WO2014199119A1

WO2014199119A1 - Method for determining a probability of a major adverse cardiac event (mace)

Info

Publication number: WO2014199119A1
Application number: PCT/GB2014/051250
Authority: WO
Inventors: Richard Body
Original assignee: The University Of Manchester
Priority date: 2013-06-10
Filing date: 2014-04-22
Publication date: 2014-12-18
Also published as: GB201310290D0

Abstract

Embodiments of the present invention provide A method of determining a likelihood of a major adverse cardiac event (MACE) of a subject within a predetermined period of time, comprising determining a presence of electrocardiographic (ECG) ischemia of said subject, observing a presence of vomiting, sweating, hypotension and worsening angina of the subject, determining quantities of heart-type fatty acid binding protein (H-FABP) and troponin (Tn) in a sample taken from said subject, determining a probability value P indicative of a likelihood of a MACE of the subject within a predetermined period of time, wherein P is calculated based on the quantities of H-FABP and Tn and values indicative of the presence of each of the ECG ischemia, pain radiating to the right arm or shoulder, vomiting, sweating, hypotension and worsening angina of the patient.

Description

Method for Determining a Probability of a Major Adverse Cardiac Event

(MACE)

Background

Coronary heart disease is the leading cause of death in the United Kingdom. Although mortality rates have more than halved since the 1980s, the economic cost continues to rise. Chest pain is the commonest cause of emergency hospital admission and the number of admissions is increasing. Suspected cardiac chest pain accounts for over a quarter of acute medical admissions, although only a quarter of these patients have an acute coronary syndrome (ACS). At present, patients are routinely admitted to hospital to undergo testing for troponin (the reference standard biomarker) at least 10-12 hours after symptom onset and often for additional inpatient investigations thereafter. Reducing unnecessary admissions would benefit both the health service and a large number of service users.

Clinical decision rules are widely used in emergency medicine for diverse conditions, ranging from ankle injury to suspected pulmonary embolism. Unlike simple risk scores, they suggest a course of action to clinicians and have been used to make more judicious use of healthcare resources. Two recent systematic reviews identified that there have been several attempts to derive and validate a clinical decision rule for patients with suspected cardiac chest pain. The reviews demonstrated that the available decision tools are either validated with outdated reference standards, insufficiently sensitive (and would therefore miss diagnoses) or insufficiently specific (so that the proportion of patients discharged is as low as 4%). One clinical decision rule, accepted for publication after these systematic reviews, had a sensitivity of 100.0% for predicting adverse events within 30 days but (a) has not been validated and (b) only identified 7.1% of the population as potentially eligible for early discharge. Like the published decision rules, accelerated 'rule out' protocols using biomarkers measured at the point of care are similarly non-specific and are not cost- effective.

It is an object of embodiments of the invention to at least mitigate one or more of the problems of the prior art. Summary of the Invention

According to an aspect of the present invention there is provided a method of determining a likelihood of a major adverse cardiac event (MACE) of a subject within a predetermined period of time, comprising determining a presence of electrocardiographic (ECG) ischemia of said subject, observing one or more of vomiting, sweating , hypotension and worsening angina of the subject, determining quantities of heart-type fatty acid binding protein (H-FABP) and troponin (TnT) in a sample taken from said subject, determining a probability value P indicative of a likelihood of a MACE of the subject within a predetermined period of time, wherein P is calculated based on the quantities of H-FABP and Tn and values indicative of the presence of each of the ECG ischemia, pain radiating to the right arm or shoulder, vomiting, sweating, hypotension and worsening angina of the patient. The step of determining the quantities of heart-type fatty acid binding protein (H- FABP) and troponin (TnT) may be carried out in vitro.

