Manuscript accepted on :09-Nov-2018
Published online on: 23-11-2018
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Reviewed by: Mina T. Kelleni
Second Review by: Huseyin Ede
Final Approval by: Prof. Juei-Tang Cheng
Mortality Rate and Its Associated Factors in Patients with Non ST-Elevation-Acute Coronary Syndrome in Bali: Results from A Single Center Registry
I. Made Junior Rina Artha1,3 and I. Made Pande Dwipayana2,3
1Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Udayana, Sanglah General Hospital, Denpasar, Bali, Indonesia.
2Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Udayana, Sanglah General Hospital, Bali, Indonesia.
3Doctoral Program of Medical Science, Faculty of Medicine, University of Udayana, Sanglah General Hospital, Denpasar, Bali, Indonesia.
Corresponding Author E-mail: email@example.com
Non-ST elevation – acute coronary syndrome (NSTE-ACS) consisted of non-ST elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP) diagnoses, which are common cardiac events in Indonesia, including Bali. To evaluate in-hospital mortality and its associated factors in patients with NSTE-ACS patients in the Province of Bali. This was a cross-sectional study using data from ACS 2016 registry in Bali. Subjects were adult ACS patients who were hospitalized in Sanglah General Hospital (SGH), Denpasar, Bali Island. Diagnosis of ACS was grouped into NSTEMI and UAP. Demography, clinical data, and anticoagulant treatment were analyzed. Clinical outcome was in-hospital mortality. A total of 421 NSTE-ACS patients were diagnosed; 300 (71.3%) among them were men. Patients’ mean age was 59 + 12.0 years. Diagnoses were UAP in 260 (61.8%) and non-STEMI in 161 (38.2%) cases. Heparin treatment was given to 409 (97.1%) patients, consisted of 96 (22.8%) unfractionated heparin (UFH), 177 (42.0%) fondaparinux, and 136 (32.3%) enoxaparin. There were 8 (1.9%) patients who underwent early PCI. The overall mortality rate of NSTE-ACS patients was 6.4%; it was higher in NSTEMI than UAP patients (13.0% vs. 2.3%; p<0.001; OR = 6.350; 95% CI = 2.504 – 16.101). Components of GRACE risk score and a score of >140 were risk factor for in-hospital death. Mortality rate was 12.5% with heparin therapy, 6.6% in patients treated with enoxaparin, and 2.3% in patients receiving fondaparinux. GRACE risk score is the only independent risk factor of death. Mortality of NSTE-ACS patients is still high (6.4%). High GRACE score is a significant risk factor of in-hospital death. The use of fondaparinux as anticoagulant agent may improve survival. Further studies are needed to confirm this finding.
Acute Coronary Syndrome; Acute Myocardial Infarction; Non-ST-Elevation Myocardial Infarction (NSTEMI); Non-ST-Elevation Acute Coronary Syndrome (NSTE-ACS); Unstable Angina (UA)
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Artha I. M. J. R, Dwipayana I. M. P. Mortality Rate and Its Associated Factors in Patients with Non ST-Elevation-Acute Coronary Syndrome in Bali: Results from A Single Center Registry. Biomed Pharmacol J 2018;11(4).
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Artha I. M. J. R, Dwipayana I. M. P. Mortality Rate and Its Associated Factors in Patients with Non ST-Elevation-Acute Coronary Syndrome in Bali: Results from A Single Center Registry. Biomed Pharmacol J 2018;11(4). Available from: http://biomedpharmajournal.org/?p=24208
Acute myocardial infarction (AMI) is the highest cause of death in Indonesia with an estimated incidence rate of 200 events per 100,000 populations annually.1 Patients with AMI could present with ST-elevation (STEMI) or non-STEMI (NSTEMI). Those without ST-elevation are generally diagnosed as non-ST elevation acute coronary syndrome (NSTE-ACS), which will be further categorized as having NSTEMI or unstable angina (UA).2 At myocardial tissue, the pathology in NSTEMI is cardiomyocyte necrosis, whereas UA is marked by myocardial ischemia without cell loss.
