Drug-eluting stents have shown promising clinical results in the treatment of coronary artery disease, including in women. Studies with first-generation drug-eluting stents, however, have reported higher rates of stent thrombosis (ST). The aim of this study was to evaluate the safety and efficacy of second-generation everolimus-eluting stents (EES) versus first-generation sirolimus-eluting stents (SES) in women. The study included 1,649 women; 1,152 (70%) received SES and 497 (30%) received EES. In-hospital and 1-, 6-, and 12-month clinical outcomes were analyzed and compared. Correlates of major adverse cardiac events and ST were identified. Baseline clinical characteristics were similar between stent types, although more peripheral vascular disease and family history of coronary artery disease were seen in the SES group, while more unstable angina pectoris at initial diagnosis was more prevalent in the EES group. The EES group had more type C and distal lesions. There was a higher rate of target vessel revascularization and major adverse cardiac events in the SES group (14.7% vs 10.8%, p = 0.04) at 1 year. ST tended to be higher in the SES group (1.5% vs 0.4%, p = 0.06) at 6 and 12 months. After adjustment, multivariate analysis indicated that the EES group was less likely to have target vessel revascularization and major adverse cardiac events (hazard ratio 0.67, 95% confidence interval 0.47 to 0.95, p = 0.024) and had lower rates of ST (hazard ratio 0.09, 95% confidence interval 0.01 to 0.70, p = 0.022) at 1 year. In conclusion, contemporary use of EES in women is associated with improvement in efficacy and safety profiles compared to SES; however, a large randomized trial is needed to confirm this conclusion.
Coronary artery disease is the leading cause of mortality in women. Earlier studies have suggested that women, compared to men, have increased mortality after percutaneous coronary intervention, which may be partly explained by differences in co-morbid clinical conditions. Drug-eluting stents decrease the frequency of restenosis in patients who undergo percutaneous coronary intervention in randomized clinical trials and in large patient cohorts. First-generation sirolimus-eluting stents (SES) markedly reduce neointimal hyperplasia and restenosis rates compared to bare-metal stents but are associated with an increased rate of delayed stent thrombosis (ST). Second-generation everolimus-eluting stents (EES) are currently available, although with conflicting evidence for significantly improved safety and clinical results compared to first-generation drug-eluting stents. We aimed to evaluate the safety and efficacy of EES in women who undergo percutaneous coronary intervention and to compare these results to those obtained in patients treated with SES.
Methods
Identified from our institution’s registry, the study group included 1,649 women with coronary artery disease who underwent percutaneous coronary intervention with EES (Xience V, Abbot Vascular, Santa Clara, California; or Promus, Boston Scientific Corporation, Natick, Massachusetts; n = 497 [664 lesions]) or SES (Cypher, Cordis Corporation, Miami Lakes, Florida; n = 1,152 [1,694 lesions]) implantation from January 2004 to May 2011. Clinical and demographic data, as well as clinical events during hospitalization, were collected from hospital charts, reviewed by qualified personnel, and entered prospectively into a general percutaneous coronary intervention database. Every patient underwent 1-, 6-, and 12-month clinical follow-up by qualified personnel via telephone interview or during clinic visit. Clinical events were adjudicated via source documentation by independent physicians not involved in the procedures. The analysis was conducted in accordance with our local institutional review board regulations.
Interventional strategy was at the discretion of the operating interventional cardiologist. All patients received aspirin 325 mg before the procedure and were recommended to continue this regimen indefinitely. In addition, clopidogrel 75 mg/day after a 300- or 600-mg loading dose was begun before the procedure and subsequently continued for 12 months. During the percutaneous coronary intervention, patients were anticoagulated with bivalirudin (0.75 mg/kg bolus followed by a 1.75 mg/kg/hour infusion) or unfractionated heparin (40 U/kg bolus with an additional dose to achieve an active clotting time of 250 to 300 seconds).
