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April 2011 1 H-FABP IT Assay Launch Pack 1.0 Introdution H-FABP IT Assay 2.0 Background What is Cardiovascular Disease? What are the types of Myocardial Infarction? What is ACS? Universal Definition of MI (2007) How are chest pain patients typically managed in secondary care? Background of acute cardiac biomarker development o Release kinetics o Traditional markers o Contemporary markers 3.0 H-FABP background Description, Discovery & Evolution of H-FABP Key publications 4.0 H-FABP Story Schema Key messages on H-FABP Introduction Diagnostic Value Prognostic Value Other applications of H-FABP Conclusion 5.0 Target Market & Sales Strategy Triangle of Cardiology/ED/Biochemistry Key areas to communicate Sales Approach Potential sales blocks and how to over come them Marketing activities 6.0 H-FABP Assay performance details Assay performance details Correlation vs BAT Assignment of 99 th percentile 7.0 Marketing Toolkit 8.0 MultiStat Cardiac 9.0 Competitors POCT competitors Biomarker strategies Other candidate biomarkers 10.0 Glossary of terms

Transcript of H-FABP IT Assay Product Launch Pack (May 2011) (2)

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H-FABP IT Assay Launch Pack

1.0 Introdution

• H-FABP IT Assay 2.0 Background

• What is Cardiovascular Disease? • What are the types of Myocardial Infarction? • What is ACS? • Universal Definition of MI (2007) • How are chest pain patients typically managed in secondary care? • Background of acute cardiac biomarker development

o Release kinetics o Traditional markers o Contemporary markers

3.0 H-FABP background

• Description, Discovery & Evolution of H-FABP • Key publications

4.0 H-FABP Story Schema

• Key messages on H-FABP • Introduction • Diagnostic Value • Prognostic Value • Other applications of H-FABP • Conclusion

5.0 Target Market & Sales Strategy

• Triangle of Cardiology/ED/Biochemistry • Key areas to communicate • Sales Approach • Potential sales blocks and how to over come them • Marketing activities

6.0 H-FABP Assay performance details

• Assay performance details • Correlation vs BAT • Assignment of 99th percentile

7.0 Marketing Toolkit 8.0 MultiStat Cardiac 9.0 Competitors

• POCT competitors • Biomarker strategies • Other candidate biomarkers

10.0 Glossary of terms

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1.0 Introduction

H-FABP IT Assay

The H-FABP Assay is an immunoturbidimetric (IT) assay for the quantitative determination of Heart-type

Fatty Acid Binding Protein (H-FABP) in serum. This is a rapid, fully automated, wet chemistry assay and is

suitable for use on a wide range of analysers, with the first result available in 10-14 minutes.

H-FABP has only previously been available from Randox via biochip array technology (e.g. Evidence &

Investigator), so this new assay enables us to promote the test as part of the standard cardiac profile used

clinically in hospital biochemistry laboratories. Whilst this launch pack focuses on the H-FABP IT assay,

please note that the H-FABP IT assay and MultiStat Cardiac panel (incorporating H-FABP, TnI and CK-MB)

are complementary. The availability each of these in the Randox product portfolio enables the targeting of

both the main laboratory and near-patient testing target markets.

This launch pack is intended to provide you with sufficient background knowledge to target relevant

customers in your area for the uptake of H-FABP.

2.0 Background

What is Cardiovascular Disease?

Cardiovascular disease (CVD) is a general term used to describe disorders that affect the heart and/or the

blood vessels (arteries and veins). It includes conditions such as coronary heart disease (CHD),

cerebrovascular disease (e.g. stroke), congenital heart disease and peripheral heart disease.

The most common form of CVD is coronary heart disease (CHD). This occurs when the coronary arteries

(the arteries that supply blood and oxygen to the heart muscle) become narrowed by a gradual build-up of

fatty material within their walls. This condition is called atherosclerosis and the fatty material is called

atheroma.

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In time, the artery may become so narrow that it cannot deliver enough oxygenated blood to the heart

muscle, particularly at times when there is more demand - such as during periods of physical exertion. The

pain or discomfort that occurs as a result is called angina. This is a relatively low risk condition and can be

managed by “GTN” spray and lifestyle considerations. However, if this pain occurs while the individual is at

rest or at an unpredictable threshold, it is known as unstable angina (UA), which is a much more serious

condition and is regarded as a medical emergency.

If the atheroma (fatty plaque) becomes weakened, a piece may break off and lead to a blood clot forming. If

the blood clot then blocks a coronary artery, the heart muscle (myocardium) is starved of blood and oxygen

(ischemia). If the myocardium is starved of blood for a prolonged period of time, the muscle cells will start to

die – this is known as myocardial necrosis (illustrated as the blackening of the muscle above).

Once a patient is found to have suffered myocardial necrosis (resulting from ischemia), they can be

diagnosed as having a heart attack or Acute Myocardial Infarction (AMI or MI) and should receive emergency

treatment to restore the blood flow (known as reperfusion) via drugs or via surgery, and to treat the effects of

the damage caused.

What are the types of Myocardial Infarction?

The classification of MI type is primarily made using the results from an ECG machine, and whether there

are any changes to the ST-segment of the electrical impulses sent from the heart:

• ST-elevated myocardial infarction (STEMI) – an MI which DOES include changes to the ST-

segment of the ECG

• Non ST-elevated myocardial infarction (NSTEMI) – an MI which does NOT include changes to the

ST-segment of the ECG, but may include other changes and/or positive Troponin/CK-MB

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What is ACS?

Acute Coronary Syndrome (ACS) refers to a spectrum of clinical presentations including unstable angina,

NSTEMI and STEMI. ACS is a serious and life threatening condition and requires immediate hospitalisation.

Also, it should be noted that stable angina is not classified as ACS, as illustrated by the diagram below.

Universal Definition of MI (2007)

The four major international cardiology societies joined together in year 2000, to construct a consensus

document on how MI and ACS should be diagnosed. This document was then updated in 2007 and named

the “Universal definition of MI”, which is now one of the cornerstones of cardiology worldwide. Although it is

not necessary to have detailed knowledge of the new definition, a summary is included below for reference

purposes.

“Criteria for Acute Myocardial Infarction. The term myocardial infarction should be used when there is

evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Under these

conditions, any one of the following criteria meets the diagnosis for myocardial infarction:

Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th

percentile together with evidence of myocardial ischemia along with at least one of the following:

• Symptoms of ischemia;

• ECG changes indicative of new ischemia

• Development of pathological Q waves in the ECG;

• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

The preferred biomarker for myocardial necrosis is cardiac troponin (I or T), which has high myocardial tissue

specificity as well as high clinical sensitivity, thereby reflecting even microscopic zones of myocardial

necrosis (3). An increased value for cardiac troponin is defined as a measurement exceeding the 99th

percentile of a normal reference population (URL = upper reference limit). Detection of a rise and/or fall of the

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measurements is essential to the diagnosis of acute myocardial infarction (6). The above-mentioned

discriminatory percentile is designated as the decision level for the diagnosis of myocardial infarction, and

must be determined for each specific assay with appropriate quality control (7–9) Optimal precision

(coefficient of variation [CV]) at the 99th percentile URL for each assay should be defined as 10%. Better

precision (CV 10%) allows for more sensitive assays (10,11). The use of assays that do not have

independent validation of optimal precision (CV 10%) is not recommended”

With regards to biomarkers, it recommends that Troponin (either I or T) be used as the primary marker of

myocardial necrosis, while CK-MB can be used as an alternative (if Troponin is not available) or as a marker

of re-infarction. It also suggests that an “early rise” biomarker can be used, and suggested that Myoglobin

had the greatest weight of evidence (at that time e.g. 2006).

