American Journal of Emergency Medicine 32 (2014) 1339–1344
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Original Contribution
Prospective validation of Thrombolysis in Myocardial Infarction and front door Thrombolysis in Myocardial Infarction risk scores in Chinese patients presenting to the ED with chest pain☆ Colin A. Graham, MD, MPH ⁎, Jannet W.M. Chan, BMedSci, MBBS, Cangel P.Y. Chan, BSc, PhD, Giles N. Cattermole, MA, BM, BCh, Timothy H. Rainer, BSc, MD Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR
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Article history: Received 26 May 2014 Received in revised form 11 August 2014 Accepted 12 August 2014
a b s t r a c t Background: Chest pain is a common complaint among emergency department (ED) patients. The Thrombolysis in Myocardial Infarction (TIMI) and front door TIMI (FDTIMI) scores are used to risk stratify chest pain patients in many Western countries; they have not been validated in patients with undifferentiated chest pain in Asia. Our objective was to establish the relationship between the TIMI and FDTIMI scores and the 30 day rate of major adverse cardiac outcomes (MACE) in Chinese patients presenting to the ED with chest pain. Methods: Prospective, single-center, observational cohort study of consecutive patients presenting with chest pain from July 2009 until March 2010 to a Hong Kong university hospital ED. Data collected included patient characteristics, TIMI items and past medical and medication history. Primary outcome was MACE within 30 days of presentation. MACE was a composite outcome of any of the following: death (all causes), readmission with myocardial infarction, acute coronary syndrome not diagnosed at initial ED presentation and coronary revascularization. Results: One thousand patients recruited with complete 30-day follow-up. STEMI patients (n = 75) were excluded. Mean patient age 66.8 ± 13.9 years; 51.7% male. 119 (12.9%) patients had MACE within 30 days of presentation. The incidence of MACE ranged from 0 for TIMI0 to 37.5% for patients with TIMI6/7. Increasing TIMI and FDTIMI scores were associated with a higher incidence of MACE. Conclusions: This validation suggests that the TIMI/FDTIMI scores can be employed in Hong Kong Chinese; they may be useful for risk stratification of Chinese ED patients with undifferentiated chest pain elsewhere. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Chest pain is a common presentation to the emergency department (ED) and early identification of acute coronary artery disease (CAD) is critically important. The World Health Organization reported that CAD is the commonest cause of death worldwide, claiming 7.2 million deaths in 2004 [1]. However, only a small proportion of ED chest pain patients have a diagnostic electrocardiogram (ECG) on presentation, and the challenge for the emergency physician and cardiologist is to risk stratify the patient with possible acute coronary syndrome (ACS). While it is clearly important not to discharge patients with ACS, the sheer volume of chest pain patients presenting to the ED makes admission of all patients logistically and financially impossible in most settings.
☆ Grant support: Health and Health Services Research Fund, Government of the Hong Kong Special Administrative Region, HHSRF 07080351, HK $488 480 (US $62 625). ⁎ Corresponding author. Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR. Tel.: +852 2632 1033; fax: +852 2648 1469. E-mail address: [email protected] (C.A. Graham). http://dx.doi.org/10.1016/j.ajem.2014.08.032 0735-6757/© 2014 Elsevier Inc. All rights reserved.
In the United States, approximately 8% of adults ≥ 20 years or older have previously suffered from ACS, contributing to one in six deaths in 2008 [2]. In Hong Kong, heart disease is the second most common cause of death, claiming 6777 lives in 2008, with coronary heart disease accounting for 67.5% of total cardiac mortality [3]. There is a significant difference in coronary event rates between Chinese patients and patients of Western origin [2] which may be due to the difference in lifestyle and body habitus between different ethnicities. The MONICA project demonstrated a significant difference of event rates and coronary death between various countries [4], and it is clear that the Chinese had a very low rate of cardiac events compared with Western participants. The Chinese had a lower rate of coronary deaths, three times lower than that of Indians [5]. Forouhi and Sattar [6] suggested that the difference in event rates could be due to lower levels of hyperlipidemia and obesity in the Chinese population. Validation of risk stratification tools, such as the Thrombolysis in Myocardial Infarction (TIMI) score and the front door TIMI score (FDTIMI), are therefore essential for Chinese populations, even though the score has been validated in Western countries. Antman [7] derived TIMI on patients with unstable angina or non– ST-segment elevation myocardial infarction (NSTEMI). One point is given for each of the components of TIMI, yielding a range of 0–7.
