Optimum of Dual Antiplatelet Duration and Followed Monotherapy in Diabetes Mellitus After Percutaneous Coronary Intervention With Drug-Eluting Stent Implantation: A Bayesian Network Meta-Analysis of 20536 Patients From 18 Randomized Trials

Background: To evaluate the ecacy and safety of short-term ( ≤ 3-month) dual antiplatelet therapy (DAPT), midterm (6-month) DAPT, standard-term (12-month) DAPT and extended-term ( (cid:0) 12-month) DAPT in diabetes after percutaneous coronary intervention (PCI) with drug-eluting stent (DES). To Compare discontinuation of DAPT followed by aspirin with P2Y12 inhibitor monotherapy for detailed optimal scheme. Methods: Randomized, controlled trials were searched using PubMed, Web of Science, Embase, Cochrane library and clinicaltrials.gov. up to October 10, 2020. A Bayesian network meta-analysis was conducted with a random-effect model. Results: A total of 18 randomized trials encompassing 20536 diabetic patients were included. Network analysis showed that short-term DAPT is best for reducing primary endpoint, which is superior to extended-term DAPT (odds ratio 0.48, 95% CI 0.25 to 0.85). Standard-term was also associated with reduce risk of primary endpoint in comparison with prolonged DAPT (0.56, 0.32 to 0.90). There was no noticeable difference with respect to primary endpoint between short-term DAPT followed by aspirin monotherapy and P2Y12 inhibitor monotherapy. No signicant differences were observed in secondary endpoints, including all-cause mortality, cardiac mortality, MI, stroke, TVR, denite or probable stent thrombosis and major bleeding. Conclusions: Short-term DAPT was associated with the better primary endpoint benet for patients with diabetes after PCI with DES, compared with extended-term DAPT. Although the optimal duration should balance risk-benet ratio between personal ischemic and bleeding events, this study suggested short term DAPT followed by P2Y12 inhibitor monotherapy may be the optimal therapy for most diabetes after PCI with DES.


Background
Diabetes mellitus (DM) patients are a well-known high-risk group of severe coronary artery disease (CAD), and the incidence of postoperative adverse clinical events is higher than that of general population [1,2].
Dual antiplatelet therapy (DAPT), aspirin and a P2Y12 inhibitor, is the cornerstone to prevent the stent thrombosis and reduce ischemic events after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation [3,4]. As the contradiction between ischemia bene ts and hemorrhagic risks of DAPT, the optimal duration is pivotal factor to strike a balance for patients to bene t ultimately [5]. Due to impaired glucose metabolism, usage of hypoglycemic and hypolipemic drugs, such as statins which share the same cytochrome P450 isoenzyme 3A4 (CYP3A4) pathway with clopidogrel, and glucose uctuation, the standard 6-12-month DAPT following DES implantation that current clinical practice guidelines recommend for general population may not be suitable for the diabetes in particular [6].
Furthermore, debates that whether prolong or abbreviate the DAPT treatment still exist [7,8]. Multiple randomized clinical trials (RCTs) and observational studies have explored the t time with contradictory conclusions among diabetes [9,10,11]. Previous meta-analysis qualitatively showed that there is no signi cantly difference between extended and short term DAPT therapy in ameliorating adverse clinical outcomes among subjects with diabetes mellitus, except ascending bleeding in prolonged DAPT use [12,13]. Yet the evidence appraising the role of diabetes in the choice of the optimal time remains limited.
In addition, despite the safety and e cacy of discontinuing aspirin in favor of P2Y12 inhibitor monotherapy remains ambiguous, there are currently no head-to-head RCTs comparing discontinuation of DAPT followed by aspirin or P2Y12 inhibitor monotherapy [14]. Further network analysis compared among diabetes could be conducted to shed a light from indirect comparison.
Therefore, we performed this network meta-analysis (NMA) on a variety of DAPT duration strategies to probe the favorable duration and discontinuation of DAPT followed appropriate monotherapy which is applicable for diabetic population for clinical guidance and subsequent studies.

Methods
Search strategy and data sources An electronic search was conducted systematically for literature published up to October 10, 2020. The database comprised PubMed, Embase, Web of Science, clinicaltrials.gov. and Cochrane Library, and references of related articles were also searched to ensure the integrity of the data as far as possible. The following search terms were made of use: "dual antiplatelet", "drug-eluting stent", "percutaneous coronary intervention" and "randomized controlled trial". The detailed search strategy was provided in Additional le 1.