The universal definition also outlined the requirements for analytical precision for cardiac biomarkers. This

stated that whichever biomarker or assay that is used (but especially for Troponin), the assay should be

capable of achieving 10% CV at the 99th percentile (i.e. the recommended diagnostic cut-off point for MI).

and any which cannot meet this criteria should not be used.

This created a significant hurdle for all major diagnostic manufacturers, as virtually none of the assays

available on the market fulfilled these guidelines. Following a period of intensive R&D (from 2008 onwards),

the new generation of assays began to be released in 2010 (starting with Roche’s hsTnT). The

improvements made in precision also meant improvements in sensitivity, meaning that these new assays

have become commonly known as “highly sensitive” Troponins.

The 2007 guidelines are currently being updated, with the new version expected to be published at the end

of 2011, or early 2012. However, the changes included are anticipated to be minor, rather than a

comprehensive overhaul.

How are chest pain patients typically managed in secondary care?

The first test that will be conducted following presentation (either via an ambulance or walking into the

emergency department) will be an ECG test. This is primarily to establish whether the patient has any

abnormal electrical impulses in their heart, which are likely to have been the result of a heart attack. This is

largely done by checking for any changes to the ST-segment of the ECG trace. If these exist, the patient can

be diagnosed as having had an ST-elevated Myocardial Infarction (STEMI).

These patients are at highest risk of death and so (in many countries) are sent straight to the catheter lab to

have a coronary stent fitted (using a tiny balloon to open the blockage) and restore the blood flow around the

heart (known as “reperfusion”). This procedure is known as “Primary Percutaneous Coronary Intervention” or

primary PCI, and in many countries hospitals aim to carry this out within 90 minutes of a patient arriving

(“door-to-balloon time”).

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PCI can also be carried out as an “elective” procedure for lower risk patients, in which they visit hospital as

an outpatient. In general, STEMI patients are relatively straight forward to diagnose and there is limited

benefit of biomarkers in such patients.

However, the majority of patients arriving at an ED with chest pain (e.g. >80%) have no ST changes on their

ECG (i.e. non STEMI), and therefore the hospital must diagnose whether they have stable angina, unstable

angina, NSTEMI or another condition (cardiac related or not). Biomarkers and clinical assessment are crucial

in these areas.

Background of acute cardiac biomarker development

The last 25 years has seen major steps forward in the field of acute cardiac biomarkers, and they are now

central to the diagnosis of MI/ACS.

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As illustrated by the diagram above, the traditional biomarkers of ACS have been CK, CK-MB and

Myoglobin. The evolution of Troponins and the new definitions of MI (2000 & 2007) have meant that these

are now central to the diagnostic process. However, although the use of CK-MB and Myoglobin has declined

in recent years, they are still used in some hospitals and some geographical markets. The below table

outlines some of the key characteristics of these markers, and compares them to H-FABP.

Biomarker Molecular

Weight (kDa)

Initial Elevation in blood

Time to peak

Return to normal

Type of Marker Comments

H-FABP 15kDa 1-2 hrs 6-8 hrs 24 hrs Ischemic Early rise Highly specific

Myoglobin 17kDa 1-3 hrs 5-8 hrs 16-24 hrs Ischemic Early rise Highly unspecific

Troponin I (TnI) 22kDa 3-6 hrs 14-18 hrs 5-10 days Necrotic Late rise

Very Highly specific

Troponin T (TnT) 33kDa 3-6 hrs 10-48 hrs 10-15 days Necrotic Late rise

Very Highly specific

CK-MB 86kDa 3-8 hrs 9-24 hrs 48-72 hrs Necrotic Late rise Relatively specific

Release Kinetics

As shown below, H-FABP is the earliest rise biomarker after onset of chest pain symptoms. It has a similar

release kinetic to Myoglobin (i.e. early rise & returns to normal within 24 hours), but a key difference is that

H-FABP is approximately 20 times more cardiac specific than Myoglobin. Lack of cardiac specificity is a

major problem with Myoglobin, but not with H-FABP.

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A side benefit of the release kinetics of H-FABP (beyond earlier detection of ischemia), is that it can also be

used as a marker for re-infarction (i.e. repeat heart attack). This commonly occurs within the 3-4 days

following the first MI, a period during which Troponin & CK-MB would still be elevated from the initial infarct.

Traditional markers of ACS

• CK-MB: the original marker of ACS and widely used due its inclusion in the original WHO guidelines

(late 1970s). However, the improved specificity of Troponins has led to them now becoming the

preferred markers. CK-MB is still used in some hospitals, but mainly as an adjunct to Troponin or as

a marker of re-infarction.

• Myoglobin: an early rise biomarker that has been historically used as an adjunct to Troponin during

the early hours after chest pain onset. However, usage has declined in recent years due to issues

with its lack of cardiac specificity (it is a generic marker of skeletal muscle damage).

• Troponin T (TnT): the original type of Troponin, as discovered and patented in the late 1980s. The

patent is jointly held by Roche Diagnostics & Prof. Hugo Katus (University of Heidelberg, Germany),

and largely limits the use of TnT to Roche instruments.

• Troponin I (TnI): a different part of the Troponin compound, but not exclusively patented to has

enabled a wide range of manufacturers to produce their own version of assay. There is very little

difference between TnI and TnT, and their selection normally depends on which company has won

the tender for a laboratories biochemistry service.

Contemporary markers of ACS

• Highly sensitive Troponins (hsTn): the new ACC/ESC guidelines on the definition of MI (2000 &

2007) led to the requirement for manufacturers to produce Troponin assays which are precise

enough to have less than 10% CV at the 99th percentile cut-off. The development of these improved

assays has led to the introduction of so-called “highly sensitive Troponins”, which has been

pioneered by Roche’s hsTnT assay. The other major manufacturers are expected to launch their “hs”

versions throughout 2011 & 2012. Below is a table of currently (or soon to be) available Troponin

assays and those highlighted in green are assays which meet the guidelines (updated Jan 2011).

The original version of this table is published by the IFCC on their website.

• H-FABP: has a rapidly building evidence base surrounding potential applications in ACS. Covered in

more detail later, it has emerged as one of the leading candidate markers that can be used

alongside Troponin (or hsTroponin) in the modern era. Although it is not yet widely used in all

countries, the recent wave of publications has created a huge amount of interest on its potential

integration into clinical practice.

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Commercially available assays - Company/ platform(s)/ assay

LoB#

(µg/L) LoD* (µg/L)

99th perc. (µg/L)

%CV at 99thperc.

