Abstract
Objective:
There is a scarcity of comparative studies between Endeavor Resolute®-zotarolimus-eluting stent (R-ZES) and Resolute Integrity®-ZES (I-ZES) during long-term follow-up periods. Although the stent alloy and the polymer of these two ZESs are similar, the platform and the design of these two stents are different. This study was conducted to compare the efficacy and safety of these two different ZESs in the all-comer Korean patients who underwent percutaneous coronary intervention (PCI) during a 3-year follow-up period.
Methods:
This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. In this single-center, retrospective, and all-comer patients’ cohort study, a total of 889 patients who underwent PCI with R-ZES (n=394) or I-ZES (n=495) were enrolled. The primary endpoint was the occurrence of major adverse cardiac events (MACEs) defined as all-cause death, nonfatal myocardial infarction (MI), any repeat revascularization including target lesion revascularization (TLR), target vessel revascularization (TVR), and non-TVR, and the secondary endpoint was stent thrombosis (ST) at 3 years.
Results:
To adjust for any potential confounders, the propensity score-adjusted multivariable analysis was performed using the logistic regression model (C-statistics=0.689). The cumulative incidence rates of MACEs [adjusted hazard ratio (aHR), 1.341; 95% confidence interval (CI), 0.615–2.922; p=0.461], all-cause death, nonfatal MI, any repeat revascularization, and ST (aHR, 2.090; 95% CI, 0.163–26.77; p=0.571) were similar between the two groups during the 3-year follow-up period.
Conclusion:
R-ZES and I-ZES demonstrated comparable efficacy and safety after PCI during a 3-year follow-up period. However, these results can perhaps be more precisely defined by other large and long-term follow-up studies in the future.
Keywords: zotarolimus, drug-eluting stent, outcomes
Introduction
After the approval of the U.S. Food and Drug Administration (FDA) for the sirolimus-eluting stent (SES, Cypher®, Cordis Corp., Miami Lakes, Florida, USA) in April 2003, and for the paclitaxel-eluting stent (PES, Taxus®, Boston Scientific, Natick, Massachusetts, USA) in March 2004 (1), the zotarolimus-eluting stent (ZES) received FDA’s approval approximately 4 years later and has been widely used in clinical practice (2). Zotarolimus has similar antiproliferative capacity and is more lipophilic compared with sirolimus (3). The Endeavor Resolute®-ZES (R-ZES, Medtronic Cardiovascular, Santa Rosa, California, USA) and the Resolute Integrity®-ZES (I-ZES, Medtronic Cardiovascular, Santa Rosa, California, USA) are cobalt-based alloy stents with a thin biocompatible BioLinx-polymer coating system (4-6). Compared with phosphorylcholine polymer, the BioLinx-polymer coating system is composed of three different components such as hydrophilic C19, hydrophobic C10, and a water-soluble polyvinyl pyrrolidinone component and offers potentially improved biocompatibility and extended release of zotarolimus, with 85% of the drug being released within 60 days and the remainder up to 180 days (7, 8). Therefore, this BioLinx-polymer system decreased restenosis and maintained low stent thrombosis (ST) rates through sustained longer duration of zotarolimus release (7). Although the stent alloy and the polymer of these two ZESs are similar, the platform and the design of these two stents are different. R-ZES used Driver® bare-metal stent (BMS) and modular technology, whereas I-ZER used Integrity® BMS and continuous sinusoidal technology. This enhanced sinusoidal technology offers improved flexibility, tracking, and deliverability (9). However, the thickness of the platform of these two stents was similar at 91 µm. Compared with the first-generation drug-eluting stents (DESs), ZESs have more advanced strut design, polymer system, and antiproliferative material to reduce the risk of in-stent restenosis (ISR) (10).
However, it is unclear whether the advanced stent platform and design can improve long-term clinical outcomes, especially in the same class of ZESs. Although Di Santo et al. (7) reported that the clinical performance and safety were similar between R-ZES and I-ZES, several previous studies have compared the efficacy and safety among different classes of DESs (7, 8, 10). Therefore, there are limited long-term clinical outcome data comparing the clinical outcomes among the same class of DESs, especially according to the different stent platform, stent design, and identical polymer in all-comer patients who have undergone successful percutaneous coronary intervention (PCI). Therefore, we investigated the efficacy and safety of these two different ZESs in patients after PCI during a 3-year follow-up period.
In Korea, a more recently developed ZES, Resolute Onyx®-ZES, was launched by Medtronic Korea in March 2015. Due to the short follow-up period after Resolute Onyx®-ZES deployment, we excluded those patients. Regarding this launching time, R-ZES and I-ZES are the latest ZESs in Korea. Therefore, we compared the clinical outcomes between these two stents in this study.
