Academic Research Consortium Definition of High Bleeding Risk in Clinical Practice　― Validation and Beyond ―

Since the advent of percutaneous coronary intervention (PCI), a delicate balance has existed between bleeding complications and ischemic events, such as myocardial infarction and stent thrombosis. Significant advances in medical therapy (e.g., statin and dual antiplatelet therapy) and device technology (e.g., new-generation drug-eluting stents and intracoronary imaging) have contributed to a reduced risk of ischemic events in patients with coronary artery disease undergoing PCI,¹ whereas the rate of bleeding events has been unchanged or even increased over the past 2 decades.² Both ischemic and bleeding events have a similar effect on subsequent mortality after PCI,³ and clinical investigations in recent years have focused on bleeding risks as well as ischemic events. In 2019, the Academic Research Consortium (ARC) proposed a set of high bleeding risk (HBR) criteria to promote consistency across trials evaluating this vulnerable subset of patients.⁴ The ARC-HBR criteria were not necessarily developed as a clinical decision support tool, but rather to simplify comparisons between trials. This multistakeholder expert consensus document arbitrarily defined HBR as an estimated risk of Bleeding Academic Research Consortium (BARC) Type 3 or 5 ≥4% or a risk of intracranial hemorrhage ≥1% at 1 year.⁴ Thereafter, several studies have addressed the applicability and validity of the ARC-HBR criteria in clinical practice.^5–11

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Validation of ARC-HBR Criteria

Table lists large-scale international and Japanese clinical studies validating the ARC-HBR. Overall, these studies consistently showed that the ARC-HBR consensus definition was able to identify patients with a high and low bleeding risk. In this issue of the Journal, Miura et al add important findings to this literature.¹² Their single-center retrospective analysis included 3,453 patients who underwent second-generation coronary drug-eluting stent implantation, of whom 53.3% were found to be HBR. Notably, HBR in that study was determined retrospectively using the original ARC-HBR criteria, despite the potential for underestimation. Because only 1 study has evaluated the discriminative accuracy of the complete ARC-HBR criteria so far (Table),⁵ this is an important point. At 1 year, patients with HBR had an increased risk of major bleeding (BARC 3 or 5) than those without HBR (3.6% vs. 0.5%; P<0.001).¹² Probably because of the study design, the bleeding event rates appear low compared with previous studies despite the long-term use of dual antiplatelet therapy. Nevertheless, the diagnostic ability of the ARC-HBR criteria for 1-year bleeds, assessed by Miura et al using the C-index, was consistent with other studies. Therefore, the study of Miura et al reinforces the applicability of the ARC-HBR criteria in real-world clinical practice in Japan.

Table. Key Clinical Studies Validating the ARC-HBR Criteria

Study	Design	Sample size	ARC-HBR definition	HBR rate (%)	Bleeding definition	Bleeding rates in HBR vs. non-HBR patients at 1 year (%)	C-index (95% CI)B
International studies
Bern PCI registry5	Prospective, single center	16,580	Original	34.7	BARC 3 or 5	7.9 vs. 2.5	0.68 (0.66–0.70)
Bern PCI registry6	Prospective, single center	12,121	Modified	39.4	BARC 3 or 5	6.4 vs. 1.9	0.69 (0.66–0.71)
XIENCE PMS7	Prospective, international PMS	10,502	Modified	33.4	GUSTO or TIMI major bleeding	4.3 vs. 1.3	NR
Mount Sinai registry8	Prospective, single center	9,623	Modified	44.4	Study specificA	9.1 vs. 3.2	0.68 (0.65–0.71)
Studies in Japan
CREDO-Kyoto9	Prospective, multicenter	13,058	Modified	42.7	GUSTO moderate/severe	10.4 vs. 3.4	NR
PENDULUM10	Prospective, multicenter	6,267	Modified	50.8	BARC 3 or 5	4.2 vs. 1.4	0.68 (0.64–0.72)
PRASFIT-Practice II11	Prospective, multicenter PMS	4,155	Modified	40.1	TIMI major/minor	3.4 vs. 1.3	NR
Kurashiki Central Registry12	Retrospective, single center	3,453	Original	53.3	BARC 3 or 5	3.6 vs. 0.5	0.68

