Five-year outcomes of biodegradable versus second-generation durable polymer drug-eluting stents used in complex percutaneous coronary intervention

Abstract

Background: 

There are few data comparing clinical outcomes of complex percutaneous coronary intervention (CPCI) when using biodegradable polymer drug-eluting stents (BP-DES) or second-generation durable polymer drug-eluting stents (DP-DES). The purpose of this study was to investigate the safety and efficacy of BP-DES and compare that with DP-DES in patients with and without CPCI during a 5-year follow-up.

Methods: 

Patients who exclusively underwent BP-DES or DP-DES implantation in 2013 at Fuwai hospital were consecutively enrolled and stratified into two categories based on CPCI presence or absence. CPCI included at least one of the following features: unprotected left main lesion, ≥2 lesions treated, ≥2 stents implanted, total stent length >40 mm, moderate-to-severe calcified lesion, chronic total occlusion, or bifurcated target lesion. The primary endpoint was major adverse cardiac events (MACE) including all-cause death, recurrent myocardial infarction, and total coronary revascularization (target lesion revascularization, target vessel revascularization [TVR], and non-TVR) during the 5-year follow-up. The secondary endpoint was total coronary revascularization.

Results: 

Among the 7712 patients included, 4882 (63.3%) underwent CPCI. Compared with non-CPCI patients, CPCI patients had higher 2- and 5-year incidences of MACE and total coronary revascularization. Following multivariable adjustment including stent type, CPCI was an independent predictor of MACE (adjusted hazard ratio [aHR]: 1.151; 95% confidence interval [CI]: 1.017–1.303, P = 0.026) and total coronary revascularization (aHR: 1.199; 95% CI: 1.037–1.388, P = 0.014) at 5 years when comparing with non-CPCI patients. The results were consistent at the 2-year endpoints. In patients with CPCI, BP-DES use was associated with significantly higher MACE rates at 5 years (aHR: 1.256; 95% CI: 1.078–1.462, P = 0.003) and total coronary revascularization (aHR: 1.257; 95% CI: 1.052–1.502, P = 0.012) compared with that of DP-DES, but there was a similar risk at 2 years. However, BP-DES had comparable safety and efficacy profiles including MACE and total coronary revascularization compared with DP-DES in patients with non-CPCI at 2 and 5 years.

Conclusions: 

Patients underwent CPCI remained at a higher risk of mid- to long-term adverse events regardless of the stent type. The effect of BP-DES compared with DP-DES on outcomes was similar between CPCI and non-CPCI patients at 2 years but had inconsistent effects at the 5-year clinical endpoints.

Introduction

The introduction of first-generation drug-eluting stents (DES), such as paclitaxel- and sirolimus-DES, has reduced the rate of stent restenosis and ischemia-driven target lesion revascularization (TLR) compared with that of bare metal stents.^[1] Second-generation durable polymer drug-eluting stents (DP-DES), such as everolimus- and zotarolimus-eluting stents, have been widely used to decrease the incidence of early stent thrombosis and repeated revascularization.^[2] However, safety issues with DES have emerged, particularly the incidence of very late stent thrombosis (VLST), which is likely caused by delayed vessel healing, incomplete endothelialization, allergy, chronic inflammation, and the presence of bio-incompatible durable polymers.^[3] Thus, biodegradable polymer drug-eluting stents (BP-DES) have been designed to overcome long-term adverse outcomes when drug elution is complete by improving the DES safety and maintaining its efficacy.

Previous studies have demonstrated the advantages of BP-DES and DP-DES compared with that of first-generation DES in reducing the risk of late stent thrombosis (ST) and TLR in the overall population and in high-risk populations such as patients who undergo percutaneous coronary intervention (PCI) of bifurcation lesions.^[4,5] Additionally, BP-DES showed comparable safety and efficacy profiles after both short- and long-term follow-ups compared with those of DP-DES in the overall PCI population.^[6,7] However, it remains unclear if the BP-DES is potentially superior to the DP-DES in patients in high-risk lesion subsets.

The use of coronary stent devices in high-risk populations is increasing. It is well-known that anatomic and lesion complexity can influence PCI outcomes. Complex percutaneous coronary intervention (CPCI) patients are characterized by multivessel disease, bifurcation disease, left main disease, and calcified lesions.^[4,5,8-10] These features are associated with a high risk of interventional surgery, lower procedural success rates, higher recurrence rates, and a poor prognosis. Previous studies had a small sample size and short to medium follow-up duration of 1–3 years, and their role in evaluating the potential benefit of BP-DES compared with that of DP-DES is limited.^[11] Additionally, the biopolymer can be completely degraded at a longer follow-up time.

