Comparison of Percutaneous Coronary Intervention, Coronary Artery Bypass Grafting and Medical Therapy in Non-ST Elevation Acute Coronary Syndrome Patients With 3-Vessel Disease

Abstract

Background: The aim of this study is to compare the long-term prognosis of non-ST elevation acute coronary syndrome (NSTE-ACS) patients with 3-vessel disease (3VD) who underwent percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) or medical therapy (MT).

Methods and Results: Overall, 3,928 NSTE-ACS patients with 3VD were consecutively enrolled from April 2004 to February 2011 at Fu Wai Hospital. Patients were followed up for a median of 7.5 years, and were divided into PCI, CABG or MT groups according to their treatment. Compared with patients undergoing PCI, CABG patients had lower rates of myocardial infarction (MI), unplanned revascularization, major adverse cardiovascular and cerebrovascular events (MACCE) and a higher rate of stroke (all P<0.05). Compared with MT, PCI and CABG had lower incidences of all adverse outcomes (all P<0.05), except for a similar rate of stroke between PCI and MT. Kaplan-Meier analysis showed similar results. After adjusting for confounders, CABG was independently associated with a lower risk of cardiac death, revascularization and MACCE compared with PCI (all P<0.05). Compared with MT, PCI reduced long-term risk of death, whereas CABG reduced long-term risk of death, revascularization and MACCE events (all P<0.05).

Conclusions: In NSTE-ACS patients with 3VD, CABG is independently associated with a lower risk of long-term cardiac death, revascularization and MACCE compared with PCI. Patients who received MT alone had the highest risk of long-term MACCE.

Percutaneous coronary intervention (PCI) has emerged as a potential alternative to coronary artery bypass grafting (CABG) for patients with complex coronary artery disease (CAD).¹ Although a number of randomized clinical trials (RCTs) have compared the efficacy and safety between PCI and CABG in patients with multivessel CAD,^2–8 evidence in patients having both 3-vessel disease (3VD) and presenting as having non-ST elevation acute coronary syndrome (NSTE-ACS) is relatively limited.

Editorial p ????

The 2018 European Society of Cardiology (ESC) / European Association for Cardio-Thoracic Surgery (EACTS) guidelines on myocardial revascularization recommended to base the revascularization strategy (ad hoc culprit-lesion PCI, multivessel PCI or CABG) on the clinical status, co-morbidities and disease severity in NSTE-ACS patients according to the principles for stable CAD (I, B).⁹ The 2017 American College of Cardiology (ACC) / American Heart Association (AHA) guidelines made similar recommendations.¹⁰ Previous studies comparing PCI and CABG in non-stable CAD patients have yielded inconsistent results. A pooled analysis of the BEST (Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease), PRECOMBAT (Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) and SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) trials showed that NSTE-ACS patients who underwent CABG had a lower rate of major adverse cardiovascular events (MACE), repeat revascularization and myocardial infarction (MI) than those who underwent PCI, although the risks of death and stroke were similar between the 2 groups.¹¹ However, in a propensity-matched comparison from the ACUITY trial, moderate- and high-risk ACS patients with multivessel disease treated with PCI had a lower rate of peri-procedural stroke, MI, major bleeding and renal injury, but had a similar rate of long-term mortality, MI, MACE and higher rate of recurrent ischemia.³ To the best of our knowledge, there is not a large-sample study with long-term follow up available involving NSTE-ACS patients with 3VD comparing long-term clinical outcomes of PCI and CABG.

Furthermore, a number of patients with NSTE-ACS received only medical therapy (MT) without PCI or CABG. Although previous studies have shown that PCI failed to reduce the long-term risk of death, MI or other MACE compared with optimal MT,^12,13 limited data are available for the same comparison in the setting of NSTE-ACS.

Therefore, we aimed to make a comprehensive comparison of long-term prognosis among NSTE-ACS patients undergoing PCI, CABG or MT alone in our real-world, prospective cohort of Chinese patients.