Methods
Study population
This study was a single-center, retrospective, all-comer patients’ registry designed to reflect the “real-world” practice since 2004. Data were collected by trained study coordinators using a standardized case report form. This study has been examined and approved by the Local Ethics Committee, and the subjects provided informed written consent. This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. A total of 4041 patients who underwent PCI between January 2004 and December 2014 at the Cardiovascular Center of Korea University Guro Hospital, Seoul, South Korea, were enrolled. Exclusion criteria were cardiogenic shock or cardiopulmonary resuscitation (n=38), other types of DES (except for R-ZES or I-ZES) implantation (n=3072), and lost to follow-up or did not participate (n=42). Finally, 889 patients who were treated with R-ZES (n=394) or I-ZES (n=495) were eligible for this study (Fig. 1).
Figure 1.
Flow chart
PCI - percutaneous coronary intervention, CPR - cardiopulmonary resuscitation, R - Endeavor Resolute®, I - Resolute Integrity®, ZES - zotarolimus-eluting stent, * - other type of stents except for R-ZES and I-ZES
PCI procedure and medical treatment
A diagnostic coronary angiography (CAG) and PCI were performed through either the femoral or the radial artery after an administration of unfractionated heparin (70–100 IU/kg). Patient’s activated clotting time was maintained at >250 s during the procedure. All patients received a loading dose of 200–300 mg aspirin and 300–600 mg clopidogrel as the dual antiplatelet therapy (DAPT) and were maintained with 100 mg aspirin and 75 mg clopidogrel. The use of cilostazol (Pletaal®, Otsuka Pharmaceutical Co., Tokyo, Japan) or platelet glycoprotein IIb/IIIa receptor blockers was left to the discretion of the individual operators. After stent implantation, DAPT (100mg daily aspirin and 75 mg daily clopidogrel) was prescribed at least for 12 months. During hospitalization, the enrolled patients had taken cardiovascular beneficial medications, including all types of antiplatelet agents (aspirin, clopidogrel), beta-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and lipid-lowering agents. After discharge, the patients were recommended to stay on the same medications they received during hospitalization.
Study definitions and clinical follow-up
All the cardiovascular risk factors and past medical histories were based on patients’ self-report. The primary endpoint was the occurrence of major adverse cardiac events (MACEs) defined as all-cause death, nonfatal myocardial infarction (MI), any repeat revascularization including target lesion revascularization (TLR), target vessel revascularization (TVR), and non-TVR, and the secondary endpoint was ST at 3 years.
All-cause deaths were defined as cardiac (CD) or non-CD. Nonfatal MI was defined as the presence of clinical symptoms, electrocardiographic changes, or abnormal imaging findings of MI, combined with an increase in the creatine kinase myocardial band fraction (CK-MB) above the upper normal limits or an increase in troponin-T/troponin-I to greater than the 99th percentile of the upper normal limit (4). TLR was defined as a revascularization of the target lesion due to restenosis or reocclusion within the stent or 5 mm in and adjacent of the distal or proximal segment. TVR was defined as a revascularization of the target vessel or any segment of the coronary artery containing the target lesion. Non-TVR was defined as a revascularization of any segment of the nontarget coronary artery. ST was defined as acute (0–24 h), subacute (24 h to 30 days), late (30 days to 1 year), and very late (>1 year) according to the onset time of ST (11). The participants were required to visit the outpatient department of cardiology at the end of the first month and then every 3–6 months after the index PCI procedure, and we were able to follow-up on the clinical data of all the enrolled patients through face-to-face interviews at regular outpatient clinic, medical chart reviews, and telephone contacts. Therefore, all the enrolled patients had completed their follow-up program.
Statistical analysis
All data were processed with SPSS 20 (SPSS Inc., Chicago, IL, USA). For continuous variables, differences between the two groups were evaluated using the unpaired t-test or the Mann–Whitney U rank test. Data are expressed as mean±standard deviation or median (quartile 1 to quartile 3). For discrete variables, differences are expressed as counts and percentages and analyzed using χ2 or Fisher’s exact test between the groups as appropriate. To adjust for any potential confounders, the propensity score (PS)-adjusted multivariable analysis was performed using the logistic regression model. We included all meaningful confounding covariates (p<0.005) or those having predictive values in the multivariable Cox proportional hazard regression analysis. These covariates included men, age, ST-segment elevation MI (STEMI), non-NSTEMI, previous cerebrovascular accidents, peripheral vascular disease, chronic kidney disease, routine angiographic follow-up, CK-MB, total cholesterol, low-density lipoprotein-cholesterol, treated chronic total occlusive lesion, diffuse long lesion (>30 mm), small vessel disease (≤2.25 mm), bifurcation, mean total stent length, mean stent diameter, number of stents/patient, and post-PCI medications (aspirin, clopidogrel, BBs, ACEIs, and ARBs). The PS was estimated using the C-statistics for the logistic regression model, and the PS for the two groups was 0.689 in this study. For all analyses, a 2-sided p<0.05 was considered as statistically significant.