Under these conditions, we studied the long-term safety and efficacy outcomes of BP-DES compared with those of DP-DES in a large, real-world, single-center population with or without CPCI over a 5-year follow-up period. The objectives of the current study were to: (1) demonstrate the effect of procedural complexity in patients undergoing PCI; and (2) evaluate the safety and efficacy of BP-DES compared with those of DP-DES in patients undergoing CPCI during a mid- to long-term follow-up.

Methods

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki. The Ethics Committee at Fuwai Hospital approved the research protocol (Ethics application number: IRB2021-HG-18 and approval number: 2021–1501), and all patients provided their written informed consent.

Study population

There were 10,724 consecutive patients at a single center (Fuwai Hospital, National Center for Cardiovascular Diseases, Beijing, China) who underwent PCI from January to December, 2013. These patients were enrolled in this study, and their data were collected prospectively. The exclusion criteria were as follows: (1) patients who underwent only percutaneous transluminal coronary angioplasty without stent implantation; and (2) patients who received multiple types of stents concurrently or who did not receive either BP-DES or DP-DES. Finally, 7712 patients were enrolled who received either BP-DES (n = 1590) or DP-DES (n = 6122) [Figure 1]. The study population was stratified into two categories based on the PCI complexity. CPCI was defined as having at least one of the following features: unprotected left main lesion, ≥2 lesions treated, ≥2 stents implanted, total stent length >40 mm, moderate-to-severely calcified lesion, chronic total occlusion (CTO), or bifurcated target lesion.^[12] The stent type and surgical strategy were at the surgeons’ discretion. The following stent types were used at our center: BP-DES including sirolimus-eluting stents (FIREHAWK: MicroPort Medical, Shanghai, China; Excel: JW Medical, Weihai, China; BuMA: Sino Medical, Tianjin, China; NOYA: Medfavour Medical, Hangzhou, China; and Tivoli: Essen Technology, Beijing, China); DP-DES including zotarolimus-eluting stents (Endeavor and Endeavor Resolute: Medtronic, Santa Rosa, CA, USA); everolimus-eluting stents (Xience V and Xience Prime: Abbott Vascular, Temecula, CA, USA; and Promus and Promus Element: Boston Scientific, Natick, Massachusetts, USA); and domestic sirolimus-eluting stents (Firebird2: MicroPort Medical, Shanghai, China). If patients underwent PCI treatment in multiple stages due to multivessel disease, we combined the data from all treatment phases.

Figure 1: The flow-chart of patients enrollment in the study of 5-year outcomes of biodegradable vs. second-generation durable polymer drug-eluting stents used in complex percutaneous coronary intervention. BP-DES: Biodegradable polymer drug-eluting stents; CAG: Coronary angiography; DP-DES: Durable polymer drug-eluting stents; PCI: Percutaneous coronary intervention.

Procedural details

The PCI strategy and stent type were at the discretion of the operating surgeon. Before the procedure, selected PCI patients who were not taking long-term aspirin and/or P2Y12 inhibitors received oral administration of aspirin (300 mg) and clopidogrel (loading dose of 300 mg). Patients with acute coronary syndrome (ACS) who were scheduled to undergo PCI received the same dose of aspirin and clopidogrel (a loading dose of 300 or 600 mg) as soon as possible. During the procedure, unfractionated heparin (100 U/kg) was administered to all patients, and glycoprotein (GP) IIb/IIIa inhibitors were used in accordance with the surgeon's judgment. If PCI proceeded for >1 h, an additional 1000 U of heparin sodium was administered. After the procedure, aspirin was prescribed at a dose of 100 mg daily indefinitely, and clopidogrel 75 mg daily or ticagrelor 90 mg twice daily for at least one year was recommended after PCI.

Follow-up

All patients were evaluated by clinic visits or telephone calls at 1, 3, 6, and 12 months and annually thereafter. Follow-up data were collected using medical records, telephone calls, or clinical visits, and an independent group of follow-up investigators was in charge of the data collection and revision. Patients were advised to return for coronary angiography if indications of ischemic events occurred. Overall, the 5-year follow-up was completed for 91.5% patients (9817/10,724). In this study, 682 patients were lost to follow-up, and therefore, the response rate was as high as 91.2% (7030/7712).

