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Nephrology Dialysis Transplantation
This is the overview page
The quest for equilibrium: exploring the thin red line

between bleeding and ischaemic risks in acute coronary
syndrome management of chronic kidney disease patients
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Journal: Nephrology Dialysis Transplantation
Manuscript ID NDT-01764-2016.R2
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Manuscript Type: NDT Perspectives - review (INVITED ONLY)

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Date Submitted by the Author: 03-Feb-2017
Complete List of Authors: Burlacu, Alexandru; "Gr. T. Popa" University of Medicine and Pharmacy,
Cardiology
Genovesi, Simonetta; Università degli Studi di Milano-Bicocca, Monza,
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Dipartimento di Medicina e Chirurgia, Clinica Nefrologica

Ortiz, Alberto; Universidad Autonoma, Fundacion Jimenez Diaz
Kanbay, Mehmet; Koc Universitesi Tip Fakultesi, Department of Medicine,
Division of Nephrology
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Rossignol , Patrick; Inserm 1433, Nancy University Hospital & University of

Lorraine, Clinical Investigation Centre
Banach, Maciej; Medical University of Lodz, Poland, Department of
Cardionephrology and Hypertension;
Malyszko, Jolanta; Medical University, Department of Nephrology and
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Transplantology
Goldsmith, David; Guy's and St Thomas' Hospital, Renal, Dialysis and
Transplantation Unit
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Covic, Adrian; CI Parhon Univ. Hospital, Iasi, Dialysis and Transplantation

Center;
Chronic kidney disease, Bleeding risk, Ischaemic risk, guidelines,

Keyword list:
Antithrombotic medication, acute coronary syndrome
Page 1 of 30 Nephrology Dialysis Transplantation
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Title:
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5 The quest for equilibrium: exploring the thin red line between bleeding and ischaemic risks
6 in the management of acute coronary syndromes in chronic kidney disease patients
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9 Authors:
10 Alexandru Burlacu, Simonetta Genovesi, Alberto Ortiz, Mehmet Kanbay, Patrick Rossignol,
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12 Maciej Banach, Jolanta Małyszko, David Goldsmith, Adrian Covic
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14 Affiliation:
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16 AB: Department of Interventional Cardiology - Cardiovascular Diseases Institute, and 'Grigore
17 T. Popa' University of Medicine, Iasi, Romania
18 SG: Department of Medicine and Surgery, University of Milan Bicocca and Nephrology Unit,
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20 San Gerardo Hospital, Monza, Italy
21 AO: IIS-Fundacion Jimenez Diaz UAM, FRIAT and REDINREN, Madrid, Spain
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MK: Department of Medicine, Division of Nephrology, Koc University School of Medicine,
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24 Istanbul, Turkey
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25 PR: Inserm, Centre d’Investigations Cliniques- Plurithématique 14-33, Inserm U1116, CHRU
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27 Nancy, Université de Lorraine, Association Lorraine de Traitement de l’Insuffisance Rénale
28 (ALTIR) and F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
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29 MB: Department of Hypertension, Chair of Nephrology and Hypertension, Medical University

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31 of Lodz, Poland
32 JM: 2nd Dept Nephrology, Med Univ, Bialystok, Poland
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33 DG: Renal, Dialysis and Transplantation Unit, Guy's and St Thomas' Hospital, London, UK
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35 AC: Nephrology Clinic, Dialysis and Renal Transplant Center - 'C.I. Parhon’ University
36 Hospital, and 'Grigore T. Popa' University of Medicine, Iasi, Romania
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Nephrology Dialysis Transplantation Page 2 of 30
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Abstract
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5 Coronary artery disease and acute coronary syndrome (ACS) are both common in
6 patients with chronic kidney disease (CKD). CKD patients have higher risks of bleeding and
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thrombosis. However, they remain under-represented in major randomised clinical trials (RCTs),
9 and there is no medical evidence-based foundation to issue specific recommendations about the
10 management of ACS in CKD. CKD patients with ACS frequently are diagnosed later, receive
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12 fewer acute interventions, and are at increased risk of over-dosage of medications and under-
13 prescription / under-performance of interventional treatments. The lack of RCTs should not
14 discourage reliance on clinical common sense, while clearer decisional algorithms with better
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16 outcomes are a priority for urgent development. Future Guidelines should further refine the
17 assessment of CKD with ACS, while placing much greater emphasis on the correct dosing of
18 medications based on contemporaneous renal function. Until a strategy is designed with specific
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20 measures translated in actual decrease of bleeding risk, providers will be forced to balance the
21 equilibrium on a thin red line that is not clearly established.
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24 Keywords: acute coronary syndrome, coronary artery disease, chronic kidney disease, mortality,
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25 antithrombotic medication, antiplatelet therapy, anticoagulation, novel oral anticoagulants

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27 bleeding risk, ischaemic risk, guidelines
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1. Introduction: how thin is the “thin red line”?
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6 Chronic kidney disease (CKD) and coronary artery disease (CAD) are closely
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intertwined, sharing many etiological co-promotors. CKD is present in 30-40% of patients with
9 acute coronary syndrome (ACS)(1, 2), ST-segment elevation myocardial infarction (STEMI)(3)
10 or non-STEMI(4), with or without associated heart failure(5). This presence of CKD determines
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12 a more severe manifestation of ACS which includes both a worse (short- and long-term)
13 prognosis(6) and more numerous and severe complications including high rates of mortality and
14 bleeding. In fact, the American Heart Association proposed CKD as a “CAD equivalent”(7).
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16 Despite these observations, recommendations in the European Society of Cardiology
17 (ESC) STEMI Guidelines(3), the ESC Non-STEMI(8) and the ESC/EACTS Guidelines on
18 myocardial revascularisation(9) are hard to apply in the special setting of CKD, as they are
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20 limited and leave much room for individual interpretation. For the CKD population evidence is
21 sparse and is based solely on the analysis of registries such as SWEDEHEART(10) and
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ACTION(1), and on retrospective subgroup analyses from large cohort studies(9, 11). Both the
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24 ESC Guidelines and the meta-analyses state that CKD patients do not seem to receive evidence-
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25 based therapy (EBT) with respect to the antithrombotic medication, as well as to the early use of
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27 invasive strategies to decrease mortality. Numerous analyses on the same topic indicate that the
28 management algorithm of CKD patients with ACS could be “less likely” to include drugs of
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29 proven benefit(12). The same data sources also emphasise the frequent overdosing of
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31 antithrombotic drugs, more numerous subsequent haemorrhagic complications, and significantly
32 more peri-procedural and percutaneous coronary intervention (PCI)-related complications(13,
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33 14).
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35 The usual significance of the phrase “proven benefit” has limited relevance to the CKD
36 population, due to the fact that most studies have systematically excluded the patients with renal
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dysfunction. Moreover, the comparison with the non-CKD population could prove to be
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39 misguided and invalid, as there are very different health and disease trajectories in the long-term
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40 management of CKD compared to the general population. It has been reported that simply
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applying dose adjustment of the medication in relation to the extent of impaired renal function
43 does not necessarily translate into the same results as those seen in the non-CKD population. On
44 the basis of the accumulated evidence regarding this particular pathological setting, we believe
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46 that it is essential to acknowledge and identify the thin red line between coronary thrombosis,
47 myocardial ischaemia, and bleeding, generated not only by the risks and therapy of ACS, but
48 also by thrombotic and haemorrhagic consequences of CKD(15) itself.
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50 One unresolved key issue is how specifically to define clinical events such as ACS in
51 patients with CKD, including end stage renal disease (ESRD), and whether the recently
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developed standardised definitions(16) for cardiovascular endpoints are well suited across all of
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54 the CKD stages. Serum tropinin concentrations, an important constituent of the diagnosis of ACS
55 are often elevated in patients with “healthy” CKD subjects (sometimes to >99th centile values).
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Thus changes in serial serum troponin concentration in haemodialysis patients with chronically
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elevated cardiac troponin concentrations have uncertain clinical implications and are thus
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5 challenging to interpret(17, 18).
6 Consequently, this current enterprise aims to: a) acknowledge the clinical, therapeutic
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and prognostic peculiar characteristics of CKD patients with ACS; b) explore the current
9 situation of the recommendations in the European Guidelines; c) identify and comment on “the
10 sensible areas” in the Guidelines; d) suggest future directions regarding management strategies
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12 for ACS in CKD patients.
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14 2. Metabolic milieu
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17 Why does CKD predispose patients to both thrombosis and bleeding?
18 CKD patients have higher rates of bleeding and also of arterial thrombosis than do
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20 patients with normal renal function. This divergent coagulopathy increases mortality(19-21). In
21 addition, responses to antiplatelet or anticoagulant drugs may differ from those seen in non-CKD
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patients, especially in advanced stages of CKD. For example, in a recent meta-analysis of
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24 observational studies, warfarin increased the risk of major bleeding for dialysis patients with
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25 atrial fibrillation while it had no effect on the risk of stroke. However, for non-dialysis CKD
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27 patients with atrial fibrillation, warfarin had no effect on major bleeding, although it lowered the
28 risk of stroke(22).
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29 Understanding the cellular and molecular mechanisms behind this divergent biological
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31 behaviour is key to developing successful therapeutic approaches that would limit both bleeding
32 and thrombosis risks simultaneously. Recent reviews present a more complex picture,
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33 characterised by multifactorial platelet dysfunction facilitating bleeding through defective

