Cardiovascular Revascularization Medicine 15 (2014) 334–339

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Cardiovascular Revascularization Medicine

Safety and efficacy of everolimus-eluting stents compared with first-generation drug-eluting stents in patients undergoing primary percutaneous coronary intervention Ricardo O. Escárcega, Nevin C. Baker, Marco A. Magalhaes, Michael J. Lipinski, Sa’ar Minha, Rebecca Torguson, Lowell F. Satler, Augusto D. Pichard, William O. Suddath, Ron Waksman ⁎ Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC

a r t i c l e

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Article history: Received 7 August 2014 Accepted 7 August 2014 Keywords: Everolimus-eluting stent ST-elevation myocardial infarction Sirolimus-eluting stent Paclitaxel-eluting stent

a b s t r a c t Objective: To assess the safety and efficacy everolimus-eluting stents (EES) compared with first-generation drug-eluting stents (DES) in patients with acute myocardial infarction (MI) undergoing primary percutaneous coronary intervention (PCI). Background: EES have been associated with improved clinical outcomes compared to paclitaxel-eluting stents (PES) and with similar outcomes compared to sirolimus-eluting stents (SES). Methods: A total of 520 patients who presented with ST-elevation myocardial infarction (STEMI) from 2003 to 2013, who underwent primary PCI with DES, were retrospectively analyzed. Of these, 247 received SES, 136 PES, and 137 EES. Patients were followed up to 2 years for major adverse cardiac events (MACE). Univariate and multivariate models detected correlates to outcome. Results: EES implantation, compared with PES and SES, resulted in comparable rates of MACE (8.8% vs. 16.2%, p = 0.06 and 8.8% vs. 12.6%, respectively, p = 0.26), stent thrombosis, MI, and target lesion revascularization. Patients who received EES had lower rates of all-cause mortality (3.7% vs. 12.6% vs. 9.4%, p = 0.03) at 1-year follow up. However, in the univariate and multivariate analyses, stent type was not independently associated with the primary outcome or with all-cause mortality. Diabetes mellitus and number of stents implanted were independently associated with the primary outcome. Conclusion: While EES seem to be associated with better outcome when compared to PES, the main correlates of STEMI patients are the presence of diabetes and number of stents implanted, and not the type of stent used for intervention. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Primary percutaneous coronary intervention (PCI) in patients presenting with ST-segment elevation myocardial infarction (STEMI) leads to significantly improved clinical outcomes compared with thrombolytic therapy [1]. Meta-analyses of randomized trials showed similar safety and superior efficacy of 1st-generation drug-eluting stents (DES) over bare metal stents in primary PCI for STEMI, driven primarily by lower rates of target lesion revascularization (TLR) [2]. Long-term studies have suggested that both 1st-generation DES achieve similar clinical outcomes [3]. The XIENCE V everolimus-eluting stent (EES) (Abbott Vascular, Santa Clara, CA) was approved in the United States in 2008 after the Everolimus-Eluting Coronary Stent System in the Treatment of Patients with de novo Coronary Artery Lesions (SPIRIT) randomized trial series [4–7] demonstrated its safety and efficacy compared with 1st-generation DES. Two prospective, ⁎ Corresponding author at: MedStar Washington Hospital Center, 110 Irving St., NW, Suite 4B1, Washington, DC 20010. Tel.: +1 202 877 2812; fax: +1 202 877 2715. E-mail address: [email protected] (R. Waksman). http://dx.doi.org/10.1016/j.carrev.2014.08.002 1553-8389/© 2014 Elsevier Inc. All rights reserved.

randomized clinical trials have compared the XIENCE V stent with 1stgeneration DES in primary PCI for patients presenting with acute myocardial infarction (MI) in a selected population. Xience V stent vs. Cypher stent in primary PCI for Acute Myocardial Infarction (XAMI) [8] and the European Comparison of the Everolimus-eluting XIENCE V stent with the paclitaxel eluting TAXUS Liberté stent in all-comers: a randomized open label trial (COMPARE) trials [9] evaluated EES vs. sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES), respectively. The present study assessed the long-term safety and efficacy of EES compared with the 1st-generation DES in patients who presented with STEMI. 2. Methods From 2003 to 2012, 520 patients underwent primary PCI for new STsegment elevation in 2 contiguous leads or a new left bundle branch block, cardiogenic shock (defined as systolic blood pressure b90 mm Hg for at least 30 minutes or cardiac index b 2.2 L min−1 m −2, and increased filling pressures), or significant ventricular arrhythmia with either PES, SES, or EES. This study complied with the principles of the