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Antman [7] validated TIMI in three separate cohorts of patients, demonstrating that TIMI could predict the rate of cardiac events in patients with unstable angina or NSTEMI, the TIMI score increasing with the rise in event rates. This study was not conducted in an unselected chest pain population, but retrospectively recruited all patients with a diagnosis of ACS, so these results may only be valid in patients with intermediate to high risk of adverse cardiac outcomes. Chase [8] prospectively recruited 1481 consecutive ED patients with unselected chest pain and demonstrated that TIMI could predict the risk of 30-day cardiac outcomes. A TIMI score of 0 did not infer no risk of ACS; this group still had a 1.7% risk of adverse outcomes. Soiza [9] validated TIMI using 869 patients with possible ACS. Only four of seven TIMI components directly correlated with event rates. TIMI was shown to be more effective in diagnosing ACS compared to ECG changes and troponin alone. In this study, the event rate may have been underestimated as TIMI was only validated in admitted patients. Morris [10] recruited 998 consecutive ED patients who had chest pain suggestive of cardiac origin and the rate of major adverse cardiac outcomes (MACE) was measured 30 days after ED presentation; TIMI had a good correlation with 30 day MACE. Other studies also suggest that TIMI correlates with adverse cardiac outcomes [11–13], although one suggested it was not valid [14]. Morris also studied FDTIMI, which is similar to TIMI, except it does not require cardiac markers for completion [10], yielding a range of 0 to 6. FDTIMI could be useful for prehospital personnel in identifying high risk patients prior to ED arrival. FDTIMI retained its ability to risk stratify patients, with high scores correlating with a higher incidence of cardiac events, although FDTIMI was not as sensitive or specific as TIMI [10]. The aim of this study was to validate TIMI and FDTIMI in Chinese ED patients presenting with undifferentiated chest pain by establishing the relationships between TIMI and FDTIMI and the 30-day MACE event rate. 2. Methods Ethical approval was obtained from the local Institutional Research Ethics Committee for this study (CRE 2008.351). This prospective observational cohort study was conducted in the ED of Prince of Wales Hospital (PWH). PWH is located in Shatin in Hong Kong; it is a university hospital with 1400 beds. It sees more than 150 000 new ED patients per annum and serves a local population of approximately 800 000 people. Consecutive ED patients ≥20 years old, with a chief complaint of chest pain or discomfort, were recruited from July 29, 2009, to March 12, 2010. Patients were excluded if they had a clearly non-cardiac cause of chest pain, such as spontaneous pneumothorax. Confirmed STEMI patients at ED presentation were also excluded as they do not have undifferentiated chest pain. Written informed consent was obtained from each patient or patient’s relative after a verbal and written explanation of the study was provided, in Chinese or English. Patients were informed that they may voluntarily withdraw from the study at any time. 2.1. Questionnaire design and data collection Data were collected from ED patients using a standardized questionnaire. The characteristics of the chest pain, vital signs, patient’s past medical history, family history of CAD and other information that help to make a diagnosis of ACS were recorded. Data were also obtained from the Clinical Management System (CMS). CMS is an integrated electronic system that allows inspection of the medical records of patients in public hospitals and clinics. The system does not contain information for patients who are followed up by private doctors, but those patients were asked to provide information about their past medical history in as much detail as possible. Data was collected on the scoring criteria for TIMI and FDTIMI. Patients scored one point for fulfilling each of the criteria, giving a total score of seven for TIMI and six for FDTIMI. As there is
inconsistency in the literature in classifying the seven characteristics of the scores, in this study the TIMI variables were defined as: 1. Age of 65 or older 2. At least 3 risk factors for CAD (including current smoker, hypertension, hyperlipidemia, diabetes mellitus and family history of CAD). 3. Known coronary stenosis of ≥50%. These include documented coronary stenosis ≥50%, previous MI, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). 4. ST deviation in the initial ECG. This was defined as at least 0.5 mm of STsegment elevation or depression in the first ECG. ECGs were routinely performed on all patients with suspected cardiac chest pain. The first ECG for each patient was reviewed by a single emergency medicine consultant for consistency, who was blinded to any patient information. 5. At least 2 episodes of angina in the past 24 hours. As people perceive pain in different ways, angina was defined as any chest pain, regardless of the pain nature and severity. If the patient reported that their pain started and never stopped, it was considered one episode of pain. Pain lasting ≥48 hours was entered into the database as 48 hours of pain. 6. Use of aspirin in the last seven days or more. This included patients who visited general practitioners or private hospitals and were given aspirin prior to ED presentation. Patients were asked whether they took aspirin and the researcher rechecked the CMS’s drug record to confirm long-term use of aspirin for patients who had follow-up in public clinics. 7. Raised cardiac markers at initial presentation, which was cardiac troponin T (cTnT) ≥0.03 μg/L according to local laboratory standards at the time of the study. Record logbooks at the ED triage station and the resuscitation rooms were used to ensure that all patients presented with chest pain had been recruited. ACS is an umbrella term for a spectrum of symptoms that are compatible with acute myocardial ischemia [15], consisting of unstable angina, NSTEMI and STEMI [16]. 2.2. Chest pain protocol (CPP) Guidelines recommend that patients with possible ACS but with a normal initial ECG and cardiac markers should be observed in a chest pain unit, where continuous cardiac monitoring and repeated measurement of cardiac markers is available [16]. In our centre at the time of the study, patients had their serum cTnT analyzed and the first ECG was performed at triage. These patients stayed in the ED for at least six hours to have their second cTnT sample analyzed and a second ECG performed. During this period, patients would be admitted if the cTnT level was elevated or the ECG showed abnormalities. Patients were discharged after six hours if they were pain free with two negative troponin tests (cTnT b 0.03 μg/L) and two ECGs with no new changes. 2.3. Outcomes 2.3.1. Primary outcome The primary outcome measure was the number of MACE occurring in 30 days after the patient attended the ED with chest pain. MACE was considered positive if at least one of the following had occurred within 30 days of ED presentation: 1. 2. 3. 4.
Death (all causes) Readmission with MI ACS not diagnosed at initial presentation Coronary revascularization (including PCI and CABG)
2.3.2. Secondary outcomes Each of the above events was individually considered to be a secondary outcome if it occurred within 30 days of ED presentation.
C.A. Graham et al. / American Journal of Emergency Medicine 32 (2014) 1339–1344
2.4. Follow-up Patients were followed up at day 30 (± 5 days) by reviewing CMS records. All deaths and admission records in the Hong Kong public health care system are recorded on the CMS. Patients were contacted by telephone if they did not reattend ED or were not readmitted to public hospitals during the follow up period to ensure that any MACE that occurred outside Hong Kong or under the care of private hospitals were detected.
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a CABG. The initial ED diagnosis for the patients in the study included acute myocardial infarction (22, 2.4%), ischemic heart disease (238, 25.7%), unstable angina (30, 3.2%), atypical chest pain (460, 49.7%) and non-ischemic chest pain (175, 18.9%).
3.2. TIMI and FDTIMI Table 1 shows the number of patients fulfilling each of TIMI criteria. Fig. 1 shows the distribution of TIMI and FDTIMI scores in the study.
