Invasive treatment strategy in patients aged 80 years or older with non-ST-elevation acute coronary syndromes: a retrospective cohort study

Introduction

Ischemic heart disease, including acute coronary syndrome (ACS), is the leading cause of mortality both in China and worldwide (1,2). Since age is a major risk factor for ACS, the global disease burden of ACS will inevitably increase in the coming decades due to the aging population. With the advancement of invasive coronary strategies, pharmacological therapies, and lifestyle interventions, the mortality rate of ACS has been gradually reduced over the past decades (3,4). Nevertheless, this reduction has been mostly presented in patients with ST-segment elevation myocardial infarction (STEMI) but not in those with non-ST-elevation acute coronary syndrome (NSTE-ACS) (5).

According to several guidelines, NSTE-ACS patients are recommended to undergo an invasive coronary angiography (CAG), followed by revascularization if necessary, unless their risk stratification is low (6-8). However, patients with advanced age are at higher risk, and thus are less likely to receive invasive treatment (9-11). This treatment-risk paradox may be partly attributed to a higher incidence of comorbidities, which may result in procedure-related complications and mortality in higher-risk patients. Furthermore, the underrepresentation of elderly patients in clinical trials has led to limited evidence for the invasive strategies for those ≥80 years of age. The aim of the present study was to analyze data from a clinical database to determine the impact of invasive treatment strategies on long-term mortality in patients aged 80 years or older presenting with NSTE-ACS. We present the following article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-21-650/rc).

Methods

Study population and data collection

The study population in this single-center, retrospective, cohort study was identified from the ACS patient database of the Cardiovascular Center of Beijing Friendship Hospital, a tertiary center with emergency departments, which includes consecutive ACS inpatients over the age of 18 from December 2012 onward. Patients who met the following inclusion criteria were enrolled in the study: ≥80 years old and discharged with non-ST-elevation myocardial infarction (NSTEMI) or unstable angina (UA) as the principal diagnosis between December 2012 and July 2019. For patients who had more than one record during this period, only the first record that met the inclusion criteria was included.

All clinical data were collected and entered into the database by trained researchers. Data elements collected in this study included patient demographics, medical history, cardiovascular risk factors, blood pressure and heart rate at admission, laboratory test results in the first 24 hours after admission, in-hospital procedures and discharge medications. Barthel index at admission was also collected as a reflection of frailty in elderly patients. To determine the associations between invasive treatment strategies and long-term mortality, patients were divided into invasive and conservative groups, based on whether they received CAG during hospitalization or not, respectively. Patients who died in the first 3 days after admission without receiving invasive treatment were excluded to limit bias. We further divided the invasive intervention group into subgroups to better understand outcomes: timely invasive group (invasive time ≤1 d in high-risk patients or ≤3 d in intermediate risk patients) and delayed invasive group (invasive time >1 d in high-risk patients or >3 d in intermediate-risk patients), based on the guideline recommendation at that time (6-8).

Follow-up survival information was collected by contacting patients and their families at outpatient visits or by phone calls at 1 month, 3 months, 6 months, 1 year and then annually after discharge. The follow-up period ended in April 2020. The primary outcome was all-cause mortality. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Beijing Friendship Hospital, Capital Medical University (project number: 2020-P2-083-01) and individual consent for this retrospective analysis was waived.

Definitions

NSTE-ACS was defined according to published guidelines (6-8). Invasive strategy was defined as optimal medical treatment, CAG during hospitalization, with or without further percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Conservative strategy was defined as optimal medical treatment only. Hyperuricemia was defined as serum uric acid >417 µmol/L (7.0 mg/dL) for males and >357 µmol/L (6.0 mg/dL) for female patients. Thrombocytopenia was defined as platelet count <100×10⁹/L. Estimate glomerular filtration rate (eGFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation modified for Chinese population (12). Severe renal insufficiency was defined as end stage renal disease or eGFR <30 mL/min/1.73 m² (13).

Statistical analysis

Data are presented as means (standard deviation, SD), medians with interquartile range (IQR) or numbers and percentages where appropriate. Student’s t-test or Wilcoxon-Mann-Whitney U test was used to compare continuous variables, and the Chi-squared test or Fisher’s exact test was used to compare categorical variables between the two groups. The N-terminal pro-brain natriuretic peptide (NT-pro BNP) was transformed to log10 (NT-pro BNP) because of its highly skewed distribution.