Endpoints and definitions

The primary endpoint was the composite of major adverse cardiac events (MACE), which was defined as the occurrence of all-cause death, recurrent myocardial infarction, and total coronary revascularization during follow-up. Myocardial infarction (MI) was defined using the Third Universal Definition of Myocardial Infarction.^[13] The secondary endpoint was total coronary revascularization including TLR, target vessel revascularization (TVR), and non-TVR.^[14] TVR was defined as revascularization for a new lesion on the target vessel either by PCI or by coronary artery bypass grafting (CABG). TLR was defined as revascularization for a new lesion at or within 5 mm of the previously implanted stent either using PCI or by CABG. Non-TVR was defined as a revascularization of any segment of the non-target coronary artery. Death that could not be attributed to a non-cardiac etiology was considered to be a cardiac death. Bleeding was quantified in accordance with the Bleeding Academic Research Consortium criteria, and bleeding types 2, 3, and 5 were included in the analysis.^[15] Two independent physicians who were blinded to the laboratory data results adjudicated the events after reviewing the source documents.

Statistical analysis

Continuous variables were reported as mean ± standard deviation or the median and interquartile range, and categorical variables were presented as number (percentage). Comparisons between continuous variables were performed using an independent sample Student's t-test or the Mann–Whitney U test, and the chi-squared test was used for categorical variables. Survival curves were constructed using the Kaplan–Meier method and compared with the log-rank test. Cumulative event rates in the study groups were calculated using the Kaplan–Meier method and compared with the log-rank test. For these analyses, the total follow-up was defined as the time from the index procedure until death, last follow-up date, or 5 years, whichever came first. In the adjusted analysis evaluating the effect of CPCI on outcomes, non-CPCI was the reference category. For the DES-level analysis, DP-DES was the reference category. Univariable and multivariable Cox proportional hazard regression analyses were performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) and to evaluate the associations between DES-level or CPCI and the clinical outcomes. The multivariable model was adjusted for the following covariates in an all-enter manner: age, gender, ostial lesions, de novo type B2 or C lesions, diabetes mellitus, previous myocardial infarction, ACS type, mean stent diameter, ejection fraction, serum creatinine, and/or stent type. We also conducted the landmark analysis to assess outcomes at 2 years and between 2 and 5 years in the overall population.

Two-sided P value <0.05 was considered to be statistically significant. Analyses were performed using SPSS software version 26.0 (IBM Corp., Armonk, NY, USA).

Results

Baseline, angiographic, and procedure characteristics

Among the 7712 included patients, 4882 (63.3%) underwent CPCI. There were 1051 patients with CPCI underwent BP-DES. Among these patients, the Excel was used in 70.4%, the BuMA in 7.4%, the NOYA in 1.9%, and the Tivoli in 21.2%. Clinical baseline characteristic and medication data based on PCI complexity are presented in Supplementary Table 1, https://links.lww.com/CM9/B343. Patients who underwent CPCI were older and had a higher prevalence of diabetes mellitus, hypertension, previous MI, higher preoperative creatinine level, and lower left ventricular ejection fraction (LVEF) compared with those who did not undergo CPCI. For the clinical presentation, patients underwent CPCI had more stable angina compared with those without CPCI, and patients without CPCI had a higher prevalence of NSTE-ACS type compared with those with CPCI. For medication during hospitalization, the proportion of patients using β-blockers and GPIIb/IIIa inhibitors was significantly higher in the CPCI group than that in the non-CPCI group.

Angiographic and procedural characteristics are reported in Supplementary Table 2, https://links.lww.com/CM9/B343. Patients who underwent CPCI had more complex coronary artery disease (CAD), with a higher prevalence of type B2/C lesions, ostial lesions, mean score of synergy between PCI with Taxus and cardiac surgery (STNTAX), and longer total stent length compared with those in patients who did not undergo CPCI. Patients with CPCI had significantly more lesions, vessels treated, and stents implanted compared with those who did not undergo CPCI. CPCI patients had 1.33 ± 0.51 mean treated vessels, a mean of 1.54 ± 0.69 lesions, and 2.13 ± 0.91 coronary stents implanted per patient. There was no significant difference in the mean stent diameter per patient between the groups. For the procedural aspects, the frequency of pre- and post-dilatation and overlap were significantly higher in the CPCI group than those in the non-CPCI group, and there was no significant difference in the extraction rate. Application of intravascular ultrasound (IVUS) and intra-aortic balloon pump (IABP) was more common in CPCI patients compared with non-CPCI patients. BP-DES were used in 21.5% (1051/4882) and 19.0% (539/2830) of patients and DP-DES were used in 78.5% (3831) and 81.0% (2291) of patients in the CPCI and non-CPCI groups, respectively. Baseline characteristic differences between BP-DES and DP-DES in patients grouped by PCI complexity are shown in Supplementary Tables 3, https://links.lww.com/CM9/B343, and 4, https://links.lww.com/CM9/B343.