2.5. Sample size calculation Based on previously published ED work from the UK with similar rates of ischemic heart disease [10], the event rate in low risk patients could be as high as 9.0% and that in high risk patients could be as low as 14.8%. To achieve adequate power to address the objective, using an α of 0.05 and a β of 0.2, the minimum number of patients was 972. 2.6. Statistical analysis Statistical analysis was performed using SPSS v17.0 (SPSS Inc, Chicago, IL) and Medcalc v9.5 (MedCalc Software, Mariakerke, Belgium). Categorical data were compared using Pearson’s chi-square test and receiver operating characteristic (ROC) curves were plotted to determine the sensitivity and specificity of the TIMI and FDTIMI. Statistical significance was set at P b .05. 3. Results 3.1. Baseline characteristics Between July 2009 and March 2010, 1028 consecutive patients were enrolled. 28 patients were excluded (12 patients refused to give consent, 15 patients could not communicate and one patient did not have chest pain). This left 1000 patients for possible analysis: 75 confirmed STEMI patients at ED presentation were then excluded, leaving 925 patients for analysis. 478 (51.7%) patients were male, the median age was 68 years (IQR 56-78) and 516 (55.8%) were 65 years or older. Men presented at a mean age of 64.6 years compared to women at 69.2 years. The mean duration of chest pain was 3.6 hours (SD 7.5 hours; range, 0-48). Among the 420 patients placed in the chest pain protocol, 50 were admitted to the general wards and 370 were discharged from the ED. The mean (SD) in-patient length of stay was 4.0 (4.29) days. During the 30-day follow up period, 16 (1.7%) patients died; 4 (0.4%) died of cardiac disease. 47 (5.1%) patients received CCU care and 81 (8.8%) patients had coronary revascularization, including 12 (1.3%) who had
Table 1 TIMI and FDTIMI components TIMI variables
No. (%)
1. Age ≥65 years old 2. At least 3 risk factors for coronary artery disease • Hypertension • Diabetes • Hyperlipidemia • Family history of coronary artery disease • Current smoker 3. Known coronary artery stenosis • Known coronary stenosis of ≥50% • Prior myocardial infarction • Prior PCI • Prior CABG 4. ST-segment deviation at initial presentation 5. At least 2 episodes of angina in prior 24 h 6. Use of aspirin for the past 7 days or more 7. Elevated cardiac markers
516 157 579 208 309 118 113 196 164 78 132 18 101 426 320 198
(55.8) (17.0) (62.6) (22.5) (33.4) (12.8) (12.2) (21.2) (17.7) (8.4) (14.3) (1.9) (10.9) (46.1) (34.6) (21.4)
Fig. 1. A, Distribution of TIMI among ED chest pain study participants. B, Distribution of FDTIMI among the participants.
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Table 2 Relationship between TIMI and 30 day MACE⁎ TIMI
No of patients in each TIMI group
Cardiac death (n = 4)
All-cause mortality (n = 16)
Readmit with MI (n = 9)
ACS not diagnosed at initial presentation (n = 30)
Coronary revascularization (n = 81)
MACE within each TIMI group (n = 119)
0 1 2 3 4 5 6/7
138 230 228 172 92 49 16
0 (0) 0 (0) 0 (0) 2 (1.2) 1 (1.1) 0 (0) 1 (6.2)
0 2 3 5 3 2 1
0 (0) 0 (0) 1 (0.4) 3 (1.7) 5 (5.4) 0 (0) 0 (0)
0 4 10 9 3 4 0
0 (0) 7 (3.0) 23 (10.1) 19 (11.0) 17 (18.5) 10 (20.4) 5 (31.2)
0 10 34 32 24 13 6
(0) (0.9) (1.3) (2.9) (3.3) (4.1) (6.2)
(0) (1.7) (4.4) (5.2) (3.3) (8.2) (0)
(0) (4.3) (14.9) (18.6) (26.1) (26.5) (37.5)
MACE are classified as the presence of at least one of the outcomes in 30 days: all-cause mortality, readmission with MI, ACS not diagnosed at initial presentation, and coronary revascularization. ⁎ All data are numbers (%).
3.3. TIMI and outcome within 30 days of ED presentation
4.1. Comparison between the performance of the TIMI and FDTIMI
In keeping with Morris' study [10], we combined TIMI 6 and 7 as the numbers in each group were small. The relationship of TIMI with the primary outcome is shown in Table 2 and Fig. 2. The all-cause mortality rate in our study (1.7%) was similar to those reported by Morris [10] (1.6%, P = .86, χ2 test) and Chase [8] (1.0%, P = .19, χ2 test).
TIMI was superior to FDTIMI for predicting MACE in clinical settings. However, there was no statistically significant difference between the performance of TIMI and FDTIMI, similar to Morris’ study [10]. The event rate of 12.9% was similar to the rate reported in UK and US studies [8,10]. The mean age in our study was 67 years, considerably older than in Morris’ study (59 years) [10] and Chase's study (53 years) [8]. The number of our patients who had coronary revascularization (81, 68%) was much higher than that of Morris [10] with a rate of 23% and slightly higher than that of Chase [8] with a rate of 55%. This may be due to increasing rates of cardiac catheterization and the fact that coronary revascularization (in particular, PCI) is now performed more frequently [18]. There were nine readmissions with acute myocardial infarction (AMI) while only one case and three cases were reported by Morris [10] and Chase [8] respectively. The all-cause mortality rate in our study (1.7%) was similar to that reported by Morris [10] and Chase [8].
3.4. FDTIMI and outcome within 30 days of ED presentation In keeping with Morris’ study [10], we combined FDTIMI 5 and 6 as the numbers in each group were small. Table 3 and Fig. 3 show the relationship of FDTIMI with the primary outcome. 3.5. ROC analysis for TIMI and FDTIMI ROC curve analysis for predicting MACE at 30 days gave an area under the curve for TIMI of 0.732 (95% CI 0.690–0.773, P b .001) and an area under the curve for FDTIMI of 0.652 (95% CI 0.602–0.701, P b .001).
4.2. Applying TIMI and FDTIMI in the ED setting 4. Discussion This is the first large scale prospective validation study on a Chinese population to establish the relationship between TIMI and FDTIMI and 30 day MACE. Our study included all ED patients with possible cardiac chest pain and was thus composed of more patients with low and intermediate risks of adverse cardiac outcomes than some of the previous studies [7,11]. Our results were similar to those of previous studies, showing a rise in 30 day MACE with increasing TIMI [8,10,11] and FDTIMI [10]. This suggests that TIMI may be a useful tool to stratify risk in Chinese patients with chest pain. This large study confirms previous findings in our initial study [17].