Assigning all patients who died during hospitalization without invasive management to the conservative group could cause immortal time bias and lead to results in favor of the invasive group. Some of these patients could have undergone invasive strategy if they had survived. To limit such bias, patients who did not receive invasive management and died within 3 days after admission (which is the median invasive time in the invasive group) were excluded.

Multivariable Cox proportional hazards regression models were used to assess whether treatment strategies were related to long-term mortality. Five adjusted models were built successively. Model 1 adjusted for GRACE risk score (age, systolic blood pressure, heart rate, Killip class, creatinine, ST-segment deviation and elevated troponin). Model 2 adjusted for Model 1 plus cardiovascular risk factors (gender, body mass index, dyslipidemia, hypertension, diabetes mellitus, LDL-c at admission and recent cigarette smoking). Model 3 adjusted for covariates in Model 2 along with high bleeding risk factors in ARC-HBR criteria (13) (hemoglobin <110 g/L, long-term oral anticoagulation, severe or end-stage chronic kidney disease, thrombocytopenia, previous stroke, active malignancies and prothrombin activity). Model 4 adjusted for Model 3 plus medications (antiplatelet drug, ACEI/ARBs, β-blockers and statins). Model 5 adjusted for Model 4 plus other important clinical conditions and laboratory test results (prior myocardial infarction, prior coronary revascularization, NT-pro BNP at admission, triglyceride, hyperuricemia and Barthel index). Model 5 also included CAG results for timely versus delayed invasive analysis. The proportional hazards assumption was tested based on Schoenfeld residuals. Covariates that did not meet the proportional hazard assumption were added to the model as strata. Subgroup analysis was performed to test whether the effect of invasive strategies was consistent across groups. The cutoff point for GRACE risk scores used medians because very few patients had GRACE scores <140.

Propensity score matching (PSM) and inverse probability weighting (IPW) were also preformed to control for differences in baseline covariates between groups as sensitivity analysis. The propensity scores (PS) were driven by logistic regression using variables in Model 5. In PSM, we 1:1 matched two groups without replacement, using 0.1 of the standard deviation of the PS as the caliper via the nearest neighbor matching. In IPW, we used stabilized weights to prevent enlarging of sample size and type I error due to weighting (14). The balance of baseline covariates between the two groups in the matched or weighted cohort was assessed by computing absolute standardized mean differences (ASMD), with differences of ≤0.1 indicating a negligible difference in potential confounders between the two groups. Kaplan-Meier curves were plotted to display cumulative survival rates.

For 10 variables with missing data (missing rate between 0.4% and 10.2%, Table S1), 10 imputed datasets were generated using multiple imputations by chained equations (15). Each one of these imputed datasets was independently analyzed, and then pooled together following Rubin’s rule (16). All P values are presented for two-tailed tests, and <0.05 was considered statistically significant. All analyses were performed with the R statistical software version 4.0.3 (R Core Team, 2014).

Results

Baseline characteristics

Of the 15,728 consecutive ACS patients who were enrolled in the CBD-BANK database during the study period, 1,829 patients were 80 years or older. After excluding 336 repeated hospitalization records and 287 STEMI patients, the study included 1,206 patients with a median age of 82 years (IQR, 81–84 years). Among them, 656 patients underwent invasive management during hospitalization and 550 patients did not. After excluding 5 patients who died during hospitalization within 3 days without invasive management, 1,201 patients were included in baseline analysis (Figure 1).

Figure 1 Patient screening flow chart. ACS, acute coronary syndrome; CBD, Cardiovascular Center of Beijing Friendship Hospital Database; NSTE-ACS, non-ST-elevation acute coronary syndromes; STEMI, ST-segment elevation myocardial infarction.

The patient’s clinical characteristics are summarized in Table 1. Patients in the conservative group had more comorbidities and worse conditions than the invasive group at admission. The conservative group was older, slimmer, had a lower rate of prior revascularization, and a higher prevalence of previous stroke, malignancy, anemia, tachycardia, hyperuricemia and severe renal insufficiency. The conservative group also had higher mean levels of NT-pro BNP, GRACE risk score, as well as lower levels of prothrombin activity and Barthel index.

CAG and revascularization

Most patients (76.1%) in the invasive group showed three-vessel disease and/or left main disease after CAG. In the invasive group, 57.9% patients underwent PCI during hospitalization (n=380), 3.2% were treated with CABG (n=21), and 38.9% did not receive revascularization (n=255). The details of stent implantation and other information are shown in Table 2.