Effect of CPCI on 5-year clinical outcomes

There was a significantly increased incidence of 2- and 5-year MACE and total revascularization in CPCI patients compared with non-CPCI patients (P < 0.05 for both) [Table 1]. A univariable Cox analysis showed that patients with CPCI were associated with a higher 2- and 5-year crude risk of MACE and total coronary revascularization, but there was no association with the other endpoints. Cumulative free survival in the whole cohort based on PCI complexity was estimated using Kaplan–Meier curves and revealed similar results at 5 years [Figure 2] (P < 0.001). Supplementary Figure 1, https://links.lww.com/CM9/B343 also presents the landmark analysis of MACE and total revascularization events that occurred within and after the 2-year follow-up. Rates of clinical outcomes after 2 years were similar between the two groups as shown by the landmark analysis. After adjusting for covariates including the stent type, CPCI remained an independent risk factor for 2-year MACE (adjusted hazard ratio [aHR]: 1.256; 95% CI: 1.059–1.489, P = 0.009) and total revascularization (aHR: 1.346; 95% CI: 1.106–1.637, P = 0.003), as well as for 5-year MACE (aHR: 1.151; 95% CI: 1.017–1.303, P = 0.026) and total revascularization (aHR: 1.199; 95% CI: 1.037–1.388, P = 0.014) compared with those of non-CPCI patients.

Table 1 - Comparison of unadjusted and adjusted 2- and 5-year clinical outcomes of 7712 included patients exclusively underwent BP-DES or DP-DES implantation according to PCI complexity.

Endpoints	Complex PCI (n = 4882)	Non-complex PCI (n = 2830)	Crude HR (95% CI)	Crude P values	Adjusted HR (95% CI)	Adjusted P values
2-year outcomes
Death	61 (1.2)	30 (1.1)	1.181 (0.763–1.828)	0.457	0.935 (0.577–1.514)	0.783
Cardiac death	35 (0.7)	16 (0.6)	1.270 (0.703–2.294)	0.428	1.030 (0.532–1.992)	0.930
MI	103 (2.1)	40 (1.4)	1.496 (1.039–2.156)	0.030	1.273 (0.853–1.901)	0.237
Total coronary revascularization	396 (8.1)	160 (5.7)	1.466 (1.220–1.762)	< 0.001	1.346 (1.106–1.637)	0.003
Stroke	66 (1.4)	31 (1.1)	1.235 (0.806–1.893)	0.332	1.288 (0.800–2.072)	0.298
Death or MI	147 (3.0)	66 (2.3)	1.296 (0.969–1.732)	0.080	1.102 (0.800–1.516)	0.553
MACE	514 (10.5)	218 (7.7)	1.396 (1.191–1.636)	< 0.001	1.256 (1.059–1.489)	0.009
Bleeding	326 (6.7)	190 (6.7)	0.996 (0.833–1.191)	0.965	0.954 (0.784–1.162)	0.642
5-year outcomes
Death	182 (3.7)	87 (3.1)	1.218 (0.943–1.572)	0.131	1.039 (0.788–1.370)	0.787
Cardiac death	98 (2.0)	55 (1.9)	1.037 (0.745–1.443)	0.829	0.891 (0.622–1.277)	0.531
MI	316 (6.5)	165 (5.8)	1.117 (0.925–1.348)	0.249	1.072 (0.872–1.317)	0.509
Total coronary revascularization	660 (13.5)	308 (10.9)	1.277 (1.116–1.462)	< 0.001	1.199 (1.037–1.388)	0.014
Stroke	160 (3.3)	84 (3.0)	1.110 (0.852–1.446)	0.438	1.106 (0.829–1.478)	0.493
Death or MI	472 (9.7)	248 (8.8)	1.111 (0.952–1.295)	0.181	1.036 (0.877–1.225)	0.676
MACE	902 (18.5)	432 (15.3)	1.246 (1.111–1.397)	< 0.001	1.151 (1.017–1.303)	0.026
Bleeding	647 (13.3)	368 (13.0)	1.019 (0.896–1.158)	0.775	1.028 (0.893–1.183)	0.700

