Antiplatelet Therapy in Percutaneous Coronary Intervention Patients with Concurrent High Ischemic and Bleeding Risk

Managing antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) who present with both high ischemic risk (HIR) and high bleeding risk (HBR) remains a clinical challenge. Current guidelines recommend transitioning to antiplatelet monotherapy after a mandatory period of dual antiplatelet therapy (DAPT), that is 6 months for PCI patients with a chronic coronary syndrome (CCS) and 12 months for those with an acute coronary syndrome (ACS). However, whether this strategy sufficiently mitigates the risk of ischemic events in dual-risk patients remains unclear.[1] [2] [3] [4] Prolonged DAPT reduces ischemic events but increases the risk of bleeding, which has both early and long-term prognostic implications.[5]

In this issue of the Journal, Jang et al investigated the optimal long-term antiplatelet strategy for dual-risk patients, using a South Korean multicenter PCI registry.[6] Patients (n = 1,003) were classified using the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria for bleeding risk and the DAPT score (≥2) or complex and high-risk interventional procedures (CHIP) criteria for ischemic risk. They were stratified into three groups after 12 ± 3 months of DAPT with aspirin and clopidogrel: clopidogrel monotherapy (28.0%), aspirin monotherapy (27.3%), and continued DAPT (44.7%). Using inverse probability treatment weighting, outcomes were analyzed over a median follow-up of 3.2 years. Clopidogrel monotherapy was associated with significantly lower all-cause mortality compared with prolonged DAPT, driving reductions in net adverse clinical events (NACE) and combined ischemic endpoints, but with no significant differences in bleeding, myocardial infarction (MI), or stroke. The authors concluded that clopidogrel monotherapy is the preferred long-term strategy for dual-risk patients.

This study provides valuable insights into a population that has been underrepresented in previous clinical trials. However, several limitations should be considered. First, it was conducted exclusively in South Korea, limiting the generalizability of the findings. Indeed, there are described differences between Asians and non-Asians in relation to thrombotic (e.g., stroke) and bleeding complications,[7] [8] with Asians having an increased propensity to bleeding on antithrombotic therapy, the so-called “East Asian paradox.”[9] [10]

Second, clopidogrel was the sole P2Y₁₂ inhibitor assessed, precluding insights into the efficacy of alternative agents. Third, the observational design, with physician-determined treatment strategies and despite careful adjustment, is prone to unavoidable bias. Fourth, patients on oral anticoagulants were excluded, though they comprise a significant dual-risk PCI subset. Fifth, patients with CCS or ACS were analyzed together despite differing guideline recommendations. Finally, the primary benefit—reduced all-cause mortality—occurred without significant reductions in major ischemic or bleeding events, raising questions about the underlying mechanisms.

These limitations notwithstanding, the findings of this study align with growing interest in P2Y₁₂ inhibitor monotherapy for HBR patients.[11] Trials such as STOPDAPT-2 and SMART-CHOICE demonstrated that early P2Y₁₂ inhibitor monotherapy (after 1 to 3 months) was noninferior to 12-month DAPT in preventing major adverse cardiac and cerebrovascular events, with lower bleeding risk.[12] [13] However, these studies did not focus on dual-risk patients. The HOST-EXAM trial compared clopidogrel versus aspirin monotherapy in 5,530 South Korean patients (72.1% with an ACS) following 6 to 18 months of DAPT post-PCI.[14] With a median 5.8-year follow-up, clopidogrel was superior in reducing both thrombotic and bleeding events, including in the HBR subgroup (23% of the population), although dual-risk patients were not specifically analyzed. The MASTER-DAPT trial randomized 4,434 patients (48.3% with an ACS) to abbreviated DAPT (53.9% clopidogrel monotherapy) versus standard therapy.[15] One month of DAPT was noninferior in preventing NACE and reduced the risk of bleeding. Importantly, none of these trials addressed patients with concomitant HIR.

The first randomized trial specifically enrolling dual-risk patients, OPT-BIRISK, provides recent evidence.[16] This double-blind study randomized 7,758 ACS patients post-PCI to either clopidogrel monotherapy or DAPT prolongation after 9 to 12 months. Clopidogrel monotherapy for an additional 9 months significantly reduced the bleeding risk without increasing ischemic events. Although study population and selection criteria differed from the study by Jang et al, these results further support clopidogrel monotherapy over prolonged DAPT and reinforce the concept that bleeding risk mitigation may improve outcomes in dual-risk patients.

A shift toward abbreviated DAPT in dual-risk patients is emerging, emphasizing bleeding risk reduction. In these patients, keeping the P2Y₁₂ inhibitor rather than switching to aspirin monotherapy appears to be a preferable approach. In both the study from Jang et al and OPT-BIRISK, the transition to clopidogrel monotherapy occurred relatively late, between 9 and 15 months. It is important to emphasize that neither study demonstrated the superiority of immediate (i.e., earlier) post-PCI clopidogrel monotherapy over continued aspirin and clopidogrel.

Defining dual-risk patients remains challenging due to inconsistent criteria. [Fig. 1] describes the HIR and HBR criteria endorsed by European Society of Cardiology (ESC) guidelines.[1] [17] [18] While ARC-HBR criteria are widely accepted and validated for HBR, heterogeneity persists across studies.[18] Jang et al applied the ARC-HBR criteria, whereas OPT-BIRISK used alternative definitions, with female sex (which is not included among ARC-HBR criteria) as a common risk factor (∼40%). Conversely, only 25% met ARC-HBR criteria, potentially selecting a lower-risk cohort. HIR definitions also vary. The ESC defines HIR based on complex coronary artery disease and specific clinical/procedural criteria.[17] Jang et al used the DAPT score and CHIP criteria, whereas OPT-BIRISK introduced 11 different HIR criteria, including troponin-positive ACS (46% of the cohort), which is absent from ESC-defined HIR. These inconsistencies highlight the need for standardized dual-risk assessment. The ARC has proposed a trade-off model to estimate ischemic versus bleeding risk in HBR patients.[19] This tool integrates 12 clinical and procedural variables associated with stent thrombosis/MI (HIR) or BARC type 3 to 5 bleeding (HBR) within 1 year of PCI, offering a valuable approach to risk stratification when ischemic and bleeding risks coexist.

Fig. 1 Factors associated with an increased risk of both ischemic and bleeding events after percutaneous coronary intervention. The left panel illustrates ischemic risk factors as defined by the European Society of Cardiology (ESC) guidelines. The right panel illustrates high bleeding risk criteria as defined by the Academic Research Consortium for High Bleeding Risk (ARC-HBR) and endorsed by the ESC guidelines. *Complex revascularization: left main, bifurcation stenting with >2 stents implanted, chronic total occlusion, stenting of last patent vessel. bAVM, brain arteriovenous malformation; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; ICH, intracranial hemorrhage; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drug; OAC, oral anticoagulation; ST, stent thrombosis.

Overall, the current body of evidence suggests that prolonged DAPT should be avoided in dual-risk patients, favoring P2Y₁₂ inhibitor monotherapy. A personalized DAPT duration, incorporating robust risk stratification, is clearly essential for optimizing PCI outcomes while minimizing both thrombotic and bleeding risks. Further research is needed to refine the identification of dual-risk patients and to determine the optimal timing and agent for P2Y₁₂ monotherapy.

Publication History

Received: 19 February 2025

Accepted: 21 February 2025

Accepted Manuscript online:
24 February 2025

Article published online:
24 March 2025

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