CLINICAL PERSPECTIVE
WHAT IS NEW?
In this prospective, single-blinded, multicenter, randomized controlled clinical trial, MiStent , a novel microcrystalline biodegradable polymer drug-eluting stent (BP-DES), was non-inferior to another BP-DES TIVOLI for in-stent late lumen loss at 9 months among patients with de novo coronary lesions.
Moreover, MiStent had a comparable rate of ischemic events to TIVOLI during 12-month follow-up among these patients.
WHAT ARE THE CLINICAL IMPLICATIONS?
Different to previous studies, the present study compared angiographic and clinical outcomes of MiStent system vs. a mature post-marketing BP-SES, and demonstrated that MiStent is non-inferior to other BP-DESs in both angiographic and clinical aspects.
This study solidly identified the considerable efficacy and safety of advanced, well-designed MiStent system, which is fairly eligible to be a good choice for treatment of coronary heart disease.
1. Introduction
Although second-generation drug-eluting stents (DESs) have substantially reduced rates of restenosis and revascularization in patients with coronary heart disease (CHD), in comparison with bare metal stents (BMS) and first-generation DESs,[ 1–3 ] the technological improvement of newer-generation DESs driven by the necessity of reducing risks of late and very late stent thrombosis (ST) is still advancing. To minimize hypersensitivity reactions and endothelial dysfunction of the coronary artery induced by durable polymers (DP),[ 4 , 5 ] biodegradable polymer (BP) DESs with a thinner strut were designed to have comparable clinical benefits with DP-DESs and prevent vascular inflammation and neointimal proliferation simultaneously.[ 6 , 7 ]
The MiStent system (Micell Technologies, Durham, North Carolina, USA), as a novel stent platform that consists of a cobalt chromium (CoCr) alloy with a 64-µm ultrathin strut and a biodegradable microcrystalline sirolimus-eluting polymer, is theoretically proven to have good biocompatibility and anti-inflammation ability.[ 8 , 9 ] With the microcrystalline form of sirolimus, MiStent can produce a prolonged inhibition of neointimal hyperplasia for up to 270 d, even though the absorbable polymer is totally dissolved within 90 d to avoid inflammatory reactions.[ 9 , 10 ] Several randomized trials comparing clinical outcomes of the MiStent system vs. DP stents have been reported.[ 11–13 ] In the DESSOLVE III trial (a sirolimus-eluting bioabsorbable polymer-coated stent (MiStent ) vs . an everolimus-eluting DP stent (Xience) after percutaneous coronary intervention), MiStent showed non-inferiority for a composite of cardiac death, target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (TLR) compared with Xience (Abbott Vascular, Santa Clara, California, USA) DP everolimus-eluting stent at both 1 and 3 years.[ 13 , 14 ] However, to date, no clinical trials have been conducted to compare MiStent with BP-DESs, and whether patients with CHD could receive comparable benefits from the MiStent system as other BP-DESs already available on the market remain unknown. To address this concern, we intended to conduct the DESSOLVE-C Trial (Clinical Trial on the Efficacy and Safety of Sirolimus-Eluting Stent (MiStent ® System)), a randomized trial comparing the angiographic efficacy and clinical outcomes of MiStent system vs . a post-marketing BP-DESs (TIVOLI; EssenTech, Beijing, China) in patients with de novo CHD.
2. Methods
2.1. Study design and patients
A prospective, single-blinded, multicenter, randomized, controlled clinical trial (NCT02448524) was conducted at 16 sites in China [Supplementary Appendix 1, https://links.lww.com/CD9/A24 Declaration of Helsinki and its later amendments. From July 2015 to November 2017, patients aged between 18 and 75 years, with stable and unstable angina pectoris (AP), old myocardial infarction (OMI), acute MI beyond 7 d prior to procedure, or confirmed evidence of myocardial ischemia who presented as primary de novo coronary lesions (up to 2 target lesions and up to 2 stents per lesion) were recruited from 16 investigational sites. The lesions were ≥70% (by visual measurement) with a reference diameter of 2.5 to 3.5 mm (by visual measurement) and with length ≤40 mm (by visual measurement). Details of inclusion and exclusion criteria are listed in Supplementary Appendix 2 (https://links.lww.com/CD9/A24 https://links.lww.com/CD9/A24
Patients were randomly assigned to groups based on implantation with either MiStent BP-DES (MiStent group) or TIVOLI BP-DES (TIVOLI group) in a 1:1 ratio. Randomization was performed by a central randomization system. An independent coronary angiography core laboratory (CCRF Medical Technology Co., Ltd., Beijing, China), the data management and statistical center, clinical events committee (CEC), and clinical audit agency were responsible for collection, collation, statistical analysis, and adjudication of all relevant clinical and angiographic data.
