Following the placement of a drug-eluting stent (DES), antiplatelet therapy is critical for secondary prevention in patients with acute coronary syndrome (ACS) (1). Balancing bleeding and ischemic risks is key to maximizing the benefits of antiplatelet therapy for patients. After DES implantations, it is currently advised in clinical practice that ACS patients receive dual antiplatelet treatment (DAPT) for at least 12 months, with the possibility of an additional 30 months if necessary (1). Data from the EPICOR-Asia trial indicated that a significant proportion of patients underwent prolonged DAPT treatment beyond 12 months to lower their risk of ischemia (2). Meanwhile, extended DAPT treatment does result in an elevated bleeding risk (3). However, An estimated 40% of ACS patients face high risks of both ischemia and bleeding events, and these individuals have been said to comprise a “bi-risk” ACS population (4). Accordingly, the optimal DAPT treatment duration for these bi-risk patients remains uncertain (5, 6).

This study was a post hoc analysis of the prospective Optimal Antiplatelet Therapy for Chinese patients with Coronary Artery Disease (OPT-CAD, NCT01735305) registry (7), designed to explore the feasibility of identifying a population of ACS patients facing both high risks of ischemia and bleeding (bi-risk) following PCI based on the OPT-BIRISK (4) criteria, with an additional focus on extended dual antiplatelet therapy (DAPT) treatment safety and efficacy beyond 12 months in these bi-risk ACS patients after receiving standard 9–12 months of DAPT without experiencing any adverse events under real-world conditions.

This post hoc hypothesis-generating study conducted the first real-world evaluation of the safety and efficacy of extended DAPT treatment following PCI in ACS patients meeting the OPT-BIRISK assessment criteria. Primary study findings included the following: (1) the OPT-BIRISK criteria were able to effectively identify ACS patients facing both high risks of ischemic and bleeding events at 5 years after PCI; (2) bi-risk individuals comprise a large proportion of ACS patients following PCI, and these patients exhibit a poorer prognosis than non-bi-risk patients, including higher rates of both ischemic and bleeding events; and (3) among those bi-risk ACS patients that were able to tolerate DAPT for 12 months, the further extension of DAPT treatment was related to a significant decrease in stroke risk without any corresponding rise in bleeding events during 12–24 months.

ACS patients often present with risk factors for both ischemia and bleeding event, and certain risk factors can potentially trigger both of these adverse event types. Mohamed et al. (10) found that one in three ACS patients exhibited high-risk factors for both bleeding and ischemic events while also observing higher rates of major adverse cardiovascular events (MACE; cardiac death and reinfarction) and all-cause bleeding events as compared to non-bi-risk patients, in line with the present results. However, in the current study cohort, 58.8% of patients were classified as bi-risk individuals, since prior studies have included bi-risk patients among the overall ACS patient population. In contrast, this study specifically focused on ACS patients that had undergone PCI. In addition, this study included ACS patients ≥75 years of age, who are often excluded from other studies and are underrepresented in such research. This is noteworthy given the evidence that individuals of advanced age comprise ∼40% of patients hospitalized with ACS (11), and these individuals face a higher risk of both cardiovascular event incidence and death such that they represent the most common and clinically relevant bi-risk population. Finally, this study employed different criteria for identifying bi-risk patients relative to prior studies. In previous work, the GRACE ischemic score and the CRUSADE bleeding score were used to identify these patients even though GRACE scores only take age, cardiac enzyme levels, and laboratory findings into account without assessing comorbidities or the characteristics of coronary lesions, thereby potentially failing to detect bi-risk patients.

