Methods

From January 2001 to March 2005, the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study enrolled patients with type 2 DM and stable ischemic heart disease. The BARI 2D protocol has been previously published. Briefly, patients were randomized to 2 simultaneous treatment strategies. First, patients were assigned to either PR with IMT versus IMT alone. All patients underwent clinically indicated coronary angiography before randomization. The revascularization strategy was based on clinical and angiographic criteria, procedural safety, expectation of symptom relief, and expected durability of the procedure. The cardiothoracic surgeon strived to bypass all stenoses that were believed to contribute to the patients’ symptoms. Similarly, PCI operators aimed to successfully and safely dilate all significant lesions believed to cause symptoms of ischemia. IMT consisted of 2 simultaneous strategies: pharmacologic therapy and lifestyle modification. Pharmacologic therapy included the administration of antianginal medications, such as β blockers, calcium channel blockers, and long-acting nitrates. In addition, specific risk factor targets were (1) blood pressure ≤130/80 mm Hg, (2) low-density lipoprotein <100 mg/dl, (3) triglycerides <150 mg/dl, and (4) hemoglobin A1c <7.0%. Antianginal medications were further categorized by whether the patient required none, one, or multiple pharmacologic agents for symptomatic control. Strategies for lifestyle modifications include: dietary changes, weight loss, and regular physical exercise as well as smoking cessation. Second, patients were simultaneously assigned to either insulin provision or insulin sensitization therapy to achieve a target glycated hemoglobin level <7.0%. Patients were followed for 6 years or until December 1, 2008. The inclusion criteria were as follows: age 25 or older, type 2 DM, ≥1-vessel CAD (≥50% stenosis) amenable to revascularization, a positive stress test or documented typical angina (with ≥70% stenosis in at least one major epicardial coronary artery), and suitability for PCI or CABG. Patients were excluded if they required immediate revascularization or had left main coronary disease, a creatinine level >2.0 mg/dl, a glycated hemoglobin level >13.0%, heart failure class III or IV, hepatic dysfunction, or previous PCI or CABG within the last 12 months.

CTO was defined as an interruption of blood flow (Thrombolysis in Myocardial Infarction grade 0 flow) of an epicardial coronary artery secondary to complete atherosclerotic luminal stenosis, typically of ≥3 months duration. Angiographic characteristics were assessed at clinical sites. Baseline and index postprocedure angiograms were interpreted by angiographic core laboratory (Stanford University, Palo Alto, California). The revascularization strategy for patients with CTO with PCI or CABG was at the discretion of the treating physician. Patients with CTOs, 3-vessel disease, and proximal left anterior descending artery stenosis were more likely to be treated with CABG. Patients in the PR group were to undergo the procedure within 4 weeks after randomization. Revascularization in the IMT group during follow-up was dictated clinically by the progression of angina or the development of an acute coronary syndrome or severe ischemia. Patients were seen monthly for the first 6 months and then every 3 months thereafter. The primary end point of the study was all-cause mortality. The secondary outcome was a composite of death, myocardial infarction (MI), or stroke.

Continuous variables were presented as medians and interquartile ranges and compared using the Kruskal–Wallis test. Categorical variables were summarized as frequencies and percentages and compared using the chi-square and Fischer exact tests, as appropriate. The main outcome measure was all-cause mortality. The secondary outcome measure was major adverse cardiovascular event (MACE), defined as a composite of death, MI, and stroke. To examine the association between CTO status (patients with vs without CTO) and mortality, Kaplan–Meier curves were fitted; univariate and multivariate Cox proportional hazard ratio (HR) models were used. Observations were censored at the time of occurrence of the outcome or at the end of the study period. Multivariate models were adjusted for patient demographics, serum creatinine, angina within 6 weeks of enrollment, a history of MI, congestive heart failure, hypertension, dyslipidemia, and cerebrovascular accident. Similar methods were used to assess the association between CTO status and secondary outcome of death, MI, or stroke. To assess whether our outcomes of interest differed by treatment status for patients with and without CTO, we further stratified our cohort by the treatment arm in which they were randomized: PR and IMT versus IMT alone. Kaplan–Meier survival curves, univariate, and multivariate Cox proportional hazard models were fitted to each treatment arm group separately. Within each arm, these models tested the association between CTO status and all-cause mortality and MACE. Multivariate analyses were adjusted for patient demographics and co-morbidities pertinent to CAD (see previously). The HRs compare CTO versus non-CTO in patients managed with IMT (i.e., in patients assigned to IMT) and similarly, compare CTO versus non-CTO in patients managed with PR. Furthermore, patients with CTOs were stratified according to the number of lesions with ≥70% diameter stenosis. Within each arm, all-cause mortality and MACE were presented by the number of coronary lesions. Statistical significance was defined as a 2-sided p <0.05. All analyses were performed using SAS, version 9.3 (SAS Institute, Cary, North Carolina) and Stata 11.0 software (Stata Corporation, College Station, Texas). The BARI 2D public use, limited access data set (devoid of personal identifiers) was obtained from the National Heart, Lung, and Blood Institute (National Institutes of Health, Bethesda, Maryland). The Institutional Review Board of the University of Miami Miller School of Medicine (Miami, Florida) then approved the present study.

