Diagnosis and management of ACS in patients with ESRD on haemodialysis: a comprehensive review

Acute coronary syndromes (ACS) are common in patients with end-stage renal disease (ESRD). Diagnosis may be challenging given diverse symptomatology, absence of classical symptoms on presentation, and difficulties in the interpretation of biomarkers. Morbidity and mortality in this patient population remain high compared with patients with normal renal function, partly due to a lack of evidence for optimal management. This review presents a summary of the diagnostic features and early management of ACS in patients with ESRD on haemodialysis.

Introduction

Acute myocardial infarctions (AMI) occur with an increased frequency in patients receiving long-term dialysis treatment for end-stage renal disease (ESRD). Moreover, these patients have additional comorbidities, such as diabetes mellitus and systemic arterial hypertension, further predisposing individuals to the development of coronary artery disease.^1,2 By its very nature, haemodialysis (HD) therapy may be highly disruptive to patients’ lifestyles, as those receiving regular sessions are less likely to perform regular exercise, adhere to a healthy diet, face difficulties complying with medications or adopt health-seeking behaviour including early reporting of cardiac symptoms.^3,4 The fourth universal classification of myocardial infarction (MI) further outlines the various classes of MI based on underlying pathophysiology.⁵ Myocardial ischaemia in the absence of obstructive coronary artery disease, including type II AMIs,⁵ can be a common presentation of AMI in this population. Chronic anaemia and fluid overload result in the development of left ventricular hypertrophy, which subsequently raises the myocardial oxygen demand. The substantial fluctuations in fluid balance and blood pressure during haemodialysis exacerbate the mismatch between oxygen supply and demand.⁴ Furthermore, repeated cycles of cardiac injury from impaired coronary flow during HD therapy,⁶ may predispose these patients to adverse cardiac events,⁷ often associated with regional wall motion abnormalities and myocardial stunning during dialysis therapy.^8,9

The prevalence of acute coronary syndrome (ACS) in the US population among chronic HD patients was 13.3% (2015) compared with 3.0% in the rest of the population (2013–2016).^10,11 Despite improvements in the standard of care, the odds of death in patients on dialysis sustaining AMI remains unchanged in the period between 1996/97 and 2012/13 when compared with matched dialysis population (odds ratio [OR] 1.99, 95% confidence interval [CI] 1.52 to 2.60, and OR 2.04, 95%CI 1.62 to 2.58, for 1996/97 and 2012/13, respectively, p=0.34).¹² This is reflected further through the National Cardiovascular Data Registry Chest Pain – Myocardial Infarction Registry, where in-hospital mortality and bleeding rates remained high post-ACS in the HD patients,¹³ with a significant impact on two-year survival following ACS (HD 59.4% vs. 78.6% preserved kidney function).¹⁰

AMI patients on HD frequently present with atypical clinical features and have poor outcomes.^14,15 Despite the well-documented association between AMI and ESRD, patients with advanced chronic kidney disease (CKD) are frequently excluded from trials of new diagnostic and therapeutic strategies.^1,16 In the absence of robust evidence to support treatment decisions, practice has varied in the acute management of patients presenting with features of AMI. This review is aimed at addressing challenges around the diagnosis and early management in acute care settings in patients receiving long-term dialysis treatment who present with suspected AMI. This includes patients who present to emergency departments, develop symptoms during dialysis sessions, or develop typical or atypical features of ACS while an inpatient.

Diagnosis

The diagnosis of ACS relies heavily on clinical presentation with presence of typical features of ischaemia, rise in cardiac biomarkers and significant electrocardiographic (ECG) findings. The interpretation of these, however, is difficult in HD-dependent patients due to the complexity of ESRD causing uraemia-associated cardiac changes and dialysis itself.¹⁷

Clinical presentation of ACS in patients with ESRD on dialysis

Patients receiving maintenance HD are less likely to present with chest pain typically associated with ACS;¹⁸ chest pain is present in 41–67% of ESRD patients on dialysis compared with 90% of individuals with preserved kidney function.^19,20 Further review of symptomatology in the literature suggests that certain key characteristics of cardiac chest pain, such as radiation to upper limbs, jaw and neck with associated diaphoresis, are less likely to develop in patients with ESRD.²¹ One potential aetiology for the lack of classical symptoms may be related to autonomic neuropathy secondary to diabetes and uraemia.¹⁸ Dyspnoea^19,21 and heart-failure-associated clinical signs, such as rales, jugular vein distension and gallop rhythm, are common (38–42.2%),^19,20 and more likely to be the presenting features (CKD OR 1.73, 95%CI 1.40 to 2.15; no CKD OR 0.48, 95%CI 0.41 to 0.57).²¹

