Abstract
Background
Intravascular ultrasound (IVUS) was only rarely used in landmark trials comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with multivessel disease.
Objectives
The authors aimed to evaluate clinical outcomes after optimal IVUS-guided PCI in patients undergoing multivessel PCI.
Methods
The OPTIVUS (OPTimal IntraVascular UltraSound)-Complex PCI study multivessel cohort was a prospective multicenter single-arm study enrolling 1,021 patients undergoing multivessel PCI, including left anterior descending coronary artery using IVUS, aiming to meet the prespecified criteria (OPTIVUS criteria: minimum stent area > distal reference lumen area [stent length ≥28mm], and minimum stent area >0.8 × average reference lumen area [stent length <28mm]) for optimal stent expansion. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE) (death/myocardial infarction/stroke/any coronary revascularization). The predefined performance goals were derived from the CREDO-Kyoto (Coronary REvascularization Demonstrating Outcome study in Kyoto) PCI/CABG registry cohort-2 fulfilling the inclusion criteria in this study.
Results
In this study, 40.1% of the patients met OPTIVUS criteria in all stented lesions. The cumulative 1-year incidence of the primary endpoint was 10.3% (95% CI: 8.4%-12.2%), which was significantly lower than the predefined PCI performance goal of 27.5% (P < 0.001), and which was numerically lower than the predefined CABG performance goal of 13.8%. The cumulative 1-year incidence of the primary endpoint was not significantly different regardless of meeting or not meeting OPTIVUS criteria.
Conclusions
Contemporary PCI practice conducted in the OPTIVUS-Complex PCI study multivessel cohort was associated with a significantly lower MACCE rate than the predefined PCI performance goal, and with a numerically lower MACCE rate than the predefined CABG performance goal at 1 year.
Key Words: coronary stent, intravascular ultrasound, percutaneous coronary intervention
Central Illustration
Coronary artery bypass grafting (CABG) is recommended as a standard coronary revascularization modality in patients with multivessel coronary artery disease, although substantial improvements have been reported in the field of percutaneous coronary intervention (PCI).1,2 A pooled analysis from 11 randomized controlled trials (RCTs) comparing PCI and CABG in patient with multivessel disease showed higher mortality risk of PCI compared with CABG.3 More recently, the FAME 3 (Fractional Flow Reserve vs Angiography for Multivessel Evaluation) trial reported that fractional flow reserve (FFR)–guided PCI relative to CABG was associated with worse outcomes in patients with 3-vessel disease.4 However, intracoronary imaging such as intravascular ultrasound (IVUS) was only rarely used in these landmark RCTs comparing PCI with CABG.3, 4, 5, 6, 7 The benefit of IVUS in reducing ischemic events after PCI was well established in previous RCTs, and patients with optimal stent expansion were reported to have better outcomes when compared with patients with suboptimal stent expansion.8,9 Nevertheless, there is a scarcity of data on clinical outcomes after optimal IVUS-guided PCI in patients undergoing multivessel PCI. In our previous observational study, compared with CABG, PCI remained associated with a higher long-term risk for myocardial infarction and any coronary revascularization in patients with 3-vessel disease despite a high prevalence of IVUS use during PCI.10 We hypothesized that simply using IVUS during PCI may not necessarily lead to optimal stent expansion, which could explain why PCI was still worse than CABG. In the present study, 1-year clinical outcomes in patients undergoing multivessel IVUS-guided PCI aim to meet the prespecified optimal IVUS criteria were assessed and compared with the predefined performance goals derived from our previous observational study.11
Methods
Study design and population
The OPTIVUS-Complex PCI (Optimal Intravascular Ultrasound Guided Complex Percutaneous Coronary Intervention) study was a prospective multicenter single-arm study that enrolled patients undergoing left main coronary artery (LMCA) PCI or multivessel PCI including a target lesion in left anterior descending coronary artery (LAD). The participating centers were encouraged to enroll consecutive patients who were planned to undergo IVUS-guided PCI for LMCA or multivessel disease including LAD target. The PCI operators were mandated to perform optimal IVUS-guided PCI with a target for the prespecified criteria (OPTIVUS criteria) for optimal stent implantation. The exclusion criteria were those patients with ST-segment elevation myocardial infarction, cardiogenic shock, and previous history of CABG. 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.12 Written informed consent was provided from all enrolled patients.
In this paper, we report 1-year clinical outcomes in the multivessel cohort. Between March 2019 and April 2021, 1,134 patients were screened and planned to undergo multivessel PCI including a target lesion in LAD (Figure 1). Of those, 1,023 patients actually underwent IVUS-guided multivessel PCI including LAD target in 90 Japanese centers. Excluding 2 patients who withdrew consent, the current study population consisted of 1,021 patients.
Figure 1.
Study Flow
Between March 2019 and April 2021, 1,134 patients were screened and planned to undergo multivessel percutaneous coronary intervention (PCI) including a target lesion in the left anterior descending coronary artery (LAD). Of those, 1,023 patients actually underwent intravascular ultrasound (IVUS)–guided multivessel PCI including LAD target. Excluding 2 patients who withdrew consent, the current study population consisted of 1,021 patients. CABG = coronary artery bypass grafting; GDMT = guideline-directed medical therapy; LMCA = left main coronary artery; OPTIVUS = OPTimal IntraVascular UltraSound.
