Efficacy and Safety of TiNO-Coated Stents versus Drug-Eluting Stents in Acute Coronary Syndrome: Systematic Literature Review and Meta-Analysis

(1) Background: Practice guidelines define drug-eluting stents (DES) as the standard of care in coronary percutaneous coronary intervention (PCI), including in acute coronary syndrome (ACS). This is based on comparisons with bare-metal stents (BMS). However, non-drug-eluting titanium-nitride-oxide-coated stents (TiNOS) have not been taken into account. The objective of this study is to determine whether TiNOS can be used as an alternative to DES in ACS. (2) Methods: A prospective systematic literature review (SLR), conducted according to the PRISMA guidelines, was performed, wherein multiple literature databases from 2018 and 2022 were searched. Prospective, randomised, controlled trials comparing outcomes after PCI with TiNOS vs. DES in any coronary artery disease (CAD) were searched. Clinical outcomes were meta-analytic pooled risk ratios (RR) of device-oriented Major Adverse Cardiac Events (MACE) and their components. The analysis stratified outcomes reported with ACS-only vs. ACS jointly with chronic coronary syndrome (CCS). (3) Results: Five RCTs were eligible, comprising 1855 patients with TiNOS vs. 1363 with DES at a 1-year follow-up. Three enrolled patients presented with ACS only and two with ACS or CCS. The latter accounted for most of the patients. The one-year pooled RRs in those three RCTs were as follows: MACE 0.93 [0.72, 1.20], recurrent myocardial infarction (MI) 0.48 [0.31, 0.73], cardiac death (CD) 0.66 [0.33, 1.31], clinically driven target lesion revascularization (TLR) 1.55 [1.10, 2.19], and stent thrombosis (ST) 0.35 [0.20, 0.64]. Those results were robust to a sensitivity analysis. The evidence certainty was high in MACE and moderate or low in the other endpoints. (4) Conclusions: TiNOS are a non-inferior and safe alternative to DES in patients with ACS.


Introduction
Coronary Artery Disease (CAD) is classified into two broad groups: Acute Coronary Syndrome (ACS) and chronic coronary syndromes (CCS) [1]. CCS have a variety of presentations but are without acute symptoms.
Patients with ACS have ongoing acute myocardial ischemia that can cause various symptoms ranging from cardiac arrest to electrical or haemodynamic instability and cardiac mechanical disorders. The leading ACS symptom is chest discomfort or pain. ACS with acute chest pain and persistent (>20 min) ST-segment elevation on an electrocardiogram (ECG) often reflects an acute total or subtotal coronary occlusion. Most patients with this type of ACS develop ST-segment elevation myocardial infarction (STEMI) [2]. Patients with acute chest discomfort and no persistent ST-segment elevation (NSTE-ACS) often develop non-ST-segment elevation myocardial infarction (NSTEMI), but some of them do The studies' identification, screening, and selection are described in the PRIS flowchart ( Figure 1). One hundred and eighteen references were identified and nine lications with first-hand data about five RCTs were eligible for inclusion in the meta-a ysis.

Eligible Study Characteristics
Five RCTs were eligible, as their baseline characteristics complied with the PI specification ( Table 1).
The studies reported 1-year follow-up data for 1855 patients in the TiNOS arm 1363 in the DES arm. The quantities of available patients at 5-year follow-up were 78 773.
Three RCTs reported outcomes in patients with ACS only (TITAX-AMI, BASE-A and TIDES-ACS). The two others reported outcomes in patients presenting ACS or without stratification: TIDE enrolled 143 patients with ACS (47%) and TITANIC-XV rolled 112 (64.7%).

Eligible Study Characteristics
Five RCTs were eligible, as their baseline characteristics complied with the PICOS specification ( Table 1).
The studies reported 1-year follow-up data for 1855 patients in the TiNOS arm vs. 1363 in the DES arm. The quantities of available patients at 5-year follow-up were 783 vs. 773.
Three RCTs reported outcomes in patients with ACS only (TITAX-AMI, BASE-ACS, and TIDES-ACS). The two others reported outcomes in patients presenting ACS or CCS without stratification: TIDE enrolled 143 patients with ACS (47%) and TITANIC-XV enrolled 112 (64.7%).

