Intravascular Imaging in Patients With Complex Coronary Lesions and Chronic Kidney Disease

This cohort study evaluates whether the outcomes of intravascular imaging–guided procedural optimization would be different according to the presence of chronic kidney disease.


Exclusion criteria
① Target lesions not amenable to PCI based on operators' review ② Cardiogenic shock (Killip class IV) at presentation ③ Intolerance to aspirin, clopidogrel, prasugrel, ticagrelor, heparin, or everolimus ④ Known true anaphylaxis to contrast medium (not allergic reaction but anaphylactic shock) ⑤ Pregnancy or breast feeding ⑥ Non-cardiac co-morbid conditions are present with life expectancy <1 year or that may result in protocol non-compliance (per site investigator's medical judgment) ⑦ Unwillingness or inability to comply with the procedures described in this protocol.

Primary and Secondary Endpoints Primary Endpoint
Target vessel failure A composite of cardiac death, target vessel MI, and clinicallydriven target vessel revascularization.

Secondary Endpoints
Target

Supplementary Statistical Analysis
Hypothesis: An intravascular imaging-guided PCI strategy for patients with complex coronary artery lesions would reduce target vessel failure (a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization), compared with an angiography-guided PCI strategy.
Null hypothesis: An intravascular imaging-guided PCI strategy for patients with complex coronary artery lesions would not reduce target vessel failure (a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization), compared with an angiography-guided PCI strategy.The current trial was designed as a superiority trial to follow enrolled patients until a prespecified follow-up duration of the last patient enrolled.Since the follow-up duration of the previous studies varied, we assumed that the annual incidence of target vessel failure in the angiography-guided PCI group would be 6.0%, based on the results of the CTO-IVUS, RESET, and IVUS-XPL studies.These 3 studies were selected because they were randomized trials conducted in South Korea and the follow-up duration was 1 year.As presented in the above table, the relative risk reduction of target vessel failure of the 3 studies ranged from 38.4% to 63.4%.To be conservative, we assumed that the relative risk reduction at 1 year would be 40% and, in turn, the annual incidence of target vessel failure in the intravascular imaging-guided PCI group would be 3.6%.

Sample Size Calculation
◼ Primary endpoint: Time to occurrence of target vessel failure (a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization) ◼ Assumed annual event rate of target vessel failure: o Intravascular imaging-guided PCI group (3.6%) vs. Angiography-guided PCI group (6%) ◼ Alpha = 0.05 (2-sided), β = 10%, Power (1-β) = 90% ◼ Accrual time: 3 years ◼ Total follow-up time: one year after last patient enrollment (median 2.5 years) ◼ 2:1 Randomization ◼ Primary statistical method: Kaplan-Meier survival analysis with log-rank test ◼ Assumed dropout: total 5.0% Based on the above assumptions, a total of 1620 patients (1080 and 540 patients for the intravascular imaging-guided group and the angiography-guided group, respectively) would be needed to evaluate the primary hypothesis with consideration of dropouts.

Consideration of 2:1 Randomization
Although previous randomized controlled trials were potentially limited by enrolling a small number of patients, limited follow-up duration, or enrolling patients with highly selected coronary artery lesion subsets, they consistently showed the potential benefit of intravascular imaging-guided PCI compared with angiography-guided PCI. 2,3,5,7,8In this regard, the executive committee members tried to maximize the potential benefit of intravascular imagingguided PCI in the treatment of complex coronary artery lesions.While we did not collect the exact proportion of PCI cases done with intravascular imaging guidance from all the participating centers, the adoption rate of intravascular imaging-guided PCI in Korea is about 27.5% to 28.6% according to the Korean Percutaneous Coronary Intervention (K-PCI) Registry that includes 92 participating centers. 9Considering the adoption rate of intravascular imagingguided PCI in Korea, a 2:1 randomization ratio should not introduce bias when interpreting the trial results.