2.2. Procedures
The MiStent system consists of 4 parts: a BMS, delivery system, absorbable polymer coating, and anti-proliferative drug sirolimus. The metallic body, which is made of an ultrathin laser-cut and electro-polished CoCr stent, and the delivery catheter are mature products on the market (EuroCor GmbH, Bonn, Germany). The polymer coating is composed of polylactic-co-glycolic acid (PLGA) and crystalline sirolimus.[ 10 ] With the biodegradable and biocompatible PLGA as a carrier, crystalline sirolimus enables controlled release of the drug during the period of vascular recovery. The polymer is totally absorbed within 90 d after implantation. However, the crystalline sirolimus continues to minimize the neointimal hyperplasia up to 270 d.[ 9 ]
The BP-SES TIVOLI is a mature, post-marketing, thin strut CoCr BP-SES. The randomized I-LOVE-IT 2 (Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment of Coronary) trial showed that TIVOLI was non-inferior to a CoCr DP-SES (Firebird 2, MicroPort, Shanghai, China) for 1-year target lesion failure (TLF) in patients with de novo coronary lesions.[ 15 ] To obtain the approval of the China Food and Drug Administration for MiStent , TIVOLI was selected as a fairly suitable control device in our randomized trial because of sufficient clinical evidence.[ 15–17 ] Specifications of MiStent vs. TIVOLI are presented in Supplementary Appendix 4 (https://links.lww.com/CD9/A24
The implantation procedures of the 2 kinds of DES were performed in accordance with standard techniques. Balloon pre-dilation was performed for each lesion, followed by balloon post-dilation, if the stent was not fully dilated. If more stents were needed for implantation (all patients enrolled with a maximum of 2 target lesions in different blood vessels and maximum of 2 stents per lesion), stents of the same brand were used. Use of different brands for 1 patient was not allowed, except for salvage with implantation of other brands of stents. Within 24 h before procedures, a loading dose of 300 mg aspirin and 300 mg (or 600 mg within 2–6 h before procedures) clopidogrel was administered. During procedures, heparin (according to the standard of each hospital) at a dose of 100 U/kg of body weight was used to maintain the activated clotting time at ≥250 s. According to the study protocol, patients received aspirin and clopidogrel as the strategy of dual antiplatelet therapy (DAPT) for 12 months after the procedure. Other concomitant medications were prescribed at physicians’ discretion.
Patients were followed up by hospital visits for angiography at 9 months after index procedure, and by phone at 1, 6, 9, and 12 months, and yearly at 2 to 5 years. During the angiographic follow-up, late lumen loss (LLL) was measured by quantitative coronary angiography (QCA). QCA data were analyzed at an independent angiographic core laboratory (CCRF Medical Technology Co.).
