Long-Term Outcomes in Patients With Chronic Total Occlusion and Left Ventricular Systolic Dysfunction　― A Single-Center Inverse Probability of Treatment Weighting Analysis ―

Abstract

Background: The optimal treatment strategy for patients with coronary chronic total occlusion (CTO) and left ventricular systolic dysfunction (LVSD) remains unclear. This study investigated the long-term outcomes of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and medical therapy (MT) in this specific patient cohort.

Methods and Results: This retrospective cohort study included 987 consecutive patients with CTO and LVSD who met the inclusion criteria and underwent either CTO-PCI (n=277), CTO-CABG (n=222), or CTO-MT (n=488) between 2014 and 2020. The primary outcome was all-cause mortality during follow-up. Secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) and their components, including cardiovascular mortality, myocardial infarction (MI), stroke, unplanned revascularization, and hospitalization for heart failure. During a median follow-up of 5.3 years, 232 (23.51%) patients died from any cause. In the unadjusted analysis, CTO-MT was associated with worse long-term survival prospects. After inverse probability of treatment weighting and variable adjustment, CTO-PCI and CTO-CABG demonstrated significant reductions in the long-term risks of all-cause and cardiovascular mortality. Notably, CTO-CABG was associated with the lowest long-term risks of MACCE, MI, unplanned revascularization, and hospitalization for heart failure.

Conclusions: For patients with CTO and LVSD, successful CTO revascularization significantly improved long-term survival compared with CTO-MT. CTO-CABG can be regarded as the optimal treatment modality for better long-term prognosis.

The debate regarding the benefits of revascularization for chronic total occlusion (CTO) has persisted for over a decade, primarily due to inconsistencies in the findings of observational studies and randomized controlled trials.¹ Most observational studies support CTO revascularization to improve survival, whereas randomized controlled trials have predominantly yielded negative results.^2–5 Despite the higher level of evidence provided by randomized controlled trials, the controversy surrounding CTO revascularization persists due to some non-negligible limitations in these studies.⁶ Optimizing clinical outcomes for specific clinical subgroups has become the current research direction for precision treatments. Notably, because CTO represents the advanced stage of coronary atherosclerosis, left ventricular systolic dysfunction (LVSD) occurs in approximately 10–19% of patients and is associated with more severe comorbidities and worse long-term outcomes.^7–9 Patients with LVSD are often excluded from most clinical studies, highlighting the importance of examining whether such patients benefit from coronary revascularization.¹⁰ The Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) revealed a significant improvement in survival rates for patients with LVSD undergoing coronary artery bypass grafting (CABG) compared with medical therapy (MT).¹¹ However, the latest Revascularization for Ischemic Ventricular Dysfunction-British Cardiovascular Society-2 (REVIVED-BCIS2) trial demonstrated negative results for percutaneous coronary intervention (PCI).¹² Whether this discrepancy persists in the context of CTO with LVSD remains unclear. Currently, there are no guidelines or consensus regarding the optimal management of this complex patient population. Therefore, we designed a large-sample, long-term follow-up study to investigate the long-term outcomes of different CTO treatment strategies for patients with CTO and LVSD.

Methods

Study Design and Population

This was a retrospective cohort study. Consecutive patients with CTO and LVSD who underwent coronary angiography at Beijing Anzhen Hospital, Capital Medical University, between January 2014 and December 2020 were enrolled. Patients with prior CABG, non-coronary cardiac surgery, hybrid coronary revascularization, and those lost to follow-up were excluded from the final analysis.

LVSD was defined as a left ventricular ejection fraction (LVEF) ≤40% based on the last transthoracic echocardiogram performed at Beijing Anzhen Hospital prior to coronary angiography.¹³ CTO was defined as total occlusion of the coronary artery without antegrade flow, presumed to have been occluded for at least 3 months.¹⁴ The CTO SYNTAX score was derived from the ratio of the SYNTAX score specific to the CTO lesion site to the overall total SYNTAX score.¹⁵ Based on the treatment of CTO lesions within 90 days after the index angiogram, the study cohort was divided into 3 groups: CTO-PCI, CTO-CABG, and CTO-MT groups. The treatment strategies were collaboratively established by the patients and the heart team.

This study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (No. 2023026X). The requirement for written informed consent from patients was waived because of the retrospective nature of the study. The study was conducted in accordance with the principles of the Declaration of Helsinki. The study flowchart is shown in Figure 1.

Figure 1.

Study flowchart. CABG, coronary artery bypass grafting; CTO, chronic total occlusion; LVSD, left ventricular systolic dysfunction; MT, medical therapy; PCI, percutaneous coronary intervention.

