Long-Term Comparison of Platinum Chromium Everolimus-Eluting Stent vs. Cobalt Chromium Zotarolimus-Eluting Stent　― 3-Year Outcomes From the HOST–ASSURE Randomized Clinical Trial ―

Abstract

Background: There are limited data on the long-term outcome of platinum chromium-based everolimus-eluting stents (PtCr-EES) vs. cobalt chromium-based zotarolimus-eluting stents (CoCr-ZES).

Methods and Results: A total of 3,755 patients undergoing percutaneous coronary intervention (PCI) were randomized 2:1 to PtCr-EES or CoCr-ZES, and 96.0% of patients completed the 3-year clinical follow-up. The primary outcome was target lesion failure (TLF), defined as a composite of cardiac death, target vessel-related myocardial infarction (MI), and clinically-driven target lesion revascularization (TLR). At 3 years, TLF occurred in 5.3% and in 5.4% of the PtCr-EES and CoCr-ZES groups, respectively (hazard ratio 0.978; 95% confidence interval 0.730–1.310, P=0.919). There were no significant differences in the individual components of TLF. Routine angiographic follow-up was performed in 38.9% of the total patients. In a landmark analysis of the subgroup that had follow-up angiography, the clinically-driven TLR rate of CoCr-ZES was significantly higher than PtCr-EES group during the angiography follow-up period (P=0.009). Overall definite and probable stent thrombosis rates were very low in both groups (0.5% vs. 0.6%, P=0.677).

Conclusions: PtCr-EES and CoCr-ZES had similar and excellent long-term outcomes in both efficacy and safety after PCI in an all-comer population.

The platinum chromium (PtCr) alloy has greater radial strength, radio-opacity, and flexibility compared with the cobalt chromium (CoCr) alloy, which may result in potential advantages when developed into coronary stents. We previously reported the 1-year outcomes from the Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Safety & Effectiveness of Drug-Eluting Stents & Anti-platelet Regimen (HOST–ASSURE) randomized controlled trial (RCT), in which the PtCr-EES (Promus Element, Boston Scientific, Natick, MA, USA) was non-inferior to the CoCr-EES in terms of target lesion failure (TLF) with very low rates of stent thrombosis (ST) in patients undergoing percutaneous coronary intervention (PCI).^1–3 This study reports the long-term 3-year outcomes of PtCr-EES vs. CoCr-ZES in all-comers undergoing PCI. Additionally, this was the first long-term comparison of these stents in an Asian population.

Methods

Study Design

The HOST–ASSURE was a prospective, randomized, single-blind, blinded endpoint evaluation, multicenter trial conducted at 40 sites in South Korea. The study was an all-comers study, with a 2×2 design of the type of drug-eluting stent (DES) and the type of 1-month intensified antiplatelet therapy followed by conventional dual antiplatelet therapy (DAPT).¹ Major exclusion criteria were severe left ventricular systolic dysfunction, cardiogenic shock, symptomatic heart failure, and an increased risk of bleeding. Participants were randomized 2:1 to PtCr-EES or CoCr-ZES and 1:1 to triple antiplatelet therapy or double-dose DAPT. The study was approved by the ethics committees at the participating centers and was performed in accordance with the Declaration of Helsinki. Written informed consent was given by all participants.

Procedures and Endpoints

Participants were randomly assigned to the PtCr-EES or CoCr-ZES group by a web-based online randomization system after diagnostic angiography. After the first month of intensified antiplatelet therapy, maintenance of DAPT was left to the discretion of individual physicians with a general recommendation of at least 1 year. PCI was performed according to standard techniques using standard devices by physician’s decision. The primary endpoint was TLF, a composite of cardiac death, target vessel-related myocardial infarction (TV-MI), and clinically-driven target lesion revascularization (TLR). Clinically-driven TLR was defined as a revascularization procedure with at least one of the following: (1) recurrence of chest pain; (2) positive non-invasive test; and (3) angiographically significant stenosis with diameter >70%, for which PCI was deemed necessary. Secondary endpoints included all of the individual components of the primary endpoint as well as ST, patient-oriented clinical outcome (POCO), and all components of POCO (all-cause death, all-cause MI, and any repeat revascularization). All deaths were considered cardiac unless a definite non-cardiac cause could be established. ST was defined as definite or probable according to the Academic Research Consortium (ARC) classification.⁴ An independent clinical event adjudication committee, whose members were unaware of the study group assignments, assessed all of the clinical endpoints. The primary analysis was on an intention-to-treat basis. Routine angiographic follow-up was not mandated, but if performed, was recommended to be done at 12–15 months after the index procedure according to the individual treating physicians’ judgment.