2.3. Endpoints
The primary endpoint was a non-inferiority comparison at 9 months after index procedure of in-stent LLL between the MiStent group and TIVOLI group. LLL was defined as the difference between the minimum lumen diameter post-procedure and at 9 months. Secondary endpoints included success rate of stent implantation (including device success, lesion success, and clinical success); binary restenosis rates (defined as ≥50% diameter stenosis) in-stent, at proximal or distal edge of the stent, and in-segment; in-segment LLL and percentage of diameter stenosis (defined as difference between reference vessel diameter and minimal lumen diameter/reference diameter × 100) in-segment; TLF, which was defined as the device-related clinical cardiovascular composite endpoint, including cardiac death, target vessel MI, and clinically driven TLR; patient-oriented composite endpoint (PoCE), including all-cause death (cardiac and non-cardiac), nonfatal MI, any revascularization, and stroke; ST (definite, probable, possible ST at early, late, and very late periods), according to the definition of the Academic Research Consortium (ARC).[ 18 ] Details of the primary and secondary endpoints are shown in Supplementary Appendix 5(https://links.lww.com/CD9/A24
Except death definitely identified as non-cardiac cause, any death caused by cardiac or unknown cause (including procedure or treatment cause) was defined as cardiac death. MI was defined based on the WHO’s extended definition.[ 19 ] TLR was defined as repeated percutaneous coronary intervention in any target lesion or coronary artery bypass grafting in any target vessel. TLR with ischemic electrocardiograph in consistence with target lesion, or in-lesion diameter stenosis >50% by QCA with ischemic symptoms, or in-lesion diameter stenosis >70% by QCA without ischemic symptoms was defined as clinically driven TLR. Stroke was defined as the sudden onset of vertigo, numbness, dysphasia, weakness, visual field defects, dysarthria, or other focal neurological deficits due to vascular lesions of the brain, such as hemorrhage, embolism, thrombosis, and rupturing aneurysm, that persist for >24 h.
2.4. Statistical analysis
This randomized controlled trial was designed to perform a non-inferiority test between the MiStent system and TIVOLI BP-SES for the primary endpoint, LLL, at 9 months after the index procedure. Assuming the mean LLL of TIVOLI at 9 months after the procedure was 0.25 mm, according to previous studies,[ 16 ] and the efficacy on the LLL of MiStent was equal to that of TIVOLI, the non-inferior margin was 0.12 mm with the standard deviation (SD) of 0.33 mm. Based on this margin and a 1-sided type I error of 0.025, 320 participants (160 participants in each group) assigned by a 1:1 ratio would have at least 90% power for the non-inferiority. Considering that 25% of participants were lost to follow-up, 428 patients (214 patients in each group) were to be randomized.
Continuous variables were reported as mean ± SD or median (Q1, Q3) and compared using the t test or Wilcoxon rank test. Categorical variables were presented as counts and percentages and were compared using the chi-squared or Fisher exact test. Kaplan-Meier curves and log-rank tests were used to compare the cumulative rates of TLF between both groups. All principal statistical analyses were performed according to the intention-to-treat principle. A 2-sided P value <0.05 indicated statistical significance. The statistical analyses were performed using SPSS software version 25 (IBM, New York, USA).
3. Results
3.1. Baseline and procedure characteristics
We randomly assigned 428 patients to either the MiStent group (216 patients, 290 lesions) or TIVOLI group (212 patients, 274 lesions) [Figure 1 ]. Baseline and procedure characteristics were similar between both groups [Tables 1 and 2 ]. Changes in proportions of prescribed antiplatelet treatment from discharge to 1-year follow-up are presented in Supplementary Table 1 (https://links.lww.com/CD9/A25 MiStent group (79.31%) was higher than that in TIVOLI group (73.36%), no significant difference was found between both groups.