Study procedures and OPTIVUS criteria
Enrolled patients were to undergo PCI using platinum-chromium everolimus-eluting stents (Synergy, Boston Scientific). IVUS-guided PCI was mandatory to optimize stent expansion and apposition according to the OPTIVUS criteria. The most important criteria for stent expansion in lesions other than LMCA were defined as follows: minimum stent area (MSA) > the distal reference lumen area if the stent length ≥28 mm, and MSA >0.8 × average reference lumen area if the stent length <28 mm (average reference lumen area = [proximal reference lumen area + distal reference lumen area]/2). All of the OPTIVUS criteria were described in the Supplemental Materials. These criteria were determined according to the IVUS-XPL (Impact of IntraVascular UltraSound Guidance on Outcomes of Xience Prime Stents in Long Lesions) trial and the expert consensus document of the European Association of Percutaneous Cardiovascular Interventions.8,13 Preintervention IVUS was also recommended to help choose the appropriate balloon/stent sizes and the modalities for lesion preparation. Quantitative and qualitative coronary angiography analysis was to be performed in all target lesions, and IVUS analysis was to be performed in all target lesions with stenting by an independent core laboratory (Cardiocore). Among 1,021 study patients, coronary angiograms and IVUS images were available in 1,021 patients (100%) and 1,013 patients (99.2%), respectively, and were deemed suitable for evaluation by the core laboratory in 1,017 patients (99.6%) and 982 patients (96.2%), respectively.
In addition to the IVUS-related recommendations, there were other recommendations to adopt the contemporary clinical, procedural, and pharmacological practice. Target lesions were to be selected based on a stress imaging or physiological assessment (FFR or instantaneous wave-free ratio). Radial access was recommended as the standard approach. PCI for chronic total occlusion (CTO) was to be performed by a dedicated CTO operator. Use of rotational atherectomy was recommended in severely calcified lesions. Proximal optimization technique was recommended in bifurcation lesions. Kissing balloon inflation was recommended if bifurcation lesions were treated with 2-sent techniques. Scheduled follow-up coronary angiography after PCI was discouraged in asymptomatic patients. Recommended pharmacological management included use of high-intensity statins 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 a major adverse cardiac and cerebrovascular events (MACCE) defined as a composite of death from any cause, myocardial infarction, stroke, or any coronary revascularization. Myocardial infarction was adjudicated according to the academic research consortium definition.14 Stroke was defined as ischemic or hemorrhagic stroke with neurological symptoms lasting >24 hours. Scheduled staged coronary revascularization procedures performed within 3 months after the index PCI were not regarded as follow-up events but were included in the index procedure. The definitions of secondary endpoints are described in the Supplemental Appendix. 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
The event rate for the primary endpoint in this single-arm study was compared against the predefined performance goals. To define the performance goals in this study, we used data from 945 and 1,248 patients in the PCI and CABG groups, respectively, from the CREDO-Kyoto (Coronary REvascularization Demonstrating Outcome Study in Kyoto) PCI/CABG registry cohort-2 who fulfilled the inclusion criteria for the multivessel cohort in the OPTIVUS-Complex PCI study.11 IVUS was used during the PCI procedure in 60.3% of patients in the CREDO-Kyoto registry cohort-2. The rate of MACCE in the registry was 27.5% (95% CI: 24.7%-30.4%) and 13.8% (95% CI: 11.9%-15.8%) at 1 year and 51.2% (95% CI: 48.0%-54.4%) and 32.5% (95% CI: 29.8%-35.0%) at 5 years in the PCI and CABG groups, respectively, which were regarded as the performance goals in the present study. Based on the protocol of this present study, superiority analysis is to be performed for the performance goal derived from the PCI patients, whereas noninferiority analysis is to be performed for the performance goal at 5 years derived from the CABG patients. The sample size of the multivessel cohort was calculated based on the performance goal at 1 year derived from the PCI patients. Assuming a 15% relative risk reduction, a sample size of 892 patients would provide a power of 80% with 1-sided alpha of 2.5%. We decided to enroll 1,000 patients considering the possible dropouts. The sample size of 1,000 patients would provide 96% power for the noninferiority analysis relative to the performance goal at 5 years derived from the CABG patients with a noninferiority margin of 1.38 on the HR scale.
Categorical variables were presented as number and percentage and were compared with the chi-square test. Continuous variables were expressed as mean ± SD or median (IQR) and were compared using the Student’s t-test or Wilcoxon rank-sum test depending on their distributions. The cumulative incidence was estimated with the Kaplan-Meier method. We used the 1-sample binominal test to compare the 1-year incidence of the primary endpoint in this study with the performance goal of 27.5% derived from the PCI patients. In addition, we estimated the 1-year incidence of the primary endpoint in this study with the reference of the performance goal of 13.8% derived from the CABG patients.
The cumulative 1-year incidences of the primary and secondary endpoints were assessed between patients meeting and not meeting OPTIVUS criteria (meeting in all stented lesion, not meeting in some lesion[s], and not meeting in any lesion).
All P values were 2-sided, and P values <0.05 were considered statistically significant except for the assessment to fulfill the performance goal, where 1-sided P values <0.025 were considered statistically significant. All analyses were performed with JMP version 15.2 software (SAS Institute Inc) and R version 4.1.2 (R Foundation for Statistical Computing).
Results
Baseline characteristics
The mean age of the OPTIVUS study population was 71.2 years, 78.6% of the patients were men, and 14.2% of the patients presented with acute coronary syndrome (Table 1). The prevalence of diabetes and academic research consortium-high bleeding risk were 54.8% and 52.8%, respectively. Regarding the angiographic and procedural characteristics, a noninvasive test for ischemia and FFR or instantaneous wave-free ratio were performed in 21.1% and 29.8% of the patients, respectively. The prevalence of radial approach was 87.5%. The prevalence of patients who had 3-vessel disease was 20.4%, and the mean SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) score was 18.1, with 78.5% of patients <23. In patients with IVUS evaluation at the core laboratory, 40.1% of the patients met the OPTIVUS criteria in all stented lesions, and 40.9% of the patients did not meet OPTIVUS criteria in at least 1 lesion, while 18.9% of the patients failed to meet OPTIVUS criteria in all lesions. In terms of medications at discharge, the selected P2Y12 inhibitors were clopidogrel in 55.1% and reduced dose (20 mg loading and 3.75 mg maintenance) prasugrel in 44.3%. The prescription rates of statins and high-intensity statins were 91.7% and 36.6%, respectively (Table 1).
Table 1.
