Short‐term dual antiplatelet therapy in diabetic patients admitted for acute coronary syndrome treated with a new‐generation drug‐eluting stent

Abstract Background The optimal duration of dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) admitted with acute coronary syndrome (ACS) and treated with a drug‐eluting stent (DES) remains unclear. This is a prespecified sub‐study from the Randomised Evaluation of short‐term DUal antiplatelet therapy in patients with acute Coronary syndromE treated with a new generation DES (REDUCE) trial that was designed to determine the efficacy and safety of short‐term versus standard 12 months DAPT in diabetic patients with ACS undergoing percutaneous coronary intervention (PCI) using the COMBO stent. Methods In this study we included ACS diabetic patients enroled in the REDUCE trial treated with the COMBO stent and randomly assigned to either 3 or 12 months of DAPT. The primary study endpoint was the composite of all‐cause mortality, myocardial infarction (MI), stent thrombosis (ST), stroke, target vessel revascularisation (TVR), and bleeding complications at 12 and 24 months follow‐up. Results A total of 307 diabetic patients were included, of which 162 (52.8%) in the 3 months DAPT group and 145 (47.2%) in the 12 months DAPT group. Patient characteristics, PCI success, and number of stents used were similar in the 3 and 12 months DAPT groups. Occurrence of the primary study endpoint at 12 and 24 months follow‐up was comparable between the two groups (3.1 vs. 3.5%, p = 0.865, and 15.8 vs. 14.9%, p = 0.824, respectively). Moreover, the prevalence of the specific clinical outcome parameters (all‐cause mortality), MI, ST, stroke, TVR, and bleeding was similar in both study groups. Conclusions This sub‐analysis shows similar clinical outcomes following 3 months DAPT as compared to 12 months DAPT in diabetic patients undergoing PCI for ACS using the COMBO stent. These results suggest that, even in this particular subset of patients, short duration of DAPT might be considered safe. Future larger studies are warranted to provide more precise estimations in terms of safety and efficacy of short term DAPT in these high‐risk patients.


Funding information
OrbusNeich Medical Inc. Open Access Funding provided by Universita degli Studi di Sassari within the CRUI-CARE Agreement.
using the COMBO stent. These results suggest that, even in this particular subset of patients, short duration of DAPT might be considered safe. Future larger studies are warranted to provide more precise estimations in terms of safety and efficacy of short term DAPT in these high-risk patients. Balancing bleeding and thrombotic risk, especially in high risk patients, remains a topic of debate. Although some studies show promising results in patients on short-term DAPT, contradictory results prevail. [4][5][6][7] In an attempt to reduce the risk of ST, the COMBO dual therapy stent was introduced. The characteristic property of this new generation stent is the abluminal release of sirolimus (preventing neointima formation and ST) in combination with capturing endothelial progenitor cells (enhancing endothelization), which showed promising results. 8,9 The COMBO stent was studied to compare 3 months of DAPT versus conventional 12 months of DAPT in the Randomised Evaluation of short-term DUal antiplatelet therapy in patients with acute Coronary syndromE treated with a new generation DES (REDUCE) trial. 10 The results of the first analysis supported the hypothesis that 3 months is non-inferior to 12 months DAPT. 11 Certain comorbidities are known to be associated with an increased risk of thrombotic events, including diabetes. In diabetes mellitus (DM), enhanced platelet reactivity and aggregation as well as hypercoagulability contribute to the pro-thrombotic state, resulting in an increased risk of ACS as well as the recurrence of thrombotic events. 12 The independent association with thrombotic events led to inclusion of DM in the so-called DAPT score, which is designed to aid clinicians in assessing which patient benefits from prolonged DAPT. 13 This strongly suggests that patients with DM undergoing PCI should be on prolonged rather than short duration of DAPT. On the other hand, bleeding complications are more common among diabetics using DAPT. 14 To date, no data have been provided on the optimal duration of DAPT in diabetic patients with ACS undergoing DES implantation, hence the aim of the current analysis.