Angiography

Quantitative analysis of angiographic images was performed at a central core laboratory, the Seoul National University Hospital by specialized technicians who were unaware of the purpose of this study and used validated software (CAAS 5.7., Pie Medical Imaging, Maastricht, The Netherlands). A longitudinal stent deformity (LSD) was defined as any inconsistency in the radiodensity pattern along the length of the stent, or other gross irregularities or deformities.

Statistical Analysis

Continuous variables are presented as mean±SD and compared using Student’s t-test. Categorical variables are presented as counts with percentages and compared using chi-square or Fisher’s exact test, as appropriate. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using the Cox proportional-hazards method. Cumulative event rates were estimated using the Kaplan-Meier method. Time-to-event curves were compared using log-rank tests. In patients undergoing routine angiography follow-up, landmark analyses (3 periods: before, during and after routine angiography follow-up period) were performed to determine whether there was a difference in outcomes according to the allocated stent during the routine angiography follow-up period. All analyses were performed using SPSS version 22.0 (IBM Co., Armonk, NY, USA).

Results

Baseline Characteristics and Procedures

A total of 3,755 patients were enrolled at 40 centers in South Korea from June 2010 to November 2011. These patients were randomly allocated to PtCr-EES (2,503 patients) or CoCr-ZES (1,252 patients). A flowchart of the study is provided in Figure 1; 96.0% (3,606/3,755 patients, PtCr-EES group: 96.0% and CoCr-ZES group: 96.2%) of the enrolled patients completed the 3-year follow-up. The baseline patient characteristics are shown in Table 1. There was no difference in demographic characteristics except for the frequency of males and current smokers, who were more frequent in the PtCr-EES group. Table 2 shows the baseline lesional and procedural characteristics. The detailed angiographic parameters were noted in our previous report and there were no significant differences between the 2 groups.³

Figure 1.

Study flowchart. CoCr-ZES, cobalt chromium-based zotarolimus-eluting stent; PtCr-EES, platinum chromium-based everolimus-eluting stent.

Table 1. Baseline Demographic Characteristics

	PtCr-EES (n=2,503)	CoCr-ZES (n=1,252)	P value
Age, years	63.1±10.8	60.78±9.68	0.312
Male	1,746 (69.8)	820 (65.6)	0.010
BMI, kg/m2	24.6±3.2	24.7±3.2	0.189
Hypertension	1,706 (68.2)	852 (68.1)	0.862
Diabetes	795 (31.8)	401 (32.0)	0.862
Dyslipidemia	1,601 (64.0)	822 (65.7)	0.335
Current smoker	823 (32.9)	369 (29.5)	0.040
Chronic renal failure	59 (2.4)	36 (2.9)	0.283
Peripheral artery disease	41 (1.6)	27 (2.2)	0.263
Cerebrovascular disease	172 (6.9)	79 (6.3)	0.486
Previous PCI	247 (9.9)	120 (9.6)	0.691
Previous CABG surgery	16 (0.6)	10 (0.8)	0.580
Previous MI	116 (4.6)	49 (3.9)	0.338
Congestive heart failure	41 (1.6)	13 (1.0)	0.123
Clinical diagnosis			0.708
Silent ischemia	119 (4.8)	63 (5.0)
Stable angina	746 (29.8)	367 (29.3)
Unstable angina	903 (36.1)	476 (38.0)
NSTEMI	452 (18.1)	209 (16.7)
STEMI	283 (11.3)	137 (10.9)
Acute coronary syndrome	1,645 (65.4)	828 (65.7)	0.827

Values are given as mean±standard deviation or n (%). BMI, body mass index; CABG, coronary artery bypass graft; CoCr-ZES, cobalt chromium-based zotarolimus-eluting stent; PCI, percutaneous coronary intervention; PtCr-EES, platinum chromium-based everolimus-eluting stent; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

