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Abstract
Objectives Accurately predicting short-term MACE (major adverse cardiac events) following primary percutaneous coronary intervention (PCI) remains a clinical challenge. This study aims to assess the effectiveness of four established risk scores in predicting short-term MACE after primary PCI.
Design Prospective observational study.
Setting The National Institute of Cardiovascular Diseases, Karachi, Pakistan.
Participants We enrolled a cohort of consecutive adult patients diagnosed with ST-elevation myocardial infarction undergoing primary PCI over a 6-month period, from 1 January 2022 to 30 June 2022.
Outcome measures All the patients were followed at intervals of 3 months up to 12 months, and MACE events were recorded. Thrombolysis in Myocardial Infarction (TIMI), Primary Angioplasty in Myocardial Infarction (PAMI), Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) and Global Registry of Acute Coronary Events (GRACE) scores were obtained.
Results A total of 2839 patients (79.3% male, mean age 55.6±11.2 years) were included. Over a median follow-up of 244 days, the composite MACE rate was 18.4% (521). All-cause mortality was 13.5% (384), reinfarction requiring revascularisation was 4.3% (121), heart failure-related rehospitalisation was 2.7% (76), stent thrombosis occurred in 5.6% (160) and cerebrovascular accident events were documented in 1% (28). The area under the curve for TIMI, PAMI, CADILLAC and GRACE scores was 0.682 (95% CI 0.655 to 0.709), 0.688 (95% CI 0.663 to 0.713), 0.686 (95% CI 0.66 to 0.711) and 0.695 (95% CI 0.669 to 0.72), respectively, for the prediction of MACE. On multivariable Cox regression, high-risk categories based on GRACE score were independent predictors of MACE with adjusted HR of 1.88 (95% CI 1.28 to 2.77; p=0.001).
Conclusions A significant proportion of patients experienced short-term MACE after primary PCI. While none of the assessed scores demonstrated significant predictive power, the GRACE score exhibited comparatively better predictive ability than the TIMI, PAMI and CADILLAC scores.
- CARDIOLOGY
- Coronary intervention
- Heart failure
- Ischaemic heart disease
Data availability statement
Data are available on reasonable request. Data and material will be available on request to the corresponding author of this manuscript.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This study was conducted in a large, comprehensive cohort of 2839 ST-elevation myocardial infarction patients.
Well-established risk scores, namely Thrombolysis in Myocardial Infarction, Primary Angioplasty in Myocardial Infarction (PAMI), Global Registry of Acute Coronary Events (GRACE) and Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC), were employed to predict major adverse cardiac event (MACE).
The observational nature of the study and the single-centre setting are the main limitations, including with respect to the generalisability of the findings.
The non-uniformity of the length of follow-up from patient to patient is another possible factor that may affect the incidence of MACE.
Introduction
Despite a decline in myocardial infarction (MI) rates over the past five decades, MI remains a significant contributor to morbidity across genders, with ischaemic heart disease persisting as the primary global cause of death.1 While advancements in medical therapy and primary percutaneous coronary intervention (PCI) have substantially improved clinical outcomes for acute MI (AMI) patients in recent years, the pathophysiology, severity, management and prognosis vary among individuals.2
Survivors of MI face a heightened risk of major cardiovascular events postdischarge, although with considerable variability among patients. Lifestyle modifications, quality care and adherence to guideline-directed medical therapy play pivotal roles in secondary prevention.3 Patient-specific characteristics also influence cardiovascular event risk, underscoring the importance of identifying these traits to better inform patients, families and healthcare providers, enabling intensive follow-up and risk factor modification.3 Major adverse cardiovascular events (MACE), including recurrent MI, stroke and heart failure, significantly impact patients’ quality of life and are collectively more prevalent than mortality.4–7 Emphasising long-term outcomes beyond mortality is imperative, particularly in non-Western nations, to comprehensively evaluate patients’ healthcare experiences.
