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Examining Renal Impairment as a Risk Factor for Acute Coronary Syndrome: A Prospective Observational Study
CARDIOLOGY/ORIGINAL RESEARCH
Examining Renal Impairment as a Risk Factor for Acute Coronary Syndrome: A Prospective Observational Study Jaimi H. Greenslade, PhD; Louise Cullen, MBBS; Lauren Kalinowski, MBBS; William Parsonage, DM; Suetonia Palmer, PhD; Sally Aldous, MD; Mark Richards, PhD; Kevin Chu, MBBS; Anthony F. T. Brown, MB CHB; Richard Troughton, PhD; Chris Pemberton, PhD; Martin Than, MBBS
Study objective: This study seeks to examine whether the finding of an abnormal estimated glomerular filtration rate (eGFR) in the emergency department (ED) was associated with acute coronary syndrome in the population of patients presenting for investigation of chest pain. Methods: We used prospectively collected data on adult patients presenting with suspected acute coronary syndrome to 2 EDs in Australia and New Zealand. Trained research nurses collected clinical data with a customized case report form. Creatinine measurements were taken on presentation, and the glomerular filtration rate ([GFR]; milliliters per minute per 1.73 m2) was estimated with the chronic kidney disease epidemiologic collaboration equation. The primary endpoint was acute coronary syndrome within 30 days of presentation, as adjudicated by cardiologists using standardized guidelines. Logistic regression analyses examined the relationship between eGFR and acute coronary syndrome. Results: Acute coronary syndrome was diagnosed in 421 (21%) of the 1,968 patients recruited. Compared with patients with an eGFR greater than 90 mL/minute per 1.73 m2, patients with an eGFR between 60 and 90 mL/ minute per 1.73 m2 and patients with an eGFR less than 60 mL/minute per 1.73 m2 were 1.64 (95% confidence interval 1.10 to 2.44) and 1.70 (95% confidence interval 1.01 to 2.77) times more likely to receive a diagnosis of acute coronary syndrome after controlling for age, sex, hypertension, dyslipidemia, family history of cardiac disease, diabetes, patient history of cardiac disease, cardiac troponin level, and ECG findings. Conclusion: There is an independent association between eGFR and acute coronary syndrome risk in patients presenting to the ED with chest pain; this association is independent of age, traditional cardiac risk factors, medical history, troponin level, and ECG findings. Reduced eGFR should be considered an acute coronary syndrome risk factor, and clinicians should maintain high clinical suspicion for acute coronary syndrome in patients with abnormal renal function results regardless of whether they have known kidney disease, traditional acute coronary syndrome risk factors, or abnormal diagnostic test results. Risk stratification tools should include reduced eGFR as a high-risk feature. [Ann Emerg Med. 2013;xx:xxx.] Please see page XX for the Editor’s Capsule Summary of this article. 0196-0644/$-see front matter Copyright © 2013 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2013.01.011
INTRODUCTION Background The evaluation of emergency department (ED) patients presenting with possible acute coronary syndrome is challenging and resource intensive.1,2 International guidelines for the investigation of acute coronary syndrome require that physicians use clinical features in addition to ECG and troponin testing to assess acute coronary syndrome risk.3-5 However, signs and symptoms6 and traditional risk factors7,8 have been found to have limited utility in diagnosing acute coronary syndrome in the ED setting. An improved understanding of factors that distinguish patients with acute coronary syndrome from non–acute coronary syndrome in an ED setting could provide clinicians useful information to assist in identifying this syndrome. Volume xx, . x : Month
Recent population studies indicate that patients with reduced estimated glomerular filtration rate (eGFR) have a higher prevalence of coronary artery disease, myocardial infarction, and cardiovascular death compared with the remainder of the population.9 Patients with chronic renal impairment also have a poorer outcome after acute coronary syndrome than patients without renal impairment.10-14 Some cardiac risk assessment scores include kidney disease, assessed through baseline serum creatinine level, as a risk factor for mortality.15,16 Although patients with chronic kidney dysfunction have an acute coronary syndrome risk higher than that of the general population, ED-based studies have failed to find a link between the finding of abnormal kidney function on presentation and Annals of Emergency Medicine 1
Renal Impairment as a Risk Factor for Acute Coronary Syndrome
Editor’s Capsule Summary
What is already known on this topic Traditional cardiac risk factors do not help identify which chest pain patients have acute coronary syndrome. What question this study addressed Whether estimated glomerular filtration rate (eGFR) is associated with diagnosis of acute coronary syndrome within 30 days of presentation. What this study adds to our knowledge In a study of 1,968 patients, after controlling for age, cardiac risk factors, troponin level, and ECG, low eGFR was associated with risk of acute coronary syndrome (adjusted odds ratio 1.64 for eGFR 60 to 90 mL/minute per 1.73 m2 and 1.70 for eGFR ⬍60 mL/minute per 1.73 m2). How this is relevant to clinical practice This is unlikely to change practice, though clinicians should be aware that abnormal renal function is associated with acute coronary syndrome risk in emergency department patients with chest pain. acute coronary syndrome in the population of patients investigated for chest pain.17-19 Importance Current risk-stratification procedures miss up to 6% of all acute coronary syndrome–related conditions,20-22 and individuals with a missed diagnosis of acute coronary syndrome have short-term mortality of 10% to 26%.23-25 Patients with renal impairment are a particular diagnostic challenge for clinicians. They are twice as likely to have a missed acute myocardial infarction,26 as they often present with symptoms that are atypical for acute coronary syndrome. For patients who present with abnormal kidney function results in the absence of previous test results, it is difficult to determine the acuity of these findings. It is unclear whether abnormal kidney function (irrespective of whether there is known or unknown kidney disease) on ED presentation is associated with higher acute coronary syndrome risk. Describing the sample of patients who present to the ED with abnormal kidney function and identifying the predictive value of abnormal kidney results on ED presentation (irrespective of known preexisting kidney disease) will provide physicians with important information to assist in acute coronary syndrome risk stratification. Goals of This Investigation The major goal is to determine whether the finding of abnormal kidney function in ED patients is predictive of 30-day 2 Annals of Emergency Medicine
Greenslade et al risk for acute coronary syndrome in the population of adult ED patients presenting with symptoms of possible acute coronary syndrome. Our hypothesis, based on population studies, was that there would be an independent association between the eGFR and acute coronary syndrome. This study also sought to describe the presenting features of patients with and without abnormal kidney results.
MATERIALS AND METHODS Study Design and Setting This is an analysis of prospectively collected data from 2 EDs: Brisbane, Australia, and Christchurch, New Zealand. Most participants were recruited as part of the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT),27 but we also included additional patients through ongoing post-ASPECT recruitment at both centers. Selection of Participants Patients were recruited during working hours (8 AM to 5 PM) and included if they were aged 18 years or older, presented to the ED with at least 5 minutes’ worth of chest pain suggestive of acute coronary syndrome (in accordance with American Heart Association case definitions28), and were being evaluated for acute coronary syndrome. The American Heart Association describes pain suggestive of acute coronary syndrome as acute chest, epigastric, neck, jaw, or arm pain or discomfort or pressure without an apparent noncardiac source. Recruitment was performed by research staff in collaboration with the senior treating clinician. Patients were excluded if there was a clear non–acute coronary syndrome cause for their symptoms, they were unwilling or unable to provide informed consent (eg, language barrier), staff considered that recruitment was inappropriate (eg, terminal illness), they were transferred from another hospital, were pregnant, were previously recruited to the study within the past 45 days, or were unable or unwilling to be contacted after discharge. Recruitment included consecutive eligible cases during working hours at each site. Enrollment occurred between November 2007 and July 2010. However, each site started and finished at different times according to local logistics. All patients were managed according to standard care at their local hospital, which uniformly included ECG and troponin testing on presentation and greater than or equal to 6 hours after presentation to the ED. Methods of Measurement Data were collected prospectively, using definitions outlined by Cullen et al.29 Trained research nursing staff collected demographic and clinical data directly from patient interviews in a standardized manner. Patient interviews also were crosschecked with patient notes. A patient was presumed to be positive for a risk factor if the factor was self-reported during the interview or if a cardiologist or senior emergency physician recorded the risk factor in the medical record. Patients were Volume xx, . x : Month
Greenslade et al recorded to have a family history of coronary artery disease (CAD) if they had a first-degree relative with CAD who was younger than 65 years. Troponin measurements were taken as part of standard care. One hospital used the Beckman Coulter second-generation AccuTnI (Beckman Coulter, Chaska, MN). The second used the Abbott Architect cTnI assay (Abbott, Inc., Chicago, IL). A value above the 99th percentile of greater than 0.04 g/L and greater than 0.030 g/L, respectively, was considered abnormal. Each patient’s serum creatinine level was measured on the first blood sample drawn on admission to the ED. GFR was estimated with the chronic kidney disease epidemiologic collaboration equation, with the modification of diet in renal disease (MDRD) equation also calculated for use in sensitivity analyses. Telephone follow-up and medical record review was conducted 30 days after initial attendance for the diagnosis of acute coronary syndrome. This follow-up was conducted by trained research nurses. Information was obtained from the patient and from hospital databases about whether there had been any cardiac events, investigations, or contact with any health care providers during the 30-day period. All follow-up information was verified through contact with the health care provider, and original copies of medical records and investigations were obtained. Data coordination, monitoring, and source verification were performed by an independent university clinical research organization at a nonrecruitment location in Australia (CCRE Therapeutics, Monash University, Melbourne). Approval was obtained from local ethics committees, and all patients provided written informed consent. Outcome Measures The primary outcome was a diagnosis of acute coronary syndrome (including adverse cardiac events) occurring on presentation or within 30 days of admission. The acute coronary syndrome endpoint included death (cardiovascular), cardiac arrest, revascularization procedure, cardiogenic shock, acute myocardial infarction, and unstable angina pectoris. Local cardiologists adjudicated the outcome independently, using predefined standardized reporting guidelines. Cardiologists had knowledge of the clinical record and ECG and troponin results from standard care. Creatinine results were available to the cardiologists, but they did not have knowledge of the study hypothesis at adjudication. A second cardiologist conducted a blind review of all acute coronary syndrome cases and 10% of non–acute coronary syndrome cases. In cases of disagreement, endpoints were agreed on by consensus. This was achieved for all endpoints. Criteria used to diagnose acute myocardial infarction and unstable angina pectoris are outlined in Figure 1. Primary Data Analysis Power calculations were conducted with G-Power (version 3.1; Heinrich Heine Universität, Dusseldorf, Germany).30 Research in the Asia Pacific region has found baseline rates of cardiac events between 15%31 and 20%.6 Previous ED Volume xx, . x : Month
Renal Impairment as a Risk Factor for Acute Coronary Syndrome
Figure 1. Criteria used to diagnose acute myocardial infarction (AMI) and unstable angina pectoris (UAP). ACS, Acute coronary syndrome.