The primary end point was the combination of target vessel revascularization (TVR) and major adverse cardiac events (TVR-MACE) at 1 year, defined as the composite of death, Q-wave myocardial infarction, and TVR. We defined death as all-cause mortality. Q-wave myocardial infarction was defined as an increment of creatine kinase-MB twice the maximum normal values, associated with the development of a new Q wave, deeper than ≥1 mm, in ≥2 contiguous leads. Hypercholesterolemia was defined as fasting cholesterol >250 mg/dl or the use of lipid-lowering therapy. Systemic hypertension was defined as blood pressure >140/90 mm Hg or the use of antihypertensive therapy. Renal impairment was defined as serum creatinine >1.2 mg/dl. Congestive heart failure was defined as evidence of fluid retention from cardiac causes before admission. Major bleeding was defined as the composite of major hematoma, gastrointestinal bleeding, and hematocrit decrease >15%. Angiographic success was defined as final stenosis after the procedure ≤30% or Thrombolysis In Myocardial Infarction (TIMI) flow grade 3. Target lesion revascularization was defined as ischemia-driven percutaneous or surgical repeat intervention in the stent or within 5 mm proximal or distal to the stent. ST was defined in accordance with the Academic Research Consortium definitions as definite or probable ST.
Statistical analyses were performed using the SAS version 9.1 (SAS Institute Inc., Cary, North Carolina). Continuous variables were compared using Student’s t tests and are expressed as mean ± SD. Categorical variables were compared using chi-square or Fisher’s exact tests, as appropriate, and are expressed as numbers and percentages. Statistical significance was defined as p <0.05. The Kaplan-Meier method was used to obtain event-free survival curves for 1-year follow-up TVR-MACE and ST in the 2 groups. A Cox regression analysis was run to obtain the predictive variables for TVR-MACE and ST. Variables in the multivariate model were selected on the basis of overall clinical relevance, with particular attention paid to clinical and procedural factors that would make TVR-MACE and ST more likely. Covariates for the multivariate model included stent type, age, African American race, peripheral vascular disease, family history of coronary artery disease, number of treated lesions, acute myocardial infarction as initial diagnosis, type C lesion, ostial lesion, and intravascular ultrasound performed during the percutaneous coronary intervention. The covariates in the model are expressed as hazard ratios with 95% confidence intervals.
Results
A total of 1,649 patients were analyzed. Of them, 1,152 (70%) received SES and 497 (30%) received EES. Baseline patient characteristics were generally comparable between the groups ( Table 1 ). SES patients had more family histories of coronary artery disease (55.5% vs 45.7% in EES patients, p <0.001). EES patients had a lower incidence of peripheral vascular disease (13.7% vs 18%, p = 0.03) and presented with a higher rate of unstable angina pectoris as the initial diagnosis (55.5% vs 45.8%, p <0.001).
| Variable | SES (n = 1,152) | EES (n = 497) | p Value |
|---|---|---|---|
| Age (yrs) | 66.54 ± 12.32 | 65.05 ± 11.63 | 0.02 |
| African American | 361 (31.3%) | 237 (47.7%) | <0.001 |
| Body mass index (kg/m 2 ) | 30.55 ± 7.83 | 31.17 ± 6.93 | 0.11 |
| Insulin-requiring diabetes mellitus | 181 (15.9%) | 88 (17.8%) | 0.35 |
| Oral antidiabetic medicine–requiring diabetes mellitus | 269 (23.6%) | 110 (22.2%) | 0.53 |
| Current smokers | 211 (18.3%) | 95 (19.1%) | 0.70 |
| Systemic hypertension ∗ | 1,021 (88.8%) | 447 (89.9%) | 0.49 |
| Dyslipidemia † | 1,011 (88.5%) | 429 (86.3%) | 0.23 |
| Family history of coronary artery disease | 609 (55.5%) | 226 (45.7%) | <0.001 |
| Heart failure class III or IV | 74 (6.9 %) | 38 (7.7%) | 0.57 |
| Chronic renal insufficiency ‡ | 164 (14.4%) | 76 (15.3%) | 0.61 |
| Dialysis | 38 (3.3%) | 17 (3.4%) | 0.92 |
| Previous myocardial infarction | 212 (19.6%) | 105 (21.8%) | 0.31 |
| Previous coronary artery bypass grafting | 168 (14.6%) | 82 (16.5%) | 0.32 |
| Previous percutaneous coronary intervention | 307 (27.9%) | 154 (31.6%) | 0.14 |
| Peripheral vascular disease | 205 (18%) | 68 (13.7%) | 0.03 |
| Clinical presentation | |||
| Stable angina pectoris | 302 (26.3%) | 145 (29.2%) | 0.22 |
| Unstable angina pectoris | 527 (45.8%) | 276 (55.5%) | <0.001 |
| Acute myocardial infarction | 147 (12.8%) | 44 (8.9%) | 0.02 |
| Left ventricular ejection fraction (%) | 0.49 ± 0.14 | 0.52 ± 0.13 | 0.004 |
∗ History of hypertension diagnosed and/or treated with medication or currently being treated with diet and/or medication by a physician.