Methods

Subjects and Study Design

This study was an observational prospective cohort study. A total of 8,943 patients with 3-vessel CAD (3VD) were consecutively enrolled from April 2004 to February 2011 in Fu Wai Hospital, Chinese Academy of Medical Sciences (Beijing, China). The inclusion criteria were: subjects diagnosed as having 3VD (defined as angiographically confirmed stenosis of ≥50% in all 3 main coronary arteries, including left anterior descending artery, left circumflex artery and right coronary artery, with or without left main coronary artery involved), and were willing to be followed up. Before the enrollment, the study underwent a review meeting organized by the Ethics Committee of the Fu Wai Hospital. The protocol of our study was comprehensively evaluated and approved by all the committee members. Based on contemporary practice guidelines,^14,15 the treatment strategy (PCI, CABG or MT) assigned to each individual patient enrolled in our study was finally determined through heart team discussion involving interventional cardiologists, cardiac surgeons and physicians (details are available in the Supplementary File 1). Patients who refused to receive the assigned treatment chose an alternative strategy based on heart team suggestions and their own preferences. Enrolled patients were followed up according to the study protocol. Baseline and procedural data of all participants were collected into our database by independent clinical research coordinators. The follow up was performed by a telephone interview, follow-up letter, or clinic visit, with a response rate of 98.4%. All events were carefully checked and verified by an independent group of clinical physicians. Investigators’ training, blinded questionnaire filling and telephone recording were performed to achieve high-quality results.

Endpoints and Definitions

The primary endpoint was all-cause death. Secondary endpoints included cardiac death and major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause death, MI, stroke, or unplanned revascularization. All deaths were considered to be cardiac unless proven by an unequivocal non-cardiac cause. Revascularization was defined as repeated revascularization for ischemic symptoms and events driven by PCI or surgery of any vessel. MI was defined according to the consensus document from The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of MI.¹⁶

Statistical Analysis

Summary statistics were presented as frequency and percentage for categorical variables, and as means with standard deviations for continuous variables. The Student’s t-test or analysis of variance (ANOVA) was performed for the comparison of mean difference for continuous variables. A Pearson chi-squared test was performed for the comparison of categorical variables. Survival curves were constructed using the Kaplan-Meier method, and a log-rank test was performed to compare clinical endpoints over time. Patients who were lost to follow up were censored at the last available contact. Multivariate Cox regression analysis was performed to identify independent predictors of the adverse clinical outcomes. Risk factors including left main disease, age, gender, history of diabetes, history of MI, history of peripheral artery disease (PAD), history of chronic kidney disease (CKD), clinical presentation (acute MI, unstable angina), left ventricular ejection fraction (LVEF), serum creatinine, creatinine clearance, hemoglobin, preprocedural SYNTAX score, medication at discharge (angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blockers, aspirin, clopidogrel, statins, nitrates, calcium channel blockers) were entered into the Cox proportional hazards models. Proportional hazards assumption was evaluated by testing the significance of an interaction term of the PCI strategy and follow-up time. A time-dependent Cox regression model was applicated when the proportional hazards assumption was violated. However, no adjustment was made for 3-group comparisons among PCI, CABG and MT. Subgroup analysis was performed to evaluate the effect of the revascularization strategy on all-cause death and MACCE in specific patient subsets using the Cox regression models with tests for interaction. Missing values were imputed using the median for continuous variables or the mode for categorical variables. The proportion of each missing variable was reported in Supplementary Table 1. All statistical significance levels were defined as a 2-sided α=0.05. Statistical analysis was performed using IBM® SPSS® v22.0.0.0 software (SPSS Inc., Chicago, IL, USA).

Results

Among 8,943 patients with 3VD, a total of 3,928 patients presenting as NSTE-ACS were included in this study. Enrolled patients were subsequently divided into the following groups according to their primary treatment strategy: MT (n=1,109), PCI (n=1,589) or CABG (n=1,230) (Figure 1). Compared with patients who underwent PCI, patients who received CABG or MT were more frequently male patients, with more risk factors and comorbidities, including higher rate of diabetes, previous MI, PAD and CKD. Furthermore, patients who received CABG had a higher SYNTAX score and a higher rate of significant left main coronary disease, whereas patients who only received MT had a higher proportion of low LVEF (<40%) and lower creatinine clearance (Table 1). During the primary procedure, complete revascularization, defined as a residual SYNTAX score of 0, was achieved in 5.2% in patients who underwent PCI.

