proCardio 2016

10th International Symposium August 25–26th, 2016, Rome, Italy

Empowering the use of cardiac biomarkers to

optimize care and improve outcomes

Disclaimer This material summarizes presentations and discussions that occurred during the meeting and therefore reflects individual expert opinions for which Roche Diagnostics International is not responsible.

proCardio 2016

Empowering the use of cardiac biomarkers to

optimize care and improve outcomes

Faculty

James Januzzi Harvard Medical School, Boston, MA, USA

Yigal Pinto Academic Medical Center, Amsterdam, The Netherlands

Bonnie Ky University of Pennsylvania Medical School, Philadelphia, PA, USA

Richard Nowak University of Michigan, Ann Arbor, MI, USA

Mario Plebani Padua University Hospital, Padua, Italy

Sandra Sanders-van Wijk Maastricht University Medical Center, The Netherlands

Hugo Katus Heidelberg University Hospital, Heidelberg, Germany

Carsten Stengaard Aarhus University Hospital, Aarhus, Denmark

Mitja Lainscak University of Ljubljana, Slovenia

Hanna Gaggin Massachusetts General Hospital, Boston, MA, USA

Mauro Panteghini University of Milan Medical School, Milan, Italy

Christophe Meune University Hospital Avicenne, Paris, France

Kenneth McDonald St. Vincent’s University Hospital, Dublin, Ireland

Carolyn Lam Duke-National University of Singapore Graduate Medical School, Singapore

Martin Than Christchurch Hospital, New Zealand

Christie Ballantyne Baylor College of Medicine, Houston, TX, USA

Mark Richards National University Heart Centre, Singapore

Kazuomi Kario Jichi Medical University Center of Excellence, Tochigi, Japan

Christian Mueller Basel University, Switzerland

Lars Wallentin University Hospital Uppsala, Sweden

Ewa Jankowska Medical University, Wroclaw, Poland

Scott Solomon Harvard Medical School, Boston, MA, USA

Evangelos Giannitsis Heidelberg University Hospital, Heidelberg, Germany

Antoni Bayes-Genis Autonomous University, Barcelona, Spain

Kirkwood Adams University of North Carolina, Chapel Hill, NC, USA

Brian Lindman Washington University School of Medicine, St. Louis, MO, USA

Rick Body University of Manchester, Manchester, UK

Dirk Sibbing Ludwig-Maximilians University, Munich, Germany

Martin Huelsmann Medical University of Vienna, Austria

Adriaan Voors University of Groningen Medical Center, The Netherlands

James McCord Wayne State School of Medicine, Detroit, MI, USA

Joachim Thiery University Hospital Leipzig, Germany

Abbreviations

ACEi Angiotensin-converting enzyme inhibitor ED Emergency department

ACS Acute coronary syndrome EF Ejection fraction

ADHF Acute decompensated heart failure ESC European Society of Cardiology

AHF Acute heart failure GC Guanylate cyclase

AMI Acute myocardial infarction GDF-15 Growth differentiation factor 15

ANP Atrial natriuretic peptide HF Heart failure

AS Aortic stenosis HFmrEF Heart failure with mid range ejection fraction

AVR Aortic valve replacement HFpEF Heart failure with preserved ejection fraction

BNP Brain natriuretic peptide HFrEF Heart failure with reduced ejection fraction

cGMP Cyclic guanosine monophosphate HR Hazard ratio

CHD Coronary heart disease hs-cTnT High sensitivity cardiac troponin T

CHF Chronic heart failure LAV Left atrial volume

CI Confidence intervals LDL Low-density lipoprotein

CK-MB Creatine kinase-MB Lp(a) Lipoprotein(a)

CNP C-type natriuretic peptide LVEF Left ventricular ejection fraction

CRP C-reactive program MACE Major adverse cardiac event

cTn Cardiac troponin MACS Manchester Acute Coronary Syndrome

CV Cardiovascular MI Myocardial infarction

ECG Electrocardiogram MMP Matric metalloproteins

Abbreviations

MR-proADM Mid-regional pro-andromedullin PFT Platelet function test

NO Nitric oxide PH Pulmonary hypertension

NP Natriuretic peptide POC Point-of-care

NPV Negative predictive value NSTEMI Non-ST segment elevation myocardial infarction

NT-proBNP N-terminal prohormone of brain natriuretic peptide RAAS Renin–angiotensin–aldosterone system

NYHA New York Heart Association PFT Platelet function test

PAH Pulmonary arterial hypertension PH Pulmonary hypertension

PCI Percutaneous coronary intervention RCT Randomized controlled trial

PCSK9 Proprotein convertase subtilisin/kexin type 9 SD Standard deviation

PDE Phosphodiesterase sGC Soluble guanylate cyclase

TGF-β Transforming growth factor -β

Executive overview 2016 marked the 10th annual proCardio meeting

• Over the past decade, proCardio has proved to be a highly successful and engaging scientific event

featuring a world-class international faculty to discuss cardiac biomarkers

• This meeting brought together 250 experts from a record 46 countries across Europe, North and

Latin America, Middle East and Asia Pacific, with expertise in a wide range of disciplines

including cardiology, emergency medicine and laboratory medicine

• This event has two key objectives:

1. To communicate the latest scientific evidence and clinical trial data related to the clinical use of cardiac

biomarkers

2. To facilitate the discussion of new ideas to help shape future pathways in the field of cardiac biomarkers

and to identify and address the unmet medical needs across multiple countries and regions

• The meeting was broken out into six distinct sessions containing a total of 25 presentations

• Two parallel breakout sessions were also included. These provided an open forum for discussion

around the role for biomarkers in optimizing HF therapy and the impact of sacubitril/valsartan

on natriuretic peptide measurement

• Each of these sessions is detailed on the following slides with key observations from each session

and key messages from the advisor discussions during the breakout sessions

“There is currently a biomarker tsunami, a rising wave of publications focused on biomarker testing in HF” James Januzzi

Welcome to the world of proCardio

Welcome and introduction R.C. Schimmer and J-J. Palombo, Roche Diagnostics

J. Januzzi, USA

Session 1 Heart failure management and biomarkers: what’s new?

