Treatment inequity in antiplatelet therapy for ischaemic heart disease in patients with advanced chronic kidney disease: releasing the evidence vacuum

Abstract Chronic kidney disease (CKD) is a global health problem and an independent risk factor for cardiovascular morbidity and mortality. Despite evidence-based therapies significantly improving cardiovascular mortality outcomes in the general population and those with non-dialysis-dependent CKD, this risk reduction has not translated to patients with end-stage kidney disease (ESKD). Absent from all major antiplatelet trials, this has led to insufficient safety data for P2Y12 inhibitor prescriptions and treatment inequity in this subpopulation. This review article presents an overview of the progression of research in understanding antiplatelet therapy for ischaemic heart disease in patients with advanced CKD (defined as eGFR <30 mL/min/1.73 m2). Beyond trial recruitment strategies, new approaches should focus on registry documentation by CKD stage, risk stratification with biomarkers associated with inflammation and haemorrhage and building a knowledge base on optimal duration of dual and single antiplatelet therapies. Plain Language Summary What is the context? Patients with kidney disease are more likely to experience a heart attack than those without. Those with advanced kidney disease have a higher risk of death following a heart attack. Over the past two decades, advances in treatment following a heart attack have reduced the risk of death, however this has not translated to those with advanced kidney disease. Progression of kidney disease influences antiplatelet (e.g. clopidogrel) treatment efficacy. What is new? This contemporary review analyses registry and trial data to highlight some of the issues surrounding treatment inequity in patients with advanced kidney disease. This article describes potential mechanisms by which progression of kidney disease can influence clotting, bleeding and antiplatelet treatments. What is the impact? Further research into antiplatelet therapy for patients with advanced kidney disease is required. Registry and trial data can improve upon classification of kidney disease for future research. Future trials in antiplatelet therapy for advanced kidney disease are anticipated.


Introduction
Chronic kidney disease (CKD) is a major health problem worldwide and an independent risk factor for cardiovascular morbidity and mortality [1].The 2015 global census accredited 8.92 million deaths to ischaemic heart disease (IHD) and 1.2 million to CKD [2].Associated with an accelerated disease course, these figures do not reflect the significant proportion of deaths from IHD underpinned by CKD [3].The incidence estimates suggest 12 ,000 excess myocardial infarctions (MIs) occurred in CKD patients in England (2009-2010) compared to the incidence of MI in age-and gender-matched controls without CKD [4].This incurred estimated costs of £174-178 million [4].With CKD progression, it is estimated that 70% of patients have significant coronary atherosclerosis and 40% have symptomatic IHD or heart failure by the time of dialysis [5].Registry data of 289,699 cases of acute MI reported that a proportionally higher percentage (79%) of dialysis-treated MI patients presented with non-ST-segment elevation MI (NSTEMI) and only 21% presented with ST-segmentelevation MI (STEMI) [6].While the greatest proportion of sudden cardiac death relates to non-atherosclerotic disease in dialysis patients [7], patients on dialysis who have an MI have twice the risk of death over the general dialysis population, and this risk has remained unchanged for more than a decade [6].This is in stark contrast to patients experiencing MI who are not on dialysis, where there has been an impressive 3-to 5-fold reduction in risk of death over the same period [6].Furthermore, while 1-year mortality following MI on dialysis has improved from ≈60% to 41%, this does not appear to correlate with advances in evidence-based therapies for managing acute coronary syndromes (ACS) [6].This vast disparity in treatment outcomes for patients with advanced CKD suggests a historically neglected research population.
Recently updated, the European Society of Cardiology (ESC) guidelines [8] on management of non-ST-segmentelevation ACS subheads CKD within special populations and highlights insufficient safety data for P2Y 12 inhibitor prescription in those with end-stage kidney disease (ESKD), defined when estimated glomerular filtration rate (eGFR), an index of kidney function, is less than 15 mL/min/1.73m 2 .Contemporary reviews of P2Y 12 inhibition within the CKD subgroup demonstrate inequity through the absence of robust evidence due to underrepresentation or exclusion from the informing clinical trials [3].Previous data have questioned the increased risk of harm, through bleeding, with more potent P2Y 12 inhibitors with advanced CKD [3] when eGFR is <30 mL/min/1.73m 2 .However, these statements are based on lower-grade evidence and neglect to consider individualised risk stratification of bleeding and thrombotic risks.Some risk scores predicting bleeding risk with dual antiplatelet therapy (DAPT) include renal function [9,29], but none has been validated for patients with advanced CKD.
