Chronic treatment with oral anticoagulants (e.g., warfarin) is essential for most atrial fibrillation (AF) patients with CHA₂DS₂VASc scores ≥ 2. Treatment of patients with AF who have undergone percutaneous coronary intervention with a drug-eluting stent (PCI-DES) further requires follow-up antiplatelet therapy to minimize thrombotic events. Triple therapy, such as warfarin plus dual antiplatelet agents (DAPT), aspirin and clopidogrel, has been used for many years in patients with AF who have undergone PCI-DES (1).

The European Society of Cardiology recommended a short period of therapy with VKA, aspirin, and clopidogrel for such patients (2). The 2019 AHA/ACC/HRS guidelines for the management of patients with AF suggested that “Triple therapy should be administered to these patients with bare-metal stents for 1–3 months and much longer in patients with a drug-eluting stent (3–6 months) followed by one anticoagulant plus clopidogrel 75 mg/day or aspirin 100 mg/day” (3).

RCT studies as well as retrospective analyses all suggested that the combination of oral anticoagulation with a P2Y12 inhibitor and aspirin in patients with AF undergoing PCI-DES is associated with a high bleeding risk (4, 5). Triple antithrombotic therapy, particularly if consisting of a OAC, aspirin and a P2Y12 inhibitor, is associated with a increasing of bleeding, including major and intracranial hemorrhages (6). However, pooled data from meta-analysis (7) have shown a possible increase of ischemic events in the dual therapy with clopidogrel, for example Galli et al. confirmed that dual therapy with clopidogrel with a significant increase of stent thrombosis risk in the overall population and a significant 43% increase of MI in the ACS/PCI subgroup (8) sparkling the interest for the use of alternative antithrombotic agents. In addition to this, clopidogrel, but not ticagrelor, is characterized by an interindividual variability in the pharmacodynamic profile, leading to insufficient platelet inhibition and increased ischemic events in up to 40% of treated patients and thus Most recent investigations support the clinical benefit of a genetic guided selection of antiplatelet therapy in patients undergo PCI (i.e., switching to prasugrel or ticagrelor) (9, 10).

Recently, randomized clinical trials and recent evidence have supported the ESC recommendation for dual antithrombotic therapy in patients with AF who have undergone PCI-DES (6, 11). As is well-known, the recent guidelines (2018–2020 ECS Guidelines) supported the current trend of antithrombotic therapy using a combination of one antiplatelet drug and one anticoagulant (12–14), for example,2020 ESC Guidelines presented that In AF patients with ACS undergoing an uncomplicated PCI, early cessation (<1 week) of aspirin and continuation of dual therapy with an OAC and a P2Y12 inhibitor for up to 12 months is recommended if the risk of stent thrombosis is low or if concerns about bleeding risk prevail over concerns about risk of stent thrombosis, irrespective of the type of stent used. However,1 week triple therapy with clopidogrel can be associated to increased ischemic events.

The TWILIGHT trial proved that ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, without higher risks of death, myocardial infarction, or stroke, again suggesting that ticagrelor is a more potent antiplatelet drug (15, 16).

The recent AUGUSTUS study was designed for AF patients who had ACS or had undergone PCI and were taking a P₂Y₁₂ inhibitor to receive apixaban or warfarin and aspirin or a matching placebo for 6 months (17, 18). However, more than 90% of the individuals in this trial were treated with clopidogrel instead of more potent agents, such as ticagrelor. Among published clinical studies such as PIONEER trial, ENTRUST trial and Re-Dual trial, the Re-Dual study included the most patients received ticagrelor were only 12% (19–21). The use of ticagrelor can potentially overcome the increased rate of ischemic events as the rate of non-responders to this drug is very low.

On the other hand, triple therapy with ticagrelor in these previous trials was somewhat unfounded and in particular lacked the support of ESC guidelines. Thus, the rationale for our study is that ticagrelor were used only in a minority of the 4 RCTs on the topic (PIONEER, RE-DUAL, AUGUSTUS and ENTRUST-AF), which implied that there are not many data from prospective studies on a dual therapy including this potent P2Y12 inhibitors.

Therefore, we performed the present study to compare the combination of ticagrelor and warfarin with traditional triple therapy, with the aim to evaluate the safety and efficacy of ticagrelor as one of dual antithrombins.

There are many issues surrounding antithrombotic treatment of patients with AF undergoing PCI that remain unresolved. Whether ticagrelor as a part of dual therapy would exhibit favorable safety and efficacy is unknown. Some meta-analysis suggested that the use of ticagrelor as part of dual or triple antithrombotic therapy is associated with significantly higher rates of clinically relevant hemorrhagic complications compared with clopidogrel (27).

What's different is that our trial primarily confirmed the safety of ticagrelor as a dual therapy regimen didn't increasing bleeding rates, especially total bleeding rates. We further found that most of the total TIMI bleeding events were minimal and minor events. This result indicates that ticagrelor, even with its potent antithrombotic effect, did not increase the risk of fatal bleeding after 6 months as dual therapy when combined with warfarin and administered to AF patients after they underwent PCI-DES.

