A serial optical frequency-domain imaging study of early and late vascular responses to bioresorbable-polymer sirolimus-eluting stents for the treatment of acute myocardial infarction and stable coronary artery disease patients: results of the MECHANISM-ULTIMASTER study

The purpose of this study was to assess early and late vascular healing in response to bioresorbable-polymer sirolimus-eluting stents (BP-SESs) for the treatment of patients with ST-elevation myocardial infarction (STEMI) and stable coronary artery disease (CAD). A total of 106 patients with STEMI and 101 patients with stable-CAD were enrolled. Optical frequency-domain images were acquired at baseline, at 1- or 3-month follow-up, and at 12-month follow-up. In the STEMI and CAD cohorts, the percentage of uncovered struts (%US) was significantly and remarkably decreased during early two points and at 12-month (the STEMI cohort: 1-month: 18.75 ± 0.78%, 3-month: 10.19 ± 0.77%, 12-month: 1.80 ± 0.72%; p < 0.001, the CAD cohort: 1-month: 9.44 ± 0.78%, 3-month: 7.78 ± 0.78%, 12-month: 1.07 ± 0.73%; p < 0.001 respectively). The average peri-strut low-intensity area (PLIA) score in the STEMI cohort was significantly decreased during follow-up period (1.90 ± 1.14, 1.18 ± 1.25, and 1.01 ± 0.72; p ≤ 0.001), whereas the one in the CAD cohort was not significantly changed (0.89 ± 1.24, 0.67 ± 1.07, and 0.64 ± 0.72; p = 0.59). In comparison with both groups, differences of %US and PLIA score at early two points were almost disappeared or close at 12 months. The strut-coverage and healing processes in the early phase after BP-SES implantation were significantly improved in both cohorts, especially markedly in STEMI patients. At 1 year, qualitatively and quantitatively consistent neointimal coverage was achieved in both pathogenetic groups. Supplementary Information The online version contains supplementary material available at 10.1007/s12928-021-00777-4.


MECHANISM-ULTIMASTER-AMI and MECHANISM-ULTIMASTER -Elective
• Exploring the MECHANISM of early and late vascular responses to ULTIMASTER sirolimus-eluting stents for the treatment of ST-elevation Acute Myocardial Infarction: principal investigator; Hiromasa Otake, MD • MECHANISM of the pro-healing advantage of ULTIMASTER sirolimus-eluting stents assessed by early and late optical frequency domain imaging in Elective cases: principal investigator; Yoshihiro Morino, MD These studies comply with the Declaration of Helsinki. The ethical committee of each participating institution approved the study protocols, and all patients provided written informed consent before inclusion.

Inclusion criteria
The patient inclusion criteria for the MECHANISM-ULTIMASTER-AMI study are as follows: AMI is defined according to the Third Universal Definition issued by the ESC/ACCF/AHA/WHF Task Force. The concrete definition is that cardiac troponin I or T rises or falls, with at least one value exceeding the 99 th -percentile upper reference limit, and at least one of the following factors is also present: 1) ischaemic symptoms, 2) a new or expected significant ST-T change or a new left bundle branch block, 3) the appearance of an abnormal Q wave on electrocardiograms, 4) reduction of viable myocardium with imaging evidence of new wall motion abnormality, 5) identification of an intracoronary thrombus by angiography or necropsy. The ECG diagnosis of STEMI was defined by the presence of ischaemic ST-segment elevation on more than two consecutive leads on ECG.
The cut-off ST-altitude value was defined as >0.1 mV for all leads except V2 and V3 and as >0.2 mV in males or > 0.15 mV in females for V2 and V3.
The patient inclusion criteria for the MECHANISM-ULTIMASTER-Elective study were as follows: 1) patients must be good candidates for PCI for novel lesions using DES in the coronary arteries; 2) patients must be over 20 years and under 85 years of age at the time of enrolment; 3) patients must have provided written consent on their own behalf; 4) PCI treatment for other branch lesions must take place by OFDI 1 month or 3 months after initial stent placement, and the site must be observable; 5) the stent indwelling sites must be observable by OFDI 12 months after initial treatment.

Exclusion criteria
The exclusion criteria for the MECHANISM-ULTIMASTER-AMI study were defined as follows: 1) difficulty in completing 12 months of clinical follow-up, 2) no obvious ACS findings by coronary angiography (judgement by operator), 3) cardiogenic shock, 4) culprit lesion in the main trunk of the left coronary artery, 5) lesions with a reference 4 vessel diameter of less than 2.0 mm or more than 4.5 mm on visual inspection, 6) AMIrelated artery at the site where a prior stent has already been placed, 7) chronic renal failure with a serum creatinine concentration of 2.0 mg/dl or higher at the time of admission, 8) current haemodialysis, 9) cancerous tumour accompanied by a life expectancy of 2 years or less, 10) plans to undergo surgery requiring withdrawal of antiplatelet agents within 3 months, 11) current pregnancy or plans to become pregnant, and 12) a history of drug side effects from aspirin or clopidogrel (not limited to patients for whom ticlopidine is confirmed to be safe).
The exclusion criteria for the MECHANISM-ULTIMASTER-Elective study were defined as follows: 1) difficulty in completing 12 months of clinical follow-up, 2) acute myocardial infarction or cardiogenic shock, 3) heart failure, 4) lesions of the main trunk of the left coronary artery, 5) reference vessel diameter of less than 2.0 mm or more than 4.5 mm, 6) in-stent restenosis, 7) chronic renal failure (serum creatinine ≥2.0 mg/dl), 8) haemodialysis, 9) cancer accompanied by a life expectancy of less than 2 years, 10) elective surgeries requiring withdrawal of dual antiplatelet therapy, 11) current or planned pregnancy, 12) a prior history of allergies to aspirin or clopidogrel, and 13) being judged inappropriate by investigators for any other reason.
The patient in-and exclusion criteria for the both studies are described in of details on the

