Diabetes is associated with increased risk of major adverse cardiac events (MACEs) after percutaneous coronary intervention. The purpose of this substudy of the SORT OUT IV trial was to compare clinical outcomes in patients with and without diabetes mellitus treated with everolimus-eluting stents (EESs) or sirolimus-eluting stents (SESs). In total 2,774 patients (390 with diabetes, 14.1%) were randomized to stent implantation with EESs (n = 1,390, diabetes in 14.0%) or SESs (n = 1,384, diabetes in 14.2%). Randomization was stratified by presence/absence of diabetes. The primary end point was MACEs, a composite of cardiac death, myocardial infarction, definite stent thrombosis, or target vessel revascularization within 18 months. MACEs were higher in diabetic than in nondiabetic patients (13.1% vs 6.4%, hazard ratio [HR] 2.08, 95% confidence interval [CI] 1.51 to 2.86). In diabetic patients, MACEs were seen in 10.3% of those treated with EESs and in 15.8% of those treated with SESs (HR 0.63, 95% CI 0.36 to 1.11). In nondiabetic patients, MACEs occurred in 6.6% of EES-treated and in 6.3% SES-treated patients (HR 1.06, 95% CI 0.77 to 1.46). In diabetics, cardiac death occurred in 3.1% of EES-treated and in 4.6% of SES-treated patients (HR 0.67, 95% CI 0.24 to 1.89), myocardial infarction occurred in 0.5% of EES-treated and in 3.6% of SES-treated patients (HR 0.14, 95% CI 0.02 to 1.16), and clinically driven target lesion revascularization was needed in 3.1% of EES-treated and in 7.7% of SES-treated patients (HR 0.40, 95% CI 0.15 to 1.02). No interaction between diabetes status and type of drug-eluting stent was found for the end points. In conclusion, patients with diabetes have higher MACE rates than nondiabetics. No significant differences in safety or efficacy outcomes after EES or SES implantation were present in nondiabetic or diabetic patients.
In this article we report the results of a substudy of the Randomized Comparison of Everolimus-Eluting and Sirolimus-Eluting Stents in Patients Treated with Percutaneous Coronary Intervention (SORT OUT) IV comparing the efficacy and safety of everolimus-eluting stents (EESs) to those of sirolimus-eluting stents (SESs) in patients with and without diabetes mellitus.
Methods
SORT OUT IV is a randomized, multicenter, all-comer, 2-arm, noninferiority trial comparing EESs to SESs in treating atherosclerotic coronary artery lesions. The inclusion period was August 2007 to June 2009. A detailed study protocol was provided in the main publication. Briefly, patients were eligible if they were ≥18 years old, had chronic stable coronary artery disease or acute coronary syndromes, and ≥1 coronary lesion with >50% diameter stenosis. If multiple lesions were treated, the allocated study stent was used in all lesions. There were no restrictions in number of treated lesions, number of treated vessels, or lesion length. Exclusion criteria were life expectancy of <1 year; allergy to aspirin, clopidogrel, sirolimus, or everolimus; participation in another randomized trial; or inability to provide written informed consent.
Patients were enrolled by the investigators and randomly allocated to treatment groups after diagnostic coronary angiography and before percutaneous coronary intervention. Block randomization by center (permuted blocks of random sizes 2/4/6) was used to assign patients in a 1:1 ratio to receive the EES (Xience V, Abbott Vascular, Santa Clara, California; or PROMUS, Abbott’s privately-labeled XIENCE V Everolimus Eluting Coronary Stent System distributed by Boston Scientific Corporation) or the SES (Cypher Select+, Cordis, Johnson and Johnson, Warren, New Jersey). Randomization was stratified by presence/absence of diabetes. An independent organization generated by computer the allocation sequence, stratified by gender and presence of diabetes. Patients were assigned to treatment through an automated telephone allocation service.
The EES was available in diameters of 2.25 to 4.0 mm and lengths of 8 to 28 mm. The SES was available in diameters of 2.25 to 3.5 mm and lengths of 8 to 33 mm. Stents were implanted according to standard techniques. Angiographic variables were visually estimated by the operators. Direct stenting without previous balloon dilation was allowed. Before or at the time of the procedure, patients received aspiring ≥75 mg, clopidogrel 600-mg loading dose, and an unfractionated heparin dose (5,000 IU or 70 to 100 IU/kg). Glycoprotein IIb/IIIa inhibitors and bivalirudin were used at the operators’ discretion. Recommended postprocedure dual antiplatelet regimens were aspirin 75 mg/day lifelong and clopidogrel 75 mg/day for 1 year.
