Dr Emma O'lone

Fred Apple

James Burton

Fergus Caskey

Jonathan Craig

Christopher Defilippi

Derek Forfang

Karen Hicks

Vivekanand Jha

Kenneth Mahaffey

O'lone

Apple Fs

Burton Jo

Caskey Fj

Craig Jc

Filippi Cr

Hicks Ka

Mahaffey Kw

Mark Pb

Rossignol

Scholes-Robertson

Viecelli Ak

Wang Ay

Wheeler Dc

Herzog Ca

Kimberly Smith

Aliza Thompson

Defining myocardial infarction in trials of people receiving hemodialysis: consensus report from the SONG-HD MI Expert Working group

Keywords: hemodialysis, myocardial infarction, outcome, definition, trials, recommendations One, Medtronic, Merck, Mount Sinai, Mundi Pharma, Myokardia, NIH

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of death in patients with kidney failure requiring replacement therapy 1 . The incidence of myocardial infarction (MI) in patients receiving hemodialysis is at least 4-times higher than in the general population and is associated with substantially poorer outcomes 1-3 . One-year mortality after a MI in patients receiving hemodialysis is also 60% compared to less than 10% in the general population [4][5][6][7] .

The higher prevalence of MI in the hemodialysis population is multifactorial. Traditional cardiovascular (CV) risk factors, including hypertension and diabetes, are more common. In addition, there are risk factors that are unique to patients receiving hemodialysis, including dysregulation of bone and mineral metabolism leading to increased vascular calcification and uremic toxins. Dialysis also results in rapid hemodynamic changes, heightened inflammation, endothelial and immune dysfunction [8][9][10][START_REF] Herzog | Sudden cardiac death and acute myocardial infarction in dialysis patients: 2 perspectives of a cardiologist[END_REF] .

Patients receiving hemodialysis are usually excluded from large-scale CV interventional trials 12 but when included the most frequently measured and reported CV outcomes are surrogate endpoints such as serum biomarkers which may be of uncertain clinical significance and of little relevance to patients 13,14 . Composite CV outcomes in this population are frequently used to achieve adequate statistical power however, across different trials use different components (e.g. stroke, MI, heart failure) to form each composite outcome 13 . MI, which in a recent international survey including patients and clinicians has been shown to be of the highest importance to patients receiving hemodialysis 15 , is frequently a component of a CV composite endpoint but is defined inconsistently 13,16 . A review of five large CV trials in patients receiving hemodialysis demonstrated four different definitions of MI (Table 1) and different adjudication processes.

Applying an alternative definition or adjudication process to each trial potentially lead a to clinically significant difference in number of reported events. Although not specific to trials in this population, the lack of a standardized and validated definition for MI in patients receiving hemodialysis and the heterogenous measurement and reporting of MI limit the comparison of interventions across trials.

The Standardised Outcomes in Nephrology (SONG) Initiative, a National Health and Medical Research Council (NHMRC) funded project, has established core outcome sets across the spectrum of kidney disease since 2014. A core outcome set is an agreed standardized set of outcomes that should be measured and reported, as a minimum, in all clinical trials in specific areas of health 17 . The core outcomes are based on priorities defined by patients, caregivers, and health professionals. Through the SONG-HD (hemodialysis) consensus process involving over 1500 patients, caregivers, and health professionals from more than 70 countries, CVD was identified as a core outcome, with MI established as the core outcome measure 15,18 . To use MI as a core outcome measure in trials involving patients receiving hemodialysis, consensus on a uniform definition for MI in this population is needed.