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Table 1 Baseline characteristics. Variable

EES (n = 137)

PES (n = 136)

SES (n = 247)

Overall (n = 520)

p Value

Age (years) Men European American African American Hispanic Diabetes mellitus Chronic renal failure Systemic hypertension⁎ Hypercholesterolemia⁎⁎

60 ± 11.4 91 (66%) 79 (57%) 49 (36%) 3 (2.2%) 43 (32%) 16 (12%) 104 (76%) 100 (73%) 18 (13%) 13 (9.5%) 50 (36%) 42 (31%) 27 (20%) 29(21%) 10 (7%) 6 (4.4%)

61 ± 12.3 94 (69%) 80 (59%) 42 (31%) 2 (1.5%) 49 (36%) 18 (13%) 104 (77%) 110 (81%) 10 (8%) 13 (10%) 58 (42%) 55 (43%) 11 (8%) 18 (14%) 18 (13%) 24 (18%)

61 ± 12.7 156 (63%) 176 (71%) 53 (21%) 3 (1.2%) 62 (25%) 34 (14%) 198 (81%) 204 (84%) 18 (8%) 24 (10%) 96 (39%) 110 (48%) 39 (16%) 38 (16%) 25 (10%) 41 (17%)

61 ± 12.2 341 (65%) 335 (64%) 144 (28%) 8 (1.5%) 154 (30%) 68 (13%) 406 (79%) 414 (81%) 46 (9%) 50 (10%) 204 (40%) 207 (42%) 77 (15%) 85 (17%) 53 (10%) 71 (14%)

0.45 0.55 b0.01 b0.01 0.89 0.08 0.82 0.42 0.02 0.16 0.99 0.57 b0.01 0.02 0.27 0.27 b0.01

Heart failure Peripheral vascular disease Current smoker Family history of coronary disease Previous myocardial infarction Previous coronary intervention Previous coronary artery bypass graft Cardiogenic shock

⁎ History of systemic hypertension diagnosed and/or treated with medication or currently being treated with diet and/or medication by a physician. ⁎⁎ Includes patients with a previously documented diagnosis of hypercholesterolemia. The patient may be treated with diet or medication. A new diagnosis can be made during this hospitalization with an elevated total cholesterol N160 mg/dl. Does not include elevated triglycerides.

Declaration of Helsinki regarding investigation in humans and was approved by our institutional review board. All patients underwent primary PCI by standard techniques according to clinical guidelines current at the time of procedure. The choice of stent type, interventional strategy, and use of adjunctive devices and pharmacotherapy were at the discretion of the operator. All patients received aspirin 325 mg before the procedure. A clopidogrel loading dose of 300–600 mg or prasugrel 60 mg was co-administered. Aspirin was continued indefinitely and clopidogrel 75 mg/day was continued for ≥12 months after PCI. During the procedure, patients were anticoagulated with bivalirudin or unfractionated heparin. The use of glycoprotein IIb/IIIa inhibitors was left to the discretion of the operator. The primary end point was major adverse cardiovascular events (MACE) at 1 year, defined as the composite of all-cause death, MI, and TLR. All-cause death was defined as death from any cardiac or noncardiac cause. Q-wave MI was defined as evidence of new pathological Q waves in N2 contiguous leads on the electrocardiogram. MI was defined as a total creatinine kinase increase of N 2× the upper limit of normal and/or creatinine kinase (MB fraction) N20 ng/ml, along with symptoms and/or electrocardiographic changes suggestive of myocardial ischemia. TLR was defined as ischemia-driven percutaneous or surgical repeat intervention in the stent or within 5 mm proximal or distal to the stent. Stent thrombosis (ST) was defined according to the

Academic Research Consortium definitions as definite or probable ST. Systemic hypertension was defined as a blood pressure N140/90 mm Hg or the use of antihypertensive therapy. Hypercholesterolemia was defined as fasting cholesterol of N250 mg/dl or the use of lipid-lowering therapy. Congestive heart failure was defined as evidence of fluid retention from cardiac causes before admission. Angiographic success was defined as postprocedural stenosis b 30% and Thrombolysis In Myocardial Infarction flow grade 3. Statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC). Continuous variables are expressed as mean ± SD for normally distributed variables. Categorical variables are expressed as percentages. Analyses of the differences among the 3 groups were performed using analysis of variance for continuous variables and chi-square test or Fisher exact test for categorical variables. Cox proportional hazard analysis was performed to detect predictors of 1year MACE. Variables were selected on the basis of overall clinical relevance. Variables included in the model were blood transfusion, bivalirudin use, hypercholesterolemia, systemic hypertension, diabetes mellitus, type C lesion, type B1/2 lesion, stent type (EES, paclitaxel-eluting stent, or sirolimus-eluting stent), total stent length per lesion, number of stents implanted, and left anterior descending artery stent implantation. After univariate analysis, variables with a p value of b0.1 were incorporated into the multivariate analysis. The results are presented