Table 1 -
Baseline characteristics of patients with
de novo coronary lesions to receive
MiStent or TIVOLI BP-SES
Variables
MiStent (n = 216)TIVOLI (n = 212)
P
Age (years), mean ± SD
59.55 ± 9.21
60.39 ± 8.62
0.33
Male, n (%)
148 (68.52)
137 (64.62)
0.40
BMI (kg/m2 ), mean ± SD
24.78 ± 3.37
25.09 ± 3.31
0.33
Diabetes mellitus, n (%)
53 (24.54)
57 (26.89)
0.58
Hypertension, n (%)
122 (56.48)
119 (56.13)
0.94
Hyperlipidemia, n (%)
29 (13.43)
26 (12.26)
0.72
Family history of CAD, n (%)
26 (12.04)
31 (14.62)
0.43
Smoking status, n (%)
0.15
Current
94 (43.52)
91 (42.92)
Previous
41 (18.98)
27 (12.74)
Never
81 (37.50)
94 (44.34)
Previous MI, n (%)
23 (10.65)
35 (16.51)
0.08
Previous CABG, n (%)
0 (0)
1 (0.47)
0.50
Indication, n (%)
0.26
Asymptomatic ischemia
1 (0.46)
1 (0.47)
Stable angina
27 (12.50)
22 (10.38)
Unstable angina
141 (65.28)
146 (68.87)
Myocardial infarction
41 (18.98)
30 (14.15)
OMI
6 (2.78)
13 (6.13)
Anemia, n (%)
8(3.74)
10(4.72)
0.62
eGFR (mL/min·1.73 m2 ), mean ± SD
102.10 ± 25.44
99.32 ± 23.28
0.23
LVEF (%), mean ± SD
63.48 ± 6.92
64.17 ± 7.20
0.32
All patients diagnosed with myocardial infarction were enrolled after 7 d from index events (which did not conflict with exclusion criteria item 1, see Supplementary Appendix 2,
https://links.lww.com/CD9/A24 ).
BMI: Body mass index; BP-SES: Biodegradable polymer sirolimus-eluting stent ; CABG: Coronary artery bypass grafting; CAD: Coronary artery disease; eGFR: Estimated glomerular filtration rate; LVEF: Left ventricular ejection fraction; MI: Myocardial infarction; OMI: Old myocardial infarction; SD: Standard deviation.
Table 2 -
Baseline lesion characteristics of patients with
de novo coronary lesions to receive
MiStent or TIVOLI BP-SES
Variables
MiStent (216 patients, 290 lesions)TIVOLI (212 patients, 274 lesions)
P
Vessel location, n (%)
0.14
Left anterior descending artery
137 (47.24)
126 (45.99)
Left circumflex artery
50 (17.24)
46 (16.79)
Left main artery
0 (0)
0 (0)
Right circumflex artery
95 (32.76)
83 (30.29)
Others
8 (2.76)
19 (6.93)
Pre-procedural TIMI flow, n (%)
0.77
0
5 (1.72)
3 (1.09)
1
3 (1.03)
3 (1.09)
2
16 (5.52)
11 (4.01)
3
266 (91.72)
257 (93.08)
Number of target lesions per patient, mean ± SD
1.39 ± 0.50
1.30 ± 0.46
0.44
Stent characteristics, mean ± SD
Number of stents implanted per lesion
1.25 ± 0.45
1.26 ± 0.45
0.83
Total stent length per lesion (mm)
25.45 ± 9.98
25.68 ± 10.26
0.78
Stent diameter per lesion (mm)
2.86 ± 0.36
2.88 ± 0.37
0.63
Post-procedural TIMI flow, n (%)
0.11
0
0 (0)
0 (0)
1
0 (0)
2 (0.73)
2
0 (0)
1 (0.36)
3
289 (99.66)
271 (98.91)
BP-SES: Biodegradable polymer sirolimus-eluting stent ; SD: Standard deviation; TIMI: Thrombolysis in myocardial infarction.
Figure 1:: Flow chart of DESSOLVE-C trial.
3.2. Quantitative angiographic analysis
Pre-procedural QCA measures were balanced between both groups [Table 3 ]. Stent implantation success occurred in all patients in both groups. Additionally, post-procedural QCA measures were similar between both groups, except for the in-stent diameter stenosis. The rate of in-stent diameter stenosis in the MiStent group was higher than that in the TIVOLI group (6.39% vs. 5.57%; P = 0.04) [Table 3 ].