Pharmacological treatment and follow-up

Patients who underwent invasive therapy were treated with antiplatelet drugs and statins at discharge more often than the conservative group. The proportion of patients treated with ACEI/ARB, β-blockers, and oral anti-coagulation drugs was similar in both groups. The median follow-up duration was 3.0 years. During the study period, 181 patients (33.2%) in the conservative group and 115 patients (17.5%) in the invasive group died (Table 1). The unadjusted Kaplan-Meier curve showed a significant reduction in mortality in the invasive group (HR 0.48, 95% CI: 0.38–0.60, P<0.001, Figure 2A).

Figure 2 Comparison of unadjusted and adjusted survival curves of patients ≥80 years of age stratified by different strategies. (A) Unadjusted Kaplan-Meier curve. (B) Inverse probability weighted Kaplan-Meier curve. Adjusted for GRACE risk score, gender, body mass index, dyslipidemia, hypertension, diabetes mellitus, LDL-c at admission, recent cigarette smoking, hemoglobin <11 g/dL, long-term oral anticoagulation, severe or end-stage chronic kidney disease, thrombocytopenia, previous stroke, active malignancies, prothrombin activity, antiplatelet drug, ACEI/ARBs, β-blockers, statins, prior myocardial infarction, prior coronary revascularization, NT-pro BNP at admission, triglyceride, hyperuricemia and Barthel index. The weight for each patient was calculated though the average propensity score in all imputations. GRACE, global registry of acute coronary events; LDL-c, low-density lipoprotein cholesterol; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; NT-pro BNP, N-terminal pro-brain natriuretic peptide.

Following adjustment for GRACE risk score and cardiovascular risk factors, the mortality HR of the invasive group compared to the conservative group was attenuated to 0.58 (95% CI: 0.46–0.74, P<0.001). After adjustment for Model 5, which included risk scores, cardiovascular and bleeding risk factors, drug use, other comorbidities and activities of daily living, patients who underwent invasive management compared with those who were managed conservatively had a 30% reduction in mortality (HR =0.70, 95% CI: 0.54–0.92, P=0.01, Table 3). Using IPW and PSM adjustment, we built a good balance between the two groups. The PS and ASMD before and after adjustment were shown in Figures S1,S2. The mortality HR of the invasive with conservative groups was 0.67 (95% CI: 0.53–0.84) after IPTW and 0.69 (95% CI: 0.50–0.94) following PSM adjustment (Table 3, Figure 2B). Figure 3 shows the effect of invasive treatment in different subgroups. The invasive treatment seemed to be more efficient in females, patients with elevated cTn at admission, without diabetes, HGB ≥110 g/L and with a higher GRACE risk score. However, tests for interaction were insignificant in all subgroups.

Figure 3 Forest plots for associations of invasive treatment with long-term mortality in subgroup analyses. cTn, cardiac troponin; GRACE, global registry of acute coronary events.

The distribution of the number of days from admission to invasive management among patients in the invasive group is shown in Figure S3. The median invasive time was 3 days (IQR, 1–5 days). Only 26.2% of patients underwent CAG within a guideline-recommend time (≤1 day in the high risk group or ≤3 days in the median risk group). The baseline characteristics, results of angiography, revascularization and pharmacological treatment of timely and delayed invasive patients are shown in Table S2. The patients in the two groups were homogeneous, except in the delayed invasive group patients had worse Killip class and higher GRACE risk scores. The crude HR of timely vs. delayed invasive therapy was 1.12 (95% CI: 0.77–1.62, P=0.549). After adjustment for Model 5, there was no association between timing of invasive treatment and long-term mortality (HR =0.93, 95% CI: 0.62–1.41, P=0.746, Table S3). The IPW adjusted Kaplan-Meier plot based on model 5 showed two closing survival curves for the two groups (Figure 4, Figure S4). The difference between patients who had coronary disease but had no further intervention after CAG and those who had revascularization was also explored (Table S4, Figure S5).

Figure 4 Comparison of unadjusted and adjusted survival curve of patients ≥80 years of age who underwent invasive treatment stratified by different timing of invasive intervention. (A) Unadjusted Kaplan-Meier curve. (B) Inverse probability weighted Kaplan-Meier curve. Adjusted for GRACE risk score, gender, body mass index, dyslipidemia, hypertension, diabetes mellitus, LDL-c at admission, recent cigarette smoking, hemoglobin <11 g/dL, long-term oral anticoagulation, severe or end-stage chronic kidney disease, thrombocytopenia, previous stroke, active malignancies, prothrombin activity, antiplatelet drug, ACEI/ARBs, β-blockers, statins, prior myocardial infarction, prior coronary revascularization, NT-pro BNP at admission, triglyceride, hyperuricemia, Barthel index and coronary angiography result. The weight for each patient was calculated though the average propensity score in all imputations. GRACE, global registry of acute coronary events; LDL-c, low-density lipoprotein cholesterol; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; NT-pro BNP, N-terminal pro-brain natriuretic peptide.