Statistical Analysis
Continuous variables were presented as means ± standard deviations or median and interquartile range and were compared using Welch's t-test.Categorical variables are presented as number and relative frequency (%) and are compared using the Chi-square test.The assumption of proportional hazards model was evaluated using Schoenfeld residuals.

Death
Death as defined by the Academic Research Consortium is as follows: 10 All death was considered to be cardiac death unless an unequivocal noncardiac cause can be established.Specifically, any unexpected death, even in patients with coexisting potentially fatal noncardiac disease (eg, cancer, infection), should be classified as cardiac.The cause of death (cardiac vs. non-cardiac) was adjudicated by an independent clinical events adjudication committee.
Cardiac death: Any death due to a proximate cardiac cause (eg, myocardial infarction, lowoutput failure, fatal arrhythmia), unwitnessed death and death of unknown cause, and all procedure-related deaths, including those related to concomitant treatment, was classified as cardiac death.
Non-cardiac death: Any death not covered by the above definitions, such as death caused by infection, malignancy, sepsis, pulmonary causes, accident, suicide, or trauma.

Myocardial Infarction
The definition of myocardial infarction used in this trial was based on the Third Universal Definition of Myocardial Infarction for spontaneous myocardial infarction, 11 and the Society for Cardiovascular Angiography and Interventions definition for procedure-related myocardial infarction. 12

Spontaneous Myocardial Infarction
Myocardial infarction was considered to be present when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. 11Under these conditions any one of the following criteria meets the diagnosis for myocardial infarction: 1) Detection of a rise and/or fall of cardiac troponin with at least one value above the 99th percentile upper reference limit and with at least one of the following: ◼ Symptoms of ischemia.◼ New or presumed new significant ST-segment-T wave changes or new left bundle branch block (LBBB).◼ Development of pathological Q waves in the ECG.◼ Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.◼ Identification of an intracoronary thrombus by angiography or autopsy.
2) Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or before cardiac biomarker values would be increased.
3) Stent thrombosis associated with myocardial infarction when detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker values with at least one value above the 99th percentile upper reference limit.

Procedure-Related Myocardial Infarction
Procedure-related myocardial infarction is defined as follows: 12 1) In patients with normal baseline CK-MB, myocardial infarction was considered to have occurred when the peak CK-MB measured within 48 hours of the procedure rises to at least 10 times the local laboratory upper reference limit; or to at least 5 times the upper reference limit with new pathologic Q-waves in at least 2 contiguous leads or new persistent LBBB; or in the absence of CK-MB measurements and a normal baseline cardiac troponin (cTn), a cTn (I or T) level measured within 48 hours of the PCI rises to at least 70 times the local laboratory upper reference limit; or at least 35 times upper reference limit with new pathologic Q-waves in at least 2 contiguous leads, or new persistent LBBB.
2) In patients with an elevated baseline CK-MB (or cTn) in whom the biomarkers are stable or falling, the definition was based on when CK-MB (or cTn) rises by an absolute increment equal to those levels recommended above from the most recent pre-procedure level.
3) In patients with an elevated baseline CK-MB (or cTn) in whom the biomarker levels have not been shown to be stable or falling, the definition is based on when CK-MB (or cTn) rises by an absolute increment equal to those levels recommended above plus new ST-segment elevation or depression plus signs consistent with a clinically relevant MI, such as new onset or worsening heart failure or sustained hypotension.