Definitions of end points were provided in the main publication. The primary end point of this substudy was a composite of safety (cardiac death, myocardial infarction [MI], definite stent thrombosis) and efficacy (clinically indicated target vessel revascularization) parameters within 18 months of stent implantation. Individual components of the primary end point comprised the secondary end points: cardiac death; MI; definite stent thrombosis; clinically indicated target vessel revascularization; probable, possible, and overall stent thrombosis according to the Academic Research Consortium definition ; and symptom-driven target lesion revascularization (TLR).
To capture co-morbidity, we used the Danish National Registry of Patients to obtain data on all hospital diagnoses in study patients from 1977 until the implantation date. We then computed Charlson Co-Morbidity Index scores, which cover 19 major disease categories including heart failure, cerebrovascular diseases, and cancer.
Clinically driven event detection was used to avoid study-induced reinterventions. Data on mortality, hospital admission, coronary angiography, repeat percutaneous coronary intervention, and coronary bypass surgery were obtained for all randomly allocated patients from the following national registries: Civil Registration System; Western Denmark Heart Registry ; Danish National Registry of Patients, which maintains records on all hospitalizations in Denmark; and Danish Registry of Causes of Death. An independent event committee, which was blinded to treatment group assignment during the adjudication process, reviewed all end points and source documents to adjudicate causes of death, reasons for hospitalization, and diagnosis of MI. In addition, the committee reviewed cine films to classify stent thrombosis and target vessel revascularization (with percutaneous coronary intervention or coronary artery bypass grafting).
The Danish National Health Service provides universal tax-supported health care, guaranteeing residents free access to general practitioners and hospitals. The Danish Civil Registration System has kept electronic records on gender, birthdate, residence, emigration date, and vital status changes since 1968 with daily updates; the 10-digit civil registration number assigned at birth and used in all registries allows accurate record linkage among registries. The Civil Registration System provided vital status data for our study participants and minimized loss to follow-up. The Causes of Deaths and the Registry of Patients provided information on causes of death and diagnoses assigned by the treating physician during hospitalizations (coded according to the International Classification of Diseases, Tenth Revision ).
Distributions of continuous variables were compared between study groups using 2-sample t test (or Cochran test for cases of unequal variance) or Mann–Whitney U test depending on whether the data followed a normal distribution. Distributions of categorical variables were compared using chi-square test. In analyses of every end point, follow-up continued until the date of an end-point event, death, emigration, or 18 months after stent implantation, whichever came first. Survival curves were constructed based on cumulated incidences, accounting for death as a competing risk. Hazard ratios (HRs) were computed using Cox proportional hazards regression analysis. HRs were calculated for major adverse cardiac events (MACEs) at 18-month follow-up. Because several baseline characteristics differed between diabetic and nondiabetic patients in the trial population, an adjusted analysis was performed where we controlled for hypertension, hypercholesterolemia, previous coronary artery bypass operation, clinical indication, long-term total occlusion, lesion type, lesion length, procedure time, and co-morbidity. To improve the precision of risk estimates, we used the change-in-estimate method, which entailed retaining variables that changed relative risk estimates for an outcome by >10%. Number of variables included in the final regression models varied from 0 to 1. The intention-to-treat principle was used in all analyses. A 2-sided p value <0.05 was considered to indicate statistical significance. Analyses were conducted using SAS 9.2 (SAS Institute, Cary, North Carolina). This trial is registered with ClinicalTrials.gov ( http://www.ClinicalTrials.gov , number NCT00552877 ).
Results
Baseline patient ( Table 1 ) and procedure ( Table 2 ) characteristics were well balanced between patients treated with EESs versus SESs in the diabetic and nondiabetic subgroups. Compared to patients without diabetes, those with diabetes were more frequently treated for hypertension (76.9% vs 51.5%, p <0.0001) or hypercholesterolemia (85.2% vs 68.7%, p <0.0001) before the index percutaneous coronary intervention. They also had higher rates of previous coronary artery bypass surgery (12.3% vs 8.2%, p = 0.01), a higher body mass index (29.2 ± 5.4 vs 27.1 ± 4.3 kg/m 2 , p = 0.0001), and a larger percentage with a co-morbidity index score of ≥3 (35.1% vs 10.4%, p <0.001). The clinical indication was more often stable angina pectoris in patients with diabetes compared to patients without diabetes (65.6% vs 53.3%, p <0.001). Regarding procedural characteristics, patients with diabetes had longer procedure times (33.2 ± 22.6 vs 26.7 ± 19.8 minutes, p = 0.0001) and longer stents per lesion (22.8 ± 15.6 vs 20.1 ± 12.0 mm, p <0.001) and per patient (29.6 ± 20.8 vs 26.0 ± 17.3 mm, p = 0.002). They also were treated more frequently for type C lesions (45.5% vs 37.0%, p = 0.004) compared to patients without diabetes.
