Optimal Revascularization Strategy for Acute Coronary Syndromes With High Bleeding Risk　― It Is Hard to Please All Parties ―

The advancements of new-generation drug-eluting stents and potent antiplatelet drugs have dramatically reduced ischemic and thrombotic events (e.g., stent thrombosis [ST]) over the past 10 years (Figure). In contrast, the risk of bleeding events has gradually increased as percutaneous coronary intervention (PCI) becomes widely performed in elderly patients with coronary artery disease (CAD) and atrial fibrillation.^1,2 However, the rate of major bleeding varies widely among clinical trials due to the lack of a standardized definition. In 2019, the Academic Research Consortium (ARC) introduced a new consensus document with 20 criteria to define high bleeding risk (HBR).³ According to the ARC-HBR definition, HBR patients were reported to be up to 50% in clinical practice, although more than 250,000 PCI were performed annually in Japan.^3,4 The reason why bleeding events are a concern is their significant negative effect on 30-day and 1-year outcomes, including death.^5–7 Therefore, the current revised JCS guideline recommends that the bleeding risk of patients should be evaluated before PCI.⁸ This algorithm means that the PCI operator should mostly decide the period of dual antiplatelet therapy (DAPT) before any procedure.

Figure.

Temporal trend of risk of ischemic and thrombotic events (blue line) and bleeding events (red line). DAPT, dual antiplatelet therapy; DES, drug-eluting stent; PCI, percutaneous coronary intervention.

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Given the importance of bleeding complications after PCI, we welcome the work of Natsuaki et al in this issue of the Journal.⁹ They should be commended for conducting one of the largest and longest follow-up studies to extend previous findings. Moreover, 5-year outcomes following PCI were evaluated, reflecting real clinical practice, from the CREDO-Kyoto PCI/CABG Registry Cohort-3, consisting of 13,258 patients treated first with PCI, including 5,521 cases of acute coronary syndromes (ACS) and 7,737 of stable CAD. The primary bleeding endpoint was BARC type 3 or 5 bleeding, and the primary ischemic endpoint was a composite of myocardial infarction (MI) and ischemic stroke. Natsuaki et al focus on whether differences in clinical presentation, ACS or stable CAD, were related to the occurrence of bleeding and ischemic events. The main findings are summarized in the following 3 points: (1) HBR patients treated with PCI in Japan comprised 48%; (2) regarding bleeding events, ACS patients had a significantly high incidence compared with stable PCI regardless of HBR, and the difference was remarkably observed 30 days after PCI; and (3) regarding ischemic events, there was no difference in the incidence between ACS and stable AP; rather, HBR itself was associated with an increased risk of ischemic events.

Here, we would like to mention the points that need to be paid attention in the interpretation of this study, separately for ischemic and bleeding events.

First, regarding ischemic events, ACS patients are generally recognized as having a high rate of future ischemic events following PCI compared with stable CAD. Importantly, the primary ischemic events of the present study counted for the only incidence of MI and ischemic stroke, but excluded cardiac death and ST. Indeed, ACS patients had significantly higher rates of cardiac death (12.0% vs. 5.9%, P<0.0001) and definite ST (1.3% vs. 0.5%, P<0.0001) compared with stable CAD. They explain that the incidence of cardiac death and ST was excluded to avoid “bias” caused by the index ACS itself, but that is what ACS may be, we think. Moreover, stroke was defined as ischemic or hemorrhagic with neurological symptoms lasting >24 h. However, the incidence of hemorrhagic stroke may have been better omitted from primary ischemic events.³ Therefore, a discussion is still needed to achieve consensus with maximum freedom from bias related to the definition of ischemic events in ACS patients. Moreover, the findings of the present study should be noted as not supporting the shortening of DAPT in ACS patients. Persistent DAPT discontinuation was almost the same between ACS and stable CAD patients (37.1% vs. 29.5% and 77.6% vs. 73.3% at 1 and 5 years; electronic Supplementary Figure 1⁹). Also, it should be considered that clopidogrel is mostly used (96%) as a P2Y12 receptor inhibitor for ACS patients.

Second, regarding bleeding events, the 30-day event rate was 11.1% and unacceptably high. However, stable CAD was 3.0%. It may be associated with somewhat outdated procedural and antithrombotic strategies such as the use of transfemoral approach (>70%), lack of information on the use of mechanical support device, lower prevalence of proton pump inhibitors, and so on. In the recently launched PENDULUM registry, which enrolled 6,422 all-comer patients from 67 hospitals in Japan, the rate of major bleeding at 1 year was 3.0% and 2.7% in ACS and stable CAD patients, respectively.⁴ Arguably, improvements and ingenuity of perioperative strategies have contributed to reducing the risk of bleeding events during the 30 days following PCI.

Finally, another important finding in the present study reconfirmed that an HBR patient has conflicting risks. Consequently, ACS patients with HBR have significantly higher 30-day bleeding events compared with stable CAD with HBR (15.4% vs. 4.3%), whereas HBR patients are at high risk of 5-year ischemic events regardless of ACS presentation (15.7% in ACS+HBR vs. 14.9% in stable CAD+HBR). The key to the problem in HBR patients shortened the DAPT duration. Several clinical trials with a 1- or 3-month duration of DAPT have succeeded in reducing bleeding complications without increased risk of ischemic events.^10,11

Future Perspective

Few data exist on the optimal DAPT duration after PCI in ACS presentation and HBR patients. Thus, we expectantly await the results of future clinical trials such as STOP-DAPT 3 and ISAR-REACT 6. The ongoing STOP-DAPT 3 trial was designed to investigate the benefit of prasugrel monotherapy without aspirin, so-called “Zero-DAPT,” as compared with 1-month DAPT with aspirin and prasugrel, in terms of reducing bleeding events after PCI in patients with HBR or ACS.¹² Although zero-DAPT definitely reduces bleeding events during 30 days, the risk of ischemic events seems to hang in the balance (Figure). Forthcoming evidence may suggest that the net clinical DAPT benefit in ACS and HBR patients should give the confidence to drop aspirin immediately after drug-eluting stent implantation.

References

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