In-hospital mortality related to ACS in Asia-Pacific is still relatively high at about 5%.3 Patient factors are more important determinants of clinical outcome than community or hospital factors.4 There are established guidelines for the management of NSTE-ACS patients, which includes optimal medical therapy, and invasive management for patients at intermediate- to high-risk.5,6 In addition, initial risk stratification to estimate the patient’s mortality risk, such as the Global Registry in Acute Coronary Events (GRACE)7 and the Thrombolysis in Myocardial Infarction (TIMI) risk scores, should also be done.8
ACS registry in Bali was started in 2016 as part of the Indonesia STEMI project. This registry provides information about diagnostic work-up for ACS symptoms, risk stratification, acute management of STEMI, and in-hospital mortality. By analyzing a large data set in the ACS registry, clinical outcomes and the problems of delivering timely effective therapies could be studied and improved in the future. The Province of Bali lies between Java and Lombok Islands. It consists of Bali Island as the main island and several smaller islands with a total area of 5,634.40 hectares.9 Sanglah General Hospital is a hospital employed by the Government of Bali with 746-bed capacity and a comprehensive cardiac care.10
Although international guidelines for ACS management are clear and concise, it is not known how these guidelines applied in the real practice, especially in rural areas with limited PCI-capable centers. This study was aimed to evaluate the characteristics of patients with ACS and clinical outcome after reperfusion therapy in patients with NSTE-ACS in the Province of Bali, Indonesia.
Study Design and Subjects
Data from ACS registry 2016 in Bali was used in this cross-sectional study. Subjects were adult patients (aged 18 years or more) presenting with chest symptom and confirmed by electrocardiography and/or cardiac markers of myocardial infarction. Patients were hospitalized in Sanglah General Hospital (SGH), Denpasar City, Bali Island. SGH is a third referral hospital in Bali Island and has a specialized heart center with cardiac surgery facility and catheterization laboratory.
The study protocol and case report form were approved by the Ethical Committee in all of the participating institutes of Indonesia STEMI. Patients were enrolled between January and December 2016. History and clinical data were compiled by trained general physicians from medical records. Data entry was done through the website of Indonesia STEMI registry and then were cleaned by an external auditor before verified and analyzed.
Diagnosis of ACS
Diagnosis of non-STEMI (NSTEMI) was determined by chest pain compatible with ACS and abnormal ST depression or T wave inversion with elevated biochemical markers of myocardial necrosis. If cardiac markers were normal, the patient was diagnosed as unstable angina pectoris (UAP).
Patients’ demography and clinical data were presented descriptively. Categorical variables were expressed in number and percentage, while continuous variables were expressed as mean and standard deviation. Comparison between two groups was tested using Chi-square test or Fisher’s exact test. Mean differences were analyzed using student t test for normally distributed data Mann-Whitney U test for skewed data. A p value of less than 0.05 was considered significant.
A total of 421 NSTE-ACS patients were diagnosed during the study period; 300 (71.3%) among them were men. Patients’ mean age was 59 + 12.0 years, ranging from 19 to 90 years old. About 60% of patients were self-walk-in. Diagnoses were UAP in 260 (61.8%) and NSTEMI in 161 (38.2%) cases. Other clinical characteristics were presented in Table 1. Anticoagulant therapy was given to 409 (97.1%) patients, consisting 96 (22.8%) unfractionated heparin (UFH), 177 (42.0%) fondaparinux, and 136 (32.3%) enoxaparin. Eight (1.9%) patients underwent early PCI. Other treatments received were nitrate (89.1%), aspirin (99.0%), and clopidogrel (86.2%) or ticagrelor (7.8%).
Table 1: Characteristics of the study subjects (n=421).