Discussion

In the present study, we used a routinely curated clinical database from a large tertiary hospital with emergency departments to estimate the effect of invasive management on long-term survival in patients ≥80 years with NSTE-ACS compared with conservative management. Our data showed that invasive treatment was associated with a 30%-reduction in mortality rates during a median of 3 years follow-up.

In the contemporary reperfusion era, the superiority of invasive treatment for NSTE-ACS has been verified by numerous studies. However, in patients aged 80 years or older, physicians prefer conservative strategies rather than invasive approaches, as advanced age has become an independent predictor for conservative treatment (17). Data from the China Acute Myocardial Infarction (CAMI) registry revealed the same trend in China, where the angiography rate was significantly reduced in NSTEMI patients ≥75 years compared with their younger counterparts (25.4% vs. 52.0%) (18). In our study, the invasive rate was 54.4%, similar to previous studies (19,20). Patients who were managed conservatively were more likely older, slimmer, had higher NT-pro BNP levels, more comorbidities, and worse renal function. Such differences indicated a higher risk of complications and a worse outcome, raising the risk-benefit ratio of invasive procedure in those patients.

Few studies have focused on elderly patients, although older individuals comprise a large proportion of NSTE-ACS patients. To the best of our knowledge, the Italian Elderly ACS study (n=313) (21), the After Eighty study (n=457) (22), the MOSCA study (n=106) (23) and the RINCAL trial (n=251) (24) were the only 4 randomized controlled trials focusing on invasive treatment strategies in elderly NSTE-ACS patients. However, the results were contradictory: while the After Eighty study successfully demonstrated the benefit of an invasive strategy in elderly patients (HR =0.48, 95% CI: 0.37–0.63), the other 3 studies showed no difference between the two treatment strategies. Some observational registry studies also focused on this topic (20,25-27). In a meta-analysis published in 2018, researchers pooled results and demonstrated the benefits of an invasive strategy in reducing 12-month mortality compared with the conservative approach. However, none of these studies considered immortal bias (28).

In our cohort, the invasive strategy in elderly patients with NSTE-ACS revealed a significant reduction in all-cause mortality during a median of 3 years follow-up. Compared with the After Eighty study, patients in the present study were younger (medium age: 82 vs. 85 years), with a lower rate of previous myocardial infarction (13.2% vs. 43.1%) and troponin elevation at admission (27.9% vs. 93.0%) (22). These differences reflected a worse condition in patients from the After Eighty study than ours, which might have suppressed the potential benefits of invasive treatment on survival and lead to a negative result of all cause death in the After Eighty study.

In the recently published SENIOR-NSTEMI study, researchers retrospectively analyzed 1,976 NSTEMI patients aged 80 years and older from five UK hospitals. After careful adjustment for observed differences and immortality bias, the study concluded that invasive management improves long-term survival was consistent with our findings (19). The main difference between the two studies was that, in the SENIOR-NSTEMI study, the patients who underwent invasive management after 3 days of peak troponin concentration were assigned to the conservative group, while in our study, the patients who completed CAG during hospitalization were included in the invasive group.

Based on the guidelines during the study period, an invasive strategy was recommended for patients at high risk within 24 hours and at intermediate risk within 72 hours. However, delayed angiography is common in clinical practice, especially in elderly patients. In the US, 42.5% of NSTEMI patients who were directed to admission to a PCI center underwent delayed angiography, and older patients were more likely to be delayed (29). In China, 44.8% of moderate to very high-risk patients who underwent invasive treatment were delayed for more than 72 hours (30). Meanwhile, the optimal timing of CAG in patients with advanced age remains poorly defined. In one of the largest collaborative meta-analyses that included 5,324 participants from 8 trials, the relationship between early invasive and reduced mortality in patients aged ≥75 years was only described as “might” because of an insignificant statistical result (31). In our study, timing of invasive treatment did not impact long-term mortality in elderly patients (HR =0.93, 95% CI: 0.62–1.41, P=0.746). These findings may suggest that invasive therapy itself, rather than the timing of invasive therapy, might be the key factor for improving late clinical outcomes in elderly patients. An adequate pharmaceutical treatment before delayed catheterization could theoretically stabilize the patient and facilitate further surgery, and thus may be used as an alternative approach for patients over 80 years of age.