Figure 1.

Patient flowchart. Median follow-up time was 7.5 years. 3VD, 3-vessel disease; CABG, coronary artery bypass grafting; F/U, follow up; MT, medical therapy; NSTE-ACS, non-ST elevation acute coronary syndrome; PCI, percutaneous coronary intervention; SCAD, stable coronary artery disease; STEMI, ST elevation myocardial infarction.

Table 1. Baseline Characteristics of the Study Population

Variable	MT (n=1,109)	PCI (n=1,589)	CABG (n=1,230)	P value
Age (years)	64.25±10.03	61.08±10.10	61.67±8.70	<0.001
Male	824 (74.3)	1,205 (75.8)	978 (79.5)	0.008
Body mass index (kg/m2)	25.65±3.15	25.84±3.01	25.86±3.08	0.191
Risk factors and comorbidities
Hypertension	805 (72.6)	1,133 (71.3)	873 (71.0)	0.659
Diabetes mellitus	427 (38.5)	535 (33.7)	415 (33.7)	0.018
Previous MI	494 (44.5)	505 (31.8)	461 (37.5)	<0.001
Hyperlipidemia	619 (55.8)	947 (59.6)	694 (56.4)	0.094
Stroke	135 (12.2)	148 (9.3)	130 (10.6)	0.058
Peripheral artery disease	127 (11.5)	61 (3.8)	152 (12.4)	<0.001
Chronic kidney disease	23 (2.1)	8 (0.5)	13 (1.1)	0.001
Smoker	580 (52.3)	861 (54.2)	660 (53.7)	0.620
Clinical presentation
Unstable angina pectoris	905 (81.6)	1,320 (83.1)	1,087 (88.4)	<0.001
NSTEMI*	204 (18.4)	269 (16.9)	143 (11.6)	<0.001
Killip Class				<0.001
1	146 (13.2%)	234 (14.7%)	122 (9.9%)
2	46 (4.1%)	32 (2.0%)	14 (1.1%)
3	9 (0.8%)	2 (0.1%)	4 (0.3%)
4	3 (0.3%)	1 (0.1%)	3 (0.2%)
Left main disease	296 (27.1)	198 (12.6)	459 (38.1)	<0.001
LVEF <40%	96 (10.1)	18 (1.3)	38 (3.3)	<0.001
Creatinine (μmol/L)	86.81±26.54	83.08±17.98	84.70±20.33	<0.001
Creatinine clearance (mL/min)	79.04±27.37	85.21±25.74	83.80±25.56	<0.001
Hemoglobin (g/L)	134.63±15.86	137.43±15.26	135.20±15.88	<0.001
Pre-procedural SYNTAX score
≤22	421 (38.0)	923 (58.1)	248 (20.2)	<0.001
23–32	352 (31.7)	489 (30.8)	469 (38.1)	<0.001
≥33	301 (27.1)	151 (9.5)	473 (38.5)	<0.001
Medication upon discharge
ARBs	257 (23.2)	345 (21.7)	31 (2.5)	<0.001
Aspirin	1,035 (93.3)	1,558 (98.0)	1,153 (93.7)	<0.001
Clopidogrel	394 (35.5)	1,476 (92.9)	98 (8.0)	<0.001
β-blockers	977 (88.1)	1,411 (88.8)	1,064 (86.5)	0.174
ACEIs	502 (45.3)	720 (45.3)	133 (10.8)	<0.001
Nitrates	1,037 (93.5)	1,474 (92.8)	1,155 (93.9)	0.466
Calcium channel blockers	584 (52.7)	847 (53.3)	232 (18.9)	<0.001

Data are presented as n (%) or mean±standard deviation. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CABG, coronary artery bypass grafting; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MT, medical therapy; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention.