A recent systematic review and meta-analysis comprising small trials and observational data suggest that prasugrel and ticagrelor can provide beneficial clinical outcomes compared to clopidogrel with no significant increase in major bleeding events [10].While both offer dose adjustments, these have yet to be fully evaluated in advanced CKD [11][12][13].The reduced efficacy of clopidogrel in this cohort is well substantiated and is associated with poor clinical outcomes [10,[14][15][16].Contemporary trials are boosting efforts to understand treatments in this subpopulation [17][18][19][20].Outcomes of the forthcoming TROUPER trial [17] ticagrelor or clopidogrel in severe CKD patients (eGFR <30 ml/ min/1.73m 2 or chronic dialysis) undergoing percutaneous coronary intervention (PCI) for ACS -are eagerly anticipated.

Aims and objectives
This review article provides an overview of antiplatelet agents in advanced CKD with an overarching aim to highlight areas for future research.This is not a comprehensive systematic review of each topic area and is therefore limited in this regard.Evidence readily informing ESC guidelines in the management of ACSs [8] is included.Additional literature search terms were performed on PubMed to include 'advanced CKD', 'hemodialysis', 'dialysis', 'end stage kidney disease', 'end stage renal disease' and 'peritoneal dialysis', pertaining to each of the objectives.This article provides a snapshot of advanced CKD across the following areas: (1) How is advanced CKD represented within ACS registries?
(2) Consideration of mechanisms within CKD that increase bleeding and thrombotic risk (3) Representation of advanced CKD within major clinical trials and selection of antiplatelet regimen (4) How relevant are bleeding and thrombotic risk scores in advanced CKD?I displays a subset of registries for ACS available across the globe.Spanning nearly two decades, publications evaluating patients with advanced CKD were analysed.Those without advanced CKD data were excluded.These indicate a high prevalence of CKD within the ACS population.The proportion with at least moderate CKD (eGFR <60 ml/min/1.73m 2 ) ranges from 30% to 43% in the United States [11], 23% in Malaysia [28], 20% in Australia [29], 40% in Taiwan [30] and 33% in Sweden [24].The proportion with advanced CKD (CKD stage 4 or 5; eGFR <30 ml/min/1.73m 2 ) ranges from 13.4-14.5% in CRUSADE and GRACE registries [21,23] to 6.6% in SWEDEHEART [24].

Advanced CKD within ACS registries
Strong correlations exist between advancing CKD, recurrent thrombotic events and major bleeding events.Subgroup analysis from the PEGASUS-TIMI-54 trial showed independent, inverse and graded relationships between eGFR and ischaemic risk [33].A literature review of 43 000 dialysis patients from the US Renal Database System (USRDS) showed heterogeneity, with in-hospital mortality outcomes following a STEMI, reported as 26% in ESKD patients on dialysis compared to 4-8% in patients not receiving dialysis [34].Even those perceived to have relatively preserved kidney function with stage 3 CKD (eGFR 30-59 ml/min/1.73m 2 ) have a substantially increased risk of cardiovascular mortality.In patients with CKD stage 3 or 4 (eGFR range 15-59 ml/min/1.73m 2 ), 35-50% [5] of Treatment inequity in antiplatelet therapy 5 mortality is ascribed to CVD, three times that of patients with eGFR >90 ml/min/1.73m 2 .An analysis of >100 000 patients with CKD demonstrated the hazard for cardiovascular mortality increases exponentially by CKD stage [1] (adjHR 5.39 (CI 3.30-8.80)for eGFR 15-29 ml/min/1.73m 2 compared to eGFR ≥90 ml/min/1.73m 2 ).Reinfarction, ventricular tachycardia, ventricular fibrillation and cardiac arrest are nearly three times more likely in those with eGFR <60 mL/min/1.73m 2 versus those without [24].Outcomes from the PLATO trial also showed that, for every 5 mL/min reduction in creatinine clearance (CrCl), relative increases in total mortality rates were 19%, MI 8% and major bleeding 4% (all P < .001)[35].