Study Groups

In the CTO-CABG group, the cardiac center required the surgical team to perform revascularization based on standard bypass grafting techniques. Complete revascularization via CABG was defined as the successful revascularization of all coronary artery lesions with ≥50% diameter stenosis.¹⁶ The CABG SYNTAX score was calculated to estimate residual risk after CABG.¹⁷ The residual SYNTAX score was calculated following PCI, and a residual SYNTAX score ≤8 was considered reasonable incomplete revascularization.^16,18 Patients with unsuccessful CTO-PCI who did not experience 30-day mortality and opted to undergo CTO-CABG were assigned to the CTO-CABG group. In contrast, those with no intention of further revascularization were assigned to the CTO-MT group. If a patient’s initial treatment strategy was determined as CTO-MT as recorded in their medical history but they underwent unplanned revascularization within 90 days after the index angiogram, it was documented as an adverse event. Unless contraindicated, aspirin 100 mg daily was prescribed indefinitely, and a P2Y₁₂ receptor inhibitor was added according to clinical guidelines. Typically, patients were also prescribed statins. The decision to combine antiangina and heart failure medications was made by the attending physician.

Data Collection

Detailed data on patient demographics and clinical characteristics, laboratory test results, echocardiographic parameters, angiographic data, surgical records, and complications were obtained from electronic medical records. Any disputed data were submitted to an expert committee for adjudication.

Follow-up and Outcomes

The index date for analysis for the CTO-PCI and CTO-CABG groups was the date of the revascularization, whereas for the CTO-MT group it was the date of the first coronary angiography where the CTO was discovered. The primary endpoint of this study was all-cause mortality. Secondary endpoints included major adverse cardiac and cerebrovascular events (MACCE) and their components (cardiovascular death, myocardial infarction [MI], stroke, unplanned revascularization, and hospitalization for heart failure). Cardiovascular mortality was defined as death from cardiovascular causes; unless other explicit causes of death were identified, all cases were categorized as cardiovascular mortality.¹⁴ A diagnosis of stroke was made by independent neurologists following the latest Neurologic Academic Research Consortium classification.¹⁹ The diagnosis of MI was based on the fourth universal definition of MI.²⁰ Unplanned repeat revascularization was defined as any unscheduled revascularization of any coronary artery driven by clinically indicated or ischemic reasons.²¹ Hospitalization for heart failure was defined as unplanned inpatient care due to deteriorating symptoms or signs of heart failure lasting for at least 24 h.¹⁴

Follow-up data were collected from hospital medical records or obtained by contacting patients, their representatives, or referring physicians. Clinical outcomes were adjudicated by the clinical event committee.

Statistical Analysis

Continuous variables are presented as the mean±SD or median with interquartile range (IQR). Comparisons between groups were performed using analysis of variance or the Kruskal-Wallis test. Categorical variables are presented as frequencies and percentages, with group comparisons conducted using a Chi-squared test or Fisher’s exact test.

Considering the differences in baseline characteristics among different groups, the inverse probability of treatment weighting (IPTW) method based on propensity score was used to balance these disparities. Generalized boosted models were used to derive the propensity score weights. A balancing metric based on the average of the absolute standardized mean difference (ASMD) of the covariates was selected.^22,23 To ascertain the optimal outcomes, 10,000 iterations were executed. Covariates in the IPTW model included sex, age, body mass index, smoking status, hypertension, diabetes, dyslipidemia, chronic kidney disease, previous stroke, previous MI, previous PCI, previous ventricular tachycardia/ventricular fibrillation, chronic obstructive pulmonary disease, peripheral vascular disease, New York Heart Association functional class, ST-segment elevation MI (STEMI), creatinine clearance, LVEF, multivessel disease, left main disease, SYNTAX score, left anterior descending artery CTO, in-stent CTO, Rentrop grade, J-CTO (Multicenter CTO Registry of Japan) score, and PROGRESS CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) score. The overall ASMD among the 3 groups after IPTW calculation was computed, with an ASMD ≤0.2 generally considered to indicate that the groups were comparable.

Cumulative incidence curves for each clinical endpoint were constructed using Kaplan-Meier estimates. Subsequently, a Cox proportional hazards model was established with the endpoint as the dependent variable and the treatment group as the independent variable. Specifically, 2 distinct Cox hazard models were developed: (1) an unadjusted model; and (2) an adjusted model that further accounted for baseline covariates exhibiting imbalance (ASMD >0.2) between groups based on IPTW. Hazard ratios (HRs) and 95% confidence intervals (CIs) for clinical outcomes between groups were reported for each model. Additional sensitivity analyses were conducted to compare differences in endpoint events between patients who underwent CTO-PCI with a residual SYNTAX score ≤8 or >8 and those in the CTO-CABG group. Subgroup analyses were also performed based on clinically relevant variables, and tests for interaction were executed to assess the heterogeneity of treatment effect among subgroups.

Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA) and R 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was defined as 2-sided P<0.05.

