Transcript Document

Corus™ CAD Overview
Corus CAD Intended Use Statement referenced at the end of this presentation
Better Diagnostic Methods are Needed to Stratify
Patients for Elective Invasive Angiography8
120
% of total patients
100
80
38%
obstructive
coronary
artery
disease
60
40
20
0
Pre-Coronary Angiography
Patient population:
• 397,954 stable patients with clinical
risk factors and/or symptoms of CAD
(but no prior history of CAD)
undergoing cardiac catheterization
for evaluation
Study found:
• 62% of patients who underwent
elective cardiac catheterization did
not have significant CAD
• 40% of patients had minimal to no
CADi
• Majority of patients (83.9%) received
noninvasive diagnostic testsii prior to
referral to catheterization
Post-Coronary Angiography
i
N=397,954
N=149,739
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ii
Minimal to no CAD is defined as < 20% stenosis
Resting ECG, exercise or pharmacological stress, echocardiography,
radionucleotide, CT scans, or other heart scans
The Challenge of Assessing CAD1-5
• Despite advances in imaging technology, non-invasive
assessment of obstructive CAD continues to be subjective and
challenging
• The complexity of CAD diagnosis lies not only in the variation
of presenting symptoms, but also in the patient’s unique
characteristics
• Implementation of standard of care involving non-invasive
imaging assessment of CAD is highly variable regarding the
type, number, and sequence of tests
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Cardiac Imaging Procedures Deliver Significant
Amounts of Ionizing Radiation6
Estimates of Effective Doses for Selected
Cardiac Imaging Procedures (in mSv)
Study reported:
•
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MPI procedures contributed to
74.2% of cumulative effective
radiation dose from overall
cardiac imaging procedures
MPI is the Largest Contributor of Radiation Overall6
Contribution to Cumulative Effective Radiation Dose
by Type of Cardiac Imaging Procedures (in mSv)
Study design:
•
This is a subset of the NEJM
Fazel 2009 study, focused
only on cardiac imaging
procedures
Study reported:
•
•
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MPI procedures contributed to
74.2% of cumulative effective
radiation dose from overall
cardiac imaging procedures
Radiation dose and risk
accumulates over a person’s
lifetime
Women Receive Higher Radiation Dosing From
Medical Imaging7
In 2009, the NEJM reported:
• Cumulative effective doses of
radiation from imaging
procedures were higher in
women than in men
• Computed tomography and
nuclear imaging accounted for
75.4% of the cumulative effective
dose
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Genomics: A New Era in Medicine
The Human Genome Project has ushered in the era of genomic
medicine and the promise of more individualized patient care
• Genomic testing has the power to inform about
disease processes at the molecular and cellular
level
• CardioDx delivers the first and only clinically
validated gene expression test to turn the
promise of genomic medicine into practice for
assessing obstructive* coronary artery disease
(CAD)
*Obstructive CAD is defined as at least one atherosclerotic plaque causing ≥50% luminal diameter stenosis in a major coronary artery
(≥1.5mm lumen diameter) as determined by invasive quantitative coronary angiography (QCA).