Baseline and Procedural Characteristics of the OPTIVUS Study Population (per Patient Basis) (N = 1,021)
| Clinical characteristics | |
| Age, y | 71.2 ± 10.0 |
| ≥75 y | 427 (41.8) |
| Men | 803 (78.6) |
| Body mass index, kg/m2 | 24.1 ± 3.5 |
| <25.0 kg/m2 | 666 (65.2) |
| Acute coronary syndrome | 145 (14.2) |
| Acute myocardial infarction | 68 (6.7) |
| Unstable angina | 77 (7.5) |
| Hypertension | 860 (84.2) |
| Diabetes mellitus | 560 (54.8) |
| on insulin therapy | 95 (9.3) |
| Current smoking | 176 (17.2) |
| Heart failure | 178 (17.4) |
| Prior hospitalization for heart failure | 87 (8.5) |
| Current heart failure at index hospitalization | 133 (13.0) |
| Left ventricular ejection fraction, % | 57.7 ± 12.3 |
| <40% | 114 (11.2) |
| Mitral regurgitation grade ≥3/4 | 30 (2.9) |
| Prior myocardial infarction | 180 (17.6) |
| Prior stroke | 119 (11.7) |
| Peripheral vascular disease | 116 (11.4) |
| eGFR <30 mL/min/1.73 m2 or hemodialysis | 97 (9.5) |
| eGFR <30 mL/min/1.73 m2, without hemodialysis | 38 (3.7) |
| Hemodialysis | 59 (5.8) |
| Atrial fibrillation | 85 (8.3) |
| Anemia (hemoglobin <11.0 g/dL) | 96 (9.4) |
| Thrombocytopenia (platelet <100 × 109/L) | 10 (1.0) |
| Malignancy | 126 (12.3) |
| Severe frailtya | 39 (3.8) |
| ARC-HBR | 539 (52.8) |
| Procedural characteristics | |
| Preprocedure noninvasive test | 215 (21.1) |
| Stress electrocardiogram | 104 (10.2) |
| SPECT | 94 (9.2) |
| Cardiac magnetic resonance | 9 (0.9) |
| Stress echocardiography | 3 (0.3) |
| FFR-CT | 10 (1.0) |
| Invasive FFR or iFR use | 304 (29.8) |
| IVUS use | 1,021 (100.0) |
| Radial artery approach | 893 (87.5) |
| Femoral artery approach | 235 (23.0) |
| Brachial artery approach | 56 (5.5) |
| Number of patients with angiographic evaluation in the core angiographic laboratory | 1,017 (99.6) |
| Extent of coronary artery disease | |
| 2-vessel disease | 813 (79.6) |
| 3-vessel disease | 208 (20.4) |
| SYNTAX scoreb | 18.1 ± 7.2 |
| Low <23 | 794 (78.5) |
| Intermediate 23-32 | 173 (17.1) |
| High ≥33 | 44 (4.4) |
| Number of target lesions | 2.5 ± 0.8 |
| Total number of stents | 3.0 (2.0-4.0) |
| Total stent length, mm | 80.1 ± 37.5 |
| Target of proximal LAD | 1,009 (98.8) |
| Target of chronic total occlusion | 151 (14.8) |
| Target of bifurcation | 616 (60.3) |
| Bifurcation with 2 stents | 22 (2.2) |
| New-generation DES use | 1,021 (100.0) |
| Everolimus-eluting stent (SYNERGY) use | 851 (83.3) |
| Staged PCI | 775 (75.9) |
| PCI procedure success (per patient)c | 1,021 (100.0) |
| Complete success | 999 (97.8) |
| Partial success | 22 (2.2) |
| Procedural complications | 67 (6.6) |
| Side branch occlusion (post-TIMI flow grade ≤2) | 22 (2.2) |
| Slow flow | 32 (3.1) |
| Acute occlusion | 6 (0.6) |
| Perforation | 12 (1.2) |
| Cardiac tamponade | 0 (0) |
| Stent dislodgement | 1 (0.1) |
| Stent thrombosis | 0 (0) |
| Number of patients with IVUS evaluation in the core IVUS laboratory | 982 (96.2) |
| OPTIVUS criteria | |
| Meeting in all stented lesions | 394 (40.1) |
| Not meeting in at least one lesion | 402 (40.9) |
| Not meeting in any lesion | 186 (18.9) |
| Baseline medications | |
| Antiplatelet therapy | |
| P2Y12 inhibitors | 1,018 (99.7) |
| Clopidogrel | 563 (55.1) |
| Prasugrel | 452 (44.3) |
| Aspirin | 960 (94.0) |
| Cilostazol | 6 (0.6) |
| Other medications | |
| Statins | 936 (91.7) |
| High-intensity statinsd | 374 (36.6) |
| Beta-blockers | 454 (44.5) |
| ACE-I/ARB | 584 (57.2) |
| Nitrates | 148 (14.5) |
| Calcium-channel blockers | 444 (43.5) |
| Oral anticoagulants | 99 (9.7) |
| Warfarin | 19 (1.9) |
| DOAC | 80 (7.8) |
| Oral anticoagulants in patients with atrial fibrillation (n = 85) | 63 (74.1) |
| Warfarin in patients with atrial fibrillation (n = 85) | 7 (8.2) |
| DOAC in patients with atrial fibrillation (n = 85) | 56 (65.9) |
| Proton pump inhibitors or histamine type-2 receptor blockers | 903 (88.4) |
| Proton pump inhibitors | 876 (85.8) |
| Histamine type-2 receptor blockers | 28 (2.7) |
Values are mean ± SD, n (%), or median (IQR). Left ventricular ejection fraction was missing in 7 patients. SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score was missing in 10 patients.
ACE-I = angiotensin converting enzyme inhibitors; ARB = angiotensin II receptor blockers; ARC-HBR = academic research consortium for high bleeding risk; DES = drug-eluting stent; DOAC = direct oral anticoagulant; eGFR = estimated glomerular filtration rate; FFR = fractional flow reserve; FFR-CT = fractional flow reserve-computed tomography; iFR = instantaneous wave-free ratio; IVUS = intravascular ultrasound; LAD = left anterior descending coronary artery; OPTIVUS = OPTimal IntraVascular UltraSound; SPECT = stress single photon emission computed tomography; TIMI = Thrombolysis In Myocardial Infarction.