Covariates for the adjusted model: gender, age, stent type, ostial lesions, de novo lesion, type B2 or C lesions, diabetes mellitus, prior myocardiol infarction, ACS type, mean diameter, ejection fraction, and serum creatinine. Data were presented as n (%); P values < 0.05 indicate statistical significance. ACS: Acute coronary syndrome; BP-DES: Biodegradable polymer drug-eluting stent; CI: Confidence interval; DP-DES: Durable polymer drug-eluting stent; HR: Hazard ratio; MACE: Major adverse cardiovascular events; MI: Myocardial infarction; PCI: Percutaneous coronary intervention.

Figure 2: Cumulative incidence curves for 5-year primary and secondary outcomes of patients exclusively underwent BP-DES or DP-DES implantation based on PCI complexity. (A) MACE and (B) total coronary revascularizations. BP-DES: Biodegradable polymer drug-eluting stents; DP-DES: Durable polymer drug-eluting stents; MACE: Major adverse cardiac events; PCI: Percutaneous coronary intervention.

Five-year outcomes of BP-DES and DP-DES

Univariable and multivariable Cox analyses showed that the incidence of MACE and total coronary revascularization were not significantly different between the BP-DES and DP-DES groups at the 2-year follow-up regardless of PCI complexity. Similar results were reported in non-CPCI patients at the 5-year follow-up [Table 2 and Supplementary Table 5, https://links.lww.com/CM9/B343].

Table 2 - Comparison of adjusted 2- and 5-year clinical outcomes between BP-DES and DP-DES in patients according to PCI complexity.

	Complex PCI				Non-complex PCI
Endpoints	BP-DES (n = 1051)	DP-DES (n = 3831)	∗Adjusted HR (95% CI)	P values	BP-DES (n = 539)	DP-DES (n = 2291)	∗Adjusted HR (95% CI)	P values	Interaction P values
2-year outcomes
Death	16 (1.5)	45 (1.2)	1.222 (0.677–2.207)	0.505	8 (1.5)	22 (1.0)	1.267 (0.539–2.980)	0.587	0.867
Cardiac death	7 (0.7)	28 (0.7)	0.873 (0.379–2.012)	0.751	3 (0.6)	13 (0.6)	0.593 (0.132–2.674)	0.497	0.710
MI	22 (2.1)	81 (2.1)	0.992 (0.618–1.593)	0.973	12 (2.2)	28 (1.2)	1.839 (0.907–3.370)	0.091	0.203
Total coronary revascularization	96 (9.1)	300 (7.8)	1.215 (0.964–1.530)	0.099	33 (6.1)	127 (5.5)	1.151 (0.782–1.693)	0.475	0.773
Stroke	16 (1.5)	50 (1.3)	1.152 (0.655–2.026)	0.624	3 (0.6)	28 (1.2)	0.338 (0.080–1.428)	0.140	0.116
Death or MI	36 (3.4)	111 (2.9)	1.153 (0.787–1.691)	0.465	19 (3.5)	47 (2.1)	1.563 (0.893–2.736)	0.118	0.397
MACE	127 (12.1)	387 (10.1)	1.235 (1.009–1.512)	0.041	49 (9.1)	169 (7.4)	1.213 (0.876–1.680)	0.245	0.944
Bleeding	62 (5.9)	264 (6.9)	0.831 (0.626–1.105)	0.203	33 (6.1)	157 (6.9)	0.907 (0.622–1.325)	0.615	0.670
5-year outcomes
Death	49 (4.7)	133 (3.5)	1.290 (0.925–1.800)	0.134	21 (3.9)	66 (2.9)	1.203 (0.727–1.988)	0.472	0.902
Cardiac death	26 (2.5)	72 (1.9)	1.269 (0.807–1.995)	0.302	9 (1.7)	46 (2.0)	0.688 (0.324–1.461)	0.330	0.194
MI	72 (6.9)	244 (6.4)	1.109 (0.850–1.445)	0.446	35 (6.5)	130 (5.7)	1.130 (0.766–1.668)	0.537	0.870
Total coronary revascularization	163 (15.5)	497 (13.0)	1.257 (1.052–1.502)	0.012	67 (12.4)	241 (10.5)	1.187 (0.901–1.564)	0.222	0.711
Stroke	45 (4.3)	115 (3.0)	1.425 (1.008–2.015)	0.045	13 (2.4)	71 (3.1)	0.742 (0.401–1.375)	0.343	0.084
Death or MI	117 (11.1)	355 (9.3)	1.200 (0.972–1.483)	0.090	55 (10.2)	193 (8.4)	1.156 (0.847–1.576)	0.361	0.719
MACE	225 (21.4)	677 (17.7)	1.256 (1.078–1.462)	0.003	94 (17.4)	338 (14.8)	1.158 (1.916–1.463)	0.220	0.571
Bleeding	116 (11.0)	531 (13.9)	0.784 (0.639–0.962)	0.020	64 (11.9)	304 (13.3)	0.900 (0.683–1.185)	0.451	0.411