Observational studies suggest a 10 ml decrease in CrCl has a similar adverse impact to a 10-year advancement in age [21].Notwithstanding the unmitigated proportional risk attributed to pathophysiological processes, there remains considerable potential to improve outcomes post-ACS, with targeted therapeutics in advanced CKD.

Antiplatelet options for ACS in advanced CKD
Not only is CKD an independent predictor of death and further cardiovascular events [3,36], but also it additionally is associated with increased health-care costs per event.For example, the estimated cost of stay of a patient with ACS and ESKD receiving haemodialysis (HD) is approximately 1.6 times that of patients without CKD and 1.3 times higher than non-dialysis -dependent kidney disease (NDDKD) [34].Prescription of evidence-based medications, timing of revascularisation and selection for reperfusion or medical therapy are less predictable in this population.Despite limitations in delineation of CKD patients, registry data globally demonstrate wide variation in clinical practice and outcomes in ACS management (Table I) [21,23,24,29,31,32].Lower prescriptions for evidencebased medications in advanced CKD reportedly relate to concerns about drug toxicity, deterioration in renal function, bleeding and overall paucity in the evidence base [11,24,28,37,38].Historical failure of registry datasets to capture CKD stage has also missed trends in antithrombotic prescriptions in advanced diseases.The proportion of dialysis patients prescribed DAPT following MI in 2012/13 reflects clinical practice from 10 years earlier in patients not receiving dialysis [6].Furthermore, historically found in 40-55% [13], studies reporting in-hospital bleeding complications often neglect to consider the impact of overdosing in patients with eGFR <30 ml/min/1.73m 2 , with co-prescription of intravenous antiplatelets (i.e.glycoprotein IIa/IIIb inhibitors) during PCI.
Efficacy of DAPT with aspirin and clopidogrel is affected by CKD progression [10,25,38].Recognition of the pharmacological challenges in managing antiplatelet therapy in advanced CKD is growing [3,10].This demands awareness of the pharmacodynamics and pharmacokinetics of P2Y 12 inhibitors in this subgroup.Circulating platelet volume, reactivity and plasma constituents involved in platelet aggregation, coagulation and fibrinolysis all contribute to bleeding and thrombotic risks.Therapeutic targets of antiplatelets, as illustrated in Figure 1, include platelet activation via adenosine diphosphate (ADP)mediated activation of the P2Y 12 receptor, cyclooxygenase (COX)-1-mediated production of thromboxane A 2 (TXA 2 ) and thrombin-mediated activation of protease-activated receptor (PAR)-1 and PAR-4 [39][40][41].However, the safety profile of vorapaxar, in particular regarding the increased risk of ICH, leaves PAR-1 as an unattractive target [42], especially given higher bleeding risks associated with advanced CKD.
Aspirin therapy has proven benefit in secondary prevention of established ACS, with reported absolute risk reductions of 38 per 1000 patients treated for -month post-acute MI [44].However, the CKD subgroup is not well evidenced in this analysis.Aspirin is a non-selective, irreversible inhibitor of COX-1 (antiplatelet) and, less sensitively, COX-2 (anti-inflammatory) enzymes.Oral bioavailability is 30-40% and peak plasma levels occur 30-40 min after ingestion of plain or dispersible aspirin [45] (or 3-4 h for enteric-coated formulations).Inactivation of COX-1 inhibits the formation and release of TXA 2 , a platelet activator and vasoconstrictor, and this effect lasts for the lifespan of the platelet.The mean lifespan of the human platelet is around 7-10 days.As approximately 10% of the platelet pool is replenished per day, once-daily dosing should be sufficient to maintain almost complete inhibition [45].However, the plasma half-life is short with differential exposure to platelet and systemic endothelium, leading to inconsistent efficacy in groups with accelerated platelet Figure 1.Graphical abstract of platelet activation pathways and mechanism of action of antiplatelet and antithrombotic therapies.Adapted from and reproduced with permission from Storey, 2006 [43].
turnover [46].This can be improved with twice-daily dosing [46].In those with enhanced inflammatory state, such as end-stage CKD, platelet turnover is demonstrably higher [47], but the efficacy of twice-daily dosing has yet to be evaluated in this setting.
