Abstract
Background: Data on clinical outcomes after intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) in patients with multivessel disease and left ventricular (LV) dysfunction are scarce.
Methods and Results: The OPTIVUS-Complex PCI study multivessel cohort was a prospective multicenter single-arm trial enrolling 1,010 patients undergoing multivessel IVUS-guided PCI including left anterior descending coronary artery target with an intention to meet the prespecified OPTIVUS criteria for optimal stent expansion. We compared clinical outcomes between patients with and without LV dysfunction. The primary endpoint was a composite of death, myocardial infarction, stroke, any coronary revascularization, or hospitalization for heart failure. There were 763 patients (75.5%) with preserved LV function (LV ejection fraction [LVEF] >50%), 176 patients (17.4%) with moderate LV dysfunction (35<LVEF≤50%), and 71 patients (7.0%) with severe LV dysfunction (LVEF ≤35%). The cumulative 1-year incidence of the primary endpoint was 9.5%, 18.9%, and 17.1%, respectively, in patients with preserved LV function, moderate LV dysfunction, and severe LV dysfunction (log-rank P<0.001). After adjusting confounders, there was a significantly higher risk of moderate LV dysfunction and a numerically higher risk of severe LV dysfunction relative to preserved LV function for the primary endpoint (hazard ratio (HR), 1.71; 95% confidence interval (CI), 1.08–2.71; P=0.02; and HR, 1.52; 95% CI, 0.77–2.97; P=0.23).
Conclusions: Among patients undergoing multivessel IVUS-guided PCI with contemporary practice, 1-year clinical outcomes were worse in patients with LV dysfunction.
Coronary artery disease (CAD) is one of the most common causes of heart failure in real clinical practice.1 In patients with both CAD and left ventricular (LV) systolic dysfunction, coronary revascularization in addition to medical therapy is reported to improve mortality rates.2–5 In previous randomized clinical trials enrolling patients with CAD and severe LV dysfunction, coronary artery bypass grafting (CABG) reduced mortality rates compared with medical therapy alone, while percutaneous coronary intervention (PCI) compared with medical therapy alone failed to reduce cardiovascular outcomes.2,3,6 The optimal revascularization strategy in patients with multivessel disease and LV dysfunction is still unknown, because the previous randomized clinical trials comparing PCI with CABG in patients with multivessel disease included only a very small proportion of patients with LV dysfunction.7–9 In addition, intracoronary imaging such as intravascular ultrasound (IVUS) was only rarely used in the PCI arm in the previous randomized clinical trials comparing PCI with CABG or medical therapy alone.6–9 In the multivessel cohort of the OPTIVUS-Complex PCI (Optimal Intravascular Ultrasound Guided Complex Percutaneous Coronary Intervention) study, patients who underwent multivessel IVUS-guided PCI combined with contemporary PCI practice had significantly lower incidence of cardiovascular events than the predefined PCI performance goal, and had numerically lower incidence of cardiovascular events than the predefined CABG performance goal derived from the CREDO-Kyoto (Coronary REvascularization Demonstrating Outcome Study in Kyoto) registry.10 Because of the scarcity of data on clinical outcomes after optimal IVUS-guided PCI in patients with multivessel disease and LV dysfunction, we conducted the present study to compare clinical outcomes between those patients with and without LV dysfunction in the OPTIVUS-Complex PCI study multivessel cohort.
Methods
Study Population
The OPTIVUS-Complex PCI study multivessel cohort was a prospective multicenter single-arm trial that enrolled patients undergoing multivessel IVUS-guided PCI including a target lesion in the left anterior descending coronary artery. The exclusion criteria were patients with ST-segment elevation myocardial infarction, cardiogenic shock, and previous history of CABG. The design, patient enrollment, and main results at 1 year have been reported in detail.10 The study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. The study protocol was approved by the central review board, Kyoto University Certified Review Board, based on the enforcement of the Clinical Trials Act in Japan. Written informed consent was obtained from all enrolled patients.
Between March 2019 and April 2021, 1,023 patients who underwent IVUS-guided multivessel PCI were enrolled in 90 Japanese centers. The study population consisted of 1,010 patients after excluding 2 patients who withdrew consent, 4 patients for whom written informed consent documents were not retained, and 7 patients without information on baseline LV ejection fraction (LVEF) (Figure 1). We compared the clinical outcomes between those patients with and without LV dysfunction (preserved LV function: LVEF >50%, moderate LV dysfunction: 35<LVEF≤50%, and severe LV dysfunction: LVEF ≤35%). LVEF was measured either by echocardiography or contrast left ventriculography.
Study Procedures and OPTIVUS Criteria
The PCI operators were mandated to perform optimal IVUS-guided PCI to meet the prespecified criteria (OPTIVUS criteria) for optimal stent implantation. The details of the study procedures and the definitions of the OPTIVUS criteria are described in the Supplementary File. The key criteria for stent expansion were: minimum stent area > the distal reference lumen area if the stent length ≥28 mm, and minimum stent area >0.8*average reference lumen area if the stent length <28 mm. Quantitative and qualitative coronary angiography analyses were to be performed for all target lesions, and IVUS analysis was performed for all target lesions with stenting by an independent core laboratory (Cardiocore, Tokyo, Japan).
In addition to the IVUS-related recommendations, there were other recommendations to adopt contemporary clinical, procedural, and pharmacological practices. Target lesions were to be selected based on a stress imaging or physiological assessment (fractional flow reserve or instantaneous wave-free ratio). Radial access was recommended as the standard approach. PCI for chronic total occlusion was to be performed only by a dedicated operator. Use of rotational atherectomy in severely calcified lesions was recommended, and the proximal optimization technique was recommended for bifurcation lesions. Kissing balloon inflation was recommended if bifurcation lesions were treated with a 2-stent technique. Scheduled follow-up coronary angiography after PCI was discouraged in asymptomatic patients. Recommended pharmacologic management included use of high-intensity statin therapy with the maximum approved dose of strong statins in Japan, and short duration (3–6 months) of dual antiplatelet therapy (DAPT) after PCI.
