Complete Revascularization versus Culprit-only Revascularization in Older Adults with ST-elevation Myocardial Infarction: Systematic Review and Meta-analysis of Randomized Controlled Trials

Abstract

Background:

Randomized controlled trials of complete revascularization (CR) versus culprit-only revascularization (COR) in patients with ST-elevation myocardial infarction (STEMI) have shifted the recommendation for CR from class III to class I in the AHA/ACC/SCAI guidelines, but it remains unclear if the benefit of CR over COR extends to older adults, who have greater bleeding risk, comorbidity burden, and complexity of lesions. We performed a meta-analysis to place the results of the previous RCTs in the context of the recently published FIRE trial and the subgroup analysis of the COMPLETE trial in adults ≥75 years old.

Methods:

We searched the literature from inception to October 21, 2023. RCTs of CR versus COR in STEMI were selected if it reported results for older adults, defined as either age >65 years or >75 years. Integrated hazard ratios were calculated using random effects models. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were major bleeding and contrast-associated acute kidney injury (CA-AKI).

Results:

In this meta-analysis of 5 RCTs including 3,513 older adults, CR was associated with a lower hazard of MACE than COR (HR 0.60, 95% CI 0.37–0.99, p=0.047). Sensitivity analysis including trials that defined older adults as age >65 years resulted in a lower hazard of MACE with CR versus COR, but not in trials that defined older adults as age >75 years. There was no difference in the hazard of major bleeding or CA-AKI between CR and COR.

Conclusions:

In this largest meta-analysis to date investigating CR compared with COR in older adults with STEMI, CR was associated with reduced MACE without a concomitant increase in major bleeding or CA-AKI compared with COR. These results can help cardiologists and geriatricians involved in shared decision-making with patients and caregivers when contemplating whether to pursue CR in older adults.

Introduction

Randomized controlled trials (RCTs) of complete revascularization versus culprit-only revascularization in patients with ST-elevation myocardial infarction (STEMI) have shifted the recommendation for complete revascularization in STEMI from class III to IIb to I in the AHA/ACC/SCAI guidelines of 2013, 2015, and 2021, respectively.¹ However, it remains unclear whether the benefit of complete revascularization over culprit-only revascularization extends to older adults, who have been historically underrepresented:² mean age was 62 in The Fractional Flow Reserve Versus Angiography in Guiding Management to Optimize Outcomes in Patients With Stable Coronary Artery Disease (PRAMI) trial,³ 65 in The Fractional Flow Reserve Versus Angiography in Guiding Management to Optimize Outcomes in Patients With Stable Coronary Artery Disease (CvLPRIT) trial,⁴ 63 in Danish Study of Optimal Acute Treatment of Patients with ST-elevation Myocardial Infarction 3 - Primary PCI in Multivessel Disease (DANAMI-3 PRIMULTI) trial,⁵ and 62 in Complete vs. Culprit-Only Revascularization Strategies to Treat Multivessel Disease After Early PCI for STEMI (COMPLETE) trial.⁶

Older adults have greater bleeding risk, frailty, complex coronary anatomy, comorbidities, and post-procedural complications.⁷ Recently, the The Fractional Flow Reserve Versus Angiography in Guiding Management to Optimize Outcomes in Patients With Stable Coronary Artery Disease (FIRE) trial showed that physiology-guided complete revascularization resulted in a 27% lower risk of major adverse cardiovascular events (MACE) in older adults ≥75 years-old compared with culprit-only revascularization.⁸ Thus, we performed a meta-analysis to contextualize the results of FIRE as well as the COMPLETE sub-group analysis in those ≥75 years.⁶

Methods

We systematically reviewed Cochrane, Google Scholar, Embase, Medline, PubMed, Scopus, and Web of Science from inception to October 2023 for RCTs comparing complete revascularization and culprit-only revascularizationby PCI in myocardial infarction (MI) that reported results for older adults, defined as either age >65 or >75 years (protocol: DOI 10.17605/OSF.IO/46K2G). Our study was exempt from institutional review board assessment because it is a study-level meta-analysis. The primary outcome was MACE, with follow-up time detailed in Table 1. Secondary outcomes were major bleeding and contrast-associated acute kidney injury. Integrated hazard ratios (HR) and 95% confidence intervals (CI) were generated using random effects models based on inverse variance. Higgins and Thompson’s I² statistics and τ² were calculated to assess the heterogeneity among the studies. All statistical analyses were conducted using the meta package in in R version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria). The authors declare that all supporting data are available within the article.