| METHODS
In the REDUCE trial (clinicaltrials.gov, NCT02118870), the COMBO stent (OrbusNeich, Fort Lauderdale, USA) was studied in patients undergoing PCI for ACS. 10 The REDUCE trial is a multicentre, openlabel, prospective, randomized, and investigator-initiated trial. The medical ethical committees of all participating study centres approved the study. Detailed data on inclusion and exclusion criteria have already been described. 10 In the current sub-analysis, only patients with a previous diagnosis of DM were included. Patients presenting with ACS successfully treated with COMBO stent (postprocedural TIMI 3 flow with residual stenosis <20% based on visual estimation, with no clinical adverse event during hospitalisation) were randomized in a 1:1 fashion to either 3 months or 12 months DAPT. Treatment assignment was performed centrally through a dedicated website as part of the electronic case report form according to computer-generated random permuted blocks with stratification by site.
Patients were treated with aspirin (ASA) and a P2Y12 inhibitor, with a preference of prasugrel or ticagrelor to clopidogrel. The final choice of the P2Y12 inhibitor was left at the discretion of the treating physician. Patients received DAPT according to their randomization group and continued ASA monotherapy afterwards. In case of an emerging contraindication for ASA, monotherapy with P2Y12 inhibition was allowed.

| Statistical analysis
Distribution of continuous parameters was assessed for normality. In case of non-normally distributed parameters, values were expressed as median [25th-75th percentile] and categorical data as percentages. Mann-Whitney U or independent samples t-tests were used depending on data distribution. Chi 2 testing or Fisher's exact test, when appropriate, were used for assessment of categorical variables.
The initial sample size calculation was based on a non-inferiority design, with a power of 80%, a margin for non-inferiority of 5%. 7 No sample size calculation was performed for the present substudy.
Patient characteristics were similar between the two groups. Females composed of 24% of the study population, and the median age was around 61 years. Presentation with STEMI was observed in more than 40% of patients in both groups (Table 1). Conventional cardiovascular risk factors were present in most patients, with hypertension being the most common with a prevalence of approximately 74%, followed by hypercholesterolaemia, in around 67% of patients.
A history of previous revascularisation procedures or stroke was equally prevalent across groups. PCI was performed previously in 14.8% and 18.6% of patients in the 3 and 12 months DAPT groups, respectively (p = 0.371). Patients in the 3 months DAPT group showed higher troponin and creatinine kinase values at presentation compared to the 12 months DAPT groups, though not statistically significant.

| Coronary intervention
Single vessel coronary artery disease was the most common finding for the index coronary lesion, resulting in treatment by a single DES to be the most prevalent in this study population (Table 2). Total stent length and diameter did not differ in the 2 study arms. In both groups, all patients showed a complete procedural success, defined as thrombolysis in myocardial infarction grade 3 flow following target vessel PCI.

| Clinical outcomes
At 12 months follow-up, 3 and 1 patients were lost to follow-up in the 3 and 12 months DAPT groups, respectively. At maximum followup (24 months), 4 patients were lost to follow-up in both groups.
In terms of the composite endpoint, no differences were found between the 3 and 12 months DAPT groups (Table 3). More specifically, groups showed no differences in mortality rates, occurrence of bleeding complications, ST, stroke, or recurrent MI (Table 3).At any particular point during follow-up, the composite endpoint occurred in similar rates in the 3 and 12 months DAPT groups. Comparable results were found for specific outcome parameters, including ST, bleeding, recurrent MI, and mortality (Table 4, Figure 1).

