Ultrathin-strut Biodegradable Polymer Sirolimus-eluting Stents With P2Y12 Inhibitor-based Single Antiplatelet Therapy vs. Conventional DAPT for Unprotected Left Main Coronary Artery Disease (ULTIMATE-LM)

1. Myocardial revascularization for left main coronary artery diseaseSignificant left main coronary artery disease (LMCA) is observed in 5‐7% of patientsundergoing coronary angiography. Coronary revascularization for patients with LMCAdisease with stenosis >50% and documented ischemia or FFR ≤0.80 for diameterstenosis <90%, is recommended with a class of recommendation I and level of evidence(LOE) A by the 2018 European Society of Cardiology (ESC) guidelines for myocardialrevascularization. However, the optimal management of patients with LMCA diseaserequiring myocardial revascularization in contemporary clinical practice remainsmatter of debate. 2. Coronary artery bypass grafting vs. percutaneous coronary intervention for left maincoronary artery diseaseThe available evidence from randomized controlled trials (RCTs) and meta‐analysescomparing coronary artery bypass grafting (CABG) with percutaneous coronaryintervention (PCI) using drug‐eluting stents (DESs) among patients with LMCAsuggests equivalent results for the safety composite of death, myocardial infarction(MI), and stroke up to 5 years of follow‐up. A significant interaction with time isnotable, providing early benefit for PCI in terms of MI and peri‐interventionalstroke, which is subsequently offset by a higher risk of spontaneous MI duringlong‐term follow‐up. The need for repeat revascularization is higher with PCI thanwith CABG. The largest RCT among patients with LMCA disease so far performed, EXCEL(Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness ofLeft Main Revascularization), compared CABG with PCI using new‐generation DESs among1,905 patients with significant LMCA. At 3 years of follow‐up, the primary endpointof death, stroke, or MI occurred with similar frequency in the CABG and PCI group(14.7% vs. 15.4%; HR 1.00, 95% CI 0.79‐1.26, p=0.98). The pre‐planned landmarkanalysis from 30 days to 3 years showed a significant difference for the primaryendpoint in favour of CABG (7.9% vs. 11.5%, p=0.02). The NOBLE(Nordic‐Baltic‐British Left Main Revascularization Study) randomized trial comparedCABG with PCI using new‐generation biolimus‐eluting stents among 1,201 patients withsignificant LM disease (mean SYNTAX score of 23). At a median follow‐up of 3.1years, the primary endpoint of death, non‐procedural MI, stroke, and repeatrevascularization occurred more frequently in the PCI than the CABG group (29% vs.19%; HR 1.48, 95% CI 1.11‐1.96, p=0.007). A recent collaborative individual patientdata pooled analysis of RCTs including 11,518 patients reviewed the currentlyavailable evidence from RCTs comparing CABG with PCI for LMCA or multivesseldisease. The primary outcome was all‐cause mortality. In the overall cohort, CABGwas associated with a significant survival benefit during a mean follow‐up of3.8±1.4 years (5‐year all‐cause mortality 11.2% after PCI vs. 9.2% after CABG; HR1.20, 95% CI 1.06���1.37, p=0.0038). There was a linear trend for HRs of deathincreasing with increasing SYNTAX terciles (p=0.0011 for trend). However, among4,478 patients with LMCA, those randomly assigned to CABG or PCI with a meanfollow‐up of 3.4±1.4 years reported similar risks for the primary outcome all‐causemortality (PCI, 10.7% vs. CABG, 10.5%; HR 1.07, 95% CI 0.87‐1.33, p=0.52) at 5years. There were no significant differences in mortality between PCI and CABG insubgroup analyses according to SYNTAX scores. Nevertheless, in patients with a highSYNTAX score, a trend towards better survival was noted with CABG. The proportion ofpatients with a high SYNTAX score was limited in view of the inclusion criteria ofthe respective studies. Current evidence indicates that PCI is an appropriatealternative to CABG in LMCA and low‐to‐intermediate anatomical complexity. Amongpatients with LMCA and low anatomical complexity, there is evidence that theoutcomes with respect to major clinical endpoints are similar for PCI and CABG,resulting in a class I recommendation. Among patients with LMCA and high anatomicalcomplexity, the number of patients studied in RCTs is low due to exclusion criteria;the risk estimates and cIs are imprecise but suggest a trend towards better survivalwith CABG. Therefore, PCI in this setting cannot be endorsed as reflected by a classIII recommendation. For PCI in LMCA with intermediate anatomical complexity, theprevious class iIa recommendation was maintained in view of the incomplete 5‐yearfollow‐up of the two largest RCTs in this setting. 