The SONG-HD initiative convened an international working group of experts at a roundtable meeting in Washington, D.C. on November 8, 2019. The expert working group was formed using purposive sampling to represent a broad range of countries and experience. It included cardiologists, nephrologists, clinical trialists, a clinical chemist, representatives from regulatory bodies and registries, and patients with experience of hemodialysis, to recommend a uniform definition of MI for use in clinical trials evaluating patients receiving hemodialysis as well as potential for use in clinical practice. We began by considering whether the 4 th Universal Definition of Myocardial Infarction (UDMI) 19 , a standard definition formulated for the general population, was applicable to patients receiving hemodialysis. This definition has not been specifically validated in the dialysis population although it is felt to be applicable to all patients with the caveat that there may be a greater percentage with chronic myocardial injury. There remain several limitations to the definition in people receiving hemodialysis. Specific considerations raised in the SONG-HD CVD consensus workshop regarding criteria required for an appropriate definition of MI informed the deliberations 18 . These considerations included consistency, applicability and specificity of the definition to patients receiving hemodialysis, the importance of the type of MI, variability in MI symptoms in patients receiving hemodialysis, and the uncertainty in the clinical utility of biomarkers specific to hemodialysis. This report summarizes the meeting discussion and the resulting recommendations.

THE 4 TH UNIVERSAL DEFINITION OF MYOCARDIAL INFARCTION

In 2018 the European Society of Cardiology (ESC)/ American College of Cardiology (ACC)/the American Heart Association (AHA)and the World Heart Federation (WHF) jointly published an expert consensus document designated the Fourth UDMI 19 (Box 1). This definition was based on studies of MI in the general population. Although the document briefly discusses myocardial injury/infarction in patients with chronic kidney disease (CKD), including those with kidney failure, the publication does not address patients receiving hemodialysis specifically. Box 2 summarizes the limitations of the 4 th UDMI and its applicability to Type 1 MI in people with kidney failure receiving hemodialysis.

TYPES OF MI

The Fourth UDMI classifies MI into five types. Criteria for the types of MI as laid out by the 4 th UDMI are summarised in Box 1. The criteria required for diagnosing type 1 and 2 MIs in people requiring hemodialysis are outlined below. In brief, MI is defined as follows: (1) a rise and/or fall in cTn with at least 1 value >99 th percentile URL in patients with an initial cTn ≤99 th percentile URL; and (2) a >20% rise and/or fall in cTn in patients with an initial cTn >99 th percentile URL.

Patients receiving hemodialysis have both a high prevalence of acute myocardial injury and are predisposed to acute MI, due to underlying pathophysiological features. Diagnosis of a type 2 MI requires consideration of both the context and mechanism leading to the imbalance of oxygen supply and demand. This is of particular importance to patients receiving hemodialysis, a process which has been shown to have significant hemodynamic effects which increase myocardial oxygen demand 20 . Hemodialysis also induces significant global and segmental reductions in myocardial blood flow 21 . Underlying pathophysiological changes related to kidney failure, including left ventricular hypertrophy and associated capillary/myocyte mismatch, reduced peripheral arterial compliance, endothelial dysfunction, anemia, and reduced coronary flow reserve, predispose patients requiring hemodialysis to demand ischemia. The prevalence of type 2 MIs is high in the hemodialysis population 69 . Estimating prevalence is difficult because differentiation between MI types 1 and 2 often requires expert adjudication in large clinical cohorts and ideally includes coronary angiography to definitively exclude coronary thrombosis 22 .

To establish appropriate treatment according to current guidelines 27,28 , it is important to classify MI into ST-elevation MI (STEMI) or non-ST-elevation MI (NSTEMI). In the setting of a STEMI, primary percutaneous coronary intervention or thrombolytic therapy may be required and in the setting of a NSTEMI, coronary angiography may be indicated. Further classification into a Type 1 or 2 MI is not as well defined and there are limited quantitative data on the efficacy of coronary angiography in differentiating a type 1 from type 2 MI. Short and long-term mortality rates for type 2 MI are higher than for type 1 MI, although it is unclear whether there are differences in attributable cause-specific mortality [23][24][25][26] . Treatment of type 2 MI largely consists of addressing the underlying supply and demand imbalance noninvasively. In the case of hemodialysis, reducing "demand" may be possible through reducing ultrafiltration rates but there are often patient or centre based limitations to moving away from standard short intermittent dialysis sessions. Even in the general population long-term treatment strategies for type 2 MI in the absence of coronary artery disease lack trial data or guidelines 29 . Differentiating type 1 from type 2 MIs is challenging for adjudication experts as well as clinicians. Recent published guidelines advocate that in the absence of a clear alternative cause, the initial working diagnosis for most patients with evidence of acute myocardial injury and signs and symptoms consistent with ischemia should prompt classification and management according to established guidelines for type 1 MI 29 . Although treatment based on the type of MI may differ, the working group considered MI, regardless of type, to be the most important outcome captured in clinical trials. Evidence-based protocols for the management of type 2 MI remain limited.