According to an aspect of the present invention there is provided a computing device for determining a likelihood of a major adverse cardiac event (MACE) of a subject within a predetermined period of time, comprising a memory storing values indicative of each of a presence of electrocardiographic (ECG) ischemia, vomiting, sweating , hypotension and worsening angina of the subject, and quantities of heart- type fatty acid binding protein (H-FABP) and troponin (Tn) in a sample taken from said subject; and a processor arranged to operatively execute a software module to determining the likelihood of MACE of the subject based on the quantities of H- FABP and Tn and the values indicative of the presence of each of the ECG ischemia, pain radiating to the right arm or shoulder, vomiting, sweating, hypotension and worsening angina of the patient. Brief Description of the Drawings

Embodiments of the invention will now be described by way of example only, with reference to the accompanying figures, in which: Figure 1 shows a method according to an embodiment of the invention.

Detailed Description of Embodiments of the Invention Embodiments of the present invention provide a method for determining a likelihood or probability value associated with a major adverse cardiac event (MACE) within a predetermined duration of time. The MACE may include death, an acute myocardial infarction (AMI) or the need for coronary revascularisation. MACE may also include coronary stenosis of greater than a predetermined percentage such as 50%. The predetermined duration may be relatively short, such as 1, 2 or 3 months, or may be a matter of days. In some embodiments, the short duration is within 30 days.

Figure 1 illustrates a method 100 according to an embodiment of the invention. The method is a method of determining a probability value P indicative of a MACE within a predetermined period. The probability value P is a numeric value of between 0 and 1. Thus embodiments of the present invention do not merely "rule in" or "rule out" the presence of, for example, AMI but instead provide numeric indication of the probability of MACE. A step 110 comprises measuring one or more parameters of a patient. The parameters may include measuring an electrocardiograph (ECG/EKG) of the patient. The ECG may be used to determine the presence of an ECG ischemia.

Step 110 may further comprise measuring the blood pressure of the patient. The blood pressure measurement may be used to determine a systolic blood pressure of the patient. In some embodiments, step 110 may comprise determining whether the systolic blood pressure is below a predetermined threshold, for example lOOmmHg. It will be realised, however, that other threshold values may be used. In step 120 one or more attributes of the patient may be observed. The attributes may be one or more of:

The presence of vomiting by the patient; The presence of sweating by the patient, which may be as observed for example by a clinician; and/or

The presence of worsening angina, which may be in a professional opinion of the clinician.

Some embodiments of the method may comprise observing an attribute of pain radiating to the right arm or shoulder of the patient and/or whether the patient is a smoker. The presence of the above symptoms may be noted as a yes or no indicative of the presence of the respective condition.

In step 130 a level of a regulatory protein, Troponin (Tn), which may also be referred to as cardiac troponin (cTn), is measured. The Tn may be Troponin I or Troponin T. The level of Tn is measured in a sample removed from the patient. The level of Tn in the sample may be measured in a laboratory environment and/or using an assay. The level of Tn may be measured in units of ng/L. The sample may be a whole blood sample extracted from the patient or may be in serum or plasma. The assay may be, for example, an Elecsys (RTM) Troponin (TnT) assay available from Hoffman-La Roche Ltd. In some embodiments, the assay may be a high sensitivity Troponin (hs- Tn) assay, which may also be referred to as high sensitivity cardiac Troponin (hs- cTn). In particular, the assay may be an Elecsys (RTM) high sensitivity troponin (hs- Tn) assay available from Hoffman-La Roche Ltd. It will be realised that other assays, including assays that measure troponin I (Tnl) and highly sensitive assays for measuring troponin I (high sensitivity troponin I; hs-Tnl) may be used. The cardiac troponin testing sample from which Tn is measured may be taken as soon as possible after symptom onset. Hs-cTn levels below a measurement limit for the assay (<3ng/L) may be entered as 2ng/L in some embodiments. In step 140 a level of heart-type fatty acid binding protein (H-FABP) is measured. The level of H-FABP is measured in the sample removed from the patient. The level of H-FABP in the sample may be measured in a laboratory environment and/or using a point of care assay, which permits measurement at the patient's bedside. The sample may be the whole blood sample extracted from the patient or may be in a serum or plasma sample. The assay may be, for example, an assay available from Randox Laboratories Ltd, although it will be realised that other assays may be used. The level of H-FABP may be measured in ng/ml. In step 150 the probability value associated with the MACE within the predetermined period is determined. The probability value may be determined by a suitably programmed computer.