Results

Of 2,368 patients enrolled in BARI 2D, 972 patients (41%) had a CTO. Three patients had missing data and were excluded from the analysis. There were no significant differences in age, body mass index, dyslipidemia, glycated hemoglobin, or angina between patients with and without CTO. Patients with CTOs and significant disease were more likely to be men, Caucasian, to have previous MI, hypertension, congestive heart failure, and previous revascularization. Patients with CTO compared to patients without CTO had a higher myocardial jeopardy score (52.0 vs 37.0, p <0.001) and were more likely to have abnormal Q waves (24.7% vs 14.9%, p <0.001), abnormal ST depressions (22.7% vs 13.7%, p <0.001), and abnormal T waves (48.6% vs 38.2%, p <0.001; Table 1 ). Patients with CTO were more likely to have abnormal baseline left ventricular systolic function (left ventricular ejection fraction <50%: CTO 229 [24%] vs 171 [13%], p value <0.001).

Of patients with CTOs, 482 (41% of total PR group) and 490 (41% of total IMT group) were randomized to PR with IMT and IMT only groups, respectively. Within the PR group, patients with CTO were more often treated with CABG because of greater extent and severity of CAD (CABG in CTO 49% vs CABG in non CTO 21%, p <0.001). Within the PR group, the unadjusted all-cause mortality occurred more frequently in patients with CTO (vs without CTO). Similarly, patients with CTO treated with IMT group had higher all-cause, cardiac, and cardiovascular mortality, compared to patients without CTO. Patients without CTO were more likely to have a subsequent PCI on follow-up ( Table 2 ). Kaplan–Meier survival curve showed an increased risk of all-cause mortality in patients with significant disease and CTO at >5 years of follow-up (HR 1.35 [1.08 to 1.78], p = 0.013; Figure 1 ). Physiological risk factor goals for guidelines contemporaneous with BARI 2D in patients with CTO (vs without CTO) by treatment groups are presented in Table 3 .

Survival of patients with and without CTOs.

Table 3

Physiologic risk factor goals for guidelines contemporaneous with BARI 2D in patients with total occlusion (vs no total occlusion) of coronary arteries by treatment groups

Variable ∗	Early Revascularization		p -value †	Intensive Medical Therapy		p -value †
	Total Occlusion	No Total Occlusion		Total Occlusion	No Total Occlusion
Total Number of Visits (n=31,796)
Target Sitting Systolic Blood Pressure < 140 (mmHg)	75%	71%	<0.001	70%	68%	0.014
Low-Density Lipoprotein Cholesterol < 100 (mg/dL)	59%	62%	0.001	58%	58%	0.736
Hemoglobin A1C < 7 (%)	43%	39%	<0.001	39%	40%	0.183
Regular Exercise	24%	28%	<0.001	28%	26%	0.003
Smoking within One Year	17%	14%	<0.001	16%	14%	<0.001
Year 1 (n = 8,576)
Target Sitting Systolic Blood Pressure < 140 (mmHg)	76%	70%	<0.001	70%	68%	0.111
Low-Density Lipoprotein Cholesterol < 100 (mg/dL)	59%	61%	0.303	59%	58%	0.532
Hemoglobin A1C < 7 (%)	43%	39%	0.018	38%	40%	0.220
Regular Exercise	24%	27%	0.015	28%	25%	0.040
Smoking within One Year	13%	12%	0.106	12%	14%	0.089
Year 2 (n = 8,054)
Target Sitting Systolic Blood Pressure < 140 (mmHg)	76%	71%	0.001	70%	68%	0.176
Low-Density Lipoprotein Cholesterol < 100 (mg/dL)	60%	61%	0.757	58%	59%	0.661
Hemoglobin A1C < 7 (%)	43%	39%	0.006	38%	40%	0.298
Regular exercise	24%	28%	0.022	28%	26%	0.178
Smoking within One Year	10%	12%	0.104	11%	13%	0.031
Year 3 (n = 7,171)
Target Sitting Systolic Blood Pressure < 140 (mmHg)	75%	71%	0.005	70%	70%	0.606
Low-Density Lipoprotein Cholesterol < 100 (mg/dL)	60%	62%	0.205	58%	59%	0.622
Hemoglobin A1C < 7 (%)	44%	38%	0.001	38%	39%	0.335
Regular Exercise	25%	27%	0.127	27%	26%	0.763
Smoking within One Year	11%	9%	0.091	11%	11%	0.537
Year 4 (n = 4,847)
Target Sitting Systolic Blood Pressure < 140 (mmHg)	74%	71%	0.151	70%	70%	0.915
Low-Density Lipoprotein Cholesterol < 100 (mg/dL)	59%	62%	0.123	57%	59%	0.519
Hemoglobin A1C < 7 (%)	44%	39%	0.008	42%	40%	0.322
Regular exercise	26%	30%	0.069	28%	28%	0.850
Smoking within One Year	13%	9%	0.007	10%	9%	0.743
Year 5 (n = 2,595)
Target Sitting Systolic Blood Pressure < 140 (mmHg)	72%	75%	0.222	69%	72%	0.226
Low-Density Lipoprotein Cholesterol < 100 (mg/dL)	59%	68%	0.001	55%	59%	0.114
HbA1C < 7%	44%	38%	0.042	47%	42%	0.119
Regular Exercise	26%	31%	0.035	26%	29%	0.245
Smoking within One Year	13%	11%	0.179	10%	12%	0.386

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