Severe frailty was regarded as present when the hospital chart documented the inability to perform usual activities of daily living.
SYNTAX score was evaluated in the core angiographic laboratory.
Percutaneous coronary intervention (PCI) procedure success was defined as successful dilatation of target lesion with residual diameter stenosis <50%.
High-intensity statin therapy was defined as the use of maximum approved doses of strong statins in Japan (eg, rosuvastatin 10 mg, atorvastatin 20 mg, or pitavastatin 4 mg).
Baseline characteristics were not different between patients meeting and not meeting OPTIVUS criteria except for a few aspects (Supplemental Table 1).
Angiographic, IVUS, and procedural characteristics
On angiography, the mean lesion length was 23.5 mm, and the mean reference vessel diameter was 2.6 mm (Table 2). Among 2,595 lesions, 2,379 lesions (91.7%) were treated with stents. The prevalence of direct stenting and postdilatation were 7.7% and 77.3%, respectively. In the IVUS analysis in stented lesions after index procedure, the proximal reference lumen area, MSA, and distal reference lumen area were 8.3, 5.7, and 5.8 mm2, respectively. The rate of meeting OPTIVUS criteria was 61.0% in all lesions, 54.1% in lesions with stent length ≥28 mm, and 71.3% in lesions with stent length <28 mm (Figure 2).
Table 2.
Angiographic, Procedural, and IVUS Characteristics in the Core Angiographic and IVUS Laboratory in the OPTIVUS Study (per Lesion Basis, Number of Target Lesions = 2,595)
| Angiographic and procedural characteristics | |
| Number of lesions with angiographic evaluation in the core angiographic laboratory | 2,299 |
| Preprocedure | |
| Lesion length, mm | 23.5 ± 13.7 (n = 2,072) |
| Reference vessel diameter, mm | 2.6 ± 0.6 (n = 2,295) |
| Minimum lumen diameter, mm | 0.8 ± 0.4 (n = 2,296) |
| Percent diameter stenosis, % | 68.7 ± 14.1 (n = 2,296) |
| Thrombus | 53/2,297 (2.3) |
| Total occlusion | 174/2,297 (7.6) |
| In-stent restenosis | 81/2,297 (3.5) |
| Bifurcation | 1,092/2,297 (47.5) |
| Moderate or severe calcification | 722/2,297 (31.4) |
| Index procedure | |
| Invasive FFR or iFR use | 413/2,595 (15.9) |
| IVUS use | 2,529/2,595 (97.5) |
| Stent use | 2,379/2,595 (91.7) |
| PCI procedure successa | 2,571/2,595 (99.1) |
| Number of stents used per lesion | 1.0 (1.0-1.0) (n = 2,377) |
| Stent length per lesion, mm | 34.4 ± 18.5 (n = 2,377) |
| Minimum stent diameter, mm | 2.5 (2.5-3.0) (n = 2,377) |
| Cutting or scoring balloon use | 883/2,595 (34.0) |
| Rotational atherectomy use | 171/2,595 (6.6) |
| Orbital atherectomy use | 42/2,595 (1.6) |
| Direct stenting | 183/2,377 (7.7) |
| Maximum stent inflation pressure, atm | 12.7 ± 3.1 (n = 2,372) |
| Post-dilatation | 1,838/2,377 (77.3) |
| Maximum balloon size, mm | 3.2 ± 0.6 (n = 1,838) |
| Maximum balloon inflation pressure, atm | 18.0 ± 4.3 (n = 1,834) |
| Postprocedure | |
| Minimum lumen diameter, mm | |
| In-stent | 2.5 ± 0.5 (n = 2,299) |
| In-segment | 2.2 ± 0.6 (n = 2,299) |
| Percent diameter stenosis, % | |
| In-stent | 14.4 ± 6.7 (n = 2,299) |
| In-segment | 23.7 ± 10.0 (n = 2,299) |
| Acute gain, mm | |
| In-stent | 1.7 ± 0.5 (n = 2,296) |
| In-segment | 1.4 ± 0.6 (n = 2,296) |
| Procedural complications | 75/2,595 (2.9) |
| Side branch occlusion (post TIMI flow grade ≤2) | 23/2,595 (0.9) |
| Slow flow | 36/2,595 (1.4) |
| Acute occlusion | 6/2,595 (0.2) |
| Perforation | 13/2,595 (0.5) |
| Cardiac tamponade | 0/2,595 (0) |
| Stent dislodgement | 1/2,595 (0) |
| Stent thrombosis | 0/2,595 (0) |
| IVUS analysis postprocedureb | |
| Number of lesions with IVUS evaluation in the core IVUS laboratory | 2,046 |
| Proximal reference vessel area, mm2 | 16.1 ± 5.6 (n = 1,684) |
| Proximal reference lumen area, mm2 | 8.3 ± 3.3 (n = 2,046) |
| Minimum stent area, mm2 | 5.7 ± 2.0 (n = 2,046) |
| Distal reference vessel area, mm2 | 9.8 ± 5.1 (n = 1,974) |
| Distal reference lumen area, mm2 | 5.8 ± 2.6 (n = 2,046) |
| Thrombus or protrusion | 261/2,046 (12.8) |
| Incomplete stent appositionc | 745/2,046 (36.4) |
| Dissection | 96/2,046 (4.7) |
| Meeting OPTIVUS criteria | 1,246/2,044 (61.0) |
| Stent length ≥28 mm | 664/1,228 (54.1) |
| Stent length <28 mm | 582/816 (71.3) |
Values are mean ± SD, n/N (%), or median (IQR).
Abbreviations as in Table 1.
PCI procedure success was defined as successful dilatation of target lesion with residual diameter stenosis <50%.