Although aspirin is a recommended option for secondary prevention, primary prevention studies of aspirin in non-end-stage CKD showed no clear benefit, with a statistically significant doubling of major bleeding and progressive renal dysfunction [48].Hence, despite impairment of haemostasis, COX-1 inhibition in this cohort was insufficient in primary prevention of thrombotic events.HD patients were not well represented in this meta-analysis, and only studies evaluating the patency of dialysis access were included [48].Smaller studies have shown pharmacodynamic variation in aspirin response in CKD [49].One crosssectional study [49] (N = 116) demonstrated impaired response to aspirin with higher on-treatment TXA 2 levels indicative of high on-treatment platelet reactivity (HTPR) in patients with eGFR <60 ml/min/1.73m 2 .As an NSAID, aspirin is also potentially nephrotoxic, and even doses of 75 mg OD have shown a small, but significant, reduction in serum creatinine, which is resolved after cessation of therapy [50].Additionally, it has been noted to have pro-inflammatory properties in a human endotoxaemia model, in contrast to the anti-inflammatory effects of P2Y 12 inhibition [51].Further assessment of aspirin dosing and efficacy in moderate and severe CKD is required [52][53][54].Trends, however, are shifting toward the benefits of single antiplatelet therapy (SAPT) with P2Y 12 inhibitor monotherapy.The TWILIGHT-CKD subgroup analysis suggested that ticagrelor monotherapy leads to a lower incidence of bleeding compared with DAPT in patients with CKD without necessarily increasing the risk of cardiovascular events although the analysis was underpowered to provide robust evidence on this [55,56].Larger trials for monotherapy with a more potent P2Y 12 inhibitor in dialysisdependent and advanced CKD are required.
Clopidogrel is a second-generation thienopyridine prodrug requiring intestinal absorption and metabolisation by liver enzymes to produce an active metabolite that binds irreversibly to the P2Y 12 receptor for the life of the platelet [57].Renal dysfunction significantly suppresses biotransformation, and genetic variation in absorption and cytochrome P450 (CYP) polymorphism leads to unpredictable variations in the on-treatment platelet reactivity [14,15].Table II shows a subset of pharmacodynamic and pharmacokinetic studies within advanced CKD across the globe to include a meta-analysis (N = 10) evaluating the prevalence of HTPR in CKD patients treated with clopidogrel, linked to poorer clinical outcomes [14].HTPR with clopidogrel is reportedly up to 84% with advanced CKD [58].This exceeds estimates of 30% within the general population [59,61,64].Consistent evidence of poor response across a variety of research studies [14,15,52,59,61] has fuelled exploration of the safety and efficacy of newer P2Y 12 inhibitors in advanced CKD.The timely TROUPER trial -clopidogrel compared with ticagrelor following PCI in ACS [17] -is a step towards closing treatment disparities within this subgroup.
Prasugrel is a newer prodrug, with significantly enhanced potency in reduction of platelet activation compared to clopidogrel.Rapidly hydrolysed by intestinal hydroxyesterases followed by CYP bioactivation, maximum plasma concentration of the active metabolite is reached at 30-60 min [65].Like clopidogrel, this third-generation thienopyridine blocks ADP binding to the P2Y 12 receptor irreversibly and effectively reduces multiple aspects of platelet activation and associated responses [66].Maximum effect of platelet inhibition after loading with 60 mg prasugrel is seen at 1 h compared to clopidogrel where maximum effects of a 300 mg loading dose are seen at >6 h and 600 mg at 2-4 h [65,67].Furthermore, small studies suggest that low-dose prasugrel, as well as clopidogrel, demonstrates a reduction in platelet inhibition post-HD (mean P2Y 12 reaction units >208), which requires further exploration [63].