| Variable | Diabetes Mellitus | Nondiabetes Mellitus | p Value Diabetes vs Nondiabetes | ||||
|---|---|---|---|---|---|---|---|
| EES (n = 194) | SES (n = 196) | p Value | EES (n = 1,196) | SES (n = 1,188) | p Value | ||
| Age (years), mean (SD) | 63.9 (10.4) | 63.3 (10.3) | 0.63 | 64.3 (10.9) | 64.2 (10.9) | 0.80 | 0.29 |
| Men | 146 (75.3%) | 144 (73.5%) | 0.69 | 909 (76.0%) | 897 (75.5%) | 0.78 | 0.55 |
| Systemic hypertension | 135 (78.0%) | 138 (75.8%) | 0.62 | 554 (53.2%) | 511 (49.9%) | 0.13 | <0.001 |
| Hypercholesterolemia ⁎ | 154 (88.0%) | 151 (82.5%) | 0.14 | 712 (68.3%) | 708 (69.1%) | 0.69 | <0.001 |
| Current smoker | 41 (24.3%) | 48 (27.7%) | 0.46 | 303 (30.0%) | 305 (30.8%) | 0.69 | 0.10 |
| Body mass index (kg/m 2 ), mean ± SD | 29.6 ± 5.5 | 28.8 ± 5.2 | 0.17 | 27.1 ± 4.4 | 27.1 ± 4.2 | 0.85 | <0.001 |
| Previous myocardial infarction | 45 (25.7%) | 42 (22.8%) | 0.52 | 231 (22.0%) | 217 (21.1%) | 0.59 | 0.26 |
| Previous percutaneous coronary intervention | 51 (29.1%) | 32 (17.4%) | 0.008 | 213 (20.2%) | 18 (21.2%) | 0.61 | 0.30 |
| Previous coronary artery bypass grafting | 26 (14.9%) | 18 (9.8%) | 0.14 | 92 (8.7%) | 79 (7.7%) | 0.37 | 0.01 |
| Indication for percutaneous coronary intervention | 0.53 | 0.45 | <0.001 | ||||
| ST-segment elevation myocardial infarction | 8 (4.1%) | 12 (6.1%) | 114 (9.5%) | 133 (11.2%) | |||
| Non–ST-segment elevation myocardial infarction or unstable angina pectoris | 53 (27.3%) | 54 (27.6%) | 405 (33.9%) | 399 (33.6%) | |||
| Stable angina pectoris | 131 (67.5%) | 125 (63.8%) | 642 (53.7%) | 629 (52.9%) | |||
| Other | 2 (1.0%) | 5 (2.6%) | 35 (2.9%) | 27 (2.3%) | |||
| Co-morbidity index score | 0.24 | 0.97 | <0.001 | ||||
| 0 | 79 (40.7%) | 82 (41.8%) | 589 (49.2%) | 591 (49.7%) | |||
| 1–2 | 90 (46.4%) | 78 (39.8%) | 486 (40.6%) | 479 (40.3%) | |||
| ≥3 | 25 (12.9%) | 36 (18.4%) | 121 (10.1%) | 118 (9.9%) | |||
| Variable | Diabetes Mellitus | Nondiabetes Mellitus | p Value Diabetes vs Nondiabetes | ||||
|---|---|---|---|---|---|---|---|
| EES (n = 247) | SES (n = 259) | p Value | EES (n = 1,558) | SES (n = 1,520) | p Value | ||
| Target lesions per patient | 0.61 | 0.58 | 0.57 | ||||
| 1 | 152 (78.4%) | 145 (74.0%) | 910 (76.1%) | 927 (78.0%) | |||
| 2 | 36 (18.6%) | 41 (20.9%) | 220 (18.4%) | 203 (17.1%) | |||
| 3 | 4 (2.1%) | 8 (4.1%) | 56 (4.7%) | 46 (3.9%) | |||
| >3 | 2 (1.0%) | 2 (1.0%) | 10 (0.8%) | 12 (1.0%) | |||
| Number per patient | 1.3 ± 0.7 | 1.3 ± 0.6 | 0.45 | 1.3 ± 0.6 | 1.3 ± 0.6 | 0.34 | 0.85 |
| Target coronary artery location | 0.05 | 0.05 | 0.24 | ||||
| Left main | 6 (2.4%) | 3 (1.2%) | 31 (2.0%) | 22 (1.4%) | |||
| Left anterior descending | 90 (36.4%) | 105 (40.5%) | 648 (41.6%) | 700 (46.1%) | |||
| Left circumflex | 67 (27.1%) | 60 (23.2%) | 367 (23.6%) | 337 (22.2%) | |||
| Right | 78 (31.6%) | 91 (35.1%) | 503 (32.3%) | 446 (29.3%) | |||