|Characteristics||Mean + SD
|Age (years)||59.0 + 11.96|
|History of acute myocardial infarction||85||20.2|
|History of acute myocardial infarction||85||20.2|
|History of previous PCI||44||10.5|
|History of peripheral vascular disease||2||0.5|
|History of coronary artery bypass grafting||1||0.2|
|History of hypercholesterolemia||61||14.5|
|History of premature CAD in family||7||1.7|
|History of heart failure||142||33.7|
|History of asthma or COPD||10||2.4|
|History of angina||126||29.9|
|History of cerebrovascular disease||20||4.8|
|Sign of heart failure|
|Rales in <1/3 field||82||19.5|
|Rales in >1/3 field||11||2.6|
|Heart rate (bps)||83 + 28.0|
|Systolic blood pressure (mmHg)||130 + 27.0|
|Diastolic blood pressure (mmHg)||80 + 15.6|
|Creatinine serum (mg/dL)||1.9 + 2.53|
|CK-MB1||7.0 + 21.78|
|Troponin T1||188.9 + 356.29|
|GRACE risk score (n=161)||117.7 + 32.36|
|Median TIMI score||3 (1-6)|
|Median time since onset to hospital admission (hours)||7 (0-193)|
The overall mortality rate of NSTE-ACS patients was 6.4%; it was higher in NSTEMI than UAP patients (13.0% vs. 2.3%; p<0.001; OR = 6.350; 95% CI = 2.504 – 16.101). Mortality was associated with older age, higher heart rate, lower blood pressures, higher serum creatinine levels, higher troponin T1 levels, higher GRACE, and CRUSADE scores. Patients with cardiac arrest, sign of heart failure, and GRACE risk score of >140 had increased risk of death (Table 2 and Table 3). TIMI risk score was only available in 161 (38.2%) cases; therefore, no further analysis was performed.
Table 2: Clinical factors associated with mortality in NSTE-ACS patients (n=421).
|Male||18 (6.0%)||282 (94.0%)||0.586*||0.794||0.347-1.821|
|Female||9 (7.4%)||112 (92.6%)|
|Yes||7 (5.2%)||128 (94.8%)||0.480*||0.727||0.300-1.764|
|No||20 (7.0%)||266 (93.0%)|
|Yes||10 (8.2%)||112 (91.8%)||0.340*||1.481||0.658-3.333|
|No||17 (5.7%)||282 (94.3%)|
|Yes||10 (4.2%)||226 (95.8%)||0.040*||0.437||0.195-0.979|
|No||17 (9.2%)||168 (90.8%)|
|Yes||2 (3.3%)||59 (96.7%)||0.400^||0.454||0.105-1.969|
|No||25 (6.9%)||335 (93.1%)|
|History of CVD|
|Yes||2 (10.0%)||18 (90.0%)||0.372^||1.671||0.367-7.610|
|No||25 (6.2%)||376 (93.8%)|
|Yes||3 (50.0%)||3 (50.0%)||0.004^||16.292||3.121-85.045|
|No||20 (7.8%)||237 (92.2%)|
|Sign of heart failure|
|Yes||20 (18.9%)||86 (81.1%)||<0.001*||10.233||4.188-25.000|
|No||7 (2.2%)||308 (97.8%)|
|GRACE risk score|
|>140||12 (33.3%)||24 (66.7%)||<0.001^||6.444||2.444-16.993|
|<140||9 (7.2%)||116 (92.8%)|
|UFH||12 (12.5%)||84 (87.5%)||0.003||3.297||1.450-7.493|
|Other||13 (4.2%)||300 (95.8%)|
*Chi-square test ^Fisher’s exact test.
Table 3: Clinical Factors Associated with Mortality in NSTE-ACS patients (n=421).
|Variable||Died (n=25)||Alive (n=247)||p*|
|Mean age (years)||64.5||58.6||0.013|
|Mean Heart rate (bps)||110.5||81.9||<0.001|
|Mean systolic blood pressure (mmHg)||119.3||131.5||0.023|
|Mean diastolic blood pressure (mmHg)||73.3||80.3||0.029|
|Mean serum creatinine level (mg/dL) (n=418)||3.5||1.8||<0.001|
|Mean CKMB1 level (ng/mL) (n=253)||13.6||6.5||0.106|
|Mean Troponin T1 level (ng/mL) (n=161)||470.7||168.4||<0.001|
|Mean GRACE risk score (n=161)||143.6||113.8||<0.001|
|Mean CRUSADE score (n=161)||58.3||40.2||<0.001|
*Mann-Whitney U test.
Table 4: Association between type of anticoagulant therapy and death (n=409).
|UFH||10 (19.6%)||41 (80.4%)||0.051^||2.575||0.974-6.806|
|Other||9 (8.7%)||95 (91.3%)|
*Fisher’s exact test; ^Chi-square test
Mortality rate was 12.5% with unfractionated heparin therapy, 6.6% in patients treated with enoxaparin, and 2.3% in patients receiving fondaparinux. Patients with NSTEMI who were treated with UFH had increased risk of death compared with patients treated with low-molecular weight heparin (LMWH) (Table 4). In multivariate analyses, GRACE score of more than 140 was the only independent risk factor for in-hospital mortality. However, the use of fondaparinux as anticoagulant, which reached a borderline significance, could be an important protective factor of in-hospital death (Table 5).