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35 platelet response to vessel wall injury, with faulty activation, recruitment, adhesion, and
36 aggregation; at the same time there is increased platelet-derived procoagulant activity, a greater
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propensity to platelet aggregation and plasma abnormalities in the enzymatic coagulation
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39 cascade consistent with a hypercoagulable state(12).
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Dose adjustment – when “enough” is not enough
43 Ideally dose adjustment should be based on results from randomised control trials
44 (RCTs). In the particular setting of CKD, besides differential urinary excretion of an active drug
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46 or metabolites, there are further issues that may influence the efficacy and safety of a drug,
47 including altered bioavailability, protein binding, and cellular responses.
48 One of the key issues for drug dose adjustment is the assessment of eGFR, which in real
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50 life remains challening, due to the different serum creatinine based equations used, incorporating
51 characteristic variables (e.g. weight, ethnicity), with results expressed in different units (ml/min
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or ml/min/1.73 m2). Moreover, in many drug registration trials (for example with novel oral
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54 anticoagulants, NOACs), renal function is calculated with the use of the Cockcroft-Gault
55 equation, while in routine clinical practice, it is estimated by means of the CKD-EPI equation (at
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best). Hence, using a more accurate eGFR equation would likely result in CKD re-classification
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with major impact on drug dosing recommendations(23, 24). In a clinically-unstable situation,
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5 eGFR is even less valid as a proxy for renal function.
6 Frequently, in CKD the concentration of a specific drug may be modified by changes in
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protein binding related to uraemic toxin accumulation. Furthermore, CKD is associated with
9 severe persistent aPTT prolongation in STEMI patients undergoing primary PCI (pPCI), due to
10 impaired plasma protein binding and reduced unfractioned heparin (UFH) elimination(25).
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13 3. Specific aspects in management of ACS in CKD patients
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16 Trials – sometimes a trap in evolution?
17 A recent systematic review estimated the representation of patients with CKD in 371
18 RCTs assessing cardiovascular disease interventions (i.e. in heart failure (HF) or ACS)
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20 randomising 590,040 participants. Overall, more than half (57.1%, 212) trials excluded patients
21 with CKD. Subjects with CKD were more likely to be included in trials of patients with HF vs.
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trials of patients with ACS (63.2% vs 53.6%). CKD patients were excluded from 55% of 9
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24 fibrinolysis trials, 52% of 45 antiplatelet trials, and 88% of 17 anticoagulant trials. Strikingly,
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25 this systematic review also showed that CKD was rather poorly defined, since most trials
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27 excluded patients by serum creatinine levels instead of reliance on eGFR(26).
28 Moreover, haemodialysis patients are almost systematically excluded from major
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29 cardiovascular prevention trials(19). In some instances (e.g. NOACs(27)), such an absence of

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31 evidence may have contributed to a widespread off-label use of new drugs which leads to
32 potential harms for CKD patients.
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35 ESC Guidelines recommendations – real help or just “the bed of Procrustes”?
36 There is a tendency to correlate the poor evolution and more numerous complications
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post-ACS recorded in CKD patients with the under-treatment according to Guidelines
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39 recommendations(4, 28) – a fact recognised as „therapeutic nihilism”(29). CKD patients have a
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40 particular profile characterised by increased prevalence of hypertension, diabetes mellitus,