ECG and echocardiographic findings

Non-ST-elevation myocardial infarction (NSTEMI) is the most common cause of ACS in ESRD, attributing to ~80% of known ACS events, according to the US Renal Data System.²² Recent data presented following subanalysis of the landmark Proactive IV Iron Therapy in Haemodialysis Patients trial reported an increased likelihood of NSTEMI compared with ST-elevation myocardial infarction (STEMI) in this population (6.6 times greater; NSTEMI 3.3/100 patient-years, STEMI 0.5/100 patient-years).²³ Pre-existent ECG findings suggestive of left ventricular hypertrophy, Q waves and conduction abnormalities are common. Moreover, ESRD complications, such as uraemic pericarditis and electrolyte disturbances (e.g. hyperkalaemia) can cause ECG changes. Bedside transthoracic echocardiography (TTE) may be used to identify regional wall motion abnormalities, which can aid the diagnosis of ACS. However, these changes may pre-date the index presentation as HD patients may already have pre-existent systolic and diastolic dysfunction and regional wall motion abnormalities, and, therefore, it is important to correlate with previous imaging, if available.^24,25

Cardiac troponins

Serum cardiac troponins T and I (cTnT, cTnI) are markers of myocardial strain and damage. High-sensitivity (hs) assays for both are readily available and often show detectable levels even in healthy subjects.²⁶ In the general population, a significant rise in cTnT or cTnI, defined as a cTnT rise above the 99^th percentile of the population’s upper reference limit (URL) value or >20% in absolute value in those with chronically elevated results, should alert clinicians to the possibility of ACS, as per guidance from the American Heart Association (AHA) and the European Society of Cardiology (ESC).^27,28

Cardiac troponins are often chronically elevated in patients with ESRD receiving regular dialysis.¹⁸ This is not due to impaired excretion, as hs-cTn has a kidney extraction index of 8–19%, but more likely due to ongoing cardiomyocyte damage secondary to ESRD and dialysis.²⁹ The latter represents a cycle of repeat myocardial stunning, reduced myocardial perfusion and increased cardiac strain, as indicated by cardiac magnetic resonance imaging (MRI) studies on HD patients.³⁰ Studies indicate that troponin concentration, specifically cTnT, may be affected by the time interval from a haemodialysis session.³¹

Currently, there are no universally accepted URL values specific to the HD population, and associated evidence can only be derived from studies encompassing the entire CKD spectrum. This is highlighted in a systematic review of literature reporting large heterogeneity between studies in terms of the baseline population and assays used to detect cTnT and cTnI.³² A prospective multi-centre study (n=4,726; 19% reduced estimated glomerular filtration rate [eGFR], 0.3% HD) has highlighted the lack of understanding of cut-off values in relation to CKD. It observed a lower positive-predictive value (PPV) and specificity at the 99^th centile (30 ng/ml) in patients with renal impairment with regards to cTnI (CKD PPV 50.0%, 95%CI 45.2 to 54.8%, specificity 70.9%, 95%CI 67.5 to 74.2%; non-CKD PPV 62.4%, 95%CI 58.8 to 65.9%, specificity 92.1%, 95%CI 91.2 to 93.0%).³³ A further observational study (n=1,555, HD=78) highlighted a reduction in specificity of cTnI with declining eGFR from 93–95% in those with normal renal function to 40–41% in HD patients.³⁴

Yang and colleagues attempted to address this problem by comparing changes in hs-cTnT levels in CKD (ACS n=302, HD=24; no ACS n=187, HD=72).³⁵ Using hs-cTnT assay, they calculated sensitivity, specificity and area under the curve (AUC) of 79.2%, 81.9% and 0.85, respectively, for cTnT cut-off of 149.35 ng/L for ACS prediction.³⁵ A similar approach regarding cTnI was employed in a retrospective review of 82 patients (HD=75, peritoneal dialysis=7). An optimal cut-off of 75 ng/L was defined (sensitivity 93.33%, specificity 60.76%, AUC 0.87).³⁶ Evidence from non-dialysis dependent (NDD)-CKD patients suggests that implementation of a single cut-off point could be difficult due to inter-assay differences.^32,37 In addition, the nature of haemodialysis appears to dictate the trends in increase and elimination of hs-cTnT.³⁸