research17 found an odds ratio (OR) for acute coronary syndrome of 1.65. Using this OR, using a 15% baseline event rate as the most conservative figure, and presuming a moderate correlation between confounders (R2⫽0.3), a minimum of 1,285 participants would be required in this study to achieve power of 95% with ␣⫽.05. The eGFR was categorized according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative classification of chronic kidney disease,32 which uses the following ranges: greater than or equal to 90, 60 to 89, 30 to 59, 15 to 26, and less than 15 mL/minute per 1.73 m2. However, in line with previous research,33 we combined 30 to 59, 15 to 29, and less than 15 mL/minute per 1.73 m2 into 1 category because of inadequate numbers in the lower 2 categories (n⫽50 and 12, respectively). For the remainder of the article, we term eGFR greater than or equal to 90 mL/minute per 1.73 m2 normal renal function, eGFR 60 to 89 mL/minute per 1.73 m2 borderline renal impairment, and eGFR less than 60 mL/minute per 1.73 m2 renal impairment. For all inferential statistics, age was categorized as younger than 40 years, 40 to 65 years, and older than 65 years, in accordance with previous research.7 Data were analyzed with SPSS (version 19; SPSS, Inc., Chicago, IL). Annals of Emergency Medicine 3
Renal Impairment as a Risk Factor for Acute Coronary Syndrome Baseline characteristics of the sample were described for patients across the 3 categories of eGFR, using number and proportion for categorical data and median and interquartile range for continuous data. Unadjusted rates of clinical outcomes and 95% confidence intervals (CIs) for each category of eGFR also were reported. To describe the sample of patients presenting with and without reduced eGFR, we report the presenting features of patients across categories of eGFR. The proportion of patients with various symptoms, new ischemia on ECG, and positive troponin results was calculated for each category of eGFR. To ensure that such proportions were not obscured by potential differences in the proportion of patients with acute coronary syndrome in each eGFR category, adjusted proportions were reported. Specifically, we adjusted the proportions in each eGFR category for acute coronary syndrome by directly standardizing to the acute coronary syndrome distribution in the overall sample. Multivariate logistic regression analyses were then performed to assess the primary goal of this study, namely, whether eGFR was associated with acute coronary syndrome. We included a priori– determined confounders, including age, sex, hypertension, dyslipidemia, family history of cardiac disease, diabetes, previous acute myocardial infarction, previous coronary artery bypass grafting (CABG), previous revascularization, previous angina, cardiac troponin level on presentation (normal versus abnormal), and ECG (new ischemic changes versus no new ischemic changes). These variables were chosen because they comprise the main risk factors and diagnostic methods currently used in ED setting as recommended by international guidelines.3-5 All risk factors were entered as dichotomous variables in the regression model. For details of additional regression analyses, see Figure E1 (available online at http://www.annemergmed.com). For the logistic regression analyses, we used only patients who required investigation for acute coronary syndrome in the ED. Therefore, we removed 40 patients with ST-segment elevation on their initial ECG because this group had a clear diagnosis and required urgent reperfusion. No other patients had a known diagnosis on presentation to the ED. Regression diagnostics were performed to test for collinearity among the explanatory variables. In all instances, the tolerance was above 0.2 and the variance inflation factor below 5 (values less than 0.1 and greater than 10, respectively, indicate issues with multicolinearity). Three sets of sensitivity analyses also were conducted. The first categorized the sample into low or intermediate/high risk for acute coronary syndrome according to the thrombolysis in myocardial infarction (TIMI) risk score. The proportion of patients with acute coronary syndrome across categories of eGFR was then compared for low-risk patients and for intermediate/high-risk patients. The purpose of this analysis was to determine whether an abnormal eGFR result was predictive for acute coronary syndrome even for those patients whose acute 4 Annals of Emergency Medicine
Greenslade et al coronary syndrome risk is otherwise low. Previous research has indicated that patients with a TIMI score of 0 or 1 are low risk for acute coronary syndrome.34 Therefore, low-risk patients were those with a TIMI score of 0 or 1, whereas intermediate/ high-risk were those with a TIMI score greater than 1. The second sensitivity analysis repeated the logistic regression analyses above but incorporated the MDRD equation for estimating GFR instead of the epidemiologic collaboration equation. Such analyses sought to ensure that the method of estimating GFR did not influence the results. The third repeated the logistic regression analysis, using acute myocardial infarction rather than acute coronary syndrome as the outcome to ensure that the results were not altered by the large proportion of patients with unstable angina pectoris.
RESULTS Of the eligible cohort for this study, 192 patients declined participation and 8 patients were excluded because they had incomplete data. No enrolled patients were lost to follow-up. A total of 1,968 patients had complete data for this analysis. The sample was predominantly men (60%), with a median age of 60 years (interquartile range [IQR] 49 to 72 years). There were 421 patients (21.4%) with an adverse cardiac event or diagnosis of acute coronary syndrome within 30 days. Of these 421 patients, 407 (96.6%) had a cardiac event diagnosed while they were in the hospital. The predominant diagnoses were unstable angina (n⫽120) or non–ST-elevation myocardial infarction (NSTEMI) (n⫽272), with patients being able to have more than 1 event. Patients with renal impairment were older, more likely to be women, less likely to be current smokers, and more likely to have hypertension, dyslipidemia, diabetes, and a history of cardiac illness than patients with normal renal function (Table 1). After adjusting for diagnosis of acute coronary syndrome, the proportion of patients with new ischemia on their presentation ECG was similar across groups. However, the proportion of patients with a positive troponin result was higher for patients with lower eGFR. Patients with reduced eGFR were less likely to report that various factors exacerbated their chest pain, such as inspiration, palpation, and exertion. They also were more likely to report chest pain that occurred at rest and less likely to report diaphoresis (Table 2). The unadjusted proportion of patients who had an event increased sharply as the estimated GFR decreased, ranging from 10.7% with normal renal function to 34.5% with renal impairment (Figure 2). The unadjusted proportion of patients with ST-elevation myocardial infarction (STEMI) was similar across all categories of eGFR. The proportions of patients with NSTEMI increased from 5.6% with normal renal function to 25.3% with renal impairment. Similarly, the proportion of patients with unstable angina pectoris increased from 3.7% with normal renal function to 8.5% with renal impairment (Table E1, available online at http://www.annemergmed.com). The results of the logistic regression model found that after controlling for baseline characteristics, risk factors, ECG findings, and troponin level, patients with borderline renal Volume xx, . x : Month
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Table 1. Baseline characteristics for patients according to the eGFR on presentation.* eGFR on Presentation, mL/min per 1.73 m2 Characteristic Age, y Male sex Hypertension Dyslipidemia Diabetes Family history of CAD Smoking Number of risk factors† 0 1 2 or more Medical history CHF Stroke Myocardial infarction PCI CABG Angina PAD
Total Cohort, nⴝ1,968
>90, nⴝ694 (Normal Renal Function)
60–89, nⴝ886 (Borderline Renal Impairment)
<60, nⴝ388 (Renal Impairment)
60 (49–72) 1,180 (60.0) 1,016 (51.6) 1,117 (56.8) 259 (13.2) 1,121 (57.0) 371 (18.9)
49 (41–56) 463 (66.7) 231 (33.3) 287 (41.4) 66 (9.5) 353 (50.9) 219 (31.6)
62 (54–71) 514 (58.0) 483 (54.5) 538 (60.7) 116 (13.1) 536 (60.5) 123 (13.9)
78 (70–83) 203 (52.3) 302 (77.8) 292 (75.3) 77 (19.8) 232 (59.8) 29 (7.5)
222 (11.3) 472 (24) 1,274 (64.7)
116 (16.7) 217 (31.3) 361 (52.0)
86 (9.7) 202 (22.8) 598 (67.5)
20 (5.2) 53 (13.7) 315 (81.1)
153 (7.8) 217 (11.0) 471 (23.9) 357 (18.1) 170 (8.6) 709 (36.0) 69 (3.5)
8 (1.2) 36 (5.2) 93 (13.4) 69 (9.9) 22 (3.2) 126 (18.2) 9 (1.3)
59 (6.7) 94 (10.6) 204 (23) 175 (19.8) 71 (8.0) 326 (36.8) 18 (2.0)
86 (22.2) 87 (22.4) 174 (44.8) 113 (29.1) 77 (19.8) 257 (66.2) 42 (10.8)
CHF, Congestive heart failure; PCI, percutaneous coronary intervention; PAD, peripheral arterial disease. *Data are median (IQR) or No. (%). † Using risk factors defined in the TIMI risk score.