| Saphenous vein graft | 6 (2.4%) | 0 (0.0%) | 9 (0.6%) | 15 (1.0%) | |||
| Lesion type | 0.036 | 0.61 | <0.01 | ||||
| A | 29 (11.7%) | 38 (14.7%) | 258 (16.6%) | 227 (14.9%) | |||
| B1 | 54 (21.9%) | 74 (28.6%) | 435 (27.9%) | 425 (28.0%) | |||
| B2 | 50 (20.2%) | 31 (12.0%) | 301 (19.3%) | 293 (19.3%) | |||
| C | 114 (46.2%) | 116 (44.8%) | 564 (36.2%) | 575 (37.8%) | |||
| Long-term total occlusion lesions | 22 (9.1%) | 24 (9.7%) | 0.82 | 89 (5.9%) | 81 (5.5%) | 0.64 | <0.01 |
| Bifurcation lesions | 32 (13.2%) | 37 (14.9%) | 0.60 | 183 (12.2%) | 180 (12.3%) | 0.92 | 0.26 |
| Lesion length >18 mm | 93 (37.7%) | 94 (36.3%) | 0.75 | 464 (29.8%) | 434 (28.6%) | 0.45 | <0.001 |
| Lesion length (mm) | |||||||
| Mean ± SD | 18.4 ± 12.4 | 19.2 ± 15.4 | 0.53 | 16.2 ± 10.7 | 16.5 ± 11.3 | 0.47 | <0.001 |
| Median (interquartile range) | 15 (10.0–23.0) | 15 (10.0–22.0) | 0.85 | 13.0 (10.0–20.0) | 15.0 (10.0–20.0) | 0.68 | <0.001 |
| Reference vessel size (mm), median (interquartile range) | 3.2 (3.0–3.5) | 3.2 (3.0–3.6) | 0.75 | 3.2 (3.0–3.6) | 3.2 (3.0–3.5) | 0.03 | 0.76 |
| Number of stents | |||||||
| Per patient | 1.7 ± 1.1 | 1.7 ± 1.0 | 0.87 | 1.6 ± 1.0 | 1.6 ± 0.9 | 0.19 | 0.05 |
| Per lesion | 1.3 ± 0.7 | 1.3 ± 0.7 | 0.32 | 1.2 ± 0.6 | 1.2 ± 0.6 | 0.42 | 0.03 |
| Total stent length (mm) | |||||||
| Per patient | 29.3 ± 20.6 | 29.9 ± 21.1 | 0.77 | 25.9 ± 17.0 | 26.1 ± 17.6 | 0.87 | <0.01 |
| Per lesion | 23.0 ± 14.9 | 22.6 ± 16.2 | 0.89 | 19.9 ± 11.8 | 20.4 ± 12.3 | 0.29 | <0.001 |
| Direct stenting | 44 (17.9%) | 53 (20.5%) | 0.45 | 359 (23.1%) | 308 (20.4%) | 0.06 | 0.20 |
| Stent delivery failure | 3 ± 1.2 | 5 ± 1.9 | 0.52 | 50 ± 3.2 | 31 ± 2.0 | 0.04 | 0.37 |
| Maximum pressure (atm) | 16.8 ± 4.6 | 18.2 ± 4.5 | <0.001 | 16.3 ± 4.2 | 17.5 ± 4.1 | <0.001 | <0.01 |
| Length of procedure (minutes) | 35.0 ± 23.6 | 31.4 ± 21.5 | 0.11 | 26.0 ± 19.1 | 27.3 ± 20.4 | 0.12 | <0.001 |
| Fluoroscopic time (minutes) | 11.0 ± 9.0 | 10.7 ± 9.8 | 0.79 | 8.9 ± 8.5 | 9.5 ± 9.0 | 0.08 | <0.001 |
| Contrast (ml) | 133.1 ± 81.9 | 136.0 ± 98.8 | 0.75 | 119.6 ± 86.1 | 122.1 ± 85.2 | 0.47 | <0.01 |
| Use of glycoprotein IIb/IIIa inhibitors | 33 (17.0%) | 34 (17.3%) | 0.93 | 180 (15.1%) | 200 (16.8%) | 0.23 | 0.54 |
The composite primary end point occurred in 51 diabetic patients (13.1%) and in 153 nondiabetic patients (6.4%, HR 2.08, 95% confidence interval [CI] 1.51 to 2.86 p <0.0001; Figure 1 ). Rates of the following events were higher in diabetic than in nondiabetic patients: cardiac death (n = 15, 3.9%, vs 35, 1.5%, HR 2.63, 95% CI 1.44 to 4.82, p = 0.002), TLR (n = 21, 5.4%, vs 60, 2.5%, HR 2.16, 95% CI 1.32 to 3.55, p = 0.002; Figure 2 ), and target vessel revascularization (n = 34, 8.7%, vs 110, 4.6%, HR 1.92, 95% CI 1.30 to 2.81, p <0.001). In contrast, rates of definite stent thrombosis, definite/probable stent thrombosis, and MI were not significantly different for diabetic and nondiabetic patients.