10% CV (µg/L)

Abbott AxSYM ADV 0.02 0.04 14.0 0.16

Abbott ARCHITECT <0.01 0.028 14.0 0.032

Abbott i-STAT (POCT) 0.02 0.08 16.5 0.10

Alere Triage SOB (POCT) 0.05 NA NA NA

Alere Triage Cardio 3 (revised) (POCT) 0.01 NA 17.0 (at 0.02) NA

Beckman Coulter Access Accu 0.01 0.04 14.0 0.06

bioMerieux Vidas Ultra 0.01 0.01 27.7 0.11

Mitsubishi Chemical PATHFAST (POCT) 0.008 0.029 5.0 0.014

Ortho Vitros ECi ES 0.012 0.034 10.0 0.034

Radiometer AQT90 FLEX TnI (POCT) 0.0095 0.023 17.7 0.039

Radiometer AQT90 FLEX TnT (POCT) 0.010 0.017 15.2 0.025

Response Biomedical RAMP (POCT) 0.03 NA 18.5 (at 0.05) 0.21

Roche Cardiac Reader cTnT (POCT) <0.05 NA NA NA

Roche E 2010 /cobas e 411 / E 170 / cobas e 601 / 602 TnT (4th gen) 0.01 NA NA 0.03

Roche E 2010/cobas e 411 / E 170 / cobas e 601 / 602 hs-TnT 0.005 0.014 10.0 0.013

Roche E 2010/cobas e 411 / Roche E 170/cobas e 601 / 602 cTnI 0.16 0.16** NA 0.3

Siemens Centaur Ultra 0.006 0.04 8.8 0.03

Siemens Dimension RxL 0.04 0.07 20.0 0.14

Siemens Dimension EXL 0.017 0.056 10.0 0.05

Siemens Immulite 2500 STAT 0.1 0.2 NA 0.42

Siemens Immulite 1000 Turbo 0.15 NA NA 0.64

Siemens Stratus CS (POCT) 0.03 0.07 10.0 0.06

Siemens VISTA 0.015 0.045 10.0 0.04

Tosoh ST AIA-PACK 0.06 0.06** 8.5 NA

Research assays - not yet commercially available

Beckman Coulter Access hs-cTnI 0.0020 0.0086 10.0 0.0086

Nanosphere VeriSens hs-cTnI 0.0002 0.0028 9.5 0.0005

Singulex hs-cTnI 0.00009 0.0101 9.0 0.00088 *LoB = limit of blank *LoD = limit of detection NA = Not Available

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3.0 H-FABP background

Description, Discovery & Evolution of H-FABP

Heart-type Fatty Acid-Binding Protein (H-FABP) is a small cytoplasmic protein (molecular weight of15 kDa)

released from cardiac myocytes (muscle cells) following an ischemic episode. Like the nine other distinct

FABPs that have been identified, H-FABP is involved in active fatty acid metabolism, where it transports fatty

acids from the cell membrane to mitochondria for oxidation.

Although H-FABP was discovered in 1989, early results and applications were largely hindered by the lack of

good quality assays. It has only been in the last few years that high quality results have been possible, due

to the recent development of monoclonal antibodies.

Key publications

Diagnostic value in ACS • McMahon CG, Lamont JV, Curtin E, McConnell RI, Crockard M, Kurth MJ, Crean P, Fitzgerald SP.

Diagnostic accuracy of heart-type fatty acid-binding protein for the early diagnosis of acute

myocardial infarction. Am J Emerg Med. 2011 Jan 3

• McCann CJ, Glover BM, Menown IB, Moore MJ, McEneny J, Owens CG, Smith B, Sharpe PC,

Young IS, Adgey JA. Novel biomarkers in early diagnosis of acute myocardial infarction compared

with cardiac troponin T. Eur. Heart J. 2008;29(23):2843-50.

Prognostic Value in ACS • McCann CJ, Glover BM, Menown IB, Moore MJ, McEneny J, Owens CG, Smith B, Sharpe PC,

Young IS, Adgey JA. Prognostic value of a multimarker approach for patients presenting to hospital

with acute chest pain. Am. J. Cardiol. 2009:103(1):22-8.

• Kilcullen N, Viswanathan K, Das R, Morrell C, Farrin A, Barth JH, Hall AS; EMMACE-2 Investigators.

Heart-type fatty acid-binding protein predicts long-term mortality after acute coronary syndrome and

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identifies high-risk patients across the range of troponin values. J. Am. Coll. Cardiol.

2007;50(21):2061-7.

• Viswanathan K, Kilcullen N, Morrell C, Thistlethwaite SJ, Sivananthan MU, Hassan TB, Barth JH,

Hall AS. heart-type fatty-acid binding-protein (H-FABP) predicts long-term mortality and re-infarction

in consecutive patients with suspected acute coronary syndrome who are troponin negative. J. Am.

Coll. Cardiol. 2010;55(23): 2590-8

• Pearson IR, Hall AS, Gale CP, Sivananthan MU, Viswanathan K, Kilcullen N, Barth JH, In Acute

Coronary Syndromes, Heart-type Fatty Acid Binding Protein is a More Accurate Predictor of Long

Term Prognosis than Troponin. Circulation. 2010;122:A11374

Value in Pulmonary Embolism

• Puls M, Dellas C, Lankeit M, Olschewski M, Binder L, Geibel A, Reiner C, Schäfer K, Hasenfuss G,

Konstantinides S. Heart-type fatty acid-binding protein permits early risk stratification of pulmonary

embolism. Eur Heart J. 2007 Jan;28(2):224-9.

• Dellas C, Puls M, Lankeit M, Schäfer K, Cuny M, Berner M, Hasenfuss G, Konstantinides S.

Elevated heart-type fatty acid-binding protein levels on admission predict an adverse outcome in

normotensive patients with acute pulmonary embolism. J Am Coll Cardiol. 2010 May

11;55(19):2150-7.

Value in Cardiac Bypass Surgery • Muehlschlegel JD, Perry TE, Liu KY, Fox AA, Collard CD, Shernan SK, Body SC. Heart-type fatty

acid binding protein is an independent predictor of death and ventricular dysfunction after coronary

artery bypass graft surgery. Anesth Analg. 2010;111(5):1101-9.

A summary of all these papers is included in the A5

Randox brochure, H-FABP Summary of Publications

(LT242) – see image of front cover opposite.

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4.0 H-FABP

Key messages on H-FABP

Generic Messages on H-FABP

• H-FABP is a complementary biomarker to Troponin – it is not designed to replace it.

• H-FABP improves the diagnostic & prognostic information already provided by Troponin.

• Even though they have similar release kinetics (early rise, early fall), H-FABP is 20 times more

cardiac specific than Myoglobin. It is therefore of much greater utility than Myoglobin in the

cardiac setting, as Myoglobin is well renowned for leading to false positive results.

• H-FABP is a more effective marker of re-infarction than CK-MB, due to H-FABP’s quicker

return to baseline levels

Diagnostic Value of H-FABP

• Biomarker of myocardial ischemia

• Detectable as early as 30 minutes after ischemic episode (e.g. onset of chest pain)

• Significantly earlier rise than Troponin (I or T) or CK-MB

• Can be used for earlier rule-in of MI in the absence of ECG changes or a raised Troponin (e.g.

