Impact of Total Coronary Occlusion on Long-term Outcomes in Patients with ST-segment Elevation Myocardial Infarction
Article information
Trans Abstract
Purpose
This study aimed to investigate the impact of preprocedural total coronary occlusion on long-term cardiovascular outcomes in patients with ST-segment elevation myocardial infarction (STEMI) in the contemporary percutaneous coronary intervention (PCI) era.
Methods
Of 13,707 patients from the Korea Acute Myocardial Infarction Registry-National Institutes of Health database, 2,920 consecutive patients with STEMI having single-vessel disease within 48 hours of symptom onset who underwent primary PCI were categorized by preprocedural Thrombolysis In Myocardial Infarction (TIMI) flow grade: 0 (n = 1,966), I or II (n = 583), and III (n = 371). Co-primary outcomes were all-cause death and major adverse cardio-cerebrovascular event (MACCE) at 3 years.
Results
Patients with preprocedural TIMI flow grade 0 were more likely to have longer symptom-to-door time, higher body weight, higher Killip class, lower left ventricular ejection fraction, higher peak troponin I, and lower postprocedural TIMI flow grade 3 (94.5% vs. 100%, P < 0.001) compared to those with preprocedural TIMI flow grade 3. Kaplan–Meier analysis showed no significant difference in all-cause mortality (8.1% in TIMI 0 vs. 5.9% in TIMI 3, log-rank P = 0.161) and MACCE (14.1% vs. 13.7%, log-rank P = 0.931) between the two groups. In a Cox time-to-event multivariable model with preprocedural TIMI flow grade 3 as the reference, the preprocedural TIMI flow grade 0 was not independently associated with mortality or MACCE.
Conclusion
In a nationwide prospective Korean registry, total coronary occlusion before PCI was not associated with worse clinical outcomes at 3 years in patients with STEMI and single-vessel disease when treated with primary PCI.
Introduction
Acute myocardial infarction is commonly classified as either ST-segment elevation myocardial infarction (STEMI) or non-STEMI to identify patients who will benefit from rapid reperfusion therapy [1]. There has been a consistent need to develop methods that can identify patients with STEMI early who are at risk of subsequent adverse events that might be reduced by personalized adjunctive therapies. Pathophysiologically, STEMI results from acute coronary occlusion associated with transmural myocardial ischemia. However, the coronary artery is not completely occluded in more than one-third of patients with STEMI [2-4]. Thrombolysis In Myocardial Infarction (TIMI) flow grade was established to assess the coronary perfusion associated with the degree of coronary obstruction [5]. Previous studies regarding the prognostic value of low preprocedural TIMI flow grade in patients with STEMI have shown conflicting results [6-9]. Furthermore, a meta-analysis involving 40,777 patients with non-ST-elevation myocardial infarction suggested that patients with a totally occluded culprit vessel on coronary angiography are at higher risk of mortality and major adverse cardiac events [10]. Therefore, the present study aimed to investigate the impact of preprocedural total coronary occlusion on long-term cardiovascular outcomes in patients with STEMI in the contemporary percutaneous coronary intervention (PCI) era using data from a large, prospective, nationwide Korean registry.
Methods
Study population
The Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) was designed to evaluate real-world practice and long-term clinical outcomes in patients with AMI between November 2011 and December 2015. The 20 tertiary university hospitals having facilities for PCI and onsite cardiac surgery consecutively enrolled patients. Data about baseline characteristics, laboratory findings, and cardiovascular outcomes were collected online by a clinical research coordinator. Out of 13,707 patients enrolled in the KAMIR-NIH, 6,366 consecutive patients diagnosed with STEMI within 48 hours of symptom onset were identified. Patients who had been treated with thrombolysis, had a symptom-to-door time (S2DT) > 48 hours, did not receive primary PCI, had multivessel disease, or were lost to follow-up at 6 months were excluded (Fig. 1). Consequently, a total of 2,920 patients with STEMI (60.8 ± 12.8 years; men, 80.1%) were analyzed and categorized into preprocedural TIMI flow grade 0 (n = 1,966), preprocedural TIMI flow grade 1-2 (n = 583), or preprocedural TIMI flow grade 3 (n = 371). PCI was performed according to standard guidelines. All patients received loading doses of aspirin (300 mg) and a P2Y12 inhibitor (clopidogrel, 600 mg; ticagrelor, 180 mg; prasugrel, 60 mg), followed by corresponding maintenance doses for at least 1 year. Adjunctive drugs to support PCI, thrombus aspiration, and the use of intravascular imaging were left to the physician’s discretion. Medications such as statins, beta-blockers, and renin–angiotensin–aldosterone system blockers were prescribed as per the guidelines. The completeness of follow-up at 3 years ( ≥ 1,005 days) was 93.3% (2,725/2,920). The study protocol was approved by the ethics committee of each participating center. The present study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants.