Heart failure and biomarkers in 2016 J. Januzzi, USA

ESC heart failure guidelines 2016 K. McDonald, Ireland

Biomarkers: what‘s next in HFpEF? A.M. Richards, Singapore

Session 2 Optimized heart failure therapy and biomarkers

Update on the GUIDE-IT trial K. Adams, USA

Natriuretic peptide-guided therapy in primary care M. Huelsmann, Austria

NT-proBNP-guided therapy in acute heart failure Y. Pinto, The Netherlands

Cost effectiveness of natriuretic peptide-guided therapy S. Sanders-van Wijk, The Netherlands

Q&A and discussion J. Januzzi, USA

Session 3 Heart failure and biomarkers: breakout sessions

Session 4 What’s next in heart failure?

Sacubitril/valsartan and the use of biomarkers S. Solomon, USA

HFpEF: treatments in the pipeline C. Lam, Singapore

Utility of biomarkers in patients with aortic stenosis B. Lindman, USA

GDF-15 in acute heart failure: results from RELAX-AHF A.A. Voors, The Netherlands

The role of biomarkers in detecting cardiotoxicity due to cancer therapy B. Ky, USA

Heart failure and diabetes M. Huelsmann, Austria

Q&A and discussion J. Januzzi, USA

Thursday August 25, 2016

Session 5 Early diagnosis of acute coronary syndrome

Featured lecture: 25-year anniversary of troponin T H. Katus, Germany

Shortening AMI diagnosis to 1 hour with hs-cTnT

From 2015 ESC guidelines... to clinical practice

Interactive clinical-based discussion

C. Mueller, Switzerland

Common or gender–specific cut-offs?

From the literature... to clinical practice

Interactive clinical-based discussion

E. Giannitsis, Germany

Early rule-out of AMI with a single measurement R. Body, UK

The HEART Score and hs-cTnT J. McCord, USA

hs-cTnT measurements in emergency department patients who have

not experienced AMI

R. Nowak, USA

Fast assessment and management of NSTEMI with pre-hospital

troponin T measurements

C. Stengaard, Denmark

Session 6 Future applications for biomarker testing

hs-cTnT for risk prediction in the population C. Ballantyne, USA

Future applications for GDF-15 across cardiovascular disease L. Wallentin, Sweden

Multiple biomarker strategies for risk stratification in heart failure A. Bayes-Genis, Spain

Monitoring platelet function in clinical practice:

focus on PCI-treated patients

D. Sibbing, Germany

The post-statin era and PCSK9: do we need more precise

lipid biomarkers?

J. Thiery, Germany

Meeting close J. Januzzi, USA

Friday August 25, 2016

Welcome and

introduction James Januzzi

The first proCardio meeting took place in

Lisbon in 2003

proCardio has evolved into a meeting with

a great deal of academic gravitas

providing opportunities for researchers

and clinicians to engage in interactive

discussions and collaborative efforts on

cardiac biomarkers

The 2016 meeting focused on bringing

biomarkers to the bedside and using them

to define patient phenotypes and

empower clinicians to make decisions that

will improve patient care and outcomes

“A guideline should also lay out what the best approach should be to management,

advocating for resources to be made available for best possible care”

Kenneth McDonald

Heart failure and biomarkers in 2016

James Januzzi

ESC heart failure guidelines 2016

Kenneth McDonald

Biomarkers: what‘s next in HFpEF?

Mark Richards

Session 1 Heart failure management and

biomarkers: what’s new?

Co-chairs: Mario Plebani and Mitja Lainscak

Heart failure and biomarkers in 2016

• A lot has changed in the field of HF over the last decade, including altered patient demographics and increased use of therapies, as well as new therapeutic options

• The ESC and AHA guidelines recommend the use of NPs for diagnosis and in the prognosis of HF (Class IA)

• To be widely used in clinical practice, novel biomarkers should provide information other than that which is already available by routine physical examination and laboratory evaluation, reflect important alternative pathophysiological processes in HF disease, and be measured using a robust assay

• Biomarkers are increasingly used as pivotal tools in clinical trials for novel drug development, including as inclusion criteria, surrogate endpoints, to explain efficacy, as markers of toxicity, and/or as targets of therapy

• Increasing attention is also being paid to using biomarkers as mediators, which can be modulated to improve outcome

– Plausible potential bio-targets include remodeling markers (Orexin A), diastolic dysfunction markers (IGFBP7) and markers of fibrosis (galectin, sST2 and GDF-15)

• Future perspectives: approaching the concept of personalized healthcare with "one biomarker – one drug”

• It is plausible that in the future biomarkers will be used to identify the mediators of disease and allow them to be modulated accordingly in order to improve patient outcomes

ESC heart failure guidelines 2016

• Optimal cut-offs of NPs were selected to minimize the risk of false-negative results

• NP assessment should not be considered as optional and should be routinely used in the diagnostic work-up of patients in the hospital for more efficient and cost-effective patient management

• There is more visibility for the use of NPs to rule-out ADHF and in prevention of HF, as reflected in the STOP-HF study

– There is a need to develop biomarkers to improve clinical outcomes

• Sacubitril/valsartan is recommended for treatment of patients with HFrEF who remain symptomatic despite optimal treatment

– Concerns about implementation as >95% of patients will remain symptomatic and have elevated NPs

– Will significantly increase workload

– Earlier introduction would reduce the number of visits

– However, up-titration of ACEi could allow the target to be reached whilst avoiding increased expenditure on sacubitril/valsartan

• Most of the discussion surrounding the new guidelines has focused on the new classification of HF, HFmrEF

– May provide insights into new etiologies, or etiologies of varying dominance

– May just be the “transition zone” between HFrEF and HFpEF

– Measurements of LVEF may be too imprecise to carefully define this subgroup

Observations

ESC heart failure guidelines 2016

• A large number of “HF patients” are not receiving specialist care or investigation and the consequences of this are a less than optimal approach

• Currently only a minority of patients get access to ongoing benefits of what is advocated by the guidelines

• There is a general consensus in the expert community that developments in HF patient management need to be applied to the wider population in HF

Observations

Biomarkers: what’s next in HFpEF?