Table 2. Presenting features of patients directly standardized for diagnosis of acute coronary syndrome according to the eGFR on presentation.* eGFR on Presentation, mL/min per 1.73 m2 Characteristic
>90, nⴝ694 (Normal Renal Function)
60–89, nⴝ886 (Borderline Renal Impairment)
<60, nⴝ388 (Renal Impairment)
82.1 (79.0–85.2) 29.9 (26.4–33.4) 11.5 (9.2–13.8) 12.2 (9.7–14.8) 53.6 (49.7–57.5) 7.3 (5.0–9.6) 15.5 (12.9–18.2)
85.6 (83.2–87.9) 16.5 (14.1–19.0) 6.9 (5.2–8.6) 5.5 (4.0–7.0) 50.8 (47.5–54.1) 6.7 (5.2–8.3) 16.5 (14.5–18.4)
88.3 (85.0–91.6) 17.6 (13.6–21.5) 5.7 (3.2–8.2) 4.5 (2.3–6.7) 45.7 (40.5–50.8) 6.0 (3.7–8.3) 21.8 (18.4–25.1)
Presenting symptoms Pain occurred at rest Pleuritic pain Pain on palpation Pain on exertion Diaphoresis New ischemia on ECG Positive troponin result *Reported data are percentage (95% CI).
impairment were 1.64 (95% CI 1.10 to 2.44) times as likely to have acute coronary syndrome compared with patients with normal renal function. Similarly, patients with renal impairment were 1.7 times (95% CI 1.01 to 2.77) more likely to have acute coronary syndrome compared with patients with normal renal function. Other significant predictors of acute coronary syndrome were male sex (OR⫽1.6), age (4.2 for aged 40 to 65 years and 6.1 for aged ⬎65 years), hypertension (OR⫽1.6), family history (OR⫽1.6), dyslipidemia (OR⫽1.49), ischemic ECG (OR⫽2.14), and positive troponin result (OR⫽23.92) (Figure 3). Sensitivity Analyses The proportion of patients with acute coronary syndrome across categories of eGFR was calculated for the 872 patients Volume xx, . x : Month
with TIMI score 0 or 1 (low risk) and for the 1,049 patients with TIMI score greater than 1 (intermediate- to high-risk patients). There were 5 patients without necessary data to calculate a TIMI score, and so these patients were not included in the analysis. For low risk, 53.8% of patients had normal renal function, 41.6% had borderline renal impairment, and 4.6% had renal impairment. The proportion of patients with acute coronary syndrome increased from 4.1% for patients with normal renal function to 11.3% with borderline renal impairment (percentage difference⫽7.2%; 95% CI 3.6% to 11.2%); 7.5% of patients with renal impairment had acute coronary syndrome. However, the small number of patients with an eGFR less than 60 mL/minute per 1.73 m2 meant that the uncertainty around this percentage was high (95% CI 2.6% to 19.9%). Annals of Emergency Medicine 5
Renal Impairment as a Risk Factor for Acute Coronary Syndrome
Greenslade et al
Figure 2. Proportion of patients with ACS, STEMI, NSTEMI, and UAP according to estimated GFR. Error bars represent 95% CIs.
For intermediate/high-risk patients (TIMI score ⬎1), 19.8% had normal renal function, 47.9% had borderline renal impairment, and 32.3% had renal impairment. The proportion of patients with acute coronary syndrome was 22.6% for normal renal function. This increased to 31.7% in patients with borderline renal impairment (percentage difference⫽9.1%; 95% CI 1.8% to 15.7%) and 37.2% with renal impairment (percentage difference 14.6%; 95% CI 6.7% to 21.9%). Analyses were repeated with the MDRD equation for estimating GFR. Such analyses supported the results above. The unadjusted proportion of patients with acute coronary syndrome was 8.8%, 20.6%, and 31.4% in normal renal function, borderline renal impairment, and renal impairment groups, respectively. After controlling for baseline characteristics, risk factors, ECG, and troponin level, patients with an MDRD eGFR indicating borderline renal impairment were 1.9 times (95% CI 1.2 to 3.0) more likely to have acute coronary syndrome compared with patients with normal renal function. Patients with an MDRD eGFR indicating renal impairment were 2.0 times (95% CI 1.2 to 3.4) more likely to have acute coronary syndrome compared with patients with normal renal function. Analyses also were repeated with acute myocardial infarction rather than acute coronary syndrome as the endpoint. There were 280 patients (14.5%) who met the criteria for acute myocardial infarction. Results again yielded findings similar to those of the primary analyses. Adjusted ORs for acute myocardial infarction were 2.0 (95% CI 1.17 to 3.53) in the group of patients with borderline renal impairment and 2.33 (95% CI 1.2 to 4.7) in the group of patients with renal impairment. 6 Annals of Emergency Medicine
LIMITATIONS Our study has several limitations. First, we used a single measurement of creatinine on presentation to estimate the patient’s GFR. Therefore, patients with renal impairment but normal creatinine levels would belong in the group of patients with normal renal function. Second, some patients in groups with reduced eGFR may have acute kidney injury, rather than chronic renal impairment and we are unable to distinguish between these patients by using creatinine on presentation. It is likely that patients with chronic and acute renal impairment have different acute coronary syndrome risk, and therefore future research could benefit from using serial creatinine measurements or assessing reported history of chronic kidney disease to identify acute versus chronic renal impairment. However, emergency physicians are often presented with a single creatinine measurement in the absence of knowledge of previous test results, and thus the use of a single measurement is clinically relevant. Second, recruitment occurred during local working hours. Data are not available on the number of patients presenting after hours or the cohort who met exclusion criteria in this study; thus, the extent of potential selection bias is unable to be quantified. Third, the study was not powered to determine whether there were differences in the proportion of patients with STEMI across categories of eGFR. Therefore, it is possible that the null result in the STEMI analysis was due to a lack of power. Fourth, we did not collect data on whether troponin elevations were acute or chronic. Patients with chronic troponin elevations and renal impairment are likely to have a Volume xx, . x : Month
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Figure 3. Logistic regression analysis examining the association between eGFR and ACS. Triangles are ORs and whiskers are 95% CIs. ORs are adjusted for risk factors, troponin level greater than 99th percentile, and new ischemic changes on presentation ECG. The comparator for eGFR is greater than 90 mL/minute per 1.73 m2. Data are presented on a logarithmic scale. MI, Myocardial infarction.
poor prognosis and further clarity on the development of acute coronary syndrome could be gained by incorporating such data.
DISCUSSION Our study found that reduced eGFR on presentation (irrespective of whether it is acute or chronic) is associated with increased risk of NSTEMI and unstable angina pectoris in the population of patients presenting to the ED with chest pain. The increased risk of acute coronary syndrome occurred both for minor and more severe renal impairment and was independent of risk factors, ischemic ECG, and abnormal troponin findings. Patients with reduced eGFR were at higher acute coronary syndrome risk regardless of whether they had low or high acute coronary syndrome risk according to the TIMI score. Our findings align with those of large population-based studies investigating the risk of coronary events in patients with renal dysfunction.9,33 They support the body of literature indicating that poor renal function portends poor prognosis in patients receiving a diagnosis of acute coronary syndrome.10-14 Our study extends previous research by finding an association of similar magnitude to that reported in population studies in the population of patients presenting to the ED for chest pain. However, these finding are in contrast to those of previous research conducted in the ED setting. Limkakeng and Volume xx, . x : Month
Renal Impairment as a Risk Factor for Acute Coronary Syndrome Chandra17 studied a low-risk population of patients evaluated for acute coronary syndrome in an emergency setting and found that renal impairment did not increase the risk of acute coronary syndrome in patients without risk factors. Similarly, a study of intermediate-risk patients presenting to the ED with chest pain found that patients with chronic kidney disease had a higher admission rate but had similar rates of acute myocardial infarction, revascularization, and inhospital death than patients without kidney disease.18 Finally, Chang et al19 found that abnormal creatinine values were not predictive of inhospital acute myocardial infarction but were associated with increased odds of 30-day cardiovascular events. A number of differences between our study and the previous research may account for the contradictory results. First, with the exception of the study by Chang et al,19 previous studies have used smaller cohorts, which may have resulted in reduced power to detect a relationship between renal impairment and acute coronary syndrome. Second, previous studies have used slightly different patient populations (ED patients at low or intermediate risk for acute coronary syndrome) and different endpoint classification such as the diagnosis of acute coronary syndrome according to a positive stress test result17 or diagnosis of acute myocardial infarction during admission rather than 30-day acute coronary syndrome.18 The major clinical implication of our research is that a finding of reduced eGFR on presentation is a marker of increased acute coronary syndrome risk regardless of whether the patient has other risk factors or abnormal diagnostic test results on presentation. Even for patients who would otherwise be considered low risk for acute coronary syndrome, a mildly abnormal eGFR is associated with an increased likelihood of acute coronary syndrome. Patients with a reduced eGFR are twice as likely to have a missed acute myocardial infarction compared with patients with normal renal function26 and are less likely to receive anticoagulant therapy and revascularization for acute myocardial infarction.35 Our study finding supports the need for thorough cardiac assessment and treatment in patients with a reduced eGFR. Such testing may subsequently affect their overall morbidity and mortality by reducing the delays to treatment that are associated with poor outcomes.36-38 The second implication of our study is that it supports the decision to include reduced eGFR as a risk factor in some riskstratification models, including the Global Registry of Acute Coronary Events (GRACE) score and the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand guidelines.15,16 Our finding that patients with renal impairment present with different symptoms than patients without renal impairment extends on previous research. Patients with renal dysfunction have been shown to be less likely to present with chest pain and more likely to present with other symptoms such as dyspnea.35,39 Our findings were contradictory, indicating that patients with reduced eGFR are less likely to present with atypical symptoms, which is likely to be related to the different Annals of Emergency Medicine 7