Differentiating types 1 and 2 MI can be challenging. Improving our ability to recognize and treat MIs is a priority for future research.

MI should be a core outcome reported in clinical trials involving people with kidney failure receiving hemodialysis and a uniform definition should be used.

CRITERIA USED TO DEFINE TYPES 1, 2 AND 3 MI 1. Ischemic symptoms

Studies indicate that patients with CKD, and particularly those receiving hemodialysis, often do not describe typical symptoms of MI. The classic triad of chest discomfort, arm/jaw pain and sweating is experienced by less than 50% of patients with CKD 30 . In patients receiving hemodialysis, the most common "ischemic symptom" is shortness of breath, experienced by nearly 50% of patients receiving dialysis 30,31 . Chest pain or discomfort associated with MI is experienced by less than 20% of patients receiving dialysis compared to over 35% of patients with normal kidney function 31 . Patient receiving dialysis described a background level of pain and discomfort and felt that non-specific symptoms or a change in sensation or degree of unwellness should also raise suspicion as an "ischemic symptom." It is important to note that highlighting more nonspecific ischemic symptoms may result in increased diagnosis of myocardial injury as well as MI [START_REF] Iseki | Long-term prognosis and incidence of acute myocardial infarction in 59[END_REF] .

In a patient receiving hemodialysis, atypical symptoms or any changes in symptoms should raise a high index of suspicion for a potential MI and prompt further investigation and treatment.

ELECTROCARDIOGRAM

Fluid and electrolyte changes during hemodialysis affect ECG waveforms. The removal of fluid over the course of a dialysis session has been shown to augment the P wave as well as the QRS amplitude and duration 33 . Similarly, electrolyte shifts during dialysis have been shown to affect the P wave, QRS, and QTc 33,34 . Whether an ECG is acquired during, before or after dialysis should be considered in its interpretation; persistent changes such as left bundle-branch-block (BBB) are unlikely to be influenced by variations in dialysis.

Patients receiving hemodialysis often have abnormal baseline ECGs making it difficult to determine acute change. In one series approximately 30% of such patients were found to have electrical conduction abnormalities including left and right BBB on a baseline ECG. ST elevation occurs in less than 20% of patients with an MI on dialysis compared to over 35% of patients who are not on dialysis 35 . A non-specific ECG change is the most common finding in patients presenting with MI on hemodialysis 35. Patients with CKD are significantly less likely to develop a pathological Q wave than patients without CKD (19% compared to 34%) 30 . It is important that non-specific ECG findings are taken in the context of the clinical presentation and in combination with troponin findings to help rule-in an MI though may not help ruling out MI.

Although patients with CKD, and particularly patients receiving hemodialysis, have a higher prevalence of silent MI compared to the general population 36, 37 , there is no consensus regarding whether routine (annual or more frequent) collection of ECGs in this population confer incremental value in the absence of other clinical or biochemical abnormalities. Hence, for the purposes of clinical trials, the working group recommends obtaining ECGs in association with acute events but recommends where relevant discussing with regulators prior to study conduct, to consider whether baseline ECG and any subsequent changes consistent with silent MI events should be considered as an MI in a trial.

Patients indicated that an additional ECG at baseline "would not be a burden because it is noninvasive" and clinicians thought a baseline ECG would better inform trial endpoint definitions and patient care.

A baseline ECG in all patients receiving hemodialysis when stable and asymptomatic may aid in the interpretation of acute ECG changes on subsequent tracings in the setting of acute clinical symptoms or biomarker changes suggestive of MI. On trial entry, we suggest performing a single baseline ECG on each patient. We also recommend obtaining serial ECGs during an acute event followed by another ECG when the patient is clinically stable.

