Era of Focusing on Bleeding Events　― Trend Towards No Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention ―

Restenosis¹ and coronary thrombosis have been considered the Achilles heel of percutaneous coronary intervention (PCI) since its inception in 1977. Recent innovations, such as new-generation drug-eluting stents have successfully minimized the drawbacks of PCI and interventional cardiologists are now focusing on problems surrounding PCI, such as the prevention of new atherosclerotic lesions, indication for chronic coronary syndrome, choice of modality to diagnose significant coronary stenosis, cost effectiveness, management during non-cardiac surgery, and bleeding events that are primarily caused by antiplatelet therapy, which is mandatory post-PCI. Of these, the diminution of bleeding events is one of the most effective approaches to improving survival, because of the stronger association of bleeding events with all-cause death than with myocardial infarction.²

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The first step in achieving the aforementioned diminution involves the development of a risk score to identify the patients at high risk for bleeding. However, it is difficult to select from among several described risk scores, such as Reduction of REACH,³ dual antiplatelet therapy (DAPT),⁴ PARIS,⁵ PRECISE-DAPT,⁶ and CREDO-Kyoto.⁷ This problem resulted in the development of the Academic Research Consortium for high bleeding risk (ARC-HBR) to standardize the definition.⁸ Despite the applicability of the ARC-HBR definition in Japanese patients,⁹ it fails to include some factors that are related to bleeding complications in Japanese patients. Low body weight, frailty, heart failure, and peripheral vascular disease are reportedly independently associated with bleeding events in Japan.¹⁰ Thus, the Japanese guideline focused update on antithrombotic therapy in patients with coronary artery disease has advocated the Japanese version of HBR (J-HBR), including these specific factors (Table).

Table. Japanese Version of High Bleeding Risk (J-HBR) Score

Major		Minor
		Age	≥75 years. Biological age and chronological age may differ, and the age is highly individual, so it is not proper to evaluate uniformly. Bleeding risk may be highly increased in patients of age >80 years.
Low body weight, Frailty	Low body weight (<55 kg for men, <50 kg for women) is the bleeding risk factor, which is important for Japanese, but not for Westerners. A particular notice is necessary for an elderly woman. Traumatic bleeding risk may be increased in the setting of frailty as a result of more frequent falls.
Severe CKD (hemodialysis)	The bleeding risk increases incrementally with worsening CKD, especially when eGFR <30 mL/min/1.73 m2, or on hemodialysis in both ACS and non-ACS patients PCI for hemodialysis patients is more common in Japan.	Moderate CKD	eGFR 30–59 mL/min/1.73 m2.
Moderate to severe anemia	Hemoglobin <11 g/dL. Bleeding risk may be increased according to the degree of anemia.	Mild anemia	Hemoglobin 11–12.9 g/dL for men and 11–11.9 g/dL for women.
Heart failure	Heart failure increases bleeding risk. A particular notice is necessary, because PCI for an elderly patient with heart failure is more common in Japan.
Anticipated use of long-term oral anticoagulation	Long-term use of oral anticoagulation (in about 10% of PCI patients) may increase the risk of bleeding. It is not rare for elderly patients to have new-onset atrial fibrillation during follow-up after PCI.	Long-term use of oral NSAIDs or steroids	Long-term use of oral NSAIDs or steroids may increase the risk of gastrointestinal bleeding.
Peripheral vascular disease	Peripheral vascular disease is one of the most common clinical presentations of general atherosclerosis, and is related to high bleeding risk.
History of non-traumatic bleeding events	Gastrointestinal bleeding or urinary tract bleeding requiring hospitalization or transfusion in the past 6 months or at any time, if recurrent.		First non-traumatic bleeding event requiring hospitalization or transfusion in the past 6–12 months.
Previous Ischemic Stroke or ICH	Previous spontaneous ICH (at any time), previous traumatic ICH within the past 12 months and presence of a bAVM. Moderate or severe ischemic stroke within the past 6 months. The risk of ICH may be increased in Japanese patients taking aspirin.		Any ischemic stroke at any time not meeting the major criterion.
Thrombocytopenia	Platelet count <100×109/L.
Active malignancy	Active malignancy. Active malignancy is defined as diagnosis within 12 months and/or ongoing requirement for treatment (including surgery, chemotherapy, or radiotherapy). Cancer that is considered to be in complete remission or requires only maintenance therapy is not considered active.
Liver cirrhosis with portal hypertension	Liver dysfunction is a risk factor for bleeding complication in early phase, especially in patients with portal hypertension.
Chronic Bleeding Diatheses	Included in the ARC-HBR criteria.
Nondeferrable major surgery on DAPT	Included in the ARC-HBR criteria.
Recent major surgery or major trauma within 30 days before PCI	Consensus is obtained in the ARC-HBR criteria.

