Effect of complete revascularization in acute coronary syndrome after 75 years old: insights from the BleeMACS registry

Abstract

BACKGROUND

The prognostic benefit of complete revascularization in elderly patients (aged over 75 years) with multi-vessel disease and acute coronary syndrome (ACS) is currently unclear. This study aimed to determine the long-term prognostic impact of complete revascularization in this population.

METHODS

We conducted this study using data obtained from the BleeMACS (Bleeding complications in a Multicenter registry of patients discharged after an Acute Coronary Syndrome) registry, which was carried out from 2003 to 2014. The objective was to categorize older patients diagnosed with ACS into two groups: those who underwent complete revascularization and those who did not. Propensity score matching and the Kaplan-Meier analysis were employed to examine differences in one-year clinical outcomes. The primary endpoint was major adverse cardiovascular event (MACE), which encompassed a combination of all-cause mortality and myocardial infarction.

RESULTS

Out of 1263 patients evaluated, 445 patients (35.2%) received complete revascularization. Patients who underwent complete revascularization had a higher prevalence of hypertension and prior percutaneous coronary intervention compared to those who did not. During the one-year follow-up period, complete revascularization was associated with a significantly decreased risk of MACE [13.7% vs. 20.5%, hazard ratio (HR) = 0.63, 95% CI: 0.45–0.88, P = 0.007] and a lower risk of myocardial infarction (5.9% vs. 9.9%, HR = 0.55, 95% CI: 0.33–0.92, P = 0.02). However, it was not linked to a lower risk of all-cause death (9.5% vs. 13.5%, HR = 0.68, 95% CI: 0.45–1.02, P = 0.06). Similar results were observed in the subgroup analysis.

CONCLUSIONS

Long-term clinical improvements were observed in ACS patients aged over 75 years with multi-vessel disease who achieved complete revascularization. Therefore, adhering to guidelines for complete revascularization should be recommended for elderly patients.

Aging has emerged as a significant global phenomenon since the 20^th century, attributed to declining fertility rates and increased life expectancy. Statistics indicate that by 2030, one in six people worldwide will be aged 60 years or older, while the number of octogenarians is projected to triple from 2015 to 2050.^[1] Ischemic heart disease, including acute coronary syndrome (ACS), accounts for half of the world’s total deaths.^[2] Current ACS guidelines are founded on evidence from numerous randomized trials that primarily focus on medical and percutaneous interventions.^[3,4] However, it is somewhat surprising that recommendations regarding studies involving older patients reveal a mismatch between clinical needs and the available representative supportive data.

Whether complete revascularization should be achieved in patients with ACS and multi-vessel disease has been a subject of debate for many years.^[5] Recent randomized controlled trials have indicated that there may be a prognostic benefit to complete revascularization in this population.^[6–8] In light of this evidence, the latest revascularization guideline recommends complete revascularization before discharge if the patient is in a stable condition.^[9] However, older patients present a unique challenge, as they are more complex and often have a higher rate of comorbidities. Unfortunately, most studies have excluded older patients or only included those who were at low risk and relatively young. As a result, the optimal treatment strategy for older patients with an indication for revascularization remains unclear.

In this study, we sought to address this inadequate knowledge regarding older patients with ACS and multi-vessel disease using a global, multicenter registry. Specifically, we characterized the clinical features of patients aged over 75 years and determine the rate of recurrent cardiovascular outcomes during the one-year follow-up period.

METHODS

Study Design and Patient Selection

The study utilized data from the BleeMACS (Bleeding complications in a Multicenter registry of patients discharged after an Acute Coronary Syndrome) registry, an international, multicenter, retrospective database that included 15,401 ACS patients who underwent percutaneous coronary intervention (PCI) at fifteen sites across ten countries in North America (Canada), South America (Brazil), Europe (Germany, Poland, Netherlands, Spain, Italy, and Greece) and Asia (China and Japan). Eligible patients had a discharge diagnosis of ACS, including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation ACS (NSTE-ACS).^[3,10] The protocol was approved by the Institutional Review Board/Ethics Committee in each participating site. Additional information can be found in previous publications and on ClinicalTrials.gov (Identifier: NCT02466854).^[11]

All consecutive patients with the multi-vessel disease aged over 75 years from the BleeMACS registry were included in this study. Patients who were younger than 75 years old or had missing data were excluded from the analysis.