Compared with the CABG group, 30-day short-term unadjusted clinical outcomes showed lower incidence of all-cause death, cardiac death, MI, stroke and death/MI/stroke associated with PCI group (all P<0.05) (Supplementary Table 2). After adjusting for confounders, the MT group had a significantly higher risk of 30-day revascularization (HR=4.025, 95% CI: 1.413–11.468) and MACCE (HR=4.029, 95% CI: 1.496–10.850) compared with the PCI group, whereas the CABG group had a significantly lower risk of revascularization (HR=0.297, 95% CI: 0.089–0.986) compared with the MT group. All other differences became non-significant (Supplementary Tables 3–5).

The median follow-up time is 7.5 years (IQR 5.9–9.2), with a maximum of 11.7 years. The last follow up was completed in 2016. Over a median follow-up time of 7.5 years, the incidence of primary and all secondary endpoints are significantly different among the 3 groups (P<0.05). Compared with the PCI group, despite a higher rate of stroke (10.5% vs. 7.1%, P=0.002) and a similar rate of all-cause, cardiac death and death/MI/stroke (P>0.05), patients in the CABG group had a significantly lower rate of MACCE (25.7% vs. 32.9%, P<0.001), which is mainly driven by a lower rate of MI (2.7% vs. 8.4%, P<0.001) and unplanned revascularization (3.0% vs. 13.3%, P<0.001). Compared with the MT group, both CABG and PCI significantly reduced risk of all-cause death, cardiac death, death/MI stroke and MACCE (P<0.05, respectively), but patients in the PCI group had a higher rate of MI (8.4% vs. 5.0%, P=0.001) and unplanned revascularization (13.3 vs. 8.6%, P<0.001), whereas patients in the CABG group had a higher rate of stroke (10.5% vs. 6.9%, P=0.002), lower rate of MI (2.7% vs. 5.0%, P=0.004) and unplanned revascularization (3.0% vs. 8.6%, P<0.001) (Table 2). Kaplan-Meier survival analysis showed similar results (Figure 2).

Table 2. Long-Term Primary and Secondary Outcomes (Unadjusted)

Outcome	Treatment strategy	No. of patients with event (%)	P value
All-cause death			Overall	<0.001
	MT (n=1,109)	308 (27.8)	PCI vs. CABG	0.761
	PCI (n=1,589)	209 (13.2)	PCI vs. MT	<0.001
	CABG (n=1,230)	157 (12.8)	CABG vs. MT	<0.001
Cardiac death			Overall	<0.001
	MT (n=1,109)	193 (17.4)	PCI vs. CABG	0.223
	PCI (n=1,589)	90 (5.7)	PCI vs. MT	<0.001
	CABG (n=1,230)	57 (4.6)	CABG vs. MT	<0.001
MACCE			Overall	<0.001
	MT (n=1,109)	464 (41.8)	PCI vs. CABG	<0.001
	PCI (n=1,589)	554 (32.9)	PCI vs. MT	<0.001
	CABG (n=1,230)	316 (25.7)	CABG vs. MT	<0.001
MI			Overall	<0.001
	MT (n=1,109)	55 (5.0)	PCI vs. CABG	<0.001
	PCI (n=1,589)	133 (8.4)	PCI vs. MT	0.001
	CABG (n=1,230)	33 (2.7)	CABG vs. MT	0.004
Stroke			Overall	0.001
	MT (n=1,109)	76 (6.9)	PCI vs. CABG	0.002
	PCI (n=1,589)	113 (7.1)	PCI vs. MT	0.796
	CABG (n=1,230)	129 (10.5)	CABG vs. MT	0.002
Unplanned revascularization			Overall	<0.001
	MT (n=1,109)	95 (8.6)	PCI vs. CABG	<0.001
	PCI (n=1,589)	211 (13.3)	PCI vs. MT	<0.001
	CABG (n=1,230)	37 (3.0)	CABG vs. MT	<0.001
Death/MI/stroke			Overall	<0.001
	MT (n=1,109)	404 (36.4)	PCI vs. CABG	0.123
	PCI (n=1,589)	419 (26.4)	PCI vs. MT	<0.001
	CABG (n=1,230)	293 (23.8)	CABG vs. MT	<0.001

MACCE, major adverse cardiac and cerebrovascular events. Other abbreviations as in Table 1.