IVUS analyses were to be performed in all target lesions with stenting.
Incomplete stent apposition was defined as the presence of blood flow between stent struts and vessel wall.
Figure 2.
The Distribution of Minimum Stent Area After Percutaneous Coronary Intervention
The histogram for (A) minimum stent area/distal reference lumen area in lesions with stent length ≥28 mm, and (B) minimum stent area/average reference lumen area in lesions with stent length <28 mm. Average reference lumen area was defined as the mean of proximal and distal reference lumen area. The red line represents the cutoff point of OPTIVUS criteria.
The lesions not meeting OPTIVUS criteria more often had complex lesions such as long lesions, bifurcation lesions, and calcified lesions compared with the lesions meeting OPTIVUS criteria (Supplemental Table 2). Postdilatation with a larger balloon size was more often performed in the lesions not meeting OPTIVUS criteria than in the lesions meeting OPTIVUS criteria (Supplemental Table 2). In the IVUS analysis after index procedure, MSA was greater in the lesions meeting OPTIVUS criteria than in those not meeting OPTIVUS criteria, and proximal and distal reference lumen area were smaller in the lesions meeting OPTIVUS criteria than in those not meeting OPTIVUS criteria (Table 3).
Table 3.
IVUS Findings in Lesions Meeting vs Not Meeting OPTIVUS Criteria (per Lesion Basis)
| OPTIVUS Criteria |
P Value | ||
|---|---|---|---|
| Meeting | Not Meeting | ||
| Entire study population | (n = 1,246) | (n = 798) | |
| Proximal reference vessel area, mm2 | 15.5 ± 5.3 (n = 1,041) | 16.9 ± 5.9 (n = 641) | <0.001 |
| Proximal reference lumen area, mm2 | 7.9 ± 3.1 | 8.8 ± 3.5 | <0.001 |
| Minimum stent area, mm2 | 5.7 ± 2.0 | 5.5 ± 2.1 | 0.03 |
| Distal reference vessel area, mm2 | 9.3 ± 4.7 (n = 1,203) | 10.4 ± 5.6 (n = 769) | <0.001 |
| Distal reference lumen area, mm2 | 5.2 ± 2.2 | 6.7 ± 2.9 | <0.001 |
| Thrombus or protrusion | 158 (12.7) | 102 (12.8) | 0.95 |
| Incomplete stent appositiona | 389 (31.2) | 354 (44.4) | <0.001 |
| Dissection | 68 (5.5) | 28 (3.5) | 0.04 |
| Stent length ≥28 mm | (n = 664) | (n = 564) | |
| Proximal reference vessel area, mm2 | 16.9 ± 5.3 (n = 523) | 17.1 ± 5.6 (n = 443) | 0.59 |
| Proximal reference lumen area, mm2 | 8.6 ± 3.4 | 8.7 ± 3.3 | 0.91 |
| Minimum stent area, mm2 | 5.4 ± 1.8 | 5.5 ± 2.0 | 0.32 |
| Distal reference vessel area, mm2 | 8.3 ± 4.1 (n = 645) | 10.0 ± 5.1 (n = 545) | <0.001 |
| Distal reference lumen area, mm2 | 4.5 ± 1.7 | 6.6 ± 2.6 | <0.001 |
| Thrombus or protrusion | 92 (13.9) | 83 (14.7) | 0.67 |
| Incomplete stent appositiona | 251 (37.8) | 246 (43.6) | 0.04 |
| Dissection | 39 (5.9) | 22 (3.9) | 0.11 |
| Stent length <28 mm | (n = 582) | (n = 234) | |
| Proximal reference vessel area, mm2 | 14.2 ± 5.0 (n = 518) | 16.5 ± 6.7 (n = 198) | <0.001 |
| Proximal reference lumen area, mm2 | 7.1 ± 2.6 | 9.2 ± 3.9 | <0.001 |
| Minimum stent area, mm2 | 6.1 ± 2.2 | 5.6 ± 2.3 | 0.003 |
| Distal reference vessel area, mm2 | 10.5 ± 5.0 (n = 558) | 11.4 ± 6.6 (n = 224) | 0.03 |
| Distal reference lumen area, mm2 | 5.9 ± 2.5 | 6.9 ± 3.5 | <0.001 |
| Thrombus or protrusion | 66 (11.3) | 19 (8.1) | 0.17 |
| Incomplete stent appositiona | 138 (23.7) | 108 (46.2) | <0.001 |
| Dissection | 29 (5.0) | 6 (2.6) | 0.12 |
Values are mean ± SD. Categorical variables are presented as number and percentage.
Abbreviations as in Table 1.
Incomplete stent apposition was defined as the presence of blood flow between stent struts and vessel wall.
The prevalence of procedural complications was acceptably low (Tables 1 and 2). The rates of side branch occlusion and slow flow were higher in patients not meeting OPTIVUS criteria in any lesion than in those meeting OPTIVUS criteria in all stented lesions and in those not meeting OPTIVUS criteria in at least 1 lesion (Supplemental Table 1).
Changing PCI strategy based on the preintervention and postintervention IVUS evaluation
Among lesions evaluated by preintervention IVUS, PCI strategy was changed based on the IVUS findings in 41.2% of the lesions (Supplemental Table 3). Among lesions evaluated by postintervention IVUS, PCI strategy was changed based on the IVUS findings in 39.6% of the lesions (Supplemental Table 4).
DAPT discontinuation
The cumulative incidences of DAPT discontinuation at 60 days, 180 days, and 1 year were 17.3%, 37.4%, and 68.6%, respectively (Supplemental Figure 1). As an antiplatelet monotherapy after stopping DAPT in patients with DAPT discontinuation, 60.8% of the patients continued P2Y12 inhibitors (Supplemental Table 5). In patients who were on oral anticoagulants at discharge from the index PCI hospitalization, the cumulative incidences of DAPT discontinuation at 60 days, 180 days, and 1 year were 82.8%, 93.9%, and 97.0%, respectively (Supplemental Figure 2).