^∗Covariates for the adjusted model: gender, age, ostial lesions, de novo lesion, type B2 or C lesions, diabetes mellitus, prior myocardiol infarction, ACS type, mean diameter, ejection fraction, serum creatinine. Data were presented as n (%);P values < 0.05 indicate statistical significance.BP-DES: Biodegradable polymer drug-eluting stent; DP-DES: Durable polymer drug-eluting stent; CI: Confidence interval; HR: Hazard ratio; MACE: Major adverse cardiovascular events; MI: Myocardial infarction; PCI: Percutaneous coronary intervention.

However, in patients who underwent CPCI, those who received BP-DES were associated with a higher 5-year crude risk of MACE (crude HR: 1.227; 95% CI: 1.055–1.427, P = 0.008) and total coronary revascularization (crude HR: 1.209; 95% CI: 1.013–1.443, P = 0.035) compared with those who received DP-DES [Supplementary Table 5, https://links.lww.com/CM9/B343]. Following multivariable adjustment, BP-DES use remained an independent predictor of 5-year MACE (aHR: 1.256; 95% CI: 1.078–1.462, P = 0.003) and total coronary revascularization (aHR: 1.257; 95% CI: 1.052–1.502, P = 0.012) at 5 years compared with those who received DP-DES [Table 4]. Furthermore, B2 or C lesions and the mean stent diameter were significantly associated with a higher 5-year MACE and total coronary revascularization in patients with CPCI compared with those without CPCI. Therefore, the magnitude and direction of the effect of BP-DES compared with those of DP-DES on outcomes were uniform between CPCI and non-CPCI patients at 2 years. There was no evidence of interaction for the studied endpoints, and inconsistent effects on the CPCI subgroups at the 5-year clinical endpoints were observed. Kaplan–Meier analysis showed that the cumulative incidence of MACE and total coronary revascularization were significantly greater in the BP-DES group compared with that in the DP-DES group in patients with CPCI at the 5-year follow-up (21.4% [225/1051] vs. 17.7% [677/3831] for MACE and 15.5% [163] vs. 13.0% [497] for total coronary revascularization, P < 0.05 for both). However, total coronary revascularization and MACE beween BP-DES and DP-DES group showed no significant difference in the non-CPCI group [Figure 3]. Supplementary Figure 2, https://links.lww.com/CM9/B343 also presents the landmark analysis of MACE and total coronary revascularization events that occurred within and after the 2-year follow-up based on PCI complexity and DES generation.

Figure 3: Cumulative incidence curves for 5-year primary and secondary outcomes of patients exclusively underwent BP-DES or DP-DES implantation based on PCI complexity and DES generation. (A) MACE and (B) total repeat revascularization. BP-DES: Biodegradable polymer drug-eluting stents; CPCI: Complex percutaneous coronary intervention; DES: Drug-eluting stents; DP-DES: Durable polymer drug-eluting stents; MACE: Major adverse cardiac events; PCI: Percutaneous coronary intervention.