Table 1.

Main characteristics of the included trials

CR/Culprit-lesion-only	FIREa	COMPLETEa,c	DANAMI-3-PRIMULTIa	CvLPRITb	PRAMIb
Demographics
Number of older adults	1445	1613	110	152	193
Enrollment years	2019–2021	2013–2017	2011–2014	2011–2013	2008–2013
Country	Italy, Spain, Poland	Multinational	Denmark	United Kingdom	United Kingdom
Agef, median, years	81/80	72.5/72.7	80/80	64.6/65.3	62/62
Female sex, %	36.5/36.6	28.0/27.6	32.0/31.7	14.7/23.3	24/19
Intervention Characteristics
Approach	Physiology-guided	Angiography-guided	FFR-guided	Angiography-guided	Angiography-guided
Timing of CR	Staged or immediate	Staged (either during or after index admission)	Staged (2 days after initial PCI during index admission)	Immediate (but can be staged during index admission)	Immediate
Immediate, %	32	-	-	59	100
Staged, %	34	100	100	27	-
Time until staged PCI, median (IQR), day(s)	3 (2–4)	1 (1–3)d, 23 (12.5–33.5)e	2 (2–4)	1.5 (NR)	-
STEMI, %	35.2	100	100	100	100
Radial access	94.8/92.7	79.7/78.9	-	76.7/72.9	-
Follow-up time for ascertainment of outcomes	12 months	Median follow-up of 35.8 months	Median follow-up of 27 months	12 months	Median follow-up of 23 months
Comorbidities
Hypertension, %	82.4/81.7	59.5/58.4	60.0/56.7	36.6/36.4	40/40
Dyslipidemia, %	53.3/51.7	40.1/40.1	-	27.9/24.3	-
Diabetes mellitus, %	31.9/32.1	20.3/19.9	8.0/6.7	12.9/14.3	15/21
Current smoker, %	8.5/8.6	22.2/21.6	16.0/21.7	34.3/26.8	50/45
Prior MI, %	14.4/16.0	8.7/7.8	10.0/6.7	4.8/3.6	8/7
Prior PCI, %	16.8/18.8	8.3/6.7	-	4.1/2.1	-
Atrial fibrillation, %	12.6/15.0	-	0.0/8.3	-	-
Peripheral artery disease, %	16.9/17.5	-	-	-	-
Prior stroke, %	7.8/8.7	4.7/4.0	10.0/5.0	-	4/4
Chronic kidney disease	-	3.6/3.6	-	0.7/0.7	-
BMI, mean, kg/m2	-	27.7/27.5	-	-	-
GFR, mL/min	45.8/45.8	-	-	-	-
LVEF, %	49.4/49.0	-	50/50	45.8/45.1	-
Anatomic Characteristics
Culprit vessel, %
Left main	4.9/5.7	0.4/0.4	-	0/0	-
Left anterior descending	45.7/45.5	33.5/31.4	-	34.0/32.2	26/32
Circumflex	18.9/18.3	14.9/16.0	-	6.0/8.9	-
Right coronary	28.3/28.8	51.2/52.3	-	34.6/36.9	-
Ramus intermedius	2.2/1.7	-	-	-	-
Non-culprit vessel, %
Left anterior descending	31.2/30.6	40.8/43.3	-	47.3/48.0	-
Circumflex	32.5/33.5	33.5/35.3	-	13.3/13.7	-
Right coronary	32.7/33.6	25.1/21.3	-	31.3/30.9	-
Ramus intermedius	3.6/2.2	-	-	-	-
Non-culprit lesion ≥2, %	30.1/29.7	23.9/23.5	36.0/38.3	20.7/24.7	39/33
SYNTAXg score, median	-	16.4/16.2	-	-	-

^aCharacteristics in older adult population

^bCharacteristics in both younger and older adult populations combined as those exclusively in older adults were not reported

^cCharacteristics in older adults >65 years-old (c.f. not >75 years-old)

^dIf non-culprit-lesion PCI was intended during index admission

^eIf non-culprit-lesion PCI was intended was intended after discharge

^fMedian age in the complete revascularization group is provided before the slash, while median age in the culprit lesion only group is provided after the slash. This format for summarizing characteristics of patients in each arm is followed for the variables in subsequent rows as well.