Accurate risk assessment enhances patient care, with objective risk assessment proving more effective than intuitive physician estimations for risk discrimination.8 Various clinical indices and scoring systems have been proposed for risk stratification in ST-segment elevation MI (STEMI) patients, among which the Thrombolysis in Myocardial Infarction (TIMI), Primary Angioplasty in Myocardial Infarction (PAMI), Global Registry of Acute Coronary Events (GRACE) and Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) scores are commonly used.9–12 Initially developed to predict in-hospital mortality in acute coronary syndrome (ACS) patients, the GRACE score has evolved into a guideline-recommended tool for MI management, while the CADILLAC score originates from a cohort of STEMI patients undergoing primary PCI.13 The TIMI score is also widely employed for mortality risk assessment in STEMI patients.9
However, the efficacy of these scores in predicting MACE or mortality beyond 30 days, particularly in South Asian populations, remains largely unknown or uncertain. Hence, we conducted a study using a single-centre-based cohort of STEMI patients post-primary PCI to evaluate the predictive efficacy of four established risk scores—TIMI, PAMI, GRACE and CADILLAC—in predicting short-term MACE after primary PCI.
Methods
Study design, setting and patient population
The National Institute of Cardiovascular Diseases is the largest tertiary care cardiac centre in Pakistan. At this centre, we provide free of cost primary PCI services to all the patients who present with STEMI. A cohort of consecutive adult patients diagnosed with STEMI was recruited for this prospective observational study. Patients of either gender, age ≥18 years, diagnosed with STEMI and who underwent primary PCI were included. Patients who refused to give consent for participation in the study were excluded. Patients who were discharged alive from the hospital but didn't show up for even a single follow-up or did not respond to any of our follow-up calls were excluded from the analysis (figure 1). The study was conducted according to the ‘principles of the Declaration of Helsinki’.
Patient flow chart. PCI, percutaneous coronary intervention.
Routine clinical assessment and management
All the patients were managed in accordance with the recent clinical guidelines. A routine 12-lead ECG was performed for the diagnosis of STEMI in addition to the routine standard blood test and physical examination. All the preprocedure and postprocedure pharmacological and non-pharmacological management of patients were practised and monitored by the consultant cardiologists in accordance with institutional protocol and recent clinical practice guidelines. All the patients were followed during the hospital stay and after discharge from the hospital as per the routine practice. Additionally, telephonic follow-up calls were made to all the patients at the interval of 3 months up to 12 months.
With the help of routinely assessed clinical parameters, four well-established risk assessment scores were computed, and patients were categorised into three groups. The risk scores were TIMI score (low risk: 0–4, medium risk: 5–9 and high risk: >9), PAMI score (low risk: 0–2, medium risk: 3–6 and high risk: >6), CADILLAC score (low risk: 0–2, medium risk: 3–5 and high risk: >5) and GRACE score (low risk: 49–124, medium risk: 125–154 and high risk: >154).
Variables and definitions
Diagnostic criteria for STEMI were ‘history of typical chest pain for at least 20 min’ and presenting ECG finding of ‘ST elevation in at least two contiguous leads >2 mm in men or >1 mm in women in leads V2 to V3 and/or >1 mm in other contiguous chest leads or limb leads’.
The short-term MACE was defined as the occurrence of at least any one of the events, namely all-cause mortality, re-MI needing repeat revascularisation, rehospitalisation due to heart failure, cerebrovascular accident (CVA) or stent thrombosis. As per the (Academic Research Consortium), definite and probable acute and subacute stent thrombosis were considered.
Sample size
The sample size for the study was determined based on an expected short-term MACE rate of 19.1%,6 with a 95% confidence level and a 2% margin of error, resulting in a calculated sample size of 1484 patients. Accounting for an anticipated 30% loss to follow-up, the total required sample size increased to 1929 patients. To minimise observation and selection bias, we decided to recruit consecutive patients meeting the inclusion criteria over a 6-month period, from 1 January 2022 to 30 June 2022.