Ticagrelor is a cyclopentyl triazolopyrimidine, or nucleoside analogue, that is bound 99.8% to plasma proteins and does not require metabolic activation [68].Median time to maximum platelet inhibition is 2 h with declining plasma concentration at ~12 h, requiring twice-daily dosing [57].Compared to clopidogrel, ticagrelor has shown more consistent P2Y 12 inhibition, with a lower proportion of HTPR [69] and the lowest proportion of non-responders, reportedly ≈10% on dialysis [52] and 0% with NDDKD [15].Pharmacokinetic and pharmacodynamic data suggest that, unlike clopidogrel and prasugrel, ticagrelor's platelet inhibition response remains unchanged during HD [62].
Significantly higher risks of MACE, MI and stent thrombosis are associated with 'non-responders' or HTPR (identified by either light transmission aggregometry, VerifyNow P2Y 12 and/or vasodilator-stimulated phosphoprotein phosphorylation assays), as reported in a meta-analyses of 10 studies in advanced CKD [14].Personalised antiplatelet therapy through genotyping to predict clopidogrel poor metabolisers and guide selective treatment with clopidogrel instead of ticagrelor or prasugrel was shown to be non-inferior to standard therapy with ticagrelor or prasugrel in reducing risk of MACE but did lower bleeding risk [70].Only 10% of this sample was represented by advanced CKD and subgroup analysis of this cohort was not reported.Proportionately fewer (3%) were included in TROPICAL-ACS [60], which was also non-inferior for guided de-escalation of prasugrel therapy by platelet-function testing.Most of the dedicated trials for platelet function testing failed to meet end-points [60] and the disproportionately low recruitment of advanced CKD undermines applicability for this cohort.Despite this, a role for platelet-function testing in those with either 'on-treatment stent thrombosis', or 'recent PCI on DAPT requiring cardiac or non-cardiac surgery' remains [60].It should be noted that low haematocrit in patients with CKD may affect results obtained with the VerifyNow P2Y 12 assay [71] and the optimal pharmacodynamic assay in advanced CKD patients remains to be established [72].

Bleeding risk on antiplatelet therapy in advanced CKD
Bleeding complications are higher in CKD compared to the general population.This has implications for antiplatelet therapy.A large observational study [73] reported a 1.6-fold (95% CI 1.2-2.2) increased risk of bleeding during antiplatelet therapy if diagnosed with CKD (defined as eGFR <60 mL/min/1.73m 2 or albuminuria) relative to the non-CKD population [73].In the CKD population, the majority of bleeding events (62%, N = 172) were unspecified nonintervention-related, followed by 30% (N = 83) interventionrelated and 6.6% (N = 18) due to ruptured abdominal aneurysm [73].These figures can be criticised for lack of risk stratification by stage since bleeding rates have been shown to increase with CKD progression.Clinically significant haemorrhage rates (of various aetiology) in ESKD reportedly range from 2.1 to 16.1 per 100 person-years [74].The adjusted hazard ratio (HR, inclusive of aspirin use) for upper gastrointestinal bleeding in HD patients is increased to 1.27 (95% CI 1.03-1.57)compared to a population without CKD [75], with the risk of upper gastrointestinal bleeding in ESKD more than 3.5-fold higher than those with CKD stage 3 [76].The interactions between bleeding, atherothrombosis and CKD are illustrated in Figure 2. Treatment inequity in antiplatelet therapy 9

Advanced CKD in antiplatelet trials
Table III describes the distribution of CKD populations within the major trials over the past 20 years.Treatment inequalities have manifest because advanced CKD is poorly ascribed within these trials.Recruitment of patients with eGFR <60 mL/min/1.73m 2 has historically comprised <25% across all major trials [3].Developing robust generalised findings for DAPT/SAPT in this cohort is paramount.Few trials segregate CKD by disease stage, dichotomising as 'non-CKD' and 'CKD' for eGFR ≥60 and <60 ml/min/1.73m 2 , respectively.Evidence is heavily reliant upon subgroup analyses.Recent head-to-head trial evaluation of more potent P2Y 12 inhibitors in ISAR-REACT-5 [20,82] also did not stratify CKD further than eGFR <60 mL/min/1.73m 2 (N = 760/ 4012 [18.9%]), and ESKD was excluded.While a reduction in