Given the ambiguity of a pre-specified cut-off value, dynamic changes of cTn can help distinguish between acute and chronic cTn elevation. The timing of repeat measurement and degree of cTn change are, however, uncertain. The ESC has recently advocated the use of the 0/1-hour algorithm, an assessment of baseline cTnT and comparison with subsequent changes within the first hour of admission, for detection of NSTEMI.²⁷ A large prospective multi-centre study of this algorithm enrolled patients with suspected NSTEMI (total n=3,254, eGFR <60 ml/min/1.73 m²; no HD patients n=487) and reported decreased overall efficacy in patients with reduced eGFR in ruling out myocardial injury.³⁹ A similar issue surrounds the 0/3-hour algorithm using cTnI: a large disparity in specificity exists between patients with preserved renal function (92.9%, 95%CI 90.6 to 95.3%) and HD patients (41.0%, 95%CI 25.6 to 56.5%) despite similar sensitivity.³⁴ A mixed cohort study (n>8,500) utilised optimised cut-off values and reported that an increase of 2.8-fold in cTnI or 2.5-fold in cTnT at three hours yielded better ability in positively detecting ACS compared with the current conventional approach.⁴⁰ This study was specific to NDD-CKD patients and, therefore, the exact change in cut-off (hs-cTnI 54 ng/L; hs-cTnT 50 ng/L) and degree of increase cannot be applied in HD patients.⁴⁰ Additional evidence regarding the importance of comparison with previous cTn results comes from a prospective review of weekly hs-cTnT measurements in 42 stable HD patients. This study concluded that in this population, significant variation in serial hs-cTnT concentrations may occur, however, a 25% decrease or 33% increase in the concentration levels may highlight an underlying additional myocardial injury process and should not be attributed to analytical or biological variations alone.⁴¹

Newer diagnostic cardiac biomarkers, such as serum soluble suppression of tumorigenicity 2 (sST2) factor, a molecule associated with the interleukin-1 family that is upregulated during increased cardiac stress but also noted to have levels correlated with peak creatinine kinase in ACS, are under investigation.²⁹

Treatment

Interventional approach – is time truly muscle?

The general principles of treatment for STEMI are the same for patients receiving dialysis as in the general population, including reperfusion using medical and invasive therapies. The aim for these patients is to rapidly assess the safety of primary percutaneous coronary intervention (PCI).^42,43 Such a task should be undertaken with close collaboration between cardiology and nephrology teams, ensuring urgent PCI management and safe provision of dialysis when necessary.

The evidence of proven therapies in the management of NSTEMI is lacking in HD patients. While the timing of intervention is well-guided through risk-stratification scores (Thrombolysis in Myocardial Infarction – TIMI, Global Registry of Acute Coronary Events – GRACE score) in patients with normal kidney function, these are not validated in the HD population.^27,28 There is persistent underrepresentation/exclusion of patients with significant renal disease in randomised-controlled trials (RCTs). Large registries, such as the Swedish Web-system for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) and Korea Acute Myocardial Infarction Registry (KAMIR), have reported no benefit with early revascularisation,^44,45 while a meta-analysis (seven trials; n=23,234) concluded improved one-year mortality with early intervention, irrespective of renal function, but reduced improvement with decreasing eGFR,⁴⁶ potentially reflecting the notion of worsening outcomes with decreasing eGFR post-ACS.⁴⁷

The recently completed ISCHEMIA-CKD (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches – Chronic Kidney Disease) study attempted to answer whether, in stable coronary artery disease, an early interventional approach is beneficial in patients with advanced CKD (eGFR <30 ml/min/1.73 m²).⁴⁸ The study included 415 HD patients and demonstrated comparable three-year event rates, irrespective of management (early-invasive 38.1%; conservative 39.9%; hazard ratio [HR] 1.0, 95%CI 0.72 to 1.39), reporting no evidence supporting initial invasive strategy in death or nonfatal MI risk reduction.⁴⁸ The ISCHAEMIA-CKD EXTEND study will follow-up on surviving patients from the above trial in the long term to assess for cardiovascular outcomes and mortality differences between the two arms.⁴⁹ Intriguingly, a meta-analysis including eight studies (HD-CKD n=1,685) noted a significantly reduced long-term all-cause mortality compared with conservative therapy in known coronary artery disease, but failed to signal any benefits of such an approach in ACS.⁵⁰