Study Definitions

Predefined definitions were utilized across all sites for variable collection. Patient medical histories and procedural details were obtained from their medical records and collected into the database by the investigators. Multi-vessel disease was defined as significant stenosis ≥ 70% (50% for left main coronary artery disease) in two or more major coronary arteries or their major branches with a diameter of 2.5 mm or more. The culprit lesion was defined as the coronary lesion involved in the initial ACS, while any other lesion was considered a non-culprit lesion. The identification of these lesions was left to the operator’s discretion during the procedure.

Patients were classified into to the complete revascularization group if they achieved an angiography result without coronary stenosis ≥ 70% in major epicardial coronary arteries or stenosis ≥ 50% in the left main coronary artery disease after the procedure. For cases of STEMI, complete revascularization was not performed during the index procedure but was staged. Conversely, for cases of NSTE-ACS, complete revascularization was performed at the operator’s discretion. Patients who did not achieve complete revascularization were categorized as belonging to the incomplete revascularization group.

Endpoints and Follow-up

The primary endpoint of this study was defined as the occurrence of major adverse cardiovascular event (MACE) within one year after the index procedure, which included myocardial infarction (MI) or all-cause death. Bleeding events were also collected during the one-year follow-up period. In addition, the study collected data on in-hospital events such as MI, heart failure, bleeding, and blood transfusions.

MI as an in-hospital event refers to reinfarction during hospitalization or follow-up. In-hospital bleeding was defined as any major or minor bleeding according to the Thrombolysis in Myocardial Infarction definition. During the first year after index ACS, bleeding events during follow-up were defined as readmission or any transfusion due to bleeding.

Patients’ clinical status was monitored for one year following discharge. Data on cardiovascular and bleeding events were reported by physicians through clinical visits or telephone.

Statistical Analysis

Continuous variables with a normal distribution were reported as mean ± SD, while those with a skewed distribution were presented as medians (interquartile range). Categorical variables were presented as counts (percentages) using either the Pearson’s chi-squared test or the Fisher’s exact probability test. Kaplan-Meier analysis was used to illustrate the primary endpoint of MACE, and comparisons between groups were performed using the log-rank test.

To consolidate our findings, we also performed propensity score matching (PSM) to balance the differences between the complete and incomplete revascularization groups. Patients were matched 1:1 between two groups based on nearest-neighbor matching, using variables such as hypertension, peripheral artery disease, prior PCI, STEMI, Killip classification ≥ 2, drug-eluting stent, prior MI, percutaneous transluminal coronary angioplasty, and discharge with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) in the logistic regression model for propensity score. Subgroup analysis was performed to verify the consistency of our results.

The incomplete revascularization group was used as the reference in all analyses. All tests were two-tailed, and P-value < 0.05 was considered statistically significant. All statistical analyses were performed using SAS 9.3 (SAS Institute Inc., Cary, NC, USA).

RESULTS

Baseline Characteristics

Of the 15,401 ACS patients enrolled in the BleeMACS registry, 1263 patients (8.2%) who were over 75 years old and had multi-vessel disease were selected for this analysis. Of these, 445 patients (35.2%) achieved complete revascularization (Figure 1). For the PSM analysis, 818 patients were included, with 409 patients (50%) in the complete revascularization group and 409 patients (50%) in the incomplete revascularization group.

Figure 1.

Study flowchart.

BleeMACS: Bleeding complications in a Multicenter registry of patients discharged after an Acute Coronary Syndrome registry.

Patients’ baseline characteristics, including demographics and medical treatments, were shown in Table 1. Patients who underwent complete revascularization were less likely to have peripheral artery disease or a history of bleeding compared to those who did not, but they had a higher prevalence of hypertension and prior PCI. Additionally, they were also more often receiving drug-eluting stent instead of angioplasty, and frequently prescribed ACEI/ARB at discharge. The PSM cohort achieved well-balanced baseline characteristics between the two groups.

Table 1. Baseline characteristics.