Discussion

Our prospective, observational study from a large-scale cardiovascular center in China compared the efficacy and safety between BP-DES and DP-DES in a large group of patients based on PCI complexity. Throughout the 5-year follow-up period, our key findings were as follows: (1) procedural complexity was associated with an increased 2- and 5-year risk of MACE and total repeat revascularization after DES implantation, irrespective of stent devices; (2) compared with DP-DES, the use of BP-DES in CPCI was associated with higher incidences of 5-year MACE and total repeat revascularization. Additionally, BP-DES was an independent predictor of 5-year MACE and total repeat revascularization; and (3) BP-DES had comparable safety and efficacy profiles including MACE and total repeat revascularization compared with DP-DES in patients without CPCI at 2- and 5-year follow-up.

BP-DES compared with DP-DES in patients underwent CPCI

Previous studies, such as the “Limus Eluted from a Durable versus ERodable Stent Coating” (LEADERS) trial, have demonstrated that BP-DES and DP-DES have significant clinical benefits compared with those of the first-generation DES.^[4] Recently, the long-term clinical performance of these two stents has been investigated. Numerous randomized controlled trials have been performed comparing the efficacy and safety between DP-DES and BP-DES in an overall population. The randomized trial “Study of the Orsiro Drug Eluting Stent System” (BIOFLOW-II) reported that there were no differences in clinical outcomes between biodegradable polymer sirolimus-eluting stents (BP-SES) and durable polymer everolimus-eluting stents (DP-EES) over a 5-year follow-up after stent implantation.^[16] The trial “A Comparison of an Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent with a Durable Polymer Everolimus-Eluting Stent for Patients with Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention” (BIOSTEMI) also showed that BP-SES could significantly reduce the risk of target lesion failure compared with DP-EES at 1-year follow-up.^[17] However, a more recent meta-analysis indicated that biodegradable polymer biolimus-eluting stents (BP-BES) may be associated with a higher risk of TVR up to 3 years after stent deployment compared with DP-EES.^[18] Thus, we postulate that these differences in the above analysis could be affected by factors such as the sample size, polymer type, eluting drug, follow-up duration, and clinical outcome definitions.

Coronary artery stents implantation is increasingly being used to treat high-risk anatomy patients with CAD. However, it is currently unclear if the clinical performance of BP-DES compared with that of DP-DES is similar in complex percutaneous revascularization procedures. In the present study, the use of BP-DES was associated with similar safety and efficacy profiles including all-cause death, cardiac death, MI, total repeat revascularization, and MACE at 2- and 5-year without CPCI. Similarly, recent 5-year follow-up results from the trial “Abluminal Biodegradable Polymer Biolimus-Eluting Stent versus Durable Polymer Everolimus-Eluting Stent” (COMPARE II), in which 1- and 5-year outcomes were compared between BP-BES and DP-EES, confirmed similar safety and efficacy outcomes in this overall PCI population.^[6] This is consistent with the “Randomized Clinical Comparison of Biomatrix Flex and Resolute Integrity” (SORT OUT VI), which showed no difference between the biocompatible durable-polymer zotarolimus-eluting stents (DP-ZES) and the BP-BES in unselected coronary patients.^[7] Previous studies have concluded that the stent type, strut thickness, time to polymer biodegradation, drug release, and newer-generation stents such as those with improved stent geometry, presence of polymer type, and type of eluting drug may determine the DES outcomes.^[19-22] Biodegradable polymers, in contrast to durable polymers, can be completely metabolized, potentially reducing the risk of late adverse events. However, DP-DES with novel stent platforms, thinner struts, and more biocompatible durable polymers offset the benefit of using a biodegradable polymer,^[23] and they may resolve the similarity between the two stents.

Our study showed that, compared with DP-DES, application of BP-DES in CPCI patients is associated with a higher rate of 5-year MACE and total repeat revascularization, but there was no difference between these two stents among all endpoints at the 2-year follow-up. There may be several reasons for this lack of difference. Biodegradable polymer is completely degraded by approximately 3–14 months after stent implantation, and this may lead to a reduced risk of adverse cardiovascular events. Therefore, longer-term follow-up might be needed to clarify the potential differences in BP-DES compared with those of DP-DES. MACE is a composite endpoint that includes all-cause death, MI, and total repeat revascularization; thus, it represents a safety and efficacy outcome. In patients with CPCI in our study, clinical conditions were more complex in BP-DES implantation, with a higher proportion of hypertension, previous MI, previous CVD, and a higher serum creatinine level than those with DP-DES implantation. Additionally, in patients with CPCI, de novo and B2/C lesions were independent predictors of MACE at 5 years.