<6 hours from chest pain onset)

• Can be used for earlier rule-out of MI in combination with Troponin (98% NPV at 3-6 hours,

AJEM 2011 paper)

• H-FABP & hsTnT provides a 98.7 NPV for AMI on presentation (EuroMedLab 2011)

• Combination of H-FABP, hsTnT & ECG provides a 100% NPV on admission & enables

immediate exclusion of AMI in 48% of patients on presentation (EuroMedLab 2011)

• Can be used to significantly improve the cardiac specificity of hsTroponin and reduce numbers

of false positives being transferred to Cardiology

Prognostic Value of H-FABP

• Biomarker of myocardial ischemia

• Negative H-FABP & negative Troponin at 12-24 hours post-admission provides 0% mortality

over next six months - reduces the number of patients being mistakenly sent home (JACC

2007)

• Positive H-FABP at 12-24 hours post-admission is strongly predictive of mortality over next 6

years, regardless of whether patient is Troponin positive or negative (JACC 2007). This is

particularly important for Troponin negative patients as they may be sent home (Troponin

positive are treated as high risk anyway)

• Positive H-FABP is still strongly predictive of mortality in Troponin negative patients, even

when a hsTroponin assay is used (Siemens TnI-ultra) (JACC 2010)

• Increased concentrations of H-FABP correlates to increased risk – illustrates importance of a

quantitative & precise H-FABP assay

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H-FABP Story Schema Hook

I am delighted to be able to talk to you today about a revolutionary new cardiac diagnostic test that is available for use on your ………..(Randox rep names the relevant analyser e.g. Roche Cobas 6000). The simple addition within your laboratory of this early rise ischemic marker enables the early rule out of MI and provides a level of prognostic data that has caused the world of cardiology to seriously begin to consider this marker as a complementary assay to High sensitivity troponin.

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Introduction A small cytoplasmic protein that’s 20 times more specific to the cardiac muscle than myoglobin, its potential as a cardiac biomarker was first discovered by Prof Jan Glatz in 1988.

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A marker of Ischemia, its cytoplasmic location means that this stable protein is released within thirty minutes of the cell membrane disruption caused by the ischemic epsiode. Released much earlier then cTn – a marker of necrosis, it peaks at six hours and returns to baseline within 24 hours. This means that is a better marker for the early rule out of MI and for the diagnosis of re-infarction, given that Troponin remains raised for several days after an MI.

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The Diagnostic Value H-FABP is the most accurate and sensitive ischemic marker in the first few hours after chest pain onset as you can see from these two studies. When you get to later time points, its clear that Troponin becomes more sensitive and accurate, but this is in part due to the fact that H-FABP has returned to baseline.

A combination of H-FABP and cTnI is 20% more sensitive than Troponin alone.

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In this study conducted in the busy Emergency Department of St James’ Hospital Dublin, over 1000 pts with suspected MI who presented across the course of one year had bloods taken at serial timepoints. The investigator’s wanted to know if a multi-marker approach using Randox’s BAT could provide a high Negative Predictive Value (NPV) for MI at an early time point in comparison to single markers. They found that a combination of H-FABP and cTnI produced an NPV of 98% at 3-6h. This enabled the earlier rule out of MI and a more accurate risk stratification of low to medium risk chest pain pts. This finding is highly significant in terms of health economics. The ability to rule out MI with a high degree of certainty at 3 hours, enables physicians to discharge pts who would ordinarily be taking up a bed waiting for a negative 12 hour Troponin test. The cost savings that the addition of this simple extra cardiac biomarker could therefore generate are substantial.

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The Prognostic Value Prognostically, H-FABP is creating a huge amount of interest. McCann et al have clearly demonstrated that the presence of H-FABP equals increased risk. Indeed, alongside D-dimer, NT-proBNP and peak cTnT, it was the only cardiac biomarker that they looked at that proved to be a statistically significant predictor of death or MI at one year. Indeed, this prognostic information was importantly found to be independent of Troponin T, ECG and clinical examination.

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Two landmark papers published in the Journal of the American College of Cardiology (JACC) from Prof Alistair Hall’s research group in Leeds, England, have clearly demonstrated that the risk associated with H-FABP is dependent upon its concentration. Kilcullen et al found that pts who were TnI –ve but H-FABP +ve had a 17% increased risk of all cause mortality within one year compared to those pts who were TnI +ve but H-FABP –ve. This finding has created huge interest given that H-FABP is currently not routinely measured. Currently these TnI +ve pts are prioritised for angioplasty, and the TnI –ve pts are considered to be of a lower priority, yet the additional of a simple complementary test helps identify pts who are currently slipping through the net and allows physicians to more appropriately manage this hidden high risk group.

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The investigators also discovered that if both biomarkers were negative, there was 0% mortality at 6 months, in the authors own words this “represents a particularly worthwhile clinical outcome, especially because it was observed in pts admitted into hospital for suspected ACS” These patients have now been followed up for six years, and it will come as no surprise that the Troponin +ve pts have a better prognosis than Troponin –ve patients – there would be little point in spending so much time and money on Angioplasty if this was not the outcome achieved. What is striking though, is that the key discriminator in terms of poor prognosis is not whether you are Troponin +ve or –ve, its what your H-FABP is.

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But its not enough just to know if the patients H-FABP is positive or negative. The 2010 JACC paper from Prof Hall’s group clearly demonstrates that the greater the concentration of H-FABP, the greater the increase in risk of death or MI within the next year. This highlights why a fully quantitative test for H-FABP, of which Randox are the only manufacturer, is absolutely vital.

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Indeed H-FABP indicates risk across the whole ACS spectrum. It doesn’t matter whether we look at UA, NSTEMI or STEMI, low H-FABP concentrations confers low risk, whereas high H-FABP concentrations indicate pts who are at a much higher risk of future events. This ability to diagnose all ACS patients means that unlike ECG or Troponin, H-FABP is the first true global ACS marker.

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Many cardiologists have asked about how Randox’s H-FABP assay measures up against the new generation of high sensitivity Troponin assays that are beginning to be adopted by many central laboratories. The 2010 JACC paper clearly shows the high quality of Randox’s H-FABP assay, as it was found to have a similar sensitivity and specificity to a hs Troponin assay.

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Other applications of H-FABP However, its not only in ACS that H-FABP is beginning to prove its worth. Only H-FABP has been proven to significantly predict 30 day mortality in Acute Pulmonary Embolism.

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H-FABP is superior to both Troponin and NT-proBNP in distinguishing between low and intermediate risk normotensive Pulmonary Embolism (PE = a clot in the lung) patients. From a single sample on admission, H-FABP helps risk stratify patients and identify those who are at a 4.5 fold increased risk of death, thereby allowing rapid, appropriate and targeted intervention to increase the likelihood of preserving life.

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…and H-FABP is more effective than Troponin T in risk stratifying Chronic Heart failure patients.

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As an early rise ischemic marker, H-FABP also holds the promise of providing interventional cardiologists and surgeons, with a rapid test to determine myocardial injury and re-infarction in the minutes and hours post procedure. As you can see from this study of over 9000 samples, only H-FABP was able to discriminate between graft failure with massive tissue necrosis and ischemia reperfusion injury within the crucial time window of the first 24 hours post Coronary Artery Bypass Graft.

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….and H-FABP can also be used as a rapid marker of brain damage and clinical severity in patients who have suffered an acute ischemic stroke.

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Conclusion H-FABP is also beginning to create interest with researchers who have found emerging evidence that indicates a role for this biomarker in differentiating between different neurodegenerative diseases. So, where do you see H-FABP fitting in to your hospital?....

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5.0 Target Markets & Sales Strategy

Triangle of Cardiology/ED/Biochemistry

In order to achieve the successful and long-term introduction of H-FABP into a hospital, it is vital that a wide

range of stakeholders are involved in the discussions & promotional efforts.