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smoking, history of MI or stroke, which distinctly aggravate the evolution and prognosis of ACS.
43 These patients also have a more advanced age and multisite atherosclerotic disease, aspects
44 which favour haemorrhagic complications.
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46 It is a well-known fact that the presence of CKD “changes fundamentally the manner in
47 which patients manifest ACS”(29). The level of atypical pain correlates directly with the degree
48 of CKD(4), the percentage of dialysis patients who report absence of pain being as high as
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50 40%(30). Presentation occurs less often with ST-segment elevation and more in the shape of
51 non-specific modifications of the ST-segment and consequent nonspecific aberrations in
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repolarisation(29). A retrospective analysis(1, 29) showed that patients with CKD and ACS did
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54 not benefit from early PCI which may be due to the erroneous interpretation of non-specific MI
55 manifestations for almost half of CKD patients.
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Another key reason for ACS misdiagnosis lies within the absence (atypical presentation)
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5 of pain specific for CKD patients, which is also responsible for delayed hospital presentation,
6 with a consequent advanced systolic left ventricular dysfunction. Moreover, the particular profile
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of ACS and CKD patients also includes presence of HF symptoms in a significantly higher
9 proportion (50%), as reported by two recent studies(31, 32).
10 Guidelines recognise the difficulties encountered in the diagnosis of ACS in the CKD
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12 context: “the diagnosis of non-ST-ACS in patients with CKD may be more challenging as both
13 mild elevations in cardiac troponin and ECG abnormalities are frequent” and suggest that
14 elevated troponin is no longer considered benign and cannot be simply blamed on creatinine
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16 clearance(33). Moreover, for CKD patients with high troponin levels, the main diagnosis still
17 seems to be acute myocardial infarction (AMI)(34).
18 Additionally, the recommendations for coronary angiography in non-STEMI regard the
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20 presence of CKD as an intermediate risk criterion, which benefits from invasive strategies with a
21 class IA indication for coronary angiography in the first 72 hours(8).
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24 4. To risk or not to risk? – is this the (real) question?
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27 The drawing of our thin red line should be facilitated by the risk scores mentioned by the
28 Guidelines, which state that ”ischaemic and bleeding risks need to be weighed in the individual
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29 patient, although many of the predictors of ischaemic events are also associated with bleeding
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31 complications”(8).
32 The GRACE score is the only class I recommendation risk score (level of evidence B) in
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33 the ESC Guidelines and it contributes to stratification of major adverse cardiovascular events
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35 risk, while directing the management towards early or delayed approaches. It takes into account
36 renal dysfunction (as opposed to TIMI and Heart score). A score of over 140 leads to an
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indication for an early (<24 hours) invasive strategy. However, unfortunately, it does not factor
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39 in creatinine clearance or eGFR, rather only creatinine levels (an insufficiently strong parameter
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40 for the characterisation of renal dysfunction, especially for patients across different ages and
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body masses). Hence, an insensitive parameter influences greatly the decision about when to
43 perform invasive procedures in the <24 or <72hours groups.
44 Both, the CRUSADE and the ACUITY haemorrhage-propensity scores take into account
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46 the assessment of renal function on admission (a supplementary argument which supports the
47 early measurement of creatinine). Unfortunately, that is as far as the actual contribution of these
48 two scores goes. If the computation of the ischaemic risk score has a class I indication (level of
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50 evidence B), the calculation of CRUSADE score (“may be considered in patients undergoing
51 coronary angiography”) has a class IIB indication (level of evidence B) (8, 35). This biases risk
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assessment with the ischaemic risk being deemed higher and more evidence-based. Furthermore,
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54 the practical utility of these scores is mediocre at best, since their “model performance is
55 modest”, while they apply only to those patients where an interventional procedure is intended,
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and their predictive power for patients on NOACs not yet being fully validated.
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Under these circumstances, why should we compute this bleeding risk score and to what
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5 purpose? A fair question since many interventional cardiologists go so far as to ignore it since
6 regardless of its level, the score does not change much in the management of the patient.
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New data show that in ACS, the CHADS2 score has a strong prognostic value
9 (independent of atrial fibrillation, AF) in predicting stroke and mortality, and even greater
10 prognostic value in patients without AF(36). A new modified CHADS-VASc score, which
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12 includes renal function (GFR estimated using the MDRD formula), R2-CHA2DS2-VASc was
13 evaluated in a retrospective registry study, which concluded that it predicts death comparably
14 well when compared to the use of the GRACE score at 3 and 5 years(37). Consequently, its
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16 further evaluation in post-hoc re-analyses of older studies would be recommendable, in order to
17 corroborate its results and reinforce its strength.
18 In summary, the ambiguity and low utility of calculating an imprecise score fails to
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20 identify the patients where coronary angiography is not recommended, or to reduce or withhold
21 various medication usually recommended for ACS patients.
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24 5. Invasive could be intrusive: interventional management of ACS patients with CKD
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27 Despite its significantly increased prevalence, the issues raised by the presence of CKD
28 in the invasive approach of ACS are often considered as secondary by the interventional
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29 cardiologist.
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31 For STEMI patients, the reperfusion strategy of choice is the same as for non-CKD
32 patients, pPCI being mandatory where the emergency network enables transport to a PCI-capable
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33 hospital. There is no doubt as to the benefits of invasive therapy for STEMI CKD patients(3). If
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35 the PCI procedure is not within reach in the first 120 minutes, the ESC STEMI Guidelines
36 recommend prehospital fibrinolysis, which is not contraindicated in CKD.
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In the invasive approach, we must distinguish between two categories of patients: with
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39 unknown CKD (where protocol will be applied the same as for any other patient) and with
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40 known CKD.
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STEMI Guidelines indicate that “Decisions on reperfusion in patients with STEMI have
43 to be made before any assessment of renal function is available, but it is important to estimate
44 the glomerular filtration rate as soon as possible after admission”. Table 18 in the same
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46 Guideline summarises the recommendations regarding dose adjustment or choice of
47 antithrombotic medication for patients with CKD(3).
48 However, by the time a diagnosis of CKD is considered, the dice have already been
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50 thrown: initial medication doses have been made only considering body mass and not creatinine
51 clearance or eGFR. This puts CKD patients at increased risk for post-procedural bleeding. Most
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antithrombotic agents do not carry CKD-specific experience in the literature and by the time
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54 creatinine clearance or eGFR is considered, the physician ends up switching between
55 antithrombotic drugs. Moreover, the development of contrast-induced nephropathy (CIN) / acute
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kidney injury (AKI) can further complicate the issue, due to the particular behaviour of serum
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creatinine, which is relatively insensitive to the rapid GFR changes(38). This characteristic
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5 feature would require a continuous adjustment of the entire medication in correlation with the
6 rapidly and unpredictably deteriorating renal function, and, consequently, would also impose a
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variably inaccurate adjustment of the risk scores.
9 Therefore, the authors believe that the next set of clinical Guidelines should recommend
10 mandatory assessment of eGFR before the pPCI procedure, a reasonably easy, rapid, and
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12 accessible evaluation. Point of care devices may additionally be valuable in this setting.
13 Moreover, better than no evidence at all, a post-market approval specific appraisal of the
14 benefit/risk ratio in advanced CKD patients should be considered by regulatory bodies,
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16 especially for those NOACs with only pharmacokinetic/pharmacodynamics data available
17 instead of RCTs. The position of the authors is that for one third of STEMI patients (those with
18 renal dysfunction(1)), peri-procedural medication is inappropriately administered due to
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20 ignorance of the renal function and that in the 21st century no peri-procedural medication should
21 be left unadjusted for renal function.
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The Revascularisation Guidelines(9) state that ”in patients referred for acute PCI, the
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24 first dose of an antithrombotic drug does not usually add to the risk of bleeding in the case of
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25 CKD. In the absence of contra-indications, patients with CKD should receive the same first line
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27 treatment as any other patient”. This statement biases the decisional process towards
28 antithrombotic drugs not recommended in CKD (i.e. there is no experience in advanced CKD for
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29 prasugrel and ticagrelor). In ACTION registry, patients with STEMI and CKD 3a had two-fold
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31 more bleeding events as opposed to non-CKD patients, while for CKD 3b and further, the
32 number of bleeding events increased up to 4-times(1). It is obvious that these numbers are due to
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33 administration of “standard” initial doses (and not factoring in eGFR from the start).
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35 To summarise, across all Guidelines, the main information regarding ACS with CKD is
36 that patients are less frequently managed invasively and thus revascularised (either by
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interventional or surgical procedures) than non-CKD patients. The thin red line is most
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39 conspicuous in the case of the non-STEMI group. The little information that exists is based
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40 solely on registry analyses, which are limited by the number of patients, consequently mirrored
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in the level of evidence and decisional power. Afflicted by the severe shortage of information,
43 the invasive approach finds itself confronted with a variety of clinical scenarios which not only
44 lack coverage in the Guidelines, but the ambiguous formulation thereof leaves wide room for
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46 interpretations and heterogeneous decision-making.
47 The two questions guiding the interventional approach of a non-STEMI in CKD patients
48 should be: a) Should we or should we not perform an invasive procedure? b) If we should, then
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50 what is the time frame?
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a) To treat or not to treat?
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54 The ACTION registry shows that mortality increases as CKD progresses both for
55 invasively and conservatively managed patients(1). An additional risk-treatment paradox is that
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as the renal impairment and thus the risk increases, these patients benefit significantly less often
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of interventional treatment(39). The lack of demonstrable treatment benefit for a certain segment
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5 in the CKD population may find a theoretical explanation in the high incidence of complications
6 such as fatal bleeding and acute kidney injury, and the more severe prognosis brought about by
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advanced coronary disease. As there are no RCTs investigating the benefit of the invasive
9 algorithm on CKD patients, the numerous gaps in the evidence produce uncertainty regarding the
10 benefit brought by early intervention on mortality and long term evolution.
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12 Therefore, the question we actually should be asking is: “should we or should we not
13 perform PCI in ACS with advanced CKD?” The ESC Guidelines based on the conclusions
14 yielded by SWEDEHEART registry(10) indicate that the benefit of the invasive strategy
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16 decreases concurrently with the progression of CKD up until lack of benefit on mortality on
17 CKD 5 and 5D.
18 However, Yu(39) signals deep flaws in the statistical significance of the data and
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20 concludes that there are not sufficient reasons to assume benefits of invasive therapy for ACS,
21 stressing the need for dedicated RCTs in order to assess safety and efficacy of new invasive
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therapies for patients with various stages of CKD. Furthermore, a similarly defective assessment
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24 of mortality risk also complicates the decision to treat CKD patients(40, 41).
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25 Biased patient selection (those with severe renal function are less often referred towards
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27 an invasive procedure, and those referred have poor results) yields an equally biased conclusion
28 that the benefit of invasive procedures for patients with severe CKD is low. This behaviour is
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29 deemed as unsuitable by certain researchers(42), who name it „renalism” and define it as

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31 „inappropriately low rates of coronary angiography in elderly individuals with renal
32 insufficiency”.
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33 Finally, a small clarification is brought by a recent meta-analysis(43), which indicated a

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35 net benefit in the mortality rate for all CKD patients, further highlighting the crucial significance
36 of conceiving a set of homogeneous criteria for adequate patient selection.
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39 b. If we should intervene, then what is the optimal time frame?
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40 Regrettably, we do not have a definitive answer for this question either.