3. Percutaneous coronary intervention with drug‐eluting stents for left main coronaryartery diseaseThe optimal DES therapy for patients with significant LMCA disease undergoingpercutaneous coronary intervention (PCI) in contemporary practice remainsundetermined. In the Intracoronary Stenting and Angiographic Results: Drug‐ElutingStents for Unprotected Coronary Left Main Lesions (ISAR‐LEFT MAIN‐2) (n=650) trial,the cumulative incidence of the primary endpoint, a composite of all‐cause death,myocardial infarction, or target lesion revascularization was 17.5% in thethin‐strut durable polymer zotarolimus‐eluting stent group (Resolute, Medtronic,USA) and 14.3% in the thin‐strut biocompatible durable polymer everolimus‐elutingstent group (Xience®, Abbott Vascular, USA) (relative risk 1.26; 95% CI]: 0.85 to1.85; p=0.25) at 12 months. In the Evaluation of XIENCE versus Coronary ArteryBypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial, therates of the primary composite endpoint of all‐cause death, stroke, or MI, occurredsimilarly in patients undergoing PCI with the newer‐generation thin‐strut durablepolymer everolimus‐eluting stent (Xience®) and coronary artery bypass graft surgery(CABG) (22.0% vs. 19.2%, p=0.13) at 5 years. In the Nordic‐Baltic‐British left mainrevascularisation (NOBLE) trial, the rates of the primary composite endpoint ofall‐cause death, non‐procedural MI, any repeat coronary revascularization, andstroke, was 29% in patients undergoing PCI with a thick‐strut biodegradable polymerbiolimus‐eluting stent (Biomatrix Flex®, Biosensors, Switzerland) versus 19% inpatients undergoing CABG (HR 1.48, 95% CI 1.11‐1.96, CABG significantly better thanPCI, p=0.0066) at 5 years. In the Improved Drug Eluting stent for All‐comers LeftMain (IDEAL‐LM) randomized clinical trial, the rate of the primary endpoint, acomposite of all‐cause death, MI, or clinically indicated target vesselrevascularization at 2 years did not differ between patients undergoing PCI with abiodegradable polymer everolimus‐eluting stent (Synergy®, Boston Scientific, USA)combined with 4‐month Dual Antiplatelet Therapy (DAPT) (14.6%) and those undergoingPCI with a durable polymer everolimus‐eluting stent (Xience®, Abbott Vascular, USA)combined with 12‐month DAPT (11.4%) (p=0.17). Newer‐generation thin‐strutpolymer‐free drug‐coated stents have the potential to further mitigate chronicinflammation and promote faster re‐endothelialisation. No dedicated randomizedclinical trial to date has evaluated the safety and efficacy of newest‐generationpolymer‐free drug‐coated stents for PCI in patients with LMCA disease. 4. Antiplatelet therapy after percutaneous coronary intervention for left main coronaryartery diseaseThe 2018 ESC guidelines on myocardial revascularization recommend at least 6(chronic coronary syndrome) and 12 (acute coronary syndrome) months of DAPT afterPCI with newer‐generation DES among patients with unprotected LMCA stenosis.However, a recent meta‐analysis of five large‐scale randomized clinical trialsincluding a total of 32'145 patients, of whom 972 (3%) patients were treated forLMCA disease, indicated that 1‐3 months of DAPT followed by P2Y12 inhibitor singleantiplatelet therapy (SAPT) after second‐generation DES implantation in patientswith chronic and acute coronary syndromes was associated with lower risk for majorbleeding (random‐effects model: HR 0.63, 95% 0.45‐0.86) and similar risk for stentthrombosis (random‐effects model: HR 1.19, 95% CI 0.86‐1.65), all‐cause death(random‐effects model: HR 0.85, 95% CI 0.70‐1.03), MI (random‐effects model: HR1.05, 95% CI 0.89‐1.23), and stroke (random‐effects model: HR 1.08, 95% CI0.68‐1.74) compared with conventional DAPT. These findings suggest that a potentP2Y12 inhibitor‐based SAPT following a short DAPT course (1‐3 months) may representa preferable treatment option, which is associated with similar ischemic, but lowerbleeding risk, for patients undergoing PCI with newer‐generation DES compared tostandard conventional 12 months DAPT. However, the safety and efficacy of a potentP2Y12 receptor inhibitor‐based aspirin‐free SAPT after complex PCI, such as PCI forLMCA disease, has not been investigated to date. 5. Newer‐generation ultrathin‐strut drug‐eluting stents for percutaneous coronaryinterventionNewer‐generation drug‐eluting stents with ultrathin‐strut metallic platforms have beenshown to reduce the risk of target lesion failure compared with thicker‐strutdrug‐eluting stents among all‐comer patients undergoing PCI, a difference mainly drivenby a lower risk of ischemia‐driven target lesion revascularization. Supraflex Cruz(Sahajanand Medical Technologies Ltd., Surat, India) is a novel newer‐generationdrug‐eluting stent consisting of an L‐605 cobalt‐chromium alloy metallic stent platformwith ultrathin struts (60 