Endpoints
The primary endpoint was major adverse cardiac and cerebrovascular events defined as a composite of all-cause death, myocardial infarction, stroke, any coronary revascularization, or hospitalization for heart failure. Myocardial infarction was adjudicated according to the Academic Research Consortium definition.11 Stroke was defined as ischemic or hemorrhagic stroke with neurological symptoms lasting >24 h. Hospitalization for heart failure was defined as hospitalization due to worsening heart failure requiring intravenous drug therapy. The definitions of secondary endpoints are described in the Supplementary File. All endpoints were assessed at 1 year (between 335 and 394 days), with censoring on day 366. All clinical events comprising the primary endpoint were adjudicated based on the source documents by an independent clinical event committee.
Statistical Analysis
Categorical variables are presented as number and percentage and compared with the chi-square test. Continuous variables were expressed as mean±standard deviation or median with interquartile range and were compared using analysis of variance or Kruskal-Wallis test depending on their distribution. The cumulative incidence was estimated with the Kaplan-Meier method, and the difference was compared with the log-rank test. The risks of moderate LV or severe LV dysfunction relative to preserved LV function for the primary endpoint were expressed as hazard ratios (HRs) and their 95% confidence intervals (CIs) estimated by the Cox proportional hazard models, adjusting for 16 clinically relevant factors (age ≥75 years, male sex, body mass index <25.0 kg/m2, acute coronary syndrome, hypertension, diabetes, mitral regurgitation grade ≥3/4, prior myocardial infarction, estimated glomerular filtration rate <30 mL/min/1.73 m2
or hemodialysis, hemoglobin <11.0 g/dL, severe frailty, 3-vessel disease, target of chronic total occlusion, β-blockers, renin-angiotensin system inhibitors [RASi], and sodium-glucose cotransporter-2 [SGLT2] inhibitors), which were selected based on clinical relevance and consistency with previous studies from the OPTIVUS-Complex PCI study multivessel cohort.10,12 In the Cox proportional hazard models, we developed dummy code variables for moderate and severe LV dysfunction, with preserved LV function as the reference.
All P values were two-sided and P<0.05 was considered statistically significant. All analyses were performed with R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Study Population
In the present study population, the mean LVEF was 57.7%. There were 763 patients with preserved LV function (75.5%), 176 patients with moderate LV dysfunction (17.4%), and 71 patients with severe LV dysfunction (7.0%) (Figure 1). The mean LVEF was 63.4% in patients with preserved LV function, 44.3% in patients with moderate LV dysfunction, and 29.0% in patients with severe LV dysfunction (Table 1). The prevalence of prior hospitalization for heart failure and current heart failure at index hospitalization was 4.6% and 5.2% in patients with preserved LV function, 19.9% and 28.4% in patients with moderate LV dysfunction, and 23.9% and 60.6% in patients with severe LV dysfunction (Table 1).
Table 1.
Baseline Characteristics (per Patient Basis)
| |
Preserved LV
function
(LVEF >50%)
(N=763) |
Moderate LV
dysfunction
(35<LVEF≤50%)
(N=176) |
Severe LV
dysfunction
(LVEF ≤35%)
(N=71) |
P value |
| Clinical characteristics |
| Age (years) |
71.3±9.6 |
70.5±11.4 |
72.0±11.1 |
0.50 |
| ≥75 |
316 (41.4) |
73 (41.5) |
34 (47.9) |
0.57 |
| Men |
594 (77.9) |
138 (78.4) |
62 (87.3) |
0.18 |
| Body mass index (kg/m2) |
24.3±3.4 |
23.6±3.8 |
23.5±3.9 |
0.02 |
| <25.0 |
478 (62.6) |
129 (73.3) |
52 (73.2) |
0.01 |
| Acute coronary syndrome |
115 (15.1) |
23 (13.1) |
6 (8.5) |
0.28 |
| Acute MI |
50 (6.6) |
12 (6.8) |
5 (7.0) |
|
| Unstable angina |
65 (8.5) |
11 (6.2) |
1 (1.4) |
|
| Hypertension |
637 (83.5) |
160 (90.9) |
56 (78.9) |
0.02 |
| Diabetes |
405 (53.1) |
107 (60.8) |
42 (59.2) |
0.14 |
| On insulin |
61 (8.0) |
24 (13.6) |
8 (11.3) |
|
| Current smoking |
129 (16.9) |
