The preceding exposition has delineated the definition and development of both HIR and HBR as well as their respective characteristics. However, for patients who exhibit both proclivities for bleeding and ischemia, they are designated as the bi-risk population. This group can be bifurcated into two subcategories based on the different risk factors they possess: (1) those individuals who inherently exhibit factors that elevate both bleeding and thrombotic risks, such as chronic kidney disease, advanced age, ischemic stroke, and so forth; and (2) those who have both HIR and HBR risk factors. To date, there is no standardized definition that clearly delimits this population, but one study’s protocol has proposed their definition of bi-risk patients [1]. We have combined their definition with our collection and integration of existing evidence to present our own definition of bi-risk patients, as shown in Table 1 (Ref. [1]). This population is not uncommon and necessitates judicious selection and management to balance their competing risks of bleeding and thrombosis.

DAPT consisting of aspirin and a P2Y${}_{\text{12}}$ receptor inhibitor serves as the foundation of pharmacological treatment for patients post-PCI. It aims to prevent post-procedure thromboembolic events, such as stent thrombosis and re-infarction, by suppressing platelet aggregation.

Since the definition of ARC-HBR proposed in 2019, studies have focused extensively on PCI-HBR population. Subsequent research such as management of high bleeding risk patients post bioresorbable polymer coated stent implantation with an abbreviated versus prolonged DAPT regimen (MASTER-DAPT) [35], TWILIGHT-HBR [7], evaluate safety and effectiveness of the tivoli drug-eluting stents (DES) and the firebird DES for treatment of coronary revascularization (I LOVE-IT-2) [36] and STOPDAPT-2 [37], all suggest that PCI-HBR patients have a higher risk of bleeding and a worse prognosis, and attenuating antithrombotic regimens in this group of patients can improve the prognosis of HBR patients, by greatly reducing the risk of bleeding, without increasing the risk of ischemia. The MASTER-DAPT study involved 4579 patients with HBR who underwent PCI using biodegradable polymeric sirolimus-eluting stents. The study concluded that a one-month DAPT regimen was equally effective as three months or more of DAPT, and even showed a reduced occurrence of major or clinically relevant non-major bleeding [35]. Similarly, the STOPDAPT-2 study demonstrated that shortening DAPT to one month, followed by clopidogrel monotherapy, did not lead to an increase in ischemic events. On the contrary, it resulted in a decrease in major bleeding events, particularly benefiting the HBR subgroup [37].

Research has unveiled that individuals belonging to the PCI-HBR patient cohort often face a heightened likelihood of encountering ischemic events [38, 39, 40]. Given the aging of the global population, patients with coronary artery disease (CAD) are increasingly presenting with comorbidities, more complex coronary lesions, and more severe disease. Features associated with a high risk of ischemia, such as multi-vessel disease, diffuse disease, bifurcation lesions, calcified lesions, long lesions, recurrent myocardial infarctions, as well as comorbidities such as diabetes and renal dysfunction, are becoming more prevalent in patients. These high ischemic factors, in turn, make this group of patients require more potent antithrombotic regimens to control the significantly elevated ischemic events [41]. For CAD patients with both a high risk of bleeding and a high risk of ischemia, it is crucial to exercise caution in selecting their antiplatelet therapy. An overly aggressive approach may increase the risk of bleeding, while an approach that is too weak may lead to ischemic events such as myocardial infarction and in-stent thrombosis. Therefore, the bi-risk population has been defined to raise awareness and assist cardiologists in better managing these special individuals [1]. Thus, given the evidence regarding antiplatelet strategy above, we propose for the first time the concept of TAILOR-BIRISK for the treatment of the bi-risk population undergoing PCI (Fig. 1). We emphasize that a short course of DAPT in combination with clopidogrel monotherapy is feasible for this population, and that short-term DAPT combined with maintenance treatment with ticagrelor 60 mg BID is also feasible. TAILOR-BIRISK also impliesthat the use of the CYP2C19 gene test to guide de-escalating strategies can help to better individualize and customize the anti-thrombotic regimen.

Fig. 1.