Publication Bias
The funnel plot and the Harbord test (p = 0.263) did not detect a risk of publication bias regarding the RR of MACE in all CAD cases at 1-year follow-up ( Figure 2).

Publication Bias
The funnel plot and the Harbord test (p = 0.263) did not detect a risk bias regarding the RR of MACE in all CAD cases at 1-year follow-up (Figur Similar conclusions were found for the other six endpoints at the 1-yea all CAD cases.

Individual Study Bias
The compiled risk of bias across the studies ( Figure 3) shows an over that is generally less than 75%, except for operator blinding. The individu bias is reported with the pooled 1-year MACE RR ( Figure 4).
There were some differences in the definitions of MACE and MI betwe they were applied similarly in both treatment arms.  Similar conclusions were found for the other six endpoints at the 1-year follow-up in all CAD cases.

Individual Study Bias
The compiled risk of bias across the studies ( Figure 3) shows an overall risk of bias that is generally less than 75%, except for operator blinding. The individual RCT risk of bias is reported with the pooled 1-year MACE RR ( Figure 4).

Publication Bias
The funnel plot and the Harbord test (p = 0.263) did not detect a risk of pu bias regarding the RR of MACE in all CAD cases at 1-year follow-up ( Figure 2). Similar conclusions were found for the other six endpoints at the 1-year follo all CAD cases.

Individual Study Bias
The compiled risk of bias across the studies ( Figure 3) shows an overall ris that is generally less than 75%, except for operator blinding. The individual RC bias is reported with the pooled 1-year MACE RR ( Figure 4).
There were some differences in the definitions of MACE and MI between stu they were applied similarly in both treatment arms.

Pooled Outcome Risk Ratios
The stratified, pooled RRs of the primary endpoint, 1-year MACE (i.e., ACS-only vs ACS and CCS, and total), show no significant risk difference between TiNOS and DES and low individual study risk bias except for operator blinding (Figure 4). The ACES only vs. ACS and CCS subgroups display no significant heterogeneity according to the Q-test (p = 0.17), which is in line with the overlapping CIs. The 47.1% I² between subgroups quantifies the visual difference.
The pooled 5-year MACE RR shows a significantly lower pooled RR favouring Ti-NOS in the ACS-only subgroup. Heterogeneity between the two strata is larger than at one 1-year (I² = 66%), but the confidence intervals overlap with a non-significant Q-test (p = 0.09) ( Figure 5).  There were some differences in the definitions of MACE and MI between studies, but they were applied similarly in both treatment arms.

Pooled Outcome Risk Ratios
The stratified, pooled RRs of the primary endpoint, 1-year MACE (i.e., ACS-only vs. ACS and CCS, and total), show no significant risk difference between TiNOS and DES and low individual study risk bias except for operator blinding ( Figure 4). The ACES only vs. ACS and CCS subgroups display no significant heterogeneity according to the Q-test (p = 0.17), which is in line with the overlapping CIs. The 47.1% I 2 between subgroups quantifies the visual difference.
The pooled 5-year MACE RR shows a significantly lower pooled RR favouring TiNOS in the ACS-only subgroup. Heterogeneity between the two strata is larger than at one 1-year (I 2 = 66%), but the confidence intervals overlap with a non-significant Q-test (p = 0.09) ( Figure 5).