Assessing ischemic and bleeding risks in individual patients receiving antiplatelet therapy is crucial to balance the potential benefits and harm. Numerous randomized trials have investigated the optimal antiplatelet regimen in various patient cohorts (3, 12–17). Strategies developed to mitigate the risk of bleeding, including shortening DAPT duration, P2Y12 inhibitor monotherapy, and de-escalation, may prevent the exposure to an excessive bleeding hazard in patients deemed at high bleeding risk upfront. In turn, patients at non-high bleeding risk might consider a standard or prolonging DAPT strategy if tolerated. Honestly, there is no doubt that patients at increased ischemic risk could benefit from more intensive antiplatelet therapy, while those at increased bleeding risk warrant less intensive therapy. However, in real-world practice, many patients are at increased risk for ischemic and bleeding events. In the present study, we found that about 60% of patients possessed high bleeding and ischemic risk characteristics. Compared with the absence of relevant features, the patients at high risk of both ischemic and bleeding events had a 2-fold increased risk of ischemic events, 3.5-fold increased risk of all-cause mortality, and 2-fold increased risk of major bleeding. Howbeit, the optimal antithrombotic treatment regimen in this patient subset remains unclear. In the DAPT study, the clinical benefit (MACCE: 4.3% vs. 5.9%) of extended thienopyridine treatment was tempered by increased bleeding events (BARC types 2, 3, or 5 bleeding: 5.6% vs. 2.9%) (3). The current study detected that extended DAPT strategy was associated with a slight risk reduction of ischemic events (1.95% vs. 2.88%), especially stroke (1.07% vs. 2.10%), without excessive risk of major bleeding complications (0.34% vs. 0.26%). The inconsistent results and lower incidence of bleeding and ischemic events might contribute to a high proportion of bleeding and ischemic events, which might contribute to a high proportion of the trial population treated with prasugrel, ethnic differences, procedural improvements, and changes in bleeding avoidance strategies over time. Nevertheless, the incidence of ischemic and bleeding events in the present study was similar to that observed between 1 and 2 years after PCI in other trials involving East Asian populations (18, 19). Considering the contemporary clinical practice, extended P2Y12 inhibitor monotherapy with clopidogrel might be an optimal antiplatelet strategy. A multicenter, prospective, double-blinded, active-controlled randomized trial, OPT-BIRISK, is designed to examine the efficacy and safety of extended P2Y12 inhibitor monotherapy with clopidogrel in patients at high risk for both ischemic and bleeding complications who had completed 9–12 months of DAPT after drug-eluting stent implantation, which will establish the optimal intensity of antiplatelet therapy (4).

Moreover, the applicability and robustness of assessment algorithm is extremely important. Briefly, the OPT-BIRISK criteria compose of twelve clinical high ischemic criteria (binary classification, “Yes” or “No”) and six high bleeding criteria (binary classification, “Yes” or “No”). Not like GRACE (20) and PRECISE-DAPT score (21), the patients could be evaluated simply and quickly. Nevertheless, an app or plug-in component, which could capture all factors relating to the OPT-BIRISK criteria in the electronic medical records, evaluate them automatically, and then quickly preset the ischemic and bleeding risk of patients, is convenient to use for clinicians and to validate in other population.

There are several limitations to this study. First, this was an observational study in China and individual DAPT regimens based on individual patient conditions existed such that not all patients may have used their medications in strict accordance with the defined DAPT groupings. As these analyses were conducted by classifying those patients remaining adherent to a DAPT regimen at 12 months postoperatively as exhibiting a prolonged (>12-month) DAPT treatment duration with no consideration for discontinuation after 12 months, the benefits of extended DAPT treatment to the risk of bleeding or ischemic events are likely underestimated. Moreover, the present trial was conducted solely in a Chinese population. Additional randomised trials are necessary to investigate the optimal antiplatelet strategy after a mandatory DAPT period further in a Western population of high-risk ACS patients. Secondly, despite the present study was adjusted by propensity score matching, we were unable to evaluate and control some unmeasured covariates which might influence the choice of antiplatelet therapy, such as physician characteristics. Additionally, owing to the observational nature of the study, the results could only provide the evidence of association. Third, considering clopidogrel was the only P2Y12 inhibitor in the present study, which might limited the promotion value in the era of potent P2Y12 inhibitors. However, recent observational studies showed that about 57%–76% of ACS patients undergoing PCI received clopidogrel-based DAPT strategy at discharge (22, 23), reflecting the gap the between guidelines-indicated and the clinical practice. For clinicians, it's important to make clinical judgments and consequently tailor the intensity and the duration of antiplatelet therapy to individual patients according to the ischemic and bleeding risk. At last, owing to only ∼3% patients received clopidogrel monotherapy in the SAPT group, analyses of the utilized type of monotherapy or the effects of different forms of medication on patient prognosis could not be conducted.

The OPT-BIRISK criteria may assist clinicians in identifying ACS patients at risk of recurrent ischemic and bleeding complications following PCI. An extended DAPT strategy, compared to antiplatelet monotherapy, could offer prospective benefits in reducing the risk of stroke without a substantial increase in major bleeding problems among patients who remained event-free after 12 months of dual antiplatelet therapy (DAPT). However, these interesting results must be validated in larger, randomized investigations.