Figure 2.

Kaplan-Meier survival curves on long-term clinical endpoints in percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) and medical therapy (MT) groups for 3-vessel disease (3VD) patients presenting with non-ST elevation acute coronary syndrome (NSTE-ACS). (A) All-cause death; (B) cardiac death; (C) unplanned revascularization; (D) myocardial infarction; (E) stroke; (F) major adverse cardiac and cerebrovascular event (MACCE); (G) death/MI/stroke.

After adjusting for confounding factors by using Cox regression analysis, we found CABG to be independently associated with lower rate of long-term cardiac death (HR=0.445, 95% CI: 0.226–0.876), revascularization (HR=0.330, 95% CI: 0.172–0.635) and MACCE (HR=0.719, 95% CI: 0.532–0.972) compared with patients undergoing PCI (Table 3). We also found that age, history of PAD and LVEF had significant effect on mortality in the PCI group, whereas age, previous MI, history of PAD, history of CKD, LVEF, usage of aspirin and usage of ACEI had significant effect on mortality in the CABG group (all P<0.05) (Supplementary Table 6). Meanwhile, MT was associated with significantly higher risk of all-cause death (HR=1.634, 95% CI: 1.265–2.111), cardiac death (HR=2.438, 95% CI: 1.724–3.448) and death/MI/stroke (HR=1.225, 95% CI: 1.004–1.496) (Table 4). When compared with patients who received MT, patients who underwent CABG were found to have a significantly lower risk of long-term all-cause death (HR=0.467, 95% CI: 0.343–0.636, P<0.001), cardiac death (HR=0.230, 95% CI: 0.148–0.358, P<0.001), revascularization (HR=0.390, 95% CI: 0.214–0.711, P=0.002), MACCE (HR=0.585, 95% CI: 0.462–0.740, P<0.001) and death/MI/stroke (HR=0.625, 95% CI: 0.487–0.801) (Table 5).

Table 3. Multivariable Cox Regression Analysis of CABG vs. PCI on Clinical Outcomes

	PCI	CABG
		HR (95% CI)		P value
All cause death	ref		0.910 (0.580–1.429)	0.683
Cardiac death	ref		0.445 (0.226–0.876)	0.019
Revascularization	ref		0.330 (0.172–0.635)	0.001
MI	ref		0.585 (0.269–1.274)	0.177
Stroke	ref		1.117 (0.636–1.962)	0.701
MACCE	ref		0.719 (0.532–0.972)	0.032
Death/MI/stroke	ref		0.884 (0.636–1.229)	0.463

Adjusted variables: left main disease, age, gender, history of diabetes, history of MI, history of peripheral artery disease, history of chronic kidney disease, clinical presentation (acute MI, unstable angina), LVEF, serum creatinine, creatinine clearance, preprocedural SYNTAX score, medication at discharge (ACEI, ARBs, aspirin, clopidogrel, statins, nitrates, calcium channel blockers), hemoglobin, assigned treatment. CI, confidence interval; HR, hazard ratio; ref, reference. Other abbreviations as in Tables 1,2.

Table 4. Multivariable Cox Regression Analysis of MT vs. PCI on Clinical Outcomes

	PCI	MT
		HR (95% CI)		P value
All cause death	ref		1.634 (1.265–2.111)	<0.001
Cardiac death	ref		2.438 (1.724–3.448)	<0.001
Revascularization	ref		0.884 (0.629–1.243)	0.479
MI	ref		0.708 (0.454–1.104)	0.128
Stroke	ref		0.975 (0.641–1.485)	0.907
MACCE	ref		1.162 (0.971–1.390)	0.100
Death/MI/stroke	ref		1.225 (1.004–1.496)	0.046

Adjusted variables: left main disease, age, gender, history of diabetes, history of MI, history of peripheral artery disease, history of chronic kidney disease, clinical presentation (acute MI, unstable angina), LVEF, serum creatinine, creatinine clearance, preprocedural SYNTAX score, medication at discharge (ACEI, ARBs, aspirin, clopidogrel, statins, nitrates, calcium channel blockers), hemoglobin, assigned treatment. Abbreviations as in Tables 1–3.