Results

Demographic and Clinical Characteristics

In all, 987 patients (mean age 59.7±10.2 years; 85.82% male) with CTO and LVSD met the inclusion criteria for final statistical analysis. Of these patients, 277 (28.06%) underwent CTO-PCI, 222 (22.49%) underwent CTO-CABG, and 488 (49.44%) underwent CTO-MT. The baseline demographic and clinical characteristics of the patients are summarized in Table 1. In this cohort, risk factors were prevalent, such as hypertension (58.66%), diabetes (53.50%), dyslipidemia (70.72%), and previous MI (64.03%). Patients in the CTO-MT group were older and exhibited lower creatinine clearance, lower LVEF, and wider left ventricular end-systolic and end-diastolic diameters than patients in the other 2 groups. Patients in the CTO-CABG group had a lower incidence of previous PCI and previous ventricular tachycardia/ventricular fibrillation than those in the other 2 groups. In addition, patients in the CTO-CABG group were less likely to seek medical attention due to STEMI, but had poorer cardiac function. Compared with the other 2 groups, patients in the CTO-PCI group had higher triacylglycerol levels. Most of the patients who underwent CTO revascularization received dual antiplatelet therapy. Other baseline demographic and clinical characteristics were generally comparable among the 3 groups.

Table 1.

Demographic and Clinical Characteristics of Patients According to Treatment Group

	CTO-PCI (n=277)	CTO-CABG (n=222)	CTO-MT (n=488)	P value
Baseline characteristics
Male sex	239 (86.28)	198 (89.19)	410 (84.02)	0.181
Age (years)	58.0±10.3	59.5±9.5	60.8±10.3	0.001
BMI (kg/m2)	25.81±3.78	25.45±3.01	25.91±3.51	0.252
Smoker	167 (60.29)	137 (61.71)	289 (59.22)	0.818
Hypertension	171 (61.73)	120 (54.05)	288 (59.02)	0.218
Diabetes	136 (49.10)	117 (52.70)	275 (56.35)	0.149
Dyslipidemia	211 (76.17)	150 (67.57)	337 (69.06)	0.058
Chronic kidney disease	19 (6.86)	14 (6.31)	49 (10.04)	0.146
Previous cerebral infarction	32 (11.55)	35 (15.77)	75 (15.37)	0.282
Previous MI	189 (68.23)	135 (60.81)	308 (63.11)	0.192
Previous PCI	103 (37.18)	55 (24.77)	179 (36.68)	0.004
Previous VT/VF	22 (7.94)	3 (1.35)	38 (7.79)	0.002
COPD	4 (1.44)	9 (4.05)	14 (2.87)	0.200
Peripheral vascular disease	13 (4.69)	17 (7.66)	34 (6.97)	0.340
NYHA class ≥3	70 (25.27)	99 (44.59)	200 (40.98)	<0.001
STEMI	24 (8.66)	9 (4.05)	50 (10.25)	0.022
Triacylglycerol (mmol/L)	1.53 [1.15–2.38]	1.40 [1.05–1.90]	1.43 [1.00–1.98]	0.003
Total cholesterol (mmol/L)	4.00 [3.37–4.75]	3.88 [3.29–4.74]	3.81 [3.29–4.61]	0.397
HDL-C (mmol/L)	0.94 [0.83–1.09]	0.94 [0.82–1.12]	0.95 [0.80–1.12]	0.821
LDL-C (mmol/L)	2.29 [1.82–2.93]	2.32 [1.82–3.03]	2.28 [1.80–2.92]	0.879
CCr (mL/min)	94.44±38.61	89.86±30.75	85.90±33.15	0.004
LVEF (%)	35.29±5.23	36.32±3.77	33.98±5.91	<0.001
LVEDD (mm)	60.05±7.37	58.66±5.98	61.01±7.38	<0.001
LVESD (mm)	47.76±8.43	46.05±6.79	48.66±8.52	<0.001
Medication
Dual antiplatelet therapy	274 (98.92)	216 (97.30)	459 (94.06)	0.002
Statin	276 (99.64)	219 (98.65)	480 (98.36)	0.346
ACEi/ARB/ARNI	195 (70.40)	153 (68.92)	359 (73.57)	0.385
β-blocker	264 (95.31)	214 (96.4)	458 (93.85)	0.334
MRA	164 (59.21)	136 (61.26)	322 (65.98)	0.145
SGLT2i	19 (6.86)	17 (7.66)	35 (7.17)	0.943
Nitrates	222 (80.14)	178 (80.18)	392 (80.33)	0.998
Diuretic	155 (55.96)	143 (64.41)	296 (60.66)	0.152

Unless indicated otherwise, data are presented as the mean±SD, median [interquartile range], or n (%). ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BMI, body mass index; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; CCr, creatinine clearance; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; MI, myocardial infarction; MRA, mineralocorticoid receptor antagonist; MT, medical therapy; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; SGLT2i, sodium-glucose cotransporter 2 inhibitors; STEMI, ST-elevation myocardial infarction; VF, ventricular fibrillation; VT, ventricular tachycardia.

