Rule Out of Exercise-Induced Myocardial Ischaemia


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Rule Out of Exercise-Induced

Myocardial Ischaemia

Professor Christian Mueller

Chair Cardiovascular Research Institute Basel (CRIB)

Universitätsspital Basel

Basel, Switzerland


Disclosures

Swiss National Science Foundation



Research support / travel support / consulting fees from several

diagnostic and pharmaceutical companies


Suspected PE: D-dimers

-

+

Stop

CT-Angiography

Suspected Coronary Artery Disease (CAD)

Sensitivity ≈95%



Could we use very low Hs-cTnI blood concentrations to rule out

functionally relevant CAD without imaging?

Aim:

to learn from

Pulmonary Embolism

Diagnosis/

Rule Out

Background

CAD is the leading cause of death

Two phenotypes:

stable CAD

AMI


1-year mortality

1-2%

15%

Current diagnostic tools

ECG/Exercise ECG

++

+++


Biomarkers

-

+++



Imaging

+++


++

Imaging is expensive, not universally



available, and associated with rare, but

potentially lethal complications

MPS (US): unnecessary tests 500 Mio $, 491



future cancers



Disconnect

between the risk/mortality of

phenotype and the resources used for

diagnosis

Great potential for novel biomarkers to be



used as gatekeepers

Methods

Advantage of unselected referral of patients with suspected CAD



Very strong methodology for the adjudication of the presence/absence of

functionally relevant CAD

Largest study world-wide





Singulex hs-cTnI:

>> other hs-cTn assays

Erenna (research platform), serum



1st Aim:

To investigate the value of hs-cTnI to rule-out functionally

relevant CAD in patients without known CAD

2nd Aim:

To derive a hs-cTnI cut-off level to achieve ≈95% sensitivity

Reference Standard

Clinical judgment



after

stress test

Clinical judgment

before

stress test



Singulex hs-cTnI

before stress test

Rest-stress MP-SPECT



Investigational Test

Derivation Study

Tanglay Y, et al. Am J Med. 2015



Results

N=167


All patients (100%)

had detectable levels

Tanglay Y, et al. Am J Med. 2015

Nearly all in the

normal range

N=547


0.64

0.69


0.70

0.73

Tanglay Y, et al. Am J Med. 2015

Methods

Advantage of unselected referral of patients with suspected CAD



Very strong methodology for the adjudication of the presence/absence of

functionally relevant CAD

Largest study world-wide





Singulex hs-cTnI:

Erenna (research platform), serum



Clarity (Clinical platform), plasma

3rd Aim:

To validate hs-cTnI (Erenna) serum

4th Aim:

hs-cTnI (Clarity) plasma

5th Aim:

To derive a hs-cTnI plasma cut-off level to achieve ≈95% sensitivity

Walter J, et al. Clin Chem. 2017, in revision



3,988 patients enrolled from January 2010 to February 2016

and provided informed written consent.



Validation (Erenna System)

Hs-cTnI analyzed in serum with the

Erenna system: 1,644 patients recruited

from August 2012 to November 2014.



Correlation (Erenna System)

Hs-cTnI analyzed in plasma and serum

with the Erenna system: 1,618 patients

recruited from January 2010 to July 2012.



Application (Clarity System)

Hs-cTnI analyzed in plasma with the

Clarity system: 1,526 patients recruited

from November 2013 to February 2016.

1,031 patients excluded due to

(overlapping n):

755 Previously known CAD

282 Atrial fibrillation or atrial flutter

22 Hemodialysis

135 Moderate or severe valvular disease

53 congestive heart failure

185 Hypertensive heart disease

52 Missing VAS

8 Missing hs-cTnI concentrations

1,012 patients excluded due to

(overlapping n):

783 Previously known CAD

194 Atrial fibrillation or atrial flutter

16 Hemodialysis

113 Moderate or severe valvular disease

32 Congestive heart failure

135 Hypertensive heart disease

34 Missing VAS

24 Missing hs-cTn concentrations

971 patients excluded due to

(overlapping n):

675 Previously known CAD

268 Atrial fibrillation or atrial flutter

21 Hemodialysis

148 Moderate or severe valvular disease

55 Congestive heart failure

171 Hypertensive heart disease

77 Missing VAS results

69 Missing hs-cTnI concentrations



613 patients available

606 patients available

555 patients available

Walter J, et al. Clin Chem. 2017, in revision



Erenna, Serum:

<1.16ng/L, sensitivity

of 95% (95%CI 90-98%)

rule out in 14% of patients.

Validation Study

Walter J, et al. Clin Chem. 2017, in revision



Erenna, r=0.921

Correlation Study

Walter J, et al. Clin Chem. 2017, in revision



Clarity, Plasma:

<0.47ng/L, sensitivity

of 95% (95%CI 89-98%)

rule out in 10% of patients

Application Study

Walter J, et al. Clin Chem. 2017, in revision



Walter J, et al. Clin Chem. 2017, in revision

MACE: AMI or CV Death

Conclusion

1)

Hs-cTnI concentrations at rest provide incremental value to

clinical judgment in the rule out of functionally relevant CAD

2)

Very low Hs-cTnI serum/plasma concentrations provide a

sensitivity of ≈95%



3)

Clarity: plasma concentrations <0.5ng/L

4)

Great appeal and may be considered for routine clinical care



5)

Allows simple rule out in 10-15% of patients; ongoing research



to increase efficacy


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