Characteristics of patients undergoing PCI with high bleeding and ischemia risk and the concept of TAILOR-BIRISK. The concept indicates de-escalating antithrombotic treatment and suggests that short-term dual antiplatelet therapy combined with clopidogrel monotherapy or ticagrelor 60 mg BID monotherapy in maintenance is feasible for this bi-risk population. The use of CYP2C19 gene testing to guide P2Y${}_{\text{12}}$ inhibitor selection can help better individualize and customize the antithrombotic regimen. STEMI, ST segment elevation myocardial infarction; CTO, chronic total occlusion; CKD, chronic kidney disease; NSAIDs, nonsteroidal anti-inflammatory drugs; CYP2C19, cytochrome P450 2C19; ST, stent thrombosis; DAPT, dual antiplatelet therapy; SMART-DATE, smart angioplasty research team-safety of 6-month duration of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome; REDUCE, short-term dual anti platelet therapy in patients with ACS treated with the COMBO dual-therapy stent; TICO, ticagrelor monotherapy after 3 months in the patients treated with new generation sirolimus stent for acute coronary syndrome; STOPDAPT-2, the short and optimal duration of dual antiplatelet therapy after everolimus-eluting cobalt-chromium stent; ACS, acute coronary syndrome; MASTER DAPT, management of high bleeding risk patients post bioresorbable polymer coated stent implantation with an abbreviated versus prolonged DAPT regimen; HBR, high bleeding risk; EVOLVE, a prospective, multicenter, single-arm study designed to assess the safety of 3-month DAPT in subjects at high risk for bleeding undergoing PCI with the SYNERGY everolimus-eluting platinum chromium coronary stent system; TWILIGHT, ticagrelor with aspirin or alone in high-risk patients after coronary intervention unfractionated heparin; I LOVE IT 2, evaluate safety and effectiveness of the tivoli DES and the firebird DES for treatment of coronary revascularization; PCI, percutaneous coronary intervention; BID, twice daily; DES, drug-eluting stents.

However, no study so far has directly investigated the possibility of reducing ticagrelor to 60 mg BID as monotherapy during the first 12 months after PCI, and there is a lack of large randomized controlled trials that compare various antithrombotic regimens in bi-risk patients. The ongoing optimal antiplatelet therapy for high bleeding and ischemic risk patients (OPT-BIRISK) Trial (NCT 03431142) compares the use of extended DAPT for maintenance treatment versus clopidogrel monotherapy after 9–12 months of DAPT; and is anticipated to provide new evidence for antithrombotic therapy during the chronic maintenance period for bi-risk patients [1]. However, given that the peri-PCI and early post-PCI periods are high-risk times for in-stent thrombosis and reinfarction, it remains essential to study the best antithrombotic strategy during this critical period. Therefore, more research should be focused on the peri-PCI stage and the early stages following PCI in bi-risk patients.

Research has confirmed that the risk of cardiovascular adverse events in individuals taking clopidogrel is directly related to their CYP2C19 gene polymorphism, as the CYP2C19 enzyme encoded by the gene is involved in the metabolism of clopidogrel [42]. Clopidogrel itself is an inactive prodrug, and about 85% of it is hydrolyzed into inactive metabolites by esterases in the small intestine after absorption, while only about 15% of clopidogrel is metabolized in the liver through the CYP2C19-mediated process to form active metabolites that irreversibly bind to the platelet membrane surface adenosine diphosphate (ADP) receptor P2Y${}_{\text{12}}$, inhibiting ADP-mediated platelet activation and aggregation [43] (Fig. 2). Therefore, CYP2C19 enzyme activity determines the metabolic efficiency of clopidogrel in patients.

Fig. 2.

Metabolism of clopidogrel and the impact of different genotypes on drug recommendations. CYP, cytochrome P450; UMs, ultrarapid metabolizers; RMs, rapid metabolizers; NMs, normal metabolizers; IMs, intermediate metabolizers; PMs, poor metabolizers.

The CYP2C19 gene has polymorphisms, and the polymorphisms at some loci can affect enzyme activity, ultimately leading to differences in the metabolic efficiency of drugs in different individuals. In large-scale meta-analyses, it has been demonstrated that patients receiving clopidogrel treatment during PCI who possess the CYP2C19 intermediate metabolizer (IM) genotype, such as *1/*2 and *1/*3, or the poor metabolizer (PM) genotype, such as *2/*2 and *2/*3, exhibit an elevated risk of experiencing MACE and stent thrombosis compared to those with the normal metabolizer (NM) genotype, i.e, *1/*1 [44, 45, 46].