Table 2. Lesional and Procedural Characteristics

	PtCr-EES (n=2,503)	CoCr-ZES (n=1,252)	P value
Angiographic diagnosis			0.989
1VD	1,150 (45.9)	580 (46.3)
2VD	807 (32.2)	400 (31.9)
3VD	546 (21.8)	272 (21.7)
Target lesions to be treated	1.5±0.8	1.5±0.7	0.069
1	1,766 (70.6)	909 (72.6)
2	570 (22.8)	286 (22.8)
≥3	167 (6.7)	57 (4.6)
No. of stents	1.62±0.92	1.56±0.85	0.061
Maximal stent diameter, mm	3.26±0.45	3.24±0.44	0.281
Total stent length, mm	37.6±24.2	37.9±25.0	0.764
Lesion data	(n=3,426)	(n=1,661)
Target lesion location			0.070
LAD	1,623 (47.4)	852 (51.3)
LCX	751 (21.9)	324 (19.5)
RCA	978 (28.5)	448 (27.0)
LM	74 (2.2)	37 (2.2)
Bifurcation	874 (25.6)	420 (25.3)	0.702
Total occlusion	422 (12.3)	193 (11.6)	0.659
Use of IVUS or OCT	1,037 (41.4)	494 (39.5)	0.495
Use of glycoprotein IIb/IIIa inhibitors	55 (2.2)	37 (3.0)	0.330

Values are given as mean±standard deviation or n (%). CoCr-ZES, cobalt chromium-based zotarolimus-eluting stent; IVUS, intravascular ultrasound; LAD, left anterior descending artery; LCX, left circumflex artery; LM, left main artery; OCT, optical coherence tomography; PtCr-EES, platinum chromium-based everolimus-eluting stent; RCA, right coronary artery.

The regimen of antiplatelet therapy during follow-up is summarized in Supplementary Table 1. Patients received, in addition to aspirin, either double-dose clopidogrel or single dose clopidogrel+cilostazol for the first month post-PCI and then were recommended to receive conventional DAPT up to 1 year. The 2 groups showed similar rates of DAPT at both 1 year and 3 years (% of patients on DAPT: 91.6% and 49.2% at 1-year and 3-year follow-up, respectively).

Clinical Outcomes at 3 Years

At 3 years, TLF had occurred in 5.3% and 5.4% of the population in the PtCr-EES and CoCr-ZES groups, respectively (HR 0.978, 95% CI 0.730–1.310, P=0.919) (Table 3; Figure 2A). There were no significant differences in the individual components of TLF (cardiac death, 2.8% vs. 2.4%, P=0.493; TV-MI, 1.0% vs. 0.7%, P=0.451; clinically-driven TLR, 2.2% vs. 2.7%, P=0.314; Figure 2B–D). POCO was also comparable between the 2 groups, and occurred in 12.6% and 13.0% of the PtCr-EES and CoCr-ZES groups, respectively (HR 0.975, 95% CI 0.807–1.178, P=0.797; Figure 3A). Among the individual components of POCO, rates of all-cause MI (1.7% vs. 1.6%, P=0.762) and any revascularization (7.6% vs. 9.1%, P=0.133) were similar between the groups (Figure 3C,D). However, the rate of all-cause death was higher in the PtCr-EES group (4.8% vs. 3.4%; HR 1.456, 95% CI 1.025–2.069, P=0.036; Figure 3B). This was because of a significant difference in the occurrence of non-cardiac death (2.1% vs 1.0%, P=0.014). The specific causes of non-cardiac deaths are summarized in Supplementary Table 2. Subgroup analyses of TLF showed consistent findings with no significant interaction between the different subgroups and the allocated stent (Supplementary Table 3). ARC-defined definite and probable ST rates were very low, and occurred in 0.5% and 0.6% in the PtCr-EES and CoCr-ZES groups, respectively (P=0.677, Supplementary Figure). There were 3 cases of very late definite ST in the PtCr-EES group, occurring on days 701, 787, and 932 from the index procedure, but not in the CoCr-ZES group. All these patients continued DAPT until 1 year after PCI, and were on aspirin monotherapy at the time of the event. Details of the individual cases of ST are described in Supplementary Table 4.