Early medical management: anticoagulant and antiplatelet agents

Anticoagulants

Parenteral anticoagulation, in the setting of ACS, is supported by clinical guidelines and indicated as a means of reduction of thrombotic events. It is recommended for at least 48 hours, or for the duration of hospitalisation if no revascularisation takes place. Large studies have supported the use of unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux and bivalirudin.^28,43 Nonetheless, numerous studies failed to include HD-dependent patients, and their use can be hindered by dose adjustment, concerns regarding side effects in low eGFR and the need for therapeutic monitoring.⁵¹

UFH has long been regarded as the anticoagulant of choice in hospitalised dialysis patients. It acts by inhibiting thrombin and potentiates the effects of natural inhibitors of factor X;⁵² it is mainly eliminated through the reticuloendothelial system.⁵³ Both the AHA and ESC favour UFH use in patients with ESRD on dialysis, as opposed to other anticoagulants.^27,28 In clinical practice, monitoring UFH infusion makes it a less than ideal choice; over- and under-anticoagulation is common,⁵⁴ and potentially hazardous. Compared with LMWH, the use of UFH was associated with a trend towards increased in-hospital bleeds and higher 30-day mortality in patients with creatinine clearance of less than 30 ml/min.⁵⁵

LMWH are factor Xa inhibitors and include, among others, enoxaparin and dalteparin. They are excreted through the renal route and, therefore, a dose adjustment is necessary in patients with renal impairment, accompanied also by monitoring of anti-factor Xa activity.⁵⁶ Enoxaparin is the most studied LMWH in patients with reduced renal function. In patients with preserved renal function, the enoxaparin dose is 1 mg/kg every 12 hours for treatment of ACS; in those with a creatinine clearance <30 ml/min a reduced dose of 1 mg/kg every 24 hours (or 0.5 mg/kg every 12 hours) has been recommended.⁵⁷ The major trials of enoxaparin use in ACS have excluded patients with advanced renal impairment.^56,58,59 A post-hoc analysis of patients with severe renal impairment included in these trials (n=143) did not show a difference in outcomes between enoxaparin and UFH.⁶⁰ These analyses did, however, reveal a six-fold increase in major bleeds risk, regardless of whether patients received enoxaparin or UFH, highlighting the increased bleeding risk in dialysis patients receiving anticoagulation. A meta-analysis of published trials (12 trials, n=4,971) of LMWH including enoxaparin, indicated ‘half-dose’ enoxaparin was not associated with increased bleeding risk.⁶¹

There are limited data on the use of dalteparin.⁵⁶ Based on data from enoxaparin use, it would be reasonable to assume that ‘half-dose’ dalteparin could be considered for treatment of ACS in dialysis patients. It should be given as a once-daily dose and, similar to enoxaparin, anti-factor Xa levels monitoring is required, which can be expensive and have logistical implications.⁶²

Fondaparinux, an indirect inhibitor of factor Xa, has become the standard of care in patients with ACS and normal kidney function since the OASIS-5 (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes) trial showed equivalent efficacy compared with enoxaparin, with significantly lower risk of bleeding.⁶³ A subanalysis of this trial showed that when patients were stratified by eGFR, fondaparinux was safer than enoxaparin in those with an eGFR <58 ml/min/1.73 m².²⁸ Patients with advanced renal disease (eGFR <20 ml/min/1.73 m² or serum creatinine >265 µmol/L) were excluded. Fondaparinux is not indicated for use in patients with eGFR <20 ml/min/1.73 m² or creatinine of >265 µmol/L. Nonetheless, there is an increasing interest in its use, and clinical experience is changing.⁶⁴