^GThe SYNTAX score is a score of the anatomic characteristics of lesion complexity across 16 segments of the coronary tree. Higher SYNTAX score (>22) suggests complex anatomy that may be more suitable for coronary artery bypass grafting, whereas lower SYNTAX score (≤22) suggests anatomy that may be more amenable for percutaneous coronary intervention.

Abbreviation: CR, complete revascularization; FFR, fractional flow reserve; GFR, glomerular filtration rate; IQR, interquartile range; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NR, not reported; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction

Results

Five RCTs reported results for older adults – PRAMI (2013),³ CvLPRIT (2015),⁴ DANAMI-3-PRIMULTI (2015),⁵ COMPLETE (2019),⁶ and FIRE (2023)⁸ – adding up to 3,513 older adults with MI, including 2,577 (73.4%) with STEMI. “Older adult” was defined as >75 years in three RCTs^{5, 6, 8} and >65 years in two RCTs^{3, 4}. All RCTs consisted exclusively of STEMI patients except FIRE⁸, which had STEMI (35.2%) and non-STEMI (64.8%) patients (Table 1). MACE was extracted from the subset of patients with STEMI in FIRE. The FIRE trial defined MACE as all-cause mortality, myocardial infarction, stroke, or ischemia-driven revascularization. The DANAMI-3-PRIMULTI trial defined MACE as all-cause mortality, myocardial infarction, or ischemic driven revascularization. The CvLPRIT trial defined MACE as all-cause mortality, myocardial infarction, heart failure, or ischemic-driven revascularization. The COMPLETE trial defined MACE as cardiovascular mortality, myocardial infarction, or ischemia-driven revascularization. The PRAMI trial defined MACE as cardiovascular mortality, myocardial infarction, or refractory angina. Two trials^{5, 6} allowed staged complete revascularization; one trial³ protocolized immediate complete revascularization; two trials allowed either immediate or staged complete revascularization.^{4, 8}

In older adults with STEMI, complete revascularization was associated with lower MACE than culprit-only revascularization (HR 0.60, CI 0.37–0.99, p=0.047) (Figure 1). A significant interaction was present between age >65 and age >75 (P-interaction <0.01). Both staged complete revascularization and either staged or immediate complete revascularization had no improvement in MACE compared with culprit-only revascularization, but there was a significant interaction between sub-groups of timing strategies favoring immediate complete revascularization (P-interaction=0.04). The observed benefits of complete revascularization in older adults were consistent across trials that utilized an angiography-based approach. Only two trials utilized a physiology-guided strategy, with effect estimates going in opposite directions. No difference in major bleeding or contrast-associated acute kidney injury was observed between complete revascularization and culprit-only revascularization (Figure 2).

Figure 1. Forest plots of major adverse cardiovascular events in older adults with ST-elevation myocardial infarction.

The forest plots illustrate the pooled hazard ratios of major adverse cardiovascular events in older adults grouped into different definitions of older adults (Figure 1A), timing of complete revascularization (Figure 1B), and approach used to guide percutaneous coronary intervention (Figure 1C). Squares and diamonds indicate hazard ratio; error bars, 95% confidence interval. Size of markers represents weight.

Abbreviations: CI, confidence interval; COMPLETE, Complete vs Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI; CvLPRIT, Complete vs Lesion-Only Primary PCI Trial; DANAMI-3-PRIMULTI, Primary PCI in Patients with ST-elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization; FIRE, Functional versus Culprit-only Revascularization in Elderly Patients with Myocardial Infarction and Multivessel Disease; HR, hazard ratio; IV, inverse variance; MACE, major adverse cardiovascular events; PRAMI, Preventive Angioplasty in Myocardial Infarction; SE, standard error

Figure 2. Forest plots of secondary outcomes in older adults with ST-elevation myocardial infarction.

The forest plots illustrate the pooled hazard ratios of major bleeding (Figure 2A) and contrast-associated acute kidney injury (Figure 2B) in older adults who underwent complete revascularization versus culprit-lesion-only revascularization. Squares and diamonds indicate hazard ratio; error bars, 95% confidence interval. Size of markers represents weight.