Table 5: Predictors of in-hospital mortality in NSTE-ACS patients (n=409).
|GRACE score >140||1.665||0.506||0.002||4.892||1.816 – 13.177|
|Fondaparinux anticoagulant||-1.860||1.058||0.079||0.156||0.020 – 1.239|
SE: standard error of b coefficient.
This is the first ACS registry in Bali reporting the outcome of NSTE-ACS patients in Sanglah General Hospital, Bali. Both European and American guidelines have been adopted in Indonesia for ACS management. Evaluation of registry data verifies the daily practice in real life and shows how recommendations are implemented into clinical practice.
Our data indicated that mortality rate of NSTE-ACS is higher (6.4%) than those reported by European registries, such as in PRAIS-UK (1.5%),11 GRACE high risk NSTE-ACS (2.8%),12 and EURO-Heart Survey ACS (2.4%).13 In Thai 2007 ACS registry, the in-hospital mortality rate of NSTE-ACS was 9.5%;14 however, a more recent single ACS registry found that in-hospital mortality was only 3.5%.15
Our data showed that older age (>60 years), higher heart rate, lower blood pressures, higher serum creatinine levels, higher troponin T1 levels, cardiac arrest, and heart failure were significantly associated with mortality in NSTE-ACS. These variables are components of GRACE risk score and thus, high GRACE score is a single risk factor for in-hospital mortality. Similar pattern was also observed in Thai ACS registry; the risk factors for in-hospital death were age >65 years (OR = 2.2; 95% CI = 1.54 – 3.09); shock at presentation (OR = 4.6; 95% CI = 2.91 – 7.32); heart failure (OR = 3.1; 95% CI = 2.15 – 4.38); positive cardiac marker (OR = 1.7; 95% CI = 1.18 – 2.53); arrhythmia (OR = 12.3; 95% CI = 8.71 – 17.35); major bleeding (OR = 2.9; 95% CI = 1.84 – 4.51), and cerebrovascular accident (OR = 4.9; 95% CI = 2.42 – 9.97).14 Furthermore, in-hospital death was higher in NSTEMI than UAP patients; NSTEMI had more cardiac death than UA (7.6% vs. 2.4%; p<0.001).16
Other than GRACE risk score, we found that anticoagulant treatment has important role for patient’s survival. Significantly more patient died when UFH was used as anticoagulant. Worldwide, UFH remains the most common used anticoagulant in NSTE-ACS patients.17 Thai ACS registry also found higher mortality rate in patients receiving UFH than LMWH (9.3% vs. 5.2%; p<0.001).16
Enoxaparin is the most widely used LMWH agent in NSTE-ACS. A meta-analysis comparing enoxaparin vs. UFH in ACS showed a slightly reduction of death or myocardial infarction at 30 days in favor of enoxaparin (10.0% vs. 11.0%; OR = 0.90; 95% CI = 0.81 – 0.996); p = 0.043).18 Mortality rate was lowest in patients receiving fondaparinux, a selective factor Xa inhibitor. It was reported to have better reduction of major bleeding and long-term survival than enoxaparin.19 Latest meta-analyses conclude that fondaparinux is a better choice than enoxaparin to prevent short to midterm bleeding events, but mortality rate was similar with enoxaparin when use to patients with NSTEMI.20
In this study, we did not assess major or minor bleeding events. However, there could be a selection bias when choosing the anticoagulant agent. We assess each patient’s bleeding risk using the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of ACC/AHA [American College of Cardiology/American Heart Association] Guidelines) score. Fondaparinux was given to only 9 (19.1%) patients with CRUSADE score >50, while enoxaparin was received by 21 (36.8%) and UFH was administered to 27 (52.9%) of patients with CRUSADE score >50 (data was not shown). Further study is needed to evaluate the practice use of anticoagulant agent in preventing bleeding events and mortality among NSTE-ACS patients.