Angiographic Characteristics

Patients’ angiographic characteristics are presented in Table 2. The incidence of multivessel disease in this cohort was 86.83%, with 585 (59.27%) patients having triple-vessel disease. The CTO-CABG group had a high incidence of multivessel disease, triple-vessel disease, and left main disease, as well as higher SYNTAX scores than the other 2 groups. Patients who underwent CTO-PCI had a higher weighting of CTO lesion score in the overall SYNTAX score.

Table 2.

Angiographic Characteristics of Patients According to Treatment Group

	CTO-PCI (n=277)	CTO-CABG (n=222)	CTO-MT (n=488)	P value
Multivessel disease	216 (77.98)	213 (95.95)	428 (87.7)	<0.001
Double-vessel disease	82 (29.60)	45 (20.27)	146 (29.92)	0.020
Triple-vessel disease	134 (48.38)	168 (75.68)	283 (57.99)	<0.001
Left main disease	20 (7.22)	48 (21.62)	68 (13.93)	<0.001
SYNTAX score	25.02±9.36	31.48±8.42	26.10±9.75	<0.001
SYNTAX score ≥33	57 (20.58)	93 (41.89)	108 (22.13)	<0.001
Recommendation for CABG based on SYNTAX score II	216 (77.98)	172 (77.48)	367 (75.20)	0.634
RCA CTO	141 (50.90)	139 (62.61)	254 (52.05)	0.015
LAD CTO	140 (50.54)	109 (49.10)	198 (40.57)	0.013
LCX CTO	92 (33.21)	79 (35.59)	178 (36.48)	0.661
LM CTO	3 (1.08)	2 (0.90)	1 (0.20)	0.188
In-stent CTO	39 (14.08)	24 (10.81)	60 (12.30)	0.540
Rentrop collateral grade ≥2	172 (62.09)	154 (69.37)	310 (63.52)	0.202
CTO SYNTAX score	0.79 [0.57–1.00]	0.62 [0.41–0.82]	0.63 [0.43–0.88]	<0.001
Blunt stump	154 (55.60)	142 (63.96)	297 (60.86)	0.146
Calcification	125 (45.13)	79 (35.59)	190 (38.93)	0.079
Bending >45°	67 (24.19)	87 (39.19)	186 (38.11)	<0.001
Occlusion length ≥20 mm	195 (70.40)	157 (70.72)	324 (66.39)	0.373
Reattempt	28 (10.11)	32 (14.41)	42 (8.61)	0.062
Proximal cap ambiguity	59 (21.30)	49 (22.07)	101 (20.70)	0.916
Absence of interventional collaterals	99 (35.74)	73 (32.88)	174 (35.66)	0.743
Moderate or severe tortuosity	27 (9.75)	39 (17.57)	79 (16.19)	0.021
J-CTO score	2 (1, 3)	2 (2, 3)	2 (1, 3)	0.272
PROGRESS CTO score	1 (0, 1)	1 (0, 1)	1 (0, 2)	0.268

Unless indicated otherwise, data are presented as the mean±SD, median [interquartile range], or n (%). CTO, chronic total occlusion; J-CTO, Multicenter CTO Registry of Japan; LAD, left anterior descending artery; LCX, left circumflex artery; PROGRESS CTO, Prospective Global Registry for the Study of Chronic Total Occlusion Intervention; RCA, right coronary artery. Other abbreviations as in Table 1.

Procedural Characteristics

Details of the revascularization procedures are presented in the Supplementary Table. The antegrade wire technique was the primary and most common final CTO wire-crossing technique, and the retrograde technique was only performed in 16 (5.78%) patients. In all, 249 (89.89%) patients who underwent successful CTO-PCI were implanted with a drug-eluting stent. Reasonable incomplete revascularization was achieved in 60.65% of patients in the CTO-PCI group. For patients undergoing CTO-CABG, off-pump CABG was the primary surgical technique, and 79.73% of patients achieved complete revascularization.

Unadjusted Outcomes

The unadjusted 30-day and long-term outcomes are summarized in Table 3. No significant difference was observed in the incidence of all-cause mortality within 30 days among the various treatment groups. The median duration of long-term follow-up was 5.3 years (IQR 3.9–6.8 years; maximum 10.5 years). Long-term primary endpoint events occurred in 232 of 987 (23.51%) patients in the whole cohort. The all-cause mortality rate was 16.61% in the CTO-PCI group, 18.02% in the CTO-CABG group, and highest (29.92%) in the CTO-MT group (P<0.001). The CTO-CABG group had a lower incidence of MACCE, cardiovascular mortality, MI, unplanned revascularization, and hospitalization for heart failure. Kaplan-Meier analysis revealed that, compared with CTO-MT, CTO revascularization exhibited a higher short-term postoperative mortality risk. However, it was associated with a greater improvement in long-term survival (P<0.001; Figure 2A). In terms of long-term MACCE, a significant separation of the curves was observed for the CTO-CABG group compared with the other 2 groups, representing a lower risk of MACCE (Figure 2B). The CTO-MT group was associated with a higher risk of cardiovascular mortality (Figure 2C), whereas the CTO-CABG group had the lowest risks of MI (Figure 2E), unplanned revascularization (Figure 2F), and hospitalization for heart failure (Figure 2G). The cumulative incidence curves for stroke overlapped among the 3 study groups, indicating a comparable risk of stroke (Figure 2D).