Table 5. Multivariable Cox Regression Analysis of CABG vs. MT on Clinical Outcomes

	MT	CABG
		HR (95% CI)		P value
All cause death	ref		0.467 (0.343–0.636)	<0.001
Cardiac death	ref		0.230 (0.148–0.358)	<0.001
Revascularization	ref		0.390 (0.214–0.711)	0.002
MI	ref		0.607 (0.296–1.242)	0.171
Stroke	ref		1.369 (0.864–2.170)	0.181
MACCE	ref		0.585 (0.462–0.740)	<0.001
Death/MI/stroke	ref		0.625 (0.487–0.801)	<0.001

Adjusted Variables: Left main disease, age, gender, history of diabetes, history of MI, history of peripheral artery disease, history of chronic kidney disease, clinical presentation (acute MI, unstable angina), LVEF, serum creatinine, creatinine clearance, preprocedural SYNTAX score, medication at discharge (ACEI, ARBs, aspirin, clopidogrel, statins, nitrates, calcium channel blockers), hemoglobin, assigned treatment. Abbreviations as in Tables 1–3.

The effect of the revascularization strategy (PCI vs. CABG) on long-term all-cause death and MACCE were consistent across all subgroups, including age, gender, diabetes, SYNTAX score and left main disease (all P for interaction >0.05) (Table 6).

Table 6. Subgroup Analysis on All-Cause Death and MACCE Between PCI and CABG

Subgroup	All-cause death					MACCE
	PCI†	CABG†	HR (95% CI)		P value*	PCI†	CABG†	HR (95% CI)		P value*
Overall	209/1,589	157/1,230		0.910 (0.580–1.429)		554/1,589	316/1,230		0.719 (0.532–0.972)
Age (years)					0.400					0.114
≥65	140/640	100/486		1.240 (0.703–2.189)		271/640	160/486		0.856 (0.556–1.319)
<65	69/949	57/744		0.526 (0.243–1.138)		283/949	156/744		0.639 (0.415–0.984)
Gender					0.491					0.213
Male	153/1,205	122/978		0.866 (0.515–1.457)		421/1,205	247/978		0.748 (0.528–1.058)
Female	56/384	35/252		1.139 (0.445–2.916)		133/384	69/252		0.724 (0.381–1.374)
Diabetes					0.614					0.928
Yes	69/535	53/415		0.832 (0.334–2.071)		190/535	112/415		0.638 (0.368–1.106)
No	140/1,054	104/815		0.887 (0.513–1.533)		364/1,054	204/815		0.738 (0.510–1.068)
LVEF (%)					–**					–**
<40	5/18	12/38		(0.127–)***		7/18	12/38		(0.181–)***
≥40	173/1,339	135/1,117		0.926 (0.583–1.469)		467/1,339	286/1,117		0.718 (0.529–0.974)
SYNTAX score					0.100					0.551
0–22	113/923	21/248		0.607 (0.255–1.446)		312/923	61/248		0.755 (0.446–1.279)
23–32	64/489	55/469		1.356 (0.625–2.941)		172/489	102/469		0.915 (0.538–1.557)
≥33	30/151	76/473		0.651 (0.253–1.675)		61/151	144/473		0.563 (0.290–1.092)
Left main disease					0.742					0.365
Yes	34/198	58/459		0.620 (0.245–1.568)		69/198	130/459		0.662 (0.360–1.218)
No	170/1,370	88/745		1.001 (0.587–1.705)		479/1,370	171/745		0.710 (0.495–1.019)
	Favor CABG			Favor PCI		Favor CABG			Favor PCI

Data are presented as (number of patients with event / total number of patients in the subgroup) in the PCI and CABG column. *P value for interaction in each subgroup analysis. **Unable to calculate the P value for this subgroup due to unreliable results of LVEF <40% subgroup. ***Unreliable result due to very wide confidence interval. ^†Number of patient with events / total number of patients in this subgroup. Adjusted variables: left main disease, age, gender, history of diabetes, history of MI, history of peripheral artery disease, history of chronic kidney disease, clinical presentation (acute MI, unstable angina), LVEF, serum creatinine, creatinine clearance, preprocedural SYNTAX score, medication at discharge (ACEI, ARBs, aspirin, clopidogrel, statins, nitrates, calcium channel blockers), hemoglobin, assigned treatment. Abbreviations as in Tables 1–3.

