Table 3. Coronary bifurcation study types and related endpoints.

Type of study	Description	Procedural endpoints	Imaging and functional endpoints	Clinical endpoints
Procedural strategies comparison	Comparison of provisional vs upfront 2-stent strategy or 2 different 2-stent strategies (as per ITT) eg, DK-Crush II trial: DK crush double stenting vs provisional stenting in coronary bifurcation103	1) Intended primary strategy success (eg, crossover rate: the placement of a second stent in the SB, as part of a declared provisional strategy in the preprocedural planning, is not considered a crossover to a 2-stent strategy in strategies comparison studies On the contrary, it is, in studies comparing 1- vs 2-stent procedures Procedural strategy reported as per MADS-2) 2) Procedural success: • Device success • Free from event during the index hospitalization (CV death, TBR, PMI, any stroke, BARC 3 or 5 bleeding) 3) Health-economic endpoints: • Procedural time (min) • Procedural cost • Fluoroscopy time (min) • Contrast medium amount (mL)	1) Acute endpoints: • Residual stenosis (bifurcation dedicated-QCA, IVUS, OCT) • Dissection • Perforation • SB temporary flow impairment or occlusion • SB loss • MV and SB TIMI flow • Postprocedural invasive functional assessment and/or image-based FFR ≤0.89104 • IVUS/OCT: underexpansion, malapposition, accidental crush, double stent layers, stent edge dissection, tissue protrusion (see Supplemental Appendix) • Post-PCI systolic-diastolic bifurcation angle B range <10°105 2) Late endpoints: • Late lumen loss or gain (in all the bifurcation segments, using the same method as per postprocedural assessment) • Binary restenosis (in all the bifurcation segments, using the same method as per postprocedural assessment) • Functional deterioration or net gain (invasive or image-based FFR ≤0.89)	1) BOCE: • CV death • Target bifurcation-related MI • Target bifurcation-related ischemia • TBR 2) Efficacy endpoint: • Target vessel revascularization • Target bifurcation-related ischemia • TBR 3) Safety endpoint: • BARC 3 or 5 • Definite ST • Any stroke • Any MI • CV death • All-cause death
Device comparison	Comparison of different devices (DCB vs stent, ie, BABILON trial106: DCB in both branches + BMS in PMV vs DES in MV only; or new dedicated bifurcation devices vs conventional devices, eg, POLBOS II trial: BiOSS LIM bifurcation dedicated stent vs conventional DES56	1) Procedural success: • Device success • SB stenting necessity (if provisional strategy) • Free from event during the index hospitalizations (CV death, TBR, PMI, any stroke) 2) Health-economic endpoints: • Procedural time (min) • Procedural cost • Fluoroscopy time (min) • Contrast medium amount (mL)	1) Acute endpoints: • Residual stenosis (bifurcation dedicated-QCA, IVUS, OCT) • Dissection • Perforation • SB temporary flow impairment or occlusion • SB loss • MV and SB TIMI flow • Postprocedural invasive functional assessment and/or image-based FFR ≤0.89104 • IVUS/OCT: underexpansion, malapposition, stent edge dissection, tissue protrusion (see Supplemental Appendix) • Post-PCI systolic-diastolic bifurcation angle B range <10°105 2) Late endpoints: • Late lumen loss or gain (in all the bifurcation segments, using the same method as per postprocedural assessment) • Binary restenosis (in all the bifurcation segments, using the same method as per postprocedural assessment) • Functional deterioration or net gain (invasive or image-based FFR ≤0.89)	1) DOCE: • CV death • Device failure-related MI • Device failure-related ischemia • TBR 2) Efficacy endpoint: • Target vessel revascularization • Target bifurcation-related ischemia • TBR 3) Safety endpoint: • BARC 3 or 5 • Definite ST • Any stroke • Any MI • CV death • All-cause death
Diagnostic assessment comparison	Comparison between different physiological evaluation (both invasive and noninvasive) (ie, FFR vs NHPR in bifurcation lesions)	1) Assessment feasibility of the intended bifurcation segment before the treatment 2) Safety: • Any complications related to the assessment 3) Health-economic endpoints: • Procedural time (min) • Procedural cost • Fluoroscopy time (min) • Contrast medium amount (mL)	1) Accuracy of the investigated evaluation method (at preprocedure, postprocedure, follow-up) 2) Reproducibility	1) BOCE: • CV death • Target bifurcation-related MI • Target bifurcation-related ischemia • TBR