A multicenter randomized controlled trial by Cavallari et al. [47] showed a higher incidence of MACE after PCI in patients with LoF gene variants treated with clopidogrel. After 1 year of follow-up, MACE was more likely to occur in the clopidogrel-treated group compared with other treatment groups amongst CYP2C19 LoF allele carriers (adjusted hazard ratio (HR) 2.21, p = 0.021). For patients receiving prasugrel or ticagrelor, the risk of MACE was similar in the CYP2C19 LoF allele group compared with the no-LoF allele group (adjusted HR 0.81, 95% CI 0.48–1.35; p = 0.41) [47]. Similarly, a meta-analysis of randomized control trials suggested a higher risk of MACE in patients with CYP219 LoF gene variants when treated with clopidogrel compared with other P2Y${}_{12}$ inhibitors (risk ration (RR) 1.42, 95% CI 1.2–1.7). For patients without LoF gene variants, the risk of cardiovascular events was similar for clopidogrel versus other P2Y${}_{12}$ inhibitor therapy (RR 1.0, 95% CI 0.8–1.25) [48]. Therefore, the theories above provide the basis for genotype-guided treatment regimens when considering patients treated with clopidogrel.

However, multiple studies aiming to demonstrate the superiority of genotype-guided antithrombotic strategies have not achieved the expected results. A meta-analysis by Bauer et al. [49] including 15 randomized controlled trials (RCTs) did not support routine CYP2C19 gene testing of patients to guide platelet therapy. Published in 2020, the Tailored Antiplatelet Initiation to Lesson Outcomes Due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention study (TAILOR-PCI) is the largest study using CYP2C19 genetic testing to guide antiplatelet treatment strategies after PCI, with 5302 PCI patients randomized to a genotype-guided strategy group and a conventional treatment strategy group and followed for 12 months. In the genotype-guided treatment group, ticagrelor was given to CYP2C19 LoF allele carriers and clopidogrel to wild-type allele carriers; all patients in the standard treatment group received clopidogrel. However, the results of the study showed that a genotype-directed post-PCI DAPT regimen did not significantly reduce adverse cardiovascular events. The difference in the composite endpoint of cardiovascular death, myocardial infarction, stroke, in-stent thrombosis, and serious recurrent ischemic events at 12 months was not statistically significant for the primary endpoint of genotype-guided versus conventional treatment strategy (4.03% vs. 5.85%, OR = 0.66, p = 0.056) [50]. Similarly, the genotype-guided treatment group in the Patient Outcome After Primary PCI (POPular) Genetics study did not significantly reduce the net clinical endpoint events compared with the conventional treatment group (5.1% vs. 5.9% in the standard treatment group; absolute rate difference 0.7%; 95% CI 2.0–0.7) [51]. All patients in the standard treatment arm of the study received prasugrel or ticagrelor. This trial also suggests that in high ischemic risk patients, genotype-guided P2Y${}_{\text{12}}$ inhibitor selection is not inferior to the routine use of potent P2Y${}_{\text{12}}$ inhibitors.

However, multiple guidelines and expert consensus currently do not routinely endorse genetic testing to inform antiplatelet therapy after PCI due to several reasons [34, 52, 53]. Firstly, there is inadequate evidence demonstrating that genetic testing can substantially enhance the efficacy and safety of antiplatelet therapy after PCI. Secondly, genetic testing may escalate treatment expenses and necessitate additional time and resources, which may not prove to be cost-effective. Thirdly, the therapeutic efficacy of clopidogrel is predominantly governed by the CYP2C19 gene, although other genetic polymorphisms such as ABCB1 and PON1, as well as the overall physiological function of the body, also play a role [54, 55]. This elucidates why gene-guided antiplatelet therapy may confer greater benefit to patients in the early post-PCI period (post-procedure to 3–6 months), whereas this benefit tends to diminish during the chronic maintenance phase. Moreover, the CYP2C19 test can only indicate possible metabolic types of clopidogrel instead of actual efficacy, and combined platelet function tests may be possible to better assess the actual effects of clopidogrel. However, platelet function tests require continuous dynamic monitoring, unlike genetic testing, which is a one-time test. Clinically, for high-risk ischemic populations, direct use of ticagrelor is often preferred rather than testing clopidogrel metabolism to guide drug use.

Although most guidelines do not routinely recommend genetic testing for patients requiring clopidogrel after PCI, some make recommendations for specific populations. The 2017 ESC guideline recommended that patients with recurrent adverse events may undergo genetic testing to guide patients on the need to change antiplatelet agents [2].