Follow-up coronary angiography
The cumulative incidence of follow-up coronary angiography at 1 year was 18.2% (Supplemental Figure 3). The cumulative incidence of clinically driven coronary angiography at 1 year was 4.8%, whereas that of scheduled coronary angiography at 1 year was 12.7% (Supplemental Figure 4).
Clinical outcomes
Complete 1-year clinical follow-up was achieved in 1,015 patients (99.4%) (Figure 1). The cumulative 1-year incidence of the primary endpoint was 10.3% (95% CI: 8.4%-12.2%), which was significantly lower than the predefined PCI performance goal of 27.5% (P < 0.001) and was numerically lower than the predefined CABG performance goal of 13.8% (Figure 3). The results for the secondary endpoints were shown in Table 3.
Figure 3.
Kaplan-Meier Curve for the Primary Endpoint
The time-to-event curve through 1 year after index percutaneous coronary intervention (PCI) for the primary endpoint (a composite of death, myocardial infarction, stroke, or any coronary revascularization) in patients enrolled in the OPTIVUS (OPTimal IntraVascular UltraSound)-Complex PCI study multivessel cohort. The cumulative incidence was estimated with the Kaplan-Meier method. One-sample binominal test was used to compare the incidence of primary endpoint with the predefined performance goals of 27.5% derived from the PCI patients in the CREDO-Kyoto (Coronary REvascularization Demonstrating Outcome study in Kyoto) registry Cohort-2.
CABG = coronary artery bypass grafting.
When comparing patients who met OPTIVUS criteria to those who did not, the cumulative 1-year incidence of the primary endpoint was similar among the groups (criteria met in all stented lesions and criteria not met in at least 1 lesion: 12.0% and 9.7%; log-rank P = 0.26 [Figure 4A]; criteria met in all stented lesions, criteria not met in at least 1 lesion, and criteria not met in any lesion: 12.0%, 9.0%, and 11.4%; log-rank P = 0.36 [Figure 4B]) (Table 4).
Figure 4.
Kaplan-Meier Curves: Patients Meeting vs Not Meeting OPTIVUS Criteria
The time-to-event curves through 1 year after index percutaneous coronary intervention (PCI) for the primary endpoint (a composite of death, myocardial infarction, stroke, or any coronary revascularization) in patients with or without meeting OPTIVUS (OPTimal IntraVascular UltraSound) criteria. (A) Comparison between patients meeting in all stented lesion and patients not meeting in at least 1 lesion. (B) Comparison among patients meeting in all stented lesions, patients not meeting in some lesion(s), and patients not meeting in any lesion. The cumulative incidence was estimated with the Kaplan-Meier method, and the differences were compared with the log-rank test.
Table 4.
Clinical Outcomes
| OPTIVUS Criteria |
|||||
|---|---|---|---|---|---|
| OPTIVUS Entire Study Population(N = 1,021) |
Meeting in All Stented Lesions(n = 394) |
Not Meeting in at Least 1 Lesion(n = 402) |
Not Meeting in Any Lesion(n = 186) |
||
| Endpoints | Patients With Event (Cumulative 1-y Incidence) | Patients With Event (Cumulative 1-y Incidence) | Log-Rank P Value |
||
| Primary endpoint | |||||
| A composite of death, myocardial infarction, stroke, or any coronary revascularization | 105 (10.3) | 47 (12.0) | 36 (9.0) | 21 (11.4) | 0.36 |
| Secondary endpoints | |||||
| All-cause death | 22 (2.2) | 10 (2.6) | 8 (2.0) | 4 (2.2) | 0.87 |
| Cardiovascular death | 9 (0.9) | 5 (1.3) | 2 (0.5) | 2 (1.1) | 0.51 |
| Cardiac death | 7 (0.7) | 3 (0.8) | 2 (0.5) | 2 (1.1) | 0.73 |
| Sudden cardiac death | 3 (0.3) | 0 (0) | 2 (0.5) | 1 (0.5) | 0.37 |
| Non-cardiovascular death | 13 (1.3) | 5 (1.3) | 6 (1.5) | 2 (1.1) | 0.91 |
| Myocardial infarction | 13 (1.3) | 5 (1.3) | 6 (1.5) | 2 (1.1) | 0.91 |
| Spontaneous | 5 (0.5) | 3 (0.8) | 2 (0.5) | 0 (0) | 0.48 |
| Periprocedural | 8 (0.8) | 2 (0.5) | 4 (1.0) | 2 (1.1) | 0.68 |
| Definite stent thrombosis | 2 (0.2) | 1 (0.3) | 1 (0.3) | 0 (0) | 0.79 |
| Stroke | 6 (0.6) | 3 (0.8) | 1 (0.3) | 2 (1.1) | 0.43 |
| Ischemic stroke | 4 (0.4) | 3 (0.8) | 0 (0) | 1 (0.5) | 0.23 |
| Hemorrhagic stroke | 2 (0.2) | 0 (0) | 1 (0.3) | 1 (0.5) | 0.39 |
| Major strokea | 5 (0.5) | 3 (0.8) | 1 (0.3) | 1 (0.5) | 0.59 |
| Hospitalization for heart failure | 18 (1.8) | 8 (2.1) | 5 (1.3) | 5 (2.7) | 0.45 |
| Major bleeding | |||||
| BARC type 3, 4, or 5 | 36 (3.6) | 13 (3.3) | 13 (3.3) | 8 (4.3) | 0.77 |
| BARC type 3 or 5 | 35 (3.5) | 12 (3.1) | 13 (3.3) | 8 (4.3) | 0.71 |
| BARC type 5 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| GUSTO moderate or severe | 31 (3.1) | 13 (3.3) | 9 (2.3) | 7 (3.8) | 0.51 |
| GUSTO severe | 17 (1.7) | 5 (1.3) | 7 (1.8) | 3 (1.6) | 0.86 |
| Target-lesion revascularization | 44 (4.4) | 20 (5.2) | 14 (3.6) | 10 (5.5) | 0.43 |
| Clinically driven target-lesion revascularization | 43 (4.3) | 19 (4.9) | 14 (3.6) | 10 (5.5) | 0.48 |
| Target-vessel revascularization | 61 (6.1) | 27 (7.0) | 20 (5.1) | 13 (7.1) | 0.45 |
| Clinically driven target-vessel revascularization | 60 (6.0) | 26 (6.7) | 20 (5.1) | 13 (7.1) | 0.50 |
| Any coronary revascularization | 71 (7.1) | 33 (8.5) | 24 (6.1) | 13 (7.1) | 0.39 |
| Clinically driven any coronary revascularization | 70 (7.0) | 32 (8.2) | 24 (6.1) | 13 (7.1) | 0.47 |
| A composite of death, myocardial infarction, or stroke | 41 (4.0) | 18 (4.6) | 15 (3.7) | 8 (4.3) | 0.84 |
Values are n (%). Cumulative 1-year incidence was estimated with Kaplan-Meier method. Definitions of the endpoints were described in the Supplemental Materials.