Table 2 Procedural and lesion characteristics. Variable Procedural characteristics Number of stents implanted Angiographic success Maximum stent diameter (mm) Total stent length (mm) Glycoprotein IIb/IIIa Bivalirudin Blood transfusion Lesion characteristics Left main Left anterior descending Left circumflex Right coronary Saphenous vein graft Type A lesion Type B1 or B2 lesion Type C lesion

EES (n = 180)

PES (n = 190)

SES (n = 372)

Overall (n = 742)

p Value

1.5 ± 0.76 179 (99%) 2.9 ± 0.3 19 ± 5.2 21 (15%) 113 (82%) 8 (6%)

1.4 ± 0.7 190 (100%) 3 ± 0.2 21.2 ± 5.3 31 (23%) 64 (47%) 18 (13%)

1.5 ± 0.7 366 (99%) 3.1 ± 2 20.8 ± 6.1 71 (29%) 96 (39%) 15 (6%)

1.5 ± 0.7 735 (99%) 3 ± 1.4 20.4 ± 5.7 123 (24%) 273 (52%) 41 (8%)

0.27 0.44 0.51 b0.01 0.01 b0.01 0.03

4 (2.2%) 63 (35%) 38 (21%) 73 (40%) 2 (1.1%) 12 (7%) 69 (38%) 99 (55%)

3 (1.6%) 67 (35%) 29 (15%) 82 (43%) 8 (4.2%) 11 (6%) 119 (63%) 57 (30.5%)

1 (0.3%) 164 (44%) 60 (16%) 137 (37%) 10 (2.7%) 17 (5%) 254 (69%) 95 (26%)

8 (1.1%) 294 (39%) 127 (17%) 292 (39%) 20 (2.7%) 40 (5.5%) 442 (60%) 251 (34%)

0.04 0.04 0.25 0.32 0.18 0.59 b0.01 b0.01

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Table 3 Clinical outcomes of everolimus-eluting stents vs. paclitaxel-eluting stents at 1 year. Variable

EES (n = 137)

PES (n = 136)

Overall (n = 273)

p Value

Major adverse cardiovascular events All-cause death Q-wave myocardial infarction Non-Q-wave myocardial infarction Target vessel revascularization Stent thrombosis

12 (8.8%)

22 (16.2%)

34 (12%)

0.06

5 (3.7%) 2 (1.5%) 2 (1.5%)

17 (12.6%) 0 1 (0.8%)

22 (8.1%) 2 (0.8%) 3 (1.2%)

0.007 0.49 N0.99

7 (5.2%) 0

6 (4.8%) 0

13 (5%) 0

0.86 NA

Table 4 Clinical outcomes of everolimus-eluting stents vs. sirolimus-eluting stents at 1 year. Variable

EES (n = 137)

SES (n = 247)

Overall (n = 384)

p Value

Major adverse cardiovascular events All-cause death Q-wave myocardial infarction Non-Q-wave myocardial infarction Target vessel revascularization Stent thrombosis

12 (8.8%)

31 (12.6%)

43 (11.3%)

0.26

5 (3.7%) 2 (1.5%) 2 (1.5%)

23 (9.4%) 0 1 (0.4%)

28 (7.4%) 2 (0.6%) 3 (0.8%)

0.04 0.13 0.55

7 (5.2%) 0

10 (4.3%) 3 (1.2%)

17 (4.6%) 3 (0.8%)