Inclusion and exclusion criteria
Screening of retrieved articles was carried out on the basis of the prede ned inclusion criteria below: (1) studies were clinical RCTs; (2) participants were adults with DM who received DAPT after PCI after DES; (3) the therapies were candidate durations of DAPT, like short term (≤6 months), standard term (12 months) and extended term ( 12 months); (4) outcomes were reported such as primary endpoint, allcause mortality, cardiac mortality, myocardial infarction (MI), stroke, target vessel revascularization (TVR), stent thrombosis and bleeding events; (5) at least 12-month follow-up.
Studies that met the following criteria were excluded: (1) they were pharmacokinetic and pharmacodynamic studies, meta-analyses, observational research, case studies or editorials; (2) patients involved were not DM; (3) they did not set adverse outcome events as their clinical endpoints; (4)they were involved the identical or reduplicate trials.

Data extraction and quality evaluation
Two independent investigators (KA and PG) assessed the studies involved, adjudicated data and reviewed the methodological quality of each eligible trial. Any disagreement occurred during the data extraction process, the opinion of a third researcher (SHW) was sought to make a nal decision.
Information concerning trial names, year of publication, sample size, treatment and control group, outcomes, clinical events reported in diabetes group, follow-up period. The bias risk among the trials and the methodological quality of the included studies was assessed by Risk of Bias 2 according to the Cochrane Collaboration's tool [15], which contains preliminary considerations, signaling questions and 5 domains plus overall risk of bias: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, bias in selection of the reported result and plus 'Overall risk of bias'. Items were scored as low risk, some concerns, or high risk of bias.

Statistical analysis
We performed Bayesian NMA conducted a random effects model, using the Markov chain Monte Carlo (MCMC) methods. The Gemtc package was run in R to call the JAGS software to achieve the Bayesian NMA. The effect was expressed by odds ratio (OR) and 95% con dence interval (CI) to summary statistics to quantify the effects of different duration. Based on non-informative uniform and normal prior distributions [16], the initial values were set for four different chains, 100,000 interactions with 50,000 burn-in samples were produced to obtain the model parameters from the posterior distributions, and 1 thinning rates were adopted for each chain. Convergence was assessed using the trace plots and Brooks-Gelman-Rubin method to check if the error was 5% of the standard deviation of the effect estimates and between-study variance [17]. The estimates of Bayesian NMA were reported as rank probabilities to identify the relative rankings of DAPT duration based on the surface under the cumulative ranking curve (SUCRA), ranging from 0% (statistically certain to be the worst treatment) to 100% (statistically certain to be the best treatment) [18,19,20].
Result heterogeneity was examined with Cochrane's Q statistic and quanti ed with inconsistency statistic (I²), which was considered as low, moderate, or high for I² values under 25%, between 25% and 50%, and over 50%, respectively [21]. P less than 0.05 was considered as statistical signi cance.
Inconsistency was conducted by Gemtc package in R, comparing the deviance residuals and deviance information criterion (DIC) statistics in tted consistency and inconsistency models to identify any loops in the treatment network where inconsistency was existed [22]. The node splitting approach was also used to assess the inconsistency of the model, in which direct and indirect evidence was separately contrasted on a particular comparison. All statistical analyses were performed using R 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) and Stata 14.2 (Stata Corporation, College Station, TX, USA).

Outcomes variables
Outcomes consisted of primary endpoint and secondary outcomes. We incorporated de nitions of the primary endpoint as applied in each trial. The secondary outcomes were the individual components of the primary outcome, containing mortality, cardiac mortality, MI, stroke, TVR, de nite or probable stent thrombosis and major bleeding. Stent thrombosis was de ned according to criteria from the academic research consortium [23]. The other outcomes were de ned differently in Additional le 2.
The t of the consistency model was similar to or better than that of the inconsistency model (Additional le 5). Inconsistency between direct and indirect estimates from the node splitting analysis did not show signi cant differences in each comparison (Additional le 6). The convergence diagnosis model can be used to predict the data effectively. We evaluated the convergence of iterations by visual inspection of the chains to establish homogenous parameter estimates and to comply with the Brooks -Gelman -Rubin diagnostic standard (Additional le 7).
Network meta-analysis E cacy and safety Network plots for different outcomes were generated to illustrate the geometries, to clarify which treatments were compared directly or indirectly in the included studies [46]. The network evidence plot of primary endpoint and was shown in Figure 3, while that of short-term DAPT followed by P2Y12 inhibitor or aspirin monotherapy and secondary outcomes was shown in Additional le 8. All of contribution plot was also demonstrated in Additional le 8. Moreover, the primary endpoint result of NMA using random-effects were summarized in Table 2. Other NMA clinical events result were demonstrated in Additional le 9.