TIMI and FDTIMI have been shown to be useful tools to risk stratify ED patients with chest pain. It is easy to calculate and the risk score components can be routinely identified by ED triage nurses and doctors. The scoring systems can guide clinicians in the management of ED patients with chest pain. The scores can identify patients with high risk features who may benefit from early aggressive intervention and early consultation with cardiologists. 4.3. Patients with TIMI of zero Patients with very low risk as defined by a TIMI and FDTIMI of zero had a 0% and 1.3% of MACE respectively. This suggests that their risk of MACE is not zero, but their risk is acceptably low. From the ROC curve, the optimum cut-off is TIMI N 0 (score 1-7) with a sensitivity of 100 (95% CI, 96.9-100.0). This implies the event rate in low risk patients (TIMI = 0) could be as high as 3.1%. The rate is similar to the percentage of patients who are discharged from EDs with undiagnosed AMI by current practice (2–4%) [8]. This suggests patients with a TIMI of zero can be safely discharged from the ED with appropriate advice, in keeping with other recently published data [19]. 4.4. Patients with TIMI greater than 0
Fig. 2. Relationship between TIMI and MACE. MACE, major adverse cardiac events are classified as the presence of at least one of the following outcomes in 30 days: allcause mortality, readmission with MI, ACS not diagnosed at initial presentation and coronary revascularization.
Patients with TIMI N0 pose a challenge to ED doctors in terms of disposition. Their risk of MACE is significantly higher than those with TIMI = 0 (TIMI 1, 4.3%; FDTIMI 1, 11.8%). Those patients should either be admitted to hospital for further investigation of chest pain or be placed in the CPP to actively exclude ACS. Future studies should explore the value of TIMI and FDTIMI in stratifying the urgency of
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Table 3 Relationship between FDTIMI and 30-day MACE Front door TIMI
No. of patients in each FDTIMI group
Cardiac death (n = 4)
All-cause mortality (n = 16)
Readmit with MI (n = 9)
ACS not diagnosed at initial presentation (n = 30)
Coronary revascularization (n = 81)
MACE within each FDTIMI group (n = 119)
0 1 2 3 4 5/6
152 263 241 146 86 37
0 (0) 0 (0) 2 (0.8) 0 (0) 1 (1.2) 1 (2.7)
0 (0) 3 (1.1) 7 (2.9) 1 (0.7) 4 (4.7) 1 (2.7)
0 (0) 0 (0) 4 (1.7) 2 (1.4) 3 (3.5) 0 (0)
0 6 12 5 5 2
2 (1.3) 27 (10.3) 14 (5.8) 14 (9.6) 18 (20.9) 6 (16.2)
2 (1.3) 31 (11.8) 33 (13.7) 20 (13.7) 25 (29.1) 8 (21.6)
(0) (2.3) (5.0) (3.4) (5.8) (5.4)
⁎All data are numbers (%). MACE are classified as the presence of at least one of the outcomes in 30 days: all-cause mortality, readmission with MI, ACS not diagnosed at initial presentation, and coronary revascularization.
medical review of discharged patients, possibly in conjunction with other cardiac biomarkers or non-invasive imaging techniques. 4.5. Application of FDTIMI FDTIMI lacks the troponin component but it is useful to risk stratify patients with chest pain when troponin results are not available at triage and in the first 1 to 2 hours. Patients with high FDTIMI should be seen by ED doctors rapidly, so immediate treatment can be given when ACS is strongly suspected. There is still a low risk of MACE (1.3%) even though patients have FDTIMI = 0. Two patients with initial FDTIMI = 0 and a troponin rise (TIMI = 1) required coronary revascularization. Therefore, at least one troponin result should be obtained for patients with undifferentiated chest pain. The event rate in patients with FDTIMI = 1 was 11.8% which is much higher than the current rate of discharged AMI (2% to 4%) [8]. Thus, those with FDTIMI N0 should either be admitted to hospital or be placed in the CPP for observation.
4.7. Limitations This was a single-center study involving exclusively Chinese patients; the results may not be applicable in other hospitals in Hong Kong or other parts of the world. As some of the patients could not be interviewed immediately on ED arrival, this may lead to recall bias. Other results were confirmed by checking the CMS to reduce bias. Some participants did not have any knowledge of cardiac risk factors and were unaware of the presence of those risk factors, such as hypertension; therefore we may have underestimated patients’ risk in each of the score groups although this reflects the realities of ED risk assessment. Also, patients may be at high risk but still refuse coronary revascularization due to personal feelings or perceived complications of the procedure, thus the rate of coronary revascularization and MACE in each of the TIMI and FDTIMI group may be slightly underestimated. However, these potential errors occurred in all of the groups, so the trend of MACE rate should not be affected significantly. 5. Conclusion
4.6. Strengths of the study Consecutive patients with chest pain were collected, this included patients who presented during out-of-office hours, reducing selection bias. It was a prospective study done in the ED. All data was prospectively collected by direct patient interview. The scoring systems were validated in patients with the full range of ACS risk, from low risk to high risk. We recruited all patients with undifferentiated chest pain, so that we are less likely to have missed any cases of discharged AMI. We recruited 1000 participants and this sample size was similar to that in previous studies [8,10]. The completeness of data for calculation (100%) and high follow-up rate (100%) makes it unlikely that patients with MACE were missed and hence withdrawal bias was minimized. All ECGs were interpreted by a single emergency medicine consultant, minimizing inter-observer bias.
Increasing TIMI and FDTIMI are strongly associated with increasing 30 day MACE of patients presenting to the ED with chest pain. This large scale prospective study suggests that TIMI and FDTIMI are valid in Chinese patients presenting to the ED with chest pain. Conflict of interest statement The authors have no conflicts of interest to report for this paper. Acknowledgments We would like to acknowledge Ms Paulina Mak for her help with data collection. References
Fig. 3. Relationship between FDTIMI and MACE. MACE are classified as the presence of at least one of the following outcomes in 30 days: all-cause mortality, readmission with MI, ACS not diagnosed at initial presentation, and coronary revascularization.