33 (18.8) |
13 (18.3) |
0.82 |
| HF |
61 (8.0) |
68 (38.6) |
49 (69.0) |
<0.001 |
| Prior hospitalization for HF |
35 (4.6) |
35 (19.9) |
17 (23.9) |
|
| Current HF at index hospitalization |
40 (5.2) |
50 (28.4) |
43 (60.6) |
|
| LVEF (%) |
63.4±6.5 |
44.3±4.3 |
29.0±5.0 |
– |
| Mitral regurgitation grade ≥3/4 |
8 (1.0) |
13 (7.4) |
9 (12.7) |
<0.001 |
| Prior MI |
106 (13.9) |
55 (31.2) |
19 (26.8) |
<0.001 |
| Prior stroke |
86 (11.3) |
25 (14.2) |
8 (11.3) |
0.55 |
| Peripheral vascular disease |
89 (11.7) |
21 (11.9) |
4 (5.6) |
0.29 |
| eGFR <30 mL/min/1.73 m2 or hemodialysis |
51 (6.7) |
31 (17.6) |
14 (19.7) |
<0.001 |
| Hemodialysis |
34 (4.5) |
21 (11.9) |
4 (5.6) |
|
| Atrial fibrillation |
64 (8.4) |
18 (10.2) |
3 (4.2) |
0.31 |
| Anemia (hemoglobin <11.0 g/dL) |
58 (7.6) |
27 (15.3) |
11 (15.5) |
0.001 |
| Thrombocytopenia (platelets <100×109/L) |
5 (0.7) |
5 (2.8) |
0 (0.0) |
0.02 |
| Malignancy |
102 (13.4) |
14 (8.0) |
9 (12.7) |
0.14 |
| Severe frailty |
21 (2.8) |
14 (8.0) |
4 (5.6) |
0.004 |
| ARC-HBR |
385 (50.5) |
102 (58.0) |
47 (66.2) |
0.01 |
| Procedural characteristics |
| IVUS use |
763 (100.0) |
176 (100.0) |
71 (100.0) |
– |
| Radial artery approach |
686 (89.9) |
139 (79.0) |
59 (83.1) |
<0.001 |
| Extent of coronary artery disease |
|
|
|
0.25 |
| 2-vessel disease |
610 (79.9) |
142 (80.7) |
51 (71.8) |
|
| 3-vessel disease |
153 (20.1) |
34 (19.3) |
20 (28.2) |
|
| SYNTAX score |
16.0 (12.0–21.0) |
19.0 (15.0–24.0) |
20.0 (14.5–28.0) |
<0.001 |
| Low <23 |
615 (81.6) |
124 (70.9) |
45 (63.4) |
<0.001 |
| Intermediate 23–32 |
118 (15.6) |
40 (22.9) |
14 (19.7) |
|
| High ≥33 |
21 (2.8) |
11 (6.3) |
12 (16.9) |
|
| No. of target lesions |
2.0 (2.0–3.0) |
2.0 (2.0–3.0) |
2.0 (2.0–3.0) |
0.17 |
| Total no. of stents |
3.0 (2.0–4.0) |
3.0 (2.0–4.0) |
3.0 (2.0–4.0) |
0.048 |
| Total stent length (mm) |
72.0 (52.5–96.0) |
80.5 (56.0–104.0) |
77.0 (56.0–103.0) |
0.051 |
| Target of proximal LAD |
754 (98.8) |
174 (98.9) |
70 (98.6) |
0.98 |
| Target of chronic total occlusion |
85 (11.1) |
43 (24.4) |
22 (31.0) |
<0.001 |
| Target of bifurcation |
456 (59.8) |
115 (65.3) |
38 (53.5) |
0.19 |
| Bifurcation with 2 stents |
16 (2.1) |
4 (2.3) |
2 (2.8) |
0.92 |
| Staged PCI |
589 (77.2) |
126 (71.6) |
58 (81.7) |
0.16 |
| OPTIVUS criteria |
|
|
|
1.00 |
| Met in all stented lesions |
295 (40.2) |
68 (40.0) |
26 (38.2) |
|
| Not met in some lesion(s) |
299 (40.8) |
70 (41.2) |
28 (41.2) |
|
| Not met in any lesion |
139 (19.0) |
32 (18.8) |
14 (20.6) |
|
| Baseline medications |
| P2Y12 inhibitors |
760 (99.6) |
176 (100.0) |
71 (100.0) |
0.61 |
| Clopidogrel |
411 (53.9) |
106 (60.2) |
42 (59.2) |
|
| Prasugrel |
348 (45.6) |
68 (38.6) |
29 (40.8) |
|
| Aspirin |
725 (95.0) |
158 (89.8) |
66 (93.0) |
0.03 |
| Statins |
706 (92.5) |
158 (89.8) |
64 (90.1) |
0.41 |
| High-intensity statins |
278 (36.4) |
68 (38.6) |
24 (33.8) |
0.76 |
| β-blockers |
275 (36.0) |
118 (67.0) |
60 (84.5) |
<0.001 |
| Renin-angiotensin system inhibitors |
420 (55.0) |
105 (59.7) |
55 (77.5) |
0.001 |
| Sodium-glucose cotransporter-2 inhibitors |
92 (12.1) |
28 (15.9) |
15 (21.1) |
0.06 |
| Calcium-channel blockers |
353 (46.3) |
68 (38.6) |
20 (28.2) |
0.004 |
| Oral anticoagulants |
61 (8.0) |
25 (14.2) |
13 (18.3) |
0.002 |
| Warfarin |
8 (1.0) |
3 (1.7) |
8 (11.3) |
|
| Direct oral anticoagulants |
53 (6.9) |
22 (12.5) |
5 (7.0) |
|
| Proton pump inhibitors |
657 (86.1) |
147 (83.5) |
63 (88.7) |
0.52 |
Categorical variables are presented as number and percentage. Continuous variables are presented as mean±standard deviation or median with interquartile range. Data were missing for SYNTAX score in 10 patients. ARC-HBR, Academic Research Consortium for High Bleeding Risk; eGFR, estimated glomerular filtration rate; HF, heart failure; IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LV, left ventricle; LVEF, left ventricular ejection fraction; MI, myocardial infarction; OPTIVUS, OPTimal IntraVascular UltraSound; PCI, percutaneous coronary intervention; SYNTAX, synergy between percutaneous coronary intervention with taxus and cardiac surgery.
