Five Years Sustained Clinical Safety and Efficacy of An Abluminal Biodegradable-Polymer Coated Sirolimus-Eluting Stent: A Randomized Controlled Trial

doi:10.21203/rs.3.rs-832407/v1

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Five Years Sustained Clinical Safety and Efficacy of An Abluminal Biodegradable-Polymer Coated Sirolimus-Eluting Stent: A Randomized Controlled Trial

https://doi.org/10.21203/rs.3.rs-832407/v1

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Background

Drug-eluting stent (DES) with durable polymers have been proven to cause late or very late adverse events. Biodegradable polymer-coated DES was developed to address the risk by avoiding persistent inflammatory irritation from persistent polymers. However, it is unknown whether the benefits of biodegradable polymer DES will occur over longer time.

Methods

The trial was a prospective, multicenter and randomized non-inferiority clinical trial done in China. Patients with indications for stent implantation were assigned into Cordimax and Xience V group in a 2:1 allocation. The composite of cardiac death, target vessel myocardial infarction (TV-MI), or clinically indicated target lesion revascularisation (CI-TLR) was the primary endpoint target lesion failure (TLF). The pre-specified endpoint at five years was major adverse cardiac event (MACE) which was defined as a composite of all-cause death, non-fatal myocardial infarction (MI), and CI-TLR.

Results

3266 patients (88.3%) completed 5-year follow-up. No difference was observed for TLF between Cordimax (7.5%) and Xience V (8.3%) group (RR: 0.90, 95% CI: 0.70 to 1.15, P = 0.39). MACE occurred in 280 patients (11.4%) in Cordimax group and 162 patients (13.1%) in Xience V group (RR: 0.85, 95% CI: 0.69 to 1.05, P = 0.13). The incidence of definite or probable stent thrombosis did not differ in both groups (Cordimax 0.7%, Xience V 0.9%; RR: 0.78, 95% CI: 0.36 to 1.66; P = 0.51).

Conclusion

The biodegradable polymer Cordimax stent showed a comparable result to the durable polymer Xience V stent at 5 years, showing its long-term safety and efficacy performance.

Trial registration:

This study is registered with ClinicalTrials.gov, number NCT03185221 (14/06/2017).

Translational Medicine

Internal Medicine

Integrative & Complementary Medicine

Drug eluting stents

biodegradable polymer

coronary artery disease

Secondary-generation durable polymer DESs have superior clinical outcomes in restenosis and stent thrombosis (ST) compared with bare-metal stents (BMS) and first-generation DES^[1]. However, permanent polymer, resulting in delayed arterial healing and hypersensitivity reactions^[2], might lead to late adverse events including late ST, delayed late luminal loss, and neoatherosclerosis after long term DES implantation^[3]. DES with biodegradable-polymer was conceived to address potential long-term adverse outcomes of durable polymers. After gradually biodegraded within approximately 3 to 9 months, biodegradable polymer eventually degrades into water and carbon dioxide and consequently produces less inflammatory reaction which underlies the spectrum of late adverse outcomes^[4]. The Cordimax (Rientech Inc., Shandong, China) biodegradable polymer sirolimus-eluting stent (BP-SES) has an asymmetric coating composed by biodegradable lactide-co-glycolide. The asymmetric drug coating can inhibits the proliferation of smooth muscle cell without affecting endothelial cell adhesion and proliferation. Its favorable drug release kinetics in vitro ^[5] and enhanced endothelialization and vascular healing in vivo ^[6] has been previously reported. When compared with Cypher (Cordis, Miami Lakes, FL, USA), first-generation DES, Cordimax showed comparable 5-year clinical results. Cordimax stent were non-inferior to the Xience V (Abbott Vascular, Santa Clara, CA, USA), newer-generation DES, at 3 years after stent implantation^[7]. On this basis, we continued to follow up patients and reported 5 year safety and efficacy of biodegradable-polymer DES in this study.

This study was a prospective, multicenter, open-label, randomized trial comparing the long term safety and efficacy of Cordimax abluminal BP-SES with Xience V durable polymer everolimus-eluting stent (DP-EES). The eligible patients were assigned into two groups in a 2:1 allocation. The details of the trial with its design, inclusion and exclusion criteria, sample size, randomization, procedures as well as description of stents have been previously described^[7].

The primary endpoint was TLF, a composite of cardiac death, TV-MI, and CI-TLR. The pre-specified endpoint was MACE, defined as all-cause death, non-fatal MI, and CI-TLR. The definition of components and ST had been mentioned in 3-year follow-up articles. Patients were systematically evaluated at 6 months, 1 year, 2 years, 3 years, 4 years and 5 years by follow-up phone calls and office visits.

