Dual antiplatelet therapy (DAPT), including aspirin and a P2Y12 receptor inhibitor, is the standard of therapy for patients after percutaneous coronary intervention (PCI) to reduce the risk of stent thrombosis (ST) and prevent coronary atherothrombotic events distal to the stented coronary segment. International guidelines suggest that DAPT should be given for at least 12 months for acute coronary syndromes (ACS) patients with drug-eluting stent (DES); and for patients with stable ischemic heart disease, DAPT should be used for a minimum of 6 months after DES [1, 2]. With the refinements of DES technologies and the emergence of potent P2Y12 receptor inhibitors, the best DAPT duration is still controversial.

The results of several randomized controlled trials (RCTs) had shown that 3–6 months of DAPT after DES had non-inferiority compared with long-term ($\ge$12 months) DAPT [3, 4, 5, 6]. The reason might be that shorter DAPT duration reduced all-cause mortality by reducing bleeding [7], whereas longer DAPT duration was related to a higher risk of any bleeding [8]. However, the risk of myocardial infarction (MI) was raised in 6 months of DAPT, which improved concerns that short-term DAPT might not be safer in ACS patients [9]. A meta-analysis also concluded that 3-month DAPT was related to higher ischemic risk in ACS, although most of the included ACS patients were at comparatively low-risk [10]. However, studies had shown that P2Y12 receptor inhibitor monotherapy after stopping short-term DAPT decreased the bleeding risk without increasing the risk of death, MI, and stroke compared with long-term DAPT [11, 12, 13, 14].

Considering the poor compliance of patients with long-term DAPT and the increasing risk of bleeding, shortening the duration and P2Y12 receptor inhibitor monotherapy may reduce bleeding risks while minimizing atheroembolic events. Therefore, we included the most recent RCTs in our meta-analysis to investigate the differences in the safety and effectiveness between short-term DAPT (3–6 months) and long-term DAPT (12 months) after PCI with DES. Subgroup analyses (ACS and single antiplatelet therapy) were also performed to assess the benefits of P2Y12 receptor inhibitor monotherapy in these patients.

We registered our protocol with PROSPERO (CRD42021260473). This meta-analysis was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15].

In this meta-analysis, we included 11 RCTs and 24,242 patients to assess the safety and effectiveness of short-term and long-term (3–6 months vs 12 months) DAPT among patients who underwent PCI with DES. Compared with 12-month duration of DAPT, short-term DAPT strategies were superior for major bleeding and any bleeding, and non-inferior for all causes of death, cardiac death, MI, definite/probable ST, TVR, and stroke. Even in ACS patients, short-term DAPT continued to be superior in reducing major bleeding. In addition, 3-month DAPT and P2Y12 receptor inhibitor monotherapy after short-term DAPT were associated with lower risks of major bleeding.

Establishing the best strategy of DAPT after DES is crucial to minimize the risk of bleeding and ischemic events. The results of several RCTs demonstrated that short-term (3–6 months) DAPT was non-inferior for the occurrence of death, ischemia, and bleeding among general and ACS patients [4, 6, 16, 20]. A network meta-analysis concluded that 12-month DAPT led to a higher incidence of any bleeding compared to short-term DAPT [8]. Furthermore, subsequent bleeding complications after successful DES implantation were strongly associated with all causes of death, and the magnitude of the effect of bleeding on mortality exceeded that of an MI [22]. Therefore, efforts to reduce the incidence of bleeding after PCI with DES may further improve outcomes in these patients. DES technology is constantly being updated. Compared with bare-metal stents, second-generation DES have been related to a lessening 1-year rate of definite ST [23]; compared with the first-generation DES, it brings out larger stent coverage, less inflammation, fewer fibrin deposits, and less thrombosis [24]. Based on these results, some researchers have questioned whether the DAPT duration should again be shortened.