Baseline Characteristics
As per patient analyses, patients with LV dysfunction more often had low body weight and comorbidities such as hypertension, mitral regurgitation, history of myocardial infarction, chronic kidney disease, anemia, thrombocytopenia, and frailty compared with those without (Table 1). Regarding the procedural characteristics, the radial approach was less often used in patients with LV dysfunction than in those without. Patients with LV dysfunction compared with those without had greater coronary anatomical complexity as indicated by higher SYNTAX score and higher prevalence of chronic total occlusion target. The rate of meeting OPTIVUS criteria was not different between patients with and without LV dysfunction. In terms of baseline medications, the prescription rates of β-blockers, RASi, and oral anticoagulants were higher in patients with LV dysfunction than in those without, while that of calcium-channel blockers was lower in patients with LV dysfunction than in those without. The prescription rate of SGLT2 inhibitors was numerically higher in patients with LV dysfunction than in those without.
Angiographic, IVUS and Procedural Characteristics
As per lesion analyses on angiography, patients with LV dysfunction compared with those without had longer lesion length, smaller minimum lumen area, and higher percent diameter stenosis (Table 2). The prevalence of total occlusion and moderate or severe calcification was higher in patients with LV dysfunction than in those without. The rate of orbital atherectomy use was higher in patients with LV dysfunction than in those without. In the postprocedural IVUS analysis of stented lesions, the proximal reference lumen area, minimum stent area, distal reference lumen area, and the rate of meeting OPTIVUS criteria were not different between patients with and without LV dysfunction. The rates of thrombus or protrusion and incomplete stent apposition were higher in patients with LV dysfunction than in those without.
Table 2.
Angiographic, Procedural, and IVUS Characteristics (per Lesion Basis)
| |
Preserved LV function
(LVEF >50%) (no. of
targetlesions=1,922) |
Moderate LV dysfunction
(35<LVEF≤50%) (no. of
target lesions=453) |
Severe LV dysfunction
(LVEF ≤35%) (no. of
target lesions=195) |
P value |
| Angiographic and procedural characteristics |
No. of lesions with angiographic evaluation
in the core angiographic laboratory |
1,713 |
398 |
164 |
|
| Preprocedure |
| Lesion length (mm) |
23.1±13.1 |
25.6±15.5 |
23.6±15.5 |
0.01 |
| Reference vessel diameter (mm) |
2.6±0.6 |
2.6±0.5 |
2.7±0.6 |
0.10 |
| Minimum lumen diameter (mm) |
0.8±0.4 |
0.7±0.4 |
0.7±0.5 |
<0.001 |
| Percent diameter stenosis (%) |
67.6±13.4 |
71.4±15.5 |
73.6±15.5 |
<0.001 |
| Thrombus |
38 (2.2) |
12 (3.0) |
3 (1.8) |
0.58 |
| Total occlusion |
96 (5.6) |
50 (12.6) |
27 (16.5) |
<0.001 |
| In-stent restenosis |
59 (3.4) |
16 (4.0) |
6 (3.7) |
0.86 |
| Bifurcation |
812 (47.5) |
192 (48.2) |
75 (45.7) |
0.86 |
| Moderate or severe calcification |
518 (30.3) |
139 (34.9) |
62 (37.8) |
0.04 |
| Index procedure |
| Stent use |
1,773 (92.2) |
413 (91.2) |
168 (86.2) |
0.01 |
| No. of stents used per lesion |
1.0 (1.0–1.0) |
1.0 (1.0–2.0) |
1.0 (1.0–2.0) |
0.03 |
| Stent length per lesion (mm) |
30.0 (20.0–38.0) |
32.0 (20.0–48.0) |
28.0 (20.0–38.0) |
0.12 |
| Cutting or scoring balloon use |
660 (34.3) |
142 (31.3) |
76 (39.0) |
0.16 |
| Rotational atherectomy use |
117 (6.1) |
36 (7.9) |
17 (8.7) |
0.17 |
| Orbital atherectomy use |
30 (1.6) |
4 (0.9) |
8 (4.1) |
0.01 |
| Direct stenting |
141 (8.0) |
29 (7.0) |
13 (7.7) |
0.81 |
| Maximum stent inflation pressure (atm) |
12.7±3.1 |
12.9±3.3 |
13.0±3.5 |
0.18 |
| Postdilatation |
1,373 (77.5) |
321 (77.7) |
124 (73.8) |
0.53 |
| Maximum balloon size (mm) |
3.2±0.6 |
3.2±0.6 |
3.2±0.6 |
0.80 |
Maximum balloon inflation pressure
(atm) |
17.9±4.2 |
18.3±4.6 |
18.5±4.1 |
0.13 |
| Postprocedure |
| Minimum lumen diameter (mm) |
| In-stent |
2.5±0.5 |
2.5±0.4 |
2.5±0.4 |
0.97 |
| In-segment |
2.2±0.6 |
2.2±0.6 |
2.1±0.6 |
0.07 |
| Percent diameter stenosis |
| In-stent |
14.3±6.8 |
14.7±6.7 |
15.7±6.7 |