In some embodiments the probability value (P) of the MACE within the predetermined time period may be determined by entering values into an equation to determine the probability value P, wherein each value is associated with a respective coefficient.

Embodiments of the invention utilise an equation for calculating a probability value (P) indicative of MACE, such as:

L = /a + a)b + vc + Td + ae + pf + 0g + 87h (l + e-¹ ) wherein each of variables a-h is indicative of an attribute or value measured observed in steps 110 to 140.

For the attributes observed in step 120 in some embodiments a 1 may be utilised to indicate the presence of the respective attribute i.e. a 1 may be associated with the answer "yes" for the presence of the respective attribute and a 0 may be associated with the absence of the respective attribute.

b The presence of ω 1 -2

worsening angina

c Pain radiation to the V 0.5-1

right arm or shoulder

d The presence of τ 1 -2

vomiting

e Sweating observed σ 1 -2

f Initial systolic blood P 1 -1 .5

pressure of <100mmHg

g Hs-Tn level θ 0.02-0.1 h H-FABP level ω 0.2-0.5

Example 1

In one example the equation may be: ψα + aib + vc + id + σβ + pf + 0g + GJh d + e-^L ) wherein each of variables a-h is indicative of an attribute or value measured or observed in steps 110 to 140.

worsening angina

c Pain radiation to the right V 1

arm or shoulder

d The presence of vomiting τ 2

e Sweating observed σ 2

f Initial systolic blood P 1

pressure of <100mmHg

g Hs-TnT level Θ 0.05

h H-FABP level ω 0.2

This example achieves a sensitivity of 100% with 25% specificity, i.e. 25% of patients are discharged on admission (rather than almost 35%) and no myocardial infarctions would be missed. It could also achieve a sensitivity of 99.4% with 49.3% specificity. The increase in specificity increases the proportion of patients for which MACE has a low probability and this may be discharged, but with a small reduction in sensitivity.

Example 2 In one example the equation may be:

L = ψα + 0)b + DC + d + oe + pf + dg + Gh - V

(1 + e-¹ ) wherein each of variables a-h is indicative of an attribute or value measured or observed in steps 110 to 140.

For the attributes observed in step 120 in some embodiments a 1 may be utilised to indicate the presence of the respective attribute i.e. a 1 may be associated with the answer "yes" for the presence of the respective attribute and a 0 may be associated with the absence of the respective attribute. Variable Attribute Coefficient Value

a The presence of ECG Ψ 1

ischemia

b The presence of ω 1

worsening angina

c Pain radiation to the right V 1

arm or shoulder

d The presence of vomiting τ 1

e Sweating observed σ 1

f Initial systolic blood P 1

pressure of <100mmHg

g Hs-TnT level θ 0.05

h H-FABP level ω 0.2

In this example, a sensitivity of 100% with 25% specificity is achieved and a sensitivity of 99.4% for 49.3% specificity. It can be appreciated that the performance is equal to that of Example 1.

Similar performance may be achieved using difference coefficients associated with the biomarker to: 9= 0.1 and GJ x 0.1. Sensitivity is 100% for a specificity of 21%; and sensitivity is 99.4% for a specificity of 45.4%. Amending the constants to 0 = 0.1 and 05 = 0.5) gives a sensitivity of 100% for a specificity 27.2%; and a 99.4% sensitivity with a 36.4% specificity.

Example 3

In one example the equation may be: L = i//a + 0)b + Dc + Td + cze + /tf + 0g + GJh - v

0 + e-' ) wherein each of variables a-h is indicative of an attribute or value measured or observed in steps 110 to 140. The constant v may assume a negative value such as in the range of -4 to -5. In one embodiment the constant V has a value of -4.83.

Example 4

Some embodiments of the present invention may include consideration of whether the patient smokes cigarettes.