eGFR was associated with increased bleeding and ischaemic events, it was concluded that this had no significant impact on the relative benefit of a prasugrel-based strategy on the primary end point of death, MI or stroke compared to a ticagrelor-based strategy (HR 1.47 [1.04-2.08])with no significant difference in bleeding risk [82].PEGASUS-TIMI-54 CKD subgroup analysis (CrCl <60 ml/min = 23.2%,N = 4849) demonstrated a more marked relative MACE risk reduction with ticagrelor (with aspirin) in those with eGFR <60 ml/min/1.73m 2 [RR 0.72, 95% CI 0.59-0.89]compared to those with eGFR ≥60 ml/ min/1.73m 2 [RR 0.83, 95% CI 0.72-0.96][33], although the interaction P value for this subgroup analysis was not significant.In contrast to PEGASUS-TIMI-54, POPular AGE, comprising 37% (N = 377) with eGFR <60 ml/min/1.73m 2 , found clopidogrel and aspirin to be non-inferior to ticagrelor and aspirin in the older population (>70 years) following NSTEMI with fewer BARC 3 and 5 bleeding events [18].These findings, however, are underpowered and any relationship to advanced CKD remains unclear.Further head-to-head comparisons of DAPT in advanced CKD are awaited [17].

Bleeding and thrombotic risk scores for ACS treatment in advanced CKD
Scores aimed at balancing the ischaemic and bleeding risks with DAPT prescription [83,84] are not robustly validated for patients with advanced CKD.The DAPT risk score was developed in a population treated with aspirin and clopidogrel with a low prevalence of CKD (15.8%) and validated with even fewer (7.7%) [83].This sample is not representative of registry demographics, has no relationship to more potent P2Y 12 inhibitors and does not consider dynamic changes in renal function or duration of DAPT.PRECISE-DAPT [85] was developed to address some of these issues by integrating dynamic variation in renal function.This score utilises haemoglobin (g/dL), age (years), white blood cells (10 9 /L), creatinine clearance (mL/ min) and prior bleeding.Derived from eight trials (N = 14 963), with median CrCl = 79.1 mL/min (range 60.8-98.0mL/ min), 44.4% had stable CAD undergoing PCI and the remainder ACS.It was validated in two cohorts, the PLATO trial (N = 8595) and the BernPCI registry 2009-2014 (N = 6172).CKD however is neither stratified by stage nor highly proportioned in either of these populations.PLATO participants with CrCl <60 mL/min comprised 21% of those with baseline measurements with median CrCl in the overall population of 84.6 mL/ min (67.3-102.9mL/min) and a similar median CrCl of 87.6 mL/min (range 65.4-105.4mL/min) within the BernPCI registry [85].The absence of categorisation of renal function means neither validation dataset includes an ac c urately observed risk relationship with progressive renal dysfunction.Failure to capture advanced CKD means that PRECISE-DAPT risk scores can therefore be criticised for extrapolating risk percentages for such cases [83].Pooled analysis of individual patient data could enhance validation of current risk tools; however, historically poor labeling, disproportionately low enrollment, and lack of dynamic renal assessment in advanced CKD are restrictive.Treatment inequity in antiplatelet therapy 11 Absent from current antiplatelet risk scores is urine albumin-to -creatinine (uACR) ratio.uACR is increasingly evidenced as an important distinguishing factor when risk profiling for CVD [86].In patients with uACR >1.1 mg/mmol (>10 mg/g), cardiovascular mortality increases independent of CKD stage, with proportionately higher risk depending on progression of CKD and uACR [1].Even in those with eGFR >90 ml/min/1.73m 2 , the presence of uACR 1.1-3.3mg/mmol (10-29 mg/g) conferred an adjusted HR for cardiovascular mortality of 1.63 (CI 1. 20-2.19) [1].These figures increase exponentially with deteriorating renal function [1].Importantly, bleeding risk is also increased with albuminuria regardless of CKD stage [73].Monitoring uACR is recommended for diabetic patients and those with eGFR <60 ml/min/1.73m 2 or suspected CKD [4].Despite therapeutic implications, in-patient testing is not routinely recommended in comparison to other risk markers, such as lipid profile and HbA1c [8,87].In-patient testing of uACR for secondary prevention of CVD in advanced CKD offers prognostic potential if utilised in targeting treatment strategies.