0.03 |
| In-segment |
23.2±9.5 |
25.1±11.2 |
25.9±11.3 |
<0.001 |
| Acute gain (mm) |
| In-stent |
1.7±0.5 |
1.8±0.5 |
1.8±0.5 |
<0.001 |
| In-segment |
1.4±0.5 |
1.4±0.6 |
1.4±0.5 |
0.20 |
| Procedural complications |
53 (2.8) |
18 (4.0) |
4 (2.1) |
0.29 |
Side branch occlusion (post TIMI
grade ≤2) |
18 (0.9) |
4 (0.9) |
1 (0.5) |
|
| Slow flow |
24 (1.2) |
11 (2.4) |
1 (0.5) |
|
| Acute occlusion |
5 (0.3) |
1 (0.2) |
0 (0.0) |
|
| Perforation |
9 (0.5) |
3 (0.7) |
1 (0.5) |
|
| Cardiac tamponade |
0 (0.0) |
0 (0.0) |
0 (0.0) |
|
| Stent dislodgement |
0 (0.0) |
0 (0.0) |
1 (0.5) |
|
| Stent thrombosis |
0 (0.0) |
0 (0.0) |
0 (0.0) |
|
| IVUS analysis postprocedure |
No. of lesions with IVUS evaluation in
the core IVUS laboratory |
1,527 |
361 |
135 |
|
| Proximal reference vessel area (mm2) |
15.9±5.5 |
16.5±5.6 |
16.6±6.6 |
0.18 |
| Proximal reference lumen area (mm2) |
8.2±3.3 |
8.5±3.5 |
8.3±3.5 |
0.49 |
| Minimum stent area (mm2) |
5.7±2.0 |
5.6±2.1 |
5.4±1.8 |
0.15 |
| Distal reference vessel area (mm2) |
9.8±5.0 |
9.7±5.3 |
10.0±5.6 |
0.80 |
| Distal reference lumen area (mm2) |
5.8±2.6 |
5.6±2.6 |
5.7±2.9 |
0.35 |
| Thrombus or protrusion |
200 (13.1) |
34 (9.4) |
24 (17.8) |
0.03 |
| Incomplete stent apposition |
524 (34.3) |
158 (43.8) |
52 (38.5) |
0.003 |
| Dissection |
75 (4.9) |
14 (3.9) |
7 (5.2) |
0.69 |
| Meeting OPTIVUS criteria |
930 (60.9) |
222 (61.5) |
78 (58.2) |
0.79 |
| Stent length ≥28 mm |
486/906 (53.6) |
124/232 (53.5) |
45/77 (58.4) |
|
| Stent length <28 mm |
444/620 (71.6) |
98/129 (76.0) |
33/57 (57.9) |
|
Categorical variables are presented as number and percentage. Continuous variables are presented as mean±standard deviation or median with interquartile range. TIMI, Thrombolysis in Myocardial Infarction. Other abbreviations as in Table 1.
DAPT Discontinuation and Follow-up Coronary Angiography
The cumulative incidence of DAPT discontinuation was numerically higher in patients with LV dysfunction than in those without at both 60 and 180 days, but it was not different between patients with and without LV dysfunction at 1 year (preserved LV function, moderate LV dysfunction, and severe LV dysfunction, respectively: 15.9%, 22.2%, and 19.9% at 60 days, 35.3%, 43.8%, and 43.1% at 180 days, and 68.6%, 69.8%, and 69.4% at 1 year, log-rank P=0.52) (Supplementary Figure 1). The cumulative incidence of follow-up coronary angiography at 1 year was not different between patients with and without LV dysfunction (preserved LV function, moderate LV dysfunction, and severe LV dysfunction: 19.1%, 15.9%, and 14.5%, respectively; log-rank P=0.50) (Supplementary Figure 2A). The cumulative incidence of clinically driven follow-up coronary angiography at 1 year was also not different between patients with and without LV dysfunction (preserved LV function, moderate LV dysfunction, and severe LV dysfunction: 4.2%, 6.5%, and 7.2%, respectively; log-rank P=0.30), while that of scheduled follow-up coronary angiography at 1 year was numerically lower in patients with LV dysfunction than in those without (preserved LV function, moderate LV dysfunction, and severe LV dysfunction: 14.1%, 9.4%, and 7.3%, respectively; log-rank P=0.12) (Supplementary Figure 2B,C).
Clinical Outcomes
The cumulative 1-year incidence of the primary endpoint was higher in patients with LV dysfunction than in those without (preserved LV function, moderate LV dysfunction, and severe LV dysfunction: 9.5%, 18.9%, and 17.1%, respectively; log-rank P<0.001) (Table 3, Figure 2). Even after adjusting for confounders, the risk of moderate LV dysfunction relative to preserved LV function was significantly higher for the primary endpoint (adjusted HR, 1.71; 95% CI, 1.08–2.71; P=0.02), and the risk of severe LV dysfunction relative to preserved LV function was numerically higher for the primary endpoint (adjusted HR, 1.52; 95% CI, 0.77–2.97; P=0.23) (Table 4). The cumulative 1-year incidences of all-cause death, cardiovascular death, myocardial infarction, hemorrhagic stroke, and hospitalization for heart failure were higher in patients with LV dysfunction than in those without (Table 3).
Table 3.