Revascularization
A coronary revascularization procedure may be either a PCI or a coronary artery bypass grafting (CABG) surgery.Revascularization is defined by the Academic Research Consortium 10 as follows: The coronary segments that were revascularized were sub-classified as: Target Lesion: A target lesion was defined as a lesion revascularized in the index procedure (or during a planned or provisional staged procedure).The left main target lesion extends from the left main stem ostium to the end of the 5 mm proximal segments of the left anterior descending and left circumflex arteries as well as the ramus intermedius if the latter vessel has a vessel diameter of at least 2 mm.Target Vessel: The target vessel was defined as the entire major coronary vessel proximal and distal to the target lesion including upstream and downstream branches and the target lesion itself.The left main coronary artery and any vessel originating from the left main coronary artery, or its major branches is, by definition, considered a target vessel for the purposes of this trial.
Target Vessel Non-Target Lesion: The target vessel non-target lesion was a lesion in the epicardial vessel or branch or graft that contains the target lesion; however, this lesion is outside of the target lesion by at least 5 mm distal or proximal to the target lesion determined by quantitative coronary angiography.
Non-Target Vessel: The non-target vessel was any vessel that was not attempted to be revascularized at the index procedure but was subsequently revascularized.
Target Lesion Revascularization: Target lesion revascularization was defined as any repeat PCI of the target lesion or bypass surgery of the target vessel performed for restenosis or other complication of the target lesion.All target lesion revascularizations were classified prospectively as clinically indicated or not clinically indicated by the investigator prior to repeat angiography.An independent angiographic core laboratory verified that the severity of the percent diameter stenosis met the requirements for clinical indication and overruled cases where investigator reports were not in agreement.The target lesion was defined as the treated segment from 5 mm proximal to the stent and to 5 mm distal to the stent.
Target Vessel Revascularization: Target vessel revascularization was defined as any repeat percutaneous intervention or surgical bypass of any segment of the target vessel.The target vessel was defined as the entire major coronary vessel proximal and distal to the target lesion, which included upstream and downstream branches and the target lesion itself.
Non-Target Lesion Revascularization: Any revascularization in a lesion other than the target lesion was considered a non-target lesion revascularization.
Non-Target Vessel Revascularization: Any revascularization in a vessel other than the target vessel was considered a non-target vessel revascularization.
All revascularization events were adjudicated as either clinically driven or non-clinically driven.Revascularization was considered clinically driven if the diameter stenosis of the revascularized coronary segment is at least 50% by quantitative coronary angiography and any of the following criteria for ischemia were met: Angiographic confirmation of stent thrombosis: The presence of an intracoronary thrombus that originates in the stent or in the segment 5 mm proximal or distal to the stent and presence of at least 1 of the following criteria within a 48-hour time window: ◼ Acute onset of ischemic symptoms at rest; or ◼ New ischemic ECG changes that suggest acute ischemia; or ◼ Typical rise and fall in cardiac biomarkers (refer to the definition of spontaneous myocardial infarction); or ◼ Nonocclusive thrombus: Intracoronary thrombus was defined as a (spheric, ovoid, or irregular) noncalcified filling defect or lucency surrounded by contrast material (on 3 sides or within a coronary stenosis) seen in multiple projections at the time of coronary angiography, or persistence of contrast material within the lumen, or a visible embolization of intraluminal material downstream.◼ Occlusive thrombus: Was defined as Thrombolysis in Myocardial Infarction (TIMI) Grade 0 flow (no flow of contrast after the thrombotic stenosis) or TIMI Grade 1 flow (flow past the thrombotic stenosis that doesn't fill the vessel entirely) within the stent or proximal to a stent up to the most adjacent proximal side branch or main branch (if the stent originates from the side branch).
Pathological confirmation of stent thrombosis: Evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved following thrombectomy.
[2] Probable stent thrombosis: The clinical definition of probable stent thrombosis was considered to have occurred after intracoronary stenting in the following cases: ◼ Any unexplained death within the first 30 days; or ◼ Irrespective of the time after the index procedure, any myocardial infarction that was related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause.
[3] Possible stent thrombosis: The clinical definition of possible stent thrombosis was considered to have occurred with any unexplained death from 30 days after intracoronary stenting until the end of trial follow-up.