Results
Baseline characteristics and angiographic characteristics
Table 1 shows the baseline clinical and angiographic characteristics. Before PSM adjustment, the mean age (62.9±10.9 vs. 64.0±11.2 years, p=0.124) and gender distribution (men, 70.8% vs. 69.9%, p=0.767) were similar between the two groups. The number of patients with STEMI, serum level of CK-MB, total cholesterol, low-density lipoprotein-cholesterol, diffuse long lesion, bifurcation lesion, and mean total stent length were significantly higher in the R-ZES group than in the I-ZES group. In contrast, the number of previous cerebrovascular accidents, peripheral vascular disease, chronic kidney disease, small vessel disease, mean stent diameter, and number of stents for each patient were significantly higher in the I-ZES group than in the R-ZES group. Furthermore, the total procedure time was similar between the two groups.
Table 1.
Baseline, angiographic characteristics, and post-PCI medications
| Variables | Total (n=889) | R-ZES (n=394) | I-ZES (n=495) | P value |
|---|---|---|---|---|
| Men, n (%) | 625 (70.3) | 279 (70.8) | 346 (69.9) | 0.767 |
| Age (years) | 63.5±11.1 | 62.9±10.9 | 64.0±11.2 | 0.124 |
| LVEF (%) | 55.1±8.6 | 55.1±8.6 | 55.0±8.6 | 0.855 |
| Stable angina, n (%) | 227 (25.5) | 94 (23.9) | 133 (26.9) | 0.306 |
| Unstable angina, n (%) | 308 (34.6) | 140 (35.5) | 168 (33.9) | 0.620 |
| STEMI, n (%) | 161 (18.1) | 105 (26.6) | 56 (11.3) | <0.001 |
| NSTEMI, n (%) | 155 (17.4) | 52 (13.2) | 103 (20.8) | 0.003 |
| Hypertension, n (%) | 580 (65.2) | 254 (64.5) | 326 (65.9) | 0.665 |
| Diabetes mellitus, n (%) | 326 (36.7) | 138 (35.0) | 188 (38.0) | 0.364 |
| Dyslipidemia, n (%) | 158 (17.7) | 66 (16.8) | 92 (18.6) | 0.477 |
| Previous CVA, n (%) | 50 (5.6) | 14 (3.6) | 36 (7.3) | 0.017 |
| Previous MI, n (%) | 1 (0.1) | 0 (0.0) | 1 (0.2) | 0.372 |
| Previous PCI, n (%) | 2 (0.2) | 2 (0.5) | 0 (0.0) | 0.133 |
| Peripheral vascular disease, n (%) | 34 (3.8) | 9 (2.3) | 25 (5.1) | 0.033 |
| Chronic kidney disease, n (%) | 44 (4.9) | 10 (2.5) | 34 (6.9) | 0.003 |
| Routine angiographic follow-up | 359 (40.4) | 183 (46.4) | 176 (35.6) | <0.001 |
| CK-MB (mg/dL), initial | 3.6 (2.1-34.8) | 3.8 (2.4-43.8) | 3.5 (1.9-36.7) | 0.016 |
| Troponin-T (ng/dL), initial | 0.019 (0.010-0.210) | 0.018 (0.010-0.150) | 0.020 (0.010-0.270) | 0.622 |
| High-sensitivity CRP (mg/dL) | 1.4 (0.6-4.6) | 1.5 (0.6-4.8) | 1.3 (0.7-4.4) | 0.290 |
| Total cholesterol (mg/L) | 175.4±29.3 | 179.1±41.8 | 171.7±45.8 | 0.019 |
| Triglyceride (mg/L) | 145.7±112.3 | 143.5±99.8 | 147.9±125.0 | 0.621 |
| HDL cholesterol (mg/L) | 43.9±10.6 | 43.5±10.5 | 44.2±11.0 | 0.429 |
| LDL cholesterol (mg/L) | 111.5±32.3 | 113.7±34.9 | 109.4±30.8 | 0.048 |
| Serum creatinine (mg/L) | 0.99±0.99 | 0.91±0.60 | 1.06±1.36 | 0.057 |
| Serum glucose (mg/dL) | 127.1±56.4 | 129.6±59.9 | 124.6±52.9 | 0.232 |
| Hemoglobin A1C (%) | 6.1 (5.6-6.9) | 6.1 (5.7-6.8) | 6.1 (5.6-7.0) | 0.195 |
| Angiographic characteristics | ||||
| Targeted vessel | ||||
| Left anterior descending, n (%) | 564 (63.4) | 254 (64.5) | 310 (62.6) | 0.571 |
| Left circumflex, n (%) | 303 (34.1) | 122 (31.0) | 181 (36.6) | 0.080 |
| Right coronary artery, n (%) | 307 (34.5) | 135 (34.3) | 172 (34.7) | 0.880 |
| Left main, n (%) | 19 (2.1) | 5 (1.3) | 14 (2.8) | 0.110 |