Table 3 -
Quantitative angiographic analysis pre-procedure, post-procedure, and at 9-month follow-up of patients with
de novo coronary lesions to receive
MiStent or TIVOLI BP-SES
Variables
MiStent TIVOLI
P
Pre-procedural QCA
Number of lesions
290
274
–
Reference vessel diameter (mm), mean ± SD
2.79 ± 0.42
2.80 ± 0.42
0.80
Lesion length (mm), mean ± SD
19.61 ± 9.03
20.34 ± 9.96
0.36
Minimal lumen diameter (mm), mean ± SD
0.92 ± 0.40
0.96 ± 0.42
0.24
Diameter stenosis (%), mean ± SD
67.22 ± 12.75
65.76 ± 13.75
0.20
Post-procedural QCA
Number of lesions
290
274
–
Minimum lumen diameter (mm), mean ± SD
In-stent
2.54 ± 0.36
2.58 ± 0.38
0.16
In-segment
2.33 ± 0.43
2.37 ± 0.44
0.28
Diameter stenosis (%), median (Q1, Q3)
In-stent
6.39 (2.55, 10.64)
5.57 (2.08, 9.38)
0.04
Proximal edge
4.85 (0.77, 11.08)
3.93 (0.95, 8.03)
0.23
Distal edge
5.56 (2.06, 10.86)
5.31 (1.64, 10.03)
0.50
In-segment
10.00 (5.36, 14.73)
8.91 (5.13, 13.96)
0.22
9-month follow-up
Number of lesions
261
232
–
Minimum lumen diameter (mm), mean ± SD
In-stent
2.31 ± 0.49
2.24 ± 0.56
0.12
In-segment
2.12 ± 0.55
2.05 ± 0.56
0.13
Diameter stenosis (%), median (Q1, Q3)
In-stent
11.86 (5.52, 19.52)
13.05 (5.51, 23.68)
0.12
Proximal edge
7.28 (2.08, 13.84)
6.11 (2.44, 13.96)
0.92
Distal edge
6.09 (1.64, 10.96)
6.69 (1.71, 13.28)
0.22
In-segment
14.32 (7.93, 24.34)
15.46 (8.46, 27.21)
0.24
Late lumen loss
In-stent (mm), mean ± SD
0.23 ± 0.37
0.34 ± 0.48
Non-inferiority <0.001; superiority 0.02
In-segment (mm), median (Q1, Q3)
0.11 (−0.01, 0.35)
0.19 (0.05, 0.47)
<0.001
Binary restenosis, n (%)
In-stent
12 (4.62)
21 (9.05)
0.04
Proximal edge
3 (1.15)
2 (0.86)
0.92
Distal edge
0 (0)
7 (3.02)
0.01
In-segment
15 (5.75)
23 (9.91)
0.06
Success rate of stent implantation (%)
100
100
–
“–” indicates the data are not available.
BP-SES: Biodegradable polymer sirolimus-eluting stent ; QCA: Quantitative coronary angiography; SD: Standard deviation.
A 9-month angiographic follow-up was completed in 261 (90.00%) lesions in the MiStent group and 232 (84.67%) lesions in the TIVOLI group. The primary endpoint, in-stent LLL, was (0.23 ± 0.37) mm with MiStent and (0.34 ± 0.48) mm with TIVOLI. The observed difference of LLL was –0.11 mm, and the 1-sided 97.5% upper limit was –0.04 mm, which was lower than the non-inferiority margin of 0.12 mm (P for non-inferiority <0.001, Table 3 , central illustration). In the superiority test, MiStent was notably superior to TIVOLI (0.14 (0.02, 0.32) mm in MiStent vs . 0.20 (0.02, 0.43) mm in TIVOLI, P for superiority = 0.02, Table 3 , central illustration). The in-segment LLL with MiStent was lower than that of TIVOLI (P <0.001, Table 3 ). The binary restenosis rates of in-stent (4.62% vs. 9.05%; P = 0.04) and distal edge (0 vs. 3.02%; P = 0.01) in the MiStent group was lower than those in the TIVOLI group at 9 months, whereas no significant difference was found in binary restenosis rates of in-segment (5.75% vs. 9.91%; P = 0.06) and distal edge between both groups (1.15% vs. 0.86%; P = 0.92, Table 3 ). No significant difference in diameter stenosis was found between both groups [Table 3 ].