Pooled Outcome Risk Ratios
The stratified, pooled RRs of the primary endpoint, 1-year MACE (i.e., ACS-on ACS and CCS, and total), show no significant risk difference between TiNOS and DES low individual study risk bias except for operator blinding ( Figure 4). The ACES on ACS and CCS subgroups display no significant heterogeneity according to the Q-tes 0.17), which is in line with the overlapping CIs. The 47.1% I² between subgroups quan the visual difference.
The pooled 5-year MACE RR shows a significantly lower pooled RR favourin NOS in the ACS-only subgroup. Heterogeneity between the two strata is larger th one 1-year (I² = 66%), but the confidence intervals overlap with a non-significant Q-te = 0.09) ( Figure 5).   The pooled RRs of recurrent non-fatal MI or CD at 1-year and 5-year follow-ups are significant and favour TiNOS in the ACS-only subgroup (Figures 6 and 7). The RRs are driven by the differences in the incidence of non-fatal MI.
Biomedicines 2022, 10, x FOR PEER REVIEW 8 of 25 The pooled RRs of recurrent non-fatal MI or CD at 1-year and 5-year follow-ups are significant and favour TiNOS in the ACS-only subgroup (Figures 6 and 7). The RRs are driven by the differences in the incidence of non-fatal MI.  The pooled RR of TLR at a 1-year follow-up is significant, with more frequent TLRs with TiNOS than DES in ACS-only vs. ACS and CCS ( Figure 8). However, the RR at 5year follow-up reduces to non-significance as the rate of TLRs in the DES arm catches up with the rate in the TiNOS arm ( Figure 9). The pooled RRs of recurrent non-fatal MI or CD at 1-year and 5-year follow-ups are significant and favour TiNOS in the ACS-only subgroup (Figures 6 and 7). The RRs are driven by the differences in the incidence of non-fatal MI.  The pooled RR of TLR at a 1-year follow-up is significant, with more frequent TLRs with TiNOS than DES in ACS-only vs. ACS and CCS ( Figure 8). However, the RR at 5year follow-up reduces to non-significance as the rate of TLRs in the DES arm catches up with the rate in the TiNOS arm ( Figure 9). The pooled RR of TLR at a 1-year follow-up is significant, with more frequent TLRs with TiNOS than DES in ACS-only vs. ACS and CCS ( Figure 8). However, the RR at 5-year follow-up reduces to non-significance as the rate of TLRs in the DES arm catches up with the rate in the TiNOS arm ( Figure 9).
The pooled RRs of CD, non-fatal MI, probable or definite ST, TD, and definite ST are reported in the sensitivity analysis ( Table 2

Sensitivity Analysis-Additional Endpoints
The sensitivity analysis (Table 2) in the ACS-only group at the 1-year follow-up shows: - The robustness of the non-significant MACE's pooled RR; - The robustness of the significant recurrent non-fatal MI's pooled RR with less frequent events in TiNOS than in DES; - The robustness of the significant probable or definite ST's pooled RR with less frequent events in TiNOS than in DES; - The robustness of the significant TLR's pooled RR with more frequent events in TiNOS than in DES; - The robustness of CD's pooled RR varied depending on the excluded study.
The total pooled RRs at the 1-year follow-up yielded similar results to ACS-only.
The sensitivity analysis in the ACS-only group at the 5-year follow-up also yielded similar results to ACS at the 1-year follow-up; however, the TLR RR became non-significant.
Sensitivity analysis in the total pooled RRs at the 5-year follow-up yielded similar results to ACS at the 5-year follow-up except for probable or definite ST, which lost robustness upon TITAX-AMI's removal. The RR of definite ST remained robust.

GRADE: Certainty of the Evidence
Given the potential bias caused by pooling ACS and CCS, and considering that the 5-year outcomes of TIDES-ACS were not published when writing this article, the GRADE analysis focused on the 1-year outcomes in the ACS-only group (Table 3). Explanations: GRADE Working Group grades of evidence: High certainty-very confident that the true effect lies close to that of the estimate. Moderate certainty-moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty-confidence in the effect estimate is limited; the true effect may be substantially different from the estimate. Very low certainty-very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate.
The certainty level of the evidence of MACE, the primary outcome measure, is high. However, the certainty levels of the secondary outcome measures are moderate, low, or very low.
The detailed explanations supporting each GRADE item rating are reported in Appendix B.