Data analysis
Data analysis was performed using ‘IBM SPSS Statistics for Windows V.25.0 (IBM SPSS Statistics, IBM)’. Descriptive summaries of data were presented as either mean±SD or median (IQR) for continuous variables and percentage (frequency) for categorical variables. The normality of the distribution of continuous variables was tested with the help of Kolmogorov-Smirnov. Patients were categorised into groups of patients with MACE and without MACE, and clinical characteristics were compared with the help of either an independent sample t-test or Mann-Whitney U test for continuous variables and a χ2 test or Fisher’s exact test for categorical variables. The univariate and multivariable proportional hazards Cox regression analysis was performed to determine clinical predictors of short-term MACE and mortality. A list of dependent variables was tested for collinearity/correlation, and variables with strong correlation were dropped from the multivariable model based on their significance in the univariable model. The multivariable Cox regression analysis was performed using the backward conditional method with 0.10 and 0.20 as the probability of entry and removal in the stepwise analysis. The HR and its 95% CI are reported for both Cox regression models. The receiver operation characteristics (ROC) curve analysis was performed for the composite outcome of MACE as well as for all-cause mortality, and the AUC (area under the curve) was compared for TIMI, PAMI, CADILLAC and GRACE scores. Additionally, Kaplan-Meier survival curves were compared for MACE and all-cause mortality rates among low, medium and high-risk groups categorised by TIMI, PAMI, CADILLAC and GRACE scores. All hypothesis testing was two tailed, and p values <0.05 were considered to indicate statistical significance.
Patient and public involvement
None.
Results
Patient characteristics
A total of 2839 were included in this analysis; 79.3% (2250) were male, and the mean age was 55.6±11.2 years (table 1). During a median follow-up duration of 244 (175–393) days, the composite MACE rate was 18.4% (521). The all-cause mortality rate was 13.5% (384), out of which 8.2% (233) was categorised as cardiac and 5.3% (151) as non-cardiac mortality. Re-MI needing revascularisation was noted in 4.3% (121), rehospitalisation due to heart failure was reported by 2.7% (76), stent thrombosis developed by 5.6% (160) and CVA event was documented in 1% (28) of the patients. The distribution and comparison of clinical characteristics between patients with MACE and without MACE are presented in table 2.
Distribution and comparison of demographic and clinical characteristics between patients with MACE and without MACE
Distribution and comparison of procedural characteristics and outcomes between patients with MACE and without MACE
Prognostic performance for MACE
There was a significant association between TIMI risk score and MACE rate (p<0.001) with MACE rate of 12.5% (249/1986), 29.4% (232/788) and 61.5% (40/65) among the low, medium and high-risk groups, respectively. The MACE rate was 12.3% (227/1845), 27.7% (238/859) and 41.5% (56/135) among low, medium and high-risk groups categorised by PAMI score, respectively. MACE rates were 8.9% (95/1063), 17% (118/696) and 28.5% (308/1080) among low, medium and high-risk groups categorised by CADILLAC score, respectively. Similarly, MACE rates were 12.9% (275/2124), 24.7% (121/489) and 55.3% (125/226) among low, medium and high-risk groups categorised by GRACE score, respectively.
The AUC for TIMI, PAMI, CADILLAC and GRACE scores was 0.682 (95% CI 0.655 to 0.709), 0.688 (95% CI 0.663 to 0.713), 0.686 (95% CI 0.66 to 0.711) and 0.695 (95% CI 0.669 to 0.72) for the prediction of MACE, respectively, and 0.714 (95% CI 0.684 to 0.743), 0.698 (95% CI 0.67 to 0.727), 0.713 (95% CI 0.685 to 0.741), and 0.735 (95% CI 0.708 to 0.763) for the prediction of all-cause mortality, respectively. ROC is presented in figure 2.
ROC curve analysis of MACE and all-cause mortality for TIMI, PAMI, CADILLAC and GRACE scores. CADILLAC, Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications; GRACE, Global Registry of Acute Coronary Events; PAMI, Primary Angioplasty in Myocardial Infarction; ROC, receiver operation characteristic; TIMI, Thrombolysis in Myocardial Infarction.
The Kaplan-Meier survival curves of MACE and all-cause mortality by TIMI, PAMI, CADILLAC, and GRACE risk categories are presented in figure 3.
Kaplan-Meier survival curves of MACE (A–D) and all-cause mortality (E–H) by TIMI, PAMI, CADILLAC and GRACE risk categories. CADILLAC, Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications; GRACE, Global Registry of Acute Coronary Events; MACE, major adverse cardiac event; PAMI, Primary Angioplasty in Myocardial Infarction; TIMI, Thrombolysis in Myocardial Infarction.