Table 3.

Thirty-Day and Long-Term Outcomes

	CTO-PCI (n=277)	CTO-CABG (n=222)	CTO-MT (n=488)	P value
30-day outcomes
All-cause mortality	8 (2.89)	11 (4.95)	10 (2.05)	0.104
MACCE	14 (5.05)	16 (7.21)	30 (6.15)	0.604
Cardiovascular mortality	7 (2.53)	10 (4.50)	9 (1.84)	0.121
Stroke	2 (0.72)	4 (1.80)	4 (0.82)	0.453
MI	6 (2.17)	5 (2.25)	5 (1.02)	0.306
Unplanned revascularization	6 (2.17)	1 (0.45)	7 (1.43)	0.290
Hospitalization for HF	1 (0.36)	2 (0.90)	13 (2.66)	0.034
Long-term outcomes
All-cause mortality	46 (16.61)	40 (18.02)	146 (29.92)	<0.001
MACCE	124 (44.77)	56 (25.23)	246 (50.41)	<0.001
Cardiovascular mortality	34 (12.27)	23 (10.36)	106 (21.72)	<0.001
Stroke	7 (2.53)	10 (4.50)	19 (3.89)	0.464
MI	34 (12.27)	13 (5.86)	71 (14.55)	0.004
Unplanned revascularization	66 (23.83)	5 (2.25)	92 (18.85)	<0.001
Hospitalization for HF	51 (18.41)	24 (10.81)	110 (22.54)	0.001

Unless indicated otherwise, data are presented as n (%). HF, heart failure; MACCE, major adverse cardiac and cerebrovascular events. Other abbreviations as in Tables 1,2.

Figure 2.

Kaplan-Meier analysis of the cumulative incidence of clinical outcomes according to treatment assignment in patients with chronic total occlusion (CTO) and left ventricular systolic dysfunction. CABG, coronary artery bypass grafting; CI, confidence interval; HR, hazard ratio; MACCE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; MT, medical therapy; PCI, percutaneous coronary intervention.

Adjusted Long-Term Outcomes

After IPTW adjustment, most of the prespecified covariates were balanced (Supplementary Figure). Adjusted long-term outcomes are presented in Table 4. Compared with CTO-MT, both CTO-PCI (adjusted HR 0.68; 95% CI 0.55–0.85; P=0.001) and CTO-CABG (adjusted HR 0.63; 95% CI 0.50–0.79; P<0.001) were associated with a lower risk of long-term all-cause mortality, which was comparable between the CTO-CABG and CTO-PCI groups (adjusted HR 0.92; 95% CI 0.71–1.20; P=0.548). Compared with CTO-MT, CTO-PCI reduced the risk of cardiovascular mortality but was associated with a higher risk of unplanned revascularization. When comparing the prognosis of the CTO-CABG and CTO-MT groups, it was observed that CTO-CABG significantly reduced the risks of long-term MACCE, cardiovascular mortality, MI, unplanned revascularization, and hospitalization for heart failure. When focusing on 2 distinct CTO revascularization strategies, the lowest long-term risks for MACCE, MI, unplanned revascularization, and hospitalization for heart failure were observed in the CTO-CABG group.

Table 4.

aHRs for Long-Term Clinical Outcomes

	CTO-PCI vs. CTO-MT		CTO-CABG vs. CTO-MT		CTO-CABG vs. CTO-PCI
	aHR (95% CI)	P value	aHR (95% CI)	P value	aHR (95% CI)	P value
All-cause mortality	0.68 (0.55–0.85)	0.001	0.63 (0.50–0.79)	<0.001	0.92 (0.71–1.20)	0.548
MACCE	1.01 (0.87–1.16)	0.940	0.49 (0.41–0.59)	<0.001	0.48 (0.41–0.59)	<0.001
Cardiovascular mortality	0.66 (0.51–0.85)	0.002	0.54 (0.41–0.72)	<0.001	0.82 (0.59–1.13)	0.225
Stroke	0.89 (0.50–1.58)	0.687	1.09 (0.64–1.87)	0.753	1.23 (0.68–2.22)	0.499
MI	0.95 (0.72–1.26)	0.739	0.48 (0.34–0.68)	<0.001	0.50 (0.35–0.72)	<0.001
Unplanned revascularization	1.29 (1.04–1.59)	0.022	0.11 (0.07–0.18)	<0.001	0.09 (0.05–0.14)	<0.001
Hospitalization for HF	1.03 (0.83–1.29)	0.777	0.51 (0.38–0.67)	<0.001	0.49 (0.37–0.66)	<0.001

The adjusted model underwent inverse probability of treatment weighting (IPTW) adjustment and was subsequently adjusted for covariates that remained imbalanced after IPTW. aHR, adjusted hazard ratio; CI, confidence interval. Other abbreviations as in Tables 1–3.