Renal Impairment as a Risk Factor for Acute Coronary Syndrome symptoms recorded and populations studied. That is, previous research has focused only on patients with confirmed acute myocardial infarction and specifically focused on pain location. Our study focused on the broader group of patients being investigated for acute coronary syndrome and examined a number of atypical symptoms. In summary, the identification of patients with potential acute coronary syndrome in the ED is complex and incorporates the physician’s evaluation of clinical risk factors. Our study indicates that there is an association between decreased eGFR (irrespective of whether this is known to be long-standing or acute) and acute coronary syndrome risk in patients presenting to the ED with chest pain. This association is independent of traditional cardiac risk factors, troponin levels, and ECG findings. Clinicians should maintain high clinical suspicion for acute coronary syndrome in patients with abnormal renal function results regardless of whether they have traditional acute coronary syndrome risk factors or abnormal diagnostic test results. Reduced eGFR should be included as a high-risk feature in ED-based risk-stratification tools. Supervising editor: Judd E. Hollander, MD Author affiliations: From the Department of Emergency Medicine (Greenslade, Cullen, Kalinowski, Chu, Brown) and Department of Cardiology (Parsonage), Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia; the School of Medicine, University of Queensland, Herston, Queensland, Australia (Greenslade, Cullen, Parsonage, Chu, Brown); the School of Public Health, Queensland University of Technology, Kelvin Grove, Queensland, Australia (Greenslade, Cullen); the School of Medicine (Palmer, Troughton, Pemberton, Than) and Christchurch Cardioendocrine Research Group (Richards), University of Otago, Christchurch, New Zealand; and the Department of Cardiology (Aldous, Richards, Troughton) and Department of Emergency Medicine (Than), Christchurch Hospital, Christchurch, New Zealand. Author contributions: JHG, LC, WP, SA, MR, and MT contributed to study design. LC, WP, SA, MR, and MT were responsible for data collection. JHG analyzed and interpreted data. JHG, LC, and LK wrote the article, and all authors made critical intellectual contribution. All authors have read and approved the article. JHG takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). This work was supported largely by the Queensland Emergency Medicine Research Foundation (grant QEMRF-PROJ-2008-002) and Christchurch Cardioendocrine Research Group (New Zealand), with small contributions from Alere Medical (⬍20%). Dr. Cullen reports receiving research grants from Alere (formerly Inverness Medical), Radiometer Pacific, Abbott Diagnostics, Roche, and Siemens; consultancy fees from Abbott Diagnostics; and support to attend meetings
8 Annals of Emergency Medicine
Greenslade et al and conferences from Abbott Diagnostics, Alere, Radiometer Pacific, Pfizer, and Boehringer Ingelheim. Dr. Parsonage reports receiving research grants from Genzyme Corp. and Inverness Medical; consultancy fees from Abbott, AstraZeneca, and Hospira; and support to attend meetings and conferences from Abbott, Sanofi-Aventis, and AstraZeneca. Dr. Richards reports accepting travel support and speakers honoraria from Alere. AFTB reports receiving consultancy fees from Boehringer Ingelheim, support to attend meeting and conferences from AstraZeneca, and educational support from Roche and Hoechst. Dr. Troughton reports receiving consultancy fees from St Jude Medical. Dr. Than reports receiving funds from Alere and Abbott for research support, speaking, and travel reimbursement. Publication dates: Received for publication October 31, 2012. Revision received December 17, 2012. Accepted for publication January 4, 2013. Address for correspondence: Jaimi H. Greenslade, PhD, E-mail [email protected]. REFERENCES 1. Goodacre S, Cross E, Arnold J, et al. The health care burden of acute chest pain. Heart. 2005;91:229-230. 2. Hollander JE. The continuing search to identify the very-low-risk chest pain patient. Acad Emerg Med. 1999;6:979-981. 3. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2777785007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50:e1-e157. 4. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007;50:2173-2195. 5. Rapezzi C, Biagini E, Branzi A. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: the Task Force for the Diagnosis and Treatment of Non-STSegment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J. 2008;29:277-278. 6. Greenslade J, Cullen L, Parsonage WA, et al. Examining the signs and symptoms experienced by individuals with suspected acute coronary syndrome in the Asia-Pacific region: a prospective observational study. Ann Emerg Med. 2012;60:777-785. 7. Han JH, Lindsell CJ, Storrow AB, et al. The role of cardiac risk factor burden in diagnosing acute coronary syndromes in the emergency department setting. Ann Emerg Med. 2007;49:145152. 8. Jayes RI Jr, Beshansky JR, D’Agostino RB, et al. Do patients’ coronary risk factor reports predict acute cardiac ischemia in the emergency department? a multicenter study. J Clin Epidemiol. 1992;45:621-626. 9. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305. 10. Langston RD, Presley R, Flanders WD, et al. Renal insufficiency and anemia are independent risk factors for death among
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patients with acute myocardial infarction. Kidney Int. 2003;64:1398-1405. Gibson CM, Dumaine RL, Gelfand EV, et al. Association of glomerular filtration rate on presentation with subsequent mortality in non-ST-segment elevation acute coronary syndrome: observations in 13,307 patients in five TIMI trials. Eur Heart J. 2004;25:1998-2005. Gibson CM, Pinto DS, Murphy SA, et al. Association of creatinine and creatinine clearance on presentation in acute myocardial infarction with subsequent mortality. J Am Coll Cardiol. 2003;42: 1535-1543. Al Suwaidi J, Reddan DN, Williams K, et al. Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes. Circulation. 2002;106:974-980. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351:1285-1295. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004;291:2727-2733. Chew D, Aroney C, Aylward P, et al. 2011 Addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the management of acute coronary syndromes (ACS) 2006. Heart Lung Circ. 2011; 20:487-502. Limkakeng AT Jr, Chandra A. Impact of renal dysfunction on acute coronary syndrome evaluation in observation unit patients. Am J Emerg Med. 2010;28:658-662. Khambatta S, Farkouh ME, Wright RS, et al. Chronic kidney disease as a risk factor for acute coronary syndromes in patients presenting to the emergency room with chest pain. Transl Res. 2011;159:391-396. Chang AM, Edwards M, Matsuura AC, et al. Relationship between renal dysfunction and outcomes in emergency department patients with potential acute coronary syndromes. Emerg Med J. [Epub ahead of print] doi:10.1136/emermed-2011-200536. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342:1163-1170. Collinson PO, Premachandram S, Hashemi K. Prospective audit of incidence of prognostically important myocardial damage in patients discharged from emergency department. BMJ. 2000; 320:1702-1705. Aldous SJ, Richards M, Cullen L, et al. A 2-hour Thrombolysis in Myocardial Infarction score outperforms other risk stratification tools in patients presenting with possible acute coronary syndromes: comparison of chest pain risk stratification tools. Am Heart J. 164:516 –523. Lee TH, Rouan GW, Weisberg MC, et al. Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room. Am J Cardiol. 1987;60: 219-224. McCarthy BD, Beshansky JR, D’Agostino RB, et al. Missed diagnoses of acute myocardial infarction in the emergency department: results from a multicenter study. Ann Emerg Med. 1993;22:579-582.
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Renal Impairment as a Risk Factor for Acute Coronary Syndrome 25. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342:1163-1170. 26. Herzog CA, Littrell K, Arko C, et al. Clinical characteristics of dialysis patients with acute myocardial infarction in the United States: a collaborative project of the United States Renal Data System and the National Registry of Myocardial Infarction. Circulation. 2007;116:1465-1472. 27. Than M, Cullen L, Reid CM, et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet. 2011;377:1077-1084. 28. Luepker RV, Apple FS, Christenson RH, et al. Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; the European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart, Lung, and Blood Institute. Circulation. 2003; 108:2543-2549. 29. Cullen L, Than M, Brown AFT, et al. Comprehensive standardized data definitions for acute coronary syndrome research in emergency departments in Australasia. Emerg Med Australas. 2010;22:35-55. 30. Faul F, Erdfelder E, Lang A-G, et al. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2009;39:175-191. 31. Than M, Cullen L, Aldous S, et al. 2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial. J Am Coll Cardiol. 2012;59:2091-2098. 32. The Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-266. 33. Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet. 2012;380:807814. 34. Macdonald SPJ, Nagree Y, Fatovich DM, et al. Comparison of two clinical scoring systems for emergency department risk stratification of suspected acute coronary syndrome. Emerg Med Australas. 2011;23:717-725. 35. Szummer KLP, Jacobson SH, Schon S, et al. Relation between renal function, presentation, use of therapies and in-hospital complications in acute coronary syndrome: data from the SWEDEHEART register. J Intern Med. 2010;268:40-49. 36. Keeley EC, Hillis LD. Primary PCI for myocardial infarction with ST-segment elevation. N Engl J Med. 2007;356:47-54. 37. Nallamonthu B, Bradley E, Krumholz H. Time to treatment in primary percutaneous coronary intervention. N Engl J Med. 2007; 357:1631-1638. 38. De Luca G, Suryapranata H, Marino P. Reperfusion strategies in acute ST-elevation myocardial infarction: an overview of current status. Prog Cardiovasc Dis. 2008;50:352-382. 39. Sosnov J, Lessard D, Goldberg RJ, et al. Differential symptoms of acute myocardial infarction in patients with kidney disease: a community-wide perspective. Am J Kidney Dis. 2006;47:378-384.
Annals of Emergency Medicine 9
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Greenslade et al Table E1. Difference between the percentage of patients with cardiac diagnosis (and 95% CI of the difference) across categories of eGFR.
Cardiac Diagnosis ACS STEMI NSTEMI UAP
eGFR % Difference (95% CI of Difference), mL/min per 1.73 m2 >90 vs 60–89
>90 vs <60
60–89 vs <60
13.4 (9.7 to 17) 23.9 (18.7 to 29.2) 10.5 (5.1 to 16.1) ⫺0.3 (⫺1.6 to 0.8) ⫺0.4 (⫺1.8 to 1.3) ⫺0.1 (⫺1.2 to 1.6) 10.2 (7.2 to 13.1) 19.6 (15.1 to 24.4) 9.5 (4.7 to 14.5) 3.6 (1.3 to 5.8) 438 (1.8 to 8.2) 1.2 (–1.9 to 4.7)
Figure E1. Additional logistic regression models.