Study flowchart. The study population was derived from the nationwide prospective KAMIR-NIH (Korea Acute Myocardial Infarction Registry-National Institutes of Health). MI, myocardial infarction; NSTEMI, non-STsegment elevation myocardial infarction; PCI, percutaneous coronary intervention; S2DT, symptom-to-door time; STEMI, ST-segment elevation myocardial infarction.
Outcomes and definition
The co-primary outcomes were all-cause mortality and major adverse cardio-cerebrovascular events (MACCE; a composite of all-cause mortality, nonfatal myocardial infarction, coronary revascularization by PCI or coronary artery bypass grafting, and nonfatal stroke) at 3 years. The secondary outcomes were individual components of MACCE at 3 years. All clinical events were identified via interview, chart review, or phone call by trained clinical research coordinators and confirmed by the principal investigator of each hospital. All data were collected in a web-based case report form. STEMI was diagnosed based on the presence of a new ST-segment elevation ≥ 0.1 mV in ≥ 2 contiguous leads ( ≥ 0.2 mV in V2 to V3 leads) or a new left bundle branch block with a concomitant elevated cardiac marker. Primary PCI was defined as when the procedure was performed as soon as possible after the diagnosis of STEMI in the index hospitalization. Off-hour admission was defined as arrival at the hospital during weekends, holidays, and night shifts (6 PM to 8 AM) on weekdays. The PCI was considered successful when residual stenosis was < 30% with final TIMI flow grade 2 or 3. Potent P2Y12 inhibitors included ticagrelor and prasugrel.
Statistical analysis
Analyses were performed using R software version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria). Categorical and continuous variables are presented as the number of cases (percentages) and mean ± standard deviation or median (interquartile range), respectively. The categorical variables were compared using the chi-square test or Fisher’s exact test and continuous variables were compared using one-way analysis of variance or the Kruskal‒Wallis test. Kaplan‒Meier analysis of the outcomes according to the groups was performed using the log-rank test. Correlates of clinical outcomes were assessed using multivariable Cox regression analysis. Baseline variables with P < 0.1 in the univariable analysis and any other baseline variables judged to be of clinical relevance from previously published studies were included in the multivariable analysis after considering the assumption of proportionality and linearity of the Cox proportional hazards model. Specifically, these variables comprised preprocedural TIMI flow grade, age, sex, body weight, symptom-do-door time, off-hour presentation, Killip class, heart rate, systolic blood pressure, diabetes mellitus, hypertension, angina, previous myocardial infarction or revascularization, family history of premature coronary artery disease, current smoker status, previous cerebrovascular accident, anemia, creatinine clearance, total cholesterol, white blood cell count, and left anterior descending artery stenosis. The following variables with missing values were included in the multivariable analysis: systolic blood pressure (n = 6), heart rate (n = 6), body weight (n = 73), hemoglobin (n = 4), creatinine clearance (n = 4), and total cholesterol (n = 92). Missing values were imputed using multiple imputation method. The assumptions of proportionality and linearity were assessed using the log-minus-log plots and the cumulative sum of martingale-based residuals, respectively. Collinearity diagnostics were assessed using the variance inflation factor and eigensystem analysis among variables included in the multivariable Cox regression analysis. A two-sided P < 0.05 was considered to indicate statistical significance.
Results
Baseline clinical and procedural characteristics
Compared with patients with preprocedural TIMI flow grade 3, those with preprocedural TIMI flow grade 0 were more likely to have longer S2DT, high body weight, high Killip class at admission, low left ventricular ejection fraction, high white blood cell count, high peak troponin I, and high low-density lipoprotein cholesterol levels (Table 1). Patients with preprocedural TIMI flow grade 0 were more likely to have shorter door-to-balloon time, right coronary artery culprit lesion, American College of Cardiology/American Heart Association lesion type B2/C, thrombus aspiration, and glycoprotein IIb/IIIa inhibitor use; they were less likely to have stenting, drug-eluting stent implantation, and postprocedural TIMI flow grade 3 (Table 2). There were no significant differences in medications at discharge among the groups.
