Objective: To assess clinical characteristics, management strategies and in-hospital outcome among high-risk patients of non-ST elevation myocardial infarction.
Methods: The retrospective cross-sectional study was conducted at Tabba Heart Institute, Karachi, and comprised data from July 2013 to December 2016 of adult non-ST elevation myocardial infarction patients who had first cardiac event having Global Registry of Acute Coronary Eventsrisk score>140. Subcategories were formed on the basis of score range 140-159, 160-189 and ?190.Stata 12.1 was used for data analysis.
Results: Of the 817 patients, 567(69.4%) were men. Overall, mean age was 66.3}9.3 years. Coronary angiography was performed in 692(84.4%). With higher risk score categories, there was less frequent use of guideline directed medical therapy, coronary angiography and percutaneous or surgical revascularisation (p<0.05 each). Overall mortality was 59(7.2%). Mortality rates increased with increase in risk score subcategory (p<0.05). Multivariable model identified higher risk score category, no revascularisation and lack of guideline directed medical therapy as significant independent predictors of mortality (p<0.05 each).
Conclusion: Mortality increased with higher risk score category. Paradoxically, high-risk patients were less likely to receive guideline directed medical therapy, to undergo coronary angiography and revascularisation, possibly suggesting a risk aversion approach by the treating physicians.
Keywords: Non-ST elevated myocardial infarction, GRACE, Mortality, High risk, Trends. (JPMA 69: 1486; 2019). doi:10.5455/JPMA.22228
Non-ST segment elevation myocardial infarction (NSTEMI) is the most common presentation of acute coronary syndrome (ACS), accounting for almost 60% of such patients.1 The patho-physiology underlying NSTEMI is more diverse with variable degree of reduction in coronary flow, but usually without complete occlusion. Early invasive management with aggressive medical management has shown a reduction in adverse outcomes in appropriately selected patients with NSTEMI-ACS. 2,3Over time the incidence of NSTEMI continues to rise, partly due to greater usage of high sensitivity cardiac troponin (hs-cTn) assays to diagnose myocardial necrosis. 1,4Patients presenting with NSTEMI are heterogeneous and include a spectrum of risk of adverse events, requiring individualisation of medical management and revascularisation decisions. Therefore early risk stratification in NSTEMI is required for management and is recommended in guidelines.5 Use of risk scoring systems such as Thrombolysis In Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) have been studied in western as well as Asian population and have shown to be accurate in predicting adverse clinical outcome and identifying patients at high risk for cardiac death. 6-8 GRACE risk score employs a number of patient characteristics such as age, heart rate (HR), systolic blood pressure (SBP), Killip class I to IV (to quantify severity of myocardial infarction in ACS and predict risk of 30-day mortality), cardiac arrest, serum creatinine, ST-segment deviation, and cardiac biomarker status to estimate in hospital mortality. 9 Patients with a GRACE risk score >140 have >3% risk of inhospital mortality compared to <1% in patients who have a low-risk score of <109. Guidelines recommend more aggressive management strategies and greater use of revascularisation in patients who are at higher risk of subsequent events. 10 The results available from the GRACE registry on the contrary report less frequent use of cardiac catheterisation and revascularisation in patients with higher GRACE score, perhaps suggesting a risk aversion approach by the treating physicians. Data regarding treatment and risk characteristics of higher-risk patients with ACS as well as the adjustment of treatment to individual patients' underlying risk is not available from South Asia. The current study was planned to assess the clinical characteristics, management strategies and in-hospital outcome among NSTMEI patients with a GRACE risk score >140.