Cardiac Troponin

Troponin is a complex of three regulatory proteins (troponin I, C and T). During myocardial injury cTnI and cTnT are released as individual subunits as well as non-covalent ternary and binary complexes 38,39 . cTnT and cTnI are now the preferred biomarkers of myocardial injury. Troponin is a biomarker for myocardial injury; the 4 th UDMI includes clinical evidence of acute myocardial ischemia with detection of a rise and/or fall of cTn values with at least one value above the 99th percentile upper reference limit (URL) plus additional criteria as summarized in Box 1.

Assay variability

High sensitivity cardiac troponin (hs-cTn) assays need to meet two criteria: a coefficient of variation (total imprecision) of < 10% at the 99th percentile URL for both men and women and measurable concentrations below the 99th percentile URL need to be detectable above the assay's limit of detection for > 50% of healthy individuals in the population of interest [40][41][42] . Sex-specific 99 th percentile URLs for hs-cTn assays have been derived and validated in the general population based on healthy individuals 42 . It is not possible to achieve disease specific thresholds due to the heterogeneity within each specific disease population. hs-Tn assays are now in widespread use and accurately and precisely measure five to 100fold lower concentrations of cTn in blood than older, contemporary assays 43,44 . The various hs-Tn assays use monoclonal antibodies to a number of different epitopes along the cTnT or cTnI protein 45 . On account of the large variations in epitopes targeted by the different antibodies used in each assay, it is not possible to standardize URLs across assays.

Biological variability

Biological variability describes the fluctuation of biomarker levels around a homeostatic setpoint in healthy individuals or those with stable disease and which is of no clinical significance. Biological variability is low, with intra-patient coefficients of variation quoted as 7.9% for weekly measurements and 12.6% for monthly measurements. Although, there may be increased biological variability when using hs-cTn 63. , over the course of a year this biological variability is minimal and if an acute event occurs, cTn subsequently returns to the individual patient's baseline 47 . Interpatient variability is high in patients on hemodialysis 46 .

Effect of dialysis on cardiac troponin:

To date only relatively small studies have been conducted to evaluate the effect of dialysis on cTn. The troponin complex (52 kDa), as well as the subunits (cTnI is 24 kDa and cTnT is 37 kDa) are classified as middle molecules by size. Older dialyzer membranes predominantly filtered out small, water-soluble molecules and not the "middle molecules", now thought to be the cause of much of the historical morbidity and mortality. New synthetic membranes and the increase in convective therapies have improved the clearance of a number of these molecules. There remains a lack of consensus regarding the effect of dialysis on cTnI and cTnT levels however there is some evidence that cTnI is adsorbed onto the surface of the dialyzer membrane [49][50][51] . High flux dialyzers may increase cTn clearance more than low flux dialyzers 52, 53 and clearance is potentially increased further still with hemodiafiltration 53 . The increasing use of nocturnal dialysis and prolonged hours dialysis may have significant effect on both the production and handling of troponin. To date, changes in levels of both cTnT and cTnI are relatively small and there is insufficient evidence at this time to suggest that the effect of standard dialysis on troponin is significant enough to alter the diagnosis of MI in patients receiving hemodialysis.

Elevated baseline troponin

Levels of cTnT and cTnI over the sex specific 99 th percentile URL have been demonstrated in up to 80% for cTnT but < 20% for cTnI of patients requiring hemodialysis 46,54,55 . Reduced kidney clearance is not the main driver of an elevated cTn in this population 56 . The exact etiology/mechanism of elevated baseline cTn, or why cTnT remains increased longer than cTnI, is not entirely clear but is likely to be multifactorial including increased instability of the cardiac myocyte membrane, microinfarctions, and myocardial necrosis as well as increased left ventricular hypertrophy and heart failure causing myocyte strain and apoptotic cell death 57-61 .

In the absence of an acute event, elevated baseline cTn in patients receiving hemodialysis is a strong predictor of adverse outcomes. It has been shown that increased cTnT and cTnI are both predictive of CV and all-cause mortality in ESKD 47,[62][63][64][65] . Identifying risk has an effect on the individual patient and the cost to healthcare. There is currently insufficient evidence to suggest a pathway in response to the identified increased risk.