3.3. Clinical outcomes
The 12-month clinical follow-up was completed in 214 (99.07%) patients in the MiStent group and 202 (95.28%) patients in the TIVOLI group. At 12 months, TLF was quantitatively lower in the MiStent group than in the TIVOLI group, although without statistical significance (3.70% vs. 6.60%, P = 0.17, Table 4 , Figure 2 , and central illustration). This difference in quantity of TLF was mainly derived from clinically driven TLR, which was quantitatively lower in the MiStent group than in the TIVOLI group (6 (2.78%) patients in the MiStent group vs. 11 (5.19%) patients in the TIVOLI group; P = 0.20, Table 4 ). Rates of cardiac death and target vessel MI were comparable between both groups [Table 4 ].
Table 4 -
The rates of efficacy endpoints according to intention-to-treat principle at 1-year follow-up of patients with
de novo coronary lesions to receive
MiStent or TIVOLI BP-SES
Variables
MiStent (n = 216)TIVOLI (n = 212)
P
TLF, n (%)
8 (3.70)
14 (6.60)
0.17
Cardiac death
1 (0.46)
2 (0.94)
0.49
Target vessel MI
1 (0.46)
1 (0.47)
0.75
Clinically driven TLR
6 (2.78)
11 (5.19)
0.20
PoCE, n (%)
11 (5.09)
25 (11.79)
0.01
All-cause death
1 (0.46)
5 (2.36)
0.10
Nonfatal MI
1 (0.46)
1 (0.47)
0.75
Stroke
0 (0.00)
1 (0.47)
0.50
Any revascularization
9 (4.17)
18 (8.49)
0.07
Stent thrombosis, n (%)
1 (0.46)
0 (0)
1.00
BP-SES: Biodegradable polymer sirolimus-eluting stent ; MI: Myocardial infarction; PoCE: Patient-oriented composite endpoint; TLF: Target lesion failure; TLR: Target lesion revascularization.
Figure 2:: Cumulative incidence of target lesion failure of MiStent vs. TIVOLI at 12 months.
The rate of PoCE was lower in the MiStent group than in the TIVOLI group (11 (5.09%) patients in MiStent vs. 25 (11.79%) patients in TIVOLI, P = 0.01, Table 4 ). This significant difference was mainly driven by the difference in rates of any revascularization. The MiStent group had a quantitatively lower rate of any revascularization than the TIVOLI group (4.17% in MiStent vs. 8.49% in TIVOLI; P = 0.07, Table 4 ), although no significant difference was observed. Rates of all-cause death, nonfatal MI, and stroke were similar between both groups. At 1 year, ARC-defined ST occurred in 1 patient who received MiStent implantation, and no patient in the TIVOLI group experienced ARC-defined ST [Table 4 ].
4. Discussion
In this prospective, single-blinded, multicenter, randomized trial, the MiStent ultrathin-strut BP-SES system was both non-inferior and superior to a mature BP-SES TIVOLI for the primary endpoint of in-stent LLL and had comparable rates of binary restenosis or proportions of diameter stenosis with TIVOLI at 9 months. At 12 months, MiStent had quantitatively lower rates of TLF and clinically driven TLR than TIVOLI.
This randomized controlled trial compared in-stent LLL as the primary endpoint between MiStent and TIVOLI and demonstrated that MiStent was non-inferior to TIVOLI detected by QCA at 9 months. The in-stent LLL of MiStent in this study was (0.23 ± 0.37) mm, which was nearly identified with in-stent LLL of MiStent ((0.27 ± 0.46) mm) in the DESSOLVE II study.[ 12 ] Angiographic measures at 9 months of both studies showed that MiStent was non-inferior to its counterparts (TIVOLI in this study and Endeavor in DESSOLVE II study). Surprisingly, the superiority of MiStent to TIVOLI, aside the non-inferiority regarding the in-stent LLL, was also observed (P for superiority = 0.02) in this study (although without intended statistical consideration for superiority). Regarding the in-stent LLL, a meta-analysis indicated that a cut-off value of <0.5 mm was associated with a low incidence of TLR at 4 years.[ 20 ] More stringently, the European Society for Cardiology/European Association of Percutaneous Cardiovascular Interventions (ESC/EAPCI) defined the value of 0.34 mm as the upper boundary of the 95% confidence interval to meet the objective performance criteria.[ 21 ] The in-stent LLL of MiStent reported by our study was lower than both 0.5 and 0.34 mm, which fully identified the device efficacy of MiStent . Moreover, in this trial, MiStent was found to be superior or at least comparable to TIVOLI in other secondary endpoints, including in-segment LLL, binary restenosis, and diameter stenosis. All these results collectively indicated the considerable effect of a well-designed MiStent system on angiographic outcomes. Unfortunately, due to the study design, no intravascular imaging inspections were performed, thus more precise intravascular information on MiStent was absent and needed to be reported further.