Sensitivity Analysis

To explore the impact of the completeness of revascularization in the CTO-PCI group on the robustness of the patients’ long-term prognosis, we conducted an additional sensitivity analysis (Table 5). Compared with CTO-CABG, patients in the CTO-PCI group with a residual SYNTAX score >8 exhibited significantly higher adjusted risks of MACCE, MI, unplanned revascularization, and hospitalization for heart failure. This increased risk remained significant when comparing the CTO-PCI group with a residual SYNTAX score of ≤8 to the CTO-CABG group. In the subgroup analysis, no significant differences in survival benefits were observed among different subgroups resulting from the 2 distinct CTO revascularization strategies (Figure 3).

Table 5.

Sensitivity Analysis for Long-Term Clinical Outcomes for Patients Treated With CTO-PCI (Residual SYNTAX Score ≤8 or >8) and CTO-CABG

	CTO-PCI	CTO-CABG	Unadjusted HR (95% CI)	P value	aHR (95% CI)	P value
CTO-PCI (residual SYNTAX score ≤8) vs. CTO-CABG
n	168	222
All-cause mortality	26 (15.48)	40 (18.02)	0.92 (0.56–1.51)	0.741	1.11 (0.79–1.56)	0.558
MACCE	69 (41.07)	56 (25.23)	1.99 (1.39–2.86)	<0.001	1.75 (1.37–2.22)	<0.001
Cardiovascular mortality	20 (11.90)	23 (10.36)	1.21 (0.66–2.22)	0.530	1.18 (0.78–1.80)	0.432
Stroke	6 (3.57)	10 (4.50)	0.88 (0.32–2.45)	0.808	1.39 (0.70–2.76)	0.349
MI	18 (10.71)	13 (5.86)	1.98 (0.96–4.09)	0.063	1.90 (1.20–2.99)	0.006
Unplanned revascularization	35 (20.83)	5 (2.25)	11.71 (4.47–30.68)	<0.001	10.44 (5.99–18.20)	<0.001
Hospitalization for HF	28 (16.67)	24 (10.81)	2.03 (1.15–3.56)	0.014	1.74 (1.20–2.55)	0.004
CTO-PCI (residual SYNTAX score >8) vs. CTO-CABG
n	109	222
All-cause mortality	20 (18.35)	40 (18.02)	1.15 (0.67–1.97)	0.614	1.24 (0.90–1.70)	0.193
MACCE	55 (50.46)	56 (25.23)	2.63 (1.80–3.83)	<0.001	2.50 (2.00–3.12)	<0.001
Cardiovascular mortality	14 (12.84)	23 (10.36)	1.36 (0.70–2.66)	0.365	1.31 (0.88–1.95)	0.178
Stroke	1 (0.92)	10 (4.50)	0.24 (0.03–1.88)	0.174	0.40 (0.15–1.08)	0.070
MI	16 (14.68)	13 (5.86)	2.93 (1.40–6.13)	0.004	2.18 (1.43–3.32)	<0.001
Unplanned revascularization	31 (28.44)	5 (2.25)	15.01 (5.82–38.71)	<0.001	12.28 (7.28–20.69)	<0.001
Hospitalization for HF	23 (21.10)	24 (10.81)	2.54 (1.42–4.54)	0.002	3.27 (2.31–4.64)	<0.001

The adjusted model underwent IPTW adjustment and was subsequently adjusted for covariates that remained imbalanced after IPTW. HR, hazard ratio. Other abbreviations as in Tables 1–4.

Figure 3.

Interaction between treatment assignment and various subgroups for the primary endpoint. CABG, coronary artery bypass grafting; CI, confidence interval; CTO, chronic total occlusion; HR, hazard ratio; LAD, left anterior descending artery; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention.

Discussion

In this large retrospective study, we compared prognostic differences in patients with CTO and LVSD between different treatment strategies, namely CTO-PCI, CTO-CABG, and CTO-MT. The main findings are as follows: (1) patients with CTO and LVSD frequently presented with more adverse clinical comorbidities and a higher complexity of coronary artery lesions; (2) over a median follow-up of 5.3 years, the mortality rate was 23.5%, with patients without successful CTO revascularization having the worst long-term survival and those undergoing successful CTO-PCI and CTO-CABG having comparable long-term mortality risks; and (3) compared with CTO-PCI, CTO-CABG was associated with lower long-term risks of MACCE, MI, unplanned revascularization, and hospitalization for heart failure.