In order to investigate whether completeness of revascularization had an effect on clinical outcomes, we compared the occurrence and adjusted risk of long-term MI, all-cause death and MACCE between patients who underwent complete revascularization during primary PCI (CR-PCI) and patients in the CABG group. Although the CR-PCI group had a higher rate of long-term MI (12.0% vs. 2.7%, P<0.001) than the CABG group, no significant effect on risk of MI, all-cause death and MACCE was found after adjusting for confounding factors (all P>0.05) (Supplementary Table 7).

Discussion

Non-ST elevation acute coronary syndrome is the leading cause of morbidity and mortality from cardiovascular disease worldwide.¹⁷ Meanwhile, 3VD is common among CAD patients, with a doubled risk of mortality compared with single-vessel CAD.¹⁸ Taken together, the patients enrolled in our study represent a high-risk population in need for an optimal treatment strategy. In patients with 3VD presenting as NSTE-ACS, the major findings in our study are as follows: (1) compared with PCI, CABG was independently associated with lower risk of long-term cardiac death, unplanned revascularization and MACCE, whereas the difference in MI and stroke became non-significant after adjusting for confounding factors; (2) compared with PCI, MT was associated with a higher risk of all-cause death, cardiac death and death/MI/stroke; and (3) compared with MT, CABG was associated with a decreased risk of death, revascularization, MACCE and death/MI/stroke.

With the groundbreaking evolution in devices and substantial improvement in techniques, PCI has emerged as a reasonable alternative revascularization strategy for patients with complex CAD. The benefit and risk among the treatment strategies for patients with stable and complex CAD has been discussed extensively in various studies, including RCTs,^2,4,5,7,19 registries²⁰ and pooled or meta-analyses.^11,21–24 In most of these studies, CABG was superior to PCI in terms of long-term repeat revascularization and MACE/MACCE, but with a similar rate to mortality, stroke or MI. In patients with ACS presentation, a propensity-matched analysis enrolling 5,627 ACS patients with multivessel disease from the ACUITY trial found patients treated with PCI had a lower rate of 1-month peri-procedural stroke, MI, major bleeding, comparable 1-month and 1-year mortality and a higher rate of repeat revascularization compared with patients treated with CABG.³ In a pooled analysis of 3 RCTs comparing PCI and CABG in NSTE-ACS patients, CABG is found to significantly reduce the risk of 5-year death, MI and stroke compared with PCI with drug eluting stents (DESs).¹¹ However, patients in these previous studies of acute clinical settings had a shorter follow-up period and less complexity in terms of number of diseased coronary arteries. Our results are partly consistent with previous trials in terms of lower risk of long-term cardiac death, unplanned revascularization and MACCE related to CABG, yet different as we observed similar long-term all-cause mortality, MI and stroke between PCI and CABG groups. Explanations for the inconsistency may include: (1) our study is an observational cohort study reflecting real-world outcomes, instead of clinical trials where patients are highly selected and randomized; (2) our study focuses on NSTE-ACS patients with 3VD and 3VD only, leading to different results from previous studies; and (3) although we attempted to adjust for differences in patient characteristics, including LVEF, risk factors, acuity of presentation, unknown confounding factors still exist, contributing to the discrepancy from previous studies.