Contrast-Induced Nephropathy
Contrast-induced nephropathy was defined as an increase in serum creatinine of at least 0.5mg/dL or at least 25% from baseline within 48-72 hours after exposure to a contrast agent. 10 Protocol for Intravascular Imaging Device Use and Angiography-guided PCI PCI was performed using standard techniques.The drug-eluting stents used were either biodegradable polymer-coated everolimus eluting stents (Synergy, Boston Scientific Corporation, San Jose, CA, USA) or biocompatible polymer-coated everolimus-eluting stents (Xience, Abbott Vascular, St. Paul, MN, USA).The trial limited stent choice to these drugeluting stents due to the well-validated efficacy and safety profile of biodegradable polymercoated everolimus eluting stents and biocompatible polymer-coated everolimus-eluting stents, 13 the fact that these two stents have the highest market share in Korea, and the availability of these drug-eluting stents in all participating centers.
For patients assigned to intravascular imaging-guided PCI, the choice of intravascular imaging device (IVUS or OCT) was at the operators' discretion.While use of intravascular imaging was allowed at any step of the PCI procedure (prior to intervention, during PCI, and after stent implantation or angioplasty when performed as a standalone procedure), intravascular imaging evaluation after PCI was mandated for optimization of the stented segment.
Standard protocols for image acquisition were used with the IVUS (Opticross TM , Boston Scientific Corporation, San Jose, CA, USA) or OCT (Dragonfly TM , Abbott Vascular, St. Paul, MN, USA) devices.Before advancing the intravascular imaging catheter, intracoronary nitroglycerin (100 to 200 μg) was administered.For IVUS, the transducer was pulled back automatically at a speed of 0.5 mm per sec.For OCT, preheated contrast media at 37 °C was flushed through the guiding catheter at a rate of 2 to 4 ml per second for approximately 3 to 6 seconds by using an injector pump to obtain the OCT images.However, the final choice of pullback speed for the IVUS device and the injection rate and the amount of contrast media used during OCT imaging was also left to the operators' discretion.In case of a staged procedure during the same hospitalization, it was strongly recommended that the operator follow the initially allocated imaging or angiography guidance strategy.
Protocols for selecting the reference segments for the lesion, for selecting the appropriate size of the stent, and for stent optimization were prespecified based on previous reports in the literature. 14In brief, proximal and distal reference sites were determined at cross-sections adjacent to the target lesion (at least 5 mm apart) that have the largest lumen and a plaque burden of less than 50% by IVUS.Using OCT, proximal and distal reference sites were determined at cross-sections adjacent to the target lesion (at least 5 mm apart) that have the most normal appearance and are free of lipid-containing plaque.The criteria used to determine optimal stent expansion were residual angiographic diameter stenosis (defined by percent diameter stenosis; ([mean reference vessel diameter -minimum lumen diameter]/mean reference vessel diameter) x 100) less than 10% and minimum stent area (defined by the lumen area measured by intravascular imaging devices at the site of the narrowest lumen inside of the stented segment) greater than 80% of the average reference lumen area or absolute minimum stent area greater than 5.5 mm 2 by IVUS or 4.5 mm 2 by OCT for a stenosis, except if the lesion was in the left main coronary artery.For a left main stenosis, an absolute minimal stent area greater than 7 mm 2 for distal left main coronary artery and greater than 8 mm 2 for the proximal left main coronary artery were used as optimization criteria, respectively. 14n optimized procedural result in the intravascular imaging-guided PCI group was defined as sufficient stent expansion without major stent malapposition and edge dissection.Specific definitions are provided in the table below.
Major stent malapposition was defined as an acute malapposition with the distance between the vessel wall and the stent of at least 0.4 mm with longitudinal length of more than 1 mm.Major edge dissection was defined as a dissection occurring within 5 mm from the edge of the stent, extending to the medial layer with a dissection angle of at least 60° of the circumference of the vessel or at least 3 mm in length of dissection flap.If one of the above findings were identified by the intravascular imaging devices, additional procedures including adjunctive post-dilatation or additional stent implantation followed by further intravascular imaging were recommended to optimize the final results.
To avoid perforation, the non-compliant balloon diameter was recommended to be no larger than the nearest reference vessel diameter, or up to 0.5 mm larger than the mean reference lumen diameter after PCI, based on findings from the intravascular imaging.The maximal inflation pressure of the non-compliant balloon was left up to the operator; however, it was recommended that the non-compliant balloon was inflated to a pressure above the nominal rated pressure for the balloon.In case a major edge dissection was identified by intravascular imaging, additional stent implantation was recommended; the stent size selected was based on findings from the intravascular imaging study.After additional procedural optimization, the intravascular-imaging study was to be repeated until the acquisition of the optimized results, as described above.However, operators could decide to consider the procedure finished if it was believed that there was the potential risk for a complication associated with additional procedural optimization interventions.