PCI procedure, OFDI acquisition at index PCI and follow-up
At the beginning of the PCI procedure, all patients were injected with a heparin bolus.
The PCI procedure and OFDI acquisition were performed according to Judkin's technique via the trans-radial or femoral approach using a >=6-French guiding catheter system. After the insertion of a 0.36 mm intervention guide wire, balloon angioplasty was performed for the target lesion, and a BP-SES was deployed to the culprit lesion. Culprit lesions were treated with either one or two BP-SES. If necessary, the use of two stents with subsequent balloon dilatation was approved. After optimal stent implantation was achieved, the final OFDI acquisition was performed. At 1-month, 3-month and 12-month follow-up, coronary angiography and OFDI were 7 performed according to a standard procedure using a ≥5-French catheter. The precise parameters were set determined by the rules of the QCA core laboratory.

Quantitative coronary angiography (QCA)
The target lesion was analysed using a QCA system (Q angio) using the external diameter of the contrast-filled guiding catheter as the calibration standard. Minimal lumen area, lesion length, percent diameter stenosis, and reference diameter were measured.
Percent diameter stenosis was calculated from the minimal lumen diameter and the reference diameter. All QCA data were evaluated at Iwate Core Analysis Laboratory (ICAL) as the central core laboratory.

Supplemental definition of OFDI image and image analysis of Core-lab
The definition of intra-stent tissue was defined as follows: Smooth protrusion was the bowing of the plaque between stent struts without disruption. Disrupted fibrous-tissue protrusion was defined as the disruption of underlying fibrous tissue protruding between stent struts into the lumen. Irregular protrusion was defined as protrusion of material with an irregular surface into the lumen between stent struts (>0.25 mm). A thrombus was defined as a mass attached of the luminal surface of a stent strut or floating within the 8 lumen (>0.25 mm).
Standard operation procedure for OFDI analysis was set up between the both corelabs before starting studies. All OFDI measurements were confirmed by multiple reviewers in each core laboratory and discussed any questionable images until a consensus was reached. Moreover, remained images were discussed until a consensus was reached between the both core laboratories.

Dual antiplatelet therapy
Patients who had not taken antiplatelet therapy beforehand were loaded with aspirin 81-200 mg and prasugrel 20 mg or clopidogrel 300 mg as early as possible before PCI.
In this study, we recommended a combination of aspirin and thienopyridine (prasugrel or clopidogrel) for 12 months (DAPT) according to the guidelines for acute coronary syndrome as well as those for stable angina pectoris. If aspirin or thienopyridine needed to be replaced by another medicine due to a drug allergy or other circumstances, we recommended continued administration for as long as possible up to 12 months.

Endpoints
Composite endpoints: The patient-oriented composite endpoint was defined to include 9 all-cause death, any MI including non-target territory, any repeat revascularization, and stroke as of the 12-month follow-up. Then, to compare device performance in the two cohorts, we defined device-oriented cardiac events (DOCEs), including cardiac death, target vessel MI and clinically driven TLR, as another endpoint.

Rationale for the number of cases: MECHANISM-ULTIMASTER-Elective
In the DISCOVERY 1TO 3 trial previously conducted in Europe, the average covered strut ratio (CSR) after 3 months of ULTIMASTER implantation was 95.7%, and the proportion of patients with CSR of 90% or more was 88% of the total. In the present study, it was assumed that the results would be equivalent, and the primary endpoint value was assumed to be 88%.
The number of cases, N, was calculated under this condition using the sample size formula (below) for testing the ratio of one group (Z1 -α = 1.64 because the one-sided significance level is 5%, Z power = 0.841 from the power of 80%).
Based on the above, the number of cases required for this verification was calculated to be 45 cases, and we decided to register 50 cases to allow for dropouts.

Rationale for the number of cases: MECHANISM-ULTIMASTER-AMI
We considered that the one-month CSR of the DISCOVERY 1TO3 trial conducted in the past was 85.8 ± 11.2% and that the DISCOVERY trial included elective cases.
Therefore, we assumed that the true value of CSR one month after the primary endpoint was 80% with an SD of 12%. From the above, since the CSR after 2 weeks of the MECHANISM-AMI test using the EES was 80%, this value was set as the performance target of ULTIMASTER's CSR. To prove that ULTIMASTER's CSR is non-inferior to that of the EES, we calculated the number of cases as below, assuming a clinical noninferiority margin of 5%. Based on this assumption, the required number of cases was calculated to be 38 cases. We decided to register 50 cases because we expected a high dropout rate due to the special situation of STEMI and because clear image acquisition There was no difference in patient characteristics between the two cohorts except that prior myocardial infarction and PCI were more frequent in the stable-CAD cohort and smoking was more frequent in the STEMI cohort. Postprocedural QCA analysis results in the two cohorts were comparable, except that the stent diameter was larger in the STEMI cohort than in the stable-CAD cohort and that stenosis as a percentage of diameter was slightly higher in the former cohort than in the latter.

Appendix: Institutes and co-investigators participating in the study
MECHANISM-ULTIMASTER-AMI and MECHANISM-ULTIMASTER-Elective study group