Without doubt, in the vast majority of hospitals the key decision makers in this process will be the

cardiologists. Staff in the biochemistry and emergency departments will generally accept that it is the

cardiologists who have the greater expertise in the area of cardiac biomarkers. It is highly unlikely that a

hospital will introduce a new cardiac biomarker without heavy involvement from the Cardiology department.

However, promotional efforts with the cardiology departments must be complemented by visits to key

decision makers in biochemistry and the ED, in order to ensure they are on-board and are aware of the

potential benefits that H-FABP will provide.

Key areas to communicate

There are a number of areas that clinicians will be keen to understand:

1. The Evidence Base of publications – this is crucial to convince them on the merit of H-FABP (e.g.

JACC 2007 & 2010 etc) – see H-FABP schema. ED doctors will be primarily interested in the

diagnostic value (e.g. early rule out and/or diagnosis), while Cardiologists will be interested in both

the diagnostic & prognostic value. Biochemists will, to a lesser extent, also be interested in both, but

may then additionally focus on analytical details of the assay.

2. Product Positioning – important to communicate that we are not promoting H-FABP to replace

troponin, but rather as a complementary test. However, it can be promoted to replace CK-MB and/or

Myoglobin as supplementary markers.

3. Financial/time benefit – cost savings that can be achieved through lowering the costs of witholding

patients to wait for a later troponin test (e.g. at 9-12h post admission/chest pain).

4. Quality of Product & Company – the majority cardiologists & ED doctors will have a low

awareness of Randox, so it is important to communicate the history, quality & innovative nature of

the company. Being a UK manufacturer may also be important in many markets.

Cardiology

Biochemistry Emergency Department

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Other key points to bear in mind:

• Relationship building and repeat contact with all three departments is key to building momentum

and “noise” in the hospital surrounding H-FABP. • Cardiologists & ED doctors are generally not interested in analytical details of assays – save this

promotion for the Biochemistry department

Sales Approach

1. Product Knowledge – build a strong knowledge & awareness on the available Randox literature &

the key publications on H-FABP (e.g. JACC 2007 & 2010, EHJ 2008, AJEM 2011)

2. Market Intelligence – include H-FABP discussions in your routine laboratory visits. Complete a

Cardiac Albertus questionnaire where possible. Build a picture of which biomarker assays are most

commonly used in your area (e.g. Roche TnT, Siemens TnI).

3. Dedicated Customer visits – Once the key departments & potential decision makers have been

identified, conduct dedicated visits with the focus on discussing H-FABP (e.g. Head of Cardiology).

Discuss potential ways in which H-FABP could be integrated into the existing cardiac biomarker

protocol.

4. Customer Presentations – Organise presentations (e.g. via lunchtime seminars) that will enable

relevant staff (from various departments) to attend & stimulate discussions with you & amongst

themselves.

5. Assay Evaluation – negotiate with the relevant biochemistry lab for them to evaluate the H-FABP

assay on their relevant instrument.

6. Commitment to Purchase – agree terms, organise PO and arrange delivery.

7. Follow-up visits & continued relationship building – regular follow-up contact & visits to provide

ongoing support for previous orders and build on the relationship to enable further revenue.

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Potential Sales blocks and how to overcome them

Sales Block Counter-strategy for H-FABP

Lack of awareness of H-FABP

• Multiple presentations of H-FABP story brochure and

publications • Published data available is excellent & highly convincing • Regular sales visits to relevant departments & decision

makers • Organisation of lunchtime seminars on H-FABP

“We only currently test Troponin”

• Counter-argument will largely depend on which Troponin assay is

being used (e.g. TnI/TnT/hsTnT) • Diagnostic value of H-FABP in early hours (e.g. during Troponin

blind period). 98% NPV and improved sensitivity <4hours. • Prognostic value over 6 months & 5 years (Leeds data)

“Its up to the cardiologists which biomarkers are used”

• Promotional efforts direct to cardiology department via visits,

presentations & seminars • Encourage the various departments to communicate with each

other & initiate dialogue on H-FABP

“We have recently started using hs-TnT from Roche”

• hsTnT improves the diagnostic sensitivity in the early hours, but at

the cost of specificity. Leads to increased numbers of referrals to the Cardiology department & false negatives for AMI/ACS

• hsTnT is a marker of myocardial injury, not myocardial infarction. It can be raised from a range of cardiac issues.

• H-FABP can be used in conjunction with hsTnT, to improve its specificity and reduce false positives. H-FABP helps identify which patients have raised hsTnT due to myocardial ischemia.

“We use BNP or NT-proBNP”

• These are primarily used as markers of heart failure, not ACS. • The majority of hospitals will not be using these in an ACS

application, largely due to the cost.

“We cannot afford to test another cardiac biomarker”

• Encourage them to look at the wider economic environment in the

hospital. • Significant costs are incurred through prolonged stays in the ED

(e.g. waiting for a 12h Troponin) and through unnecessary admissions to Cardiology (e.g. through Troponin false positives)

• The cost of the additional H-FABP (especially now with the IT assay) is rather insignificant in comparison to an overnight hospital stay or unnecessary trip to the cath lab.

“Troponin is a more established biomarker than H-FABP”

• We are not advocating that H-FABP should be used instead of

Troponin – instead it is a COMPLEMENTARY marker that works alongside Troponin

“We use Myoglobin as an early rise biomarker”

• This is a quite straight forward block to counter-act. • Myoglobin has well renowned problems with cardiac specificity

and H-FABP is a much superior biomarker • H-FABP is released earlier than Myoglobin and is 20 times more

cardiac specific • Direct them to the wealth of recent publications on H-FABP

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Marketing Activities

• Direct visits to Cardiology departments – This is crucial to raise awareness of H-FABP and gain

buy-in from the key decision makers. It is likely that Cardiology buy-in will be required at the vast

majority of hospitals in order to introduce a new cardiac biomarker into their routine protocols. Heads

of Cardiology and Cardiology consultants will be key, but also target supplementary visits to cardiac

researchers linked to the department, as well as cardiac nurses and senior doctors (pre-consultant).

• Engage with your National Society of Cardiology – Identify the key players in your relevant

national society and the dates/location of the annual conference. Organise direct visits to the key

players/sites & investigate options to attend the national conference. NB: Cardiology conference

exhibitions are often dominated by pharma companies – that is because they offer direct access to

cardiologists. It does not mean they are not appropriate to diagnostic companies.

• Organise lunchtime seminars at key sites in the Cardiology,

Biochemistry & Emergency Departments – These are an excellent way

of increasing awareness of H-FABP and stimulating discussion within the

hospital. They provide a superb opportunity to clearly present the latest

publications on H-FABP and ensure a captive audience for 15/30/60

minutes. Discuss with Randox HQ as to the most effective way of

organising & presenting these.

• Mailshots – Utilise existing biochemistry contacts & mailing lists to promote the launch of the H-

FABP IT assay, Investigate potential local sources of cardiology based contact lists.

• Translation of key brochures – Where language translations of the key H-FABP brochures are

essential, work with Randox HQ to achieve this, while maintaining the quality of the original material.

• Identify potential key reference sites for cardiac biomarkers – these can be used as the subject

of initial investment in trials kits, and act as a reputable reference that can be used throughout the

rest of the country. Also, attempt to identify the primary research interests of various sites (e.g. one

hospital may have a strong research background in cardiac biomarkers; another may have a strong

background in pharma trials or cardiovascular imaging.