Bivalirudin is a direct and reversible thrombin inhibitor, initially heralded as the successor of UFH in ACS.⁶⁵ A previous meta-analysis, including three RCTs, attempted to address the suitability of bivalirudin in renal dysfunction through stratification based on creatinine clearance (normal >90 ml/min, n=1,578; mild 60–90 ml/min, n=2,163; moderate 30–59 ml/min, n=1,255; severe <30 ml/min, n=39). It reported an increase in absolute benefit regarding ischaemic and bleeding complications with decreased renal function (normal 2.2%, mild 5.8%, moderate 7.7%, severe 14.4%; p_trend<0.001, p_interaction=0.044). All HD patients were excluded.⁶⁶ A review of the National Cardiovascular Registry identified 71,675 ESRD patients undergoing PCI that were administered bivalirudin or UFH. The bivalirudin group had lower rates of in-hospital bleeding (7.0% vs. 9.5%; adjusted OR 0.82, 95%CI 0.76 to 0.87) and mortality (2.6% vs. 4.2%; adjusted OR 0.87, 95%CI 0.78 to 0.97).⁶⁷ These results were complemented by a smaller-scale review of 4,303 HD patients undergoing PCI, which showed no difference in outcomes relevant to repeat PCI needs (adjusted OR 0.57, 95%CI 0.14 to 2.24, p=0.42) and stent thrombosis (adjusted OR 0.56, 95%CI 0.05 to 5.83, p=0.63).⁶⁸

Antiplatelet agents

Dual antiplatelet therapy (DAPT) remains fundamental in the management of ACS and includes the combination of aspirin and a P2Y12 inhibitor (clopidogrel/ticagrelor/prasugrel). P2Y12-receptor inhibitors affect the P2Y12 pathway of the adenosine diphosphate receptor through different mechanisms. Large-scale RCTs have advocated their efficacy and safety in the population with normal eGFR, highlighting the superiority of newer agents, such as ticagrelor and prasugrel, compared with clopidogrel; as such they have been incorporated into international management guidelines,^28,42 with a recommended duration of a minimum of 12 months following ACS and PCI. No currently used oral antiplatelet requires dose adjustment in HD patients. Evidence surrounding their use in HD patients is scarce, and this is reflected by the stance of the ESC and AHA advocating the use of aspirin and clopidogrel when DAPT is required (e.g. stent thrombosis prevention) and advising to avoid ticagrelor or prasugrel in ESRD.^28,43 The duration of DAPT in dialysis remains controversial,⁶⁹ while new evidence suggests P2Y12 antiplatelet agent monotherapy and shorter DAPT duration.⁷⁰ The evidence base for novel agents in ESRD is expanding, as highlighted by small-scale pharmacodynamics studies both in ticagrelor and prasugrel.^71,72

Aspirin remains at the forefront of ACS management – the Antithrombotic Trialists’ Collaboration meta-analysis (287 RCT – some including HD patients) indicated that antiplatelet management reduced the risk of serious vascular events by 41% in this population.⁷³ Data from the United Kingdom Heart and Renal Protection Study and the Dialysis Outcomes and Practice Patterns Study support the safety profile of aspirin in HD patients.⁷⁴