Table 3. Cumulative Incidence of Clinical Events Up to 3 Years

	PtCr-EES (n=2,503)	CoCr-ZES (n=1,252)	HR (95% CI)	P value
TLF	132 (5.3)	68 (5.4)	0.978 (0.730–1.310)	0.919
Patient-oriented clinical outcome	316 (12.6)	163 (13.0)	0.975 (0.807–1.178)	0.797
All-cause death	121 (4.8)	42 (3.4)	1.456 (1.025–2.069)	0.036
Cardiac	69 (2.8)	30 (2.4)	1.162 (0.757–1.783)	0.493
Non-cardiac	52 (2.1)	12 (1.0)	2.193 (1.170–4.107)	0.014
All-cause MI	43 (1.7)	20 (1.6)	1.085 (0.638–1.845)	0.762
Target vessel-related MI	24 (1.0)	9 (0.7)	1.343 (0.624–2.889)	0.451
Repeat revascularization	190 (7.6)	114 (9.1)	0.837 (0.663–1.056)	0.133
TLR	95 (3.8)	52 (4.2)	0.925 (0.660–1.297)	0.652
Clinically-driven repeat revascularization	97 (3.9)	64 (5.1)	0.763 (0.556–1.046)	0.093
Clinically-driven TLR	54 (2.2)	34 (2.7)	0.802 (0.522–1.232)	0.314
Definite or probable ST	13 (0.5)	7 (0.6)	0.839 (0.367–1.917)	0.677
Cerebrovascular accident	32 (1.3)	14 (1.1)	1.084 (0.575–2.045)	0.803
Ischemic	27 (1.1)	9 (0.7)	1.462 (0.685–3.120)	0.326
Hemorrhagic	5 (0.2)	2 (0.2)	1.012 (0.185–5.527)	0.989
All PLATO bleeding	63 (2.5)	27 (2.2)	1.220 (0.773–1.927)	0.394
Major bleeding	25 (1.0)	13 (1.0)	1.048 (0.527–2.087)	0.893
Major, life-threatening	3 (0.1)	4 (0.3)	0.507 (0.102–2.512)	0.405

Values are n (%). Target lesion failure (TLF) was a composite of cardiac death, target vessel-related myocardial infarction (TV-MI), and clinically-driven TLR; patient-oriented clinical outcome was a composite of all-cause death, all-cause MI, and any repeat revascularization. CoCr-ZES, cobalt chromium-based zotarolimus-eluting stent; PtCr-EES, platinum chromium-based everolimus-eluting stent; PLATO, PLATelet inhibition and patient Outcomes; ST, stent thrombosis; TLR, target lesion revascularization.

Figure 2.

Kaplan-Meier curves of target lesion failure (TLF) and individual components of TLF. (A) TLF, (B) cardiac death, (C) target vessel-related myocardial infarction, (D) clinically-driven target lesion revascularization (TLR). CoCr-ZES, cobalt chromium-based zotarolimus-eluting stent; PtCr-EES, platinum chromium-based everolimus-eluting stent.

Figure 3.

Kaplan-Meier curves of patient-oriented clinical outcome (POCO) and its individual components. (A) POCO, (B) all-cause death, (C) all-cause myocardial infarction, (D) any revascularization. CoCr-ZES, cobalt chromium-based zotarolimus-eluting stent; PtCr-EES, platinum chromium-based everolimus-eluting stent.

Landmark Analyses of 1–3-Year Clinical Outcomes

Landmark analyses were performed from 1 year to 3 years. TLF occurred in 3.1% and 3.6% of the population in the PtCr-EES and CoCr-ZES groups, respectively (HR 0.881, 95% CI 0.605–1.281, P=0.506). There were no significant differences in the individual components of TLF from 1 year to 3 years (cardiac death, 1.4% vs. 1.0%, P=0.731; TV-MI, 0.1% vs. 0.2%, P=0.472; clinically-driven TLR, 0.9% vs. 1.5%, P=0.122).