2019 AHA/ACC/HRS guidelines suggested that in patients with AF at increased risk of stroke (based on CHA2 DS2 -VASc risk score of 2 or greater) who have undergone PCI with stenting for ACS, double therapy with a P2Y12 inhibitor (clopidogrel or ticagrelor) and dose-adjusted vitamin K antagonist is reasonable to reduce the risk of bleeding as compared with triple therapy (3). Our results provide further evidence support and supplement for the clinical application of dual therapy with different P2Y12 inhibitor. On the other hand our results are consistent with and support the trends of using dual drug regimen in patients with atrial fibrillation and PCI-DES, as recommended by recent guidelines (12, 28, 29). In the “North American Perspective 2016–2021 Update” regarding antithrombotic treatment for these patients, triple therapy was only recommended during the peri-PCI period and dual therapy as soon as possible after hospital discharge (30–32). In other words, our study suggests a possibility that a slightly stronger dual antithrombotic with ticagrelor therapy might be used immediately after PCI in AF patients, instead of 1 week to 1 month of triple antithrombotic therapy.

The MANJUSRI trial showed that, among AF patients who had undergone PCI-DES, the anticoagulation regimen warfarin plus ticagrelor resulted in comparable total bleeding events compared with Triple therapy. The difference in risk between the ticagrelor therapy group and the Triple therapy group was 6.8% (0.87 percentage points) over ~6 months of treatment. Compared to previously published trials, bleeding rates (33, 34) in our trial appeared to be amplified. This might be attributed to several factors, firstly, patients in triple group received a relatively longer time of Antithrombotic therapy, then nearly one-third of the patients in our study used glycoprotein receptor antagonists during the perioperative period and Glycoprotein IIbIIIa receptor antagonists seemed to be used more frequently in the trial of ticagrelor group.

The rates of major TIMI bleeding were higher in the ticagrelor therapy group than in the Triple group, but the difference was not statistically significant. The difference in risk between the groups was 27.5% (3.36 percentage points), however in our trial, we must consider the particularity of certain cases themselves. In the ticagrelor therapy group, only 1 of 7 major bleeding patients suffered from intracranial bleeding, and the others all experienced gastrointestinal bleeding. However, it is important to note that 2 of the patients who experienced major bleeding were at high risk at the time of enrollment. One patient had a HASBLED score ≥3, and the other patient had an INR of 4.43. Another 3 patients' specific situations were similar to those of the 2 patients in the Triple group. In conclusion, these findings suggest a relatively balanced risk of bleeding in the prevention of thromboembolism, at least to some extent, providing clinicians with one more regimen option when considering a AF patient's risk of bleeding and the risk of thromboembolic events after PCI-DES.

The strategies for dual therapy with ticagrelor that we tested incorporated two changes relative to the previous trials of antithrombotic therapy. The first change is the incorporation of ticagrelor as part of the dual therapy regimen for all patients with AF just after PCI-DES. The proportion of patients taking ticagrelor in our trial (every patient in the dual therapy group took oral ticagrelor, so the usage rate was 100%) was greater to that in the few other trials that have investigated ticagrelor as part of the regimens in patients with atrial fibrillation and PCI-DES (3–5.5% in the PIONEER trial; 7–8% in ENTRUST trial) (15, 16). The second change refers to the use of warfarin as the basic anticoagulant for the two groups of patients, instead of NOVC. This change was mainly based on economic reasons given that most Chinese patients prefer warfarin due to its relatively lower price, and at the time of enrollment, more than 90% of the patients were taking warfarin once daily as antithrombotic therapy for AF (35, 36); Secondly, access to NOACs in China was possible only after 2016.

There several limitations in the trial though we are the first trial that systematically evaluated the safety of ticagrelor as part of a dual antithrombotic regimen. First, the primary analyses showed that the safety of ticagrelor was similar to that of Triple therapy, and the result just reached a point of non-inferiority, rather than superiority, as anticipated. This outcome might be related to the potent antiplatelet effect of ticagrelor as discussed (37), and longer duration of antithrombotic administration as well as more additional antithrombotic administration during perioperative period. Secondly, We did not compare the risk of bleeding between the two groups at 1 week and 1 month, because current guidelines only recommend the shorter-term triple antithrombotic therapy (6, 28, 29, 38). Thirdly, the rates of primary endpoints of bleeding in this study were higher than those in the previous trials on this topic; in addition to over verified minor bleeding as discussed above, we suspected that to some extent this outcome might be related to increased variability in INR during the follow-up process and Asians being prone to bleeding when treated with warfarin (39, 40). In the end, the number of patients in our trial was relatively small for various reasons, including research funding, thus restricting the power of the study to detect worthwhile differences between the two groups. In addition, the progress of the trial was relatively slow due to physicians' and patients' concerns about various issues, such as safety in subcenters during the first year. However, though the trial did take us almost 5 years to complete, the patients were not highly selected, all of the data in the trial met the random requirements and the inclusion and exclusion criteria, and the two groups of patients were relatively homogenous.

Patients with AF undergoing PCI-DES treated with ticagrelor and warfarin in this trial experienced an incidence of total bleeding events that was comparable to those receiving a traditional triple antithrombotic regimen consisting of clopidogrel, aspirin, and warfarin. In this study we found that a dual antithrombotic therapy with ticagrelor is associated with similar incidence of bleeding and ischemic events as compared to a triple therapy with clopidogrel among AF patients undergoing PCI, however, we did not demonstrated dual therapy using ticagrelor reduced bleeding events compared to triple therapy. Further studies are warranted to shed light on the potential benefit of implementing a dual antithrombotic therapy with potent P2Y12 inhibitor in this setting.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by ICE for Clinical research of Zhongda Hospital Affiliated to Southeast University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

The study was supported by AstraZeneca Pharmaceutical Co., Ltd. (No. ISSBRIL0256).

This study received funding from AstraZeneca Pharmaceutical Co., Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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