Primary endpoint
Compared with extended-term DAPT, short-term DAPT and standard-term DAPT was associated with a reduced risk of primary endpoint (OR 0.48, 0.25 to 0.85; 0.56, 0.32 to 0.9), whereas midterm DAPT showed no signi cant difference (OR 0.62, 0.33 to 1.06). Furthermore, short-term DAPT followed by P2Y12 inhibitor or aspirin monotherapy had no remarkable difference compared to short-term DAPT followed by aspirin monotherapy (OR 0.90, 0.54 to 1.5). According to the accumulative rankings by SUCRA, we found that the possible best treatment improving primary endpoint was 3-month DAPT, while the effect is consistent with midterm and standard term DAPT. In addition, in the analyses of the primary endpoint, the worst treatment was extended-term DAPT.

Secondary outcomes
All-cause mortality was similar in extended-term DAPT, 12-month DAPT, mid-term DAPT or short-term DAPT. No noticeable difference was also shown for cardiac mortality. Compared with 12-month DAPT, extended-term DAPT, mid-term DAPT and short-term DAPT showed no signi cant differences in the matter of MI or in respect of stroke. In terms of de nite or probable stent thrombosis, compared with 12month DAPT, extended-term DAPT, mid-term DAPT and short-term DAPT showed no signi cant differences. Similar result was also shown on the subject of TVR. There were no signi cant differences with respect to major bleeding between the different DAPT strategies. Figure 5 show the ranking probabilities for all treatments included (with detail ranking results for other outcomes summarized in Additional le 10 and 11). For the treatment effect of ameliorating primary endpoint, short-term DAPT and standard-term DAPT ranked rst with the highest probability (72.18% and 63.55%, respectively), while midterm and extended-term DAPT ranked last with the highest probability (62.84% and 95.32%, respectively). For the effect of reducing all-cause mortality, midterm DAPT ranked rst with the highest probability (37.59%), while the extended-term DAPT had the highest probability of ranking last in the incidence of more all-cause mortality (53.43%). The short-term DAPT had the highest probability of ranking rst in the incidence of less cardiac mortality and MI (42.98%

Figures 4 and
and 64.05%), while the midterm DAPT had the highest probability of ranking last in the incidence of more cardiac mortality and MI (52.57% and 54.27%, respectively). According to the analysis of stroke and TVR, midterm DAPT (76.61%) and standard-term (44.92%) were the treatments with the highest probability of achieving a good prognosis. In contrast, the treatments with the lowest probability were short-term and midterm DAPT, with a probability of 46.15% and 43.52%, respectively. For the effect of delaying the progression of de nite or probable stent thrombosis, short-term DAPT was the most appropriate treatment strategy for ranking rst with the highest probability (52.67%), while midterm ranked last with the highest probability (81.18%). To postpone the event of major bleeding, midterm DAPT was favorable treatment for diabetes (59.08%), while extend-term DAPT achieved the worst outcome (89.32%).