9.e1 Annals of Emergency Medicine
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Examining Renal Impairment as a Risk Factor for Acute Coronary Syndrome: A Prospective Observational Study Jaimi H. Greenslade, PhD; Louise Cullen, MBBS; Lauren Kalinowski, MBBS; William Parsonage, DM; Suetonia Palmer, PhD; Sally Aldous, MD; Mark Richards, PhD; Kevin Chu, MBBS; Anthony F. T. Brown, MB CHB; Richard Troughton, PhD; Chris Pemberton, PhD; Martin Than, MBBS
Study objective: This study seeks to examine whether the finding of an abnormal estimated glomerular filtration rate (eGFR) in the emergency department (ED) was associated with acute coronary syndrome in the population of patients presenting for investigation of chest pain. Methods: We used prospectively collected data on adult patients presenting with suspected acute coronary syndrome to 2 EDs in Australia and New Zealand. Trained research nurses collected clinical data with a customized case report form. Creatinine measurements were taken on presentation, and the glomerular filtration rate ([GFR]; milliliters per minute per 1.73 m2) was estimated with the chronic kidney disease epidemiologic collaboration equation. The primary endpoint was acute coronary syndrome within 30 days of presentation, as adjudicated by cardiologists using standardized guidelines. Logistic regression analyses examined the relationship between eGFR and acute coronary syndrome. Results: Acute coronary syndrome was diagnosed in 421 (21%) of the 1,968 patients recruited. Compared with patients with an eGFR greater than 90 mL/minute per 1.73 m2, patients with an eGFR between 60 and 90 mL/ minute per 1.73 m2 and patients with an eGFR less than 60 mL/minute per 1.73 m2 were 1.64 (95% confidence interval 1.10 to 2.44) and 1.70 (95% confidence interval 1.01 to 2.77) times more likely to receive a diagnosis of acute coronary syndrome after controlling for age, sex, hypertension, dyslipidemia, family history of cardiac disease, diabetes, patient history of cardiac disease, cardiac troponin level, and ECG findings. Conclusion: There is an independent association between eGFR and acute coronary syndrome risk in patients presenting to the ED with chest pain; this association is independent of age, traditional cardiac risk factors, medical history, troponin level, and ECG findings. Reduced eGFR should be considered an acute coronary syndrome risk factor, and clinicians should maintain high clinical suspicion for acute coronary syndrome in patients with abnormal renal function results regardless of whether they have known kidney disease, traditional acute coronary syndrome risk factors, or abnormal diagnostic test results. Risk stratification tools should include reduced eGFR as a high-risk feature. [Ann Emerg Med. 2013;xx:xxx.] Please see page XX for the Editor’s Capsule Summary of this article. 0196-0644/$-see front matter Copyright © 2013 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2013.01.011
INTRODUCTION Background The evaluation of emergency department (ED) patients presenting with possible acute coronary syndrome is challenging and resource intensive.1,2 International guidelines for the investigation of acute coronary syndrome require that physicians use clinical features in addition to ECG and troponin testing to assess acute coronary syndrome risk.3-5 However, signs and symptoms6 and traditional risk factors7,8 have been found to have limited utility in diagnosing acute coronary syndrome in the ED setting. An improved understanding of factors that distinguish patients with acute coronary syndrome from non–acute coronary syndrome in an ED setting could provide clinicians useful information to assist in identifying this syndrome. Volume xx, . x : Month
Recent population studies indicate that patients with reduced estimated glomerular filtration rate (eGFR) have a higher prevalence of coronary artery disease, myocardial infarction, and cardiovascular death compared with the remainder of the population.9 Patients with chronic renal impairment also have a poorer outcome after acute coronary syndrome than patients without renal impairment.10-14 Some cardiac risk assessment scores include kidney disease, assessed through baseline serum creatinine level, as a risk factor for mortality.15,16 Although patients with chronic kidney dysfunction have an acute coronary syndrome risk higher than that of the general population, ED-based studies have failed to find a link between the finding of abnormal kidney function on presentation and Annals of Emergency Medicine 1
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Editor’s Capsule Summary
What is already known on this topic Traditional cardiac risk factors do not help identify which chest pain patients have acute coronary syndrome. What question this study addressed Whether estimated glomerular filtration rate (eGFR) is associated with diagnosis of acute coronary syndrome within 30 days of presentation. What this study adds to our knowledge In a study of 1,968 patients, after controlling for age, cardiac risk factors, troponin level, and ECG, low eGFR was associated with risk of acute coronary syndrome (adjusted odds ratio 1.64 for eGFR 60 to 90 mL/minute per 1.73 m2 and 1.70 for eGFR ⬍60 mL/minute per 1.73 m2). How this is relevant to clinical practice This is unlikely to change practice, though clinicians should be aware that abnormal renal function is associated with acute coronary syndrome risk in emergency department patients with chest pain. acute coronary syndrome in the population of patients investigated for chest pain.17-19 Importance Current risk-stratification procedures miss up to 6% of all acute coronary syndrome–related conditions,20-22 and individuals with a missed diagnosis of acute coronary syndrome have short-term mortality of 10% to 26%.23-25 Patients with renal impairment are a particular diagnostic challenge for clinicians. They are twice as likely to have a missed acute myocardial infarction,26 as they often present with symptoms that are atypical for acute coronary syndrome. For patients who present with abnormal kidney function results in the absence of previous test results, it is difficult to determine the acuity of these findings. It is unclear whether abnormal kidney function (irrespective of whether there is known or unknown kidney disease) on ED presentation is associated with higher acute coronary syndrome risk. Describing the sample of patients who present to the ED with abnormal kidney function and identifying the predictive value of abnormal kidney results on ED presentation (irrespective of known preexisting kidney disease) will provide physicians with important information to assist in acute coronary syndrome risk stratification. Goals of This Investigation The major goal is to determine whether the finding of abnormal kidney function in ED patients is predictive of 30-day 2 Annals of Emergency Medicine
Greenslade et al risk for acute coronary syndrome in the population of adult ED patients presenting with symptoms of possible acute coronary syndrome. Our hypothesis, based on population studies, was that there would be an independent association between the eGFR and acute coronary syndrome. This study also sought to describe the presenting features of patients with and without abnormal kidney results.
MATERIALS AND METHODS Study Design and Setting This is an analysis of prospectively collected data from 2 EDs: Brisbane, Australia, and Christchurch, New Zealand. Most participants were recruited as part of the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT),27 but we also included additional patients through ongoing post-ASPECT recruitment at both centers. Selection of Participants Patients were recruited during working hours (8 AM to 5 PM) and included if they were aged 18 years or older, presented to the ED with at least 5 minutes’ worth of chest pain suggestive of acute coronary syndrome (in accordance with American Heart Association case definitions28), and were being evaluated for acute coronary syndrome. The American Heart Association describes pain suggestive of acute coronary syndrome as acute chest, epigastric, neck, jaw, or arm pain or discomfort or pressure without an apparent noncardiac source. Recruitment was performed by research staff in collaboration with the senior treating clinician. Patients were excluded if there was a clear non–acute coronary syndrome cause for their symptoms, they were unwilling or unable to provide informed consent (eg, language barrier), staff considered that recruitment was inappropriate (eg, terminal illness), they were transferred from another hospital, were pregnant, were previously recruited to the study within the past 45 days, or were unable or unwilling to be contacted after discharge. Recruitment included consecutive eligible cases during working hours at each site. Enrollment occurred between November 2007 and July 2010. However, each site started and finished at different times according to local logistics. All patients were managed according to standard care at their local hospital, which uniformly included ECG and troponin testing on presentation and greater than or equal to 6 hours after presentation to the ED. Methods of Measurement Data were collected prospectively, using definitions outlined by Cullen et al.29 Trained research nursing staff collected demographic and clinical data directly from patient interviews in a standardized manner. Patient interviews also were crosschecked with patient notes. A patient was presumed to be positive for a risk factor if the factor was self-reported during the interview or if a cardiologist or senior emergency physician recorded the risk factor in the medical record. Patients were Volume xx, . x : Month
Greenslade et al recorded to have a family history of coronary artery disease (CAD) if they had a first-degree relative with CAD who was younger than 65 years. Troponin measurements were taken as part of standard care. One hospital used the Beckman Coulter second-generation AccuTnI (Beckman Coulter, Chaska, MN). The second used the Abbott Architect cTnI assay (Abbott, Inc., Chicago, IL). A value above the 99th percentile of greater than 0.04 g/L and greater than 0.030 g/L, respectively, was considered abnormal. Each patient’s serum creatinine level was measured on the first blood sample drawn on admission to the ED. GFR was estimated with the chronic kidney disease epidemiologic collaboration equation, with the modification of diet in renal disease (MDRD) equation also calculated for use in sensitivity analyses. Telephone follow-up and medical record review was conducted 30 days after initial attendance for the diagnosis of acute coronary syndrome. This follow-up was conducted by trained research nurses. Information was obtained from the patient and from hospital databases about whether there had been any cardiac events, investigations, or contact with any health care providers during the 30-day period. All follow-up information was verified through contact with the health care provider, and original copies of medical records and investigations were obtained. Data coordination, monitoring, and source verification were performed by an independent university clinical research organization at a nonrecruitment location in Australia (CCRE Therapeutics, Monash University, Melbourne). Approval was obtained from local ethics committees, and all patients provided written informed consent. Outcome Measures The primary outcome was a diagnosis of acute coronary syndrome (including adverse cardiac events) occurring on presentation or within 30 days of admission. The acute coronary syndrome endpoint included death (cardiovascular), cardiac arrest, revascularization procedure, cardiogenic shock, acute myocardial infarction, and unstable angina pectoris. Local cardiologists adjudicated the outcome independently, using predefined standardized reporting guidelines. Cardiologists had knowledge of the clinical record and ECG and troponin results from standard care. Creatinine results were available to the cardiologists, but they did not have knowledge of the study hypothesis at adjudication. A second cardiologist conducted a blind review of all acute coronary syndrome cases and 10% of non–acute coronary syndrome cases. In cases of disagreement, endpoints were agreed on by consensus. This was achieved for all endpoints. Criteria used to diagnose acute myocardial infarction and unstable angina pectoris are outlined in Figure 1. Primary Data Analysis Power calculations were conducted with G-Power (version 3.1; Heinrich Heine Universität, Dusseldorf, Germany).30 Research in the Asia Pacific region has found baseline rates of cardiac events between 15%31 and 20%.6 Previous ED Volume xx, . x : Month
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Figure 1. Criteria used to diagnose acute myocardial infarction (AMI) and unstable angina pectoris (UAP). ACS, Acute coronary syndrome.