Although previous studies have demonstrated the effectiveness of MiStent in preventing LLL at 8 or 9 months[ 11 , 12 ] and the comparability of MiStent with DP-DES in the rate of a composite endpoint (including cardiac death, target vessel MI, and clinically indicated TLR) at 12 months in patients with CHD,[ 13 ] clinical evidence on long-term efficacy and safety of MiStent are still relatively limited. An analysis comparing MiStent BP-SES with Xience DP-everolimus-eluting stent from 3 randomized trials showed that MiStent had lower rates of TLR (2.0% in MiStent vs. 8.4% in Xience; P = 0.04) and TLF (5.0% in MiStent vs. 12.5% in Xience; P = 0.07) than Xience at 3 years.[ 22 ] Additionally, in the 3-year outcomes of the DESSOLVE III trial, the rates of a composite of cardiac death, target vessel MI, and clinically indicated TLR were similar between MiStent and Xience (10.5% in MiStent vs. 11.5% in Xience; P = 0.55).[ 14 ] Our study found that the rate of device-related clinical cardiovascular composite endpoint TLF was similar between the MiStent group and TIVOLI group at 12 months after the index procedure, which was consistent with findings from these studies. The Kaplan-Meier survival curves between both groups were “separated” after the 9-month angiographic follow-up. This phenomenon was partially due to the proportion of revascularization events within 9 to 12 months driven by the positive findings from the 9-month angiography, whereas all revascularization procedures were necessary and reasonable for improving prognosis. Furthermore, we will follow-up participants until 5 years and report more long-term clinical outcomes in the future.
In the final-3-year outcomes of the DESSOLVE III trial, the risk of any revascularization in the MiStent group was found to be lower than that in Xience (14.9% vs. 19.1%; P = 0.043)[ 14 ] ; however, this benefit of any revascularization from MiStent was deemed to be a chance finding by researchers of the DESSOLVE III trial because it was driven by a lower risk of non-TLR (8.9% vs. 12.5%; P = 0.033).[ 14 ] In our study, a quantitatively lower rate of any revascularization in the MiStent group was found. However, this reduction in any revascularization in our study was mainly derived from the quantitative difference of clinically driven TLR, which was clearly different from the results of the DESSOLVE III trial presented above. Due to the particular technique of MiStent , the generation of the crystalline form of sirolimus polymer prolonged neointimal inhibition in the coronary artery. Thus, our results of reduced clinically driven TLR (although not significant) were theoretically reasonable. Whether the MiStent system could reduce the risk of revascularization, especially for the risk of TLR, is still worth exploring.
In this study, only 1 patient assigned to the MiStent group experienced the ARC-defined ST event, and no significant difference in the risk of ST was found between both groups. An observational registry study comparing bioabsorbable vs. permanent polymer DESs reported that the Kaplan-Meier estimate for definite ST at 2 years in the BP-DES group was 0.48%,[ 23 ] which was similar to our result. Results from the DESSOLVE III trial reported <1% rate of definite or probable ST in the MiStent group at 12 months.[ 13 ] All these results from our study provided new evidence for the stability safety of the MiStent system, and showed the great potential of MiStent for application in patients with CHD.