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Genetic Testing VS Gene Expression Tests
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About Corus™ CAD
• The first clinically validated gene expression test for
assessing obstructive coronary artery disease (CAD) in
non-diabetics
• Enables more informed decision-making and risk
stratification
• Test has high sensitivity and negative predictive value
• Test score reflects the presence and extent of obstructive CAD
• Test improves classification of patient disease status
• A safe and convenient genomic test
• Blood sample collection takes minutes, and test results are
delivered promptly to the clinician’s office
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Clinically Validated Gene Expression Test for
the Assessment of Obstructive CAD10,11
Delivers a biological view into
a patient’s disease state
• Algorithm comprised of expression levels of
23 genes demonstrated to indicate
obstructive CAD
• Molecular basis includes genes and
pathways with known involvement in
atherosclerosis and its progression
• Based on the detection of a reliable molecular
signature for obstructive CAD
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Rigorous Multi-Center Product Development
and Validation
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Corus™ CAD Gene Term Examples3-8
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Corus™ CAD Algorithm Terms and Genes4
Males
Females
1) Neutrophil Activation - Apoptosis
Innate Immunity
(IL18RAP, TNFAIP6 CASP5) –
(IL8RB TNFRSF10C, TLR4, KCNE3)
1) Neutrophil Activation - Apoptosis
Innate Immunity
(IL18RAP, TNFAIP6 CASP5) –
(IL8RB TNFRSF10C, TLR4, KCNE3)
2) Neutrophil Activation/Lymphocytes
Innate Immunity/Cell Necrosis
(S100A8, S100A12, CLEC4E) - RPL28
2) Normalized Neutrophil Activation
Innate Immunity/Cell Necrosis
(S100A8, S100A12, CLEC4E) - (NCF4, AQP9)
3) NK Activation/T cells
Innate Immunity
SLAMF7, KLRC4 - TMC8, CD3D
3) NK Activation/T cells
Innate Immunity
SLAMF7, KLRC4 - TMC8, CD3D
4) B/T Ratio - Adaptive Immune Response
SPIB, CD79B - TMC8, CD3D
4) B/T Ratio - Adaptive Immune Response
SPIB, CD79B - TMC8, CD3D
5) AF2- TFCP2, HNRPF
5) AF2 - TFCP2,HNRPF
6) TSPAN - TFCP2,HNRPF
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Corus™ CAD is Multifactorial
MOLECULAR &
CELLULAR FACTORS
Gene Expression
Derived Cell Type
Ratios
CELL TYPE-SPECIFIC
GENE EXPRESSION
Gene Expression
Changes Within a
Certain Cell Type
GENDER & AGE RISK
FUNCTIONS
Gender-Specific, Age
Dependent Coronary
Disease Risk Functions
U.S. Prevalence of Coronary
Heart Disease by Age & Sex,
NHANES
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Clinical Validation Trials
PREDICT TRIAL
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Corus™ CAD Validation Data Published in
Annals of Internal Medicine – October 201010
“Rosenberg and colleagues’ study lies at the vanguard of
clinical genetics in cardiovascular care. ”
-Excerpt from AIM editorial, Donna Arnett Ph.D., M.S.P.H.
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PREDICT Summary9,10
• Prospective, multi-center, blinded* study
• 1,343 nondiabetic patients enrolled to develop and validate
Corus™ CAD
• 39 U.S. sites participated
• Study PI: Eric Topol, MD, Scripps Research Institute
• QCA Core Lab: Alexandra Lansky, MD, Columbia University/CRF
• Enrolling sites and investigators included:
Vanderbilt Heart and Vascular Institute (TN)
John McPherson, MD
Washington Hospital Center (DC)
Ron Waksman, MD
Cleveland Clinic Foundation (OH)
Steven Ellis, MD
Minneapolis Heart Institute (MN)
Robert Schwartz, MD
Duke University Medical Center (NC)
Bill Kraus, MD & Kristin Newby MD
Intermountain Medical Center (UT)
Brent Muhlestein, MD
Piedmont Hospital Research Institute (GA)
Szilard Voros, MD
Oklahoma Cardiovascular Research Group (OK)
Naeem Tahirkheli, MD
Allegheny General Hospital (PA)
Tony Farah, MD
*Data was analyzed in a blinded fashion
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PREDICT Trial Design9,10
Personalized Risk Evaluation and Diagnosis
In the Coronary Tree
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Probability of CAD in Females and Males as
Observed in PREDICT1,2
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Corus™ CAD Score is Proportional to
Disease Severity4
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Clinical Validation Trials
COMPASS TRIAL
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COMPASS Study Overview
•
•
•
•
•
•
•
Second validation study for Corus™ CAD in the intended use population
Will also evaluate MPI performance in the real-world clinical setting
Prospective, multi-center, blinded* study
450 patients to be enrolled at 21 U.S. sites
QCA Core Lab: Cardiovascular Research Foundation
Study completion: Q4 2010
Steering committee: John McPherson, MD, Alexandra Lansky, MD, Greg
Thomas, MD, Szilard Voros, MD
• Enrollees include patients referred for a clinically indicated MPI who meet
the following criteria**:
i.