Patients and Methods
The retrospective cross-sectional study was conducted at Tabba Heart Institute, Karachi, which is a single-specialty cardiac care hospital. After approval from the institutional ethics review committee, data of all consecutive patients admitted with ACS from January 2013 to December 2016 was obtained from the catheterisation laboratory and ACS database maintained according to the standard National Cardiovascular Data Registry and Acute Coronary Treatment and Intervention Outcomes Network (ACTION) registry definitions. 11,12NSTEMI was defined by the presence of following criteria: a) symptoms suggestive of acute coronary ischaemia, b) cardiac biomarkers (troponin T or I) exceeding the diagnostic criteria cut-offs of the institutional laboratory parameters with a clinical presentation consistent with or suggestive of ischaemia, and electrocardiogram (ECG) changes not meeting STEMI criteria. The variables included in GRACE risks score are age, admission HR and SBP, Killip class I to IV on admission (to quantify severity of myocardial infarction in ACS and predict risk of 30-day mortality), cardiac arrest, ST deviation on ECG, elevated troponin and creatinine. 9GRACE risk score calculator based on the GRACE study nomogram is programmed into the institutional database and automatically provides the score and predicted mortality once all the required variables are entered. 13 As recommended by the non-STelevation acute coronary syndromes (NSTEACS) guidelines, the patients in the database were categorized according to their GRACE risk score predicted in-hospital mortality as low (score<109; predicted mortality <1%), intermediate (score 109 to 140, predicted mortality 1- 3%) and high (score 140, predicted mortality >3%).14 Data of all adult patients with NSTEMI-ACS as their first cardiac event having GRACE risk score 140 was included. In order to determine the quantum of risk gradient, this high-risk population was further categorised into three groups based on the GRACE risk score 140-159, 160-189 and 190. Detailed demographics, clinical presentation characteristics, in hospital non-invasive and invasive evaluation, medical management, revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG), and in-hospital outcome were recorded. Data of patients who did not complete their treatment at the hospital were excluded. Guideline directed medical therapy (GDMT) was defined as combined use of aspirin, thienopyridine, heparin, beta blocker (BB), statin and Angiotensin-converting-enzyme (ACE-I) / Angiotensin II receptor blockers (ARBs). Stata 12.1 was used for statistical analysis. Patients were categorised according to their initial risk based on their clinical and haemodynamic features, including GRACE and TIMI risk scores. Means and standard deviations (SDs) were calculated for continuous variables and frequencies and percentages were calculated for categorical variables. Chi-square or Fisher exact tests were used for categorical variables according to expected cell counts, and independent sample t-test for continuous variables depending upon variable characteristics. Multivariable logistic regression model with stepwise approach was used to assess predictors of in-hospital mortality. Variables with p<0.25 in univariate analysis were considered significant for adjusting into multivariable model and p<0.05 were considered significant for the final model, adjusting for GRACE risk score. ACE-I/ARB was excluded from the composite GDMT variable in multivariable adjustment due to lower frequency, and also because it is a guideline recommendation only for patients with at least moderate left ventricular dysfunction (LVD).
Of the 817 patients, 567(69.4%) were men. Overall, mean age was 66.3}9.3 years. Of the total, 448(54.8) patients had diabetes and 574(70.3%) had hypertension. Killip class I was present in 463(52.4%) on arrival, CS was present in 33(4.0%) and 35(4.3%) had a cardiac arrest during their hospital stay. Of the total, 195(23.8%) patients had TIMI risk score >5 and 443(54.2%) had moderate or severe renal dysfunction (Table-1).
The optimal medical management included a high usage of aspirin, anticoagulation with heparin or low molecular weight heparin (LMWH), thienopyridine, BB agents and statin drugs. ACE-I or ARB drugs were used in 493 (60.3) patients, and use of Glycoprotein (GP) IIb/IIIa agents was very low (<5%). GDMT was given to 352(43.1%), and to 516(63.1%) patients when excluding ACE/ARB drugs. Cardiac catheterisation and CAG was performed in 692(84.4%) patients and 47(5.7%) underwent noninvasive stress test. Overall, median left ventricular ejection fraction (LVEF) was 45 (Inter-quartile range [IQR]:22). Non-obstructive coronary arteries were present in 53(7.6%) and left main or triple vessel disease was present in 266(38.4%) patients. Revascularisation was performed in 456(55.8%) patients. Median hospital stay was 3 days (IQR: 5) (Table-2).
During the hospital stay, overall mortality was 59 (7.2%). The deceased patients had significantly worse renal function, more chronic lung disease, higher Killip class, and had more frequent cardiac arrest (p<0.05 each). The deceased patients also had significantly worse haemodynamics i.e. heart rate>100 bmp, SBP<100mm/Hg, more heart failure, lower mean LVEF, and were more likely to have left main or triple vessel coronary artery disease (CAD) (p<0.05 each). Mortality rates tended to increase with increase in the GRACE risk score category (p<0.05). Multivariable model identified higher GRACE score, no revascularisation, and
lack of GDMT as significant independent predictors of mortality, adjusting for GRACE risk score 140-159 (Table-3).
There was a statistically significant trend towards increasing age with higher GRACE score categories (p<0.05). There were also trends towards more adverse baseline clinical characteristics, presentation features, lower left ventricular function (LVF), high-risk coronary anatomy and in-hospital mortality (p<0.05 each). Paradoxically, with higher GRACE risk score categories, there was a trend towards less frequent use of GDMT, CAG and percutaneous or surgical revascularisation (p<0.05 each) (Figure).