† Includes patients with previously documented diagnoses of dyslipidemia. Patients may be treated with diet or medication. A new diagnosis can be made during this hospitalization with an increased total cholesterol level >160 mg/dl. Does not include increased triglycerides.
‡ Previously diagnosed or treated with medication, diet, or dialysis by a physician. Diagnosis at admission if a baseline creatinine level >2.0 mg/dl is found.
Procedure characteristics are listed in Table 2 . Several differences were observed between groups in terms of localization and lesion type. Angiographic success was high in the 2 stent groups; however, percutaneous coronary intervention procedures were more complicated in SES patients, including more lesions treated, more intravascular ultrasound guidance, and the use of longer stents and glycoprotein IIb/IIIa inhibitors.
| Variable | SES (n = 1,694) | EES (n = 664) | p Value |
|---|---|---|---|
| Treated vessel | |||
| Left main coronary artery | 28 (1.7%) | 11 (1.7%) | 0.10 |
| Left anterior descending coronary artery | 718 (42.4%) | 226 (40.1%) | 0.30 |
| Left circumflex coronary artery | 330 (19.5%) | 153 (23%) | 0.05 |
| Right coronary artery | 545 (32.2%) | 207 (31.2%) | 0.63 |
| Saphenous vein graft | 66 (3.9%) | 26 (3.9%) | 0.98 |
| Lesion location | |||
| Ostial | 83 (4.9%) | 16 (2.4%) | 0.006 |
| Proximal | 776 (46.2%) | 168 (25.4%) | <0.001 |
| Mid | 633 (37.7%) | 295 (44.6%) | 0.002 |
| Distal | 182 (10.8%) | 165 (24.9%) | <0.001 |
| Restenosis lesion | 76 (4.5%) | 17 (2.6%) | 0.03 |
| Lesion type (American College of Cardiology/American Heart Association classification) | |||
| Type A | 135 (8.2%) | 78.0 (11.9%) | 0.005 |
| Type B1/B2 | 1,187 (71.9%) | 262 (40%) | <0.001 |
| Type C | 329 (19.9%) | 315 (48.1%) | <0.001 |
| Procedural details | |||
| Angiographic success | 1,676 (99.3%) | 662 (99.7%) | 0.37 |
| Abrupt closure | 1 (0.1%) | 0 | 1.00 |
| No reflow | 1 (0.1%) | 0 | 1.00 |
| Number of lesion treated | 1.4 ± 0.7 | 1.3 ± 0.6 | <0.001 |
| Number of stents | 1.5 ± 0.8 | 1.5 ± 0.7 | 0.83 |
| Stent length (mm) | 19.9 ± 6.5 | 18.6 ± 5.9 | <0.001 |
| Stent diameter (mm) | 3.3 ± 9.2 | 3.0 ± 0.4 | 0.21 |
| Intravascular ultrasound | 1,139 (67.6%) | 408 (61.4%) | 0.005 |
| Predilatation | 567 (35.4%) | 213 (32.1%) | 0.13 |
| Postdilatation | 281 (17.6%) | 194 (29.2%) | <0.001 |
| Cutting balloon | 70 (4.1%) | 10 (1.5%) | 0.002 |
| Rotational atherectomy | 52 (3.1%) | 28 (4.2%) | 0.16 |
| Laser | 4 (0.2%) | 1 (0.2%) | 1.00 |
| Brachytherapy | 1 (0.1%) | 0 | 1.00 |
| Glycoprotein IIb/IIIa inhibitor use | 110 (9.6%) | 7 (1.4%) | <0.001 |
In-hospital clinical and procedural complications are listed in Table 3 . No differences were found between groups.