Discussion
Practice guidelines establish the use of DES as the standard of care in PCI to treat ACS [2,9,10]. However, the 2017 Cochrane review comparing the outcomes with DES vs. BMS in ACS concluded that the "evidence in this review was of low to very low quality, and the true result may depart substantially from the results presented in this review" [45]. Therefore, the comparison of the clinical outcomes of TiNOS vs. DES in ACS is relevant to determining whether TiNOS could be an alternative to DES in that group of clinical indications.
The first hypothesis of this SLR is based on preclinical demonstrations that TiNOS are associated with less neointimal hyperplasia than BMS [14][15][16]. The second hypothesis is that patients presenting with ACS have a higher risk of SAE than patients with CCS. Given that some RCTs included both patients with ACS and CCS, the SLR analysed all RCTs that compared DES to TiNOS.
The pooled RRs of MACE, CD or recurrent non-fatal MI, clinically-driven TLR, ST, and TD at the 1-year follow-up, did not significantly differ between all-RCTs and ACS-only RCTs. The latter represented 85% of the patients, and the ACS-only pooled results drove the all-RCT results. Therefore, the internal and external validation of this meta-analysis focuses on the ACS-only subgroup.
All the results were robust to the sensitivity analysis, so no single trial significantly modified them. This confirmed that excluding any ACS-only trial due to the generation of the platform, the eluted drug (e.g., paclitaxel), or a specific patient risk factor (e.g., diabetes) had no impact on the pooled results.
The results at the 5-year follow-up were consistent with those at the 1-year follow-up, although probable ST presented reduced robustness while definite ST remained robust.
No risk of publication bias was identified, and the overall risk of bias in the individual RCTs was not serious except for non-blinding operators.
At the 1-year follow-up in the ACS-only trials, TiNOS and DES displayed a nonsignificantly different MACE rate, and the quality of evidence was high. TiNOS displayed a significantly lower rate of CD or recurrent MI than DES, and the quality of evidence was moderate due to lower precision caused by the limited number of events observed altogether. TiNOS and DES displayed a non-significantly different TLR. TiNOS displayed lower mortality and ST rates, and the quality of evidence was low or very low with fewer observed events.
Two previously published meta-analyses comparing DES vs. BMS in ACS were identified to attempt the external validation of the DES arm of this meta-analysis [45,46]. The 2017 Cochrane review included 25 RCTs, of which most focused on STEMI, with different time horizons and RRs that were reported at the maximum follow-up. Therefore, a comparison with the 1-year and 5-year outcomes of this meta-analysis was not interpretable. The 2022 individual patient data meta-analysis (IPDM) includes 14 RCTs with a total of 22,319 patients with 34.5% of the patients treated for CCS and 65.5% for ACS. The outcomes are reported at 1-year and 5-year follow-ups. The type of ACS reported in the source publications (Table 4) (Table 5). This comparability supports the validity of that endpoint in this meta-analysis. However, the pooled incidence rate of the definite ST in the DES group of this meta-analysis is 3 times higher at the 1-year follow-up than in the IPDM and 5.48 times higher at the 5-year follow-up. These ratios could have resulted from differences in the methods, the patients' baseline risk, the types of DES used, and the relatively small number of observations in this meta-analysis. Moreover, the IPDM does not report TLR or MACE rates, so IPDM does not provide an external validation basis for those three endpoints.  Overall, the robustness to the sensitivity analysis, the low level of heterogeneity between the three ACS-only RCTs, and their low risk of bias support the internal validity of this meta-analysis of TiNOS vs. DES. The similarity in the CD or MI rates between the DES arms of the IPDM and this meta-analysis support the external validity of that endpoint. One can infer from the meta-analyses that DES presents a lower risk of CD or MI than BMS and TiNOS has a lower risk than DES.
This meta-analysis shows with high certainty of evidence, according to GRADE, that TiNOS is non-inferior to DES in ACS at the 1-year follow-up. TiNOS displays a significantly lower risk of recurrent non-fatal myocardial infarctions and probable or definite ST but a significantly higher risk of TLR. The certainty of evidence concerning ST and TLR is low due to the limited number of observations, thus the limited precision in the GRADE criteria. At any rate, the risk of TLR with TiNOS can be reduced when using short stent lengths (≤28 mm) and/or large stent diameters (>3.0 mm) [42,44].
The results at the 5-year follow-up are consistent with the 1-year results but will require the publication of TIDES-ACS final data to be confirmed.