First-in-human studies	Comparison between a new device and historical data or predefined benchmarks (ie, TRYTON trial)107	1) Procedural success: • Device success • Free from event during the index hospitalizations (CV death, TBR, PMI, any stroke)	1) Acute endpoints: • Residual stenosis (bifurcation dedicated-QCA, IVUS, OCT) • Dissection • Perforation • SB temporary flow impairment or occlusion • SB loss • MV and SB TIMI flow • Postprocedural invasive functional assessment and/or image-based FFR ≤0.89104 • IVUS/OCT: underexpansion, malapposition, device fracture, stent edge dissection, tissue protrusion (see Supplemental Appendix) • Post-PCI systolic-diastolic bifurcation angle B range <10°105 2) Late endpoints: • Late lumen loss or gain (in all the bifurcation segments, using the same method as per postprocedural assessment) • Binary restenosis (in all the bifurcation segments, using the same method as per postprocedural assessment) • Functional deterioration or net gain (invasive or image-based FFR ≤0.89)	Objective performance criteria (vs historical data or predefined benchmarks)51: 1) Safety endpoint: • All-cause death CV death • Any MI • Definite ST 2) Efficacy endpoint: • Any coronary revascularization • Target vessel revascularization • TBR 3) Composite efficacy and safety: • CV death, target vessel-MI, and TBR (DOCE) • All-cause death, any MI, and any revascularization (POCE)
Postprocedural pharmacological comparison	Comparison between different antiplatelet strategies after PCI (DAPT vs SAPT; short DAPT vs long DAPT; ie, GLOBAL LEADERS bifurcation subgroup study)108	1) Final strategy adopted (ie, 1-stent vs 2-stent; procedural strategy reported as per MAD-2) 2) Procedural success: • Device success • Free from event during the index hospitalizations (CV death, TBR, PMI, any stroke, BARC 3 or 5 bleeding)	1) Acute endpoints: • Residual stenosis (bifurcation dedicated-QCA) • Dissection • Perforation • SB temporary flow impairment or occlusion • SB loss • MV and SB TIMI flow • Postprocedural invasive functional assessment and/or image-based FFR ≤0.89104 • IVUS/OCT: underexpansion, malapposition, stent edge dissection, tissue protrusion (see Supplemental Appendix) • Post-PCI systolic-diastolic bifurcation angle B range <10°105 2) Late endpoints: • Late lumen loss or gain (in all the bifurcation segments, using the same method as per postprocedural assessment) • Binary restenosis (in all the bifurcation segments, using the same method as per postprocedural assessment) • Functional deterioration or net gain (invasive or image-based FFR ≤0.89)	1) Bleeding endpoint: • BARC 3 or 5 2) POCE: • All-cause death • Any stroke • Any MI • Any revascularization 3) NACE • Bleeding endpoint • POCE 4) Nonadherence classifications according to NARC74 5) PROMs (ie, SAQ)81
Revascularization type comparison (percutaneous vs surgical)	Comparison between the 2 revascularization strategies (eg, bifurcation LM subgroups of SYNTAX, EXCEL trials109)	PCI arm 1) Procedural success: • Device success • Free from event during the index hospitalizations (CV death, TBR, PMI, any stroke, BARC 3 or 5 bleeding) CABG arm 1) Procedural success: • Successful performance of the intended coronary revascularization surgical strategy • Free from event during the index hospitalizations (CV death, TBR, PMI, any stroke, BARC 3-5 bleeding)	1) Acute endpoints: PCI arm • Residual stenosis (bifurcation dedicated- QCA, IVUS, OCT) • Dissection • Perforation • SB temporary flow impairment or occlusion • SB loss • MV and SB TIMI flow • Postprocedural invasive functional assessment and/or image-based FFR ≤0.89104 • IVUS/OCT: underexpansion, malapposition, stent edge dissection, tissue protrusion (see Supplemental Appendix) • Post-PCI systolic-diastolic bifurcation angle B range <10°105 • Residual SYNTAX score 2) Late endpoints: • Functional deterioration or net gain (invasive or image-based FFR ≤0.89) PCI arm • Late lumen loss or gain (in all the bifurcation segments, using the same method as per postprocedural assessment) • Binary restenosis (in all the bifurcation segments, using the same method as per postprocedural assessment) CABG arm • Graft stenosis >70% or graft occlusion	1) POCE: • All-cause death • Any stroke • Any repeat revascularization • Any MI 2) Bleeding endpoint: PCI arm: BARC 3 or 5 CABG arm: BARC 3, 4, or 5 3) NACE • Bleeding endpoint • POCE 4) PROMs (eg, SAQ)
BARC: Bleeding Academic Research Consortium; BMS: bare-metal stent; BOCE: bifurcation oriented composite endpoint; CABG: coronary artery bypass graft; CV: cardiovascular; DAPT: double antiplatelet therapy; DCB: drug coated balloon; DES: drug eluting stent; DK-Crush: Double Kissing Crush versus Provisional Stenting for Left Main Distal Bifurcation Lesions; DOCE: device oriented composite endpoint; EXCEL: Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; ITT: intention-to-treat; IVUS: intravascular ultrasound; MADS: Main-Across-Distal-Side; MI: myocardial infarction; MV: main vessel; NACE: net adverse clinical events; NARC: Non-adherence Academic Research Consortium; NHPR: nonhyperemic pressure ratio; OCT: optical coherence tomography; PCI: percutaneous coronary intervention; PMI: periprocedural myocardial infarction; POCE: patient oriented composite endpoint; POLBOS: POLish Bifurcation Optimal Stenting; PROMs: patient reported outcome measures; SAPT: single antiplatelet therapy; SAQ: Seattle Angina Questionnaire; SB: side branch; ST: stent thrombosis; SYNTAX: Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery; TBR: target bifurcation revascularization; TIMI: Thrombolysis In Myocardial Infarction; other abbreviations as in Tables 1 and 2