Coronary Revascularization in Patients With LVSD

Advancements in the treatment of coronary artery disease (CAD) have led to increased survival rates. However, factors such as left ventricular remodeling and chronic cardiac dysfunction, which often accompany CAD, have resulted in a growing population of patients with LVSD and CAD.²⁴ According to current guidelines,^13,25 CABG is the preferred revascularization strategy for these patients, driven primarily by STICHES.¹¹ In STICHES, patients with LVSD who were randomized to receive CABG plus MT had significantly lower rates of all-cause death, cardiovascular death, and death from any cause or hospitalization for cardiovascular causes over a median follow-up of 9.8 years compared with those who received MT alone.¹¹ When considered alongside the previously published results of Surgical Treatment for Ischemic Heart Failure (STICH) trial, it becomes apparent that CABG is linked to higher early postoperative mortality.²⁶ However, as the follow-up period was extended in STICH, the survival curves started to diverge, demonstrating an increased survival benefit of at least 10 years.²⁶ Because the survival benefits of CABG depend on many years of life expectancy, the higher incidence of adverse events in the short term after CABG may be unfavorable for elderly patients. Based on this theory, a machine-learning causal forest model using the STICHES database was developed to explore heterogeneous treatment effects.²⁷ In that post hoc analysis, CABG was associated with a significant reduction in the risk of all-cause death (adjusted HR 0.61; 95% CI 0.45–0.84) and cardiovascular death (adjusted HR 0.63; 95% CI 0.45–0.89) only among patients with a left ventricular end-systolic volume index >84 mL/m² and age ≤60.27 years.²⁷

An important theory proposed by the STICH series of studies is that restoring blood flow to a viable but hypoperfused myocardium can reverse left ventricular dysfunction and further improve survival.¹¹ This concept sparks fresh perspectives: as an alternative revascularization method, can PCI bring similar clinical benefits as CABG? Therefore, the REVIVED-BCIS2 trial was initiated to investigate whether PCI plus optimal MT can improve the prognosis of patients with LVSD. Regrettably, over the median 41-month follow-up, PCI failed to demonstrate a reduction in the incidence of all-cause mortality or hospitalization for heart failure.¹²

Although STICH and REVIVED-BCIS2 are the largest randomized controlled trials evaluating revascularization benefits for LVSD, a direct comparison between CABG and PCI remains elusive because of the heterogeneity of study designs. Unfortunately, there is currently no available information from randomized controlled trials comparing long-term prognostic differences between patients with LVSD randomly assigned to CABG or PCI. To remedy this, Pathak et al.²⁸ constructed an in silico model by matching data from the STICH trial and the Hospital Episodes Statistics in England. In that study, Pathak et al. revealed that for patients with LVSD, CABG was associated with significantly lower rates of 5-year all-cause mortality or cardiovascular hospitalization than PCI.²⁸ A meta-analysis of 14 studies (11 observational studies, 3 randomized controlled trials) using Kaplan-Meier reconstructed individual patient data found that the CABG group exhibited lower rates of all-cause mortality, repeated revascularization, and MI compared with the PCI group; the incidence of cardiovascular mortality and stroke was comparable between the groups.²⁹

In summary, most current studies indicate that CABG is superior to PCI in terms of the long-term prognosis of patients with LVSD.

Coronary Revascularization in Patients With CTO and LVSD

Patients with CTO and LVSD often have more severe comorbidities, higher surgical risks, and poor prognosis.^7–9,30,31 The presence of CTO introduces additional uncertainty in revascularization. Despite the notable enhancement in the success rate of CTO-PCI, the procedure does not always constitute an appropriate intervention across all clinical scenarios.^32,33 Currently, the average LVEF of patients in randomized controlled trials comparing the efficacy of CTO-PCI and MT is 53%, without further subgroup analysis conducted for LVSD.⁵ Consequently, it is difficult to generalize the findings of these trials to patients with CTO and LVSD. Several observational studies have explored the prognostic impact of revascularization in this specific patient population. Pinto et al.³⁴ compared the long-term prognosis of patients with CTO and LVSD who underwent CTO-PCI or MT and found that CTO-PCI significantly reduced the risk of all-cause or cardiac mortality over a 100-month follow-up period. Similarly, Wu et al.³⁵ confirmed that CTO-PCI significantly reduced the incidence of all-cause mortality, cardiac mortality, MACCE, heart failure, and rehospitalization compared with MT in patients with CTO and LVSD and significantly improved LVEF and symptoms. Kook et al.³⁶ also observed a significant decrease in the risk of all-cause and cardiac mortality among patients undergoing CTO-PCI compared with MT during follow-up. Moreover, patients with LVSD gain more survival benefits from revascularization than those with preserved left ventricular function. A small-scale study that included 256 patients investigated the prognostic differences between CTO revascularization and MT in patients with CTO and LVSD.³⁰ Over a mean follow-up period of 1,129 days, it was observed that the CTO-MT group had the worst survival rates, whereas CTO revascularization was associated with lower incidence rates of MACE, all-cause mortality, and cardiac mortality.³⁰ In multivariate analysis, CTO-CABG was independently associated with a lower risk of all-cause and cardiac mortality.³⁰ Our study confirmed that successful CTO revascularization can significantly reduce the risk of all-cause and cardiovascular mortality over a median 5.3-year follow-up period in patients with CTO and LVSD.