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Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Prospective validation of Thrombolysis in Myocardial Infarction and front door Thrombolysis in Myocardial Infarction risk scores in Chinese patients presenting to the ED with chest pain☆ Colin A. Graham, MD, MPH ⁎, Jannet W.M. Chan, BMedSci, MBBS, Cangel P.Y. Chan, BSc, PhD, Giles N. Cattermole, MA, BM, BCh, Timothy H. Rainer, BSc, MD Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR
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Article history: Received 26 May 2014 Received in revised form 11 August 2014 Accepted 12 August 2014
a b s t r a c t Background: Chest pain is a common complaint among emergency department (ED) patients. The Thrombolysis in Myocardial Infarction (TIMI) and front door TIMI (FDTIMI) scores are used to risk stratify chest pain patients in many Western countries; they have not been validated in patients with undifferentiated chest pain in Asia. Our objective was to establish the relationship between the TIMI and FDTIMI scores and the 30 day rate of major adverse cardiac outcomes (MACE) in Chinese patients presenting to the ED with chest pain. Methods: Prospective, single-center, observational cohort study of consecutive patients presenting with chest pain from July 2009 until March 2010 to a Hong Kong university hospital ED. Data collected included patient characteristics, TIMI items and past medical and medication history. Primary outcome was MACE within 30 days of presentation. MACE was a composite outcome of any of the following: death (all causes), readmission with myocardial infarction, acute coronary syndrome not diagnosed at initial ED presentation and coronary revascularization. Results: One thousand patients recruited with complete 30-day follow-up. STEMI patients (n = 75) were excluded. Mean patient age 66.8 ± 13.9 years; 51.7% male. 119 (12.9%) patients had MACE within 30 days of presentation. The incidence of MACE ranged from 0 for TIMI0 to 37.5% for patients with TIMI6/7. Increasing TIMI and FDTIMI scores were associated with a higher incidence of MACE. Conclusions: This validation suggests that the TIMI/FDTIMI scores can be employed in Hong Kong Chinese; they may be useful for risk stratification of Chinese ED patients with undifferentiated chest pain elsewhere. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Chest pain is a common presentation to the emergency department (ED) and early identification of acute coronary artery disease (CAD) is critically important. The World Health Organization reported that CAD is the commonest cause of death worldwide, claiming 7.2 million deaths in 2004 [1]. However, only a small proportion of ED chest pain patients have a diagnostic electrocardiogram (ECG) on presentation, and the challenge for the emergency physician and cardiologist is to risk stratify the patient with possible acute coronary syndrome (ACS). While it is clearly important not to discharge patients with ACS, the sheer volume of chest pain patients presenting to the ED makes admission of all patients logistically and financially impossible in most settings.
☆ Grant support: Health and Health Services Research Fund, Government of the Hong Kong Special Administrative Region, HHSRF 07080351, HK $488 480 (US $62 625). ⁎ Corresponding author. Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR. Tel.: +852 2632 1033; fax: +852 2648 1469. E-mail address: [email protected] (C.A. Graham). http://dx.doi.org/10.1016/j.ajem.2014.08.032 0735-6757/© 2014 Elsevier Inc. All rights reserved.
In the United States, approximately 8% of adults ≥ 20 years or older have previously suffered from ACS, contributing to one in six deaths in 2008 [2]. In Hong Kong, heart disease is the second most common cause of death, claiming 6777 lives in 2008, with coronary heart disease accounting for 67.5% of total cardiac mortality [3]. There is a significant difference in coronary event rates between Chinese patients and patients of Western origin [2] which may be due to the difference in lifestyle and body habitus between different ethnicities. The MONICA project demonstrated a significant difference of event rates and coronary death between various countries [4], and it is clear that the Chinese had a very low rate of cardiac events compared with Western participants. The Chinese had a lower rate of coronary deaths, three times lower than that of Indians [5]. Forouhi and Sattar [6] suggested that the difference in event rates could be due to lower levels of hyperlipidemia and obesity in the Chinese population. Validation of risk stratification tools, such as the Thrombolysis in Myocardial Infarction (TIMI) score and the front door TIMI score (FDTIMI), are therefore essential for Chinese populations, even though the score has been validated in Western countries. Antman [7] derived TIMI on patients with unstable angina or non– ST-segment elevation myocardial infarction (NSTEMI). One point is given for each of the components of TIMI, yielding a range of 0–7.