• Identifying biomarkers for use in HFpEF is complicated by the

poorly understood pathophysiology and the fact that the definition

of HFpEF is vague and there are no existing treatment guidelines

• NPs levels have become part of the definition of HFpEF and

HFmrEF in the new ESC guidelines

• A biomarker in HFpEF should help with prediction, diagnosis,

prognosis, monitoring, guiding therapy, and indicating

therapeutic targets

• An ideal HFpEF biomarker would be:

– Raised in HFpEF and not in HFrEF

– More prognostic in HFpEF versus HFrEF

– Related to pathophysiology of HFpEF

– Able to lead to effective therapy

– Able to guide titration of therapy

• Levels of NPs are markedly lower in HFpEF compared with HFrEF,

which could influence diagnostic performance outside of the

acute setting

• NPs have a strong prognostic performance in both HFpEF and

HFrEF in both the sub-acute and chronic setting

• NPs can be used as pivotal tools to enrich patient selection for

Clinical Trials in HFpEF and as surrogate endpoints

• Use of NT-proBNP may help guide therapy in HFrEF but there is

insufficient evidence for its use in HFpEF

– Further studies are required to investigate the role of

NT-proBNP-guided therapy in HFpEF

• Elements of the pathophysiology of HF and potential biomarkers:

– Myocardial stretch (cGMP/NP ratios)

– Myocyte injury (NPs, troponins)

– Matrix remodelling (MMPs, galectin-3)

– Inflammation (CRP, GDF-15, ST2, galectin-3)

– Renal dysfunction (eGFR, cystatin C)

– Neurohumoral activation (NPs, MR-proADM, RAAS)

• There is still a significant amount of information regarding the

performance of biomarkers that is not known in HFpEF

• It is unlikely that there will be an ideal biomarker in HFpEF

– A potential solution will most likely involve a

multi-assessment and multi-marker approach

Observations

Biomarkers: what’s next in HFpEF?

• There has not been any single, stand-out alternative marker candidate in HFpEF

• C-terminal propeptide of procollagen type I and N-terminal propeptide type III have a relationship to the degree of fibrosis present in

the heart

• NT-proCNP has been shown to be a stronger independent marker for mortality in patients with HFpEF compared with HFrEF

• There is no substantial difference in levels of sST2 between HFpEF and HFrEF

• Galectin-3 was also shown to have a stronger predictive value in patients with HFpEF compared with HFrEF, although the average

levels were relatively similar, indicating no diagnostic separation

• GDF-15 baseline values were similarly elevated in HFrEF and HFpEF

• Recent studies have also shown that monitoring circulating levels of selected microRNAs, in combination with NT-proBNP, can

differentiate HFpEF from HFrEF

• Metabolomics have also been shown to provide powerful diagnostic value, with plasma concentrations of metabolites showing

significant differences between HF etiologies

• Further studies are needed with larger and better characterized cohorts to confirm findings and to further differentiate

HFrEF and HFpEF

– Reproducibility

– Seek markers related to inflammation, full investigation of matrix markers

– Need to consider alternative options such as circulating nucleic acids and metabolomics

– Take advantage of broad based screening technology including multiplex assays, proximity extension assays and

mass spectroscopy

Observations

Update on the GUIDE-IT trial

Kirkwood Adams

Natriuretic peptide-guided therapy in primary care

Martin Huelsmann

NT-proBNP-guided therapy in acute heart failure

Yigal Pinto

Cost effectiveness of natriuretic peptide-guided therapy

Sandra Sanders-van Wijk

“Defining the best strategy for therapy monitoring and the ideal target patient

population remain key goals for optimizing

guided therapy”

Kirkwood Adams

Session 2 Optimized heart failure therapy

and biomarkers

Co-chairs: James Januzzi and Ewa Jankowska

Update on the GUIDE-IT trial • A more reliable indicator of patient response is needed to

optimize therapy • The PROTECT study showed that adjusting treatment based on

NT-proBNP concentrations reduced the number of CV events. However, results from other guided trials have been conflicting

• GUIDE-IT is a prospective, randomized trial designed to determine the safety, efficacy and cost effectiveness of a strategy of adjusting therapy to achieve and maintain a target NT-proBNP level of <1,000 pg/ml compared with ‘Usual Care’ in high-risk HFrEF patients

– Recruited 1,100 subjects

– Primary combined endpoint was time to CV death or first HF hospitalization

– Trial ended early due to no difference between treatment arms

• NP-guided HF trials are extremely challenging due to several factors including:

– Discrepancies in ‘Usual Care’ – variations in disease management between centers

– Definition of the best target patient population for intervention

– Randomization by site versus patient

– Definition of the optimal primary endpoint

– Co-morbidities, such as age, preventing enhancement of therapy

– Monitoring NPs – defining the target for follow-up NP level

• A fundamental component of the intervention is behavioral at the Health Care Team and Patient level

– The Health Care Team must buy into and execute the intervention

– There is the potential for patient resistance to the changes and the potential risks

• However, all NP-guided trials strongly support the close correlation of reducing NT-proBNP and improved outcomes – regardless of strategy

• Measurement of NPs at baseline identifies high-risk patients and improves detection and management of congestion, which may reduce re-hospitalization