Variables	Unmatched				Propensity score matched
	Complete group (n = 445)	Incomplete group (n = 818)	P-value		Complete group (n = 409)	Incomplete group (n = 409)	P-value
Data are presented as n (%) or median (interquartile range).
Demographics
Age, yrs	79.9 (77–83.8)	80 (77.3–83.1)	0.80		79.9 (77–83.7)	80 (77.4–83.6)	0.71
Female	179 (40.2%)	320 (39.1%)	0.70		162 (39.6%)	152 (37.2%)	0.47
Medical history
Hypertension	347 (78.0%)	595 (72.7%)	0.04		315 (77.0%)	316 (77.3%)	0.93
Hyperlipidemia	216 (48.5%)	366 (44.7%)	0.20		195 (47.7%)	182 (44.5%)	0.36
Diabetes mellitus	140 (31.5%)	274 (33.5%)	0.46		128 (31.3%)	154 (37.7%)	0.06
Peripheral arterial disease	44 (9.9%)	114 (13.9%)	0.04		42 (10.3%)	43 (10.5%)	0.91
Prior acute myocardial infarction	70 (15.7%)	162 (19.8%)	0.07		67 (16.4%)	62 (15.2%)	0.63
Congestive heart failure	20 (4.7%)	35 (5.2%)	0.71		20 (5.1%)	19 (5.2%)	0.94
Chronic kidney disease	17 (9.7%)	33 (10.9%)	0.67		17 (9.7%)	22 (11.5%)	0.58
Peptic ulcer	6 (3.3%)	16 (5.3%)	0.30		6 (3.3%)	12 (6.3%)	0.19
Prior percutaneous coronary intervention	85 (19.1%)	105 (12.8%)	< 0.01		68 (16.6%)	67 (16.4%)	0.92
Prior coronary artery bypass grafting	35 (7.9%)	60 (7.3%)	0.73		27 (6.6%)	29 (7.1%)	0.78
Prior bleeding	22 (4.9%)	65 (8.0%)	0.04		20 (4.9%)	29 (7.1%)	0.16
Malignancy	47 (10.6%)	81 (9.9%)	0.71		45 (11.0%)	34 (8.3%)	0.19
Clinical status
Type of acute coronary syndrome
ST-segment elevation myocardial infarction	167 (37.5%)	468 (57.2%)	< 0.01		159 (38.9%)	163 (39.9%)	0.77
Non-ST-segment elevation acute coronary syndrome	278 (62.5%)	350 (42.8%)			250 (61.1%)	246 (60.2%)
Killip classification ≥ 2	120 (27.9%)	171 (21.8%)	0.02		105 (25.7%)	104 (25.4%)	0.94
Hemoglobin, g/dL	13.3 (12–14.4)	13.1 (11.8–14.3)	0.21		13.3 (12–14.5)	13.06 (11.9–14.3)	0.21
Creatinine, mg/dL	1.0 (0.8–1.2)	1.0 (0.8–1.2)	0.53		1.0 (0.8–1.2)	1.0 (0.8–1.2)	0.99
Left ventricular ejection fraction, %	55 (40–60)	53 (40–60)	0.54		55 (40–60)	55.5 (45–60)	0.27
Procedures
Percutaneous transluminal coronary angioplasty	8 (1.8%)	56 (6.9%)	< 0.01		8 (2.0%)	7 (1.7%)	0.79
Drug-eluting stent	174 (39.1%)	264 (32.3%)	0.01		155 (37.9%)	140 (34.2%)	0.27
Thrombolysis	4 (0.9%)	8 (1.0%)	0.89		4 (1.0%)	4 (1.0%)	1.00
Medications at discharge
Aspirin	439 (98.7%)	798 (97.6%)	0.19		404 (98.8%)	401 (98.0%)	0.40
Clopidogrel	404 (90.8%)	751 (91.8%)	0.53		377 (92.2%)	385 (94.1%)	0.27
Ticagrelor	23 (5.2%)	29 (3.6%)	0.17		16 (3.9%)	10 (2.4%)	0.23
Prasugrel	5 (1.1%)	7 (0.9%)	0.64		5 (1.2%)	3 (0.7%)	0.48
Oral anticoagulation	43 (9.7%)	66 (8.1%)	0.34		35 (8.6%)	26 (6.4%)	0.23
Angiotensin-converting enzyme inhibitor/Angiotensin 　　II receptor blocker	347 (78.0%)	565 (69.1%)	< 0.01		313 (76.5%)	311 (76.1%)	0.87
Beta-blocker	339 (76.2%)	644 (78.7%)	0.30		309 (75.6%)	320 (78.2%)	0.36
Statins	394 (88.5%)	729 (89.1%)	0.75		365 (89.2%)	365 (89.2%)	1.00