BARC = Bleeding Academic Research Consortium.
Major stroke was defined as modified Rankin scale ≥2.
MSA and distal reference lumen area were not different in lesions between patients with and without the primary endpoint, whereas proximal reference lumen was smaller in lesions in patients with the primary endpoint than in lesions in patients without (Supplemental Table 6).
Discussion
The main findings of this prospective study were the following: 1) IVUS-guided multivessel PCI targeting the OPTIVUS criteria combined with contemporary clinical practice was associated with a significantly lower MACCE rate than the predefined PCI performance goal, and a numerically lower MACCE rate than the predefined CABG performance goal at 1 year; and 2) the rate of the primary endpoint at 1 year was not different between patients who met or did not meet the prespecified OPTIVUS criteria (Central Illustration).
Central Illustration.
OPTIVUS-Complex PCI Study Multivessel Cohort
Contemporary percutaneous coronary intervention (PCI) practice conducted in the OPTIVUS (OPTimal IntraVascular UltraSound)-Complex PCI study was associated with a significantly lower major adverse cardiac and cerebrovascular event (MACCE) rate than the predefined PCI performance goal, and with a numerically lower MACCE rate than the predefined coronary artery bypass grafting (CABG) performance goal at 1 year. DAPT = dual antiplatelet therapy; IVUS = intravascular ultrasound; MI = myocardial infarction.
The SYNTAX II study demonstrated that PCI using SYNTAX II strategy in patients with 3-vessel disease improved 5-year clinical outcomes compared with PCI in the original SYNTAX trial, and resulted in comparable 5-year clinical outcomes compared with CABG in the original SYNTAX trial.15 SYNTAX II strategy included heart team decision making, physiology-guided PCI, implantation of new-generation drug-eluting stents (DES), IVUS-guided PCI, contemporary CTO revascularization technique, and guideline-directed medical therapy. The basic concept and study design of the present OPTIVUS-Complex PCI study were similar to those of the SYNTAX II study but more focused on IVUS guidance. Consistent with the results of the SYNTAX II study, the OPTIVUS-Complex PCI study demonstrated that IVUS-guided PCI combined with contemporary clinical practice in patients with multivessel disease was associated with superior clinical outcomes at 1 year compared with the predefined PCI performance goal derived from the CREDO-Kyoto registry cohort-2, which was a real-world registry conducted in the first-generation DES era when the original SYNTAX trial was also conducted. The 1-year incidences of the MACCE in this study were consistent with the other studies which evaluated contemporary clinical practice after multivessel PCI such as the SYNTAX II study and the FAME 3 (Fractional Flow reserve versus Angiography for Multivessel Evaluation) trial (OPTIVUS-Complex PCI: 10.3%, SYNTAX II: 10.6%, and PCI arm in FAME 3: 10.6%), despite the higher prevalence of advanced age and comorbidities in this study compared with the SYNTAX II study and FAME 3 trial.4,15 This study showed clinical outcomes at 1 year not only superior to the predefined PCI performance goal, but also numerically better than the predefined CABG performance goal. The better outcome in this study compared with the predefined CABG performance goal should be interpreted with caution, because the incidence of MACCE after contemporary multivessel CABG was very low (CABG arm in FAME 3: 6.9%).4
In the SYNTAX II study, IVUS was not used in all patients (84.1% of the patients/76.4% of the lesions), and further optimization after IVUS evaluation was performed in only 30.2% of the stented lesions.15 In the OPTIVUS-Complex PCI study, IVUS was used in all patients with an intension to achieve the optimal IVUS criteria. In the previous RCTs, IVUS-guided PCI demonstrated a significant reduction in ischemic events compared with angiography-guided PCI.8,9 The mechanisms of the benefit in IVUS-guided PCI over angiography-guided PCI might include adequate evaluation of plaque morphology, selection of appropriate diameter and length of the stents and balloons, detection for complications, and poststent optimization. In this study, PCI strategy was changed in 41.2% of the lesions based on the preintervention IVUS evaluation. IVUS before stenting would lead to selection of accurate stent size and length and more appropriate lesion modification or preparation, especially in complex lesions with heavily calcified or lipid-rich plaques. In addition, PCI strategy was changed in 39.6% of the lesions based on the postintervention IVUS evaluation. IVUS after stenting would have led to more aggressive, but safe stent postdilatation intended to achieve optimal stent expansion and detection of complications such as stent edge dissections. The achievement rate of OPTIVUS criteria was 61.0%, which was not much different compared with the previous studies.8,9 However, clinical outcomes were not different between patients with and without meeting OPTIVUS criteria. Several reasons might be suggested to explain why patients who did not meet the OPTIVUS criteria did not have worse clinical outcomes compared with patients who met the OPTIVUS criteria. First, the OPTIVUS criteria might not be the appropriate criteria for stent expansion to predict clinical outcomes. A study from the ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) registry evaluated various stent expansion indexes to determine the best predictor of clinical outcomes.16 Conventional stent expansion criteria in which MSA was compared with reference lumen area such as IVUX-XPL criteria could not predict clinical events, and only MSA/vessel area at the MSA site could predict clinical outcomes.16 Reference lumen area might not be appropriate when stent length is long, when a lesion has diffuse disease, and when stent edge is located at a bifurcation. Moreover, MSA/vessel area at the MSA site could strongly predict clinical outcomes if the MSA is small (MSA <4.5 mm2), but not if the MSA is large.16 In the OPTIVUS-Complex PCI study, the lesions which did not meet the OPTIVUS criteria had large reference lumen area, and their MSA was relatively large (mean MSA = 5.5 mm2). Relative stent expansion criteria only might work if MSA is small. Further studies will be needed to explore the optimal stent expansion criteria predicting the clinical outcomes that could be used as a guide during PCI.