| DISCUSSION
The REDUCE trial was the first study conducted in ACS patients comparing short versus conventional duration of DAPT. The trial showed no differences in clinical outcomes comparing 3 versus 12 months of DAPT. 8 This prespecified sub-analysis focussed on diabetic patients admitted with ACS undergoing PCI using the COMBO stent, revealed similar clinical outcome in patients treated with short-term DAPT compared to those with conventional 12 months DAPT.
Diabetes is a known major risk factor for cardiovascular disease, 18 and it is estimated that up to 30% of patients undergoing coronary revascularisation are diabetic. 19 Moreover, DM is associated with less favourable outcomes in ACS patients in terms of coronary revascularisation, illustrated by higher rates of in-hospital MACE and target lesion revascularisation. [20][21][22][23] This is confirmed by a recent systematic review by Yuan and Xu, in which the authors concluded that late ST, defined as >30 days following PCI, was more common in diabetic patients. 24 Definite ST is estimated to occur in 2.1% of patients undergoing PCI in the following 3 years, with a peak incidence in the first 30 days. 25  Our results were in line with the previous available literature also in terms of TVR. In a study, 31 where a polymer-free biolimuscoated stent was used in high risk bleeding patients receiving merely 1 month of DAPT, around 5.1% of patients underwent clinically driven TVR at 13 months of follow-up, which is close to the current 5.7% assessed at 24 months. Conversely, the ONYX ONE trial showed an incidence of TVR of around 17% following 1 month DAPT using either a polymer-based zotarolimus or polymer-free biolimus-coated stent. 32  Apart from an increased risk of reoccurring thrombotic events, diabetic patients are more prone to major bleeding, refraining clinicians from administering more potent antiplatelet therapies in diabetic patients. 14 Several studies focussed on the efficacy and safety of prolonged DAPT in these high-risk patients, with contradicting results. [33][34][35] The ADAPT-DES study assessed bleeding rates in a large cohort of close to 9000 patients undergoing PCI, who were treated with DAPT using clopidogrel for at least 1 year. The observed bleeding rate at 30 days and 2 years follow-up was 0.7% and 8.8%, respectively. 36 Their short-term bleeding risk was similar to our study, but the long-term bleeding risk was higher, approximately a two-fold. The authors did not clarify the BARC criteria for the evaluated bleeding complications, which probably affected these reported rates. Moreover, patients in the ADAPT-DES study, as in some others, received DAPT for ''at least'' 12 months, which implies that an unknown proportion of patients who received DAPT for a prolonged period of time, was exposed to an increased risk of bleeding due to prolonged DAPT.
Similar to the current study, the RESET trial assessed outcomes in 3 versus 12 months of DAPT. 37 No differences were found between groups in terms of ST, minor, or major bleeding complications. The DAPT-STEMI trial choose a different approach, selecting patients with an uneventful first 6 months after PCI with second generation DES, randomized to either aspirin only (single antiplatelet therapy, SAPT) or DAPT for another 6 months. 38 In line with current results, the DAPT-STEMI study reported the SAPT approach to be non-inferior to DAPT with similar risks of bleeding and ST across study groups. Bleeding, however, consisted merely of BARC type 3 complications. This, in addition to the inclusion of STEMI patients only, which generally represent a younger population, may contribute to explain the relatively low incidence of bleeding complications in the DAPT-STEMI study (0.5% and 0.9% in   These results suggest that short-term DAPT, in combination with the COMBO stent, may be considered safe in this subset of high risk patients.

| CONCLUSION
This prespecified sub-study showed similar clinical outcomes following short-term DAPT (3 months) compared to conventional duration of DAPT (12 months) in both diabetic patients with ACS undergoing PCI using the COMBO stent. These results suggest that, even in this particular subset of patients, a short duration of DAPT might be considered safe. Future studies are warranted to provide more precise estimations in terms of safety and efficacy of shortterm DAPT in high risk patients.

ACKNOWLEDGEMENTS
The study was supported by a research grant from OrbusNeich Medical Inc. Fort Lauderdale, United States of America.
Open Access Funding provided by Universita degli Studi di Sassari within the CRUI-CARE Agreement.

CONFLICT OF INTEREST
The authors declared no conflict of interest. Helsinki. All patients signed the informed consent before study inclusion.

CONSENT FOR PUBLICATION
Not applicable.

AUTHOR CONTRIBUTIONS
Substantial contributions to the conception or design of the work; Data collection; Analysis and interpretation of data for the work; Draughting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are available in the supplementary material of this article.