Symptomatic (chest pain or anginal equivalent) who have been
referred for MPI for the workup of suspected obstructive CAD
ii. Non-diabetic
iii. No known obstructive CAD, prior myocardial infarction, or prior
revascularization procedure
*Data to be analyzed in a blinded fashion
**Complete inclusion and exclusion criteria may be found in protocol NCT01117506 at ClinicalTrials.gov.
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COMPASS Trial Design
•
•
•
23
All non-diabetic patients referred for clinically indicated MPI for chest pain or anginal equivalent symptoms
without known obstructive CAD, MI or revascularization were enrolled.
MPI positive patients received invasive angiography if clinically indicated.
MPI negative patients received CT angiography. If clinically indicated, patients went onto catheterization
for further evaluation.
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Rigorous Data Analysis and Approach Undertaken
in the COMPASS Trial
Invasive
Angiography
Core lab
interpretation
with QCA
QCA Core Lab:
Cardiovascular Research
Foundation
CT
Angiography
Core lab
interpretation
CTA Core Lab Readers:
Szilard Voros, MD
James R Adams, MD
MPI
On site
interpretation
Core lab
interpretation
24
MPI Core Lab Reader:
Timothy M Bateman, MD
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Corus® CAD vs. MPI Performance
Corus CAD
Site-read MPI
P-value
Sensitivity
89%
27%
p<0.001
NPV
96%
88%
p<0.001
• In the COMPASS trial, Corus CAD outperformed MPI in sensitivity and
(89% vs. 27%, p<0.001) and negative predictive value (96% vs. 88%,
p< 0.001) for ruling out obstructive coronary artery disease
*Summary statistics at a pre-specified threshold of 15
Core-read MPI Sensitivity: 36%
Core-read MPI NPV: 88%
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Corus™ CAD Decreases the Rate of False
Positive Classifications From MPI4
Case/Total
(case %)
MPI
Positive*
Corus CAD
Overall
76/223
(34%)
Corus CAD
Low
6/57
(11%)
Corus CAD
Intermediate
21/78
(27%)
Corus CAD
High
49/88
(56%)
Legend
MPI Positive
76 cases/223 patients
(34% case rate)
When Corus CAD and
MPI disagreed, Corus
CAD was correct* 89%
of the time and MPI was
correct 11% of the time
*MPIs were defined as positive if at least one reversible or fixed defect consistent with obstructive CAD was reported.
Indeterminate or intermediate defects were considered negative.
60% of PREDICT validation cohort patients had MPI.
Data from the PREDICT validation cohort, as determined by quantitative coronary angiography (QCA).
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Potential New Paradigm of Care based on
COMPASS Results
Thomas et al, Circ Cardiovasc Genetics 2 /15/2013; DOI: 10.1161/CIRCGENETICS.112.964015
27
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COMPASS Trial Follow-up: Patients with Low Corus® CAD
Scores Showed Very Low Event Rates at 6 Months
COMPASS Trial
6-month Follow-up
n=420/431 (97%)
Corus CAD ≤15
(n=192)
Corus CAD >15
(n=228)
Early Revascularization
(within 1 month)
Late Revascularization
and MACE
(between 1 and 6 months)
1 (0.5%)
0 (0%)
24 (11%)
3 (1.3%)
• Corus CAD had a sensitivity of 96% and NPV >99% for events
and revascularizations at 6-month follow-up
• Significant correlation between increasing Corus CAD scores
and increased event likelihood*
*p-value = 0.0015
28
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Relationship Between Corus® CAD Score and Percent
Coronary Artery Stenosis
• In patients with low Corus CAD scores ( ≤ 15), 96% of patients did not have
obstructive CAD
• The higher the Corus CAD score, the higher the likelihood of obstructive
(≥ 50% stenosis), minimal (1-24%) and moderate (25-49%) CAD, and the lower the
likelihood of no disease
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Corus® CAD Demonstrates Consistent, Strong
Performance in Three Independent Cohorts
CORUS CAD
PERFORMANCE
at threshold score of 15
COMPASS
PREDICT-CTA*
PREDICT
(total N=431)
(total N=216)
(total N=526)
Sensitivity
89%
83%
85%
Specificity
52%
45%
43%
NPV
96%
93%
83%
Prevalence
15%
16%
37%
• Corus CAD outperformed MPI in diagnostic accuracy in the assessment