Improved clinical outcomes in the OPTIVUS-Complex PCI might be caused not only by the IVUS-guided PCI, but also by the adoption of contemporary clinical practice. First, the patients in this study exclusively used new-generation DES. The superiority of new-generation DES compared with first-generation DES for clinical outcomes has been well established in a meta-analysis.17 Second, radial artery approach was used in 87.5% of the patients in this study. In a meta-analysis, the radial approach compared with femoral approach reduced not only major bleeding and vascular complications, but also mortality and major adverse cardiovascular events.18 Third, the prescription rate of statins was 91.7% in this study, which was much higher compared with the patients in the CREDO-Kyoto registry cohort-2 (PCI: 56%, and CABG: 31%). Moreover, high-intensity statin therapy was prescribed in 36.6% of the patients, which was almost never used in the CREDO-Kyoto registry cohort-2.19 Fourth, the discontinuation rates of DAPT at 180 days and at 1 year were 37.4% and 68.6%, and the dominant antiplatelet monotherapy after stopping DAPT was P2Y12 inhibitors in this study. A meta-analysis reported the efficacy and safety of P2Y12 inhibitors monotherapy after very short DAPT compared with standard 12-month DAPT.20 Fifth, the incidence of follow-up coronary angiography at 1 year was only 18.2% in this study, because we strongly recommended refraining from scheduled follow-up coronary angiography in asymptomatic patients. In the CREDO-Kyoto registry cohort-2, scheduled follow-up coronary angiography after PCI was a common clinical practice, which undoubtedly increased coronary revascularization by the so-called “oculo-stenotic reflex.”21 These contemporary clinical practices may have contributed to the observed better clinical outcomes in this study.
Study limitations
Most importantly, this study was not a randomized trial comparing the optimal IVUS-guided PCI with standard PCI or CABG. In addition, 1-year follow-up might be too short to evaluate the effect of IVUS-guided PCI compared with standard PCI or CABG. Second, the study for calculating the performance goal of PCI or CABG was conducted over a decade ago. Not only the PCI practice, but also the surgical techniques have improved together with adjunctive medical therapy. In addition, the coronary anatomic complexity such as SYNTAX score, and the prevalence of 3-vessel disease or chronic total occlusion target was lower in this study than in the CREDO-Kyoto registry cohort-2.11 Therefore, there were various differences in clinical practice between the present study population and the population for calculating the performance goal.11 Moreover, the present study population might represent selected patients for a clinical trial. The patient and lesion characteristics might be different between the present study and the real-world registry enrolling consecutive patients. Third, clinical outcomes were not different between patients with and without meeting OPTIVUS criteria, although we defined OPTIVUS criteria based on the previous studies. In addition to possible selected patient enrollment, OPTIVUS criteria might not be the best IVUS criteria for guiding PCI, although the intention to achieve the OPTIVUS criteria might have contributed to obtain reasonable stent expansion, even if we could not achieve the OPTIVUS criteria in certain proportion of patients. Finally, we could not evaluate any IVUS analysis in target lesions without stenting.
Conclusions
Contemporary PCI practice conducted in the OPTIVUS-Complex PCI study was associated with a significantly lower MACCE rate than the predefined PCI performance goal, and with a numerically lower MACCE rate than the predefined CABG performance goal at 1 year.
Perspectives.
COMPETENCY IN MEDICAL KNOWLEDGE: IVUS-guided multivessel PCI targeting the prespecified IVUS criteria (OPTIVUS criteria) combined with contemporary clinical practice was associated with a significantly lower MACCE rate than the predefined PCI performance goal, and with a numerically lower MACCE rate than the predefined CABG performance goal at 1 year. The cumulative 1-year incidence of the primary endpoint was not significantly different regardless of meeting or not meeting OPTIVUS criteria.
TRANSLATIONAL OUTLOOK: Further studies will be needed to explore the optimal stent expansion criteria predicting the clinical outcomes that could be used as a guide during PCI.
Funding Support and Author Disclosures
This work was supported by Boston Scientific Japan. The study sponsor is 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. Dr Morimoto has received lecturer fees from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Toray, and Tsumura; has received manuscript fees from Bristol Myers Squibband Kowa; and has served on the Advisory Board for Novartis and Teijin. Dr Tanabe has received honoraria from Abbott Medical, Boston Scientific, Japan Lifeline, Medtronic, Orbusneich, and Terumo. Dr Kimura has received a research grant from Abbott Medical and Boston Scientific; has received honoraria from Abbott Medical, Boston Scientific, Daiichi Sankyo, Sanofi, and Terumo; and has participated on the Advisory Board of Abbott Medical, Boston Scientific, and Sanofi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Acknowledgments
The authors appreciate the members of the Cardiovascular Clinical Research Promotion Department, Research Institute for Production Development, for handling a series of large clinical trials performed by Kyoto University, and the co-investigators enrolling patients, collecting follow-up data, or adjudicating clinical events.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For an expanded Materials section and supplemental tables and figures, please see the online version of this paper.
Appendix
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