Routine Angiography Follow-up

Although routine follow-up coronary angiography was not mandated, it was performed in 38.9% of the patients (median time from index PCI: 402 days, interquartile range: 41 days), and in 38 (95.0%) of the 40 centers. The decision to perform routine coronary angiography was up to each individual physician’s discretion. The proportion of patients having routine angiographic follow-up was similar between the 2 stent groups (38.2% vs. 40.4% in PtCr-EES vs. CoCr-ZES, P=0.190). In this group of patients, clinically-driven TLR occurred more frequently in the CoCr-ZES group (P=0.009, Figure 4), while the rates were similar in those that did not have routine follow-up angiography (P=0.156). No significant interaction in the clinically-driven TLR group between routine angiography follow-up and stent type was observed (P=0.911). There was no significant difference in TLF or TLR before or after the routine angiographic follow-up period.

Figure 4.

Landmark analyses of TLF and clinically-driven TLR in patients with routine angiography follow-up. (A) TLF, (B) clinically-driven TLR. Abbreviations as in Figure 2.

Long-Term Outcome of Cases With Initial Longitudinal Stent Deformation

Previously, we reported 7 cases of angiographically overt LSD at baseline, which occurred exclusively in the PtCr-EES group (2 occurred in the left main coronary artery, 4 in the left anterior descending artery (LAD), and 1 in the right coronary artery (RCA)). Of these patients, only 1 required additional stent implantation at baseline procedure (LAD); 3 of the patients stopped DAPT at 1 year post-PCI and 4 continued DAPT for 3 years. Of those who discontinued DAPT after 1 year, 1 patient continued aspirin and 2 patients continued clopidogrel as single antiplatelet treatment. At 3 years of follow-up, none of the overt LSD cases were associated with further adverse events.

Discussion

The PtCr-EES and CoCr-ZES are 2 of the most commonly implanted 2nd-generation DES. The current study reports the 3-year long-term outcomes from the HOST–ASSURE RCT, which compared these 2 stent platforms head to head for the first time in an all-comer East Asian population. The major findings of the present analysis are as follows: (1) at 3 years, PtCr-EES and CoCr-ZES had similar rates of TLF, a composite of cardiac death, TV-MI, and clinically-driven TLR, and the individual components of TLF were similar between the 2 stents; (2) the rate of repeat revascularization with the CoCr-ZES was slightly higher than with the PtCr-EES but only in those undergoing routine angiographic follow-up, suggesting an oculostenotic reflex; and (3) very late ST occurred in 3 patients in the PtCr-EES group and in none of the CoCr-ZES group. Both stents showed excellent safety with overall definite or probable ST rates below 1%.

Currently, 2nd-generation DES are the mainstay of treatment of patients with significant coronary artery disease. Innovations in stent design and alloy have allowed manufacturers to reduce the strut thickness, resulting in better deliverability and conformability. Further, the incorporation of more biocompatible polymers has resulted in less inflammatory response and vascular toxicity. This has resulted in improved clinical outcomes in both randomized studies and meta-analyses compared with bare metal stents or 1st-generation DES.^5–14 Compared with the CoCr alloy, PtCr has greater radial strength, less recoil, and greater radiopacity, which may offer potential advantages in visualization and long-term outcomes.

In the Resolute All-Comers trial, similar results for CoCr-ZES compared with CoCr-EES were shown at 1-, 2-, 4-, and final 5-year follow-up.^15–18 In the PLATINUM study, the non-inferiority of PtCr-EES to CoCr-EES in terms of safety and efficacy was shown up to 12 months post-PCI.¹⁹ However, before our study, there were no direct comparisons of CoCr-ZES and PtCr-EES. As we reported in the 1-year follow-up results of the HOST–ASSURE RCT, PtCr-EES was non-inferior to CoCr-ZES in terms of TLF.³ Also, the 2-year results of the DUTCH PEERS study showed similar results, with low event rates for both PtCr-EES and CoCr-ZES.²⁰ Our 3-year follow-up results are in line with these previous studies. Although the PtCr alloy itself has a greater radial strength and radiopacity than the CoCr alloy, it does not lead to a benefit in clinical outcome, which suggests that the general evolution in antiproliferative drugs, polymers, use of DAPT, and procedural techniques, as well as in stent alloys, has contributed to the overall improvement in the outcomes of PCI.