Therefore, although a determinant of risk, an historical baseline troponin should not contribute to the diagnosis of acute MI and we do not support the concept of acquiring a cTnI or cTnT on entry into a trial in HD dialysis patients. We acknowledge that a baseline level of cTnI or cTnT in an individual patient is a useful tool in identifying chronic myocardial injury and that the collection of a baseline troponin may offer future opportunities for further biomarker investigation and clarification of the role of troponin. However, in the assessment of a symptomatic patient presenting to the hospital, serial troponin monitoring should be used for ruling in or ruling out an MI.

Currently we do not suggest collecting a baseline (trial entry) cTn in a trial setting.

Performing baseline cTn in stable, asymptomatic patients receiving hemodialysis may identify patients at increased risk for adverse outcome but with no currently proven treatment to reduce risk, resulting in unwanted concerns for patients without contributing to the diagnosis of acute MI.

Delta Troponin

The US National Academy of Clinical Biochemistry (NACB) (redesignated as, Academy of the American Association of Clinical Chemistry [AACC]) recommended a δ in standard assays for cTn of > 50% if cTn is less than the 99 th percentile URL and ≥ 20% once values are elevated above the 99 th percentile URL. These values are calculated to distinguish a true change from one that could be attributed to biological variability alone and yet maintain sensitivity 44 .

The clinical sensitivity of hs-cTn assays to detect myocardial injury remain high in patients on hemodialysis, reported as 100% 31 however high prevalence of elevated baseline cTn can reduce specificity to as low as 40%. Hence, in a hemodialysis patient with an initial cTn value greater than the 99 th percentile URL, a rise and/or fall of more than 20% is suggestive of an acute MI and should be included in the endpoint definitions in a trial setting. Short-term intra-patient biological and analytical variability is minimal in the absence of an acute event, however, a one to two hour follow up sample after initial testing may not be sufficient to rule out MI. Patients presenting early after an MI are unlikely to be missed using a two-hour sample but for patients who present with atypical symptoms, it may be harder to know where on the cTn kinetic curve (Figure 1) they are at a given time point. Any dynamic change in cTn or strong clinical suspicion should prompt further cTn samples so as not to miss a significant delta. This may require samples to be taken after up to 6 hours to ensure an MI is not missed.

Current evidence suggests that, in the context of an initial cTn above

  the sex specific 99 th percentile URL, a δ cTn > 20% in cTn in addition to the clinical criteria should be an gut permeability and cardiovascular risk in HD patients and have received speaker honoraria from 11 NAPP, BMS and Pharmacosmos on the topics of diabetic kidney disease, cardiovascular risk and 12 anaemia. 13 FC receives honoraria from Baxter. Research funding from NIHR and Kidney Research UK 14 C de F receives grants to my institution and advisory board from Roche diagnostics: Ortho 15 diagnostics: consulting and endpoint education, Siemens Healthineers: consulting, FujiRebio: 16 consulting and Up-to-date: royalties.

  17

  VJ reports personal fees from GSK, personal fees from Bayer, personal fees from Boehringer 18 Ingelheim, personal fees from Baxter Healthcare, grants from NephroPlus, grants and personal fees 19 from Zydus Cadilla, outside the submitted work; under the policy of all payments being made to the 20 organization 21 KM has received research support and/or consulting fees from the following companies: Abbott, 22 Afferent, Amgen, Anthos, Apple, Inc, AstraZeneca, Baim Institute, Boehringer Ingelheim, Cardiva 23 Medical, Inc, CSL Behring, Elsevier, Ferring, Google (Verily), Intermountain Health, Johnson & and travel support from Bayer and Servier, owning stock options in G3 Pharmaceuticals, and fees 12 for serving as co-founder and owning stock in CardioRenal. 13 AW has received speaker honorarium from Sanofi Renal and Fresinius Kabi, and research grants 14 from Sanofi Renal and Baxter Corporation. 15 DCW has received honoraria and/or consultancy fees from Amgen, AstraZeneca, Astellas, Bayer, 16 Boehringer Ingelheim, GlaxoSmithKline, Janssen, Merck Sharpe and Dohme, Mundipharma, Napp, 17 Reata, Tricida, and Vifor Fresenius 18CH reports grants from NIDDK/NIH (USRDS Contract), during the conduct of the study; personal fees from Abbvie, grants and personal fees from Amgen, personal fees from AstraZeneca, personal 20 fees from Corvidia, personal fees from Diamedica, personal fees from FibroGen, personal fees from 21 Janssen, personal fees from NxStage, personal fees from Pfizer, grants and personal fees from 22 Relypsa, personal fees from Sanifit, personal fees from University of Oxford, grants from Bristol-the consensus workshop. David Charytan who reviewed the manuscript. 9 patients on chronic hemodialysis. The Okinawa Dialysis Study Group. Am J Kidney Dis 5 2000;36(4):820-5.