| Ramus, n (%) | 10 (1.1) | 2 (0.5) | 8 (1.6) | 0.119 |
| Number of MVD (≥2 vessels) | 263 (29.6) | 107 (27.2) | 156 (31.5) | 0.157 |
| ACC/AHA lesion type | ||||
| Type B1, n (%) | 50 (5.6) | 20 (5.1) | 30 (6.1) | 0.527 |
| Type B2, n (%) | 217 (24.4) | 93 (23.6) | 124 (25.1) | 0.618 |
| Type C, n (%) | 621 (69.9) | 281 (71.3) | 340 (68.7) | 0.395 |
| Extent of CAD, n (%) | ||||
| 1-vessel | 624 (70.2) | 287 (72.8) | 337 (68.1) | 0.123 |
| 2-vessel | 213 (24.0) | 90 (22.8) | 123 (24.8) | 0.486 |
| 3-vessel | 52 (5.8) | 17 (4.3) | 35 (7.1) | 0.082 |
| Treated CTO | 85 (9.6) | 48 (12.2) | 37 (7.5) | 0.018 |
| Ostial lesion (≤5 mm), n (%) | 162 (18.2) | 62 (15.7) | 100 (20.2) | 0.087 |
| Diffuse long lesion (>30 mm), n (%) | 417 (46.9) | 206 (52.3) | 211 (42.6) | 0.004 |
| Small vessel disease (≤2.25 mm), n (%) | 110 (12.4) | 33 (8.4) | 77 (15.6) | 0.001 |
| Bifurcation, n (%) | 342 (38.5) | 171 (43.4) | 171 (34.5) | 0.007 |
| Heavy calcification | 149 (16.8) | 69 (17.5) | 80 (16.2) | 0.592 |
| Mean total stent length (mm) | 23.1±6.5 | 23.8±6.5 | 22.2±6.6 | <0.001 |
| Mean stent diameter (mm) | 2.95±0.42 | 2.92±0.39 | 2.98±0.46 | 0.032 |
| Number of stents/patient | 1.62±0.93 | 1.50±0.83 | 1.74±1.05 | <0.001 |
| Total procedure time (min) | 43.1±43.4 | 41.3±57.2 | 44.7±29.5 | 0.262 |
| Post-PCI medications | ||||
| Aspirin, n (%) | 840 (94.5) | 379 (98.2) | 461 (93.1) | 0.047 |
| Clopidogrel, n (%) | 826 (92.1) | 379 (96.2) | 447 (90.3) | 0.001 |
| Cilostazol, n (%) | 178 (20.0) | 87 (22.1) | 91 (18.4) | 0.171 |
| Beta-blockers, n (%) | 474 (53.3) | 240 (60.9) | 234 (47.3) | <0.001 |
| Calcium channel blockers, n (%) | 311 (35.0) | 124 (31.5) | 187 (37.8) | 0.050 |
| ACEIs, n (%) | 285 (32.1) | 149 (37.8) | 136 (27.5) | 0.001 |
| ARBs, n (%) | 334 (37.6) | 131 (33.2) | 203 (41.0) | 0.018 |
| Diuretics, n (%) | 179 (20.1) | 89 (22.6) | 90 (18.2) | 0.104 |
| Lipid-lowering agents, n (%) | 786 (88.4) | 351 (89.1) | 435 (87.9) | 0.576 |
Values are expressed as numbers (percentage), mean±SD, or median (quartile 1- quartile 3). For continuous variables, differences were analyzed using the unpaired t-test or the Mann–Whitney U rank test. For discrete variables, differences were analyzed using χ2 or Fisher’s exact test. R - Endeavor Resolute®, I - Resolute Integrity®, ZES - zotarolimus-eluting stent, LVEF - left ventricular ejection fraction, STEMI - ST-segment elevation myocardial infarction, NSTEMI - non-STEMI, CVA - cerebrovascular accidents, CK - creatine kinase myocardial band, CRP - C-reactive protein, HDL - high-density lipoprotein, LDL - low-density lipoprotein, MVD -multivessel disease, ACC/AHA - American College of Cardiology/American Heart Association, CAD - coronary artery disease, CTO - chronic total occlusive lesion, PCI - percutaneous coronary intervention, ACEIs - angiotensin-converting enzyme inhibitors,ARBs - angiotensin receptor blockers
Post-PCI medications
Table 1 shows the post-PCI medications between the two groups. The prescription rates of aspirin (98.2% vs. 93.1%, p=0.047), clopidogrel (96.2% vs. 90.3%, p=0.001), BBs (60.9% vs. 47.3%, p<0.001), and ACEIs (37.8% vs. 27.5%, p=0.001) were significantly higher in the R-ZES group. However, ARBs (33.2% vs. 41.0%, p=0.018) was much more frequently prescribed in the I-ZES group than in the R-ZES group.