Clinical Outcomes

During the one-year follow-up period, patients with complete revascularization had a lower occurrence of MACE compared to those with incomplete revascularization (13.7% vs. 20.2%, P < 0.01). Additionally, patients with incomplete revascularization had a higher incidence of MI (10.4% vs. 5.6%, P < 0.01) and mortality (13.7% vs. 9.7%, P = 0.04) than those with complete revascularization. However, there was no significant difference in the incidence of bleeding between the complete and incomplete revascularization groups (4.3% vs. 5.5%, P = 0.34). After PSM adjustment, complete revascularization was associated with a significantly decreased risk of MACE [13.7% vs. 20.5%, hazard ratio (HR) = 0.63, 95% CI: 0.45–0.88, P = 0.007] and a lower risk of MI (5.9% vs. 9.9%, HR = 0.55, 95% CI: 0.33–0.92, P = 0.02). However, it was not linked to a lower risk of all-cause death (9.5% vs. 13.5%, HR = 0.68, 95% CI: 0.45–1.02, P = 0.06) or bleeding (4.7% vs. 5.4%, HR = 0.71, 95% CI: 0.39–1.28, P = 0.25) (Table 2 & Figure 2).

Table 2. In-hospital and one-year outcomes before and after propensity score matching analysis.

Variables	Unmatched				Propensity score matched
	Complete group (n = 445)	Incomplete group (n = 818)	P-value		Complete group (n = 409)	Incomplete group (n = 409)	P-value
Data are presented as n (%). Major adverse cardiovascular event including any death or myocardial infarction during the one-year follow-up period.
In-hospital events
Myocardial infarction	6 (1.4%)	18 (2.2%)	0.29		6 (1.5%)	11 (2.7%)	0.22
Heart failure	31 (7.2%)	79 (11.6%)	0.02		29 (7.4%)	29 (7.9%)	0.77
Bleeding	44 (9.9%)	103 (12.6%)	0.15		41 (10.0%)	43 (10.5%)	0.82
Blood transfusion	25 (6.0%)	66 (8.5%)	0.12		24 (6.2%)	30 (7.6%)	0.45
One-year events
All-cause death	43 (9.7%)	112 (13.7%)	0.04		39 (9.5%)	55 (13.5%)	0.08
Myocardial infarction	25 (5.6%)	84 (10.4%)	< 0.01		24 (5.9%)	40 (9.9%)	0.03
Major adverse cardiovascular event	61 (13.7%)	165 (20.2%)	< 0.01		56 (13.7%)	84 (20.5%)	0.01
Bleeding	19 (4.3%)	45 (5.5%)	0.34		19 (4.7%)	22 (5.4%)	0.63

Figure 2.

Survival curves of the primary outcome.

Cumulative Kaplan–Meier curve estimates of MACE during the one-year follow-up period in the whole study population (A) and the propensity score matching population (B). MACE: major adverse cardiovascular event.

The incidence of in-hospital heart failure in ACS patients with multi-vessel disease over the aged 75 years was 8.7% (110 cases). After adjusting for patient characteristics and hospital effect using the PSM, there was no statistically significant difference between patients with complete revascularization and those without (7.4% vs. 7.9%, P = 0.77). Similar rates of other in-hospital events were observed between the two groups, including re-infarction (1.5% vs. 2.7%, P = 0.22), bleeding (10.0% vs. 10.5%, P = 0.82), and blood transfusion (6.2% vs. 7.6%, P = 0.45) (Table 2).

Subgroup Analyses

We performed additional analyses in 16 subgroups based on clinically relevant baseline information in the entire study population, as shown in Figure 3. The findings revealed that complete revascularization was linked to a lower risk of MACE in several subgroups, including males, those with hypertension, Killip classification ≥ 2, NSTE-ACS, dual antiplatelet therapy, ACEI/ARB, and beta-blocker subgroups, which was consistent with the primary results.

Figure 3.

Subgroup analysis.

DISCUSSION

Based on the findings from the international, multi-center registry, we observed that complete revascularization was associated with a reduced risk of MACE among older ACS patients with multi-vessel disease. This benefit of complete revascularization was consistently observed in subgroups.