Predictors of MACE
On multivariable Cox regression, high-risk categorisation based on the GRACE score was found to be an independent predictor of MACE with an adjusted HR of 1.88 (95% CI 1.28 to 2.77); p=0.001 (table 3).
Univariate and multivariable proportional hazards Cox regression analysis for short-term MACE
Predictors of all-cause mortality
On multivariable Cox regression, medium and high-risk categorisation based on GRACE score was found to be independent predictors of all-cause mortality with adjusted HR of 1.42 (95% CI 1.04 to 1.95); p=0.029 and 1.56 (95% CI 1.02 to 2.38); p=0.042, respectively (table 4).
Univariate and multivariable proportional hazards Cox regression analysis for short-term all-cause mortality
Discussion
The findings of this study shed light on the ongoing challenge of accurately predicting short-term MACE following primary PCI in patients with STEMI. Despite advancements in medical care, identifying individuals at higher risk for adverse outcomes remains crucial for optimising management strategies.
This study, encompassing a cohort of 2839 consecutive adult STEMI patients undergoing primary PCI, revealed a substantial rate of MACE events over a median follow-up period of 244 days. The composite MACE rate was 18.4%, with all-cause mortality accounting for 13.5%, among which cardiac mortality constituted 8.2%. Notably, significant rates of re-MI requiring revascularisation, heart failure rehospitalisation, stent thrombosis and cerebrovascular events underscore the multifaceted nature of post-PCI complications.
The four established risk scores, namely TIMI, PAMI, CADILLAC and GRACE, demonstrated moderate discriminatory ability in predicting MACE events. However, on multivariable Cox regression analysis, only the GRACE score achieved the desired statistical significance as an independent predictor of both MACE and all-cause mortality. The GRACE score incorporates clinical, haemodynamic and renal function parameters. These features contribute to their relatively better performance compared with other scores.
There are limited available data regarding the effectiveness of various scoring systems in predicting MACE. In a study conducted by Zhao et al,14 which followed 4151 patients with MI who underwent primary PCI over a period of 698 days, 544 (13.1%) MACE events were reported. The TIMI score demonstrated a C-index of 0.782 for predicting MACE in this cohort.
Jakimov et al15 conducted a retrospective study involving 200 patients with ACS, including 116 with STEMI, and reported an 8.5% 30-day MACE rate. The AUC for the TIMI and GRACE scores in predicting MACE was 0.56 and 0.65, respectively.
In another study by Lev et al,16 comparing the predictive value of TIMI, PAMI, CADILLAC and GRACE scores for 30-day MACE prediction, a 9.1% MACE rate was observed. The AUCs for predicting 30-day MACE were 0.635, 0.65, 0.714 and 0.544 for TIMI, PAMI, CADILLAC and GRACE scores, respectively.
Kong et al17 followed 209 consecutive STEMI patients who underwent primary PCI over a 4-year period, comparing the performance of CADILLAC and GRACE scores in predicting MACE at 6 months, 1 year and 4 years postprocedure. The AUCs were found to be 0.715 vs 0.75, 0.725 vs 0.761 and 0.629 vs 0.622 for CADILLAC versus GRACE scores at the respective follow-up periods.
Similarly, Sato et al18 reported the predictive value of CADILLAC and GRACE risk scores for postdischarge MACE, with AUCs of 0.69 and 0.64, respectively, indicating modest predictive capabilities for both scoring systems.
An AUC of 0.80 or higher is typically regarded as sufficiently discriminative for meaningful clinical use. However, the literature referenced above suggests that the conventional risk scores examined have yielded low AUC values, potentially limiting their predictive accuracy for long-term events. Postdischarge major cardiovascular events are not observable at the time of discharge and may be influenced by unknown factors thereafter.
Wang et al3 conducted a study identifying nineteen risk factors for predicting the risk of 1-year MACE following AMI. These factors encompassed various aspects such as age, educational background, medical history including prior AMI, ventricular arrhythmias, hypertension, angina, prehospital medical care, time from symptom onset to admission, cardiac function indicators, renal function, vital signs, blood parameters and in-hospital complications.