In one example the equation may be:

L = ya + 0)b + lx: + 'Ul + ae + /?f + eg +nJh -v (l + e-^L ) wherein each of variables a-h is indicative of an attribute or value measured or observed in steps 110 to 140. The constant v may assume a negative value such as in the range of -4 to -5. In one embodiment the constant V has a value of -5.01. For the attributes observed in step 120 in some embodiments a 1 may be utilised to indicate the presence of the respective attribute i.e. a 1 may be associated with the answer "yes" for the presence of the respective attribute and a 0 may be associated with the absence of the respective attribute.

g Hs-TnT level Θ 0.070 1 .1 (1 .0 - 1 .1 ) <0.0001 h H-FABP level ω 0.1 7 1 .2 (1 .0 -1 .4) 0.026

In some embodiments of the invention, such as for any of the above examples, the coefficient associated with the level of Tn may be changed to 0.1 depending upon a choice of assay. Thus the coefficient associated with Tn may be in the range of 0.02- 1 or 0.05-0.5 in some embodiments.

In some embodiments, such as for all of the above examples, step 150 may comprise associating the determined probability value P with one of a plurality of groups. The group may be used to recommend a course of action for the patient. Each of the plurality of groups may be indicative of an associated MACE risk. Each of the plurality of groups may be associated with respective threshold values against which the probability value is compared to select the appropriate risk groups. In one embodiment the risk groups may be: 'very low risk', where the recommended course of action may be to discharge the patient from hospital immediately (estimated probability, p, of MACE<0.02); 'low risk', where the recommended course of action may be to admit the patient to a low dependency environment, e.g. ED observation unit, for further investigation (0.02<p<0.05); 'moderate risk', where the recommended course of action may be to admit the patient to an acute ward, e.g. medical admissions unit (0.05<p<0.95); and 'high risk', where the recommended course of action may be to admit the patient to a coronary care unit or high dependency environment (p>0.95). It will be realised that these risk groups are merely exemplary and that other risk groups, thresholds and recommended courses of action may be envisaged.

In an initial study, the embodiments of the invention had an area under the receiver operating characteristic (ROC) curve (AUC) of 0.97 (95% confidence intervals (CI) 0.96-0.99) for diagnosing AMI and 0.95 (95% CI 0.93-0.97) for predicting MACE. On external validation, the AUC was 0.96 (0.95-0.98) for AMI and 0.91 (0.88-0.95) for MACE, implying very high diagnostic accuracy. The sensitivity was 100.0% for AMI in both studies, with sensitivities of 99.4% (95% CI 96.5-100.0%) and 98.0% (95% CI 93.0-99.8%) for predicting MACE in the derivation and validation studies respectively.

Use of embodiments of the invention may avoid the need for hospital admission in approximately 25% of patients, with no missed AMIs and a low (1%) incidence of adverse events within 30 days. In addition, embodiments of the invention effectively risk stratifies patients who must still be admitted to hospital, facilitating triage to an appropriate level of care. This dual functionality reduces an important limitation of previous decision instruments, which could achieve only one of these two goals. The element of risk stratification with explicit recommendations for disposition should help to prevent rebound overuse of resources and thus improve the probability that the strategy will reduce total healthcare costs.

It will be appreciated that embodiments of the present invention can be realised in the form of hardware, software or a combination of hardware and software. Any such software may be stored in the form of volatile or non-volatile storage such as, for example, a storage device like a ROM, whether erasable or rewritable or not, or in the form of memory such as, for example, RAM, memory chips, device or integrated circuits or on an optically or magnetically readable medium such as, for example, a CD, DVD, magnetic disk or magnetic tape. It will be appreciated that the storage devices and storage media are embodiments of machine-readable storage that are suitable for storing a program or programs that, when executed, implement embodiments of the present invention. Accordingly, embodiments provide a program comprising code for implementing a system or method as claimed in any preceding claim and a machine readable storage storing such a program. Still further, embodiments of the present invention may be conveyed electronically via any medium such as a communication signal carried over a wired or wireless connection and embodiments suitably encompass the same. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The claims should not be construed to cover merely the foregoing embodiments, but also any embodiments which fall within the scope of the claims.