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At a first glance, Guidelines acknowledge the debate and confusion regarding this population,
43 and give the following indications regarding the bearing of CKD on the interventionist decision.
44 The non-STEMI Guidelines (table 5.6.9) state that presence of CKD stage 3 or higher (eGFR
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46 <60 mL/min/1.73 m2) indicates an invasive approach in less than 72 hours.
47 However, at a closer examination, the two meta-analyses providing the level IA
48 indication are mutually inconsistent. Both observe that high risk groups benefit the most from
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50 invasive procedures, while they do not mention specifically the CKD population. Furthermore, in
51 most studies incorporated into these meta-analyses, there was not a question whether the
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coronary angiography should be performed or not. Instead, they only investigated if the routine
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54 early interventional approach brings supplemental benefits. The manner in which referral of
55 CKD patients is suggested is unsubstantiated by evidence.
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A 2016 systematic review(44) that investigated the impact of early invasive versus
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5 conservative strategies for CKD patients leaned toward an early invasive approach for non-
6 STEMI patients with mild and moderate CKD (citing survival benefits). With respect to patients
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with severe CKD, the study indicates that early intervention cannot be backed by evidence, as it
9 entails high levels of risk and an understudied population. Moreover, the paper supports a
10 cautious management behaviour, as levels of in-hospital mortality and complications could be
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12 higher if associated with an early invasive approach.
13 An essential weakness of all three studies discussed above is the heterogeneous definition
14 of the “early invasive strategy”, which ranges from as long as one week (in FRISC II), to 72, 48
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16 or 24 hours in other studies(45, 46). In our opinion the time-frame of 72 hours allocated by Table
17 5.6.9. from the Guidelines (for patients with CKD without major complications) is unfounded
18 and somewhat empirical, and the large variations in the definition of the “early” concept only
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20 adds confusion.
21 In conclusion, the answer to our question cannot be scientifically articulated and
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supported by evidence, with the obvious exception of unstable cases, which are classified in the
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24 high risk group.
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27 6. Known facts regarding antithrombotic medication in ACS & CKD
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29 ESC Guidelines recommendations are organised distinctly for antiplatelet and

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31 anticoagulant medication. Although it is suggested that the choice and dose of antithrombotic
32 drugs should be considered with caution, these two main categories are approached differently:
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33 “while most anticoagulants may need dose adjustment in renal insufficiency, this is not the case
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35 for oral antiplatelet drugs”(8).
36 Table 1 presents a summary of European Guidelines recommendations regarding dose
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adjustment and drug administration for ACS patients with CKD.
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39 It is worth mentioning that there is no evidence supporting the efficacy and safety of
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40 association of GPIIb/IIIa inhibitors with aspirin and a novel antiplatelet drug (other than
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clopidogrel). Moreover, efficacy data for the use of P2Y12 inhibitors in stage 5 CKD are
43 insufficient. Therefore, in this setting, P2Y12 inhibitors should be selected for high-risk
44 indications (i.e. coronary stent thrombosis prevention), with bleeding risk carefully weighed(8).
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46 The only study that supports higher benefits in AMI for an antiplatelet agent in CKD as opposed
47 to non-CKD patients is PLATO trial(3, 47).
48 Furthermore, even though the Guidelines(9) state that the bleeding risk is not usually
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50 increased by the first dose of an antithrombotic drug, but through repeated infusion or intake, this
51 assertion is not supported by hard evidence, which requires cautiously weighed decisions from
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the first administration of the drug and solid future RCTs.
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55 7. Novel Oral Anticoagulants: useful or useless for ACS in CKD patients?
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1
2
3
Recently, NOACs have been chosen as an alternative to traditional vitamin K antagonists
4
5 (VKA) for reducing the risk of thromboembolism in patients with non-valvular AF. These
6 molecules are either direct thrombin inhibitors (ximelagatran and dabigatran), or factor Xa
7
8
inhibitors (rivaroxaban, apixaban and edoxaban). There are some data on the use of NOACs in
9 patients with CKD and AF, deriving from post-hoc analyses of RCTs that have allowed the
10 introduction of these new drugs(48-51). Subgroup analyses of CKD patients have substantially
11
12 confirmed, albeit with some differences between the various drugs, the efficacy and safety of
13 NOACs in the prophylaxis of thromboembolic risk in subjects with moderate CKD (eGFR 30-50
14 ml/min/1.73m2)(52-56).
15
16 Consequently, most recent ESC Guidelines consider the use of NOACs to be suitable
17 only in patients with AF and CKD with eGFR >30 ml/min/1.73m2 for dabigatran, rivaroxaban
18 and edoxaban, and >25 ml/min/1.73m2 for apixaban(57), whereas the European Medicine
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19
20 Agency (EMA) extends rivaroxaban, edoxaban and apixaban usage also for CKD stage 4 – see
21 Table 2. The differences are due to the fact that ESC made the recommendation based on RCTs
22
results, while EMA took into account pharmacokinetic studies.
r
23
24 Additionally, the two main drug evaluation and authorisation agencies, the EMA and the
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25 American Food and Drug Administration (FDA), have different positions with regard to the
26
27 dosage of NOACs in patients with severe CKD. The main differences are that, according to
28 EMA, dabigatran cannot be used in patients with CKD stage 4, 5 and on dialysis, while
er
29 according to FDA it can be administered at a dose of 75 mg (a dose that does not exist in Europe)
30
31 to patients with CKD stage 4. Moreover, according to the EMA, rivaroxaban and apixaban may
32 not be administered in patients with CKD stage 5 and on dialysis, while according to the FDA
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33 they may be administered on haemodialysis at the following dosages: 15 mg od for rivaroxaban,