of obstructive CAD in symptomatic patients
•
•
Corus CAD AUC** = 0.79*** and MPI AUC = 0.59****
Statistically significant with p < 0.001
*Core-lab CTA
***95% CI 0.73 - 0.84
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**AUC: Area under the curve, a method of measuring diagnostic accuracy
**** 95% CI 0.54-0.63
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Corus™ CAD Intended Patients
Corus CAD is intended for use in the following non-diabetic patients
that a clinician suspects may have coronary artery disease (CAD):
Asymptomatic High-Risk Patients
•
Patients with a recent positive or inconclusive test result (ECG, ETT, Echo,
MPI, CTA, Calcium Score)
and/or
• Patients with 3 or more major risk factors for CAD (e.g., high cholesterol,
hypertension, family history, smoker, morbid obesity, known non-cardiac
vascular disease, male > 50, female > 60)
Corus CAD is NOT intended for patients:
•
•
•
With known prior myocardial infarction, or who have had a revascularization
procedure
Younger than 21 or older than 99 years of age
Who are asymptomatic and not considered at high risk for CAD
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Corus™ CAD Patient Sample Kit
All-in-one solution in a convenient patient sample kit
• All-in-one solution: sample collection
kit, sample shipper, self-contained
cooling system
• PAXgene®-based sample collection
means no processing, no spin-down at
the clinic
• On-demand cooling system* means no
dry-ice, no ice packs for sample
shipment back to CardioDx
*Evaporative, adsorption cooling system. Validated to maintain 4°C for 48 hours.
For more information visit www.nanocool.com
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Corus™ CAD Test Requisition Form
Account
Information
Patient
Information
Billing
Information
Ordering
Clinician's
Signature
Blood Draw
Information
Comments
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Corus™ CAD Patient Report
Patient Score: Ranges
Graph: Depicts the relationship
between test score and the
likelihood of obstructive
CAD in the clinical validation
study.
between 1 and 40, with higher
values associated with higher
likelihood of obstructive CAD.
Likelihood of
Obstructive CAD:
Derives
from the patient score and
is reported with a 95% confidence
interval (CI). A 95% CI indicates
there is a 95% chance that the
actual likelihood is within this
range.
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Corus™ CAD Intended Use (page 1 of 2)
• The Corus CAD test is a quantitative in vitro diagnostic test performed in a single
laboratory, using the gene expression profile of cells found in peripheral blood
specimens to be used as an aid to identify patients who are likely to have coronary
artery stenosis of at least 50%.
• The test should be performed on patients with a history of chest pain, with
suspected anginal equivalent to chest pain, or with a high risk of coronary artery
disease, but with no known prior myocardial infarction or revascularization
procedures.
• The test is not intended for patients with acute myocardial infarction, high risk
unstable angina, systemic infectious or systemic inflammatory conditions,
diabetes, and/or who are currently taking steroids, immunosuppressive agents, or
chemotherapeutic agents.
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Corus™ CAD Intended Use (page 2 of 2)
• The test is performed on a blood specimen obtained from the patient.
• The test incorporates the expression levels of multiple genes using an algorithm
with weighted functions to generate a quantitative score.
• The results of the test should be used by clinicians in conjunction with other tests
and clinical information in their assessment of a patient’s coronary artery disease.
• The Corus CAD test is for prescription use only.
• The test is not intended to be used to screen for stenosis among patients who are
asymptomatic and not considered at high risk for coronary artery disease, to
predict or detect response to therapy, or to help select the optimal therapy for
patients.
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