Statistical analysis

The sample size was calculated with reference to the following indicators: the reported 2-year TLF of Xience V (8.3%) ^[8], assumed TLF (8.5%), non-inferiority threshold (3%), the power (80%), one-sided inspection level (0.05), and the rate of lost (20%). The estimated cases were 2440:1220 (2:1 allocation ).

Continuous variables are presented as mean ±SD and categorical variables are reported as numbers (percentages). We used t test to assess continuous variables and Cochran-Mantel-Haenszel tests or Fisher’s exact tests to categorical variables. Relative risk (RR) with 95% confidence interval (CI) and P values were reported. A two-sided P value of less than 0.05 was considered to indicate statistical significance. Time-to-event analysis was performed using the Kaplan-Meier method, with treatment groups compared using the log-rank test. Analyses were performed with the SAS 9. 3 software (SAS Institute Inc., Cary, NC, USA) and SPSS software (version 21.0, SPSS Inc.,IBM, NY, USA).

3697 patients were enrolled in the trial with a 2:1 ratio to the 2 study arms (2460 patients in Cordimax group and 1237 in Xience V group). The baseline characteristics were published previously and were well balanced between two groups. 2171 patients (88.3%) in the Cordimax group and 1095 patients (88.5%) in the Xience group completed 5 years follow-up (Fig. 1).

The primary endpoint TLF occurred in 185 (7.5%) patients in the Cordimax group and 103 (8.3%) patients in the Xience V group at 5 years. There was no difference between two groups for TLF (P > 0.05). The individual components of the primary endpoint (cardiac death, TV-MI, and CI-TLR) also did not differ significantly between groups. The safety endpoints MACE and their composite endpoints have no difference between Cordimax and Xience V group (P > 0.05) from 1 to 5 years. Stent thrombosis rates up to 5 years were similar between groups at all time points (P > 0.05). (Table 1)

Table 1

Cumulative Clinical Events
Events	Cordimax (n = 2460)	Xience V (n = 1237)	RR(95% CI)	P value
Events at 6 months
Cardiac death	0(0.0)	1(0.1)	-	0.16
TV-MI	0(0.0)	0(0.0)	-	-
CI-TLR	4(0.2)	3(0.2)	0.67(0.15–2.99)	0.60
TLF	4(0.2)	4(0.3)	0.50(0.13–2.01)	0.32
All cause death	0(0.0)	1(0.1)	-	0.16
Nonfatal MI	0(0.0)	0(0.0)	-	-
ST	0(0.0)	0(0.0)	-	-
MACE	4(0.2)	4(0.3)	0.50(0.13–2.01)	0.32
MI	0(0.0)	0(0.0)	-	-
Events at 1 year
Cardiac death	6(0.2)	3(0.2)	1.01(0.25–4.01)	0.99
Target-vassel MI	23(0.9)	9(0.7)	1.29(0.59–2.79)	0.41
CI-TLR	57(2.3)	28(2.3)	1.02(0.65–1.62)	0.92
TLF	86(3.5)	40(3.2)	1.08(0.74–1.59)	0.68
All cause death	7(0.3)	4(0.3)	0.88(0.26–3.01)	0.84
Nonfatal MI	22(0.9)	8(0.6)	1.39(0.62–3.12)	0.43
ST	4(0.2)	2(0.2)	1.01(0.18–5.50)	0.99
MACE	86(3.5)	40(3.2)	1.08(0.74–1.59)	0.68
MI	27(1.1)	8(0.6)	1.70(0.77–3.76)	0.18
Events at 2 years
Cardiac death	6(0.2)	3(0.2)	1.01(0.25–4.01)	0.99
Target-vassel MI	25(1.0)	9(0.7)	1.40(0.65–3.01)	0.39
CI-TLR	82(3.3)	49(4.0)	0.84(0.60–1.19)	0.33
TLF	113(4.6)	61(4.9)	0.93(0.69–1.26)	0.65
All cause death	7(0.3)	6(0.5)	0.59(0.20–1.74)	0.33
Nonfatal MI	25(1.0)	7(0.6)	1.80(0.78–4.18)	0.16
ST	8(0.3)	4(0.3)	1.01(0.30–3.35)	0.99
MACE	114(4.6)	62(5.0)	0.93(0.68–1.25)	0.61
MI	30(1.2)	9(0.7)	1.68(0.79–3.56)	0.17
Events at 3 years
Cardiac death	8(0.3)	5(0.4)	0.81(0.26–2.45)	0.70
Target-vassel MI	25(1.0)	10(0.8)	1.26(0.60–2.63)	0.54
CI-TLR	88(3.6)	63(5.1)	0.70(0.51–0.96)	0.03
TLF	121(4.9)	78(6.3)	0.77(0.57–1.03)	0.08
All cause death	9(0.4)	8(0.6)	0.57(0.22–1.46)	0.23
Nonfatal MI	25(1.0)	8(0.6)	1.58(0.71–3.51)	0.26
ST	9(0.4)	7(0.6)	0.65(0.24–1.74)	0.38
MACE	122(5.0)	79(6.4)	0.76(0.57–1.02)	0.07
MI	30(1.2)	11(0.9)	1.37(0.69–2.73)	0.37
Events at 4 years
Cardiac death	25(1.0)	13(1.1)	0.97(0.49–1.90)	0.92
Target-vassel MI	34(1.4)	16(1.3)	1.07(0.59–1.95)	0.83
CI-TLR	98(4.0)	64(5.2)	0.76(0.55–1.05)	0.10
TLF	157(6.4)	93(7.5)	0.84(0.64–1.09)	0.19
All cause death	63(2.6)	29(2.3)	1.09(0.70–1.71)	0.69
Nonfatal MI	48(2.0)	23(1.9)	1.05(0.64–1.73)	0.85
ST	13(0.5)	10(0.8)	0.65(0.29–1.49)	0.31
MACE	209(8.5)	116(9.4)	0.90(0.71–1.14)	0.90
MI	73(3.0)	34(2.7)	1.08(0.72–1.64)	0.71
Events at 5 years
Cardiac death	39(1.6)	16(1.3)	1.23(0.68–2.21)	0.49
Target-vassel MI	43(1.7)	19(1.5)	1.14(0.66–1.97)	0.64
CI-TLR	103(4.2)	68(5.5)	0.75(0.55–1.03)	0.07
TLF	185(7.5)	103(8.3)	0. 90(0.70–1.15)	0.39
All cause death	116(4.7)	64(5.2)	0.91 (0.66–1.24)	0.54
Nonfatal MI	61(2.5)	30(2.4)	1.02(0.66–1.59)	0.92
ST	17(0.7)	11(0.9)	0.78(0.36–1.66)	0.51
MACE	280(11.4)	162(13.1)	0.85(0.69–1.05)	0.13
MI	101(4.1)	41(3.3)	1.25(0.86–1.81)	0.24