34
35 2.5 mg bid for apixaban in the presence of age >80 years or body weight <60 kg (Tables 2 and
36 3). These assertions, however, were not tested in RCTs and are based solely on pharmacokinetic
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37
studies(58-60).
38
39 Data regarding the usefulness of NOACs in patients with ACS are scarce regardless of
ew
40 CKD status. Moreover, the Guidelines do not have specific dosage recommendations for patients
41
42
with CKD and ACS, with or without AF.
43 The rationale for the use of NOACs can be found in two groups of ACS patients: ACS
44 patients with long-term oral anticoagulant therapy (OAT) indication and ACS patients without
45
46 such an indication.
47 In this section the authors describe the available evidence regarding the use of NOACs in
48 patients with ACS and concomitant CKD, considering only data deriving from RCTs.
49
50
51 a) NOACs after ACS in CKD patients without long-term OAT indication
52
In ACS patients, anticoagulant drugs have been shown to improve overall prognosis and
53
54 combination with antiplatelet drugs is more effective than monotherapy (61). Guidelines briefly
55 mention NOACs without specifically refering to CKD patients. For example, rivaroxaban is
56
57
indicated(8) to be used in combination with aspirin and clopidogrel at a lower dose compared to
58
59
60
12
1
2
3
what is recommended in case of AF (class/level of evidence IIB). This indication originates from
4
5 the results of the ATLAS ACS 2-TIMI 51 study(62), which showed a reduction in the risk of
6 primary efficacy end point (death from cardiovascular causes, AMI or stroke) in patients with
7
8
eGFR >50 ml/min/1.73m2, slightly diminished for patients with eGFR <50 ml/min/1.73m2.
9 The other main RCTs assessing the efficacy and safety of NOACs vs placebo in ACS
10 patients on antiplatelet therapy were ESTEEM(63), APPRAISE 2(64) and REDEEM(65) that
11
12 studied ximelagatran, apixaban and dabigatran, respectively.
13 The ESTEEM study showed superiority of the ximelagatran-acetylsalicylic acid
14 combination, in terms of mortality, MI and stroke, but did not enrol any CKD patients. The
15
16 APPRAISE and the REDEEM studies showed an increase in bleeding events without any
17 positive effect for ischaemic events in patients taking NOACs.
18 A recent meta-analysis on all RCTs studying the use of NOACs in patients with ACS
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19
20 concluded that addition of these drugs to the traditional antiplatelet therapy leads to modest
21 reduction in cardiovascular end points against an important increase in haemorrhagic events(66).
22
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23
24 b) NOACs after ACS in CKD patients with long-term OAT indication
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25 In ACS patients with an indication for chronic OAT the Guidelines advise continuing the
26
27 current OAT, to be combined with antiplatelet treatment (class/level of evidence IC)(8).
28 Regarding patients with indication for PCI, this procedure should be carried out without
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29 interrupting OAT, both when VKA and NOACs are involved. In case of patients on chronic
30
31 NOACs treatment it is suggested to add parenteral anticoagulation during PCI.
32 Data on long-term antithrombotic treatment after PCI show an increase in haemorrhagic
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33 events with triple therapy(67), which is recommended only in specific cases (presence of AF and
34
35 CHA2DS2-VASc ≥2; mechanical prosthetic valves; recurrent deep venous thrombosis) and
36 should be administered for as short a period as possible, while for patients on NOACs therapy it
vi
37
is advised to reduce the doses. Again, the Guidelines do not mention patients with CKD. A
38
39 recent consensus document of the major Cardiology Societies recommends the use of NOACs
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40 instead of VKA in ACS patients with long-term indication for OAT in case of elevated levels of
41
42
HAS-BLED score. In CKD patients (eGFR between 30 and 50 ml/min/1.73m2) it is advised to
43 use 15 mg rivaroxaban once a day(68).
44 The only data obtained from a RCT comparing NOACs and VKA for efficacy and safety
45
46 in AF patients who were also on single or dual antiplatelet therapy, derive from a subgroup
47 analysis of the RE-LY study(69). Dabigatran and antiplatelet drugs significantly increased the
48 risk of major bleedings. The advantages of dabigatran compared to warfarin shown by the main
49
50 study(48) were confirmed, both in terms of efficacy and safety. The RE-LY study included
51 patients with creatinine clearance >30 ml/min; however, the article that reported the data of this
52
post-hoc analysis did not perform a separate analysis of CKD patients and consequently it is not
53
54 possible to know whether they were included in the study population.
55 In December 2016 the results of the PIONEER AF-PCI were published(70). The trial,
56
57
which included patients with AF who underwent PCI, provided three arms: Group 1: rivaroxaban
58
59
60
13
1
2
3
at a dose of 15 mg once daily (or 10 mg once daily if creatinine clearance was less than 50
4
5 ml/min) plus single antiplatelet therapy; Group 2, rivaroxaban at a dose of 2.5 mg twice daily
6 plus dual antiplatelet therapy and Group 3, vitamin K antagonist, warfarin once daily plus dual
7
8
antiplatelet therapy. Patients with creatinine clearance of 30 to 60 ml/min were 28.8% in Group 1
9 and Group 2 and 26.2% in Group 3. Patients with creatinine clearance <30ml/min were 1.2% in
10 Group 1 and Group 2 and 0.3% in Group 3. In Group 1 and Group 2 the low dose of
11
12 Rivaroxaban was associated with a lower rate of clinically significant bleeding than was standard
13 therapy with a vitamin K antagonist plus dual antiplatelet therapy (Group 3). The three groups
14 had similar efficacy rates.
15
16 Data on the use of NOACs in ACS patients with CKD are much more fragmented. The
17 few data deriving from RCTs discourage the prescription of NOACs in ACS patients with
18 reduced renal function. An exception could be made for rivaroxaban, if administered at lower
Fo
19
20 doses, in CKD patients with AF suffering from ACS. The recently completed PIONEER AF-PCI
21 has provided important information on the possibility to use rivaroxaban also in patients with
22
ACS, AF and eGFR >30 ml/min/1.73m2. At this moment no robust data are available on the use
r
23
24 of NOACs in ACS patients with ESRD on dialysis.
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25
26
27 8. Conclusions
28
er
29 CKD represents the „perfect storm” as CKD patients bleed and clot more, have very
30
31 significant co-morbidities and hence are at significantly increased risk for ACS. Accurate and
32 timely clinical diagnosis (especially for non-STEMI ACS) is difficult and thus often (too) late.
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33 CKD patients typically get fewer acute interventions, while they are also at increased risk for
34
35 over-dosage of medications and under-prescription / under-performance of interventional
36 treatments.
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37
Ongoing therapies are also confounded by dosing issues, and by lack of certainty over
38
39 longer-term benefits. There are divergent data regarding the outcomes of interventional
ew
40 procedures. Overall, CKD patients remain under-represented in major clinical trials, and when
41
42
they are included, they are often inappropriately studied. Guidelines do not yet recommend the
43 implementation of simple cost effective measures that could safeguard CKD patients, such as
44 urgent eGFR performance recommendations.
45
46 The authors believe that the lack of RCTs(71) should and must not discourage clinical
47 common sense, and more clear decisional algorithms with better outcomes could be attainable.
48 Furthermore, the authors consider that robustly designed RCTs are now urgently required in
49
50 order to scope and then plug the large existing gaps in the information framework covering this
51 particular patient population. CKD patients need specific assessment procedures, and until a
52
strategy is designed with specific measures translated in actual decrease of bleeding, providers
53
54 will be forced to keep the equilibrium on a thin red line that is not clearly established.
55
56
57
Acknowledgements
58
59
60
14
1
2
3
AO was supported by Intensificacion FEDER funds ISCIII, RETIC REDINREN RD016/0009
4
5 and PI16/02057.
6
7
8
Conflict of interests
9 AB: speaker fees: Astra Zeneca, Sanofi, Boeringher Ingelheim, Pfizer.
10 SG: speaker fees: Boeringher, Shire.
11
12 AO: consultant Sanofi Genzyme, Servier, speaker fees: Amgen, Shire, Otsuka.
13 PR: speaker and consulting fees for Astra-Zeneca, Bayer, Novartis, Relypsa, Stealth Peptides,
14 Vifor Fresenius Medical Care Renal Pharma; co - founder of CardioRenal.
15
16 MB: speaker fees: Amgen, Abbott, Actavis, KRKA, MSD, Mylan, Sanofi.
17 JM: speaker and consulting fees: Vifor-Fresenius, GE Healthcare.
18 DG: speaker and consulting fees: Sanofi, Amgen, Vifor-Fresenius, Otsuka, Roche.
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19
20 AC: speaker and consulting fees: Vifor-Fresenius, Otsuka, Roche.
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28
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Table 1. Antithrombotic medication in ACS with CKD according to ESC Guidelines
12 recommendations
13
14
15 Drugs Initial dose Dose adjustment in CKD*
16
17
adjustment Observations
18
Fo
19 Stage 3 and 4 Stage 5 and
20 CKD 5D CKD
21
22
r
23
24 Aspirin No dose No dose adjustment Lack of specific
adjustment recommendations
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25
26
27
28
P2Y12 inhibitors:
er
29
30
31
32 No dose No dose Only for Lack of specific
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33 a. Clopidogrel adjustment adjustment selected recommendations

34 indications No studies for
35
36 (stent CKD 5 &
thrombosis) Clopidogrel
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37
38 resistance
39
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40 b. Prasugrel No dose No dose Not

41
42
adjustment adjustment recommended
43 (no No benefit in
44 experience) patients >75 yrs old
45 and <60 kg
46
47
48
c. Ticagrelor No dose No dose Not
49 adjustment adjustment recommended
50 (no
51 experience)
52
53
54
55
56
57
58
59
60
16
1
2
3
4
No indication in
5 d. Cangrelor No dose No dose adjustment ESC Guidelines
6 adjustment STEMI (2012),
7 Revasc (2014);
8 Approved in March
9 2015 by EMA
10
11 Anticoagulants:
12 Widely used
13 a. UFH No dose Dose adjustment according despite consistent
14 adjustment; ACT (during PCI) and APTT evidence for
15 During PCI: (elsewhere) greater bleeding
16
17
70-100 IU/kg risk compared with
18 other strategies
Fo
19
20
21 b. Enoxaparin No dose No Contra - Anti-Xa
22
adjustment adjustment in indicated monitoring
r
23
24 CKD 3; recommended in
Doses halved CKD 4;
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25
26 in CKD 4 Crossing over to
27 UFH during PCI
28 strongly contra-
er
29
30 indicated
31
32 Considered the
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33 c. Fondaparinux No dose Doses halved Contra - most favourable

