall In-hospital death 1-year death 3-year death STEMI In-hospital death 1-year death 3-year death NSTEMI In-hospital dearth 1-year death 3-year death

TIMI (95% CI)

GRACE (95% CI)

SOFA (95% CI)

0.665 (0.585–0.745) 0.623 (0.569–0.676) 0.614 (0.569–0.659)

0.730 (0.659–0.800) 0.748 (0.702–0.794) 0.742 (0.701–0.782)

0.791 (0.712–0.869) 0.744 (0.692–0.796) 0.768 (0.726–0.810)

0.739 (0.625–0.852) 0.715 (0.635–0.796) 0.696 (0.627–0.765)

0.767 (0.663–0.871) 0.752 (0.679–0.825) 0.725 (0.660–0.790)

0.812 (0.700–0.923) 0.756 (0.674–0.837) 0.738(0.665–0.811)

0.669 (0.555–0.782) 0.639 (0.566–0.712) 0.662 (0.601–0.722)

0.697 (0.602–0.792) 0.746 (0.686–0.805) 0.762 (0.710–0.815)

0.765 (0.651–0.880) 0.723 (0.652–0.793) 0.779 (0.726–0.832)

AUCs, area under the receiver-operating characteristic curves; AMI, acute myocardial infarction; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction.

both subsets of MI with and without death at different time points up to 3 years, even though they were developed for short-term prognosis. Both SOFA score and GRACE RS demonstrated better discrimination than TIMI RS in predicting death at 1 year and 3 years (P < 0.001, respectively), but there was no difference between the SOFA score and GRACE RS, shown in Table 4. We categorized the study population into low, intermediate, and high-risk groups by ascending tertiles of the SOFA score. Fig. 1

illustrates the in-hospital, 1 year, and 3 years death by patient risk groups. Higher risk categories were associated with adverse outcome at discharge, 1 year and 3 years (chi-square for linear trend, P < 0.001). The increase in 1 point of SOFA score was associated with a 61%, 46%, and 58% significant increase in in-hospital, 1-year and 3-year mortality, which resulted in odds ratios (95% CI) of 1.61 (1.43–1.81), 1.46 (1.34–1.59), and 1.58 (1.45–1.72), respectively.

Table 4 Comparison of the predictive accuracy of the risk scores.

GRACE vs. TIMI SOFA vs. TIMI SOFA vs. GRACE

In-hospital death  (95% CI)

P

1-year death  (95% CI)

P

3-year death  (95% CI)

P

0.065 (−0.030 to 0.159) 0.123 (0.022 to 0.224) 0.062 (−0.020 to 0.143)

0.181 0.017 0.141

0.126 (0.065 to 0.186) 0.121 (0.055 to 0.187) 0.004 (−0.049 to 0.056)

<0.001 <0.001 0.891

0.128 (0.079 to 0.176) 0.154 (0.099 to 0.208) 0.027 (−0.016 to 0.070)

<0.001 <0.001 0.222

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Fig. 1. In-hospital, 1-year, and 3-year mortality rates by SOFA score (tertiles). Table 5 Multivariable analysisa of risk factors for long-term mortality. HR SOFA score Previous stroke In-hospital revascularization GRACE score Killip 3–4 vs. 1–2

1.313 2.096 0.587 1.007 1.709

95% CI 1.191–1.447 1.437–3.057 0.429–0.804 1.002–1.013 1.051–2.779

P <0.001 <0.001 0.001 0.012 0.031

a Adjusted for age, medical history (hypertension, diabetes, current smoker, previous stroke, previous MI, and prior PCI/CABG), serum creatinine and lipid profiles, Killip classification, in-hospital revascularization, TIMI score, GRACE score, SOFA score, and medications (angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker).

To address concerns over the potential for confounding variables to affect the prognostic performance of the SOFA score, we constructed a multivariable Cox regression analysis and calculated the adjusted hazard ratio (HR) using the confounders of age, medical history (hypertension, diabetes, current smoker, previous MI, previous stroke, and prior PCI/CABG), serum creatinine and lipid profiles, Killip classification, in-hospital revascularization, TIMI RS, GRACE RS, SOFA score, and medications (angiotensinconverting enzyme inhibitor and angiotensin II receptor blocker). As shown in Table 5, the SOFA score was an independent predictor of long-term mortality in patients with AMI (HR, 1.313; 95% CI, 1.191–1.447). 4. Discussion This single-center study, based on a consecutive AMI cohort, resulted in the finding that TIMI RS, GRACE RS, and SOFA score all demonstrated significant discriminatory ability for in-hospital, 1year and 3-year mortality. However, the SOFA score and GRACE RS were more accurate than TIMI RS in predicting long-term clinical outcome. Furthermore, to the best of our knowledge, the present study is the first to show that SOFA score confers prognostic value in AMI patients. These data suggest that use of the SOFA score is an acceptable method for risk stratification and prognosis of patients with AMI. In an attempt to simplify and improve risk stratification, researchers have focused their attention on the development and validation of various RSs over the past decade.10–12 To date, there are only limited data on the comparative accuracy of these RSs,13–15 despite substantial differences in their complexity, derivation cohorts, and predicted endpoints. Previously, de Araujo Goncalves et al.15 compared the predictive accuracy of TIMI RS, PURSUIT