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Antman [7] validated TIMI in three separate cohorts of patients, demonstrating that TIMI could predict the rate of cardiac events in patients with unstable angina or NSTEMI, the TIMI score increasing with the rise in event rates. This study was not conducted in an unselected chest pain population, but retrospectively recruited all patients with a diagnosis of ACS, so these results may only be valid in patients with intermediate to high risk of adverse cardiac outcomes. Chase [8] prospectively recruited 1481 consecutive ED patients with unselected chest pain and demonstrated that TIMI could predict the risk of 30-day cardiac outcomes. A TIMI score of 0 did not infer no risk of ACS; this group still had a 1.7% risk of adverse outcomes. Soiza [9] validated TIMI using 869 patients with possible ACS. Only four of seven TIMI components directly correlated with event rates. TIMI was shown to be more effective in diagnosing ACS compared to ECG changes and troponin alone. In this study, the event rate may have been underestimated as TIMI was only validated in admitted patients. Morris [10] recruited 998 consecutive ED patients who had chest pain suggestive of cardiac origin and the rate of major adverse cardiac outcomes (MACE) was measured 30 days after ED presentation; TIMI had a good correlation with 30 day MACE. Other studies also suggest that TIMI correlates with adverse cardiac outcomes [11–13], although one suggested it was not valid [14]. Morris also studied FDTIMI, which is similar to TIMI, except it does not require cardiac markers for completion [10], yielding a range of 0 to 6. FDTIMI could be useful for prehospital personnel in identifying high risk patients prior to ED arrival. FDTIMI retained its ability to risk stratify patients, with high scores correlating with a higher incidence of cardiac events, although FDTIMI was not as sensitive or specific as TIMI [10]. The aim of this study was to validate TIMI and FDTIMI in Chinese ED patients presenting with undifferentiated chest pain by establishing the relationships between TIMI and FDTIMI and the 30-day MACE event rate. 2. Methods Ethical approval was obtained from the local Institutional Research Ethics Committee for this study (CRE 2008.351). This prospective observational cohort study was conducted in the ED of Prince of Wales Hospital (PWH). PWH is located in Shatin in Hong Kong; it is a university hospital with 1400 beds. It sees more than 150 000 new ED patients per annum and serves a local population of approximately 800 000 people. Consecutive ED patients ≥20 years old, with a chief complaint of chest pain or discomfort, were recruited from July 29, 2009, to March 12, 2010. Patients were excluded if they had a clearly non-cardiac cause of chest pain, such as spontaneous pneumothorax. Confirmed STEMI patients at ED presentation were also excluded as they do not have undifferentiated chest pain. Written informed consent was obtained from each patient or patient’s relative after a verbal and written explanation of the study was provided, in Chinese or English. Patients were informed that they may voluntarily withdraw from the study at any time. 2.1. Questionnaire design and data collection Data were collected from ED patients using a standardized questionnaire. The characteristics of the chest pain, vital signs, patient’s past medical history, family history of CAD and other information that help to make a diagnosis of ACS were recorded. Data were also obtained from the Clinical Management System (CMS). CMS is an integrated electronic system that allows inspection of the medical records of patients in public hospitals and clinics. The system does not contain information for patients who are followed up by private doctors, but those patients were asked to provide information about their past medical history in as much detail as possible. Data was collected on the scoring criteria for TIMI and FDTIMI. Patients scored one point for fulfilling each of the criteria, giving a total score of seven for TIMI and six for FDTIMI. As there is
inconsistency in the literature in classifying the seven characteristics of the scores, in this study the TIMI variables were defined as: 1. Age of 65 or older 2. At least 3 risk factors for CAD (including current smoker, hypertension, hyperlipidemia, diabetes mellitus and family history of CAD). 3. Known coronary stenosis of ≥50%. These include documented coronary stenosis ≥50%, previous MI, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). 4. ST deviation in the initial ECG. This was defined as at least 0.5 mm of STsegment elevation or depression in the first ECG. ECGs were routinely performed on all patients with suspected cardiac chest pain. The first ECG for each patient was reviewed by a single emergency medicine consultant for consistency, who was blinded to any patient information. 5. At least 2 episodes of angina in the past 24 hours. As people perceive pain in different ways, angina was defined as any chest pain, regardless of the pain nature and severity. If the patient reported that their pain started and never stopped, it was considered one episode of pain. Pain lasting ≥48 hours was entered into the database as 48 hours of pain. 6. Use of aspirin in the last seven days or more. This included patients who visited general practitioners or private hospitals and were given aspirin prior to ED presentation. Patients were asked whether they took aspirin and the researcher rechecked the CMS’s drug record to confirm long-term use of aspirin for patients who had follow-up in public clinics. 7. Raised cardiac markers at initial presentation, which was cardiac troponin T (cTnT) ≥0.03 μg/L according to local laboratory standards at the time of the study. Record logbooks at the ED triage station and the resuscitation rooms were used to ensure that all patients presented with chest pain had been recruited. ACS is an umbrella term for a spectrum of symptoms that are compatible with acute myocardial ischemia [15], consisting of unstable angina, NSTEMI and STEMI [16]. 2.2. Chest pain protocol (CPP) Guidelines recommend that patients with possible ACS but with a normal initial ECG and cardiac markers should be observed in a chest pain unit, where continuous cardiac monitoring and repeated measurement of cardiac markers is available [16]. In our centre at the time of the study, patients had their serum cTnT analyzed and the first ECG was performed at triage. These patients stayed in the ED for at least six hours to have their second cTnT sample analyzed and a second ECG performed. During this period, patients would be admitted if the cTnT level was elevated or the ECG showed abnormalities. Patients were discharged after six hours if they were pain free with two negative troponin tests (cTnT b 0.03 μg/L) and two ECGs with no new changes. 2.3. Outcomes 2.3.1. Primary outcome The primary outcome measure was the number of MACE occurring in 30 days after the patient attended the ED with chest pain. MACE was considered positive if at least one of the following had occurred within 30 days of ED presentation: 1. 2. 3. 4.
Death (all causes) Readmission with MI ACS not diagnosed at initial presentation Coronary revascularization (including PCI and CABG)
2.3.2. Secondary outcomes Each of the above events was individually considered to be a secondary outcome if it occurred within 30 days of ED presentation.
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2.4. Follow-up Patients were followed up at day 30 (± 5 days) by reviewing CMS records. All deaths and admission records in the Hong Kong public health care system are recorded on the CMS. Patients were contacted by telephone if they did not reattend ED or were not readmitted to public hospitals during the follow up period to ensure that any MACE that occurred outside Hong Kong or under the care of private hospitals were detected.
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a CABG. The initial ED diagnosis for the patients in the study included acute myocardial infarction (22, 2.4%), ischemic heart disease (238, 25.7%), unstable angina (30, 3.2%), atypical chest pain (460, 49.7%) and non-ischemic chest pain (175, 18.9%).
3.2. TIMI and FDTIMI Table 1 shows the number of patients fulfilling each of TIMI criteria. Fig. 1 shows the distribution of TIMI and FDTIMI scores in the study.