In the present study, we used all-cause mortality as the endpoint rather than cardiovascular mortality. Cardiovascular-related death might more directly reflect the impact of cardiovascular treatment. However, elderly patients are complex and vulnerable, and often have frailty and other comorbidities. These factors also affect the choice of treatment strategies and life expectancy, but were not reflected in cardiovascular mortality. Strategies that could only reduce cardiovascular mortality but not all-cause mortality did not benefit the elderly. Therefore, we propose that all-cause mortality would be a more appropriate outcome for this study.

The present study has some limitations that need to be pointed out. First, as a single-center, retrospective, observational study, intervention strategies were not randomized. Although we used multiple strategies to adjust for the observed differences between groups, residual confounding by unmeasured variables may still exist. The results require further validation via prospective cohort studies (32). Second, external validity was limited. Patients in other institutions may have different characteristics. Third, bleeding events were not documented in our database, although previous studies have shown low major bleeding rates and no difference between the two strategies (21,22).

Conclusions

Our data showed that an invasive strategy was associated with lower all-cause mortality in patients ≥80 years with NSTE-ACS during a median of a 3-year follow-up. The timing of invasive treatment did not impact the outcome.

Acknowledgments

We would like to thank all the staffs who contributed to this study. We also thank Medjaden Bioscience Limited for English language editing service.