Our meta-analysis sustained the premise that the DAPT duration may be safely shortened. Short-term DAPT was related to a decreased risk of major bleeding and any bleeding. Moreover, no differences were observed in the incidence of all causes of death, cardiac death, MI, definite/probable ST, TVR, and stroke between different DAPT durations. Therefore, we concluded that short-term DAPT was as effective as 12-month DAPT with a better safety profile. These important findings supported the clinical necessity of defining a new DAPT regimen. Short-term DAPT has a more favorable balance between bleeding and ischemia, regardless of gender [25], age [26], and diabetes [27]. At the same time, clinicians should refer to the recommendations of the European Society of Cardiology guidelines [28] and the 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization [29] to determine individualized risks (low bleeding risk vs high bleeding risk).

For ACS patients, the guideline [29] recommended 12 months of DAPT, which could be extended more than 12 months if they were in low bleeding risk [29], while in patients with higher bleeding risk it should be shorten to 6 months [29]. Scientific societies supported DAPT after ACS based on results from the CURE trial [30]. CURE demonstrated that 3–12 months (mean duration, 9 months) of DAPT reduced the risk of MI and recurrent ischemia and increased the risk of major bleeding in patients with ACS without ST-segment elevation [30]. However, it was conducted 2 decades ago and compared the differences between DAPT and aspirin alone, which supported DAPT per se rather than the duration of 12 months or longer. Newer generation DES technologies have been confirmed to minimize the risks of MI and ST [31, 32]. Moreover, a landmark analysis of this trial demonstrated that DAPT achieved almost all the benefits in the first 3 months after randomization [33]. In recent years, studies on the strategies of DAPT in ACS patients, including RCTs [4, 9, 14, 20] and meta-analyses [10], had shown that short-term DAPT was non-inferior in reducing the occurrence of major bleeding, but no consistent results could be concluded in safety. The main problems were myocardial infarction and stents thrombus [9, 10]. In the multicenter SMART-DATE trial [9], a total of 2712 ACS patients were randomized to 6-month (n = 1357) or 12-month or longer (n = 1355) DAPT. As for major adverse cardiovascular and cerebrovascular events (MACCE), 6-month DAPT was non-inferior to long-term ($\ge$12 months) DAPT, while the incidence of MI was significantly higher [9]. However, there was no obvious difference in ST between the two groups [9]. It was concluded that long-term DAPT might lower the risk of MI by prevention of non-target vessel MI instead of lessening of ST. Similarly, a network meta-analysis [10] found that 3-month instead of 6-month DAPT was related to higher risks of MI and definite/probable ST, compared with 12-month DAPT. However, the number of ACS patients in their study was only 4758, which might have limited the statistical power of the study, and limited the conclusions that could be made. Conversely, no noticeable differences were observed with regard to MI and ST between different durations of DAPT in DAPT-STEMI [4], REDUCE [20] and TICO [14]. Our findings were in line with these studies. In our current meta-analysis, short-term DAPT resulted in an absolute reduction in major bleeding, whereas there were no differences in all causes of death, cardiac death, MI, definite/probable ST, TVR, and stroke among the 8890 ACS patients.

These low event rates might be attributed to the improvements in the design of the second-generation DES, or to the development of atherosclerotic plaques. Compared with stable angina pectoris (SAP), multiple complex coronary plaques are more common and coronary plaques are more unstable in ACS [34]. The unstable plaques are treated during ACS, and the remaining multiple complex lesions are generally treated during subsequent elective PCI. Regarding the unstable plaques, 75% of them seem to stabilize or heal during the 12-month follow-up and 25% remain unchanged [35]. Thus, these plaques are much more likely to maintain clinically silent or present with stable symptoms rather than ACS. DAPT used as secondary prevention may decrease cardiovascular events, but these events are uncommon. The benefits from the reduction of ischemic events by long-term DAPT are not enough to compensate for the increase in bleeding events. In summary, if clinically warranted, short-term DAPT was also feasible and safe even in ACS, especially in those with high bleeding risk.