Baseline clinical and laboratory findings according to preprocedural TIMI flow grades
Angiographic and procedural characteristics and medical treatments according to preprocedural TIMI flow grades
Clinical outcomes
Clinical outcomes were evaluated at 3 years (1,095 days; interquartile range: 1,057−1,095). Table 3 shows clinical outcomes up to 3 years according to preprocedural TIMI flow. There were no significant differences among the three groups regarding primary and secondary outcomes during the 3-year follow-up: 3.2% in preprocedural TIMI flow grade 0 vs. 2.9% in preprocedural TIMI flow grade 1 or 2 vs. 2.7% in preprocedural TIMI flow grade 3 for in-hospital mortality, P = 0.876; 8.1% vs. 7.9% vs. 5.9% for all-cause mortality at 3 years, P = 0.346, log-rank P = 0.161; and 14.1% vs. 15.1% vs. 13.7% for MACCE at 3 years, P = 0.795, log-rank P = 0.931. The cumulative time-to-event curves for all-cause mortality and MACCE among the three groups based on preprocedural TIMI flow grades over 3 years are shown in Fig. 2. For sensitivity analysis, Kaplan–Meier curves were generated for all-cause mortality and MACCE according to preprocedural TIMI flow grades in patients undergoing stenting or having postprocedural TIMI flow grade 3, which revealed no significant results (Online Fig. 1).
Clinical outcomes during 3 years according to preprocedural TIMI flow grades
Cardiovascular outcomes during 3 years according to the preprocedural TIMI flow grades. Kaplan-Meier curves for (A) all-cause mortality and (B) major adverse cardio-cerebrovascular events (MACCE) during 3 years. PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction.
Clinical significance of total coronary occlusion
In a Cox time-to-event multivariable regression analysis with preprocedural TIMI flow grade 3 as the reference, preprocedural TIMI flow grade 0 was not independently associated with increased incidence of all-cause mortality (adjusted HR: 1.00; 95% CI: 0.64 to 1.57; P = 0.996) or MACCE (adjusted HR: 0.84; 95% CI: 0.62 to 1.14; P = 0.271) at 3 years (Fig. 3). The results of the stepwise Cox proportional hazard models for correlates of all-cause mortality and MACCE are presented in Online Tables 1 and 2, respectively. We performed several subgroup analyses to ensure the robustness of the results, which are based on the TIMI risk score, S2DT < 4 hours or ≥ 4 hours, infarct related artery, and another high-risk factors (Online Figs 2 to 5). There were no significant differences in all-cause mortality or MACCE at 3 years in the subgroup analyses.
Adjusted prognostic values of variables for 3-year mortality and MACCE. Cox regression analysis using the enter method was performed with preprocedural TIMI flow grades and remaining variables in a backward elimination selection. CI, confidence interval; eGFR, estimated glomerular filtration rate; MACCE, major adverse cardio-cerebrovascular events; WBC, white blood cell. Other abbreviations as in Fig.1.
Discussion
In a large, nationwide, prospective Korean registry, patients with preprocedural TIMI flow grade 0 were more likely to be obese and have longer S2DT, higher Killip class, lower left ventricular ejection fraction, higher peak troponin I, and lower postprocedural TIMI flow grade 3 compared to those with preprocedural TIMI flow grade 3. Kaplan‒Meier analysis showed no significant difference in all-cause death or MACCE between the two groups. In a Cox time-to-event multivariable model with preprocedural TIMI flow grade 3 as the reference, preprocedural TIMI flow grade 0 was not independently associated with mortality or MACCE at 3 years. To the best of our knowledge, this is the largest observational study to investigate the impact of a preprocedural total coronary occlusion on long-term cardiovascular outcomes among all-comer STEMI patients with single-vessel disease in the contemporary PCI era.
Although the majority of patients with STEMI have a preprocedural TIMI flow grade 0 at the time of coronary angiography, approximately one in three patients with STEMI presenting within 12 hours of symptom onset have a preprocedural TIMI flow grade other than 0 [2-4,11]. Theoretically, patients with STEMI and preprocedural TIMI flow grade 0 may have worse clinical outcomes associated with larger and more irreversible infarction compared with those with preprocedural TIMI flow grade 1-3. However, there have been conflicting results regarding the prognostic value of low preprocedural TIMI flow. Stone et al. analyzed 2,507 patients with acute myocardial infarction from the four Primary Angioplasty in Myocardial Infarction (PAMI) trials and demonstrated that patients with preprocedural TIMI flow grade 3 had significantly lower rates of inhospital mortality, new-onset heart failure, and 6-month mortality compared with those without preprocedural TIMI flow grade 3 [6]. Preprocedural TIMI flow grade 3 was an independent determinant of survival in the multivariable analysis. Luca et al. analyzed 1,791 patients with acute myocardial infarction treated by primary angioplasty and demonstrated that preprocedural TIMI flow grade was related to postprocedural TIMI flow grade 3, enzymatic infarct size, predischarge ejection fraction, and one-year mortality. Multivariable analysis revealed that preprocedural TIMI flow grade 3 was an independent predictor of one-year survival in high-risk patients [7]. Recently, Bauer analyzed 1,680 patients with STEMI within 6 hours of symptom onset from the ATLANTIC (Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST-Elevation Myocardial Infarction to Open the Coronary Artery) study and demonstrated that a preprocedural TIMI flow grade < 3 was not an independent predictor of major adverse ischemic events within 30 days [8].