(the platelet glycoprotein IIb/IIIa in unstable angina: Receptor Suppression Using Integrilin)16 RS, and GRACE RS among 460 ACS patients admitted to their CCU. Both PURSUIT RS and GRACE RS demonstrated stronger discrimination than TIMI RS for death or myocardial infarction at 1 year. Recently, Yan et al.5 also showed that PURSUIT RS and GRACE RS performed better than TIMI RS in identifying patients with poor outcome both in the short-term and long-term, across the wide range of ACS. Consistent with these previous studies, our results also demonstrate that the GRACE risk model had higher prognostic value than the TIMI RS when predicting long-term mortality in AMI patients. The SOFA score was created by the Working Group on SepsisRelated Problems of the European Society of Intensive Care Medicine, with the intent of developing an objective tool to describe individual and aggregate organ failure.6 The usefulness of the score has been previously validated in large cohorts of critically ill patients.17 The SOFA score should be considered a tool which describes organ dysfunction and the severity of dysfunction of each organ, and not simply a global number giving no information on individual organ status. Even though prediction of mortality is not the primary aim of the SOFA score, a relationship exists between organ failure and death, and thus between morbidity and mortality. In a retrospective analysis, the relationship between the SOFA score and outcome has been evaluated.18 The TIMI RS, composed of dichotomous variables only and with a limited range of 0–7, likely incurred a trade-off between its ease of use and predictive accuracy. Conversely, the main limitation of the GRACE RS is its apparent “complexity” compared to other risk models. The SOFA score has several desirable characteristics for application in AMI patients, because it is easy to calculate at the bedside and includes clinical and laboratory data that are routinely available in the CCU. To the best of our knowledge, the current study is the first one indicating the predictive role of SOFA score for long-term outcomes in patients with AMI. Our data showed that patients in the high-risk group (SOFA score ≥ 6) had higher all-cause death than those in the low-risk group (SOFA score ≤ 3) at discharge, 1 year and 3 years. In addition, the SOFA score and GRACE RS showed similar predictive accuracy, but were more accurate than the TIMI RS in predicting long-term mortality in AMI patients. Further large prospective studies are required to confirm our findings. A number of reasons may account for the differences in discriminatory capacities of TIMI RS, GRACE RS, and SOFA score. First, although advanced age, ST-segment deviation, and biomarker status are common components of TIMI RS and GRACE RS, the SOFA score and GRACE RS also incorporate hemodynamic variables and renal dysfunction. These clinical characteristics, which have been shown to be powerful independent prognosticators,19–21 were not evaluated as candidate variables when TIMI RS was initially developed. Renal impairment has been shown to predict short-term22 and long-term23 mortality after an ACS, regardless of the ACS subset. This risk increases proportionally with the decline in renal function. Second, the baseline platelet counts were included in the SOFA score only. Although many cardiology studies apply a threshold of 100 × 109 /L to define thrombocytopenia, 150 × 109 /L is referenced as the lower limit of normal.24,25 Thrombocytopenia is a common occurrence among ACS patients, and patients who develop even mild thrombocytopenia incur significantly higher risks of in-hospital mortality and bleeding complications. In a large multinational registry,26 patients with ACS who developed thrombocytopenia had significantly higher rates of major bleeding, recurrent infarction, stroke, and death. Although thrombocytopenia developed more frequently among patients who were older with more co-morbidities and lower baseline platelet counts, after adjustment for these differences, patients who developed acute thrombocytopenia remained at significantly higher risk of

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in-hospital mortality and nonfatal hemorrhagic complications.27 The degree of risk strongly and independently correlates with the severity of thrombocytopenia, whether determined by the absolute nadir value or relative drop (≥50%) from baseline. Third, only the SOFA score considered liver function. Although serum bilirubin has been shown to be inversely related to cardiovascular disease in both retrospective and prospective studies,28 most studies of serum bilirubin and atherosclerosis have been performed on individuals with normal serum bilirubin concentrations (≤1.0 mg/dL, i.e. ≤17.1 ␮mol/L). However, Kunii et al.29 found that serum bilirubin and its metabolite biopyrrins are elevated in patients with AMI. The maximum biopyrrin elevation was higher in death cases and was associated with impaired left ventricular function. This is consistent with previous investigation showing that serum bilirubin level is a strong, independent predictor of an adverse prognosis in patients with left heart failure, even after adjustment for a variety of demographic, clinical, and biochemical variables.30 Whether elevated serum bilirubin is a risk factor for death in patients with AMI needs to be confirmed in further studies. Given that SOFA score numerically quantifies the number and severity of failed organs, and that organ failure worsens the outcome in AMI, not surprisingly, we found that the predictive accuracy of SOFA score is significantly superior to TIMI RS in predicting death, although there was no difference between the SOFA score and GRACE RS. These data suggest that SOFA score may be an acceptable method for risk stratification and prognosis in patients with AMI. 5. Study limitations There are some limitations that should be considered in this study. First, the study population was relatively small, and the numbers are not powered enough to draw final conclusions. Further studies in a larger number of patients are required to confirm our findings. Second, the present study was limited by being a singlecenter retrospective analysis. However, it represents a real-world unselected population of consecutive patients with AMI using contemporary management. 6. Conclusions The SOFA score provides potentially valuable prognostic information on clinical outcome when applied to patients with AMI. Compared with the simpler TIMI RS, both SOFA score and GRACE RS provide better discrimination for long-term mortality in patients presenting with AMI. These data suggest that use of the SOFA score is an acceptable method for risk stratification and prognosis of AMI patients. Conflict of interest statement None declared. References 1. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: the Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology. Eur Heart J 2007;28:1598–660. 2. Kushner FG, Hand M, Smith Jr SC, et al. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009;120:2271–306.

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