We conducted subgroup analyses based on the different strategies for DAPT. P2Y12 receptor inhibitor monotherapy after short-term DAPT was related to lower risk of major bleeding compared with 12-month DAPT, with no obvious differences in death, ischemia endpoints, and stroke. However, no such benefit was observed with aspirin monotherapy on major bleeding during the follow-up period. It must be mentioned that in 3 large RCTs [6, 14, 21] which compared 3-month DAPT with 12-month DAPT and recorded major bleeding, 2 [14, 21] of them stopped aspirin after 3-month DAPT and continued P2Y12 receptor inhibitor monotherapy for another 9 months. In the TICO trial of ACS patients, ticagrelor monotherapy brought out a significant 2% absolute reduction in the composite outcome of major bleeding and MACCE, with a significant reduction in major bleeding [14]. In the SMART-CHOICE trial, clopidogrel monotherapy was non-inferior to 12-month DAPT for MACCE and was related to a lower rate of bleeding [21]. The activation of the P2Y12 receptor is the critical part in the production of platelet thromboxane (TX) A2 in vitro and in vivo [36]. A strong P2Y12 receptor inhibitor alone can block platelet aggregation through the TXA2-dependent pathway, while aspirin has little effect [37]. In the existence of the P2Y12 receptor inhibitor, the additional inhibitory effect of aspirin on platelet aggregation may be minimal. A study has also shown that P2Y12 receptor inhibitor monotherapy and DAPT inhibit the activation of the hemostatic system to the same extent [38]. Therefore, after short-term DAPT, the P2Y12 receptor inhibitor monotherapy may be a suitable antiplatelet strategy to reduce the risk of bleeding in patients with SAP or ACS treated with DES while maintaining anti-ischemic benefits.

A meta-analysis by Li et al. [39] reached comparable conclusions to our study; however there were several differences. First, they compared 1–6 months DAPT with $\ge$12 months DAPT, while we compared 3–6 months DAPT with 12 months DAPT. Second, they extracted risk ratios (RR) and 95% CI. We included the original research results and directly extracted HR and 95% CI. Third, we included the most recent randomized controlled trial TICO [14] and ruled out the studies that accepted other anticoagulant drugs or lacked HR. Finally, we performed a subgroup analysis of ACS patients so that our conclusions could be applied to different populations.

This meta-analysis has several limitations. We included results from first generation DES no longer used in clinical practice. The data to justify shortening the duration of DAPT may be even further strengthened by using only data involving second-generation DES [24]. Finally, all trials included in our meta-analysis are open-label and may lead to bias. In addition, different studies had slightly different definitions of certain clinical endpoints, which may introduce an element of effect modification. The determination of bleeding and bleeding-related deaths is difficult, so these findings should be interpreted with caution. Although the trials we included were multicenter, most of them were from South Korea and Caucasian countries, and there was a lack of relevant data from African countries with predominate black populations. Therefore, more research is needed to confirm the safety and efficacy of different DAPT strategies worldwide.

Compared with long-term DAPT, short-term DAPT reduced bleeding after PCI with DES and was not inferior in the incidence of ischemic events. Short-term DAPT was also feasible and safely applicable in ACS patients. P2Y12 receptor inhibitor monotherapy after short-term DAPT might be an alternative anti-platelet strategy, and should be further investigated in larger studies.

HG designed the study. JY and YD performed the literature search, study selection, data extraction, quality assessment, and statistical analysis. JY drafted the manuscript. YD, RW, KW, and HG revised the draft. XL, HS, YS and ZF modified the English. All authors approved the final version of the manuscript.

Not applicable.

Not applicable.

This work was supported by grants 81973841 from National Natural Science Foundation of China, 2017YFC0908800 from National Key Research and Development Program of China, SML20180601 from Beijing Municipal Administration of Hospitals’ Mission plan, CFH2020-2-2063 from Capital’s Funds for Health Improvement and Research, 7202041 from Beijing Municipal Natural Science Foundation, and JING19-15 from Beijing Municipal Health Commission.

The authors declare no conflict of interest.