Patients are defined to be at HBR if at least 1 major or 2 minor criteria are met. ACS indicates acute coronary syndrome; ARC-HBR, academic research consortium - high bleeding risk; bAVM, brain arteriovenous malformation; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; ICH, intracranial hemorrhage; NSAIDs, nonsteroidal anti-inflammatory drugs; PCI, percutaneous coronary intervention. Reproduced from Nakamura M, et al.¹⁰

The second step involves validation of the risk score. In this issue of the Journal, Natsuaki et al¹¹ investigate the applicability of the J-HBR in the CREDO-Kyoto Registry Cohort-3. They enrolled as many as 13,258 patients and found that almost 64% of the patients met the J-HBR criteria. The cumulative incidence of bleeding events was approximately 3-fold higher in the J-HBR group than in the no-HBR group (14.0% vs. 4.1% at 1 year, 23.1% vs. 8.4% at 5 years). Thus, the J-HBR has been apparently validated in a contemporary Japanese database. This, in turn, allows Japanese physicians to confidently apply the J-HBR score in daily clinical practice. Furthermore, the focused update of the Japanese guideline proposes an antithrombotic regimen based on the J-HBR criteria (Figure). However, the effect of the regimen on reducing adverse events following PCI should be prospectively surveyed.

Figure.

Antithrombotic regimen based on the Japanese Version of HBR. (Reproduced from Nakamura M, et al.¹⁰) C/P, clopidogrel/prasugrel; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; OAC, oral anticoagulant; SAPT, single antiplatelet therapy.

The third step is increasing the popularity of the J-HBR score. The complicated score includes 19 factors (Table). Furthermore, some scores are considered useful in the decision-making process for patients with multivessel disease, such as SYNTAX,¹² STS,¹³ and Japan SCORE.¹⁴ Other scores also exist in the field of cardiology apart from ischemic heart disease. Most of them are composed of several factors that require some time for calculation. Considering the efforts of the Japanese government in promoting reforms to reduce the working hours of Japanese doctors, the scores should be automatically calculated in the electronic medical records to save physicians some labor.

The fourth step consists of decreasing serious bleeding complications based on a risk score. The practical approach involves shortening the duration of DAPT in patients with HBR. DAPT administered for 1 month, followed by clopidogrel monotherapy reportedly decreases bleeding events without excess ischemic adverse events, compared with that administered for 12 months.⁹ Considering the substantially higher incidence of bleeding outcome measures in the J-HBR group than in the no-HBR group at 30 days (8.6% vs. 2.3%),¹¹ further reduction in the DAPT period to less than 1 month would likely improve the outcomes in patients with HBR. Following PCI, aspirin-free prasugrel monotherapy has been found to be safe and feasible without any stent thrombosis in a relatively small number of patients in the ASET trial.¹⁵ DAPT was prescribed only during the procedure. Thus, further large-scale clinical trials are warranted to confirm the safety and efficacy of the No DAPT strategy after discharge. The current era of focusing on bleeding events seems to promote the No DAPT strategy post-PCI.

Disclosures

K.T. received lecture fees from Abbott Vascular, Boston Scientific, Terumo, Kaneka, Astellas Amgen BioPharma, and Daiichi-Sankyo.

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