– Knowledge of NP level promotes better utilization of evidence-based medicine, potentially reducing risk of HF progression

Observations

NP-guided therapy in primary care

• In Western countries 75% of adults are estimated to have ≥1 CV risk factor

• The principal task for primary care physicians is the prevention of significant CV disease development, by assessing the individual risk

and applying the adequate treatment to prevent or delay the onset of overt HF

– This requires appropriate tools for risk stratification

• ESC guidelines recommend NP-driven collaborative care between the primary care physician and specialist. Up-titration of cardiac

therapy with RAS antagonists and beta-blockers to maximum tolerated doses may improve outcomes in patients with increased

plasma concentrations of NPs

• The STOP-HF randomized controlled trial showed that a screening program using elevated BNP to risk stratify patients in an at-risk

population reduced newly diagnosed HF and the prevalence of significant LV systolic and/or diastolic dysfunction by 50%

• The PONTIAC study sought to assess the primary preventive effect of neurohumoral therapy in high-risk diabetic patients selected by

NT-proBNP

– A significant reduction by 60% in hospitalization/death due to cardiac disease after 2 years was found in the intensified group

(HR: 0.351; 95% confidence interval: 0.127 to 0.975, p=0.044)

• The PONTIAC II study will investigate 2,400 diabetic patients with a primary endpoint of cardiac hospitalization and death in patients

with NT-proBNP >125 pg/ml

Observations

NT-proBNP guided therapy in acute HF • Hospital admissions for ADHF are frequent and are

accompanied by high mortality and readmissions

• A recent study showed that higher absolute levels of NT-proBNP at discharge are related to worse outcomes (mortality and event rate) in patients hospitalized for ADHF

• A reduction of NT-proBNP of ≥30% during hospitalization is

associated with better outcome in terms of both cumulative mortality and event rate

• ELAN-HF score (admission and discharge NT-proBNP values) can be used for stratifying the 100-day mortality risk, improving the prediction of adverse events

• NT-proBNP-guided management can significantly increase the number of patients reaching the 30% reduction value

Cost effectiveness of NP-guided therapy

• HF is an extremely costly disease

– Healthcare expenditure on CHF in developed countries represents 1–2% of the health care budget, mostly due to HF hospitalization

– Economic analyses should include both direct and indirect costs of care

• Optimization of drug therapy represents the most effective way of reducing costs

• NP-guided therapy in HF is highly cost effective in the acute and chronic setting

– In the acute setting, costs can be reduced by $2,573 in patients with acute dyspnea/AHF

– In the chronic setting, there was a saving of $2,979 per CHF patient according to the TIME-CHF study

– NP-guided therapy >80% more cost-effective in TIME-CHF

– The probability of NT-proBNP-guided therapy being dominant was 80%

– Probability to be cost effective above reasonable threshold is >90% at a cost of 50,000 EUR/USD

• NP-guided therapy is probably less favorable in very elderly and highly comorbid patients and patients with HFpEF

• Future studies need to focus on cost-effectiveness analysis of individual patient data and on the implementation of more expensive therapies

Observations

Breakout session

Co-chairs:

James Januzzi and Hannah Gaggin

Mark Richards and Carolyn Lam

What is the role for biomarkers in

optimizing therapy, including in the

primary care setting?

The discussions focused on the current gaps and research needs for optimizing the use of biomarkers in the management of heart failure

The impact of sacubitril/valsartan on

natriuretic peptide measurement

The discussions focused on the effects of sacubitril/valsartan on BNP levels and how this would impact biomarker testing practices

“Clinical studies continue to give the same message. If you get NT-proBNP down, the

outcomes are going to be better”

Mark Richards

The discussions focused on the current gaps in our scientific understanding and the hurdles in implementation of optimized use of

biomarkers in the management of heart failure

• An important hurdle is the lack of knowledge of the role of cardiac biomarkers among primary care physicians. There is a need to improve education and increase awareness

• For more efficient education, physicians need clearer guidance on:

– Who the target population is

– How to interpret the test results

– How frequently the biomarker should be tested in different patient populations

– What target values should be considered

• Certain countries are also facing the additional hurdle of access to the test as well as the associated cost

• Point-of-care testing was proposed as a solution to help overcome the hurdle of access to testing

What is the role for biomarkers in optimizing

therapy, including in the primary care setting?

• In order to overcome the issues associated with the pricing of the test and implementation in the primary care setting, there was a proposal to position the biomarkers as part of a primary care screening strategy before more expensive diagnostic tests are performed (e.g. echocardiography)

• Regarding the need for generation of more scientific evidence, the focus areas were as follows:

– Use of biomarkers in the primary care setting

– Cost effectiveness analysis in primary care

– Different patient sub-groups such as those with co-morbidities

– Multi-marker strategies

– Use of biomarker screening to prevent HF

– Use of different endpoints in clinical studies e.g. quality of life and not just morbidity/mortality

• There is a need for more education on HF biomarkers for primary care physicians

• Biomarker guidelines addressing the applications of biomarkers need to be made

clearer, especially regarding the targeted population, the interpretation of the

results, and the impact on treatment decisions

• Access to biomarker tests needs to be improved in some countries/regions

• Further research is needed, particularly on the use of biomarkers in primary care

Key messages

• When sacubitril/valsartan is introduced, it is likely to lead to a decline in the use of BNP assays and

an increase in the use of NT-proBNP assays; healthcare centers will need to adapt their testing

practices and train staff on the new assay

• Institutes may produce their own NT-proBNP assays once patent protection has expired; this may

create serious problems due to variability in assay quality

• A task force could be set up under the umbrella of the International Federation of Clinical Chemistry

and Laboratory Medicine to help manage potential future challenges

The impact of sacubitril/valsartan on natriuretic

peptide measurement

There are several unanswered questions on the effect of

sacubitril/valsartan on BNP and NT-proBNP:

– Differences among BNP assays

– Dose response effects (short and long term)

– The prognostic and diagnostic value of BNP,

NT-proBNP and their ratios

• It is expected that sacubitril/valsartan use will be accompanied by a decline in

the use of BNP assays and an increase in the use of NT-proBNP assays

• A task force could be set up to help manage potential future challenges such as

the use of non-commercial NT-proBNP assays

• Further research is needed into the effects of sacubitril/valsartan on biomarkers

and their value as prognostic/diagnostic markers

Key messages

Session 4 What’s next in heart failure?