Discussion
In this NMA, which included 18 randomized trials covering 20536 patients, we comprehensively summarized and analyzed the comparative e cacy and safety of various duration of DAPT among diabetes patients after PCI with DES. The results showed that short-term DAPT had the highest cumulative probability of ranking rst in the effect of improving primary endpoint. The analysis of primary endpoint data showed that short-term and standard-term DAPT was signi cantly superior to extend-term DAPT. In addition, short-term DAPT followed by P2Y12 inhibitor monotherapy had a potential advantage over short-term DAPT followed by aspirin monotherapy. There was no obvious statistical difference for secondary outcomes among most treatments. In terms of cardiac mortality, MI, and de nite or probable stent thrombosis, short-term DAPT had the greatest probability of ranking rst (the lowest cardiac mortality, the lowest MI, and the lowest de nite or probable stent thrombosis), and midterm DAPT had the greatest probability of ranking last (the highest cardiac mortality, the highest MI, and the highest de nite or probable stent thrombosis). According to the evaluation of all-cause mortality, stroke and major bleeding among diabetes patients, we found that midterm DAPT was the treatments with the highest probability of achieving a good prognosis. In the matter of TVR, the treatments with the highest probability were standard-term DAPT. Our nding provided a clue to understand the prognostic signi cance of optimal DAPT duration in special diabetic subjects after PCI with DES.
Our current study indicated that short-term DAPT was correlated with better primary endpoint and there was no difference with aspect of stent thrombosis or major bleeding between short-term and extended term DAPT duration, which overturned the traditional idea that diabetes as high-risk population should prolongate DAPT duration for the risk of revascularization and better prognosis.
The nding could be explained in several aspects below. Firstly, it has been shown that statin did not in uence the platelet activation and aggregation in patients receiving clopidogrel by our previous metaanalysis [47]. Furthermore, with the re nements in DES technologies and the application of new upgrading DES and even degradable stents, it become possible to shorten the time course of DAPT rather than reduce the risk of thrombosis at the expense of bleeding even in high-risk diabetic patients [48].
A number of recent clinical trials have explored the e cacy and safety of long-term P2Y12 inhibitors monotherapy after short-term DAPT (≤ 3 months) after PCI among general population, including STOPDAPT-2 (ShorT and OPtimal duration of Dual AntiPlatelet Therapy-2) [49], TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) [50], SMART-CHOICE (SMart Angioplasty Research Team: Comparison between P2Y12 Antagonist MonotHerapy and Dual Antiplatelet Therapy in Patients UndergOing Implantation of Coronary Drug-Eluting Stents) [51] etc., which makes people begin to consider the possibility of stopping aspirin when DAPT is converted to monotherapy. The mentioned studies which were based on the comparison of P2Y monotherapy and long-term DAPT (12-15 months), did not directly answer the question of which is better between aspirin and P2Y receptor inhibitor when PCI patients are converted to monotherapy. A recent network meta-analysis which was included 17 RCTs with a total of 54625 patients also con rmed that among general population, there were no signi cant differences in the incidence of all-cause death, myocardial infarction, stent thrombosis and stroke, or bleeding events between aspirin and P2Y12 inhibitors (clopidogrel) when DAPT was converted to monotherapy in the short-term (< 6 months) [52]. Our results which focused on speci ed diabetes status found the similar result that the e cacy and safety of P2Y12 inhibitors long-term monotherapy was not better than aspirin in aspect of composite primary endpoint.
Our study was consistent with recent NMA suggested that 6-month DAPT may be considered for most patients after PCI with DES [7], meanwhile the other NMA found the similar result that among general patients, 6-month DAPT followed by P2Y12 inhibitor monotherapy reduced major and extended-term DAPT reduced MI at the expense of more bleeding risk [8]. Our result also indicated that even among highrisk diabetic population, short-term DAPT remained be considered rst to reduce composite primary endpoint.
Although there have been traditional meta-analysis studies in diabetic population, there is currently no NMA to compare various time courses of DAPT. Our research and nding ll the gap in this area, and provide direction for clinical and future research of diabetic population.
Our NMA is the rst to focus on speci ed diabetes patients, while most studies pay more attention to general population at current time when people performed the RCT or meta-analysis of dual antiplatelet duration and followed monotherapy after PCI with DES. In addition, duration of DAPT was divided into four detailed categories with standard term as control for NMA, and the strati cations can provide more vehicles in understanding the clinical signi cance of short-term DAPT in diabetes. NMAs often bring out substantially accurate summary results with a combination of direct and indirect comparisons [53].

Conclusions
In conclusion, we have found that short-term DAPT was correlated with the better primary endpoint bene t for patients with diabetes after PCI with DES, compared with extended-term DAPT. Although the optimal duration should consider risk-bene t ratio between personal ischemic and bleeding events, this study suggested short term DAPT followed by P2Y12 inhibitor monotherapy may be the optimal therapy for most diabetes after PCI with DES.

Declarations
Major Science and Technology Project of Hunan Province, The National Natural Science Foundation of China, and National Key Research and Development Projects for the submitted work; no nancial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have in uenced the submitted work.