Clinical outcomes
Table 2 shows the clinical outcomes at 30 days, 1 year, and 3 years for the two groups. During 1 month after the index PCI, the incidence of MACEs was not significantly different between the two groups (1.3% vs. 1.4%, p=0.852). At 1 year, the incidence rates of MACEs and ST were similar between the two groups. At 3 years, the incidence rates of MACEs (8.6% vs. 9.7%, p=0.585) and ST (1.0% vs. 0.6%, p=0.706) were also comparable between the two groups. The results of the PS-adjusted multivariable analysis of MACEs [adjusted hazard ratio (aHR), 1.341; 95% confidence interval (CI), 0.615–2.922; p=0.461, Fig. 2a], ST (aHR, 2.090; 95% CI, 0.163–26.77, p=0.571, Fig. 2b), all-cause death (aHR, 1.843; 95% CI, 0.401–8.480; p=0.432), cardiac death (aHR, 4.805; 95% CI, 0.500–46.17; p=0.174), nonfatal MI (aHR, 1.429; 95% CI, 0.280–7.301; p=0.668), any repeat revascularization (aHR, 1.238; 95% CI, 0.496–3.094; p=0.548), TLR (aHR, 2.284; 95% CI, 0.699–5.470: p=0.172), TVR (aHR, 1.895; 95% CI, 1.102–3.402; p=0.451), and non-TVR (aHR, 1.834; 95% CI, 0.439–7.672; p=0.406) were also similar between the two groups (Table 3). The subgroup analysis showed that in case of the non-diabetes group, the choice of I-ZES may be preferable rather than R-ZES to reduce MACEs after PCI (Fig. 3).
Table 2.
Clinical outcomes at 30 days, 1 year, and 3 years
| Outcomes | Total (n=889) | R-ZESs (n=394) | I-ZESs (n=495) | P value |
|---|---|---|---|---|
| 30 days | ||||
| MACEs | 12 (1.3) | 5 (1.3) | 7 (1.4) | 0.852 |
| All-cause death, n (%) | 8 (0.9) | 3 (0.8) | 5 (1.0) | 0.697 |
| Cardiac death, n (%) | 7 (0.8) | 3 (0.8) | 4 (0.8) | 0.938 |
| Nonfatal MI, n (%) | 7 (0.8) | 4 (1.0) | 3 (0.6) | 0.493 |
| Any repeat revascularization, n (%) | 7 (0.8) | 3 (0.8) | 4 (0.8) | 0.938 |
| TLR, n (%) | 5 (0.6) | 2 (0.5) | 3 (0.6) | 0.845 |
| TVR, n (%) | 7 (0.8) | 3 (0.8) | 4 (0.8) | 0.938 |
| Non-TVR, n (%) | 1 (0.1) | 1 (0.3) | 0 (0.0) | 0.443 |
| ST (definite, probable), n (%) | ||||
| Acute, n (%) | 3 (0.3) | 2 (0.5) | 1 (0.2) | 0.587 |
| Subacute, n (%) | 2 (0.2) | 0 (0.0) | 2 (0.4) | 0.506 |
| Total, n (%) | 5 (0.6) | 2 (0.5) | 3 (0.6) | 0.845 |
| 1 year | ||||
| MACEs, n (%) | 57 (6.4) | 25 (6.3) | 32 (6.5) | 0.942 |
| All-cause death, n (%) | 18 (2.0) | 6 (1.5) | 12 (2.4) | 0.473 |
| Cardiac death, n (%) | 12 (1.3) | 3 (0.8) | 9 (1.8) | 0.245 |
| Nonfatal MI, n (%) | 9 (1.0) | 5 (1.3) | 4 (0.8) | 0.520 |
| Any repeat revascularization, n (%) | 43 (4.8) | 19 (4.8) | 24 (4.8) | 0.986 |
| TLR, n (%) | 24 (2.7) | 11 (2.8) | 13 (2.6) | 0.880 |
| TVR, n (%) | 31 (3.5) | 13 (3.3) | 18 (3.6) | 0.855 |
| Non-TVR, n (%) | 13 (1.5) | 9 (2.3) | 4 (0.8) | 0.091 |
| ST (definite, probable), n (%) | ||||
| Late (31–365 days) | 0 (0.0) | 0 (0.0) | 0 (0.0) | - |
| Total (1–365 days) | 5 (0.6) | 2 (0.5) | 3 (0.6) | 0.845 |
| 3 years | ||||