Data from ACS registry are important to evaluate the overall quality of care given to ACS patients. Mortality of NSTE-ACS patients is still high (6.4%). Host factors, which are reflected by high GRACE score is significant risk factor of in-hospital death. The use of fondaparinux as anticoagulant agent may improve survival. Further studies are needed to confirm this finding.
- World Health Organization. Global Atlas on cardiovascular disease prevention and control. Geneva: World Health Organization. 2011.
- Hamm C. W., Bassand J., 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.
- Chan M.Y., Du X., Eccleston D., Ma C., Mohanan P. P., Ogita M., et al. Acute coronary syndrome in the Asia-Pacific region. Int J Cardiol. 2016;202:861-9.
- Chang W. C., Midodzi W. K., Westerhout C. M., Boersma E., Cooper J, Barnathan ES, et al. Are international differences in the outcomes of acute coronary syndromes apparent or real? A multilevel analysis. J Epidemiol Community Health. 2005;59:427-33.
- Amsterdam E. A., Wenger N. K., Brindis R. G., Casey D. E Jr., Ganiats T. G., Holmes D. R Jr., et al. 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. Circulation. 2014;130:e344-e426.
- Roffi M., Patrono C., Collet J. P., 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: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:267-315.
- Granger C. B., Goldberg R. J., Dabbous O., Pieper K. S., Eagle K. A., Cannon C. P., et al. Global Registry of Acute Coronary Events Investigators.; Global Registry of Acute Coronary Events Investigators. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med. 2003;163:2345-53.
- Antman E. M., Cohen M., Bernink P. J., McCabe C. H., Horacek T., Papuchis G., et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000;284:835–42.
- Government of The Province of Bali. Geography. Downloaded from: http://www.baliprov.go.id/v1/geographi.
- Sanglah General Hospital, Bali. Profile. http://sanglahhospitalbali.com/v2/
- Collinson J., Flather M. D., Fox K. A., Findlay I., Rodrigues E., Dooley P., et al. Clinical outcomes, risk stratification and practice patterns of unstable angina and myocardial infarction without ST elevation: Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS-UK). Eur Heart J. 2000;21:1450-7.
- Devlin G., Anderson F. A., Heald S., Lopez-Sendon J., Avezum A., Elliott J., et al. Management and outcomes of lower risk patients presenting with acute coronary syndromes in a multinational observational registry. Heart. 2005;91:1394-9.
- Hasdai D., Behar S., Wallentin L., Danchin N., Gitt A. K., Boersma E., et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the EuroHeart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J. 2002;23:1190-201.
- Kiatchoosakin S., Wongvipaporn C., Buakhmsri A., Sanguanwong S., Mollerergpoom W., Sarakam P., et al. Predictors of in-hospital mortality in non-ST elevation acute coronary syndrome in Thai acute coronary syndrome registry (TACSR). J Med Assoc Thai. 2007;90(1):41-50.
- Pumprueg S., Boonyapisit W., Wongsa J., Naekaew N., Decha D. Characteristics and outcomes of treatment for non-ST-segment elevation acute coronary syndrome: Results from a single center registry. J Med Assoc Thai. 2016;99:1-7.
- Angkasuwapala K., Ratanasumawong K., Ngarmukos T., Kehasukcharoen W., Boonsom W., Kamsa-ard S. Effect of un-fractionated heparin and low molecular weight heparin on hospital mortality in patients with non ST elevation acute coronary syndrome (ACS). J Med Assoc Thai. 2007;90(1):109-14.
- Silvain J., Beygui F., Barthelemy O., Pollack C Jr., Cohen M., Zeymer U., et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012;344:e553.
- Murphy S. A., Gibson C. M., Morrow D. A., Van de Werf F., Menown I. B., Goodman S. G., et al. Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum a meta-analysis. Eur Heart J. 2007;28:2077-86.
- Yusuf S., Mehta S. R, Chrolavicius S., Afzal R., Pogue J., Granger C. B., et al. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:1464-76.
- Bundhun P. K., Shaik M., Yuan J. Choosing between enoxaparin and fondaparinux for the management of patients with acute coronary syndrome: A systematic review and meta-analysis. BMC Cardiovasc Disorders. 2017;17:116 (13 pages).