Co-chairs: Kazuomi Kario and Scott Solomon

Sacubitril/valsartan and the use of biomarkers

Scott Solomon

HFpEF: treatments in the pipeline

Carolyn Lam

Utility of biomarkers in patients with aortic stenosis

Brian Lindman

GDF-15 in acute heart failure: results from RELAX-AHF

Adriaan Voors

The role of biomarkers in detecting cardiotoxicity due to cancer therapy

Bonnie Ky

Heart failure and diabetes

Martin Huelsmann

Sacubitril/valsartan and the use of biomarkers

• Neprilysin is the predominant enzyme for breakdown of NPs as well as other vasoactive substances. It is responsible for the breakdown

of ANP, BNP and CNP, as well as adrenomedullin, substance P, endothelin and angiotensin II

• Sacubitril/valsartan (previously known as LCZ696) is a combination drug for use in HF consisting of an angiotensin receptor blocker

and a neprilysin inhibitor

• In the double-blind, randomized PARADIGM-HF study including 8,442 patients, sacubitril/valsartan was associated with a significant

reduction in CV death, HF hospitalization (HR=0.80, p=0.0000004) and all-cause mortality (HR=0.84, p<0.0001). It was also effective

across the spectrum of risk and ejection fraction

• It was also estimated that treatment with sacubitril/valsartan would result in a projected benefit of 1–2 years of increased life

expectancy and survival free from HF

• NT-proBNP is not a substrate for neprilysin and therefore remains an accurate measure of severity of HF in the setting of

valsartan/sacubitril treatment

• Neprilysin inhibition leads to acutely raised levels of BNP, therefore following BNP as a marker of HF severity will be inaccurate

– Neprilysin inhibition is also associated with increased levels of cGMP, reduced levels of aldosterone and significantly reduced

levels of hs-cTnT compared with levels in patients treated with enalapril

• Patients whose NT-proBNP decreased in PARADIGM-HF had better outcomes irrespective of treatment arm

– Patients who achieved NT-proBNP ≤1,000 pg/mL had an decreased risk of CV death or HF after 1 month irrespective of

treatment

– Patients with a reduction in 1-month NT-proBNP values were associated with better outcomes

– Treatment with sacubitril/valsartan was associated with a significantly increased percentage of patients achieving NT-proBNP

≤1,000 pg/mL after randomization compared with enalapril (p<0.001)

Observations

HFpEF: treatments in the pipeline

• Half of all patients with HF have HFpEF and morbidity and mortality are similar to HFrEF

– An evidence-based, proven therapy that improves outcomes in HFpEF has still not been identified

– The guidelines for management of HFpEF have not changed in 20 years

• Disrupted endothelium-related signaling pathways have been implicated in the pathophysiology of HF. In particular, disturbances in NO-

mediated pathways and neuregulin-mediated pathways have been shown to contribute to HF development

• These signaling pathways hold the potential as pathophysiological targets for new HFpEF therapies, and may aid in patient selection

for future HF trials

• Several studies have investigated the effect of NO derivatives, sGC stimulators and activators in

patients with HFpEF

– In the RELAX-AHF study, acute HFpEF patients also benefited from treatment with serelaxin for 48 hours

– Uptitration of the organic nitrate, isosorbide mononitrate, in HFpEF did not lead to improvement of cardiac function in the NEAT trial

– Inorganic nitrate and nitrites may offer hope

– The sGC activator, cinaciguat, failed to show a benefit in HFpEF patients in the COMPOSE study due to excessive hypotension

– A single dose of the sGC stimulator, riocingulat, improved systemic vascular resistance and cardiac output safely in the DILATE-1 study

– The phase II SOCRATES trial in severe HFpEF patients with high NT-proBNP value and large LAV found that riocingulat had

no effect on NT-proBNP and LAV but did lead to an improvement in patient-reported health status

• There is a need to pay closer attention to the NT-proBNP cut-off values used for AF in HFpEF patients. AF contributes to a higher value

for NT-proBNP, even when equalizing for LAV and various co-morbidities

• The TOPCAT study is a great example of NT-proBNP values as a strong prognostic marker which is independent of EF

Observations

HFpEF: treatments in the pipeline

• Several studies have investigated the efficacy of PDE-5 inhibition in patients with HFpEF

– HFpEF-PH study showed that sildenafil was beneficial up to 1 year in patients with HFpEF and PH

– RELAX trial in patients with HFpEF regardless of PH, sildenafil for 24 weeks did not result in significant improvement in exercise

capacity or clinical status compared with placebo

– In patients with defined PAH PDE-5 inhibitors are beneficial

• Recent work looking at PDE-9 inhibitors also shows that these may be effective

– PDE-9 more selective for particulate GC produced cGMP

• The prospective, single-blinded, randomized CHAMPION trial found that hemodynamically guided management of patients with HFpEF

reduced decompensation leading to hospitalization compared with standard HF management strategies

Observations

Utility of biomarkers in patients with aortic stenosis

• AS is a prevalent disease, occurring in 3–4% of individuals >75

years of age

• The only effective treatment for AS is aortic valve replacement (AVR) and symptomatic patients with severe AS are candidates for surgery as well as certain asymptomatic patients