0.68 0.55

as adjusted hazard ratios with their 95% confidence interval and p values. MACE-free, ST-free and death-free survival rates were calculated using the Kaplan-Meier method. The log-rank test was used to compare the differences in curves among groups. A p value of b0.05 was considered to be statistically significant. 3. Results A total of 520 patients (742 lesions) were included. Of these patients, 137 patients received EES (180 lesions), 136 PES (190 lesions), and 247 SES (372 lesions). Table 1 shows the groups’

baseline characteristics. The average age of the entire population was 61 ± 12 years. The baseline characteristics were generally comparable; however, patients who received 1st-generation DES had a significantly greater prevalence of family history of coronary artery disease, hypercholesterolemia and cardiogenic shock at presentation, whereas patients who received EES had a significantly greater prevalence of prior MI. Angiographic and procedural characteristics are listed in Table 2 (listed as number of lesions treated). The anatomic and procedural characteristics were generally comparable among the 3 groups. Bivalirudin, however, was used more frequently in patients who received EES, while glycoprotein IIb/IIIa inhibitors were used more frequently in the 1st-generation DES group. The total stent length was significantly longer in the 1st-generation DES group. There were no differences in the number of stents implanted or in maximum stent diameter. The overall rate of left main intervention was 1.1%, left anterior descending 39% (significantly more patients received a stent to the left anterior descending in the SES group), circumflex artery 17%, right coronary artery 39.4%, and saphenous vein graft 2.7%. (Table 2) Patients treated with EES had more complex lesions as is evident by a near 2-fold increase in type C lesions compared with patients who received PES or SES. Table 3 depicts the adverse clinical events comparing EES to PES at 1 year. There was a significant trend towards the use of EES vs. PES in terms of MACE at 12 months (8.8% vs. 16.2%, p = 0.06), while all-cause mortality was lower in the EES group (3.7% vs. 12.6%, p = 0.007). Nevertheless, the rates of MI, TLR, and ST were not significantly different at 12 months. Table 4 shows the adverse clinical events comparing EES to SES at 1 year. The overall MACE rate was not statistically significantly different (8.8% vs. 12.6%, p = 0.26), while all-cause death was significantly lower in the EES group (3.7% vs. 9.4%, p = 0.04). The rates of MI, TLR, and ST were not statistically different at 1 year. During 1-year follow-up, overall MACE occurred in 12.5% of the entire population (EES 8.8%, PES 16.2%, SES 12.6%, p = 0.18). (Fig. 1) Allcause mortality was lowest in the EES group (EES 3.7%, PES 12.6%, SES 9.4%, p = 0.03). (Figs. 2 and 3) There was no difference in cardiac death both in- and out-of-hospital. The rates of Q-wave MI and nonQ-wave MI were not significantly different among groups. TLR rates

Fig. 1. Kaplan-Meier curve of MACE for EES, PES and SES. MACE, major adverse cardiac events; EES, everolimus-eluting stent; PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent.

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Fig. 2. A) Kaplan-Meier curve of MACE for EES vs SES; B) Kaplan-Meier curve of MACE for EES vs PES. MACE, major adverse cardiac events; EES, everolimus-eluting stent; PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent.

were also comparable among groups (EES 5.2%, PES 4.8%, SES 4.3%, p = 0.92). At 1-year follow-up, no ST was recorded in the EES and PES groups; while 3 were recorded in the SES group (p = 0.4) (Fig. 4). A multivariate model designed to assess the association among stent type, baseline and procedural characteristics, and MACE at 1 year showed that stent type was not independently associated with the primary outcome. History of diabetes mellitus and the number of stents implanted per patient were independent predictors of the primary outcome. (Table 5) In addition, multivariate analysis found a trend favoring EES vs. PES, while the comparison between EES and SES revealed no statistical difference.

4. Discussion The present study reports the clinical experience with EES and 1st-generation DES in a high volume, single-center registry of an unrestricted population of patients undergoing emergent primary PCI. In our population, when compared to 1st-generation DES, EES yielded similar rates of MI, TLR and MACE at 1-year follow-up, with a significant trend towards better MACE rates when compared with PES. Although not independently associated with MACE in multivariate analysis, patients who received EES had lower rates of all-cause mortality.

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Fig. 3. Kaplan–Meier curve of all-cause mortality for EES, PES and SES. EES, everolimus-eluting stent; PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent.