High-sensitivity troponin T is an additional risk biomarker, associated with a 2-to 5-fold increased risk of death in otherwise stable patients with ESKD [88,89], with further prognostic value in interval monitoring if receiving peritoneal dialysis treatment [90].C-reactive protein has also been shown to be an independent predictor of death in patients receiving HD [91] and peritoneal dialysis [90] after adjusting for confounders.The utility of highsensitivity CRP, as a measure of low-grade inflammation, did not show a strong predictive performance for all-cause mortality and MACE regardless of CKD stage in a large East Asian cohort [92].Geographical and ethnic variations may, however, contribute to the lower cardiovascular event rate observed in this observational study [92].Growth differentiation factor-15 (GDF15) is also associated with inflammatory conditions and prediction of major bleeding and cardiovascular events [93].Levels are significantly higher in patients with ESKD and CVD and further associated with dialysis vintage [22].The relationships between duration of DAPT, uACR, troponin and inflammatory markers, on the one hand, and bleeding and thrombotic outcomes on the other have yet to be explored.
The utility of platelet-function testing for individualisation of DAPT in HD patients with bleeding (or concerns for bleeding, such as severe anaemia) is also worth exploring, particularly as bleeding risk scores such as HAS-BLED, ATRIA, HEMORR2HAGES and ORBIT for those requiring concurrent anticoagulants have poor predictive abilities [74] and the DAPT and PRECISE-DAPT scores have yet to be validated for dialysis patients [83].An alternative strategy for de-escalation warranting further exploration is the withdrawal of aspirin and the use of ticagrelor monotherapy in DAPT-treated patients with advanced CKD and high bleeding risk.

Conclusion
This review presents an overview of advanced CKD within the ACS population.Although not exhaustive, search criteria incorporated studies targeting this sub-population to evaluate registry inclusion, antiplatelet choice and bleeding risk.Underrepresentation of advanced CKD in large RCT supporting guidelines for management of ACS has created a void in evidence for this subpopulation.In the past few years, there has been an increasing focus on this subgroup following recognition of the substantial disparity in treatments compared to those without advanced CKD.Research efforts are focussing on choice, dose and timing of antiplatelet regimens including DAPT and SAPT.Large trials specifically recruiting CKD patients offer opportunities to validate risk scores and explore markers for bleeding and thrombotic risk stratification.Study designs should involve increasing frequency of renal function measurement and consider integrating uACR, troponin and inflammatory markers into assessment.Guided de-escalation with withdrawal of aspirin and use of ticagrelor monotherapy in DAPT-treated patients with advanced CKD and high bleeding risk is also worth exploring.Such advances could help close the treatment gap for this high-risk population.

Figure 2 .
Figure 2. Graphical abstract of interactions between chronic kidney disease (CKD), atherothrombosis and bleeding in patients with coronary artery disease.CI, confidence interval; DAPT, dual antiplatelet therapy; SAPT, single antiplatelet therapy.Adapted from and reproduced with permission from the European Society of Cardiology.Parker, Storey, 2021 [56].

Table I .
Registry distribution of CKD with IHD; therapeutic patterns, mortality and bleeding events.

Table III .
CKD distribution, efficacy of antithrombotic therapies and bleeding risk in major trials.
Table IV summarises contemporary evidence for advanced CKD patients with IHD and outlines avenues for future research.