• Risk stratification is important to predict progression of disease, determine optimal timing of AVR surgery in low-risk patients with severe asymptomatic AS, determine the benefit or futility of AVR in high-risk patients and decide what type of replacement should be performed

• In a single center, prospective study of the Laval cohort, 655 patients with severe AS were referred for and treated with surgical AVR

– Using a multi-marker score including hs-cTnT, WAP HE4, CA125, GDF-15, NT-proBNP, hs-CRP and ST2, elevation of 4 or more biomarkers was associated with significantly increased mortality (p<0.001) regardless of NYHA classification or NT-proBNP level

• Biomarkers may be useful to “flag” asymptomatic patients in whom earlier AVR may be beneficial

• Levels of circulating biomarkers may also provide a molecular signature capable of predicting minimal or severe fibrosis

GDF-15 in acute heart failure: results from RELAX-AHF

• AHF is the leading cause of hospital admission globally and is associated with significant morbidity and mortality

• Many drugs have been unsuccessful at improving clinical outcome in AHF

• RELAX-HF is a randomized, double-blind, placebo-controlled phase III trial which investigated the use of serelaxin for treatment of ADHF in 1,161 patients

• Levels of GDF-15, a stress response cytokine, were measured using serum samples taken before initiation of serelaxin or placebo and at Days 2, 5, 14, and 60

• Baseline GDF-15 levels at admission were not predictive of outcome

• Treatment with serelaxin decreased GDF-15 within 14 days

• Changes in GDF-15 within 14 days were predictive of 180-day CV mortality

• Serelaxin may have anti-inflammatory and anti-oxidative properties that protect organs during an episode of AHF

• The change in GDF-15 by serelaxin might explain its beneficial effects on CV 180-day mortality

Observations

The role of biomarkers in detecting cardiotoxicity due to cancer therapy

• Cancer therapy is associated with an increased risk of cardiac

events as a result of associated cardiotoxicity

• There is a critical need to improve CV screening methods and develop strategies to identify high-risk patients

• Recent research efforts have focused on: – Understanding the relevance of existent CV biomarkers in

patients undergoing cancer therapy – Discovering and validating newer mechanistic biomarkers

• Data suggest there may be an important role for early and late

increases in hs-cTnT and NT-proBNP, respectively, in CV risk stratification and monitoring during and after cancer therapy

• Proteomics discovery methods suggest promising new biomarkers and a potential role for the immune system

– High IgE and IgE/IgG1 were associated with a decreased risk of cardiac dysfunction

• Radiation therapy also leads to significant changes in biomarkers of CV stress, inflammation and vascular function

Heart failure and diabetes

• HF is a significant problem in diabetes

• It is recommended that patients with diabetes should be classified as at high or very high risk of CV disease depending on the presence of concomitant risk factors

– However, current methods of risk stratification are suboptimal

• NT-proBNP (<125 pg/mL) has a NPV of 98% to rule-out short-term CV events and is a stronger predictor of CV mortality than C-reactive protein and albumin excretion rate in patients with diabetes

• NT-proBNP and hs-cTnT are complementary in improving the accuracy of estimation of the risk of CV events or death in patients with type 2 diabetes

• Adding hs-cTnT and GDF-15 to a zero model already including NT-proBNP led to an improved prediction of CV events and death

– NRI of 33.6% (CI 16.0–50.8%)

• Glucose lowering drugs, such as saxagliptin, are associated with an increased risk or hospitalization for HF

• NT-proBNP defines subsets of patients with increased risk of CV events due to glucose lowering drugs

Observations

Maximum change hs-cTnT (pg/mL) NT-proBNP (pg/mL)

Cardiotoxicity 29.4 105.6

No cardiotoxicity 16.5 65.2

25-year anniversary of troponin T

Hugo Katus

Shortening AMI diagnosis to 1 hour with hs-cTnT From 2015 ESC guidelines... to clinical practice

Christian Mueller

Common or gender–specific cut-offs? From the literature... to clinical practice

Evangelos Giannitsis

“Over the last three decades cardiac troponin T has

progressed from an idea to standard-of-care in diagnosis of AMI”

Hugo Katus

Session 5 Early diagnosis of acute

coronary syndrome Co-chairs: Mauro Panteghini and Martin Than

25-year anniversary of troponin T

• Discussed the critical steps in the development of troponin T assays and the challenges that were overcome in translation of this marker

• CK-MB was the previous gold standard for diagnosis of AMI

– ECG and cardiac enzymes were poor risk predictors of AMI in patients with chest pain

– Unmet clinical need

• By 1980, increased understanding of the process of cardiac muscle contraction and improvements in available technologies for the

sensitive measurement of proteins in vitro led to the development of a double sandwich assay for cardiac myosin light chains

• Measurement of cTnT was found to have superior sensitivity and specificity for AMI and by 1989 the fist cTnT assays for diagnosis of

AMI were available

• Increasing studies have also shown the prognostic value of cTnT in ACS, and the value of appropriate therapeutic interventions based on

cTnT levels

• In 2000 measurement of cTnT was included in the ESC guidelines as a preferred marker

• During recent years the analytical sensitivity and assay precision at the low measuring range of cTn assays has been continuously

improved to fulfill the analytical criteria of current guidelines

– Moved from detection of necrosis, to detection of injury and assays are now capable of detecting the remodeling process

• The availability of the hs‐cTnT assay permits precise measurement of cTnT concentrations in a significant number of apparently

illness‐free individuals and thus more precise calculation of the 99th‐percentile cTnT concentration in reference subjects

• This has allowed correlation of increasing hs-cTnT levels with total non-calcified plaque burden and prediction of CV outcomes in

patients with presumably stable CAD

Observations

Shortening AMI diagnosis to 1 hour with hs-cTnT From 2015 ESC guidelines... to clinical practice