STEMI is associated with a heightened state of thrombosis and has an increased risk of stent malaposition and under-deployment due to underlying thrombus [10]. Nevertheless, the use of DES in acute MI has not been associated with increased adverse events [11]. Multiple trials have documented the superiority of DES over bare metal stents in the treatment of STEMI patients. In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial [12], patients who received PES had lower TLR rates compared with patients who received bare metal stents (4.5% vs. 7.5%, HR = 0.59, 95% CI 0.43–0.83, p = 0.002). Similarly, a large meta-analysis of randomized trials including a STEMI-only population [13], reported that the overall risk of ST, MI and death was comparable between 1st-generation DES and bare

metal stents; however, the use of DES lead to a remarkable reduction in TLR (HR 0.38, 95% CI 0.29–0.50, p b 0.001). EES are superior to bare metal stents in STEMI patients. The everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (EXAMINATION) randomized trial [14] showed that EES significantly reduced TLR and ST rates. Furthermore, 2 randomized trials have compared the use of EES to 1st-generation DES in STEMI patients. The XAMI trial [8] reported that EES were non-inferior to SES, and superiority for MACE was suggested (EES 4% vs. SES 7.7%, p = 0.04). Compared to the present study, in XAMI N 90% of patients presented with Killip class I, and the prevalence of cardiovascular risk factors such as diabetes mellitus, systemic hypertension, and chronic renal impairment was remarkably

Fig. 4. Kaplan–Meier curve of definite/probable ST for EES, PES and SES. ST, stent thrombosis; EES, everolimus-eluting stent; PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent.

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Table 5 Univariate and multivariate analyses for predictors of major adverse cardiovascular events at 1 year. Variable

Everolimus-eluting stent vs. paclitaxel-eluting stent Everolimus-eluting stent vs. sirolimus-eluting stent Diabetes mellitus Hypercholesterolemia Systemic hypertension Bivalirudin Type C lesion Type B1 or B2 Stent length Number of stents implanted Left anterior descending artery stent implantation

Univariate

Multivariate

HR

95% CI

p Value

HR

95% CI

p Value

1.92 1.46 2.49 2.88 1.97 0.92 0.79 1.32 1.01 1.44 1.06

0.95–3.87 0.75–2.86 1.52–4.06 1.15–7.17 0.94–4.12 0.57–1.49 0.47–1.32 0.78–2.23 0.96–1.05 1.08–1.92 0.65–1.73

0.06 0.25 b0.01 0.02 0.07 0.73 0.36 0.29 0.78 0.01 0.80

1.87 1.42 2.3 2.1 1.08 1.38 -

0.91–3.82 0.72–2.81 1.4–4.02 0.85–5.63 0.48–2.3 1.01-1.88 -

0.08 0.30 b0.01 0.10 0.84 0.04 -

lower than in our population. In addition, our study compares EES to both SES and PES in an unrestricted population. Thus, a direct comparison between end points in both studies may not be appropriate. A second randomized trial comparing the efficacy and safety of EES to first-generation DES in acute MI was the COMPARE study [9], which included patients with STEMI and non-STEMI. The results showed that at 2 years’ follow-up, EES were superior to PES in terms of safety and efficacy with significant reductions in MACE (RR = 0.57, 95% CI 0.40– 0.83; p = 0.002) in the overall population. The effect was more marked in the STEMI group (RR = 0.51, 95% CI 0.30–0.87, p = 0.01). In addition, ST rates were significantly lower in the EES group. In contrast to our study, COMPARE included patients with both STEMI and non-STEMI and the prevalence of cardiovascular risk factors was lower than in our population. Prior observations have shown that PES may be associated with MACE rates N10% in patients undergoing primary PCI [15]. In our study, the use of EES yielded MACE rates b10%, while the MACE rate seen with PES was 16%. In addition, our study did not find an independent association between stent type and the primary outcome after multivariate analysis; however, there was a significant trend favoring EES when compared with PES. In contrast, the use of EES compared with SES yielded similar outcomes. Of note, our study showed reduced rates of all-cause mortality at 1-year follow-up in the EES group. Additional multivariate analyses identified that history of diabetes mellitus and number of stents implanted were independently associated with worse outcome, which is consistent with prior observations [16]. Our study had several limitations. Our analysis was a retrospective comparison of 3 drug-eluting stent types. The results may have been affected by unmeasured confounders. Furthermore, the present study included patients treated during a long time period during which changes in patients’ standard of care may have influenced the outcome, irrespective of the stent implanted. Finally our follow-up was limited to 12 months. References [1] Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13–20. [2] De Luca G, Dirksen MT, Spaulding C, Kelbaek H, Schalij M, Thuesen L, et al. DrugEluting Stent in Primary Angioplasty C. Drug-eluting vs bare-metal stents in primary angioplasty: a pooled patient-level meta-analysis of randomized trials. Arch Intern Med 2012;172:611–21. [3] Kim HS, Lee JH, Lee SW, Kim YH, Park JH, Choi SW, et al. Long-term safety and efficacy of sirolimus- vs. paclitaxel-eluting stent implantation for

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