Some studies have shown that compared with thinner struts, thicker strut platforms have increased platelet aggregation and inflammatory cell adhesion.^[24,25] The BP-DES has a relatively thick strut, and the adverse effects may be clinically prominent, particularly in patients with complex conditions. This study included several types of BP-DES, among which earlier polymers such as Excel stents were the most frequently used (70.4%), while the proportions of new BP-DES such as Tivoli, BuMA, and NOYA were relatively low. Additionally, earlier BP-DES polymer coatings had poor biocompatibility and thicker stent wires. Together, these factors promote the occurrence of MACE and total repeat revascularization with BP-DES implantation.

Outcomes in patients underwent CPCI

The present study demonstrated that CPCI patients have higher rates of MACE and total repeat revascularization at 2- and 5-year follow-up compared with non-CPCI patients. This means that CPCI had durable mid- to long-term adverse events in the PCI population. The potential mechanisms are described below. First, the present study showed that CPCI patients with multiple comorbidities including hypertension, diabetes mellitus, and previous PCI had more complex lesion features such as type B2/C lesions, ostial lesions, or de novo lesions, and they also showed procedural features of pre-dilation, post-dilation, or overlap. The CPCI population was older, and the specific characteristics that are described above show that CPCI patients are a high-risk population. Additionally, it is well known that PCI for complex lesions (for example, long lesions, chronic total occlusion [CTO] bifurcations, left main disease, or moderate-to-severe calcification) is associated with a higher risk for under expansion, malapposition, incomplete lesion coverage, and the possibility of incomplete endothelialization compared with non-CPCI.^[26] Second, the baseline CAD complexity (higher SYNTAX score) was shown to be associated with adverse clinical outcomes after PCI.^[27,28] Our analysis showed that the mean STNYAX score was higher among CPCI patients compared with that of non-CPCI patients. In summary, the higher rates of adverse ischemic events with CPCI may be directly correlated with the underlying CAD complexity.

Overall, the present study provides mid- to long-term outcome evidence for specific high-risk subgroups such as CTO, unprotected left main disease, bifurcations, long lesions, highly calcified lesions, and multivessel disease. This is consistent with previous analyses “Women in Innovation and Drug-Eluting Stents” (WIN-DES), which have reported that women underwent CPCI remain at a higher risk of 3-year adverse events, composite all-cause mortality, myocardial infarction, or TLR.^[26] The present study indicated that, irrespective of the stent type, the MACE ischemic event rate and total repeat revascularization remain high after complex revascularization compared with those of a simple PCI. However, there is no increased incidence of bleeding events, suggesting that the longer duration of platelet inhibition due to medical treatment might be beneficial in CPCI for low hemorrhagic risk.

In conclusion, patients underwent CPCI remained at a higher risk of mid- to long-term adverse events regardless of the stent device used. The effect of BP-DES on outcomes compared with that of DP-DES was similar between CPCI and non-CPCI patients at 2-year follow up, but there were inconsistent effects at the 5-year clinical endpoints. The use of BP-DES in CPCI was associated with higher incidences of 5-year MACE and total repeat revascularization. Additionally, BP-DES is an independent predictor of 5-year MACE and total repeat revascularization.

The current study had some limitations. First, important variables such as dual antiplatelet therapy (DAPT) duration and the DAPT medication dose, which are known to be associated with adverse outcomes, were not available during follow-up. Second, data on the stent thrombosis were not available, and therefore, the potential benefit of BP-DES in reducing the risk of late or very late ST during mid- to long-term follow-up compared with DP-DES remains unclear. Third, this was a single-center study, which reduces the statistical power. Multi-center studies with a large sample-size are needed to validate these results. Finally, the types of CPCI, individual stents, stent thickness, and ischemic heart disease may differ at least slightly in terms of efficacy or safety. These analyses were not performed in the present study, but this aspect may be of great importance, and related research should be conducted in the future.

Acknowledgment

We thank Jodi Smith, PhD ELS, from Liwen Bianji (Edanz) (www.liwenbianji.cn), for editing the English text of a draft of this manuscript.

Funding

This work was supported by the National Key Research and Development Program of China (Nos. 2016YFC1301300 and 2016YFC1301301); National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences (No. NCRC2020013); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (No. 2020-I2M-C&T-B-049); and the National Natural Science Foundation for Young Scholars of China (No. 81900323).

Conflicts of interest

None.