In recent years, the issue of complete revascularization in patients with multi-vessel coronary artery disease has been heatedly debated. A large amount of research evidence confirms the significance of complete revascularization in STEMI patients and obtains the recommendation of the guideline.^[7,12–15] Additionally, recent studies have suggested potential benefits of complete revascularization in NSTE-ACS patients as well.^[16,17] However, the significance of complete revascularization in the elderly remains uncertain. Epidemiological research have reported older patients with ACS represent more than one-third of hospitalization and two-thirds of ACS-related deaths.^[18] Despite this significant impact on the population, clinical evidence on revascularization in older patients with ACS is limited, primarily due to their underrepresentation in clinical studies.^[19] Our study showed that the rate of complete revascularization in older patients with ACS was 35.2%, significantly lower than the approximately 66% rate observed in previous studies in the general population.^[20] The reasons may be as follows, older patients often have multiple comorbidities, increasing the perceived risk of surgical complications and leading physicians to opt for conservative treatment strategies.^[21] Moreover, the optimal revascularization strategy for older patients remains a topic of controversy, resulting variations in the approaches chosen by doctors in different regions.^[22] Given the significant impact of ACS on the elderly and the scarcity of clinical evidence specific to this population, there is an urgent need to conduct dedicated clinical research for older patients with multi-vessel disease. Accumulating more clinical evidence in this area will aid in improving the clinical outcomes and prognosis for these patients.

Current guidelines recommend that invasive revascularization strategies should be considered appropriately in older patients after careful assessment of potential risks and benefits, life expectancy, comorbidities, quality of life, and patient preferences. A prospective cohort study found that complete revascularization was significantly associated with a reduced risk of MACE during follow-up period in ACS patients aged over 80 years.^[23] In addition, Agra-Bermejo, et al.^[24] observed a long-term benefit of complete revascularization in older patients with non-ST-segment elevation MI. Harada, et al.^[25] revealed that complete revascularization was associated with fewer ischemic events among older patients aged over 75 years with multi-vessel coronary artery disease. Our study suggests that complete revascularization reduces the one-year MACE event rate in ACS patients with multi-vessel disease aged over 75 years, and this benefit of complete revascularization was also confirmed among subgroup patients. Our data support the recommendations of existing guidelines. In total, these results suggest that in terms of multi-vessel disease, ACS patients aged above 75 years may benefit from complete revascularization. It’s worth noting that our data acquisition period spans from 2003 to 2014. Over this nearly ten-year time frame, there may have been substantial advancements in revascularization technology and related medical practices.^[26–28] These advances may affect patient outcomes and the overall efficacy of revascularization procedures to some extent. As a result, the findings and conclusions of the study should be interpreted with caution, considering the potential impact of these advancements on patient care and treatment outcomes in more recent years. It must be pointed out that previous studies, including ours, are observational studies, and the results still need to be confirmed by further randomized studies. The ongoing FIRE (Functional Versus Culprit-only Revascularization in Elderly Patients With Myocardial Infarction and Multivessel Disease) study is expected to provide stronger evidence from a randomized controlled study for this important issue.^[29]

LIMITATIONS

There are some limitations that should be noted. Firstly, inevitable limitations and biases of the observational study design exist. Although we process the data with multiple statistical adjustments, real-world studies are not explanatory and cannot identify the cause and effect relationships as randomization trials. As an international, multi-center study, our study provides evidence support for older patients with ACS. Secondly, this study did not collect the time of complete revascularization (multi-staged or single-staged). And there were no data on vascular anatomies, such as chronic occlusive lesions and severe vascular tortuosity. Nevertheless, this analysis is based on a global real-world registry, and its results are similar in clinical characteristics and event rates to those of previous studies, which indicate these limitations without huge influence on the validity of our results. Our study results reflect the pragmatic setting with clinical impact. Thirdly, there was a lack of data regarding the reasons for achieving or failing complete revascularization. Therefore, the plausible influence of unmeasured or undocumented factors on study outcomes remains indeterminate. Future studies need to collect and include such data to provide a more thorough analysis of complete revascularization and its impact on patient prognosis. Last but not least, there are no data on frailty, disability, and other aging-related variables. These variables are helpful in understanding the overall health status and prognosis of elderly patients, particularly in the context of ACS and revascularization procedures.^[30] As a result, the findings of the study should be interpreted with caution.

CONCLUSIONS

Among ACS patients aged over 75 years with multi-vessel disease, complete revascularization was associated with a decreased risk of MACE, which indicated older patients maybe also consider revascularization get with the guidelines. This finding highlights the urgent need for randomized controlled studies on this important issue.