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By Nicholas Weight
Clinical Research Fellow in Cardiology, Keele University and University Hospital North Midlands
Introduction
We have an increasingly complex, multimorbid population suffering acute myocardial infarction (AMI)1, frequently presenting with important comorbidities such as moderate or severe chronic kidney disease (CKD)2, active malignancy3 and anaemia4. Therefore, there is a clear need for a rigorous evidence base for us to understand how to safely manage these patients. With increasingly potent antiplatelet regimes5, 6, an increasing number of patients on “triple-therapy” regimes including direct oral anticoagulant therapy (DOAC)7, and advances in contemporary PCI allowing very-low contrast PCI for example8, the AMI population that could theoretically be managed invasively is continually expanding, but there are significant consequences to intervention in the wrong patients, with mortality after major bleeding events being particularly high9. Interventional cardiologists treating these patients frequently must weigh up invasive management and conservative management with medical therapy. This challenging patient group have been referred to as “High-bleeding risk” or “HBR” in the contemporary literature. Historically, patients with HBR features have not been included in clinical trials due to their multimorbidity, therefore there is not the same extensive evidence base available to inform our practice.
To guide this decision making, the Academic Research Consortium (ARC) developed their High-bleeding-risk (HBR) criteria, with patients labelled as HBR being at one-year risk of ≥4% for Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, or ≥1% risk of intracranial haemorrhage (ICH)10. These bleeding risk criteria have built upon previously used bleeding-risk scores such as Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT), which have been used previously to assess bleeding risk with DAPT following PCI for ACS 11. There is discordance between these two post-PCI bleeding risk tools, with a recent study from Lim et al suggesting that PRECISE-DAPT may underestimate bleeding risk in HBR patients12 when compared to the ARC-HBR criteria. With demonstration of the increased sensitivity of the ARC-HBR criteria in identifying major bleeding events compared to PRECISE-DAPT13, the ARC-HBR criteria are now used as the primary post-PCI bleeding risk tool.
The features comprising in the ARC-HBR criteria are summarised below in Table 1:
| Major | Minor |
| Age ≥75 y | |
| Anticipated use of long-term oral anticoagulation | |
| Severe or end-stage CKD (eGFR <30 mL/min) | Moderate CKD (eGFR 30–59 mL/min) |
| Haemoglobin <11 g/dL | Haemoglobin 11–12.9 g/dL for men and 11–11.9 g/dL for women |
| Spontaneous bleeding requiring hospitalization or transfusion in the past 6 months or at any time, if recurrent | Spontaneous bleeding requiring hospitalization or transfusion within the past 12 months not meeting the major criterion |
| Moderate or severe baseline thrombocytopenia (platelet count <100×109/L) | |
| Chronic bleeding diathesis | |
| Liver cirrhosis with portal hypertension | |
| Long-term use of oral NSAIDs or steroids | |
| Active malignancy (excluding nonmelanoma skin cancer) within the past 12 months | |
| Previous spontaneous ICH (at any time) Previous traumatic ICH within the past 12 months Presence of a arterio-venous malformation Moderate or severe ischemic stroke within the past 6 months |
Any ischemic stroke at any time not meeting the major criterion |
| Nondeferrable major surgery on DAPT | |
| Recent major surgery or major trauma within 30 d before PCI |
Table adapted from “Defining High Bleeding Risk in Patients Undergoing Percutaneous Coronary Intervention: A Consensus Document From the Academic Research Consortium for High Bleeding Risk”10
How common is HBR status and what are the features?
The prevalence of HBR features varies significantly across different populations, with a range of studies investigating the prevalence of HBR features having taken place across Europe, North America, Japan and South Korea in recent years. For example, in the Bern PCI registry from Switzerland, HBR status was noted in 39.4% of patients post PCI13. Similarly in the validation of the ARC-HBR criteria in a multicentre US study the prevalence was 44.4% 14, whereas prevalence has typically been lower in studies conducted in Asia, where Kang et al reported a prevalence of 20.4% in the South Korean post-PCI ACS population15. Care must be taken in the interpretation of HBR prevalence trends, given that there are differences in the populations that have been investigated, with cohorts mixed between post-PCI patients with ACS, and PCI populations which are a composite of acute coronary syndrome (ACS) and chronic coronary syndromes (CCS).