| MACEs, n (%) | 82 (9.2) | 34 (8.6) | 48 (9.7) | 0.585 |
| All-cause death, n (%) | 22 (2.5) | 8 (2.0) | 14 (2.8) | 0.519 |
| Cardiac death, n (%) | 12 (1.3) | 3 (0.8) | 9 (1.8) | 0.245 |
| Nonfatal MI, n (%) | 19 (2.1) | 10 (2.5) | 9 (1.8) | 0.491 |
| Any repeat revascularization, n (%) | 59 (6.6) | 25 (6.3) | 34 (6.9) | 0.755 |
| TLR, n (%) | 35 (3.9) | 16 (4.1) | 19 (3.8) | 0.846 |
| TVR, n (%) | 49 (5.5) | 19 (4.8) | 30 (6.1) | 0.422 |
| Non-TVR, n (%) | 16 (1.8) | 10 (2.5) | 6 (1.2) | 0.203 |
| ST (definite, probable), n (%) | ||||
| Very late (366–1095 days) | 2 (0.2) | 2 (0.5) | 0 (0.0) | 0.196 |
| Total (1–1095 days) | 7 (0.8) | 4 (1.0) | 3 (0.6) | 0.706 |
Values are numbers and percentages. The p values for categorical data were obtained from the chi-square test. R - Endeavor Resolute®, I -Resolute Integrity®, ZES -zotarolimus-eluting stent, MI - myocardial infarction, TLR - target lesion revascularization, TVR - target vessel revascularization, MACEs - major adverse cardiac events, ST - stent thrombosis
Figure 2.
Kaplan–Meier curved analysis of MACE-free survival (a) and stent thrombosis (b) between the R-ZES and I-ZES groups at 3 years
R - Endeavor Resolute®, I - Resolute Integrity®, ZES - zotarolimus-eluting stent, HR - hazard ratio, CI - confidence interval
Table 3.
Three-year clinical outcomes by multivariable Cox regression analysis and PS-adjusted multivariable Cox regression analysis
| Outcomes | Cumulative Events at 3 years (%) | Adjusted HR*(95% CI) | P value | PS-adjusted HR*(95% CI) | P value | ||
|---|---|---|---|---|---|---|---|
| R-ZES | I-ZES | P value | |||||
| MACEs | 34 (8.6) | 48 (9.7) | 0.585 | 1.155 (0.667-2002) | 0.606 | 1.341 (0.615-2.922) | 0.461 |
| All-cause death | 8 (2.0) | 14 (2.8) | 0.519 | 1.467 (0.396-5.437) | 0.556 | 1.843 (0.401-8.480) | 0.432 |
| Cardiac death | 3 (0.8) | 9 (1.8) | 0.245 | 3.709 (0.270-37.26) | 0.315 | 4.805 (0.500-46.17) | 0.174 |
| Non-fatal MI | 10 (2.5) | 9 (1.8) | 0.491 | 1.262 (0.436-3.654) | 0.742 | 1.429 (0.280-7.301) | 0.668 |
| Any repeat revascularization | 25 (6.3) | 34 (6.9) | 0.755 | 1.053 (0.567-1.925) | 0.867 | 1.238 (0.496-3.094) | 0.548 |
| TLR | 16 (4.1) | 19 (3.8) | 0.846 | 1.208 (0.554-2.638) | 0.634 | 2.284 (0.699-5.470) | 0.172 |
| TVR | 19 (4.8) | 30 (6.1) | 0.422 | 2.261 (0.903-4.437) | 0.107 | 1.895 (1.102-3.402) | 0.451 |
| Non-TVR | 10 (2.5) | 6 (1.2) | 0.203 | 1.627 (0.491-5.387) | 0.426 | 1.834 (0.439-7.672) | 0.406 |
| Stent thrombosis | 4 (1.0) | 3 (0.6) | 0.706 | 2.305 (0.240-39.63) | 0.209 | 2.090 (0.163-26.77) | 0.571 |
Adjusted by men, age, STEMI, NSTEMI, previous CVA, PVD, CKD, RAF, CK-MB, total cholesterol, LDL-cholesterol, treated CTO, diffuse long lesion (>30mm), small vessel disease (≤2.25mm), bifurcation, mean total sent length, mean stent diameter, number of stent/patient, post-PCI medications (aspirin, clopidogrel, BBs, ACEIs, and ARBs).