Despite improvement in procedural and long-term outcomes, periprocedural MI after PCI and CABG are still frequent complications following revascularization procedures,²⁵ and are associated with increased rates of future cardiovascular events.²⁶ In our study, we have observed that patients in the PCI group had significantly lower incidence of 30-day MI compared with the CABG group. However, the difference became non-significant after adjustment. Some of these MI events may be attributed to periprocedural MI after PCI or perioperative MI after CABG. However, necessary data to determine periprocedural or perioperative MI are missing in our study. Future studies are warranted to further compare risks of periprocedural MI between CABG and PCI groups in NSTE-ACS settings.

Although routine revascularization is recommended for most patients with ACS, as it reduces death and MI compared with conservative drug therapy only,^27–30 a substantial proportion of patients (nearly one-third) in our study still received MT only. Over a median follow up of 7.5 years, our patients treated with PCI had a significantly lower rate of all-cause death, cardiac death and MACCE, and a higher rate of MI and unplanned revascularization compared with the MT group. After adjusting for confounding factors, we found that patients in the PCI group had a lower risk of long-term all-cause death, cardiac death and death/MI/stroke compared to patients in the MT group. A meta-analysis of 28 clinical trials by Jeremias et al³¹ demonstrated that both PCI and CABG significantly reduced risk of overall mortality in patients with non-acute CAD. Furthermore, another recent meta-analysis indicated that revascularization strategies are superior to medical treatment in improving survival in patients with ischemic heart disease, and it reduced ejection fraction.³² Despite the difference in clinical presentation and complexity of CAD, our findings are consistent with these previous studies.

Patients with specific baseline characteristics including higher age,³³ being women,¹⁷ having diabetes,³⁴ reduced LVEF,³⁵ a higher SYNTAX score³⁶ and left main disease³⁷ are often deemed to be at higher risk of adverse events. In order to find out whether choice of revascularization strategies (CABG or PCI) had an effect on these clinical subgroups, a series of subgroup analyses were performed in our study. However, our results suggested that the effect of the revascularization strategy in all subgroups appeared to be consistent on long-term all-cause death and MACCE, except that we were not able to get a reliable result for the LVEF subgroup due to insufficient sample capacity. Therefore, based on the subgroup findings of our real-world observational study, CABG was associated with a lower risk of MACCE compared with PCI, which was consistent across all subgroups including age, gender, diabetic status, SYNTAX score and left main CAD.

There are several inherent limitations in our study. First, as a single-center real-world observational cohort study, confounding factors are inevitable in our analysis. Second, detailed procedural information of revascularization (such as prevalence of chronic total occlusion) and specific drugs used in the MT group were unavailable in our database. Third, although all the patients enrolled in our study were well instructed to take long-term medication therapies according to guideline recommendations upon discharge, compliance to post-discharge medication is largely unknown in our follow-up data. Fourth, the subgroup analyses were likely underpowered to detect any differences in treatment effects. Fifth, whether patients adopted treatment recommended by the heart team is not recorded, thus we are unable to analyze their clinical outcomes. Sixth, our study had a strength of longer follow up, but at the same time, newer generation devices might not be available because our study enrolled patients since 2004. This might limit generalizability into certain contemporary practice. Finally, because there was no adjustment for multiple comparisons, there is an increased risk of type I error in the overall 3-group comparisons among PCI, CABG and MT groups.

Conclusions

In patients with 3VD presenting as NSTE-ACS, CABG was independently associated with a lower risk of long-term cardiac death, unplanned revascularization and MACCE in comparison with PCI after adjusting for confounding factors. Compared with MT, PCI reduced long-term risk of death, whereas CABG reduced long-term risk of death, revascularization and MACCE events. In conclusion, CABG might be a preferred treatment strategy for reduction of long-term adverse events in NSTE-ACS patients with 3VD.

Acknowledgment

The investigators thank all staff members for data collection, data entry, and monitoring as part of this study.

Disclosures

The authors declare no conflicts of interest.

IRB Information

The present study was approved by the Ethics Committee of Fu Wai Hospital (Reference number: 2013-449).

Funding

This work was supported by the CAMS Innovation Fund for Medical Sciences (grant number 2016-I2M-1-002); the Beijing Municipal Natural Science Foundation (grant number 7181008); and the National Natural Science Foundation of China (grant number 81870286).

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-0300

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