Regarding the most common HBR features, Cao et al in their validation of the ARC-HBR criteria in the US population demonstrated that moderate or severe anaemia was the most frequently found major criteria (33%), whereas age over 75 was the most frequently present minor criterion (46.8%)14. Overall, high-bleeding risk features are increasingly common in the ACS population, and this appears to be a particular concern in the North American and European populations.
What are the outcomes of HBR patients following PCI?
It is not surprising that HBR patients are at particularly high-risk of adverse outcomes post-PCI, given the comorbidities that comprise the HBR criteria, and the increased age of the affected patients. What is particularly challenging is that patients with HBR features are at concurrent high-risk of both major-bleeding events, and ischaemic events, presenting a challenge for all interventional cardiologists that manage HBR patients15, therefore it is not necessarily as simple as reducing antiplatelet burden, given the potential consequences of ischaemic events. All-cause and cardiovascular-specific mortality are especially high in the HBR population compared to those without HBR features and is notably higher with increasing numbers of HBR features being present15. Kang et al for example showed in their recent study from an administrative dataset (Korean National Health Insurance Review and Assessment Service database) the significantly higher risk of major-bleeding events ( HR 3.12 (3.04-3.21, P<0.001) and ischaemic events (HR 2.50 (2.45-2.56, P<0.001) and substantially higher-risk of all-cause mortality in HBR patients (HR 3.73, 95% CI 3.66-3.79, P < .001), compared to those without HBR features. Although the prevalence of HBR features may vary across different populations, their poorer outcomes from bleeding, ischaemic events and all-cause mortality is consistently demonstrated 16-19.
How should we manage HBR patients?
Attention in recent years has focussed on the important choice of antiplatelet agents, and the duration of therapy, balancing the dual threats of bleeding and ischaemic events. There is increasing confidence that the conventional 12 months of dual antiplatelet therapy (DAPT) can be shortened, with the significant benefit of reducing long-term bleeding risk, but without associated increases in ischaemic events, but does this necessarily apply to HBR patients?
MASTER-DAPT demonstrated the initial noninferiority of one-month of DAPT compared to at least two-months additional therapy, for their outcomes of net adverse clinical events, major adverse cardiac or cerebral events, with a lower incidence of major bleeding events20. However, this was not a HBR specific population, and given the increased ischaemic risk of HBR patients, were these results generalisable to HBR patients?
Later analyses of the MASTER-DAPT cohort have shed light on this, in the HBR patients included, one month of DAPT was associated with reduced risk of major bleeding and no significant difference in ischaemic events21, results that have been consistent in multiple contemporary trials assessing the safety of shorter courses of DAPT in HBR patients22, 23.
Could the choice of single antiplatelet after an abbreviated course also be an area of improvement? Giacoppo et al in their recent meta-analysis suggest reduced ischaemic events, without an increase in bleeding events in those treated with clopidogrel or ticagrelor rather than aspirin. We must acknowledge that this was not exclusively in HBR patients but is a promising area of future research24, and there will be understandable caution about single therapy with ticagrelor or prasugrel in HBR patients.
Could movement away from stents be a superior approach in the HBR patients? The DEBUT trial initially showed in 2019 that PCI with drug-coated balloons (DCB) was superior to bare-metal stents (BMS) with MACE as their primary outcome 25, but how this compares to contemporary drug-eluting stents is not as clear. What does appear promising is the safety in deescalating to either a short course of DAPT (one month) following DCB angioplasty in ACS26, and there is even a suggestion that discharge with a single antiplatelet agent could be considered in patients post-DCB angioplasty27. It must be considered that that the safety of the one-month of DAPT post-DCB PCI in ACS was not demonstrated in an entirely HBR population, with a cohort that was approximately 20% with HBR features, but there is a clear shift in practice towards shorter courses of DAPT in HBR patients over recent years.
What does the future hold for the management of HBR patients?
Treatment of HBR patients will evolve to individualised therapy according to specific HBR features, considering that HBR patients are a heterogenous group, comprising older, highly multimorbid patients, alongside younger patients with active malignancy for example, reflected in the most recent ESC guidelines for ACS in 202328 in their “High-Bleeding Risk” subsection. Management of HBR patients will likely evolve to include shorter DAPT duration, potentially incorporating increasing DCB usage where appropriate, However, there must be consideration that invasive management and potent antiplatelet regimes are not suitable for all presenting ACS patients, especially those of advanced age and frailty such as the SENIOR-RITA cohort29, and there remains an important role for conservative, medical management in the most frail HBR patients.
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