Clinical Outcomes
| |
Preserved LV function
(LVEF >50%) (N=763) |
Moderate LV dysfunction
(35<LVEF≤50%) (N=176) |
Severe LV dysfunction
(LVEF ≤35%) (N=71) |
Log-rank
P value |
| No. of patients with event (cumulative incidence at 1 year) |
| Primary endpoint |
Composite of all-cause death, MI,
stroke, any coronary revascularization,
or hospitalization for HF |
72 (9.5%) |
33 (18.9%) |
12 (17.1%) |
0.001 |
| Secondary endpoints |
| All-cause death |
11 (1.4%) |
7 (4.0%) |
4 (5.7%) |
0.01 |
| Cardiovascular death |
3 (0.4%) |
3 (1.7%) |
3 (4.3%) |
0.002 |
| Cardiac death |
1 (0.1%) |
3 (1.7%) |
3 (4.3%) |
<0.001 |
| Sudden cardiac death |
0 (0.0%) |
2 (1.1%) |
1 (1.5%) |
0.01 |
| Noncardiovascular death |
8 (1.1%) |
4 (2.4%) |
1 (1.4%) |
0.41 |
| MI |
6 (0.8%) |
5 (2.9%) |
2 (2.9%) |
0.04 |
| Spontaneous |
1 (0.1%) |
2 (1.2%) |
2 (2.9%) |
0.003 |
| Periprocedural |
5 (0.7%) |
3 (1.7%) |
0 (0.0%) |
0.27 |
| Definite stent thrombosis |
1 (0.1%) |
1 (0.6%) |
0 (0.0%) |
0.45 |
| Stroke |
3 (0.4%) |
2 (1.2%) |
1 (1.4%) |
0.32 |
| Ischemic stroke |
2 (0.3%) |
2 (1.2%) |
0 (0.0%) |
0.21 |
| Hemorrhagic stroke |
1 (0.1%) |
0 (0.0%) |
1 (1.4%) |
0.048 |
| Major stroke |
3 (0.4%) |
1 (0.6%) |
1 (1.4%) |
0.48 |
| Hospitalization for heart failure |
6 (0.8%) |
7 (4.0%) |
5 (7.3%) |
<0.001 |
| Major bleeding |
| BARC type 3, 4, or 5 |
23 (3.0%) |
9 (5.2%) |
4 (5.8%) |
0.24 |
| BARC type 3 or 5 |
23 (3.0%) |
9 (5.2%) |
3 (4.4%) |
0.35 |
| BARC type 5 |
0 (0.0%) |
0 (0.0%) |
0 (0.0%) |
NA |
| Target-lesion revascularization |
28 (3.7%) |
12 (7.1%) |
3 (4.4%) |
0.16 |
Clinically driven target-lesion
revascularization |
27 (3.6%) |
12 (7.1%) |
3 (4.4%) |
0.13 |
| Target-vessel revascularization |
42 (5.6%) |
13 (7.6%) |
5 (7.3%) |
0.54 |
Clinically driven target-vessel
revascularization |
41 (5.4%) |
13 (7.6%) |
5 (7.3%) |
0.49 |
| Any coronary revascularization |
50 (6.6%) |
15 (8.8%) |
5 (7.3%) |
0.61 |
Clinically driven any coronary
revascularization |
49 (6.5%) |
15 (8.8%) |
5 (7.3%) |
0.57 |
| Composite of death, MI, or stroke |
20 (2.6%) |
14 (8.0%) |
7 (10.0%) |
<0.001 |
Composite of death, MI, stroke, or any
coronary revascularization |
68 (8.9%) |
27 (15.5%) |
9 (12.9%) |
0.03 |
The cumulative 1-year incidence was estimated by Kaplan-Meier method, and the difference was compared with the log-rank test. BARC, Bleeding Academic Research Consortium. Other abbreviations as in Table 1.
Table 4.
Cox Proportional Hazard Model for the Primary Endpoint
| |
Crude HR
(95% CI) |
P value |
Adjusted HR
(95% CI) |
P value |
| Primary endpoint |
Composite of death, MI, stroke, any
coronary revascularization, or
hospitalization for HF |
Preserved LV function |
Ref. |
|
Ref. |
|
| Moderate LV dysfunction |
2.10 (1.39–3.18) |
<0.001 |
1.71 (1.08–2.71) |
0.02 |
| Severe LV dysfunction |
1.89 (1.03–3.49) |
0.04 |
1.52 (0.77–2.97) |
0.23 |
The risks of moderate LV dysfunction and severe LV dysfunction relative to preserved LV function for the primary endpoint are expressed as HRs and their 95% CIs estimated by the Cox proportional hazard models, adjusting for 16 clinically relevant factors (age ≥75 years, male sex, body mass index <25.0 kg/m2, acute coronary syndrome, hypertension, diabetes, mitral regurgitation grade ≥3/4, prior MI, eGFR <30 mL/min/1.73 m2 or hemodialysis, hemoglobin <11.0 g/dL, severe frailty, 3-vessel disease, target of chronic total occlusion, β-blockers, renin-angiotensin system inhibitors, and sodium-glucose cotransporter-2 inhibitors). In the Cox proportional hazard models, we developed dummy code variables for moderate LV dysfunction and severe LV dysfunction with preserved LV function as the reference. CI, confidence intervals; HR, hazard ratio. Other abbreviations as in Table 1.
Discussion
The main finding of the present study was that among patients who underwent multivessel IVUS-guided PCI, and were managed with contemporary PCI practice, 1-year clinical outcomes were worse in patients with LV dysfunction.
The STICH (Surgical Treatment for Ischemic Heart Failure) trial enrolling patients with CAD and severe LV dysfunction (LVEF ≤35%), CABG compared with medical therapy alone did not reduce the mortality rate at 5-year follow-up, but did reduced it at the 10-year follow-up.2,3 On the other hand, the REVIVED (Revascularization for Ischemic Ventricular Dysfunction) trial enrolling patients with extensive CAD and severe LV dysfunction (LVEF ≤35%), PCI with medical therapy compared with medical therapy alone failed to reduce the primary cardiovascular outcome during a median follow-up of 3.4 years.6 Previous randomized clinical trials comparing PCI with CABG in patients with multivessel disease have included only a very small proportion of patients with LV dysfunction.7–9 In terms of observational studies comparing PCI vs. CABG in patients with severe LV dysfunction, 1 study reported comparable clinical outcomes between PCI and CABG,13 while other studies showed a survival benefit of CABG over PCI.14–16 Based on the results of the SITCH and REVIVED trials, the American and European guidelines only recommend CABG in addition to medical therapy in patients with multivessel disease and severe LV dysfunction as Class I, whereas PCI for patients with multivessel disease and severe LV dysfunction who were at high surgical risk are a Class IIb recommendation.17,18
One of the limitations of the previous randomized clinical trials comparing PCI vs. CABG or medical therapy alone was that intracoronary imaging such as IVUS was only rarely used in the PCI arm.6–9 The benefit of IVUS in reducing cardiovascular events after PCI was well established in previous randomized clinical trials regardless of LV dysfunction.19–21 The OPTIVUS-Complex PCI study multivessel cohort evaluated clinical outcomes after optimal IVUS-guided multivessel PCI combined with contemporary clinical practice including new generation drug-eluting stents, radial approach, high-intensity statin therapy, short DAPT regimen, and withdrawal of routine follow-up coronary angiography. In the OPTIVUS-Complex PCI multivessel cohort, the primary cardiovascular composite endpoint was much lower than the PCI performance goal, and numerically lower than the CABG performance goal derived from the CREDO-Kyoto registry.10