No significant difference was observed between two groups for MACE (P = 0.306) and TLF (P = 0.543) in the cumulative pursue rate from 1 to 5 years. (Fig. 2)

TLF, MACE, and their components between 3 and 5 years did not differ significantly between Cordimax and Xience V groups (Table 2). The values of ST rate between the two groups were equal, and there was no statistical significance.

Table 2

Outcome differences between 3 year and 5 year
Events	Cordimax (n = 2460)	Xience V (n = 1237)	RR(95% CI)	P value
All cause death	107(4.3)	56(4.5)	0.96(0.69–1.33)	0.80
Cardiac death	31(1.3)	11(0.9)	1.42(0.71–2.84)	0.32
MI	30(1.2)	11(0.9)	1.38(0.69–2.76)	0.37
Target-vassel MI	18(0.7)	9(0.7)	1.01(0.45–2.25)	0.99
CD-TLR	15(0.6)	5(0.4)	1.51(0.55–4.17)	0.42
TLF	64(2.6)	25(0.2)	1.30(0.81–2.07)	0.28
MACE	158(6.4)	83(6.7)	0.95(0.72–1.26)	0.74
ST	8(0.3)	4(0.3)	1.01(0.30–3.35)	0.99

Many trials comparing BP-DES with DP-DES have been done or are in progress. The comparison of short-term results is controversial, while the data of long-term results are few. The 3 year follow-up results of this large scale randomized controlled trial has been reported previously. On this basis, we continue to follow-up patients and reported the 5 year follow-up results in this paper. The main finding was as follows: 1) the primary outcomes TLF and its components occurred with equal frequency at 5 year in patients randomized to two groups. 2) The pre-specific outcome MACE and ST has a similar profile between two groups.