Abbreviations: CI, confidence interval; COMPLETE, Complete vs Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI; DANAMI-3-PRIMULTI, Primary PCI in Patients with ST-elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization; FIRE, Functional versus Culprit-only Revascularization in Elderly Patients with Myocardial Infarction and Multivessel Disease; HR, hazard ratio; IV, inverse variance

Discussion

In this largest meta-analysis to date investigating complete revascularization versus culprit-only revascularizationin older adults, and the first to include the results from the FIRE trial and the ≥75 year old cohort from the COMPLETE trial, we found a clear signal for lower MACE with complete revascularization compared with culprit-only revascularization. There was no concomitant increase in the rates of major bleeding or contrast-associated acute kidney injury, but the prevalence of chronic kidney disease was low (0.7–3.6%) in 2 trials^{4, 6} and unreported in 3 trials.

These results provide cardiologists and geriatricians, who are often involved in shared-decision making conversations with patients and families before and after revascularization of the initial lesion, with greater confidence to pursue complete revascularization in older adults. The reduction in MACE from complete revascularization over culprit-only revascularizationin the FIRE trial is impressive given that the benefit was seen at the 1-year timepoint, in contrast to the 3-year timepoint in the COMPLETE trial. While we did identify an attenuated benefit for complete revascularization in the >75 year old subset of participants, firm conclusions are limited by an underpowered sample size. Notably, the beneficial effect in MACE from complete revascularization was sufficiently strong that it was seen in all 3 trials using an angiography-guided strategy. While patient-level factors may still lead to heterogeneity of benefits across individuals, complete revascularization may be preferred.

Pursuing complete revascularization for non-culprit lesions may come at the expense of increased contrast volume and bleeding risk. Reassuringly, the hazard for major bleeding and contrast-associated acute kidney injury appeared similar between complete revascularization and culprit-only revascularizationin the trials which reported these outcomes. However, this must be interpreted within the context of the likely selection bias that occurs with healither candidates who are more likely to have favorable outcomes being enrolled in these RCTs. Whether the safety and effectiveness of complete revascularization differs in older adults with renal insufficiency, multimorbidity, and geriatric syndromes, remains to be seen.

This meta-analysis is limited by the open-label design of the RCTs, heterogeneity in endpoints and timing, inclusion of revascularization within some of the MACE composites, lack of data on patient frailty, and lack of patient-level data, which precludes a direct comparison of the optimal timing of complete revascularization. These results do not apply to patients with chronic total occlusions or cardiogenic shock. The trials were not powered to detect a difference in major bleeding and contrast-associated acute kidney injury, so precaution is warranted in drawing firm conclusions, especially given wide confidence intervals.

In conclusion, this meta-analysis fills an important evidence gap in older adults, demonstrating that complete revascularization is associated with reduced MACE without a concomitant increase in major bleeding or contrast-associated acute kidney injury compared with culprit-only revascularization. Future RCTs should investigate immediate versus staged complete revascularization in older adults, and whether the benefits of complete revascularization become attenuated at more advanced chronological ages.

Key points.

• Whether the benefit of complete revascularization over culprit-only revascularization extends to older adults (>65 or >75 years of age), who have greater bleeding risk, comorbidity burden, and complexity of lesions, has not been comprehensively examined.

• We performed a meta-analysis to place the results of the previous randomized controlled trials in the context of the recently published Fractional Flow Reserve Versus Angiography in Guiding Management to Optimize Outcomes in Patients With Stable Coronary Artery Disease (FIRE) trial and the subgroup analysis of the Complete vs. Culprit-Only Revascularization Strategies to Treat Multivessel Disease After Early PCI for STEMI (COMPLETE) trial in adults ≥75 years old.

• In older adults, complete revascularization was associated with a lower hazard of major adverse cardiovascular events (MACE) but without significant difference in the hazard of major bleeding or contrast-associated acute kidney injury compared with culprit-only revascularization.

Why does this paper matter?

Our findings suggest that complete revascularization should be pursued in older adults with ST-elevation myocardial infarction to reduce the risk of future major adverse cardiovascular events (MACE). Our results can be taken into consideration when performing shared decision-making with cardiologists, geriatricians, patients, and caregivers whether to perform complete revascularization in older adults.

Data Used

Data included in this study can be found as published articles in online databases.