| Event | SES (n = 1,152) | EES (n = 497) | p Value |
|---|---|---|---|
| Q-wave myocardial infarction | 6 (0.5%) | 0 | 0.19 |
| Coronary artery bypass graft surgery | 2 (0.2%) | 4 (0.8%) | 0.07 |
| Subacute stent thrombosis | 4 (0.3%) | 1 (0.2%) | 1.00 |
| Intra-arterial balloon pump | 30 (2.6%) | 12 (2.4%) | 0.80 |
| Death | 14 (1.2%) | 3 (0.6%) | 0.26 |
| Acute renal failure | 30 (2.6%) | 6 (1.2%) | 0.07 |
| Cerebrovascular accident | 5 (0.4%) | 4 (0.8%) | 0.47 |
| Major bleeding | 15 (1.3%) | 7 (1.4%) | 0.86 |
| Vascular complications | 42 (3.7%) | 10 (2.0%) | 0.08 |
Complete 1-year follow-up data were available for almost all patients ( Table 4 ). Patients with SES showed a higher rate of adverse outcomes, especially at 6-month follow-up. They tended to have slightly higher rates of TVR and ST than did EES patients (5.5% vs 3.3%, p = 0.05, and 1.5% vs 0.4%, p = 0.06, respectively). One-year TVR-MACE was lower in the EES group (10.8% vs 14.7%, p = 0.04). That difference was driven mainly by differences in all-cause mortality and ST, which tended to be lower in the EES group (4.6% vs 6.9%, p = 0.08, and 1.5% vs 0.4%, p = 0.06, respectively).
| Variable | SES (n = 1,152) | EES (n = 497) | p Value |
|---|---|---|---|
| 30-day follow-up | |||
| TVR-MACE | 38 (3.3%) | 10 (2.0%) | 0.15 |
| TLR-MACE | 31 (2.7%) | 10 (2.0%) | 0.41 |
| Death | 22 (1.9%) | 5 (1.0%) | 0.18 |
| Cardiac death, in-hospital | 8 (0.7%) | 3 (0.6%) | 1.00 |
| Cardiac death, out of hospital | 4 (0.4%) | 0 | 0.32 |
| TLR | 15 (1.3%) | 4 (0.8%) | 0.38 |
| TVR | 23 (2.0%) | 5 (1.0%) | 0.15 |
| QWMI | 2 (0.2%) | 0 | 1.00 |
| NQWMI | 5 (0.4%) | 2 (0.4%) | 1.00 |
| ST | 15 (1.3%) | 2 (0.4%) | 0.10 |
| 6-month follow-up | |||
| TVR-MACE | 104 (9.0%) | 33 (6.6%) | 0.11 |
| TLR-MACE | 82 (7.1%) | 31 (6.2%) | 0.51 |
| Death | 45 (3.9%) | 19 (3.8%) | 0.92 |
| Cardiac death, in-hospital | 8 (0.7%) | 3 (0.6%) | 1.00 |
| Cardiac death, out of hospital | 9 (0.8%) | 4 (0.8%) | 1.00 |
| TLR | 40 (3.5%) | 13 (2.7%) | 0.37 |
| TVR | 63 (5.5%) | 16 (3.3%) | 0.05 |
| QWMI | 3 (0.3%) | 0 | 0.56 |
| NQWMI | 11 (1.0%) | 6 (1.2%) | 0.64 |
| ST | 17 (1.5%) | 2 (0.4%) | 0.06 |
| 1-year follow-up | |||
| TVR-MACE | 169 (14.7%) | 54 (10.8%) | 0.04 |
| TLR-MACE | 129 (11.3%) | 50 (10%) | 0.47 |
| Death | 78 (6.9%) | 23 (4.6%) | 0.08 |
| Cardiac death, in-hospital | 8 (0.7%) | 3 (0.6%) | 1.00 |
| Cardiac death, out of hospital | 14 (1.2%) | 6 (1.2%) | 0.96 |
| TLR | 56 (5.0%) | 28 (5.8%) | 0.50 |
| TVR | 97 (8.6%) | 33 (6.8%) | 0.24 |
| QWMI | 3 (0.3%) | 1 (0.2%) | 1.00 |
| NQWMI | 16 (1.4%) | 9 (1.9%) | 0.52 |
| ST | 17 (1.5%) | 2 (0.4%) | 0.06 |
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