2.5. Sample size calculation Based on previously published ED work from the UK with similar rates of ischemic heart disease [10], the event rate in low risk patients could be as high as 9.0% and that in high risk patients could be as low as 14.8%. To achieve adequate power to address the objective, using an α of 0.05 and a β of 0.2, the minimum number of patients was 972. 2.6. Statistical analysis Statistical analysis was performed using SPSS v17.0 (SPSS Inc, Chicago, IL) and Medcalc v9.5 (MedCalc Software, Mariakerke, Belgium). Categorical data were compared using Pearson’s chi-square test and receiver operating characteristic (ROC) curves were plotted to determine the sensitivity and specificity of the TIMI and FDTIMI. Statistical significance was set at P b .05. 3. Results 3.1. Baseline characteristics Between July 2009 and March 2010, 1028 consecutive patients were enrolled. 28 patients were excluded (12 patients refused to give consent, 15 patients could not communicate and one patient did not have chest pain). This left 1000 patients for possible analysis: 75 confirmed STEMI patients at ED presentation were then excluded, leaving 925 patients for analysis. 478 (51.7%) patients were male, the median age was 68 years (IQR 56-78) and 516 (55.8%) were 65 years or older. Men presented at a mean age of 64.6 years compared to women at 69.2 years. The mean duration of chest pain was 3.6 hours (SD 7.5 hours; range, 0-48). Among the 420 patients placed in the chest pain protocol, 50 were admitted to the general wards and 370 were discharged from the ED. The mean (SD) in-patient length of stay was 4.0 (4.29) days. During the 30-day follow up period, 16 (1.7%) patients died; 4 (0.4%) died of cardiac disease. 47 (5.1%) patients received CCU care and 81 (8.8%) patients had coronary revascularization, including 12 (1.3%) who had
Table 1 TIMI and FDTIMI components TIMI variables
No. (%)
1. Age ≥65 years old 2. At least 3 risk factors for coronary artery disease • Hypertension • Diabetes • Hyperlipidemia • Family history of coronary artery disease • Current smoker 3. Known coronary artery stenosis • Known coronary stenosis of ≥50% • Prior myocardial infarction • Prior PCI • Prior CABG 4. ST-segment deviation at initial presentation 5. At least 2 episodes of angina in prior 24 h 6. Use of aspirin for the past 7 days or more 7. Elevated cardiac markers
516 157 579 208 309 118 113 196 164 78 132 18 101 426 320 198
(55.8) (17.0) (62.6) (22.5) (33.4) (12.8) (12.2) (21.2) (17.7) (8.4) (14.3) (1.9) (10.9) (46.1) (34.6) (21.4)
Fig. 1. A, Distribution of TIMI among ED chest pain study participants. B, Distribution of FDTIMI among the participants.
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Table 2 Relationship between TIMI and 30 day MACE⁎ TIMI
No of patients in each TIMI group
Cardiac death (n = 4)
All-cause mortality (n = 16)
Readmit with MI (n = 9)
ACS not diagnosed at initial presentation (n = 30)
Coronary revascularization (n = 81)
MACE within each TIMI group (n = 119)
0 1 2 3 4 5 6/7
138 230 228 172 92 49 16
0 (0) 0 (0) 0 (0) 2 (1.2) 1 (1.1) 0 (0) 1 (6.2)
0 2 3 5 3 2 1
0 (0) 0 (0) 1 (0.4) 3 (1.7) 5 (5.4) 0 (0) 0 (0)
0 4 10 9 3 4 0
0 (0) 7 (3.0) 23 (10.1) 19 (11.0) 17 (18.5) 10 (20.4) 5 (31.2)
0 10 34 32 24 13 6
(0) (0.9) (1.3) (2.9) (3.3) (4.1) (6.2)
(0) (1.7) (4.4) (5.2) (3.3) (8.2) (0)
(0) (4.3) (14.9) (18.6) (26.1) (26.5) (37.5)
MACE are classified as the presence of at least one of the outcomes in 30 days: all-cause mortality, readmission with MI, ACS not diagnosed at initial presentation, and coronary revascularization. ⁎ All data are numbers (%).
3.3. TIMI and outcome within 30 days of ED presentation
4.1. Comparison between the performance of the TIMI and FDTIMI
In keeping with Morris' study [10], we combined TIMI 6 and 7 as the numbers in each group were small. The relationship of TIMI with the primary outcome is shown in Table 2 and Fig. 2. The all-cause mortality rate in our study (1.7%) was similar to those reported by Morris [10] (1.6%, P = .86, χ2 test) and Chase [8] (1.0%, P = .19, χ2 test).
TIMI was superior to FDTIMI for predicting MACE in clinical settings. However, there was no statistically significant difference between the performance of TIMI and FDTIMI, similar to Morris’ study [10]. The event rate of 12.9% was similar to the rate reported in UK and US studies [8,10]. The mean age in our study was 67 years, considerably older than in Morris’ study (59 years) [10] and Chase's study (53 years) [8]. The number of our patients who had coronary revascularization (81, 68%) was much higher than that of Morris [10] with a rate of 23% and slightly higher than that of Chase [8] with a rate of 55%. This may be due to increasing rates of cardiac catheterization and the fact that coronary revascularization (in particular, PCI) is now performed more frequently [18]. There were nine readmissions with acute myocardial infarction (AMI) while only one case and three cases were reported by Morris [10] and Chase [8] respectively. The all-cause mortality rate in our study (1.7%) was similar to that reported by Morris [10] and Chase [8].
3.4. FDTIMI and outcome within 30 days of ED presentation In keeping with Morris’ study [10], we combined FDTIMI 5 and 6 as the numbers in each group were small. Table 3 and Fig. 3 show the relationship of FDTIMI with the primary outcome. 3.5. ROC analysis for TIMI and FDTIMI ROC curve analysis for predicting MACE at 30 days gave an area under the curve for TIMI of 0.732 (95% CI 0.690–0.773, P b .001) and an area under the curve for FDTIMI of 0.652 (95% CI 0.602–0.701, P b .001).
4.2. Applying TIMI and FDTIMI in the ED setting 4. Discussion This is the first large scale prospective validation study on a Chinese population to establish the relationship between TIMI and FDTIMI and 30 day MACE. Our study included all ED patients with possible cardiac chest pain and was thus composed of more patients with low and intermediate risks of adverse cardiac outcomes than some of the previous studies [7,11]. Our results were similar to those of previous studies, showing a rise in 30 day MACE with increasing TIMI [8,10,11] and FDTIMI [10]. This suggests that TIMI may be a useful tool to stratify risk in Chinese patients with chest pain. This large study confirms previous findings in our initial study [17].