There is lack of evidence surrounding P2Y12 inhibitors in ESRD, with data from subgroup analyses and registries to help with decision-making in clinical practice. The CLARITY-TIMI-28 (Clopidogrel as Adjunctive Reperfusion Therapy – Thrombolysis in Myocardial Infarction) trial did not include any HD patients and noted that with worsening renal function there was a qualitative decline in the efficacy of clopidogrel versus placebo.⁵¹ Clopidogrel-related concerns remain with regards to increased bleeding rates and clopidogrel resistance, as indicated by high residual platelet reactivity.⁷⁵ With regards to ticagrelor, a subgroup analysis of the landmark Study of Platelet Inhibition and Patient Outcomes (PLATO) including all NDD-CKD patients (defined as an eGFR <60 ml/min/1.73 m²; n=3,237) reported a significant reduction in primary end point (cardiovascular death, MI, and stroke at 12 months) and an absolute risk reduction that was greater than that of patients with normal kidney function (7.9% vs. 8.9%, HR 0.90, 95%CI 0.79 to 1.02). This also positively affected mortality with no significant difference in major bleeding and fatal bleeding rates between the two groups (15.1% vs. 14.3%, HR 1.07, 95%CI 0.88 to 1.30; 0.34% vs. 0.77%, HR 0.48, 95%CI 0.15 to 1.54).⁷⁶ A subgroup analysis of the TRITON-TIMI-38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel – Thrombolysis in Myocardial Infarction) study shared similar results of improved mortality and morbidity, however, limited data regarding the bleeding risk were provided.⁷⁷ A review of registry data highlights the importance of understanding the increased bleeding risk in patients on dialysis with newer agents. Data from the SWEDEHEART registry and PROMETHEUS (Use of Prasugrel vs. Clopidogrel and Outcomes in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention in Contemporary Clinical Practice) clinical trial have failed to show an improvement in composite outcome in patients with severe CKD (eGFR <30 ml/min/1.73 m²) with ticagrelor (adjusted HR 0.95, 95%CI 0.69 to 1.29)⁷⁸ and moderate CKD (eGFR <60 ml/min/1.73 m²) with prasugrel (adjusted HR 1.0, 95%CI 0.8 to 1.25).⁷⁹ Bleeding rates with ticagrelor increased with decreasing eGFR.⁷⁸ However, a meta-analysis (three RCT subanalyses, two observational study subanalyses; n=31,234) on the use of ticagrelor and prasugrel compared with clopidogrel in CKD, noted an overall association of the former with improvement in major cardiovascular events rate (pooled HR 0.88, 95%CI 0.79 to 0.99, p=0.03) without an increased risk of bleeding (pooled HR 1.10, 95%CI 0.95 to 1.27, p=0.18). The study did not include a stratification analysis based on the CKD stage or examine the effect of dialysis.⁸⁰ Looking more specifically at patients on dialysis, a meta-analysis comparing ticagrelor with clopidogrel (four cohort studies n=5,417; ticagrelor n=892, clopidogrel n=4,525) identified a significantly higher risk of major adverse cardiovascular events, all-cause death and major bleeding events with ticagrelor as opposed to clopidogrel.⁸¹ It is noteworthy that all studies included were cohort in nature, hence, allowing for bias to be introduced.⁸¹

Given the results of pharmacokinetic studies and the high risk of HD patients with ACS, the potential for a therapeutic use of ticagrelor and prasugrel represents a promising future target for research. As indicated by the Kidney Disease Improving Global Outcomes (KDIGO) group, additional research is needed to identify the optimal DAPT duration, antiplatelet agents and possibility of single antiplatelet therapy in this patient group, and has called for broadened inclusion of ESRD patients in the design of RCTs.⁸² A recently designed RCT has set out to compare the efficacy and tolerability of ticagrelor and clopidogrel in patients with eGFR <30 ml/min/1.73 m² undergoing invasive management of ACS.⁸³

Conclusion

ACS are frequently encountered in patients with CKD, especially those with ESRD on chronic haemodialysis. Outcomes, despite optimisation of interventional management and improved pharmacotherapy, remain poor. The diagnosis of ACS in such patients remains challenging, and a high index of clinical suspicion is necessary, alongside a good understanding of biomarker changes in patients with ESRD. Management is hindered by the lack of representation of this patient group in landmark clinical trials. An individualised approach to these patients, with consideration of atherothrombotic and bleeding risks, and an understanding of ESRD-associated pharmacokinetics is fundamental. Further research is necessary to aid in the development of evidence-based guidelines in this population, improving both diagnostic and early therapeutic management of these patients.

Key messages

• Patients with end-stage renal disease on haemodialysis are at higher risk of cardiovascular events with worse outcomes
• Diagnosis may be challenging as patients often have atypical features and associated electrocardiographic, echocardiographic and biomarker findings may be difficult to differentiate from pre-existing renal disease and dialysis-related changes. A high index of suspicion is required in these circumstances
• Management of these patients is also complex, as most often such patients are excluded from landmark trials and often need a highly individualised approach to medical and invasive intervention
• More studies recruiting this high-risk cohort of patients need to be carried out to establish the optimal management approach for such individuals when presenting with acute coronary syndromes

Conflicts of interest

MUS has received support and honoraria for attending meetings including travel and educational grants from Boehringer Ingelheim, unrelated to this manuscript. NA has received payment or honoraria for lectures from Medtronic and Abbott, unrelated to this manuscript. MAH, XK, AH, DNF: none declared.

Funding

None.

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