• Chest pain in patients can either be benign or an indication of life-threatening AMI

• Fast and reliable diagnosis of AMI is critical because every hour of delay to treatment increases the mortality risk

– Many patients with AMI are missed

• hs-cTnT measurement at initial presentation improves the early rule-in and rule-out of AMI

– 68% of the audience currently use a hs-cTnT assay

– 51% currently use a 0–3 hour algorithm

• Results from the TRAPID-AMI clinical study have been published confirming the efficacy of a novel approach for a more rapid diagnosis of AMI in patients with acute chest pain

• This novel strategy is based on hs-cTnT and reduces the observation time needed to rule-in or rule-out a heart attack from 3-6 hours to just 1 hour

– >75% of patients could be safely ruled-out or ruled-in using this algorithm

– A subgroup analysis also revealed that the NPV was ~99% for all groups

• The current ESC guidelines recommend (class IB) a rapid rule-out and rule-in protocol if a hs-cTnT assay with a validated algorithm is available

Common or gender-specific cut-offs? From the literature... to clinical practice

• The ability of hs-cTn assays to establish the 99th percentile in

healthy individuals has allowed discrimination of values between

the sexes

• Lower 99th percentile values for hs-cTnT in women can be

explained by cardiac anatomy and function

• Universal MI definition strongly recommends sex-specific cut-offs

for hs-cTn without proof of clinical usefulness

– 85% of audience do not use sex-specific hs-cTn cut-offs

• Diagnostic reclassification of type 1 MI using sex-specific hs-cTn

cut-offs is low and assay-specific

• Some studies indicate that lower hs-cTn cut-off values are better

– Multivariate-adjusted models showed that sex-specific cut-offs do not offer improved risk prediction

– A cut-off value slightly below the 99th percentile for hs-cTnT improved risk prediction in men and women

• Women have different coronary pathologies and are more

vulnerable to bleeding complications with anticoagulation

• The concept of diagnostic cut-offs considering sex or other

co-morbidities is too complicated and lacks practicality for

use in routine clinical practice

Observations

Early rule-out of AMI with a single measurement

Rick Body

The HEART Score and hs-cTnT

Jim McCord

hs-cTnT measurements in emergency

department patients who have not

experienced AMI

Richard Nowak

Fast assessment and management of

NSTEMI with prehospital troponin T

measurements

Carsten Stengaard

Session 5 Early diagnosis of acute

coronary syndrome

Co-chairs: Mauro Panteghini and Martin Than

Early rule-out of AMI with a single measurement • Symptoms suggestive of ACS account for approximately

5–10% of all visits to the ED. Delays in diagnosing AMI may increase the risk of complications and have fatal consequences

• A troponin algorithm for ruling-out AMI in the ED needs to be

acceptable, fast and accurate

• TRAPID-AMI enrolled 1,282 patients from 12 centers – Found that the detection of hs-cTnT <5 ng/L at admission

allows rapid, safe exclusion of AMI in 1/3 of patients without serial sampling

– However, this study does not include clinical information, provides ‘rule-out’ only, and is not validated for MACE

• The MACS rule was derived by multivariate analysis in 703 patients and combines clinical information with biomarkers, including hs-cTnT and H-FABP

– Divides patients into four risk groups – Primary outcome MACE at 30 days – Showed 100% sensitivity on external validation

• T-MACS excludes H-FABP

– Slightly reduced sensitivity but significantly improved specificity

The HEART Score and hs-cTnT

• The HEART Score was designed to risk stratify patients in the ED evaluated for possible ACS

• Addition of serial troponin leads to improved sensitivity and NPV compared to HEART Score alone

• HEART Score combines:

– Clinical suspicion – ECG – Age – Risk factors – Troponin

• The TRAPID-AMI study found that HEART Score ≤3 is effective for risk stratification when combined with 1-hour delta hs-cTnT strategy

– Sensitivity of 99.6% for 30-day AMI/death

• Modified-HEART Score strategy likely to be more impactful in the USA

– European cohort higher risk than in USA

– 58.3% ruled-out in USA using modified-HEART Score ≤3 and 1-hour delta compared with 40.1% in Europe/Australia

• HEART Score ≥4 will likely require serial hs-cTnT testing over a longer period of time and possibly further cardiac evaluation

• This study needs prospective validation

Observations

hs-cTnT measurements in emergency department patients who have not experienced AMI • hs-cTnT values have not been studied in patients suspected of

ACS but without a final ACS diagnosis

• This analysis described the baseline, 1 hour and delta hs-cTnT measurements in ED patients enrolled in the TRAPID-AMI study who did not have a final diagnosis of ACS

• The median hs-cTnT values are significantly higher in patients

with a cardiac diagnosis compared with other/unknown diagnostic groups

• hs-cTnT <5 ng/L at hour 0 is very predictive of no AMI. It also predicts the presence of an other/unknown diagnosis at ED presentation

• hs-cTnT at 0 or 1 hour can help ED physicians and cardiologists in making the correct diagnosis for patients without an ACS diagnosis (the vast majority of those evaluated for possible ACS)

• More clinical studies are needed to further define the diagnostic utility of very low levels of hs-cTnT in assessing ED patients suspected of ACS but without a final diagnosis

Fast assessment and management of NSTEMI with prehospital troponin T measurements • Guidelines recommend angiography within 24 hours in

high-risk patients with NSTEMI

• Improvement of prehospital triage is essential to ensure rapid management of patients. Prehospital quantitative POC-cTnT analysis, represents a feasible method to identify patients with AMI, and predict mortality

• The preHAP study was performed in the Central Denmark Region from May 2010 to May 2011

– Sensitivity for detection of AMI=39%

– Diagnostic accuracy=0.67

• There was a significant association between elevated prehospital POC-cTnT level above the detection level of 50 ng/L and mortality in patients with a suspected AMI

• The NON-STEMI study in 250 patients randomized to either acute or sub-acute CAG, found that diagnosing NSTEMI patients in the prehospital phase or immediately upon hospital admission was feasible and may allow for acute coronary angiography, which is associated with earlier revascularization and shorter hospital stay

Observations

hs-cTnT for risk prediction in the population

Christie Ballantyne

Future applications for GDF-15 across cardiovascular disease

Lars Wallentin

Multiple biomarker strategies for risk stratification in heart failure

Antoni Bayes-Genis

Monitoring platelet function in clinical practice: focus on PCI-treated patients

Dirk Sibbing

The post-statin era and PCSK9: do we need more precise lipid biomarkers

Joachim Thiery

“How much evidence do we need before implementation into clinical practice for high-risk primary prevention?”