research17 found an odds ratio (OR) for acute coronary syndrome of 1.65. Using this OR, using a 15% baseline event rate as the most conservative figure, and presuming a moderate correlation between confounders (R2⫽0.3), a minimum of 1,285 participants would be required in this study to achieve power of 95% with ␣⫽.05. The eGFR was categorized according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative classification of chronic kidney disease,32 which uses the following ranges: greater than or equal to 90, 60 to 89, 30 to 59, 15 to 26, and less than 15 mL/minute per 1.73 m2. However, in line with previous research,33 we combined 30 to 59, 15 to 29, and less than 15 mL/minute per 1.73 m2 into 1 category because of inadequate numbers in the lower 2 categories (n⫽50 and 12, respectively). For the remainder of the article, we term eGFR greater than or equal to 90 mL/minute per 1.73 m2 normal renal function, eGFR 60 to 89 mL/minute per 1.73 m2 borderline renal impairment, and eGFR less than 60 mL/minute per 1.73 m2 renal impairment. For all inferential statistics, age was categorized as younger than 40 years, 40 to 65 years, and older than 65 years, in accordance with previous research.7 Data were analyzed with SPSS (version 19; SPSS, Inc., Chicago, IL). Annals of Emergency Medicine 3
Renal Impairment as a Risk Factor for Acute Coronary Syndrome Baseline characteristics of the sample were described for patients across the 3 categories of eGFR, using number and proportion for categorical data and median and interquartile range for continuous data. Unadjusted rates of clinical outcomes and 95% confidence intervals (CIs) for each category of eGFR also were reported. To describe the sample of patients presenting with and without reduced eGFR, we report the presenting features of patients across categories of eGFR. The proportion of patients with various symptoms, new ischemia on ECG, and positive troponin results was calculated for each category of eGFR. To ensure that such proportions were not obscured by potential differences in the proportion of patients with acute coronary syndrome in each eGFR category, adjusted proportions were reported. Specifically, we adjusted the proportions in each eGFR category for acute coronary syndrome by directly standardizing to the acute coronary syndrome distribution in the overall sample. Multivariate logistic regression analyses were then performed to assess the primary goal of this study, namely, whether eGFR was associated with acute coronary syndrome. We included a priori– determined confounders, including age, sex, hypertension, dyslipidemia, family history of cardiac disease, diabetes, previous acute myocardial infarction, previous coronary artery bypass grafting (CABG), previous revascularization, previous angina, cardiac troponin level on presentation (normal versus abnormal), and ECG (new ischemic changes versus no new ischemic changes). These variables were chosen because they comprise the main risk factors and diagnostic methods currently used in ED setting as recommended by international guidelines.3-5 All risk factors were entered as dichotomous variables in the regression model. For details of additional regression analyses, see Figure E1 (available online at http://www.annemergmed.com). For the logistic regression analyses, we used only patients who required investigation for acute coronary syndrome in the ED. Therefore, we removed 40 patients with ST-segment elevation on their initial ECG because this group had a clear diagnosis and required urgent reperfusion. No other patients had a known diagnosis on presentation to the ED. Regression diagnostics were performed to test for collinearity among the explanatory variables. In all instances, the tolerance was above 0.2 and the variance inflation factor below 5 (values less than 0.1 and greater than 10, respectively, indicate issues with multicolinearity). Three sets of sensitivity analyses also were conducted. The first categorized the sample into low or intermediate/high risk for acute coronary syndrome according to the thrombolysis in myocardial infarction (TIMI) risk score. The proportion of patients with acute coronary syndrome across categories of eGFR was then compared for low-risk patients and for intermediate/high-risk patients. The purpose of this analysis was to determine whether an abnormal eGFR result was predictive for acute coronary syndrome even for those patients whose acute 4 Annals of Emergency Medicine
Greenslade et al coronary syndrome risk is otherwise low. Previous research has indicated that patients with a TIMI score of 0 or 1 are low risk for acute coronary syndrome.34 Therefore, low-risk patients were those with a TIMI score of 0 or 1, whereas intermediate/ high-risk were those with a TIMI score greater than 1. The second sensitivity analysis repeated the logistic regression analyses above but incorporated the MDRD equation for estimating GFR instead of the epidemiologic collaboration equation. Such analyses sought to ensure that the method of estimating GFR did not influence the results. The third repeated the logistic regression analysis, using acute myocardial infarction rather than acute coronary syndrome as the outcome to ensure that the results were not altered by the large proportion of patients with unstable angina pectoris.
RESULTS Of the eligible cohort for this study, 192 patients declined participation and 8 patients were excluded because they had incomplete data. No enrolled patients were lost to follow-up. A total of 1,968 patients had complete data for this analysis. The sample was predominantly men (60%), with a median age of 60 years (interquartile range [IQR] 49 to 72 years). There were 421 patients (21.4%) with an adverse cardiac event or diagnosis of acute coronary syndrome within 30 days. Of these 421 patients, 407 (96.6%) had a cardiac event diagnosed while they were in the hospital. The predominant diagnoses were unstable angina (n⫽120) or non–ST-elevation myocardial infarction (NSTEMI) (n⫽272), with patients being able to have more than 1 event. Patients with renal impairment were older, more likely to be women, less likely to be current smokers, and more likely to have hypertension, dyslipidemia, diabetes, and a history of cardiac illness than patients with normal renal function (Table 1). After adjusting for diagnosis of acute coronary syndrome, the proportion of patients with new ischemia on their presentation ECG was similar across groups. However, the proportion of patients with a positive troponin result was higher for patients with lower eGFR. Patients with reduced eGFR were less likely to report that various factors exacerbated their chest pain, such as inspiration, palpation, and exertion. They also were more likely to report chest pain that occurred at rest and less likely to report diaphoresis (Table 2). The unadjusted proportion of patients who had an event increased sharply as the estimated GFR decreased, ranging from 10.7% with normal renal function to 34.5% with renal impairment (Figure 2). The unadjusted proportion of patients with ST-elevation myocardial infarction (STEMI) was similar across all categories of eGFR. The proportions of patients with NSTEMI increased from 5.6% with normal renal function to 25.3% with renal impairment. Similarly, the proportion of patients with unstable angina pectoris increased from 3.7% with normal renal function to 8.5% with renal impairment (Table E1, available online at http://www.annemergmed.com). The results of the logistic regression model found that after controlling for baseline characteristics, risk factors, ECG findings, and troponin level, patients with borderline renal Volume xx, . x : Month
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Table 1. Baseline characteristics for patients according to the eGFR on presentation.* eGFR on Presentation, mL/min per 1.73 m2 Characteristic Age, y Male sex Hypertension Dyslipidemia Diabetes Family history of CAD Smoking Number of risk factors† 0 1 2 or more Medical history CHF Stroke Myocardial infarction PCI CABG Angina PAD
Total Cohort, nⴝ1,968
>90, nⴝ694 (Normal Renal Function)
60–89, nⴝ886 (Borderline Renal Impairment)
<60, nⴝ388 (Renal Impairment)
60 (49–72) 1,180 (60.0) 1,016 (51.6) 1,117 (56.8) 259 (13.2) 1,121 (57.0) 371 (18.9)
49 (41–56) 463 (66.7) 231 (33.3) 287 (41.4) 66 (9.5) 353 (50.9) 219 (31.6)
62 (54–71) 514 (58.0) 483 (54.5) 538 (60.7) 116 (13.1) 536 (60.5) 123 (13.9)
78 (70–83) 203 (52.3) 302 (77.8) 292 (75.3) 77 (19.8) 232 (59.8) 29 (7.5)
222 (11.3) 472 (24) 1,274 (64.7)
116 (16.7) 217 (31.3) 361 (52.0)
86 (9.7) 202 (22.8) 598 (67.5)
20 (5.2) 53 (13.7) 315 (81.1)
153 (7.8) 217 (11.0) 471 (23.9) 357 (18.1) 170 (8.6) 709 (36.0) 69 (3.5)
8 (1.2) 36 (5.2) 93 (13.4) 69 (9.9) 22 (3.2) 126 (18.2) 9 (1.3)
59 (6.7) 94 (10.6) 204 (23) 175 (19.8) 71 (8.0) 326 (36.8) 18 (2.0)
86 (22.2) 87 (22.4) 174 (44.8) 113 (29.1) 77 (19.8) 257 (66.2) 42 (10.8)
CHF, Congestive heart failure; PCI, percutaneous coronary intervention; PAD, peripheral arterial disease. *Data are median (IQR) or No. (%). † Using risk factors defined in the TIMI risk score.