Advantages of CABG in Coronary Revascularization

There are several possible reasons why CABG is associated with a greater survival benefit than PCI. First, bypass grafts provide direct blood supply distal to the lesion, thereby minimizing the risk of ischemia caused by the progression of proximal lesions. This beneficial mechanism is completely different from that of PCI.²⁵ Furthermore, CABG is more likely to achieve complete revascularization than PCI, because CABG targets both flow-limiting and non-flow-limiting stenoses, which may constitute potential factors for future MI.³⁷ However, achieving complete revascularization through PCI can be challenging, particularly in patients with CTO. The SYNTAX trial confirmed that total occlusion was the strongest independent predictor of incomplete revascularization following PCI, with a significant adverse effect on the long-term prognosis.³⁸ A residual SYNTAX score ≤8 is defined as reasonable incomplete revascularization and has been observed to achieve long-term survival similar to that of patients undergoing CABG.^37,39 Nevertheless, in our study, the long-term prognosis of patients with CTO and LVSD in the CTO-PCI group was inferior to that of patients with CTO-CABG, even with reasonable incomplete revascularization. It is crucial to recognize that performing CTO-PCI in patients with LVSD can be challenging, because these patients often have numerous comorbidities and a risk of hemodynamic instability, making them less tolerant of complex procedures and procedure-related ischemic stress. If achieving complete revascularization through PCI is expected to be challenging, direct referral to a cardiac surgery team can be an effective option for reducing the risk of MACCE.³⁷

Although complex guidewire-crossing techniques are not encountered in CTO-CABG as in CTO-PCI, certain adverse characteristics of CTO-CABG still pose challenges to surgical revascularization for CTO. First is the presence of a poor landing zone, which is common in vessels distal to a CTO.⁴⁰ Second is the negative remodeling that occurs after restoring blood flow to the distal of CTO, which has a certain adverse effect on graft patency.⁶ Third is the fact that transplantation of a bypass graft to the distal lesion may accelerate the progression of native CAD, even developing into CTO. Studies have confirmed that both preexisting and new CTOs following CABG significantly increase the risk of mortality, MI, and repeated revascularization.⁴¹ According to 10-year follow-up data from the Canadian CTO registry, CTO revascularization significantly reduced 10-year mortality, revascularization, and hospitalization for acute coronary syndrome compared with MT, although it did not affect hospitalization for heart failure.² In the time-varying analysis, CABG of the CTO artery provided more significant survival benefits than PCI for CTO.² Currently, there are few studies on CTO-CABG. In our study population of CTO and LVSD, CTO-CABG was associated with reduced risks of MACCE, MI, unplanned revascularization, and hospitalization for heart failure over a median 5.3-year follow-up period compared with CTO-PCI.

Study Limitations

This study has some limitations. First, although IPTW was performed to minimize selection bias, there were still some unmeasured potential factors in this retrospective study that influenced the decision regarding treatment strategy. Second, patients with certain major diseases, such as cancer or frailty, were neither identified nor excluded from the study, potentially affecting outcomes. Third, this study was conducted in a high-volume cardiac center in China; therefore, the findings may not be fully generalizable to different institutions in other regions. Fourth, due to the absence of data collection on myocardial viability testing, differences in long-term clinical outcomes based on viability could not be evaluated.

Conclusions

This large-scale, long-term follow-up observational cohort study compared the prognostic impact of CTO-PCI, CTO-CABG, and CTO-MT in patients with CTO and LVSD. Over a median follow-up of 5.3 years, significant survival improvement was observed for successful CTO revascularization, with CTO-CABG being associated with the lowest long-term all-cause mortality. Although CTO-PCI reduced the risk of cardiovascular mortality, it increased the incidence of unplanned revascularization. Conversely, CTO-CABG comprehensively reduced the risks of MACCE, cardiovascular mortality, MI, unplanned revascularization, and hospitalization for heart failure. In conclusion, CTO-CABG significantly improved the clinical outcomes of patients with CTO and LVSD. Future randomized studies are needed to further clarify the impact of different treatment strategies on clinical outcomes in this patient population and to ascertain the optimal management strategy for this high-risk group.

Acknowledgments

None.

Sources of Funding

The study was supported by the National Natural Science Foundation of China (81970291 and 82170344).

Disclosures

The authors declare that there are no conflicts of interest.

IRB Information

The study protocol was approved by the Ethics Committee of Beijing Anzhen Hospital (Approval no. 2023026X).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0655

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