34 adjustment in CKD 3; indicated efﬁcacy–safety
35
36
Contra - proﬁle (but without
indicated in CKD data);
vi
37
38 CKD 4 Catheter thrombus
39 during PCI needs
ew
40 UFH bolus
41
(increasing
42
43 bleeding risk in
44 CKD)
45
46
47 d. Bivalirudin No dose Doses halved Contra -
48
49 adjustment in CKD 3; indicated
50 Contra -
51 indicated in
52 CKD 4
53
54
55 GPIIb/IIIa
56 Inhibitors:
57
58
59
60
17
1
2
3
4
No specific No specific recommendation.
5 a. Abciximab recommendati Careful consideration of
6 on bleeding risk
7
8
9
10 b. Eptifibatide No dose Doses halved Contra-
11
12
adjustment in CKD 3; indicated No evidence for
13 Contraindicat safety and efficacy
14 ed in CKD 4; in adding GPIIbIIIa
15 inhibitors on
16
17
aspirin +
c. Tirofiban No dose No dose Not ticagrelor/prasugrel
18
adjustment adjustment in recommended
Fo
19
20 CKD 3;
21 Doses halved
22 in CKD 4
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23
24
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25
26 References: ESC STEMI Guidelines 2012 (Table 17, 18), ESC NonSTEMI Guidelines 2015
27 (Table 8, 10, 11 and Webaddenda section 5.8.3.1.), ESC Revascularisation Guidelines 2014
28 (Section 18.4.8., Table 15)
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29 * Stage 1 and 2 CKD dosing: similar to non-CKD patients.

30
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32
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18
1
2
3
4
5
6
7
8 Table 2. Novel oral anticoagulants dosage for patients with AF and CKD: European Medicines
9 Agency indications
10
11
12
13 Stage 1, 2 and 3a Stage 3b CKD Stage 4 CKD Stage 5 and
14 CKD 5D CKD
15
16 Dabigatran 150 mg b.i.d 150 or 110 mg b.i.d* None None
17
18
Fo
19 Rivaroxaban 20 mg o.d 15 mg o.d. 15 mg o.d None
20
21 Apixaban 5 mg b.i.d 2,5 mg b.i.d in 2,5 mg b.i.d None
22 presence of 2 of
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23 following: age >80
24
years, body weight
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25
26 <60 kg,
27 serum creatinine >1.5
28 mg/dL
er
29 Edoxaban 60 mg o.d 30 mg o.d 30 mg o.d None

30
31
32 * Dabigatran 110 mg is recommended in high bleeding risk patients.
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33
34
35
36
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37
38
39
ew
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
1
2
3
4
5
6
7
8 Table 3. Novel oral anticoagulants dosage for patients with AF and CKD: Food and Drug
9 Administration indications
10
11
12
13
14 Stage 1, 2 Stage 3b CKD Stage 4 CKD Stage 5 and 5D
15 and 3a CKD CKD
16
17
18
Fo
19 Dabigatran 150 mg b.i.d 150 mg b.i.d 75 mg b.i.d None
20
21
22
r
23 Rivaroxaban 20 mg o.d 15 mg o.d 15 mg o.d 15 mg o.d
24
Pe
25
26
27 Apixaban 5 mg b.i.d 2.5 mg b.i.d in presence 2.5 mg b.i.d in presence 2.5 mg b.i.d in
28 of 2 of following: age of 2 of following: age presence of age >80
er
29 >80 years, body weight >80 years, body weight years or body weight
30
31
<60 kg, serum <60 kg, serum <60 kg
32 creatinine >1.5 mg/dL creatinine >1.5 mg/dL
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33 Edoxaban 60 mg o.d 30 mg o.d. 30 mg o.d None