Conclusions
This systematic review shows that titanium-nitride-oxide-coated stents are non-inferior to drug-eluting stents when applied to acute coronary syndrome at the one-year followup in terms of device-oriented major adverse cardiac events and present a lower risk of recurrent non-fatal myocardial infarction. The interim five-year results are consistent with the one-year results and are robust. Therefore, titanium-nitride-oxide-coated stents are a safe alternative to drug-eluting stents in acute coronary syndrome.
Note: Ineligible records are listed with the references . Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.

Conflicts of Interest:
The authors declare no conflict of interest. No funder was involved in this academic research other than Bordeaux University.  Cochrane database search string: ((bioactive OR (Titanium AND nitride AND oxide) OR TiNO OR TNO OR BAS) AND stent) AND (DES OR (drug AND eluting AND stent)) AND (RCT OR ((randomised OR randomised) AND controlled AND trial)).

Appendix A. Detailed Search Strings in Each Database
Web of Science search string: (((bioactive OR (Titanium AND nitride AND oxide) OR TiNO OR TNO OR BAS) AND stent) AND (DES OR (drug AND eluting AND stent)) AND (RCT OR ((randomised OR randomised) AND controlled AND trial))) Embase search string: (((bioactive OR (Titanium AND nitride AND oxide) OR TiNO OR TNO OR BAS) AND stent) AND (DES OR (drug AND eluting AND stent)) AND (RCT OR ((randomised OR randomised) AND controlled AND trial)))/br.

Appendix B. Detailed Explanations of Each GRADE Item Rating a
The risk of bias common to all RCTs was the operator's knowledge of the type of stent. However, given the absence of significant differences in the baseline and procedural data, this risk seems to have had no effect. Other potential risks of bias appeared occasionally in some RCTs, but the sensitivity analysis shows that bias related to individual RCTs has little influence on the pooled outcomes. The study with the highest risk of bias has the smallest relative weight and does not report outcomes in ACS or at the 5-year follow-up, so the impact of the potential risk of that trial is limited. b Heterogeneity within this subgroup was low given the overlap of all the confidence intervals, the Cochran Q-test with p > 0.05, and an I 2 < 40%. c The three ACS RCTs report modified device-oriented MACE. Heterogeneity within that subgroup was high given the absence of overlap of confidence intervals, the significant Cochran Q-test with p = 0.005, and an I 2 ≥ 80%. l The definition of CD was assumed to be similar across the three ACS RCTs. This uniform reporting method across the three trials was confirmed by PK. m The 95% CI of the RR of CD is non-significant with a length > 0.5. Sensitivity analysis supports no association. A hypothetical single RCT, 1:1 randomization, 2-sided test, α = 5%, power = 80%, and a reference rate of events in the 3 trial DES arms 16/1123 = 0.014 assuming delta = 0.004 based on a targeted 30% RRR requires a total sample size of n = 21,484 patients, which is 7. 83  Heterogeneity within that subgroup was moderate given the overlap of the confidence intervals, but the Cochran Q-test was significant with p = 0.05 and I 2 ≥ 60%. q The definition of TD was assumed to be similar across the RCTs so the risk indirectness was rated as not serious. The fact that the sensitivity analysis showed that removing BASE-ACS from the pooled analysis led to a significant confidence interval in favour of TiNOS did not appear to be related to differences in TD definition. r The 95% CI of the RR of TD is non-significant with a length > 0.5. Sensitivity analysis supports no association. A hypothetical single RCT, 1:1 randomization, 2-sided test, α = 5%, power = 80%, and a reference rate of events in the 3 trial DES arms 29/1123 = 0.026 assuming delta = 0.008 based on a targeted 30% RRR requires a total sample size of n = 11,740 patients, which is 4.28 times the pooled sample size. Considering the total number of events observed is 29 + 29 = 58, reaching the GRADE rule of thumb of 300 events overall requires n = 11,740 × 300/58 = 60,724 patients to meet the OIS criterion. With the current sample size, a minimum of four events (6.9% of observed events) should be redistributed from the TiNOS arm to the DES arm for the CI to reach significance (RR 0.60 [0.37 0.97]). This result is imprecise and fragile.