Claims

A method of determining a likelihood of a major adverse cardiac event (MACE) of a subject within a predetermined period of time, comprising: determining a presence of electrocardiographic (ECG) ischemia of said subject; observing one or more of vomiting, sweating , hypotension and worsening angina of the subject; determining quantities of heart-type fatty acid binding protein (H- FABP) and troponin (Tn) in a sample taken from said subject; and determining a probability value P indicative of a likelihood of a MACE of the subject within a predetermined period of time, wherein P is calculated based on the quantities of H-FABP and Tn and values indicative of the presence of each of the ECG ischemia, pain radiating to the right arm or shoulder, vomiting, sweating, hypotension and worsening angina of the patient.

The method of claim 1, comprising observing a presence of pain radiating to the right arm or shoulder.

The method of claim 1 or 2, comprising observing whether the subject smokes.

The method of claim 1, 2 or 3 wherein P is calculated based on summed quantities of H-FABP, Tn and each of the values indicative of the presence of the ECG ischemia, vomiting, sweating, hypotension and worsening angina of the patient multiplied by respective coefficients.

The method of claim 4 when dependent upon claim 2 or 3, wherein P is calculated based on the summed quantity comprising a value indicative of the presence of pain radiating to the right arm or shoulder or whether the subject smokes, respectively.

6. The method of any preceding claim, wherein P is calculated as:

L = y a + ab + Dc + 'ttI + Oie + ff + 9g +CiJh

(l + e-¹ )

wherein:

a is the value indicative of the presence of the ECG ischemia;

b is the value indicative of the presence of worsening angina;

c is the value indicative of radiation to the right arm or shoulder or the subject being a smoker;

d is the value indicative of presence of vomiting;

e is the value indicative of sweating;

/is the value indicative of hypotension;

g is the quantity of Tn;

h is the quantity of H-FABP; and

ψ , ω ,θ, v, τ , σ , ρ and W are respective coefficient values.

The method of claim 6, wherein one or more of the coefficients assume values of: ψ =\-2, ω=1-2, υ=0.87-1, τ =1-2, σ=1-2, ρ = 1-1.46, 0=0.02-1 and67 =0.2-0.5.

The method of any preceding claim, wherein P is further calculated based on a constant value.

The method of claim 8, wherein the constant v is a negative value.

The method of claim 8, wherein the constant assumes a value of between -4.5 and -5.5.

The method of claim 10, wherein the constant value is one of -4.83 or -5.01 The method of any preceding claim, wherein the quantities of H-FABP and Tn are determined using an assay.

The method of any preceding claim, wherein the presence of hypotension is based on a blood pressure measurement of less than a predetermined threshold.

The method of claim 13, wherein the predetermined threshold is systolic blood pressure of <100mmHg.

The method of any preceding claim, wherein probability value P is determined by a computing device.

The method of claim 15 when dependent upon claim 5 or 6, wherein the computing device comprises a memory storing coefficient values associated with each of the variables a-h.

A computing device for determining a likelihood of a major adverse cardiac event (MACE) of a subject within a predetermined period of time, comprising: a memory storing values indicative of each of a presence of electrocardiographic (ECG) ischemia, vomiting, sweating , hypotension and worsening angina of the subject, and quantities of heart-type fatty acid binding protein (H-FABP) and troponin (Tn) in a sample taken from said subject; a processor arranged to operatively execute a software module to determining the likelihood of MACE of the subject based on the quantities of H-FABP and Tn and the values indicative of the presence of each of the ECG ischemia, pain radiating to the right arm or shoulder, vomiting, sweating, hypotension and worsening angina of the patient.

The computing device of claim 17, wherein the computing device comprises a user interface arranged to receive user input indicative of each of a presence of electrocardiographic (ECG) ischemia, vomiting, sweating , hypotension and worsening angina of the subject, and the quantities of heart-type fatty acid binding protein (H-FABP) and troponin (Tn).

19. The computing device of claim 17 or 18, wherein the software module is arranged to calculate the likelihood P of MACE according to the method any of claims 2 to 16.

20. Computer software which, when executed by a computing device, is arranged to perform the method of any of claims 1 to 16.

21. The computer software of claim 20 stored on a computer readable medium.