The 2022 position statement from the European Society of Cardiology Working Group on Cardiovascular Drug Therapy recommended that consideration should be given to genotyping high-risk cardiovascular patients, especially those at high risk of thrombosis or bleeding, before prescribing clopidogrel [56].

Currently, the majority of evidence suggests that routine CYP2C19 genetic testing in the PCI population is not feasible. However, the value of such testing may still be untapped in certain special populations, such as patients with high ischemic or bleeding risk, and further research in this area is needed.

As the second generation of drug-eluting stents feature unique technologies such as thin strut design and ultra-thin biodegradable polymer coating that aids rapid endothelialization and reduces the sustained risk of stent thrombosis; coupled with the recent emphasis on intensive blood pressure and lipid-lowering interventions targeting coronary risk factors, the long-term thrombotic risk has decreased compared to the past and de-escalation has therefore become a research hotspot in the field of antithrombotic therapy for PCI in recent years [57, 58]. Currently, the optimal thrombotic method for PCI in bi-risk patients remains uncertain. The trend of de-escalating antithrombotic therapy in patients with high risk of ischemia or bleeding indicates that it may be equally feasible to shorten the duration of DAPT in patients with bi- risk. From existing studies targeting patients separately with HBR or HIR, it appears that a de-escalation approach using short-term DAPT followed by a P2Y${}_{\text{12}}$ inhibitor alone is a research trend for future antithrombotic strategies in bi-risk patients undergoing PCI [6, 59, 60, 61].

While aspirin has been the preferred antiplatelet drug for CAD based on its long history and extensive clinical research, recent studies such as aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM) study [62] and HOST-EXAM extended study [63] suggest that P2Y${}_{\text{12}}$ inhibitors may have the potential to surpass aspirin in the chronic maintenance phase. For instance, the HOST-EXAM study demonstrated that compared to aspirin, clopidogrel not only reduces the risk of ischemic events but also decreases the risk of bleeding in the chronic maintenance phase. This combination of efficacy and safety benefits aligns with the needs of bi-risk patients. Therefore, we propose that P2Y${}_{\text{12}}$ receptor inhibitors may be a more favorable choice for maintenance therapy in bi-risk patients.

Roule et al. [64]’s meta-analysis provides evidence for this hypothesis. They included a specific bi-risk population, elderly patients, and demonstrated that the use of P2Y${}_{\text{12}}$ inhibitors after short DAPT is a good option for these patients. Although elderly patients are not directly listed as a HIR criterion in the 2018 ESC guidelines, many studies have shown that elderly patients often have both high ischemic and high bleeding risks.

In the context of the increasing importance of P2Y${}_{\text{12}}$ receptor antagonists, personalized selection has become crucial. In bi-risk populations, routine use of clopidogrel without considering the presence of CYP2C19 genetic polymorphisms may increase the risk of ischemia due to clopidogrel resistance. Conversely, routine use of ticagrelor to address ischemic risk may increase the risk of major bleeding in these patients. Therefore, CYP2C19 genetic testing to guide the selection of P2Y${}_{\text{12}}$ receptor antagonists in these bi-risk populations represents a promising approach.

For bi-risk patients, genetic testing can guide the selection of P2Y${}_{\text{12}}$ inhibitors during the peri-PCI period and early period after PCI; on the other hand, during the maintenance phase of antiplatelet therapy after short-term DAPT, there is lack of evidence to suggest whether CYP2C19 genetic testing may guide the use of a reduced-dose ticagrelor strategy (i.e., 60 mg BID). Certain studies have suggested that chronic maintenance treatment with ticagrelor 60 mg BID is equally effective and safe compared with ticagrelor 90 mg BID for stable CAD patients with high ischemia risk, and there was a tendency towards lower rates of respiratory distress and major bleeding events [9]. Currently, there is a paucity of research investigating the comparative efficacy of reduced-dose ticagrelor versus clopidogrel in the chronic maintenance phase for bi-risk patients with the CYP2C19 LoF allele. Therefore, we believe that in the context of genetic guidance, ticagrelor 90 mg BID in short-term DAPT duration combined with maintenance therapy with reduced-dose ticagrelor (60 mg BID) may be a promising option for bi-risk patients carrying the clopidogrel LOF gene. However, there is a lack of direct research evidence to support this conclusion, and more studies will be needed to confirm it.