Compared with other BP-DESs, the MiStent system has a unique and exceptional advantage—the microcrystalline form of sirolimus. This dedicated design of MiStent additionally produces stable and long-lasting (up to 270 d) inhibition effect on neointimal hyperplasia.[ 10 ] The gradual release of sirolimus because of its crystallized form substantially prolongs the duration of action and effectively suppresses neointimal proliferation for the prevention of early and late ST.[ 11 , 12 ] Recently, the DESSOLVE III optical coherence tomography sub-study demonstrated that the mean abluminal volume obstruction at 6 months after implantation was significantly lower in MiStent than in Xience,[ 24 ] which in combination with findings from our study further illustrated that MiStent considerably inhibited neointimal growth as a result of the crystallized sirolimus. Besides the BP with microcrystalline sirolimus, the ultrathin strut is another strength of MiStent . Series of randomized trials have demonstrated the clinical benefit of ultrathin DES in patients with CHD.[ 25–27 ] Moreover, according to a meta-analysis study, <70 µm ultrathin-strut DESs, including MiStent , improved 1-year clinical outcomes, in comparison with thicker strut DESs.[ 28 ] These results proved that the ultrathin strut of MiStent additionally provides beneficial effect for patients with CHD.
According to previous studies and this randomized trial, the MiStent system is efficacious and safe for patients with CHD. However, most of these studies were non-inferiority studies and did not have enough power to compare clinical outcomes with those of other DESs. Besides, studies comparing clinical outcomes between BP-DESs and DP-DESs sometimes produced negative results.[ 23 , 29 ] Therefore, more evidence from ongoing studies are highly anticipated to fully evaluate the clinical benefit of MiStent .[ 30 ]
Several limitations were present in our study. First, to obtain the approval of the China Food and Drug Administration for MiStent , a mature, post-marketing BP-DES TIVOLI (made in China but not approved in Europe or the United States) was selected as the control device. However, with the evidence from the DESSOLVE III trial identifying the comparable clinical benefits of MiStent and Xience (one of the most used devices globally), the reliability of MiStent will not be discounted. Second, although both angiographic and clinical outcomes were explored, the clinical outcomes in this study were secondary endpoints. Moreover, the concern is that both issues can hardly be addressed in 1 study, indicating that further studies are needed for specific investigation. Third, we did not perform additional intravascular imaging inspections, such as optical coherence tomography. Therefore, no intravascular imaging sub-study that reflects more precise angiographic information was conducted. Moreover, only patients with stable and unstable AP, OMI, or confirmed evidence of myocardial ischemia were eligible for our study, and clinical outcomes of patients with other types of CHD were not available. Fourth, only 1-year outcomes were indicated in this analysis, and 2- to 5-year outcomes will be reported in the future.
5. Conclusion
In this randomized controlled trial, the MiStent system, a new kind of BP-SES, was not only non-inferior but even superior to the mature TIVOLI BP-SES for in-stent LLL at 9 months. Additionally, it had comparable clinical benefits with TIVOLI at 1 year.
Central Illustration : DESSOLVE C Trial: Microcrystalline biodegradable polymer vs. biodegradable polymer sirolimus-eluting stent .
Funding
None.
Author contributions
Bin Wang was mainly in charge of conducting this randomized controlled trial. Sicong Ma was in charge of manuscript writing. Miaohan Qiu designed statistical plan, verified the underlying data, and conducted statistical analysis. Zhiyong Wang, Li Zhang, Hanjun Pei, Yang Zheng, Yuejin Yang, Zheng Zhang, Xinqun Hu, Ziwen Ren, Feng Zhang, Changqian Wang, Renqiang Yang, Zhiming Yang, Yuexi Wang, Guosheng Fu, Yu Cao, Zuyi Yuan, Kai Xu, Xin Zhao, and Bo Xu contributed to participant recruitment during the whole period of study. The corresponding author, Quanmin Jing, had full access to all the data in the study and takes responsibility for their integrity and data analysis. And contributed to the leadership of the entire process of study conduction, and acted in key roles of initiating, designing, conducting, and concluding the study.
Conflicts of interest
This study was supported by Micell Technologies (Durham, North Carolina, USA).
Editor note: Zuyi Yuan is a member of the editorial board of Cardiology Discovery . The article was subject to the journal’s standard procedures, with peer review handled independently of the editor and his research groups.
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