Christie Ballantyne

Session 6 Future applications for

biomarker testing

Co-chairs: Hugo Katus and Christophe Meune

hs-cTnT for risk prediction in the population • Current models widely used for risk assessment in the general

population, such as the Framingham and Reynolds Risk Score, underestimate risk of CV events, especially in the elderly as they do not include hospitalization for HF

• Several recent large RCTs, such as SPRINT, have shown that treatment of older individuals at high-risk with more intensive therapy, to prevent HF, reduces CV events

• In a previous study of participants without known CHD/stroke in the ARIC population, levels of hs-cTnT in the highest category (≥0.014 μg/L) was associated with increased risk of incident CHD, mortality and hospitalization for HF

– Minimally elevated hs-cTnT (≥0.003 μg/L) was also associated with increased risk for mortality and HF

• Elevated levels of hs-cTnT and NT-proBNP are associated with

increased risk for MI, stroke and HF and are both superior to hsCRP in the ARIC study and numerous other large population studies

• A simple sex-specific model that includes age, race, hs-cTnT and NT-proBNP provides a good model, whereas adding cTnT and NT-proBNP to clinical characteristics results in an excellent HF prediction model

Future applications for GDF-15 across cardiovascular disease

• GDF-15 is a member of the TGF-β cytokine family which is weakly expressed by human tissues under normal conditions. Cardiomyocytes produce increased levels of GDF-15 in response to stress

• In the ULSAM cohort, one SD increase in log GDF-15 was shown to improve prognostication of CV mortality and morbidity beyond established risk factors and biomarkers of cardiac and renal dysfunction and inflammation. High levels of GDF-15 have also been shown to provide incremental prognostic value above BNP and cTnT in HF

• Elevated levels of GDF-15 (>1,200 ng/L) have also shown value as a prognostic marker in both stable and unstable CAD, including in patients with NSTE-ACS and NSTEMI

• GDF-15 is a risk factor for major bleeding, mortality and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of NT-proBNP and hs-cTnT

• The ABC stroke/bleeding risk scores are biomarker-based scores for predicting risk of stroke or bleeding in patients with atrial fibrillation

– ABC-bleeding score outperformed the HAS-BLED (p<0·0001) and ORBIT (p=0·0016) risk scores in an external validation cohort

• Concentrations of GDF-15 were the most important predictors for major bleeding in patients with atrial fibrillation

Observations

Multiple biomarker strategies for risk stratification in heart failure

• The investigation of novel circulating serum and plasma biomarkers in patients with CV disease has been accelerating at a remarkable pace

• Novel CV biomarker must be measurable, add new clinical information and help the clinician to manage patients

• Scores derived from multiple biomarkers integrating diverse biologic pathways substantially improve prediction of adverse events beyond current metrics

• Identifying an ‘optimal’ panel of biomarkers for assessing HF remains critical

• An attractive combination may be:

– NT-proBNP – neurohormonal activation – strain

– hs-cTnT – myocyte injury

– GDF-15 – inflammation

– ST2 – extracellular matrix

Monitoring platelet function in clinical practice: focus on PCI-treated patients

• Standardized and clinically validated thresholds for accurate risk stratification after PCI are lacking

• Platelet reactivity assessment during antiplatelet therapy identifies PCI-treated patients at higher risk for mortality or at an elevated risk for bleeding

• The prognostic value of PFT is considered to be scientifically validated

• The potential benefit of PFT for guidance of treatment warrants further investigation

• The ongoing TROPICAL-ACS trial is an investigator-initiated, randomized, parallel-group, open-label, assessor-blinded, European, multicenter trial in 2,600 biomarker-positive ACS patients with successful PCI

• This trial will provide clinically important results on the safety and efficacy of a strategy of a PFT-guided de-escalation of antiplatelet treatment compared with standard 12-month prasugrel therapy

Observations

The post-statin era and PCSK9: do we need more precise lipid biomarkers?

• Abnormal lipids cause 49.2% of the highest population attributable risk for the incidence of MI

• Statins, which inhibit the enzyme HMG-CoA reductase, have represented the cornerstone of treatment to regulate

cholesterol production

• PCSK9 inhibitors represent a new therapy which increases the expression of LDL receptors and reduces

LDL-cholesterol levels

– Has the potential to lower LDL-cholesterol by 70–80%

– Significant reduction in the incidence of CV events

– However, the cost of this therapy is high

• More precise markers for the prediction of CHD risk and lipid treatment decision are needed to identify patients

who will benefit

• LDL-cholesterol can serve as a predictor for the severity of non-obstructive CAD

• PCSK9 levels in plasma are promising, but studies for clinical utility and validated assays are still missing

(free and LDL-bound PCSK9)

• PCSK9 inhibitors can lower Lp(a) levels by 26%

– Lp(a) should be measured in all patients with CHD risk to enhance lipid lowering treatment. Selective Lp(a) lowering drugs are

currently undergoing clinical validation

• Established cardiac markers including hs-cTnT might be important as additional biomarkers to identify non-ACS

patients with CAD risk

Observations

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