Our study analyzed 2,920 consecutive patients with STEMI and single coronary artery stenosis within 48 hours of symptom onset from a nationwide prospective Korean registry for which the recent guidelines recommend primary PCI [12]. Preprocedural TIMI flow grade 0 was not independently associated with an increased incidence of all-cause mortality or MACCE at 3 years, even in diverse high-risk subpopulations such as TIMI risk score ≥ 4, S2DT ≥ 4 hours, left anterior descending artery stenosis, diabetes mellitus, renal insufficiency, and low ejection fraction. Several explanations may account for the negative association between preprocedural total occlusion and clinical outcomes in patients with STEMI treated by primary PCI. First, compared with previous studies, patients enrolled in the present study had shorter S2DT (125 minutes, interquartile range: 60‒271) and door-to-balloon time (58 minutes, interquartile range: 46‒72), and more than 90% of patients received stenting, mainly drug-eluting stents. The rate of successful PCI was relatively high at 98.7%. Second, we should consider the natural course of coronary occlusion when interpreting the prognosis of preprocedural TIMI flow grade on clinical outcomes in patients with STEMI. Coronary occlusion may have a stuttering course with intermittent occlusion and re-canalization [13]. Therefore, pre-procedural TIMI flow grades at the time of coronary angiography may be the one of the diverse flow grades during the stuttering course. Third, the survivor cohort effect should be considered when patients with STEMI were analyzed because they have already survived the period at the highest risk of death. In a previous study, late presentation was not independently associated with an increased incidence of mortality after STEMI, which is partly explained by the survivor cohort effect [4]. Patients with a totally occluded culprit artery may be more likely to die before arriving at the hospital arrival, resulting in an attenuation of its impact of it on clinical outcomes.
Another issue we should consider is the appropriateness of TIMI flow grade as a measure of coronary circulation. The TIMI Coronary Grade Flow grade was initially established by the TIMI study group in the early 1980s to provide a uniform method of documenting epicardial perfusion on coronary arteriography. It has proven to be an effective clinical tool [14]. TIMI flow grade 0 represents a total occlusion and TIMI flow grade 3 represents normal perfusion. It is certainly easy and inexpensive, but it might be a suboptimal, incomplete measure of myocardial flow [15]. TIMI frame count, TIMI myocardial perfusion grade, and microvascular resistance index have been suggested as better measures of myocardial flow in patients with STEMI [16,17]. The corrected TIMI frame count is the number of cine frames required for the dye to first reach standardized distal coronary landmarks [18]. A faster 90-minute corrected TIMI frame count was shown to be related to improved 1-month clinical outcomes after thrombolytic administration in a multivariate model. TIMI myocardial perfusion grade was developed to assess the filling and clearance of contrast in the myocardium [19]. The TIMI myocardial perfusion grade is related to a 30-day mortality risk after the administration of thrombolytic drugs. Even among patients having TIMI flow grade 3, the TIMI myocardial perfusion grades allowed further risk stratification. The microcirculatory resistance index has been suggested as a measure of the coronary microcirculation [20]. A previous study involving 29 patients with STEMI undergoing primary PCI demonstrated that the microcirculatory resistance index correlated significantly with myocardial infarct size, whereas other microcirculation measures, such as ST-segment resolution, TIMI frame count, TIMI myocardial perfusion grade, and coronary flow reserve, did not [21].
Study limitations
Our study has several limitations. First, the KAMIR-NIH participating centers are all tertiary university hospitals with a higher patient volume, thus limiting the generalizability of the present findings. Second, we only included patients with STEMI and single obstructive coronary artery. It is also one of the strengths of our study to avoid bias associated with multivessel coronary disease and related procedures, which might not be addressed appropriately in the registry. Third, adjudication of the TIMI flow grades was performed by investigators at each participating centers without core laboratory confirmation.
Conclusions
In a large, nationwide, prospective Korean registry, STEMI patients with TIMI flow grade 0 on coronary angiography were more likely to have longer S2DT, higher body weight, higher Killip class, lower left ventricular ejection fraction, higher peak troponin I, and lower postprocedural TIMI flow grade 3 compared to those with preprocedural TIMI flow grade 3. However, in a Cox time-to-event multivariable model with preprocedural TIMI flow grade 3 as the reference, the preprocedural TIMI flow grade 0 was not independently associated with mortality or MACCE at 3 years in patients with STEMI who underwent primary PCI.
Notes
The authors declare that there are no potential conflicts of interest relevant to this article.
Funding
This work was funded by the Research of Korea Centers for Disease Control and Prevention (2016‒ER6304‒02) and the Chonnam National University Hospital Biomedical Research Institute (BCRI‒22052).
Acknowledgements
The authors thank the patients and investigators who participated in this registry. The present study was conducted in accordance with the STROBE statement.