Table 2. Presenting features of patients directly standardized for diagnosis of acute coronary syndrome according to the eGFR on presentation.* eGFR on Presentation, mL/min per 1.73 m2 Characteristic
>90, nⴝ694 (Normal Renal Function)
60–89, nⴝ886 (Borderline Renal Impairment)
<60, nⴝ388 (Renal Impairment)
82.1 (79.0–85.2) 29.9 (26.4–33.4) 11.5 (9.2–13.8) 12.2 (9.7–14.8) 53.6 (49.7–57.5) 7.3 (5.0–9.6) 15.5 (12.9–18.2)
85.6 (83.2–87.9) 16.5 (14.1–19.0) 6.9 (5.2–8.6) 5.5 (4.0–7.0) 50.8 (47.5–54.1) 6.7 (5.2–8.3) 16.5 (14.5–18.4)
88.3 (85.0–91.6) 17.6 (13.6–21.5) 5.7 (3.2–8.2) 4.5 (2.3–6.7) 45.7 (40.5–50.8) 6.0 (3.7–8.3) 21.8 (18.4–25.1)
Presenting symptoms Pain occurred at rest Pleuritic pain Pain on palpation Pain on exertion Diaphoresis New ischemia on ECG Positive troponin result *Reported data are percentage (95% CI).
impairment were 1.64 (95% CI 1.10 to 2.44) times as likely to have acute coronary syndrome compared with patients with normal renal function. Similarly, patients with renal impairment were 1.7 times (95% CI 1.01 to 2.77) more likely to have acute coronary syndrome compared with patients with normal renal function. Other significant predictors of acute coronary syndrome were male sex (OR⫽1.6), age (4.2 for aged 40 to 65 years and 6.1 for aged ⬎65 years), hypertension (OR⫽1.6), family history (OR⫽1.6), dyslipidemia (OR⫽1.49), ischemic ECG (OR⫽2.14), and positive troponin result (OR⫽23.92) (Figure 3). Sensitivity Analyses The proportion of patients with acute coronary syndrome across categories of eGFR was calculated for the 872 patients Volume xx, . x : Month
with TIMI score 0 or 1 (low risk) and for the 1,049 patients with TIMI score greater than 1 (intermediate- to high-risk patients). There were 5 patients without necessary data to calculate a TIMI score, and so these patients were not included in the analysis. For low risk, 53.8% of patients had normal renal function, 41.6% had borderline renal impairment, and 4.6% had renal impairment. The proportion of patients with acute coronary syndrome increased from 4.1% for patients with normal renal function to 11.3% with borderline renal impairment (percentage difference⫽7.2%; 95% CI 3.6% to 11.2%); 7.5% of patients with renal impairment had acute coronary syndrome. However, the small number of patients with an eGFR less than 60 mL/minute per 1.73 m2 meant that the uncertainty around this percentage was high (95% CI 2.6% to 19.9%). Annals of Emergency Medicine 5
Renal Impairment as a Risk Factor for Acute Coronary Syndrome
Greenslade et al
Figure 2. Proportion of patients with ACS, STEMI, NSTEMI, and UAP according to estimated GFR. Error bars represent 95% CIs.
For intermediate/high-risk patients (TIMI score ⬎1), 19.8% had normal renal function, 47.9% had borderline renal impairment, and 32.3% had renal impairment. The proportion of patients with acute coronary syndrome was 22.6% for normal renal function. This increased to 31.7% in patients with borderline renal impairment (percentage difference⫽9.1%; 95% CI 1.8% to 15.7%) and 37.2% with renal impairment (percentage difference 14.6%; 95% CI 6.7% to 21.9%). Analyses were repeated with the MDRD equation for estimating GFR. Such analyses supported the results above. The unadjusted proportion of patients with acute coronary syndrome was 8.8%, 20.6%, and 31.4% in normal renal function, borderline renal impairment, and renal impairment groups, respectively. After controlling for baseline characteristics, risk factors, ECG, and troponin level, patients with an MDRD eGFR indicating borderline renal impairment were 1.9 times (95% CI 1.2 to 3.0) more likely to have acute coronary syndrome compared with patients with normal renal function. Patients with an MDRD eGFR indicating renal impairment were 2.0 times (95% CI 1.2 to 3.4) more likely to have acute coronary syndrome compared with patients with normal renal function. Analyses also were repeated with acute myocardial infarction rather than acute coronary syndrome as the endpoint. There were 280 patients (14.5%) who met the criteria for acute myocardial infarction. Results again yielded findings similar to those of the primary analyses. Adjusted ORs for acute myocardial infarction were 2.0 (95% CI 1.17 to 3.53) in the group of patients with borderline renal impairment and 2.33 (95% CI 1.2 to 4.7) in the group of patients with renal impairment. 6 Annals of Emergency Medicine
LIMITATIONS Our study has several limitations. First, we used a single measurement of creatinine on presentation to estimate the patient’s GFR. Therefore, patients with renal impairment but normal creatinine levels would belong in the group of patients with normal renal function. Second, some patients in groups with reduced eGFR may have acute kidney injury, rather than chronic renal impairment and we are unable to distinguish between these patients by using creatinine on presentation. It is likely that patients with chronic and acute renal impairment have different acute coronary syndrome risk, and therefore future research could benefit from using serial creatinine measurements or assessing reported history of chronic kidney disease to identify acute versus chronic renal impairment. However, emergency physicians are often presented with a single creatinine measurement in the absence of knowledge of previous test results, and thus the use of a single measurement is clinically relevant. Second, recruitment occurred during local working hours. Data are not available on the number of patients presenting after hours or the cohort who met exclusion criteria in this study; thus, the extent of potential selection bias is unable to be quantified. Third, the study was not powered to determine whether there were differences in the proportion of patients with STEMI across categories of eGFR. Therefore, it is possible that the null result in the STEMI analysis was due to a lack of power. Fourth, we did not collect data on whether troponin elevations were acute or chronic. Patients with chronic troponin elevations and renal impairment are likely to have a Volume xx, . x : Month
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Figure 3. Logistic regression analysis examining the association between eGFR and ACS. Triangles are ORs and whiskers are 95% CIs. ORs are adjusted for risk factors, troponin level greater than 99th percentile, and new ischemic changes on presentation ECG. The comparator for eGFR is greater than 90 mL/minute per 1.73 m2. Data are presented on a logarithmic scale. MI, Myocardial infarction.
poor prognosis and further clarity on the development of acute coronary syndrome could be gained by incorporating such data.
DISCUSSION Our study found that reduced eGFR on presentation (irrespective of whether it is acute or chronic) is associated with increased risk of NSTEMI and unstable angina pectoris in the population of patients presenting to the ED with chest pain. The increased risk of acute coronary syndrome occurred both for minor and more severe renal impairment and was independent of risk factors, ischemic ECG, and abnormal troponin findings. Patients with reduced eGFR were at higher acute coronary syndrome risk regardless of whether they had low or high acute coronary syndrome risk according to the TIMI score. Our findings align with those of large population-based studies investigating the risk of coronary events in patients with renal dysfunction.9,33 They support the body of literature indicating that poor renal function portends poor prognosis in patients receiving a diagnosis of acute coronary syndrome.10-14 Our study extends previous research by finding an association of similar magnitude to that reported in population studies in the population of patients presenting to the ED for chest pain. However, these finding are in contrast to those of previous research conducted in the ED setting. Limkakeng and Volume xx, . x : Month
Renal Impairment as a Risk Factor for Acute Coronary Syndrome Chandra17 studied a low-risk population of patients evaluated for acute coronary syndrome in an emergency setting and found that renal impairment did not increase the risk of acute coronary syndrome in patients without risk factors. Similarly, a study of intermediate-risk patients presenting to the ED with chest pain found that patients with chronic kidney disease had a higher admission rate but had similar rates of acute myocardial infarction, revascularization, and inhospital death than patients without kidney disease.18 Finally, Chang et al19 found that abnormal creatinine values were not predictive of inhospital acute myocardial infarction but were associated with increased odds of 30-day cardiovascular events. A number of differences between our study and the previous research may account for the contradictory results. First, with the exception of the study by Chang et al,19 previous studies have used smaller cohorts, which may have resulted in reduced power to detect a relationship between renal impairment and acute coronary syndrome. Second, previous studies have used slightly different patient populations (ED patients at low or intermediate risk for acute coronary syndrome) and different endpoint classification such as the diagnosis of acute coronary syndrome according to a positive stress test result17 or diagnosis of acute myocardial infarction during admission rather than 30-day acute coronary syndrome.18 The major clinical implication of our research is that a finding of reduced eGFR on presentation is a marker of increased acute coronary syndrome risk regardless of whether the patient has other risk factors or abnormal diagnostic test results on presentation. Even for patients who would otherwise be considered low risk for acute coronary syndrome, a mildly abnormal eGFR is associated with an increased likelihood of acute coronary syndrome. Patients with a reduced eGFR are twice as likely to have a missed acute myocardial infarction compared with patients with normal renal function26 and are less likely to receive anticoagulant therapy and revascularization for acute myocardial infarction.35 Our study finding supports the need for thorough cardiac assessment and treatment in patients with a reduced eGFR. Such testing may subsequently affect their overall morbidity and mortality by reducing the delays to treatment that are associated with poor outcomes.36-38 The second implication of our study is that it supports the decision to include reduced eGFR as a risk factor in some riskstratification models, including the Global Registry of Acute Coronary Events (GRACE) score and the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand guidelines.15,16 Our finding that patients with renal impairment present with different symptoms than patients without renal impairment extends on previous research. Patients with renal dysfunction have been shown to be less likely to present with chest pain and more likely to present with other symptoms such as dyspnea.35,39 Our findings were contradictory, indicating that patients with reduced eGFR are less likely to present with atypical symptoms, which is likely to be related to the different Annals of Emergency Medicine 7