IVUS OCT Reference Sites
Largest size vessel lumen; Plaque burden <50%; At least 5 mm away from the target lesion Most normal looking segment; No lipid-containing plaque; At least 5 mm away from the target lesion

Stent Sizing
Vessel diameter (external elastic membrane) is measured at the proximal and distal reference sites.The averaged value of the proximal and distal reference external elastic membrane diameter is used to determine the stent diameter.
Vessel diameter is measured at the distal reference sites (in cases where ≥180° of the external elastic membrane can be identified).Stent diameter is determined using the mean external elastic membrane diameter at the distal reference, rounded down to the nearest 0.25 mm.For example, if the mean external elastic membrane reference diameter is measured as 3.15 mm, then a 3.0 mm stent diameter will be OR The lumen diameter is measured at the distal reference sites (in cases where ≥180° of the external elastic membrane cannot be identified).
Stent diameter is determined using the mean lumen diameter at the distal reference, rounded up to the nearest 0.25 mm.For example, if the mean distal reference lumen diameter is 2.55 mm, then a 2.75 mm stent diameter will be selected.

Stent Length
By measuring the distance from the distal to the proximal reference site.

Stent Optimization • Stent Expansion
Visually assess that the residual angiographic diameter stenosis is <10% "AND" • Non-left main coronary artery lesions: In-stent minimal stent lumen area > 80% of the average reference lumen area "OR" a minimal stent area of >5.5 mm 2 by IVUS and >4.5 mm 2 by OCT.• Left main coronary artery lesions: Minimal stent luminal area of >7 mm 2 for a distal left main coronary artery stenosis and >8 mm 2 for a proximal left main coronary artery stenosis by IVUS.

• Stent Apposition
No major malapposition (defined as an acute malapposition of ≥0.4 mm with longitudinal extension >1 mm) of the stent over its entire length against the vessel wall.

• Edge Dissection
No major edge dissection in the proximal or distal reference segments, defined as a location that is 5 mm from the edge of the stent, extends to the medial layer with potential to provoke flow disturbances (defined as ≥60° of the circumference of the vessel at the site of a dissection or ≥3 mm in length of the dissection flap)

If any of above findings are identified, additional procedural intervention, including additional post-dilatation of the stent or additional stent implantation is recommended.
For additional post-dilatation of the stent, the diameter of the noncompliant balloon should not be larger than the IVUS or OCT