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6.0 H-FABP assay performance details

Please see below for some assay details. Although only the Rx Daytona & Siemens ADVIA 1650 are

included below, applications for H-FABP will be available for a wide range of clinical chemistry analysers.

Category IT Assay

(Rx Daytona)

IT Assay

(Siemens

ADVIA 1650)

Evidence

Investigator Evidence

Assay Range 2.5-120ng/mL 3.49 - 132ng/mL 0.18 - 50ng/mL 0.35 – 100ng/mL

Functional

sensitivity 2.5ng/mL 3.49ng/mL 0.18ng/mL 0.35ng/mL

Intra-assay precision <8% CV <8% CV 5.0 - 8.7% CV 4.9 – 8.6% CV

Inter-assay precision <5% CV <5% CV 9.1 - 10.1% CV 6.7 – 11.6% CV

99th percentile 6.32ng/mL 6.32ng/mL 5.8ng/mL 3.0ng/mL

Performance vs BAT

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Assignment of 99th percentile

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7.0 Marketing Toolkit

The following are available from Randox HQ to assist with the promotion of the H-FABP IT assay:

• Cardiac Albertus Questionnaires

• Brochures

o H-FABP Story (LT237)

o H-FABP IT Assay (LT295)

o H-FABP Publications summary (LT242)

o H-FABP Publications List (LT243)

• Key Publications

o JACC 2007 (available for purchase via Randox HQ)

o JACC 2010 (available for purchase via Randox HQ)

o AJEM 2011 (available for purchase via Randox HQ)

• Nomadics & Totems

o Randox Cardiology Nomadic

o H-FABP totem

In addition to attending local & national events, the Randox Cardiology team also attend major international

cardiology conferences, including:

• American College of Cardiology (ACC): USA, April 2011

• European Atherosclerosis Society (EAS): Sweden, June 2011

• European Society of Cardiology (ESC): France, August 2011

• American Heart Association (AHA): USA, November 2011

All of these conferences have up to 40% international delegate attendance (beyond the host country),

enabling extensive lead generation across a vast number of countries. These are immediately distributed to

Randox’s local partners in each relevant country.

Randox HQ Cardiology Team contact details: [email protected]

• Stephen Henderson (Sales & Marketing Manager)

o [email protected]

• Michael Townsend (Cardiology Market Specialist)

o [email protected]

• Dr Mary-Jo Kurth (Business Development Manager)

o [email protected]

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8.0 MultiStat Cardiac

The MultiStat Cardiac Panel (Troponin I, CK-MB & H-FABP) is designed to complement the H-FABP IT

assay and broaden Randox’s offering the acute cardiac diagnostics market.

The availability of both a near-patient testing system and an automated lab assay, both including H-FABP,

will enable us to tailor our product offering depending on the requirements of the customer (i.e. whether they

would prefer to do cardiac testing in the lab or in the ward).

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9.0 Competitors

The primary competition for the Randox H-FABP IT assay can be separated into direct & indirect

competition:

• Direct Competition (H-FABP assay manufacturers)

o CardioDetect

o ELISA

• Indirect Competition

o Central Laboratory (instrument dependent)

o POC testing (although none have H-FABP)

Alere Triage

Roche Cobas h232

Siemens Stratus CS

Abbott i-STAT

Although the Randox H-FABP IT assay does not directly relate to POCT, it is still important to have an

awareness of which POCT systems may be used by hospitals, so that their weaknesses may be targeted.

The competition can also be dichotomised according to the existing biomarker strategy used, and other

novel biomarkers which may be available in the market. Customers may also ask how H-FABP compares to

a number of other new markers, so it is important to have an awareness of these.

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H-FABP Competitors

Assay Name Manufacturer Assay Type Advantages Disadvantages

CardioDetect®

Rennesens, Germany

Lateral flow assay

• Rapid, disposable test that is relatively simple to use

• Suitable for POCT in the ambulance, ED or Cardiology

• Choice of whole blood, serum or plasma, depending on the strip type

• Reasonable catalogue of positive publications on diagnostic value in an ED/Cardiology setting

• Poor quality – notoriously problematic QC, up to 20-25% failure rate – significant cost, time & sample wastage

• Positive/negative result open to user interpretation • Quantitative test only – unable to correlate H-FABP value with

risk • EQA not possible • Lack of landmark publications in high ranking journals on large

cohorts of patients (e.g. JACC) • Lack of data/publications on prognostic value (largely due to lack

of quantitative results) • Company turmoil – original manufacturer Rennessens has

recently been shut down and sold off – potential supply issues • Not suitable for high throughput testing • Has been cloned by a couple of even lower quality Chinese

manufacturers & distributed in some countries • Not an inexpensive test – unlike some other disposable assays

(e.g. infectious disease screening)

Various

Various ELISA

• Relatively reliable technique • Several publications using ELISA methodology for

H-FABP • Commonly used for research, as is established

technique with a reasonable sample throughput • Available through a range of manufacturers

• Not suitable for clinical practice due to batch processing and labour requirements of ELISA technique

• Consumes considerably more time & sample than an automated IT assay

• Not suitable for high throughput testing or STAT testing

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POCT Competitors

POCT instrument name Manufacturer Assays

Available & TAT Advantages Disadvantages

Triage®

Alere Medical

• Cardio1 (TnI) • Cardio2 (TnI, CK-MB) • Cardio3 (TnI, CK-MB, Myo) • SOB panel (TnI,

CK-MB, Myo, BNP, D-dimer) • BNP • D-dimer • 12-15 minute assay time

• Relatively simple & easy to use

• Established company with significant penetration in many international markets

• Established instrument that has been on the market for 8-10 years

• Notoriously high CVs (20-25%) – laboratories are rarely happy about ED/Cardiology using a Triage

• Only one sample per run

• Troponin assay does not meet ACC/ESC guidelines

• Limited LIMS connectivity

• Limited on-board storage capacity (~750 records)

• Problems with traceability of results – print-offs can be lost or confused with others

• No integral timer to advise the user of time to result

• Large sample volume required (250ul)

• Barcode scanner & LIMS software only available as optional extras

• Clinical studies frequently referenced are now dated (e.g. 2000-02) & do not compare with hsTroponin

• Lack of H-FABP assay

Cobas® h232

Roche Diagnostics

• TnT (normal sensitivity) • CK-MB • Myoglobin • NT-proBNP • D-dimer • 8-12 minute assay time

• Relatively simple & easy to use

• Established company with tendered service contracts in many biochemistry laboratories

• Portable system

• Only one assay and one sample per run

• High CVs – system regularly rejected when evaluated by the biochemistry lab

• Issues regarding cut-offs & correlation if lab is using hsTnT

• Troponin assay does not meet ACC/ESC guidelines

• Requires additional data management software

• Technology incapable of measuring hsTroponin due to inherent limitations in methodology

• Lack of H-FABP assay

i-STAT®

Abbott Diagnostics

• Chemistries • Haematology • Electroloytes • Blood gas • Coagulation • Troponin I • CK-MB • BNP • 10 minute assay time

• Relatively simple & easy to use

• Established company with tendered service contracts in many biochemistry laboratories

• Portable system

• Availability of blood gas, coagulation & electrolytes – suitable for use in primary & secondary care.