In the present study enrolling patients who underwent multivessel IVUS-guided PCI, and were managed with contemporary PCI practice, 1-year clinical outcomes were worse in patients with LV dysfunction, which was consistent with the previous studies.22–24 Baseline characteristics of the patients with severe LV dysfunction in the present study were similar to those of patients enrolled in the REVIVED trial (mean age 70.0 years, men 87%, mean LVEF 27.0%, median total number of stents 3). Considering the results from the previous studies and the present study, CABG is still the gold standard therapy for coronary revascularization in patients with LV dysfunction. Generally, physicians would expect to improve systolic LV function by coronary revascularization for ischemic cardiomyopathy with preserved myocardial viability, which could ultimately lead to improve clinical outcomes.4,5 However, 1 study from the STICH trial showed that CABG compared with medical therapy alone reduced mortality rates regardless of myocardial viability in patients with CAD and severe LV dysfunction, and there was no difference in the mortality rates between patients with and without improvement in LVEF after CABG.25 Unveiling the mechanism for the survival benefit of CABG is essential to establish the optimal revascularization strategy in patients with multivessel disease and LV dysfunction. As of now, PCI for ischemic cardiomyopathy should be performed only in patients who are not operable. Currently, the STICH3C (Canadian CABG or PCI in Patients With Ischemic Cardiomyopathy: NCT05427370) trial comparing PCI vs. CABG in patients with multivessel or left main disease and ischemic LV dysfunction (LVEF <40%) is ongoing.26 In addition, guideline-directed medical therapy is fundamental for heart failure with LV dysfunction.27,28 In the present study, the prescription rates of guideline-directed medical therapy in patients with severe LV dysfunction were not optimal (β-blockers: 84.5%, RASi: 77.5%, SGLT-2 inhibitors: 21.1%), which might have affected the worse clinical outcomes in patients with LV dysfunction. The very low prescription rate of SGLT-2 inhibitors in the present study might be associated with the enrollment period (March 2019–April 2021), which was prior to the establishment of SGLT-2 inhibitors for heart failure with LV dysfunction.27,28 The operators of coronary revascularization should be reminded that guideline-directed medical therapy is the baseline therapy in patients with CAD and LV dysfunction.
Study Limitations
First, the number of enrolled patients was relatively small, and the number of patients with events was not large enough to adjust all potential confounders, which resulted in inadequate power to evaluate the risk of LV dysfunction. Indeed, the risk of severe LV dysfunction relative to preserved LV function was numerically higher for the primary endpoint, but did not reach statistical significance. In addition, we did not have a screening log in the present study. We did not have data on how many eligible patients were not enrolled in the present study. Indeed, the incidence of the primary endpoint was numerically lower in patients with moderate LV dysfunction than in those with severe LV dysfunction. In addition, the rate of procedural complications was not different between patients with and without LV dysfunction. These observations might represent an underlying selection bias in the present study. Second, a 1-year follow-up might be too short. Third, the present study population consisted of patients who underwent multivessel disease including left anterior descending coronary artery, but the cause of LV dysfunction was not always CAD. In addition, the data on myocardial viability and changes in LVEF during follow-up were lacking. Furthermore, there were no data on those important factors in evaluating clinical outcomes of ischemic cardiomyopathy, such as prescription rates of mineralocorticoid-receptor antagonists and angiotensin-receptor neprilysin inhibitors, and prevalence of implantable cardiovascular defibrillator or cardiac resynchronization therapy. In addition, the prescription rate of SGLT-2 inhibitors was low in patients with LV dysfunction. Fourth, the rate of meeting the OPTIVUS criteria was not high (≈60%). However, we previously reported that clinical outcomes were not different between patients who did or did not meet the OPTIVUS criteria in the OPTIVUS-Complex PCI study multivessel cohort.10
In conclusion, among patients who underwent multivessel IVUS-guided PCI, and were managed with contemporary PCI practice, 1-year clinical outcomes were worse in patients with LV dysfunction.
Acknowledgments
We appreciate the members of Cardiovascular Clinical Research Promotion Department, Research Institute for Production Development handling a series of large clinical trials performed by Kyoto University and the co-investigators exaggeratedly enrolling patients, collecting follow-up data, or adjudicating clinical events.
Source of Funding
This work was supported by Boston Scientific Japan. The study sponsor was not involved in the implementation of the study, data collection, event fixation and statistical analysis. However, approval of the study sponsor should be obtained for presentation in scientific meetings and submission of papers.
Disclosures
K.Y. reports honoraria from Abbott Medical and Boston Scientific. T.M. reports lecturer’s fees from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Pfizer, Tsumura and UCB; manuscript fee from Pfizer; advisory board for GlaxoSmithKline, Novartis and Teijin. T.K. reports research grants from Abbott Medical, and Boston Scientific; honoraria from Abbott Medical, Boston Scientific, Daiichi Sankyo, Sanofi, and Terumo; participation on advisory boards of Abbott Medical, Boston Scientific, and Sanofi. K.O. is a member of Circulation Reports’ Editorial Team. The other authors have nothing to disclose.
IRB Information
Kyoto University Certified Review Board and Ethics Committee approved; OPTIVUS-Complex PCI (Y0011).
Trial Registration
jRCT: CRB5180002.
Data Availability
The deidentified participant data will not be shared.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circrep.CR-25-0005
References
- 1.