μm) across all stent diameters, highly flexible S‐linkconnectors, and a biodegradable polymeric matrix coating (poly L‐lactide, 50:50 mixturepoly D,L‐lactide‐co‐glycolide and polyvinyl pyrrolidone) eluting sirolimus at aconcentration of 1.4 μg/mm2 which is coated on the conformal surface of the stenttogether with the polymeric matrix. The average thickness of coating ranges from 4 to 5μm. The drug is 70% released within 7 days, and the remainder is released over a periodof 48 days. The polymer gradually degrades over 9‐12 months. The proprietary 'LDZ' linkdesign improves stent flexibility, transmits push force with higher efficiency, improvesoverall radial strength, and resists longitudinal compression. The open‐cell designallows for better flexibility and facilitates side branch access. In addition, the 4.0and 4.5 mm 8‐crown stent platforms which allow for an overexpansion capacity up to 5.5 mmfacilitates the treatment of patients with large coronary vessels, such as thoseundergoing LM PCI. In the TALENT prospective, single‐blind, multicenter, randomizedcontrolled trial that included 1'435 all‐comer patients undergoing PCI, the Supraflexultrathin‐strut biodegradable polymer sirolimus‐eluting stent was found non‐inferior tothe Xience® thin‐strut permanent polymer everolimus‐eluting stent (Abbott Vascular, USA)with regards to the device‐oriented composite clinical endpoint (DoCE), a composite ofcardiac death, target vessel myocardial infarction, or clinically indicated target lesionrevascularization, at 12 months of follow‐up. At 3 years, DoCE occurred in 57 patients(8.1%) in the Supraflex group, and in 66 patients (9.4%) in the XIENCE group (p=0.406).There were no significant between‐group differences in rates of cardiac death, targetvessel myocardial infarction or clinically indicated target lesion revascularization. Therates of definite or probable stent thrombosis were low and similar between groups (1.1%vs 1.4%; p=0.640). However, the TALENT trial included only 31 (1.5%) lesions located inthe left main coronary artery and randomized evidence regarding the safety and efficacyof the Supraflex ultrathin‐strut biodegradable polymer sirolimus‐eluting stent for PCI inpatients with significant LMCA disease remains therefore limited. The TAXCO studyinvestigated the OCT‐derived neointimal coverage of the Supraflex Cruz ultrathin‐strutbiodegradable polymer DES showing that 97.6% of the device struts are endothelialized at6 months after PCI, which is comparable to the neointimal coverage of the Xiencethin‐strut everolimus‐eluting stent. Equally, no significant difference was found withrespect to 6months uncovered and malapposed struts between the 2 devices. Similarly, theSiBi study evaluated the early (4 to 6 weeks) OCT‐derived neointimal coverage of theSupraflex Cruz ultrathin‐strut biodegradable polymer DES demonstrating an excellenthealing profile with a mean of 91.26% strut coverage at 35.3 ± 5 days after the indexPCI. Taken together these results indicate an appropriate balance between neointimalthickness and amount of strut coverage that may facilitate short DAPT durations.Particularly, the use of thin strut and ultrathin strut stents may lead to a favorabletrade‐off in bleeding and ischemic events in patients with high‐bleeding risk. In theCOMPARE 60/80 HBR investigator‐initiated, multicenter, prospective randomized trial whichincluded a total of 732 patients at high‐bleeding risk undergoing PCI with the SupraflexCruz ultrathin‐strut biodegradable polymer sirolimus‐eluting stent or the UltimasterTansei (Terumo Corp., Tokyo, Japan), the rates of the primary endpoint of the net adverseclinical endpoint, defined as a composite of cardiac death, myocardial infarction, targetvessel revascularization, stroke, or BARC 3 or 5 major bleeding events at 12 months were15.4% in the Supraflex Cruz group and 17.1% in the Ultimaster Tansei group, meeting theprespecified criterion for non‐inferiority of the Supraflex Cruz DES compared to theUltimaster Tansei DES (p=0.02). The median DAPT duration was 30 (0‐181) days.Importantly, a lower rate of target lesion revascularization was observed in theSupraflex Cruz group in comparison to the Ultimaster Tansei group (2.7% vs. 5.3%,p=0.078). Additionally, most other cardiac endpoints showed numerically lower values inthe Supraflex Cruz group when compared to the Ultimaster Tansei group. The safety andefficacy of the Supraflex Cruz ultrathin‐strut biodegradable polymer sirolimus‐elutingstent (Sahajanand Medical Technologies Ltd., Surat, India) combined with potent P2Y12inhibitor aspirin‐free SAPT among all‐comer patients undergoing PCI for complex coronarylesions, such as patients with LMCA stenosis, have however not been investigated to date.