Funding: The Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201838) supported this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-21-650/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-21-650/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-21-650/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Beijing Friendship Hospital, Capital Medical University (project number: 2020-P2-083-01) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017;390:1151-210. [Crossref] [PubMed]
2. Liu S, Li Y, Zeng X, et al. Burden of Cardiovascular Diseases in China, 1990-2016: Findings From the 2016 Global Burden of Disease Study. JAMA Cardiol 2019;4:342-52. [Crossref] [PubMed]
3. Sanchis-Gomar F, Perez-Quilis C, Leischik R, et al. Epidemiology of coronary heart disease and acute coronary syndrome. Ann Transl Med 2016;4:256. [Crossref] [PubMed]
4. Smolina K, Wright FL, Rayner M, et al. Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: linked national database study. BMJ 2012;344:d8059. [Crossref] [PubMed]
5. Yeh RW, Sidney S, Chandra M, et al. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med 2010;362:2155-65. [Crossref] [PubMed]
6. Roffi M, Patrono C, Collet JP, 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. [Crossref] [PubMed]
7. Amsterdam EA, Wenger NK, Brindis RG, 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:e139-228. [Crossref] [PubMed]
8. Chinese Society of Cardiology of Chinese Medical Association. Guideline and consensus for the management of patients with non-ST-elevation acute coronary syndrome (2016). Zhonghua Xin Xue Guan Bing Za Zhi 2017;45:359-76. [PubMed]
9. Kang HJ, Simon D, Wang TY, et al. The Contemporary Use of Angiography and Revascularization Among Patients With Non-ST-Segment Elevation Myocardial Infarction in the United States Compared With South Korea. Clin Cardiol 2015;38:708-14. [Crossref] [PubMed]
10. Devlin G, Gore JM, Elliott J, et al. Management and 6-month outcomes in elderly and very elderly patients with high-risk non-ST-elevation acute coronary syndromes: The Global Registry of Acute Coronary Events. Eur Heart J 2008;29:1275-82. [Crossref] [PubMed]
11. Canto JG, Rogers WJ, Goldberg RJ, et al. Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA 2012;307:813-22. [Crossref] [PubMed]
12. Yang M, Zou Y, Lu T, et al. Revised Equations to Estimate Glomerular Filtration Rate from Serum Creatinine and Cystatin C in China. Kidney Blood Press Res 2019;44:553-64. [Crossref] [PubMed]
13. Urban P, Mehran R, Colleran R, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk. Eur Heart J 2019;40:2632-53. [Crossref] [PubMed]
14. Xu S, Ross C, Raebel MA, et al. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health 2010;13:273-7. [Crossref] [PubMed]
15. White IR, Royston P, Wood AM. Multiple imputation using chained equations: Issues and guidance for practice. Stat Med 2011;30:377-99. [Crossref] [PubMed]
16. Leyrat C, Seaman SR, White IR, et al. Propensity score analysis with partially observed covariates: How should multiple imputation be used? Stat Methods Med Res 2019;28:3-19. [Crossref] [PubMed]
17. Rittger H, Schnupp S, Sinha AM, et al. Predictors of treatment in acute coronary syndromes in the elderly: impact on decision making and clinical outcome after interventional versus conservative treatment. Catheter Cardiovasc Interv 2012;80:735-43. [Crossref] [PubMed]
18. Leng W, Yang J, Fan X, et al. Contemporary invasive management and in-hospital outcomes of patients with non-ST-segment elevation myocardial infarction in China: Findings from China Acute Myocardial Infarction (CAMI) Registry. Am Heart J 2019;215:1-11. [Crossref] [PubMed]
19. Kaura A, Sterne JAC, Trickey A, et al. Invasive versus non-invasive management of older patients with non-ST elevation myocardial infarction (SENIOR-NSTEMI): a cohort study based on routine clinical data. Lancet 2020;396:623-34. [Crossref] [PubMed]
20. Bauer T, Koeth O, Jünger C, et al. Effect of an invasive strategy on in-hospital outcome in elderly patients with non-ST-elevation myocardial infarction. Eur Heart J 2007;28:2873-8. [Crossref] [PubMed]
21. Savonitto S, Cavallini C, Petronio AS, et al. Early aggressive versus initially conservative treatment in elderly patients with non-ST-segment elevation acute coronary syndrome: a randomized controlled trial. JACC Cardiovasc Interv 2012;5:906-16. [Crossref] [PubMed]
22. Tegn N, Abdelnoor M, Aaberge L, et al. Invasive versus conservative strategy in patients aged 80 years or older with non-ST-elevation myocardial infarction or unstable angina pectoris (After Eighty study): an open-label randomised controlled trial. Lancet 2016;387:1057-65. [Crossref] [PubMed]
23. Sanchis J, Núñez E, Barrabés JA, et al. Randomized comparison between the invasive and conservative strategies in comorbid elderly patients with non-ST elevation myocardial infarction. Eur J Intern Med 2016;35:89-94. [Crossref] [PubMed]
24. de Belder A, Myat A, Blaxill J, et al. Revascularisation or medical therapy in elderly patients with acute anginal syndromes: the RINCAL randomised trial. EuroIntervention 2021;17:67-74. [Crossref] [PubMed]
25. Buber J, Goldenberg I, Kimron L, et al. One-year outcome following coronary angiography in elderly patients with non-ST elevation myocardial infarction: real-world data from the Acute Coronary Syndromes Israeli Survey (ACSIS). Coron Artery Dis 2013;24:102-9. [Crossref] [PubMed]
26. Gierlotka M, Gąsior M, Tajstra M, et al. Outcomes of invasive treatment in very elderly Polish patients with non-ST-segment-elevation myocardial infarction from 2003-2009 (from the PL-ACS registry). Cardiol J 2013;20:34-43. [Crossref] [PubMed]
27. Lourenço C, Teixeira R, Antonio N, et al. Invasive strategy in non-ST elevation acute coronary syndromes: risks and benefits in an elderly population. Rev Port Cardiol 2010;29:1451-72. [PubMed]
28. Saraswat A, Rahman A, Singh K. An Invasive vs a Conservative Approach in Elderly Patients with Non-ST-Segment Elevation Myocardial Infarction: Systematic Review and Meta-Analysis. Can J Cardiol 2018;34:274-80. [Crossref] [PubMed]
29. Malta Hansen C, Wang TY, Chen AY, et al. Contemporary Patterns of Early Coronary Angiography Use in Patients With Non-ST-Segment Elevation Myocardial Infarction in the United States: Insights From the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry. JACC Cardiovasc Interv 2018;11:369-80. [Crossref] [PubMed]
30. Yang Q, Wang Y, Liu J, et al. Invasive Management Strategies and Antithrombotic Treatments in Patients With Non-ST-Segment-Elevation Acute Coronary Syndrome in China: Findings From the Improving CCC Project (Care for Cardiovascular Disease in China). Circ Cardiovasc Interv 2017;10:e004750. [Crossref] [PubMed]
31. Jobs A, Mehta SR, Montalescot G, et al. Optimal timing of an invasive strategy in patients with non-ST-elevation acute coronary syndrome: a meta-analysis of randomised trials. Lancet 2017;390:737-46. [Crossref] [PubMed]
32. ClinicalTrials.gov. The British Heart Foundation SENIOR-RITA Trial (SENIOR-RITA). Available online: https://clinicaltrials.gov/ct2/show/NCT03052036 (accessed December 11th, 2021).