Newer generation DESs were developed to overcome the limitations of early generation DESs that were associated with a higher risk of late adverse events including late stent thrombosis, delayed late luminal loss, and de novo in-stent atherosclerosis. The incomplete strut endothelialization caused by a persistent inflammatory reaction to the polymer resulted in the increased risk of late adverse events ^[9]. It seems that polymer-free DES technology represents the development trend. However, antirestenotic drugs loading in polymer coatings are important to prevent restenosis and all current U.S. Food and Drug Administration–approved DES incorporate a durable polymer matrix coating ^[10]. Even some studies have proved that the polymer-free DES is less effective than the durable polymer DES due to a too rapid drug-release and a failure to optimally suppress neointimal hyperplasia ^{[11, 12]}. Therefore, the design of stent, polymer coatings and the antiproliferative drug and its release kinetics which have been implicated as mechanisms for delayed endothelial healing and chronic inflammation are important to efficacy and clinical safety ^{[13, 14]}. Cordimax stents, which have 316L stainless steel platform and special “snap-fastener” design, coated solely at the abluminal stent site with polylactide-co-polyglycolide copolymer, are more biocompatible and less prone to hypersensitivity reactions. Besides, the asymmetric coating technology gets thinner polymer and lower drug, reducing the impact on the surrounding environment and tissues and favoring to endothelialization. The above designs may produce better performance in safety and efficacy profile.

Prior meta-analyses has established the superiority of BP-DES over BMS and first generation DP-DES, and similar safety and efficacy profiles with secondary generation DP-DES^{[15, 16]}. The short-term follow-up results showed BP-DES had higher definite ST rate ^[17] and mortality rate ^[16]. We reported 5-year follow-up results comparing BP-DES with DP-DES and found similar performance of two polymer DES in most outcomes even a better TLF in cumulative incidence in BP-DES group. The degradation process of BP may stimulate the vascular wall, so the short-term results were not as good as DP. As the coating gradually degrades to water and carbon dioxide, the irritation disappears. Hence, in the long run, BP-DES is not inferior to DP-DES. COMPARE II trial was also revealed a result that BP-DES had a similar safety and efficacy profile at 5 years compared with DP-DES^[18]. From the long-term follow-up results, BP-DES is worthy of application and research.

BP-DES

At present, stent materials, structure and processing technology can affect the effectiveness and safety of stent. In this study, Cordimax is a stainless steel stent, and Xience V is a cobalt-chromium alloy stent. From the long-term effect, the stainless steel stent is not inferior to the cobalt-chromium alloy stent. At the same time, Cordimax's unique asymmetric coating design may also contribute to the results. More detailed researches to prove which combination is the best and promote the development and progress of the stent.

This trial showed 6 months to 5-year follow-up results. We reported the continuing long-term safety and efficacy of the Cordimax stents. It confirms the comparable results of BP DES in short and long term follow-up. The positive outcomes benefit from its design and structure. More evidence should be provided in the area in future.

Drug-eluting stent (DES)

Target vessel myocardial infarction (TV-MI)

Clinically indicated target lesion revascularisation (CI-TLR)

Target lesion failure (TLF)

Major adverse cardiac event (MACE)

Myocardial infarction (MI)

Stent thrombosis (ST)

Bare-metal stents (BMS)

Biodegradable polymer sirolimus-eluting stent (BP-SES)

Durable polymer everolimus-eluting stent (DP-EES)

All other authors declare no competing interests. We declare 1) the paper is not under consideration elsewhere; 2) none of the paper’s contents have been previously published; 3) all authors have read and approved the manuscript; 4) the full disclosure of any potential conflict of interest has been listed above.

Study limitations and Acknowledgments has been reported in 3-year follow-up paper^[⁷^].

Author Contributions

Conception and design of the study: H.Z. and J.G. Acquisition of data: M.C., Y.Y., C.Z. , X.W., J. M., and F.Z.. Analysis and interpretation of the data: H.Z., M.C., J.G., W.D.. Writing and revision of the manuscript: H.Z.,Y.Y., M.C., E.T., and J.G. All authors reviewed the manuscript.

Funding

This study was supported by the National Key Technology Research and Development Program in the Twelfth Five-year Plan Period of China (No. 2014BAI11B04).

Availability of data and materials

Further details on data collection tools and any data presented in this manuscript can be obtained from the corresponding author.

Ethics approval and consent to participate

The Zhongshan Hospital Affiliated to Fudan University Ethics Committee approved the trial in November 2012. All participants wrote informed consent prior to enrolment into the trial.

Consent for publication

Not applicable

Conflict of interest

Haijun Zhang and Junbo Ge are together holding intellectual property rights on the technology, licensed to Rientech Inc., which manufacture stents based on the technology described in the paper. All other authors declare no competing interests.

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Five Years Sustained Clinical Safety and Efficacy of An Abluminal Biodegradable-Polymer Coated Sirolimus-Eluting Stent: A Randomized Controlled Trial

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Conclusion

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Background

Methods

Statistical analysis

Results

Discussion

BP-DES

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