IVUS
OCT determined mean reference external elastic membrane diameter assessed after stenting of one or both segments (proximal or distal), or if the external elastic membrane cannot be measured, no more than 0.5 mm larger than the mean reference segment lumen diameter of one or both segments (proximal or distal) nearest to the dilation site.
Among patients assigned to the angiography-guided PCI group, stent optimization was assessed and performed based on angiographic findings.A stent was considered if the angiographic residual diameter stenosis is less than 10% by visual estimation and there was no flow limiting dissection (type C through F dissection).When underexpansion of the stent was suspected based on angiography, adjunctive balloon dilatation using non-compliant balloons was recommended.To avoid perforation, the non-compliant balloon diameter was recommended to be no larger than the nearest reference vessel diameter, or up to 0.5 mm larger than the mean reference lumen diameter after PCI.The maximal inflation pressure of the noncompliant balloon was left to the operator's discretion; however, it was recommended that the non-compliant balloon inflation was pressure was at least above the nominal rated pressure of the balloon.Additional procedural optimization was recommended until the optimized results (as described above) were obtained.Operators could decide to consider the procedure finished if it was believed that there was the potential risk for a complication associated with additional procedural optimization interventions.
After the index PCI procedure, dual antiplatelet therapy was recommended for at least 3 to 6 months in patients with stable ischemic heart disease and 6 to 12 months in those with an acute coronary syndrome, regardless of allocated arms. 15,16However, the loading, maintenance dose, and duration of dual antiplatelet therapy were left up to the physicians' discretion.Regardless of the patient assignment, guideline directed medical therapy was recommended according to the current American College of Cardiology/ American Heart Association/ Society of Coronary Angiographers and Interventionalists or the European Society of Cardiology/European Association for Cardiothoracic Surgery guidelines. 17,18All coronary angiograms and intravascular imaging data were analyzed by the independent core laboratories.Supplementary Tables eTable  Data presented as mean (standard deviation) or as number and percentage.
* Optimal stent expansion was defined as a residual angiographic diameter stenosis of <10% and an in-stent minimum stent area of >80% of the average reference lumen area or an absolute instent minimum stent area of >5.5 mm 2 by IVUS imaging and >4.5 mm 2 by OCT imaging.For a left main coronary artery stenosis, optimal stent expansion was defined as an in-stent minimum stent area of >7 mm 2 for the distal left main coronary artery and >8 mm 2 for the proximal left main coronary artery was used as optimization criteria.† Major malapposition was defined as an acute stent malapposition of ≥0.4 mm with longitudinal extension >1 mm of the stent over its entire length against the vessel wall.‡ Major edge dissection was defined as a dissection that occurred 5mm from the edge of the stent, extended to medial layer with potential to create a flow disturbance (defined as ≥60° of the circumference of the vessel at the site of dissection and/or ≥3 mm in length of a dissection flap).

Supplementary Figures eFigure 1. Study Flow
Abbreviations: CKD, chronic kidney disease; PCI, percutaneous coronary intervention.The cumulative incidence and HR with 95% CI of the primary endpoint are presented between intravascular imaging-guided and angiographyguided PCI according to the degree of renal function.Note that as chronic kidney disease population was defined as having GFR≤60 mL/min/1.73m 2 or having diagnosed chronic kidney disease in the past, some of the study population are actually included in GFR≥60 mL/min/1.73m 2 subgroup.
vessel failure without procedure-related MI Cardiac death or target-vessel MI All-cause death Cardiac death Target vessel MI with procedure-related MI Target vessel MI without procedure-related MI Any MI with procedure-related MI Any MI without procedure-related MI Non-target vessel related MI Target lesion revascularization Target vessel revascularization Any revascularization (clinically-driven) Stent thrombosis Incidence of contrast-induced nephropathy Total amount of contrast use Total procedural time Total medical cost -not reported in this publication MI denotes myocardial infarction

Previous Studies of Complex PCI
functional study corresponding to the area served by the target lesion; or ◼ Ischemic ECG changes at rest in a distribution consistent with the target vessel; or ◼ Typical ischemic symptoms referable to the target lesion; or Acute/subacute can also be replaced by early stent thrombosis.Early stent thrombosis (0 to 30 days) is currently used to define stent thrombosis occurring from day 0 to day 30 by the international interventional cardiology community.†This definition includes "primary" as well as "secondary" late stent thrombosis; "secondary" late stent thrombosis was defined as stent thrombosis that occured after a target segment revascularization.
* 2) Stent Thrombosis Categories: a) Definite b) Probable, and c) Possible Definite stent thrombosis: Definite stent thrombosis was considered to have occurred by either angiographic or pathologic confirmation.