• Primarily designed for coagulation & blood gas – not optimised for cardiac biomarkers. Also, it is a dated instrument & technology

• Troponin assay does not meet ACC/ESC guidelines

• High CVs

• Only one assay & one sample per run

• Requires expensive additional software for data management

• Lack of Myoglobin assay or H-FABP assay

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POCT Competitors

POCT instrument name Manufacturer Assays Available & TAT Advantages Disadvantages

Stratus CS® Acute Care

Siemens Healthcare Diagnostics

• TnI • CK-MB • Myoglobin • D-dimer • NT-proBNP • βhCG • 14-26 minute assay time

• Lab-based methodology (utilises on-board centrifuge for whole blood samples)

• Guideline acceptable precision on TnI assay

• Established company with tendered service contracts in many biochemistry laboratories

• Dated instrument (released in late 1990s)

• Large kit sizes and short expiry dates

• One test result = 14 mins, four tests = 26 mins

• Extensive & expensive additional consumables required

• Lack of H-FABP assay

• Large sample volume required (full tube)

Mini VIDAS®

BioMerieux Clinical Diagnostics

• TnI Ultra • Myoglobin • CK-MB • NT-proBNP • D-dimer • Procalcitonin • 20 minute assay time

• Established company with tendered service contracts in many biochemistry laboratories

• Ability to run multiple samples

• Uses ELISA methodology (better than lateral flow assays)

• TnI Ultra is plasma or serum only (requires sample centrifugation)

• Troponin assay does not meet ACC/ESC guidelines

• Lack of H-FABP assay

• Limited availability of instrument internationally

AQT90 Flex®

Radiometer

• TnI • TnT (new for 2011) • CK-MB • Myoglobin • NT-proBNP • D-dimer • β-hCG • 18 minutes assay time

• Relatively new system to market

• Random access sampling

• Ability to insert sample tube straight onto system (reduces sample handling)

• First POCT system to offer TnI & TnT

• Large sample volume required (400ul tube)

• Software not particularly user friendly

• Troponin assay does not meet ACC/ESC guidelines

• Questions over reliability & customer support

• Lack of H-FABP assay

• Limited availability of instrument internationally

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Competitors by biomarker strategy currently used

Biomarker Strategy Argument for introduction of H-FABP

Troponin only

• Depends on which timepoints are being tested (e.g. 0h & 6h, or 0h & 9-12h) • In general, a negative Troponin cannot be relied upon within the first 5-6 hours of chest pain onset, so patients must be kept in hospital until after this time

period. If Troponin is still negative at 6-12 hours post chest pain or post admission, patients can be more reliably sent home. • H-FABP can be used with Troponin to reliably rule-out non ACS patients within 3-6 hours from chest pain onset (98% NPV, St James’ AJEM 2011 paper) • H-FABP can also be used to identify higher risk patients earlier (e.g. negative ECG & negative Troponin but <6 hours chest pain onset). A positive H-FABP

in these patients deems them as higher risk & they should be managed appropriately. • Regardless of which timepoints are tested, a positive H-FABP at >12 hours has been shown to correlate to higher risk (JACC 2007 & 2010 papers).

Regardless of the Troponin result at this time, these patients should also be managed as higher risk.

Troponin & CK-MB

• See above and…. • H-FABP could be promoted instead of or in addition to CK-MB. H-FABP is an earlier risk marker than CK-MB (and Troponin) and so is more effective during

the early hours after chest pain onset. • If CK-MB is being primarily used as a marker of re-infarction, H-FABP could be promoted to replace this its release kinetics make it more suitable for this

application (i.e. returns to normal with 24 hours of first event)

Troponin, CK-MB & Myoglobin

• See above and….. • If Myoglobin is being used, it is highly likely it is being applied as an early rise biomarker. However, H-FABP should definitely be used instead of Myoglobin,

as H-FABP is released earlier and is 20 times more cardiac specific. • If Myoglobin is only being used selectively (e.g. only in patients presenting within 3-4 hours of chest pain onset), H-FABP can be promoted for this purpose,

in addition to wider use in all patients (e.g. prognostic value from JACC 2007 & 2010 papers)

Hs Troponin T only

• hsTnT has been shown in large studies to improve the diagnostic ability of Troponin during earlier timepoints (e.g. NEJM papers 2009). This potentially reduces the need to hold patients to wait for a 9-12 hour definitive Troponin result.

• However, the improved sensitivity of hsTnT, has come at the cost of reduced specificity. Therefore, use of hsTnT frequently leads to increased number of patients been admitted from the ED to Cardiology, with a suspicion of ACS (due to positive hsTnT). Many of these additional patients are later found to not have ACS (as many as 70% of those sent to Cardiology).

• A key (and widely accepted) point to make is that “hsTnT is specific for myocardial injury, not myocardial infarction”. Therefore a positive hsTnT result suggests something MAY be wrong with the heart, but is can’t be assumed that it is ACS. This leads to large numbers of false positives in cardiology, CCU and cath lab.

• One UK hospital who recently switched to hsTnT, found that it led to a 70% increase in admissions to the cath lab for angiograms, but a 0% increase in angioplasty (stents). Therefore, expensive angiograms are being wasted on patients that don’t actually need them due to hsTnT.

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Other candidate biomarkers

• Copeptin: exclusively patented by BRAHMS (now owned by Thermo-Fisher Scientific), Copeptin has

been the subject of several sizeable studies (e.g. 2009/2010/2011) investigating its utility in early rule-

out of AMI/ACS. Copeptin is a marker of endogenous stress and the theory is that it can be used in

conjunction with Troponin to provide a high NPV in the early hours after presentation. However, there

are serious issues regarding its cardiac specificity and data has not yet been published on how it

compares with hsTroponin. Also, it is only available for use via BRAHMS’ dedicated KRYPTOR testing

platform. Not currently used widely in clinical practice.

• NT-proBNP or BNP: these biomarkers have been studied on a massive scale (>20,000 publications)

over the last 10-15 years and are routinely used in many countries for the diagnosis & management of

heart failure. Although there has been a number of publications on their prognostic utility in ACS, the

markers are not widely used (or recommended in all guidelines) for this application. Also, BNP & NT-

proBNP both tend to be expensive assays, and so their use is often restricted by budgetary

considerations.

• hsCRP: widely studied across a range of applications (especially in the USA), there has been a large

amount of publications on the utility of the inflammatory marker in cardiovascular disease and ACS.

However, whatever long-term prognostic value may be gained, its widespread usage in the acute

setting is restricted by the lack of cardiac specificity.

• Ischemia-Modified Albumin (IMA): a marker of decreased oxygen availability. Studies have shown

IMA to be sensitive for ischemia but not very specific, which means that it can be elevated with ischemia

in other areas of the body. Its primary value is in its negative predictive value. Although FDA cleared, it

has now been widely discredited by the biomarker community and many long-term researchers have

abandoned it. The FDA received fierce criticism for its relatively quick approval of the assay, and some

credit this as the main reason why hsTroponin has been given extensive requirements for FDA

approval.

• Myeloperoxidase (MPO): a hemoprotein that is released during inflammation and may lead to

irreversible protein and lipid modification, increasing levels of oxidized low density lipoprotein, and

promoting athrogenesis. Recently, it has been considered as a risk factor for cardiovascular diseases.

However, similar to IMA, it has recently been widely discredited by the biomarker community.