Yaku H, Ozasa N, Morimoto T, Inuzuka Y, Tamaki Y, Yamamoto E, et al. Demographics, management, and in-hospital outcome of hospitalized acute heart failure syndrome patients in contemporary real clinical practice in Japan: Observations from the prospective, multicenter Kyoto Congestive Heart Failure (KCHF) Registry. Circ J 2018; 82: 2811–2819.
- 2.
Velazquez EJ, Lee KL, Deja MA, Jain A, Sopko G, Marchenko A, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011; 364: 1607–1616.
- 3.
Velazquez EJ, Lee KL, Jones RH, Al-Khalidi HR, Hill JA, Panza JA, et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 2016; 374: 1511–1520.
- 4.
Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: A meta-analysis. J Am Coll Cardiol 2002; 39: 1151–1158.
- 5.
Brophy TJ, Warsavage TJ, Hebbe AL, Plomondon ME, Waldo SW, Rao SV, et al. Percutaneous coronary intervention in patients with stable coronary artery disease and left ventricular systolic dysfunction: Insights from the VA CART program. Am Heart J 2021; 235: 149–157.
- 6.
Perera D, Clayton T, O’Kane PD, Greenwood JP, Weerackody R, Ryan M, et al. Percutaneous revascularization for ischemic left ventricular dysfunction. N Engl J Med 2022; 387: 1351–1360.
- 7.
Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009; 360: 961–972.
- 8.
Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012; 367: 2375–2384.
- 9.
Park SJ, Ahn JM, Kim YH, Park DW, Yun SC, Lee JY, et al. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med 2015; 372: 1204–1212.
- 10.
Yamamoto K, Shiomi H, Morimoto T, Watanabe H, Miyazawa A, Yamaji K, et al. Optimal intravascular ultrasound-guided percutaneous coronary intervention in patients with multivessel disease. JACC Asia 2023; 3: 211–225.
- 11.
Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation 2007; 115: 2344–2351.
- 12.
Yamamoto K, Shiomi H, Morimoto T, Miyazawa A, Watanabe H, Nakamura S, et al. Single-session versus staged multivessel optimal IVUS-guided PCI in patients with CCS or NSTE-ACS. JACC Asia 2023; 3: 649–661.
- 13.
Bangalore S, Guo Y, Samadashvili Z, Blecker S, Hannan EL. Revascularization in Patients with multivessel coronary artery disease and severe left ventricular systolic dysfunction: Everolimus-eluting stents versus coronary artery bypass graft surgery. Circulation 2016; 133: 2132–2140.
- 14.
Sun LY, Gaudino M, Chen RJ, Bader Eddeen A, Ruel M. Long-term outcomes in patients with severely reduced left ventricular ejection fraction undergoing percutaneous coronary intervention vs. coronary artery bypass grafting. JAMA Cardiol 2020; 5: 631–641.
- 15.
Bloom JE, Vogrin S, Reid CM, Ajani AE, Clark DJ, Freeman M, et al. Coronary artery bypass grafting vs. percutaneous coronary intervention in severe ischaemic cardiomyopathy: Long-term survival. Eur Heart J 2025; 46: 72–80.
- 16.
Völz S, Redfors B, Angerås O, Ioanes D, Odenstedt J, Koul S, et al. Long-term mortality in patients with ischaemic heart failure revascularized with coronary artery bypass grafting or percutaneous coronary intervention: Insights from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J 2021; 42: 2657–2664.
- 17.
Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the management of patients with chronic coronary disease: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 2023; 148: e9–e119.
- 18.
Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J 2024; 45: 3415–3537.
- 19.
Hong SJ, Kim BK, Shin DH, Nam CM, Kim JS, Ko YG, et al. Effect of Intravascular ultrasound-guided vs. angiography-guided everolimus-eluting stent implantation: The IVUS-XPL randomized clinical trial. JAMA 2015; 314: 2155–2163.
- 20.
Zhang J, Gao X, Kan J, Ge Z, Han L, Lu S, et al. Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: The ULTIMATE trial. J Am Coll Cardiol 2018; 72: 3126–3137.
- 21.
Lee JM, Choi KH, Song YB, Lee JY, Lee SJ, Lee SY, et al. Intravascular imaging-guided or angiography-guided complex PCI. N Engl J Med 2023; 388: 1668–1679.
- 22.
Daneault B, Généreux P, Kirtane AJ, Witzenbichler B, Guagliumi G, Paradis JM, et al. Comparison of three-year outcomes after primary percutaneous coronary intervention in patients with left ventricular ejection fraction <40% versus ≥40% (from the HORIZONS-AMI trial). Am J Cardiol 2013; 111: 12–20.
- 23.
Kobayashi N, Ito Y, Kishi K, Muramatsu T, Okada H, Oikawa Y, et al. Procedural results and in-hospital outcomes of percutaneous coronary intervention for chronic total occlusion in patients with reduced left ventricular ejection fraction: Sub-analysis of the Japanese CTO-PCI Expert Registry. Catheter Cardiovasc Interv 2022; 100: 30–39.
- 24.
Gallone G, Kang J, Bruno F, Han JK, De Filippo O, Yang HM, et al. Impact of left ventricular ejection fraction on procedural and long-term outcomes of bifurcation percutaneous coronary intervention. Am J Cardiol 2022; 172: 18–25.
- 25.
Panza JA, Ellis AM, Al-Khalidi HR, Holly TA, Berman DS, Oh JK, et al. Myocardial viability and long-term outcomes in ischemic cardiomyopathy. N Engl J Med 2019; 381: 739–748.
- 26.
Fremes SE, Marquis-Gravel G, Gaudino MFL, Jolicoeur EM, Bédard S, Masterson Creber R, et al. STICH3C: Rationale and study protocol. Circ Cardiovasc Interv 2023; 16: e012527.
- 27.
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42: 3599–3726.
- 28.
Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022; 145: e895–e1032.