R - Endeavor Resolute®, I - Resolute Integrity®, ZES - zotarolimus-eluting stent, HR - hazard ratio, CI - confidence interval, PS - propensity-score, MACEs - major adverse cardiac events, MI - myocardial infarction, TLR - target lesion revascularization, TVR - target vessel revascularization, STEMI - ST-segment elevation myocardial infarction, NSTEMI - non-STEMI,
CVA - cerebrovascular accidents, PVD - peripheral vascular disease, CKD - chronic kidney disease, RAF - routine angiographic follow-up, CK-MB - creatine kinase myocardial band, LDL - low density lipoprotein, CTO - chronic total occlusive lesion, BBs - beta-blockers, ACEIs - angiotensin converting enzyme inhibitors, ARBs - angiotensin receptor blockers
Figure 3.
Subgroup analyses of MACEs
MACEs - major adverse cardiac events, R-ZES - Endeavor resolute®-ZES, I-ZES - Resolute integrity®-ZES, STEMI - ST-segment elevation myocardial infarction, ACC/AHA - American College of Cardiology/American Heart Association, LVEF - left ventricular ejection fraction
Discussion
The primary finding of this “real-world” all-comer patients’ PS-adjusted multivariable analysis study is that the cumulative incidence rates of MACEs, all-cause death, cardiac death, nonfatal MI, any repeat revascularization, TLR, TVR, and non-TVR were comparable between R-ZES and I-ZES, and the cumulative incidence of ST was not significantly different between the two groups during the 3-year follow-up period. Therefore, R-ZES and I-ZES demonstrate comparable efficacy and safety for treating CAD in the all-comer patients despite the different stent platform and stent design.
Although stent platforms, stent design, delivery system, and polymers have rapidly evolved (11), the safety and efficacy results between R-ZES and I-ZES have not been completely illuminated. In general, we expect that newer generation stents may have several advantages rather than those previously used or currently being used. Hence, it is necessary to estimate the safety and efficacy of these two ZESs in the “real-world” routine clinical practice. There is a high scarcity of comparative studies between R-ZES and I-ZES. Di Santo et al. (7) reported the comparative safety and efficacy of R-ZES versus I-ZES during a 1-year follow-up period. They reported that the unadjusted rates of MACEs [R-ZES (3.2%) vs. I-ZES (5.0%), p=0.43, odds ratio, 1.37; 95% CI, 0.46–4.07, p=0.57], mortality [R-ZES (0.9%) vs. I-ZES (1.9%), p=0.59], and nonfatal MI [R-ZES (2.3%) vs. I-ZES (3.1), p=0.75] were similar between the two groups. In our study, the rates of MACEs in all patients were 6.3% in the R-ZES group and 6.5% in the I-ZES group (p=0.942) during the 1-year follow-up period. The primary cause of this difference between our study and the study of Di Santo et al. (7) was the definition of MACEs. In the study of Di Santo et al. (7), MACEs were defined as the composite of all-cause death, nonfatal MI, and CVA not including TLR, TVR, and non-TVR. Regardless of the definition of MACEs and the number of study population, our study demonstrated a similar pattern of major outcomes as those reported in the study of Di Santo et al. (7) between the R-ZES and I-ZES groups. Therefore, based on the results of the study of Di Santo et al. (7) and those of our study, the modifications in the stent platform design do not likely translate into differences in the clinical outcomes. Because of the deficit of a randomized direct comparison of these stents, more potential advantages of this newer I-ZES stent platform remain unrevealed.
Ishikawa et al. (12) reported the results of a comparative study on the clinical outcomes between Taxus Liberte® (TAXUS-Lib; Boston Scientific, Natick, MA, USA) and Taxus Express® (TAXUS-Exp; Boston Scientific). They also reported a similar result that the only difference between these two Taxus stents is the stent design, which implies that the Taxus Liberte® stent has a thinner strut and greater space to improve uniform drug distribution. The dose of delivering drug and the release pharmacokinetics are identical between these two Taxus stents. The clinical outcomes (cardiac death, nonfatal MI, and definite ST) were not significantly different between these stents during a 700-day follow-up period. These results also suggest that the new advanced stent design could not demonstrate improved clinical outcomes compared with the old stent design in case of the Taxus stents.
To estimate the beneficial effects of sinusoidal technology, we performed a subgroup analysis of MACEs using the PS-adjusted multivariable analysis (Fig. 3). In cases of ACC/AHA type C lesion (adjusted HR, 1.27; 95% CI, 0.57–2.84; p=0.567), diffuse long lesion (>30 mm, adjusted HR, 1.18; 95% CI, 0.44–3.19; p=0.745), and heavy calcified lesion (adjusted HR, 1.50; 95% CI, 0.44–5.13; p=0.518), the adjusted HRs were not significantly different between the two groups. Therefore, unlike our expectations, the sinusoidal technology did not show beneficial effects in this study.