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7
8
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22 33. Irfan A, Twerenbold R, Reiter M, Reichlin T, Stelzig C, Freese M, et al. Determinants of high-
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23 sensitivity troponin T among patients with a noncardiac cause of chest pain. The American journal of
24 medicine. 2012;125:491-8.e1.
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25 34. Twerenbold R, Wildi K, Jaeger C, Gimenez MR, Reiter M, Reichlin T, et al. Optimal Cutoff Levels
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of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients
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28 With Renal Dysfunction. Circulation. 2015;131:2041-50.
35. Subherwal S, Bach RG, Chen AY, Gage BF, Rao SV, Newby LK, et al. Baseline risk of major
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30 bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification
31 of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA
32 Guidelines) Bleeding Score. Circulation. 2009;119:1873-82.
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33 36. Poci D, Hartford M, Karlsson T, Herlitz J, Edvardsson N, Caidahl K. Role of the CHADS2 score in
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36 fibrillation. Chest. 2012;141:1431-40.
37. Kiliszek M, Szpakowicz A, Filipiak KJ, Koltowski L, Poludniewska D, Szymanski F, et al. CHA2DS2-
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38 VASc and R2CHA2DS2-VASc scores have predictive value in patients with acute coronary syndromes.
39 Polskie Archiwum Medycyny Wewnetrznej. 2015;125:545-52.
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40 38. Rear R, Bell RM, Hausenloy DJ. Contrast-induced nephropathy following angiography and cardiac
41 interventions. Heart (British Cardiac Society). 2016;102:638-48.
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39. Yu J, Ooi SY, Sergie Z, Baber U. Is there attenuation of benefit of invasive therapy in patients
44 with chronic kidney disease? Results from randomized trials and registry data. Current cardiology
45 reports. 2012;14:521-7.
46 40. McCullough PA, Wolyn R, Rocher LL, Levin RN, O'Neill WW. Acute renal failure after coronary
47 intervention: incidence, risk factors, and relationship to mortality. The American journal of medicine.
48 1997;103:368-75.
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41. Wong JA, Goodman SG, Yan RT, Wald R, Bagnall AJ, Welsh RC, et al. Temporal management
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51 patterns and outcomes of non-ST elevation acute coronary syndromes in patients with kidney
52 dysfunction. European heart journal. 2009;30:549-57.
53 42. Chertow GM, Normand SL, McNeil BJ. "Renalism": inappropriately low rates of coronary
54 angiography in elderly individuals with renal insufficiency. Journal of the American Society of Nephrology
55 : JASN. 2004;15:2462-8.
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3 43. Huang CC, Chen JW. Contemporary Management of Coronary Artery Disease and Acute
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7 44. Shaw C, Nitsch D, Lee J, Fogarty D, Sharpe CC. Impact of an Early Invasive Strategy versus
8 Conservative Strategy for Unstable Angina and Non-ST Elevation Acute Coronary Syndrome in Patients
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10 45. Charytan DM, Wallentin L, Lagerqvist B, Spacek R, De Winter RJ, Stern NM, et al. Early
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13 the American Society of Nephrology : CJASN. 2009;4:1032-43.
14 46. de Winter RJ, Windhausen F, Cornel JH, Dunselman PH, Janus CL, Bendermacher PE, et al. Early
15 invasive versus selectively invasive management for acute coronary syndromes. The New England
16 journal of medicine. 2005;353:1095-104.
17 47. James S, Budaj A, Aylward P, Buck KK, Cannon CP, Cornel JH, et al. Ticagrelor versus clopidogrel
18 in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and
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21 48. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus
22 warfarin in patients with atrial fibrillation. The New England journal of medicine. 2009;361:1139-51.
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23 49. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in
24 nonvalvular atrial fibrillation. The New England journal of medicine. 2011;365:883-91.
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25 50. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus
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warfarin in patients with atrial fibrillation. The New England journal of medicine. 2011;365:981-92.
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28 51. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus
warfarin in patients with atrial fibrillation. The New England journal of medicine. 2013;369:2093-104.
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30 52. Hijazi Z, Hohnloser SH, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW, et al. Efficacy and
31 safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial
32 fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
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33 Circulation. 2014;129:961-70.
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53. Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, et al. Prevention of stroke and
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36 systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial
fibrillation and moderate renal impairment. European heart journal. 2011;32:2387-94.
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38 54. Hijazi Z, Hohnloser SH, Andersson U, Alexander JH, Hanna M, Keltai M, et al. Efficacy and Safety
39 of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation in Relation to Renal Function
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40 Over Time: Insights From the ARISTOTLE Randomized Clinical Trial. JAMA cardiology. 2016;1:451-60.
41 55. Bohula EA, Giugliano RP, Ruff CT, Kuder JF, Murphy SA, Antman EM, et al. Impact of Renal
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Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation. 2016;134:24-36.
44 56. Del-Carpio Munoz F, Gharacholou SM, Munger TM, Friedman PA, Asirvatham SJ, Packer DL, et al.
45 Meta-Analysis of Renal Function on the Safety and Efficacy of Novel Oral Anticoagulants for Atrial
46 Fibrillation. The American journal of cardiology. 2016;117:69-75.
47 57. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the
48 management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the
49
management of atrial fibrillation of the European Society of Cardiology (ESC)Developed with the special
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51 contribution of the European Heart Rhythm Association (EHRA) of the ESCEndorsed by the European
52 Stroke Organisation (ESO). Europace : European pacing, arrhythmias, and cardiac electrophysiology :
53 journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of
54 the European Society of Cardiology. 2016.
55 58. Wang X, Tirucherai G, Marbury TC, Wang J, Chang M, Zhang D, et al. Pharmacokinetics,
56 pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.
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3 59. Chang M, Yu Z, Shenker A, Wang J, Pursley J, Byon W, et al. Effect of renal impairment on the
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pharmacokinetics, pharmacodynamics, and safety of apixaban. Journal of clinical pharmacology.
6 2016;56:637-45.
7 60. De Vriese AS, Caluwe R, Bailleul E, De Bacquer D, Borrey D, Van Vlem B, et al. Dose-finding study
8 of rivaroxaban in hemodialysis patients. American journal of kidney diseases : the official journal of the
9 National Kidney Foundation. 2015;66:91-8.
10 61. Eikelboom JW, Anand SS, Malmberg K, Weitz JI, Ginsberg JS, Yusuf S. Unfractionated heparin
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and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis.
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13 Lancet (London, England). 2000;355:1936-42.
14 62. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients
15 with a recent acute coronary syndrome. The New England journal of medicine. 2012;366:9-19.
16 63. Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nystrom P, et al. Oral
17 ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled
18 trial. Lancet (London, England). 2003;362:789-97.
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64. Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban with antiplatelet
21 therapy after acute coronary syndrome. The New England journal of medicine. 2011;365:699-708.
22 65. Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, et al. Dabigatran vs. placebo in
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23 patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind,
24 phase II trial. European heart journal. 2011;32:2781-9.
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25 66. Oldgren J, Wallentin L, Alexander JH, James S, Jonelid B, Steg G, et al. New oral anticoagulants in
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addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review
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28 and meta-analysis. European heart journal. 2013;34:1670-80.
67. Marin F, Huber K, Lip GY. Antithrombotic therapy in atrial fibrillation and stent implantation:
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30 treatment or threats by the use of triple or dual antithrombotic therapy. Thrombosis and haemostasis.
31 2013;110:623-5.
32 68. Lip GY, Windecker S, Huber K, Kirchhof P, Marin F, Ten Berg JM, et al. Management of
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33 antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or
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undergoing percutaneous coronary or valve interventions: a joint consensus document of the European
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36 Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA),
European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of
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38 Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm
39 Society (APHRS). European heart journal. 2014;35:3155-79.
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40 69. Dans AL, Connolly SJ, Wallentin L, Yang S, Nakamya J, Brueckmann M, et al. Concomitant use of
41 antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term
42
43
Anticoagulation Therapy (RE-LY) trial. Circulation. 2013;127:634-40.
44 70. Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, et al. Prevention of
45 Bleeding in Patients with Atrial Fibrillation Undergoing PCI. The New England journal of medicine.
46 2016;375:2423-34.
47 71. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized
48 controlled trials of cardiovascular disease. Jama. 2006;296:1377-84.
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NDT-01764-2016.R1
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5 Dear Editor,
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9 We are grateful to the Editorial Board for considering a revised version of our manuscript
10 entitled “The quest for equilibrium: exploring the thin red line between bleeding and
11 ischaemic risks in acute coronary syndrome management of chronic kidney disease patients”.
12
13 We would like to thank the reviewers for their valuable time and useful contribution. We
14
15
appreciate their input which helped improve our manuscript.
16
Also, we look forward to hearing from you regarding our submission. We would be glad to
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18 respond to any further questions and comments that you may have.
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20 Please find below a detailed point-by-point reply to the comments made by editors.
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Sincerely,
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27 Adrian Covic
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NDT-01764-2016.R1
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3 -----------------------
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5 Reviewer #1:
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7 1. metabolic milieu: why does CKD predispose to both thrombosis and bleeding ?
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9 "For example, in a recent meta-analysis of observational studies, in patients with atrial
10 fibrillation and ESRD, warfarin had no effect on the risk of stroke but increased the
11 risk of bleeding, especially during the first 30 days of treatment. However, in earlier
12
13 stages of CKD this effect is not reported."
14
15 The meta-analysis both studied non dialysis CKD and dialysis CKD. For non dialysis
16 CKD, warfarin resulted in a lower risk of ischemic stroke/thromboembolism (HR 0.70
17 95%CI 0.54-0.89, p=0.004) and mortality HR 0.65 95%CI 0.59-0.72, p<0.00001) but had
18 no effect on major bleeding (HR 1.15 95%CI 0.88-1.49, p=0.31).
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20 Thank you for your pertinent observation. Indeed, the meta-analysis we discussed took into
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22 consideration both non dialysis and dialysis CKD patients.
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As we pointed out in the phrase preceding the paragraph quoted here, “responses to
24
antiplatelet or anticoagulant drugs may differ from those seen in non-CKD patients,
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26 especially in advanced stages of CKD”.
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28 As you have suggested in your comment, we believe that the dual behaviour of CKD is one
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29 of the key issues in developing effective therapies, suitably tailored as to meet the specific
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31
needs of every patient, in accordance with the respective stage of CKD diagnosed, and
32 represents one from the several focus points in our research.
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34 Therefore, in order to facilitate understanding of this particular aspect, we have rephrased this
35 paragraph as follows:
36
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37 “For example, in a recent meta-analysis of observational studies, warfarin increased the risk
38 of major bleeding for patients with dialysis CKD patients with atrial fibrillation while it had
39
no effect on the risk of stroke. However, for non dialysis CKD patients with atrial fibrillation,
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41 warfarin had no effect on major bleeding, although it lowered the risk of stroke.”
42
43
44
45 2. The other 2 chapters of metabolic milieu about physiopathology should also be
46 deleted to be more focus on clinical practices advices.
47
48 Thank you for this important comment. As you suggested, we deleted the following 2
49 phrases:
50
51 “Classically, the most common haemostasis finding in CKD is a prolongation of the bleeding
52 time due to impaired platelet function with no prolongation of the prothrombin or partial
53
54 thromboplastin times.
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56
In addition, the prothrombotic state in severe CKD has been characterised by impaired
57 fibrinolysis and increased fibrin formation despite normal levels of endogenous fibrinolysis
58 inhibitors. while excess nitric oxide (NO) production has been linked to platelet dysfunction
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NDT-01764-2016.R1
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3 and bleeding risk in uraemia. Finally, this complex scenario is further complicated by the
4 impact of aging and other medical comorbidities.”
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6
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8 3. Dose adjustment-when enough is not enough: I think that this paragraph should also
9
be deleted.
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11 We deleted the following paragraphs from the chapter you mentioned:
12
13 “One relevant example is warfarin. Warfarin is not influenced by kidney function, and
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15
therefore renal dosing adjustment is not required. Bleeding is more frequent in CKD patients
16 with International Normalised Ratio (INR) ≥4 than in those with normal GFR.
17
18 The administration of clopidogrel in CKD patients raises specific issues. Although CKD may
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19 be viewed as an independent risk factor for clopidogrel resistance, as 50-80% of patients with
20 ESRD have high on-treatment residual platelet reactivity when treated with this
21
22 antithrombotic. Clopidogrel has also been associated with increased mortality and
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23 hospitalisation from bleeding for patients with ESRD.”
24
However, in order to maintain our focus on clinical practice advices we kept a few phrases
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26 from this chapter with practical applicability which refer to issues in the Guidelines.
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28
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30 4. Page 7: "delayed hospital presentation...also confirmed by the presence of HF
31 symptoms in a significantly higher percentage for CKD": is CKD not responsible per se
32
of the higher frequency of HF? independently of the delay to come to hospital?
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34 Yes, indeed, there are clear evidences that prove the impact of CKD on the progression of
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36 HF, mostly due to ischemic heart disease. One of the several papers which investigates this
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37 relationship (Curr Opin Nephrol Hypertens. 2004 Mar;13(2):163-70) states that