The study found that NSTEMI patients admitted with GRACE risk score >140 presented with adverse clinical characteristics and had high in-hospital mortality. Independent predictors of mortality were increasing GRACE score, lack of revascularisation and sub-optimal medical treatment. The results also showed that higher risk individuals were less likely to receive aggressive medical therapy or undergo diagnostic catheterisation or revascularisation. Patients who present with NSTEMI have a risk spectrum of immediate and long-term adverse events. 7 Those who are at increased risk have a better outcome with aggressive medical therapy, invasive coronary evaluation and coronary revascularisation. 15 The utilisation of risk scores to identify individuals at risk is recommended by North American and European guidelines.10,16,17 The findings of the current study further validate the accuracy of the risk estimation by GRACE score in a high-risk South Asian population. The actual mortality of 7.2% is in keeping with the 7.3% mortality predicted by the GRACE score. Within this high-risk subset, the GRACE risk score, in our study, further stratified the patients, with mortality in the third tertile of our study population more than double of the second and more than five-fold of the first tertile. The use of a validated score such as GRACE should allow the treating physicians to identify very high-risk patients early in their care journey and, hence, attempt to prevent adverse cardiac events can be made by provision of care interventions. Our study also showed that patients identified by high GRACE score had in addition to the individual components of score, multiple advance co-morbidities. Similar to prior studies, our high-risk population had a very high >90% prevalence of obstructive CAD with more than a third having complex, very high-risk coronary anatomy. 18Additionally, these patients tended to have high likelihood of symptomatic left ventricular (LV) dysfunction with more than a third having ejection fraction <40%. In our study, even in the short term, lack of revascularisation is a predictor of increased mortality. This again lays emphasis on earlier identification of such patients with utilisation of invasive investigation and subsequent appropriate revascularisation. Clinical trials have shown greater benefit of aggressive medical therapy and revascularisation in high-risk patients and, based on this, all current management guidelines recommend therapy intensity tailored to the patients underlying risk. 19 Clinical practice in real life has shown contrary approach with less use of aggressive treatment in high-risk patients. Results from the GRACE registry and the Myocardial Ischaemia National Audit Project (MINAP) showed declining trend in the use of guideline-based care with increasing GRACE risk score in overall ACS as well as NSTEMI.20,21 Our findings also showed that even in this high-risk population, there is an inverse relationship between the patients underlying risk and the intensity of treatment. This inverse relationship is present in the declining frequency of individual guideline-recommended medical therapy, diagnostic CAG and overall revascularisation as the patients' underlying risk and mortality goes up. Prior results from the GRACE registry have not shown a reduction in CABG with increasing risk suggesting use of different decision criteria for PCI or CABG, whereas our findings showed this relationship with both modalities of revascularisation. 22 Some studies have suggested the presence of a risk aversion behaviour by clinicians and that may be one of the underlying reasons for our findings. 23 It is also possible that such patients may have had extensive comorbidities, making them not suitable for PCI or CABG. The treating clinicians may not have appreciated the increasingly adverse risk of the patients. The GRACE risk score requires an online calculator or a mobile app whereas the TIMI risk score can be easily calculated at the bedside and is used most of the times for clinical decision making. 13 In our high-risk study population, the mean TIMI risk score was in the intermediate range and did not vary significantly between the tertile of the high GRACE risk score population. This may have led to an underestimation of the risk. Our findings may suggest lower discriminatory capability of the TIMI risk score in South Asian population. However, a larger study comparing the two scores including all strata of clinical risk would be required before concluding which risk score is better suited for South Asian population. The independent predictors of early mortality in our findings included increasing GRACE risk scores. 9 This is consistent with other studies in Western and multi-ethnic Asian populations. 24 The other predictors of early mortality were sub-optimal medical therapy and lack of revascularisation, as reported in literature. 21 Although a favourable impact on outcome with use of optimal medical therapy and revascularisation has been shown before, the surprising finding in the current study is such an early difference in survival. 25This may be explained by the fact that only high-risk patients with high early event rate were included in the study and the improvement in outcome with optimal therapy and revascularisation in lower risk patient require more time to accrue. The current study represented significant trends in revascularisation and predictors of mortality in high-risk NSTEMI with respect to local population. This is the first study on high-risk NSTEMI patients stratified by GRACE risk score in South Asian population. Limitations include single-centre retrospective data. The study could be further strengthened by assessing adverse outcomes at follow-up in comparison to low and intermediate GRACE risk score outcomes. Further studies are required to assess the precision of various ACS risk calculators such as TIMI and GRACE risk scores in predicting adverse cardiac events in South Asian population.
Mortality increased with higher risk GRACE score category. Paradoxically, high-risk patients were less likely to receive GDMT, to undergo CAG and revascularisation, possibly suggesting a risk aversion approach by the treating physicians.
Conflict of Interest: None.
Source of Funding: None.
1. Rogers WJ, Frederick PD, Stoehr E, Canto JG, Ornato JP, Gibson CM, et al. Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J. 2008; 156:1026-34.
2. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999-3054.
3. Kumar A, Cannon CP. Acute coronary syndromes: diagnosis and management, part I. Mayo Clin Proc. 2009;84, 917-38.
4. Yin WH, Lu TH, Chen KC, Cheng CF, Lee JC, Liang FW, et al. The temporal trends of incidence, treatment, and in-hospital mortality of acute myocardial infarction over 15 years in a Taiwanese population. Int J Cardiol. 2016;209:103-13.
5. Kushner FG, Hand M, Smith SC, King SB, Anderson JL, Antman EM, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and
ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54:2205-41.
6. Shaikh MK, Hanif B, Shaikh K, Khan W, Parkash J. Validation of grace risk score in predicting in-hospital mortality in patients with non ST-elevation myocardial infarction and unstable angina. J Pak Med Assoc. 2014;64;807-11.
7. Chen YH, Huang SS, Lin SJ. TIMI and GRACE risk scores predict both short-term and long-term outcomes in Chinese patients with acute myocardial infarction. Acta Cardiol Sin. 2018;34:4.
8. Rangamanikandan M, Jelia S, Meena S, Meena SB, Ajmera D, Chourasiya PK, et al. Validation study of grace risk score for prognosis in Indian patients with non-STEMI. Int J Adv Med. 2017;4:1036-40.
9. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, et al. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med. 2003;163:2345-53.
10. Windecker S, Kolh P, Alfonso F, Collet J-P, Cremer J, Falk V, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541-619.
11. Brindis RG, Fitzgerald S, Anderson HV, Shaw RE, Weintraub WS, Williams JF. The American College of Cardiology-National Cardiovascular Data Registry™(ACC-NCDR™): building a national clinical data repository. J Am Coll Cardiol. 2001; 37:2240-5.
12. NCDR. Data Collection. [Accessed 11th December 2018]. Available from URL:
13. GRACE risk score calculator.[Online] [Cited 2018 December 11]. Available from: URL : https://www.outcomesumassmed.org/grace/acs_risk/acs_risk_content.html .
14. GRACE risks score Non STE-ACS: In-hospital mortality. [Online]
[Cited 2018 December 11]. Available from: URL: http://www.outcomes-umassmed.org/GRACE/grace_risk_table.aspx.
15. Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol. 2006;48:1319-25.
16. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the Management of Acute Coronary Syndromes in Patients Presenting Without Persistent ST-segment Elevation. Rev Esp Cardiol (Engl Ed). 2015; 68:1125.
17. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 64:e139-e228.
18. Kontos MC, de Lemos JA, Ou FS, Wiviott SD, Foody JM, Newby LK, et al. Troponin-positive, MB-negative patients with non-STelevation
myocardial infarction: An undertreated but high-risk patient group: Results from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network-Get With The Guidelines (NCDR ACTION-GWTG) Registry. Am Heart J. 2010; 160:819-25.
19. Bhatt DL, Roe MT, Peterson ED, Li Y, Chen AY, Harrington RA, et al.
Utilization of early invasive management strategies for high-risk patients with non–ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA. 2004; 292:2096-104.
20. Hall M, Bebb OJ, Dondo T, Yan AT, Goodman SG, Bueno H, et al. Guideline-indicated treatments and diagnostics, GRACE risk score and survival for non-ST elevation myocardial infarction. Eur Heart J. 2018; 7;39:3798-806.
21. Zaman MJ, Stirling S, Shepstone L, Ryding A, Flather M, Bachmann M, et al. The association between older age and receipt of careand outcomes in patients with acute coronary syndromes: a cohort study of the Myocardial Ischaemia National Audit Project (MINAP). Eur Heart J. 2014; 35:1551-8.
22. Fox KA, Anderson FA, Jr Dabbous OH, Steg PG, Lopez-Sendon J, Van de Werf F, et al. Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE). Heart. 2007; 93:177-82.
23. Bagnall AJ, Yan AT, Yan RT, Lee CH, Tan M, Baer C, et al. Optimal medical therapy for non–ST-segment–elevation acute coronary syndromes: exploring why physicians do not prescribe evidencebased treatment and why patients discontinue medications after discharge. Circ Cardiovasc Qual Outcomes. 2010; 3:530-7
24. Chan MY, Shah BR, Gao F, Sim LL, Chua T, Tan HC, et al. Recalibration of the Global Registry of Acute Coronary Events risk score in a multiethnic Asian population. Am Heart J. 2011; 162:291-9.
25. Yan AT, Yan RT, Tan M, Huynh T, Soghrati K, Brunner LJ, et al. Optimal medical therapy at discharge in patients with acute coronary syndromes: temporal changes, characteristics, and 1- year outcome. Am Heart J. 2007; 154:1108-15.