In the current study, we found similar rates of TLF and POCO at 3 years. One finding that was not previously reported was that the repeat revascularization rates in those having routine angiographic follow-up was slightly but statistically significantly higher in the CoCr-ZES group. This phenomenon was not observed in the subgroup without routine angiographic follow-up. Because follow-up angiography is susceptible to the oculostenotic reflex, there is a tendency to perform repeat revascularization more frequently because of a perceived degree of angiographic stenosis, especially in stents that have slightly greater late loss. We believe that the permissive nature of the study protocol regarding angiographic follow-up and repeat revascularization may have resulted in oculostenotic PCI rather than ischemia-driven revascularization. However, our results also suggested that the CoCr-ZES may have slightly greater angiographic late luminal loss and in-stent restenosis rates than the PtCr-EES, although quantitative coronary angiographic analysis was not performed in the follow-up cases. In the literature, the reported late luminal loss of CoCr-ZES is 0.27 µm,¹⁵ which is greater than that reported for PtCr-EES (0.15 µm).²¹ Regarding the risk of very late definite or probable ST, the overall rates were extremely low for both stents (0.0% vs. 0.1% for CoCr-ZES vs. PtCr-EES, P=0.220), confirming the long-term safety of both stent platforms. Furthermore, it was a relief to observe no additional adverse clinical events in the 7 cases of overt LSD at baseline.

Overall, the device-oriented event rates and patient-oriented event rates of the current study were lower than those reported in previous trials. There may be several reasons for this. First, DAPT was maintained for a long period of time in this study (56.5% at 2 years and 49.2% at 3 years). Considering that 65% of the patients had acute coronary syndrome as the clinical presentation, and the average stent length was 28 mm per lesion and 38 mm per patient, it is not surprising that a significant proportion of the treating physicians decided to maintain DAPT for longer. Second, the patients in the present study received intensified antiplatelet therapy during the first month post-PCI. Therefore, the 1-year outcomes also showed low rates of clinical events (1-year TLF 2.9%). There may have been possible “legacy effects” of the intensified antiplatelet regimens beyond the first months of therapy. Third, the percentage of patients receiving “image-guided” or at least “image-supported” PCI was 40.8%, which is significantly higher than the real-world use rate.²² It is well known from previous studies that in patients undergoing long stenting and complex PCI, imaging support can improve clinical outcomes.²³ Fourth, post-procedural cardiac enzyme measurement was not mandated in the study, and thus post-procedural MI may not have been fully captured, which could not be confirmed, and may also have lowered the rate of TLF even further. Finally, the study was conducted in an East Asian population. It is known that East Asians can have lower rates of ischemic events after PCI, the so-called “East Asian paradox”.^24,25 It has been shown in multiple trials from Korea, Japan, and China that the TLF rates are relatively low in similar clinical groups.^26–30 Even though the mechanism of lower ischemic event rates in East Asians is currently unknown, differing levels of thrombogenicity such as lower baseline inflammatory status, response to antiplatelet therapy, and hypercoagulability according to ethnicity are hypothesized to contribute to this phenomenon.³¹

Study Limitations

First, the 3-year TLF rates were lower than in other studies. However, we performed periodic monitoring and data audits throughout this trial. Also, a meticulous search of all patients who were lost to follow-up was performed and thus we had a high 3-year follow-up rate, and the occurrence of death was confirmed using a national verification system. Therefore, we believe that the possibility of event underreporting is very low. Rather, the reasons just mentioned may better explain our findings. Another limitation was the permissive nature of the study protocol regarding angiographic follow-up and repeat revascularization, which resulted in an artificially high percentage of routine angiographic follow-up. Furthermore, this may have resulted in oculostenotic PCI rather than ischemia-driven revascularization. Therefore, there may be limitations in comparing the natural clinical course of PCI using 2 different stents.

Conclusions

The PtCr-EES and CoCr-ZES had similar and excellent long-term outcomes in both efficacy and safety after PCI in an all-comer East Asian population.

Acknowledgments

This study was supported by an unrestricted grant from Boston Scientific Korea. The funding source had no role in the study design, data collection, monitoring, analysis, interpretation or writing of the manuscript.

Disclosures

The authors declare no conflict of interest.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-1303

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