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10.0 Glossary of Terms

General Cardiovascular

Atherosclerosis refers to the build up of fatty deposits called plaques in the walls of the arteries. Over time these deposits

of cholesterol, fat and the smooth muscle cells that line the arteries are transformed into a thickened and sometimes

calcified mass (atheroma). Atheroma causes the arteries to narrow and lose their elasticity, which leads to a reduction in

blood flow through the vessels. It is one of the major risk factors for all types of CVD.

Cardiovascular disease (CVD) refers to the class of diseases that involve the heart or blood vessels (arteries and veins).

While the term technically refers to any disease that affects the cardiovascular system, it is usually used to refer to those

related to atherosclerosis (arterial disease).

Coronary heart disease (CHD), also called ischemic heart disease, is the end result of the accumulation of atheromatous

plaques within the walls of the arteries that supply the myocardium (the muscle of the heart) with oxygen and nutrients.

Cardiology

Cardiology is the branch of internal medicine dealing with disorders of the heart and blood vessels. The field is commonly

divided in the branches of congenital heart defects, coronary artery disease, heart failure, valvular heart disease and

electrophysiology. Cardiology consultants should not be confused with the cardiac surgeons, who actually perform the

cardiac surgery (operative procedures on the heart and great vessels).

Acute Coronary Syndrome (ACS) is a set of signs and symptoms, usually a combination of chest pain and other features,

interpreted as being the result of abruptly decreased blood flow to the heart (cardiac ischemia); the most common cause for

this is the disruption of atherosclerotic plaque in an coronary artery. The subtypes of acute coronary syndrome include

unstable angina (UA, not associated with heart muscle damage), and two forms of myocardial infarction (non-ST & ST

elevated), in which heart muscle is damaged. ACS should be distinguished from stable angina, which develops during

exertion and resolves at rest.

Stable Angina

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Acute myocardial infarction (AMI or MI), more commonly known

as a heart attack, is a medical condition that occurs when the blood

supply to a part of the heart is interrupted, most commonly due to

rupture of a vulnerable plaque. The resulting ischemia (oxygen

shortage), if left untreated for a sufficient period, can cause damage

and/or death of heart tissue. MI can also be defined as “myocardial

cell death due to prolonged myocardial ischemia”.

STEMI (ST-elevated Myocardial Infarction) is a type of MI

characterized & diagnosed by an “ST change” in the waves from an

ECG. This is the most major form of MI and associated with the highest risk of death. In many countries, STEMI patients are

taken straight from the ambulance into the catheter lab to have PCI performed & reduce the blockages in the coronary

arteries.

NSTEMI (non ST-elevated Myocardial Infarction) is a type of MI but does not involve ST changes in the ECG. A NSTEMI

is normally diagnosed by a positive Troponin or CK-MB results, accompanied by clinical symptoms. This is still classified as

a heart attack and results in the relative medical treatment afterwards (e.g. medication, PCI).

Stable Angina is a set of ischemic symptoms (e.g. chest pain) but brought on by exercise at a predictable threshold.

Unstable Angina (UA) is a set of ischemic symptoms (e.g. chest pain) but brought on by exercise at an unpredictable

threshold and may even occur at rest

Electrocardiogram (ECG) records the rhythm and electrical activity of the heart. An

ECG can detect problems with the heart rhythm or help to tell if someone is having a

heart attack or if they have had a heart attack in the past. Sometimes an ECG can

indicate if the heart is enlarged or thickened. An ECG costs around £35 in the UK or up

to £100 for a private consultation. The instrument itself costs around £11,500 to

purchase1.

Exercise Stress Test is a test used by cardiologists to assess the cause of a patient’s chest pain and to establish whether

they are suffering from stable or unstable angina. It is done using

an exercise treadmill & ECG machine, and is normally done as a

routine procedure following a patient referral from their GP or

following a trip to the hospital with chest pain, but did not result in a

diagnosis of NSTEMI or STEMI.

1 www.epsom-sthelier.nhs.uk/about-us/the.../trust-board-papers/?asset

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Angiogram (also called cardiac catheterisation) evaluates the inside the coronary arteries to investigate any narrowings and

evaluate their severity. It is usually done by in a “Cath lab” by inserting a catheter (a small, flexible tube)

into the femoral artery via the groin, and passing it through the vessels into the heart. A special dye is

then injected into the catheter and a series of X-ray pictures are taken (see illustration). The dye shows

up all the coronary arteries on the X-rays, and this is used to identify any potential narrowings or

blockages. An angiogram costs approximately £700 per procedure in the UK2.

Percutaneous coronary intervention (PCI) is commonly known as a coronary angioplasty and is a therapeutic procedure

to treat the stenotic (narrowed) coronary arteries of the heart found in coronary heart disease. Normally performed by an

interventional cardiologist, primary PCI involves performing a

coronary angiogram (see above) to locate the blocked vessel,

followed by balloon angioplasty (and frequently the deployment of

stents – see illustration) to restore the blood flow. PCI surgery costs

approximately £6500-£8000 via a private consultation in the UK3.

This normally done in the catheter (or “cath”) operating laboratory

and is mainly done on patients with large MI (e.g. STEMI). PCI can

be non-elective (done in an emergency situation as soon as the

patient arrives at hospital) or elective (normally done 3-5 days after

the initial visit – perhaps following the diagnosis of NSTEMI).

Thrombolytic therapy is the breakdown of blood clots by pharmacological means, commonly referred to as clot busting.

The effectiveness of thrombolytic therapy is highest in the first 2 hours. After 12 hours, the risk associated with thrombolytic

therapy outweighs any benefit. Due to the fact that irreversible injury occurs within 2–4 hours of the infarction, there is a

limited window of time available for reperfusion to work.

Heart Failure or Congestive heart failure (CHF) is when the heart loses its ability to pump blood efficiently through the

body. It differs from a Myocardial Infarction because it does not occur suddenly, but rather over a long period of time or

following recovery from another condition (e.g. heart failure brought on due to reduced cardiac capacity following a large MI).

Echocardiogram (ECHO) is a sonography of the heart. It uses sound waves that echo against

structures in the heart to build up a detailed picture. This test is done to look at the structure

of the heart and how well it is functioning. It can be useful for patients who are suspected of

recently having a heart attack or are suffering from heart failure. An ECHO costs the UK

around £150 per scan4, or costs the patient £250-£300 via a private service.5

Rapid Access Chest Pain Clinic (RACPC) is a specialist service in a hospital for the early assessment of patients with

chest pain and possible symptoms of angina.

Medical Admissions Unit (MAU) (alternatively known as an Acute Admissions Unit (AAU) or Clinical Decisions Unit (CDU))

is a short-stay department in some hospitals that is sometimes part of the emergency department, although a separate

department. The MAU acts as a gateway between a patient's general practitioner, the emergency department, and the

wards of the hospital. The MAU helps the emergency department produce a healthy turnaround for patients

2 Pronostics set for European expansion with digital multiplexing solution, Clinica Diagnostics Newsletter; Issue 24 August 11 2008 3 http://www.spirehealthcare.com/Cambridge/Our-Facilities-Treatments-and-Consultants/Our-Treatments/Cardiac-catheterisation/ 4 Final Report of the BNP in Primary Care Project 2006/7, Bedfordshire and Hertfordshire Cardiac Network 5http://www.yeovilhospital.nhs.uk/Portals/0/ContentAssets/Kingston/kingston%20wing%20prices.pdf

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