TIMI and FDTIMI have been shown to be useful tools to risk stratify ED patients with chest pain. It is easy to calculate and the risk score components can be routinely identified by ED triage nurses and doctors. The scoring systems can guide clinicians in the management of ED patients with chest pain. The scores can identify patients with high risk features who may benefit from early aggressive intervention and early consultation with cardiologists. 4.3. Patients with TIMI of zero Patients with very low risk as defined by a TIMI and FDTIMI of zero had a 0% and 1.3% of MACE respectively. This suggests that their risk of MACE is not zero, but their risk is acceptably low. From the ROC curve, the optimum cut-off is TIMI N 0 (score 1-7) with a sensitivity of 100 (95% CI, 96.9-100.0). This implies the event rate in low risk patients (TIMI = 0) could be as high as 3.1%. The rate is similar to the percentage of patients who are discharged from EDs with undiagnosed AMI by current practice (2–4%) [8]. This suggests patients with a TIMI of zero can be safely discharged from the ED with appropriate advice, in keeping with other recently published data [19]. 4.4. Patients with TIMI greater than 0
Fig. 2. Relationship between TIMI and MACE. MACE, major adverse cardiac events are classified as the presence of at least one of the following outcomes in 30 days: allcause mortality, readmission with MI, ACS not diagnosed at initial presentation and coronary revascularization.
Patients with TIMI N0 pose a challenge to ED doctors in terms of disposition. Their risk of MACE is significantly higher than those with TIMI = 0 (TIMI 1, 4.3%; FDTIMI 1, 11.8%). Those patients should either be admitted to hospital for further investigation of chest pain or be placed in the CPP to actively exclude ACS. Future studies should explore the value of TIMI and FDTIMI in stratifying the urgency of
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Table 3 Relationship between FDTIMI and 30-day MACE Front door TIMI
No. of patients in each FDTIMI group
Cardiac death (n = 4)
All-cause mortality (n = 16)
Readmit with MI (n = 9)
ACS not diagnosed at initial presentation (n = 30)
Coronary revascularization (n = 81)
MACE within each FDTIMI group (n = 119)
0 1 2 3 4 5/6
152 263 241 146 86 37
0 (0) 0 (0) 2 (0.8) 0 (0) 1 (1.2) 1 (2.7)
0 (0) 3 (1.1) 7 (2.9) 1 (0.7) 4 (4.7) 1 (2.7)
0 (0) 0 (0) 4 (1.7) 2 (1.4) 3 (3.5) 0 (0)
0 6 12 5 5 2
2 (1.3) 27 (10.3) 14 (5.8) 14 (9.6) 18 (20.9) 6 (16.2)
2 (1.3) 31 (11.8) 33 (13.7) 20 (13.7) 25 (29.1) 8 (21.6)
(0) (2.3) (5.0) (3.4) (5.8) (5.4)
⁎All data are numbers (%). MACE are classified as the presence of at least one of the outcomes in 30 days: all-cause mortality, readmission with MI, ACS not diagnosed at initial presentation, and coronary revascularization.
medical review of discharged patients, possibly in conjunction with other cardiac biomarkers or non-invasive imaging techniques. 4.5. Application of FDTIMI FDTIMI lacks the troponin component but it is useful to risk stratify patients with chest pain when troponin results are not available at triage and in the first 1 to 2 hours. Patients with high FDTIMI should be seen by ED doctors rapidly, so immediate treatment can be given when ACS is strongly suspected. There is still a low risk of MACE (1.3%) even though patients have FDTIMI = 0. Two patients with initial FDTIMI = 0 and a troponin rise (TIMI = 1) required coronary revascularization. Therefore, at least one troponin result should be obtained for patients with undifferentiated chest pain. The event rate in patients with FDTIMI = 1 was 11.8% which is much higher than the current rate of discharged AMI (2% to 4%) [8]. Thus, those with FDTIMI N0 should either be admitted to hospital or be placed in the CPP for observation.
4.7. Limitations This was a single-center study involving exclusively Chinese patients; the results may not be applicable in other hospitals in Hong Kong or other parts of the world. As some of the patients could not be interviewed immediately on ED arrival, this may lead to recall bias. Other results were confirmed by checking the CMS to reduce bias. Some participants did not have any knowledge of cardiac risk factors and were unaware of the presence of those risk factors, such as hypertension; therefore we may have underestimated patients’ risk in each of the score groups although this reflects the realities of ED risk assessment. Also, patients may be at high risk but still refuse coronary revascularization due to personal feelings or perceived complications of the procedure, thus the rate of coronary revascularization and MACE in each of the TIMI and FDTIMI group may be slightly underestimated. However, these potential errors occurred in all of the groups, so the trend of MACE rate should not be affected significantly. 5. Conclusion
4.6. Strengths of the study Consecutive patients with chest pain were collected, this included patients who presented during out-of-office hours, reducing selection bias. It was a prospective study done in the ED. All data was prospectively collected by direct patient interview. The scoring systems were validated in patients with the full range of ACS risk, from low risk to high risk. We recruited all patients with undifferentiated chest pain, so that we are less likely to have missed any cases of discharged AMI. We recruited 1000 participants and this sample size was similar to that in previous studies [8,10]. The completeness of data for calculation (100%) and high follow-up rate (100%) makes it unlikely that patients with MACE were missed and hence withdrawal bias was minimized. All ECGs were interpreted by a single emergency medicine consultant, minimizing inter-observer bias.
Increasing TIMI and FDTIMI are strongly associated with increasing 30 day MACE of patients presenting to the ED with chest pain. This large scale prospective study suggests that TIMI and FDTIMI are valid in Chinese patients presenting to the ED with chest pain. Conflict of interest statement The authors have no conflicts of interest to report for this paper. Acknowledgments We would like to acknowledge Ms Paulina Mak for her help with data collection. References
Fig. 3. Relationship between FDTIMI and MACE. MACE are classified as the presence of at least one of the following outcomes in 30 days: all-cause mortality, readmission with MI, ACS not diagnosed at initial presentation, and coronary revascularization.
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