Similarly, Kumar et al6 identified several independent predictors of MACE after primary PCI over a median follow-up duration of 6 months. These predictors included admission hyperglycaemia, elevated serum creatinine levels, requirement for intubation, history of PCI or CVA, elevated left ventricular pressures, severity and location of coronary artery disease, and procedural aspects such as preballooning and thrombus burden.
Consistent with these findings, our study identified additional predictors of MACE, including gender, elevated heart rate, high random blood sugar levels, Killip class at presentation, need for intubation, arrhythmias on presentation, prior PCI or coronary artery bypass grafting, history of CVA, history of congestive heart failure, temporary pacemaker placement, left ventricular function, extent of coronary artery involvement, baseline coronary flow status and GRACE score. These factors collectively contribute to the prediction of adverse cardiovascular events postprocedure.
It is important to recognise the limitations and challenges associated with using TIMI, PAMI, CADILLAC and GRACE scores for risk assessment in STEMI patients. While each score provides valuable insights, their practical use can be constrained. For instance, the TIMI score has limited ability to distinguish between levels of risk, the PAMI score is based on outdated methodologies, and the CADILLAC score can be both complex and narrowly focused. Similarly, the GRACE score relies heavily on extensive data and specific tools, making it less accessible in certain settings. These challenges highlight the need for more comprehensive, user-friendly and versatile tools to better meet the demands of modern clinical practice.
These findings underscore the importance of conducting more detailed research to pinpoint high-risk factors for predicting MACE beyond what conventional risk scores currently offer. By delving deeper into these factors (both disease-specific as well as procedure-specific), we can potentially develop a comprehensive scoring system tailored specifically for assessing MACE risk in patients with STEMI. This would significantly improve prognostic accuracy and refine clinical decision-making within this patient population.
While our study represents the most extensive dataset available for our particular demographic, it is essential to acknowledge the inherent limitations, notably the observational nature of the study and its reliance on data from a single centre. To gain a more comprehensive understanding of MACE on both regional and global scales, there is a clear need for studies conducted with standardised definitions and consistent follow-up intervals. Only through such efforts can we fully grasp the complexities of MACE occurrence and develop more effective strategies for prevention and management.
Conclusions
A notable number of patients encountered short-term MACE following primary PCI. Although none of the evaluated scoring systems exhibited significant predictive power, the GRACE score displayed relatively superior predictive efficacy compared with the TIMI, PAMI and CADILLAC scores. However, despite this relatively better performance, the overall predictive value of these clinical scores remains modest.
Given the limitations of existing scoring systems in accurately identifying high-risk patient subgroups, further investigations are imperative. These studies should aim to elucidate an optimal mechanism for discerning individuals at heightened risk of adverse outcomes post-PCI. By refining risk assessment strategies, we can enhance patient care and tailor management approaches more effectively in this vulnerable population.
Data availability statement
Data are available on reasonable request. Data and material will be available on request to the corresponding author of this manuscript.
Ethics statements
Patient consent for publication
Ethics approval
This study was approved by the Ethical Review Committee (ERC) of the National Institute of Cardiovascular Diseases (NICVD), Karachi (ERC-01/2022). Verbal informed consent was obtained from all the patients regarding their participation in the study and publication of data while maintaining confidentiality and anonymity. Due to the observational nature of the study, the ERC waived the need for written consent and approved the verbal consent procedure.
Acknowledgments
The authors wish to acknowledge the support of the staff members of the Clinical Research Department of the National Institute of Cardiovascular Diseases (NICVD) Karachi, Pakistan.
References
Footnotes
X @rajradhaswami
Contributors RK, US, NY, SFK, KM, NK, BJ, EY and MOS contributed to the concept and design of the study; RK and MK contributed to the analysis and interpretation of data; SK, SN, KB, MA, AFT and KAM collected data and drafted the manuscript, and AH, FF, JAS and TS critically analysed for content. All authors approved the final draft of the manuscript and agreed to be accountable for all aspects of the work. RK is the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.