Renal Impairment as a Risk Factor for Acute Coronary Syndrome symptoms recorded and populations studied. That is, previous research has focused only on patients with confirmed acute myocardial infarction and specifically focused on pain location. Our study focused on the broader group of patients being investigated for acute coronary syndrome and examined a number of atypical symptoms. In summary, the identification of patients with potential acute coronary syndrome in the ED is complex and incorporates the physician’s evaluation of clinical risk factors. Our study indicates that there is an association between decreased eGFR (irrespective of whether this is known to be long-standing or acute) and acute coronary syndrome risk in patients presenting to the ED with chest pain. This association is independent of traditional cardiac risk factors, troponin levels, and ECG findings. Clinicians should maintain high clinical suspicion for acute coronary syndrome in patients with abnormal renal function results regardless of whether they have traditional acute coronary syndrome risk factors or abnormal diagnostic test results. Reduced eGFR should be included as a high-risk feature in ED-based risk-stratification tools. Supervising editor: Judd E. Hollander, MD Author affiliations: From the Department of Emergency Medicine (Greenslade, Cullen, Kalinowski, Chu, Brown) and Department of Cardiology (Parsonage), Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia; the School of Medicine, University of Queensland, Herston, Queensland, Australia (Greenslade, Cullen, Parsonage, Chu, Brown); the School of Public Health, Queensland University of Technology, Kelvin Grove, Queensland, Australia (Greenslade, Cullen); the School of Medicine (Palmer, Troughton, Pemberton, Than) and Christchurch Cardioendocrine Research Group (Richards), University of Otago, Christchurch, New Zealand; and the Department of Cardiology (Aldous, Richards, Troughton) and Department of Emergency Medicine (Than), Christchurch Hospital, Christchurch, New Zealand. Author contributions: JHG, LC, WP, SA, MR, and MT contributed to study design. LC, WP, SA, MR, and MT were responsible for data collection. JHG analyzed and interpreted data. JHG, LC, and LK wrote the article, and all authors made critical intellectual contribution. All authors have read and approved the article. JHG takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). This work was supported largely by the Queensland Emergency Medicine Research Foundation (grant QEMRF-PROJ-2008-002) and Christchurch Cardioendocrine Research Group (New Zealand), with small contributions from Alere Medical (⬍20%). Dr. Cullen reports receiving research grants from Alere (formerly Inverness Medical), Radiometer Pacific, Abbott Diagnostics, Roche, and Siemens; consultancy fees from Abbott Diagnostics; and support to attend meetings
8 Annals of Emergency Medicine
Greenslade et al and conferences from Abbott Diagnostics, Alere, Radiometer Pacific, Pfizer, and Boehringer Ingelheim. Dr. Parsonage reports receiving research grants from Genzyme Corp. and Inverness Medical; consultancy fees from Abbott, AstraZeneca, and Hospira; and support to attend meetings and conferences from Abbott, Sanofi-Aventis, and AstraZeneca. Dr. Richards reports accepting travel support and speakers honoraria from Alere. AFTB reports receiving consultancy fees from Boehringer Ingelheim, support to attend meeting and conferences from AstraZeneca, and educational support from Roche and Hoechst. Dr. Troughton reports receiving consultancy fees from St Jude Medical. Dr. Than reports receiving funds from Alere and Abbott for research support, speaking, and travel reimbursement. Publication dates: Received for publication October 31, 2012. Revision received December 17, 2012. Accepted for publication January 4, 2013. Address for correspondence: Jaimi H. Greenslade, PhD, E-mail [email protected]. REFERENCES 1. Goodacre S, Cross E, Arnold J, et al. The health care burden of acute chest pain. Heart. 2005;91:229-230. 2. Hollander JE. The continuing search to identify the very-low-risk chest pain patient. Acad Emerg Med. 1999;6:979-981. 3. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2777785007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50:e1-e157. 4. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007;50:2173-2195. 5. Rapezzi C, Biagini E, Branzi A. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: the Task Force for the Diagnosis and Treatment of Non-STSegment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J. 2008;29:277-278. 6. Greenslade J, Cullen L, Parsonage WA, et al. Examining the signs and symptoms experienced by individuals with suspected acute coronary syndrome in the Asia-Pacific region: a prospective observational study. Ann Emerg Med. 2012;60:777-785. 7. Han JH, Lindsell CJ, Storrow AB, et al. The role of cardiac risk factor burden in diagnosing acute coronary syndromes in the emergency department setting. Ann Emerg Med. 2007;49:145152. 8. Jayes RI Jr, Beshansky JR, D’Agostino RB, et al. Do patients’ coronary risk factor reports predict acute cardiac ischemia in the emergency department? a multicenter study. J Clin Epidemiol. 1992;45:621-626. 9. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305. 10. Langston RD, Presley R, Flanders WD, et al. Renal insufficiency and anemia are independent risk factors for death among
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patients with acute myocardial infarction. Kidney Int. 2003;64:1398-1405. Gibson CM, Dumaine RL, Gelfand EV, et al. Association of glomerular filtration rate on presentation with subsequent mortality in non-ST-segment elevation acute coronary syndrome: observations in 13,307 patients in five TIMI trials. Eur Heart J. 2004;25:1998-2005. Gibson CM, Pinto DS, Murphy SA, et al. Association of creatinine and creatinine clearance on presentation in acute myocardial infarction with subsequent mortality. J Am Coll Cardiol. 2003;42: 1535-1543. Al Suwaidi J, Reddan DN, Williams K, et al. Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes. Circulation. 2002;106:974-980. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351:1285-1295. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004;291:2727-2733. Chew D, Aroney C, Aylward P, et al. 2011 Addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the management of acute coronary syndromes (ACS) 2006. Heart Lung Circ. 2011; 20:487-502. Limkakeng AT Jr, Chandra A. Impact of renal dysfunction on acute coronary syndrome evaluation in observation unit patients. Am J Emerg Med. 2010;28:658-662. Khambatta S, Farkouh ME, Wright RS, et al. Chronic kidney disease as a risk factor for acute coronary syndromes in patients presenting to the emergency room with chest pain. Transl Res. 2011;159:391-396. Chang AM, Edwards M, Matsuura AC, et al. Relationship between renal dysfunction and outcomes in emergency department patients with potential acute coronary syndromes. Emerg Med J. [Epub ahead of print] doi:10.1136/emermed-2011-200536. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342:1163-1170. Collinson PO, Premachandram S, Hashemi K. Prospective audit of incidence of prognostically important myocardial damage in patients discharged from emergency department. BMJ. 2000; 320:1702-1705. Aldous SJ, Richards M, Cullen L, et al. A 2-hour Thrombolysis in Myocardial Infarction score outperforms other risk stratification tools in patients presenting with possible acute coronary syndromes: comparison of chest pain risk stratification tools. Am Heart J. 164:516 –523. Lee TH, Rouan GW, Weisberg MC, et al. Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room. Am J Cardiol. 1987;60: 219-224. McCarthy BD, Beshansky JR, D’Agostino RB, et al. Missed diagnoses of acute myocardial infarction in the emergency department: results from a multicenter study. Ann Emerg Med. 1993;22:579-582.
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Renal Impairment as a Risk Factor for Acute Coronary Syndrome 25. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342:1163-1170. 26. Herzog CA, Littrell K, Arko C, et al. Clinical characteristics of dialysis patients with acute myocardial infarction in the United States: a collaborative project of the United States Renal Data System and the National Registry of Myocardial Infarction. Circulation. 2007;116:1465-1472. 27. Than M, Cullen L, Reid CM, et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet. 2011;377:1077-1084. 28. Luepker RV, Apple FS, Christenson RH, et al. Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; the European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart, Lung, and Blood Institute. Circulation. 2003; 108:2543-2549. 29. Cullen L, Than M, Brown AFT, et al. Comprehensive standardized data definitions for acute coronary syndrome research in emergency departments in Australasia. Emerg Med Australas. 2010;22:35-55. 30. Faul F, Erdfelder E, Lang A-G, et al. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2009;39:175-191. 31. Than M, Cullen L, Aldous S, et al. 2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial. J Am Coll Cardiol. 2012;59:2091-2098. 32. The Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-266. 33. Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet. 2012;380:807814. 34. Macdonald SPJ, Nagree Y, Fatovich DM, et al. Comparison of two clinical scoring systems for emergency department risk stratification of suspected acute coronary syndrome. Emerg Med Australas. 2011;23:717-725. 35. Szummer KLP, Jacobson SH, Schon S, et al. Relation between renal function, presentation, use of therapies and in-hospital complications in acute coronary syndrome: data from the SWEDEHEART register. J Intern Med. 2010;268:40-49. 36. Keeley EC, Hillis LD. Primary PCI for myocardial infarction with ST-segment elevation. N Engl J Med. 2007;356:47-54. 37. Nallamonthu B, Bradley E, Krumholz H. Time to treatment in primary percutaneous coronary intervention. N Engl J Med. 2007; 357:1631-1638. 38. De Luca G, Suryapranata H, Marino P. Reperfusion strategies in acute ST-elevation myocardial infarction: an overview of current status. Prog Cardiovasc Dis. 2008;50:352-382. 39. Sosnov J, Lessard D, Goldberg RJ, et al. Differential symptoms of acute myocardial infarction in patients with kidney disease: a community-wide perspective. Am J Kidney Dis. 2006;47:378-384.
Annals of Emergency Medicine 9
Renal Impairment as a Risk Factor for Acute Coronary Syndrome
Greenslade et al Table E1. Difference between the percentage of patients with cardiac diagnosis (and 95% CI of the difference) across categories of eGFR.
Cardiac Diagnosis ACS STEMI NSTEMI UAP
eGFR % Difference (95% CI of Difference), mL/min per 1.73 m2 >90 vs 60–89
>90 vs <60
60–89 vs <60
13.4 (9.7 to 17) 23.9 (18.7 to 29.2) 10.5 (5.1 to 16.1) ⫺0.3 (⫺1.6 to 0.8) ⫺0.4 (⫺1.8 to 1.3) ⫺0.1 (⫺1.2 to 1.6) 10.2 (7.2 to 13.1) 19.6 (15.1 to 24.4) 9.5 (4.7 to 14.5) 3.6 (1.3 to 5.8) 438 (1.8 to 8.2) 1.2 (–1.9 to 4.7)
Figure E1. Additional logistic regression models.
9.e1 Annals of Emergency Medicine
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