^APeri-procedural National Cardiovascular Data Registry (NCDR) CathPCI Registry bleeding or post-discharge bleeding requiring either hospitalization or blood transfusion. ^BC-index for predicting 1-year bleeding events. ARC-HBR, Academic Research Consortium for High Bleeding Risk; BARC, Bleeding Academic Research Consortium; CI, confidence interval; GUSTO, Global Utilization of Streptokinase and Tissue-plasminogen activator for Occluded coronary arteries; HBR, high bleeding risk; NR, not reported; PCI, percutaneous coronary intervention; PMS, post-market surveillance; TIMI, Thrombolysis in Myocardial Infarction.

Beyond Validation of ARC-HBR Criteria

Miura et al should be commended for further addressing the diagnostic ability of the ARC-HBR criteria for long-term bleeds. Although some of the studies listed in Table evaluated clinical outcomes for 2–5 years,^7,9,11 Miura et al showed that the ARC-HBR criteria were significantly associated with a risk of bleeding events beyond 4 years and up to 7 years after PCI (mean follow-up period 7.5 years).¹² Recently, the same group reported in Circulation Journal that 6 of 17 ARC-HBR criteria were infrequently observed and so the ARC-HBR criteria could be abbreviated without impairing diagnostic ability.¹³ Even though a smartphone application has been developed for calculation of a bleeding risk score,³ the original 17 components of the ARC-HBR may be too many for daily practice. Thus, the attempt to simplify the scoring system may have a clinical impact. Conversely, the recently updated guidelines of the Japanese Circulation Society have added several Japanese-specific factors associated with HBR, such as low body weight, frailty, heart failure, and peripheral artery disease, and have developed a Japanese version of the HBR.¹⁴ The CREDO-Kyoto Registry Cohort-3 confirmed that the Japanese version of the HBR successfully identified patients at HBR after PCI, with higher sensitivity and lower specificity than the original ARC-HBR criteria.¹⁴ Furthermore, a recent report proposed the ARC-HBR “trade-off” model, in which mortality-weighted ischemic and bleeding risks were taken into account.¹⁵ Most importantly, because patients undergoing PCI have high ischemic and bleeding risks, as shown in the study of Miura et al¹² (the rates of ischemic and bleeding events were comparable), both should be carefully evaluated.

The ARC-HBR criteria have been established to have moderate discriminative accuracy for short-term bleeding events, and several approaches, including simplification, adjustment according to racial difference, the prediction of long-term clinical outcomes, and a “trade-off” model, have been reported. The ultimate goal is to demonstrate that clinical practice guided by the ARC-HBR or other predictive models improves patient care and clinical outcomes.

Disclosures

Y.K. has received lecture fees from Abbott Medical Japan, Bayer Japan, Bristol-Myers Squibb, Boehringer Ingelheim, and Daiichi-Sankyo, as well as scholarship funds from Takeda Pharmaceutical, Abbott Medical Japan, Terumo, Otsuka Pharmaceutical, Boehringer Ingelheim, Astellas, Daiichi-Sankyo, Win International, Japan Lifeline, and Nipro. Y.S. has no conflicts of interest to declare.