ST is another debatable issue in the DES era. In the first 1 month after DES implantation, the polymer plays an important role to inhibit neointimal hyperplasia by controlling drug-release kinetics (13, 14). We can expect that the B-polymer system can exhibited a decreased ST rate due to its sustained longer duration of zotarolimus release (8). In the TWENTE II trial (13), the incidence of definite or probable ST of I-ZES was 1.4% during the 3-year follow-up. In our study, the 3-year overall definite/probable ST rates of ST were 1.0% in the R-ZES group and 0.6% in the I-ZES group (p=0.706). The RESOLUTE US trial (5) reported an ST rate of 0.0% in the R-ZES group during a 1-year follow-up period. Moreover, Cassese et al. (15) suggested that first- and second-generation ZESs have similar thrombogenicity compared with other limus-eluting stents. However, this issue is debatable, and further large-scale, randomized, well-controlled trials with longer follow-up would be required to verify these findings.
The results of this study may be considered as important for several reasons. First, although I-ZES was more recently developed than R-ZES using the enhanced sinusoidal technology, these modifications in the stent platform design were not associated with improved clinical outcomes in this study. To our knowledge, any other randomized or comparative study did not deal with clinical outcomes (more than 3 years) between R-ZES and I-ZES. Regarding limited long-term clinical outcome data comparing the clinical outcomes among the same class of DESs, especially under the circumstance of different types of stent platform and stent design with the same polymer system, we speculate that our study may provide a valuable message to interventional cardiologists in the era of new-generation DESs. Second, the study population consisted of all-comer patients, not confining to a specific population, except for patients who were complicated with cardiogenic shock or those who had cardiopulmonary resuscitation on admission. In this regard, this study may have merit reflecting the “real-world” routine clinical practice.
Study limitations
This study has some limitations. First, because it is a nonrandomized registry design and single-center study, several confounding factors such as underreporting and/or missing values and selection bias may have affected the end results. Second, imaging modality-guided [e.g., intravascular ultrasound (IVUS), optical coherence tomography (OCT)] PCI can improve the clinical outcomes in terms of optimal stent expansion, minimizing geographic miss, and directing appropriate stent sizing to maximize the final stent area (16). Fractional flow reserve (FFR)-guided PCI is associated with a significantly lower rate of MACEs (17). Unfortunately, in this study, imaging or functional studies were conducted only for a small number of patients (<10%). In Korea, currently, there is very restricted reimbursement program for FFR, IVUS, OCT, or cardiac computed tomography and magnetic resonance imaging; hence, PCI decision largely depends on clinical decision in real-world clinical practice. Therefore, we could not perform fine analysis for the pattern and amount of neointimal hyperplasia between the two stents. Third, the strategy of antiplatelet therapies (e.g., DAPT or triple antiplatelet therapy) was left to the physician’s discretion, which may have influenced the major clinical outcomes. Fourth, even though this study was all-comer patients’ registry, the number of patients enrolled in this study was limited and may be underpowered to define major clinical outcome differences between the two groups.
Conclusion
This single-center, retrospective, all-comer patients’ cohort study demonstrated comparable efficacy and safety between R-ZES and I-ZES in patients after PCI during a 3-year follow-up period. However, these results can perhaps be more precisely defined by other large and long-term follow-up studies in the future.
Footnotes
Conflict of interest: None declared.
Peer-review: Externally peer-reviewed.
Authorship contributions: Concept – Y.H.K., A.Y.H., S.W.R.; Design – Y.H.K., A.Y.H., S.W.R., B.G.C.; Supervision – S.W.R., H.S.S.; Funding – None; Materials – S.W.R., Y.P., D.O.K., W.Y. J., W.K., C.U.C., H.S.S.; Data collection and/or processing – Y.H.K., A.Y.H., S.W.R., B.G.C., S.Y.C., J.K.B., Y.P., D.O.K., W.Y. J., W.K., C.U.C., H.S.S.; Analysis and/or interpretation – Y.H.K., A.Y.H., S.W.R., B.G.C., S.Y.C., J.K.B., Y.P., D.O.K., W.Y. J., W.K., C.U.C., H.S.S.; Literature search – Y.H.K., A.Y.H., S.W.R., S.Y.C., J.K.B., H.S.S.; Writing – Y.H.K., A.Y.H., S.W.R.; Critical review – Y.H.K., A.Y.H., S.W.R. H.S.S.
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