The protocol was approved by the Shanghai Jiao Tong University ethic committee and conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent.
A total of 779 consecutive patients with stable angina who were attempted to undergo CTO-PCI of at least one major epicardial coronary artery between January 2016 and December 2018 were recruited from the database of Shanghai Rui Jin Hospital PCI Outcome Program. This program utilizes clinical and angiographic information for various cardiovascular diseases to estimate risk-adjusted outcomes. Data on demographics, clinical and angiographic features, left ventricular function determined by two-dimensional echocardiography according to modified Simpson’s rule, and in-hospital management were collected retrospectively, whereas clinical outcomes during follow-up were identified prospectively.
For the purpose of this study, 98 patients were excluded because of a history of coronary artery bypass grafting (n = 56), renal failure requiring hemodialysis (n = 12), chronic heart failure with NYHA class III or IV (n = 17), pulmonary heart disease (n = 6) and malignant tumor or immune system disorders (n = 7), as these conditions could influence collateral formation. Patients with type 1 diabetes (n = 6) were excluded by measurement of C-peptide level. In the 675 eligible patients, CTO-PCI was successful in 561 patients (83%). The main causes for failed procedure included impossibility of wire (n=85) or balloon (n=15) to cross the occluded segment and major complications (coronary dissection: n=9; coronary perforation: n=5). We also excluded additional 28 (5%) patients who were lost to follow up. Thus, the remaining 533 patients were enrolled in the final analyses. Among them, 198 patients (37%) had T2DM and 335 (63%) were non-diabetics (Figure 1).
CTO was defined as those occluded arteries with a documented duration of occlusion of at least 3 months with absolutely no flow through the lesion (TIMI grade 0) 25. Estimation of the duration of coronary occlusion was based on the first onset of an abrupt worsening of existing angina, a history of myocardial infarction in the target vessel territory, or information obtained from a previous angiogram. Stable angina was diagnosed according to the criteria recommended by the American College of Cardiology/ American Heart Association 26. T2DM was defined as a fasting glucose level >126 mg/ dL or glycated hemoglobin A1c concentration greater than 6.5% assessed at least once, or the current use of oral hypoglycemic agents or insulin 27.
Coronary intervention procedure
Coronary angiography and intervention were performed with standard techniques using 6F or 7F guiding catheters via the radial or femoral approach and drug-eluting stent implantation as the default strategy (>95% cases). Before the procedure, all patients received loading dose of aspirin (300mg/d) and clopidogrel (300mg) or ticagrelor (180mg). During the procedure, an intravenous bolus of heparin (70-100 IU/kg) was given, but the use of glycoprotein IIb/IIIa inhibitors was at the operator’s discretion. CTO-PCI was performed using contemporary techniques such as bilateral injection; specialized hydrophilic, tapered tip, and stiff wires; parallel wires; microcatheters; and retrograde approach. The choice of guidewires, balloons, and drug-eluting stent type was left to the discretion of the operators. After the procedure, clopidogrel (75mg/day) or ticagrelor (90mg, twice daily) was prescribed for at least 12 months, and aspirin (100mg/day) was continued indefinitely. After discharge, all patients were encouraged to take guideline- recommended medications including statins, angiotensin-converting enzyme inhibitors and β-blockers unless contraindicated, and to receive repeat coronary angiography at 12 months during follow-up.
Technical success was defined as a residual stenosis of < 20% and restoration of TIMI grade 3 flow. Procedural success was defined as technical success without death, myocardial infarction, or emergency coronary bypass grafting. Complete revascularization was defined as restoration of TIMI grade 3 flow with residual stenosis < 20% in all three major coronary arteries and their branches (diameter ≥ 2.0mm).
Coronary collateral scoring
The degree of coronary collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded according to Rentrop classification: 0 = no visible filling of any collateral channel; 1 = filling of side branches of the artery to be perfused by collateral vessels without visualization of epicardial segment; 2 = partially filling of the epicardial artery by collateral vessels; 3 = complete filling of the epicardial artery by collateral vessels 28. Patients were categorized into poor (grade 0 or 1) or good (grade 2 or 3) coronary collateralization group. All angiograms were viewed by the two observers blinded to the other observers’ findings, and the agreement of the assessment of coronary artery disease severity and collateral classification between the two observers was 98% and 97%, respectively 29. Any difference in interpretation was resolved by a third reviewer. For those with more than one total coronary occlusion, the vessel with the highest collateral grade was chosen for analysis.
The primary study endpoint was the occurrence of composite major adverse cardio-cerebral events (MACCE) during follow-up, including all-cause death, cardiac death, non-fatal myocardial infarction, repeat revascularization, and non-fatal stroke. All-cause death was defined as any post-procedure death, and the cause was considered cardiac unless a definite non-cardiac cause was established. Myocardial infarction was defined as recurrent symptoms with new electrocardiographic changes compatible with myocardial infarction or cardiac marker level at least twice the upper limit of normal. Repeat revascularization was defined as any revascularization of either the target or non-target vessels with PCI or coronary artery bypass grafting. In-stent restenosis was defined as recurrence of lumen diameter reduction >50% within the stent or 5mm proximal or distal segment adjacent to the stent at follow-up angiography30. Atherosclerotic lesion progression was diagnosed if one of the following criteria was met: (1) ≥20% diameter reduction of a pre-existing stenosis >50%; (2) ≥30% diameter reduction of a stenosis <50%; (3) progression of any stenosis to total occlusion, or (4) development of a new stenosis >50% in a previously normal segment 31. The secondary study endpoint was the change in left ventricular ejection fraction (LVEF) determined by two-dimensional echocardiography using modified Simpson’s method.
Continuous variables are expressed as mean ± standard deviation (SD) and categorical data as percentages. Two-side Student’s t test was used to compare continuous variables, and Pearson chi-square statistics was used to compare categorical values. The rate of composite MACCE and repeat revascularization were compared by calculating risk ratio with 95% confidence intervals (CIs). Cumulative rate of individual and composite outcomes was estimated using the Kaplan-Meier methods and compared with the log-rank test. Multivariable models were built by stepwise variable selection, and covariates with p<0.10 level on univariable analysis or clinically relevant were considered candidate variables. Adjusted hazard ratios were compared by Cox regression based on: age, gender, risk factors for coronary artery disease (current smoking, hypertension, hypercholesterolemia, and diabetes), extent of coronary artery disease (categorized as 1-, 2-, or 3-vessel disease), collateral classification, glomerular filtration rate, pre-procedural LVEF, and completeness of revascularization. A probability level of p<0.05 was considered significant. All analyses were performed using the software package SPSS, version13 (SPSS Inc, Chicago, IL, USA).