References

• 1.   Saito Y, Kobayashi Y. Contemporary coronary drug-eluting and coated stents: A mini-review. Cardiovasc Interv Ther 2021; 36: 20–22.
• 2.   Simonsson M, Wallentin L, Alfredsson J, Erlinge D, Hellström Ängerud K, Hofmann R, et al. Temporal trends in bleeding events in acute myocardial infarction: Insights from the SWEDEHEART registry. Eur Heart J 2020; 41: 833–843.
• 3.   Saito Y, Kobayashi Y, Tanabe K, Ikari Y. Antithrombotic therapy after percutaneous coronary intervention from the Japanese perspective. Cardiovasc Interv Ther 2020; 35: 19–29.
• 4.   Urban P, Mehran R, Colleran R, Angiolillo DJ, Byrne RA, Capodanno D, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: A consensus document from the Academic Research Consortium for High Bleeding Risk. Eur Heart J 2019; 40: 2632–2653.
• 5.   Corpataux N, Spirito A, Gragnano F, Vaisnora L, Galea R, Svab S, et al. Validation of high bleeding risk criteria and definition as proposed by the academic research consortium for high bleeding risk. Eur Heart J 2020; 41: 3743–3749.
• 6.   Ueki Y, Bär S, Losdat S, Otsuka T, Zanchin C, Zanchin T, et al. Validation of the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria in patients undergoing percutaneous coronary intervention and comparison with contemporary bleeding risk scores. EuroIntervention 2020; 16: 371–379.
• 7.   Sorrentino S, Claessen BE, Chandiramani R, Guedeney P, Vogel B, Baber U, et al. Long-term safety and efficacy of durable polymer cobalt-chromium everolimus-eluting stents in patients at high bleeding risk: A patient-level stratified analysis from four postapproval studies. Circulation 2020; 141: 891–901.
• 8.   Cao D, Mehran R, Dangas G, Baber U, Sartori S, Chandiramani R, et al. Validation of the Academic Research Consortium High Bleeding Risk Definition in contemporary PCI patients. J Am Coll Cardiol 2020; 75: 2711–2722.
• 9.   Natsuaki M, Morimoto T, Shiomi H, Yamaji K, Watanabe H, Shizuta S, et al. Application of the Academic Research Consortium High Bleeding Risk Criteria in an all-comers registry of percutaneous coronary intervention. Circ Cardiovasc Interv 2019; 12: e008307.
• 10.   Nakamura M, Kadota K, Nakao K, Nakagawa Y, Shite J, Yokoi H, et al. High bleeding risk and clinical outcomes in East Asian patients undergoing percutaneous coronary intervention: The PENDULUM Registry. EuroIntervention 2021; 16: 1154–1162.
• 11.   Nakamura M, Kitazono T, Kozuma K, Sekine T, Nakamura S, Shiosakai K, et al. Prasugrel for Japanese patients with ischemic heart disease in long-term clinical practice (PRASFIT-Practice II): Final 2-year follow-up results of a postmarketing observational study. Circ J 2020; 84: 1981–1989.
• 12.   Miura K, Shima Y, Okabe K, Taguchi Y, Ikuta A, Takahashi K, et al. Academic research consortium for high bleeding risk definitions for early, late, and very late bleeding events. Circ J 2021; 85: 797–805.
• 13.   Miura K, Shimada T, Ohya M, Murai R, Amano H, Kubo S, et al. Prevalence of the Academic Research Consortium for High Bleeding Risk criteria and prognostic value of a simplified definition. Circ J 2020; 84: 1560–1567.
• 14.   Natsuaki M, Morimoto T, Shiomi H, Ehara N, Taniguchi R, Tamura T, et al; on behalf of the CREDO-Kyoto PCI/CABG Registry Cohort-3 Investigators. Application of the modified high bleeding risk criteria for Japanese patients in an all-comers registry of percutaneous coronary intervention: From the CREDO-Kyoto Registry Cohort-3. Circ J 2021; 85: 769–781.
• 15.   Urban P, Gregson J, Owen R, Mehran R, Windecker S, Valgimigli M, et al. Assessing the risks of bleeding vs thrombotic events in patients at high bleeding risk after coronary stent implantation: The ARC-high bleeding risk trade-off model. JAMA Cardiol 2021; 6: 410–419.