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FIGURE 1

 1 FIGURE 1 EARLY CARDIAC TROPONIN KINETICS IN PATIENTS AFTER ACUTE MYOCARDIAL

  Figure 1

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Myers Squibb, grants from University of British Columbia, personal fees from UpToDate, other

SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow

This work was supported by the National Health and Medical Research Council Australia (NHMRC; 1098815). Research, Centre for Kidney Research Locked Bag 4001 grants from Boehringer Ingelheim, personal fees and non-financial support from Pharmacosmos, submitted work. 7 PR receives consulting fees and travel support from Novartis, consulting fees from Novo Nordisk, 8 AstraZeneca, Grünenthal, and Corvidia, consulting fees, lecture fees, fees for serving on a steering 9 committee, and travel support from Relypsa/Vifor/Vifor Fresenius Medical Care, fees for serving steering committee and fees for serving on a critical event committee from Idorsia, lecture fees from Boston Scientific, other from General Electric, other from Johnson & Johnson, personal fees 1 and other from Merck, other from Hennepin Healthcare, grants and personal fees from National 2 Heart Lung and Blood Institute (NHLBI/NIH), outside the submitted work; .

accepted rise and/or fall to diagnose acute MI in the patients requiring hemodialysis. An early rule-out sample may not be sufficient to exclude MI in patients requiring hemodialysis.

SUMMARY

The (SONG-HD) Initiative convened an expert working group to discuss MI definitions most appropriate for use in clinical trials enrolling patients requiring hemodialysis. Although all definitions have limitations, the working group recommends using the 4 th UDMI and suggests that trialists and clinicians maintain a broad interpretation of "ischemic symptoms" in this population.

The working group also recommends obtaining a baseline ECG to aid in the interpretation of acute changes noted on subsequent tracings. Serial cardiac biomarkers, optimally measured by hs-cTn assays, are needed to evaluate potential events of myocardial ischemia and myocardial injury. In addition, a greater than 20% delta in cTn is required to define an acute MI event in patients on hemodialysis with a baseline (at time of presentation) cTn that exceeds 99 th percentile URL. Our future work will include validation of the use of the 4 th UDMI in patients receiving hemodialysis.

Box 3 summarizes the recommendations for clinical end point committee adjudication criteria for diagnosis of myocardial infarction in trials including people receiving hemodialysis. Supplementary material 1 outlines the recommended elements to incorporate into a Case Report Form for suspected or confirmed acute myocardial infarction events in trials including people receiving hemodialysis.

The working group has identified a number of directions for future research. At this time there are limited data in the hemodialysis population to create evidence-based guidelines. We recommend evaluating diagnostic methods for MI and MI type in patients receiving hemodialysis as well as improving the prevention and treatment of type 2 MI. We recommend investigating the reported lower percentage of STEMIs in this population and whether this is due to fewer acute coronary occlusions noted on angiography or confounders related to baseline ECG abnormalities.

We recommend determining whether these findings impact reperfusion therapy in this population.

Consistent definitions and standardized reporting should improve trial quality, reproducibility, and comparability which will assist in endeavours to improve outcomes for this high-risk population.

Disclosures