38 “Congestive heart failure is found in about one-quarter of cases of chronic kidney disease.
39
The most common cause of congestive heart failure is ischemic heart disease.”
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41
However, the focus of our endeavour was placed on the population with ACS which
42
43 associates CKD and HF, while the CKD patients that generate HF, irrespective of their
44 coronary status do not represent a subject of this investigation and therefore are not discussed
45 extensively.
46
47 Moreover, this specific paragraph comments on the issue of the atypical presentation of pain
48
for ACS patients with CKD, according to one of the quoted reference (Am J Kidney Dis.
49
50 2006 Mar;47(3):378-84) that state: “Although patients with kidney disease are at known
51 increased risk for several diseases, this study suggests that kidney disease also might change
52 how these patients experience these diseases, including acute coronary disease.
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54 Patients with kidney disease were less likely to report chest pain (adjusted odds ratio, 0.57;
55
95% confidence interval, 0.46 to 0.70), arm pain (odds ratio, 0.52; 95% confidence interval,
56
57 0.42 to 0.64), shoulder pain (odds ratio, 0.53; 95% confidence interval, 0.40 to 0.72), or neck
58 pain (odds ratio, 0.54; 95% confidence interval, 0.41 to 0.70), while being more likely to
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NDT-01764-2016.R1
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3 report shortness of breath (odds ratio, 1.35; 95% confidence interval, 1.13 to 1.62), in
4 comparison to patients without kidney disease in the setting of AMI.”
5
6 Furthermore, it is true that presence of CKD determines much more frequent HF symptoms
7
independently of the delay to come to the hospital, as you pointed out. Nevertheless, for ACS
8
9 in CKD patients, lack of pain is the actual reason for this delayed presentation, while the
10 atypical symptoms displayed by this specific population include HF as well.
11
12 Finally, in order to facilitate comprehension of our research we have rephrased this paragraph
13 as follows:
14
15 “Another key reason for ACS misdiagnosis lies within the absence or atypical presentation of
16
pain specific for CKD patients, which is also responsible for delayed hospital presentation,
17
18 with a consequent advanced systolic left ventricular dysfunction. Moreover, the particular
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19 profile of ACS & CKD patients also includes presence of HF symptoms in a significantly
20 higher percentage (50%), as reported by two recent studies[1, 2].”
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22
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24 5. page 13 and table 2: "consequently, most recent ESC guidelines consider the use of
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NOACs to be suitable only in patients with AF and CKD with GFR>30 mL/min/1.73m²
26
27 for dabigatran, edoxaban and >25 ml/min/1.73m² for apixaban." And in table 2
28 european medicines agency indications: you mention the doses for rivaroxaban,
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29 edoxaban and apixaban for stage 4 (GFR 15-30ml/min). Thank you for having added
30
31
apixaban and edoxaban into the text.
32
Thank you for your support of the manuscript and your appreciation.
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34 We have added the following phrase to this paragraph: “Consequently, most recent ESC
35
36 Guidelines consider the use of NOACs to be suitable only in patients with AF and CKD with
eGFR >30 ml/min/1.73m2 for dabigatran, rivaroxaban and edoxaban, and >25 ml/min/1.73m2
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38 for apixaban[3], whereas the European Medicine Agency extends rivaroxaban, edoxaban and
39
apixaban usage also for CKD stage 4 – see Table 2. The differences are due to the fact that
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41 ESC made the recommendation based on RCTs results, while EMA took into account
42 pharmacokinetics studies.”
43
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45
46 6. page 13 and Table 3: concerning apixaban and CKD stage 5: the conditions of age
47 and weight should be deleted because you just need one criteria for the low dose 2.5 x 2
48
which is here the renal function. In the text, CKD stage 5, "5 mg apixaban or 2.5 mg bid
49
50 in the presence of age >80 years or/and body weight< 60kg (Tables 2 and 3)." Apixaban
51 2.5 x 2 and not 5 because of creatinine >1.5mg/dL.
52
53 Thank you for your useful observation. We appreciate your comment.
54
55 The original text from FDA instructions for use of apixaban states: “Dosage and
56 administration (2.1): The recommended dose of ELIQUIS for most patients is 5 mg taken
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NDT-01764-2016.R1
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3 orally twice daily. The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with
4 at least two of the following characteristics:
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6 • age ≥80 years
7 • body weight ≤60 kg
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• serum creatinine ≥1.5 mg/dL “.
9
10
11
12 Therefore, we changed the recommendation from Table 3 - Apixaban in CKD 5 and 5D from
13 „2.5 mg b.i.d in presence of 2 of following: age >80 years, body weight <60 kg” to „2.5 mg
14 b.i.d in presence of age >80 years or body weight <60 kg.”
15
16
17 Thus, for CKD 5 and 5D we considered (as you suggested) renal dysfunction as one criterion
18 and at least another one from age or body weight.
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20 We replaced the text you highlighted: “while according to the FDA they may be administered
21
on haemodialysis at the following dosages: 15 mg od for rivaroxaban, 5 mg bid for apixaban
22
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23 or 2.5 mg bid in the presence of age >80 years or / and body weight <60 kg (Tables 2 and 3)”
24 with
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26 “while according to the FDA they may be administered on haemodialysis at the following
27 dosages: 15 mg od for rivaroxaban, 2.5 mg bid for apixaban in the presence of age >80 years
28
or body weight <60 kg (Tables 2 and 3).”
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5 Comments to the Author
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7 I congratulate the authors for this excellent article. I have no further comment.
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9 We thank the reviewer for this support of the manuscript.
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Nephrology Dialysis Transplantation

This is the overview page

The quest for equilibrium: exploring the thin red line

Journal: Nephrology Dialysis Transplantation

Manuscript Type: NDT Perspectives - review (INVITED ONLY)

Date Submitted by the Author: 03-Feb-2017

Dipartimento di Medicina e Chirurgia, Clinica Nefrologica

Rossignol , Patrick; Inserm 1433, Nancy University Hospital & University of

Covic, Adrian; CI Parhon Univ. Hospital, Iasi, Dialysis and Transplantation

Chronic kidney disease, Bleeding risk, Ischaemic risk, guidelines,

29 MB: Department of Hypertension, Chair of Nephrology and Hypertension, Medical University

25 antithrombotic medication, antiplatelet therapy, anticoagulation, novel oral anticoagulants

33 characterised by multifactorial platelet dysfunction facilitating bleeding through defective

29 cardiovascular prevention trials(19). In some instances (e.g. NOACs(27)), such an absence of

40 particular profile characterised by increased prevalence of hypertension, diabetes mellitus,

29 deemed as unsuitable by certain researchers(42), who name it „renalism” and define it as

33 Finally, a small clarification is brought by a recent meta-analysis(43), which indicated a

40 Regrettably, we do not have a definitive answer for this question either.

29 ESC Guidelines recommendations are organised distinctly for antiplatelet and

33 they may be administered on haemodialysis at the following dosages: 15 mg od for rivaroxaban,

33 a. Clopidogrel adjustment adjustment selected recommendations

40 b. Prasugrel No dose No dose Not

33 c. Fondaparinux No dose Doses halved Contra - most favourable

29 * Stage 1 and 2 CKD dosing: similar to non-CKD patients.

29 Edoxaban 60 mg o.d 30 mg o.d 30 mg o.d None

33 Edoxaban 60 mg o.d 30 mg o.d. 30 mg o.d None

33 practical aspects. Clinical kidney journal. 2014;7:442-9.

37 relationship (Curr Opin Nephrol Hypertens. 2004 Mar;13(2):163-70) states that

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