Results of ED Coronary CTA Trials

Udo Hoffmann, MD MPH

Research Grants:

Bracco Diagnostics

Bayer Healthcare

GE Healthcare

Disclosures

Anderson JL et al.Circulation. 2007;116:e148-304.

CT is especially suited for the ED setting

- ECG, initial biomarkers, and clinical presentation and traditional risk factors – no safe triage possible (Nagurney, JAMA 2006)

- goal in the ED: quick turnover and identification who do NOT need to be admitted - only 20% of patients with ACP have ACS, 80% could be discharged

- requires a fast, available and robust diagnostic imaging test with nearly perfect NPV

- CAD – No. 1 cause for ACS (80%-90%) – optimally direct visualization

Coronary Calcium in ACP

Patients with uncertain MI and no history of CAD

Reference Mod N Sens Spec PPV NPV

Laudon et al. Ann Em Med 1999 EBCT 105 1.00 N/A N/A 1.00

McLaughlin et al.Am J Cardi 1999 EBCT 134 0.88 0.37 0.08 0.98

Georgiou et al.JACC 2001 1999 EBCT 192 1.00 0.47 0.26 1.00

??% of patients have only non-calcified plaque

Important ED coronary CTA studies

Hollander et al. 568 patients, none of the discharged subjects (n=476, 84%) who all had absence of significant stenosis (>50%) suffered a cardiovascular event(cardiovascular death, non-fatal myocardial infarction) during a 30-day follow-up period

ROMICAT I – Demographics and Risk Factors

Age (years, mean SD) 52.7±12

Male Gender (n, %) 223 (61%)

Race (n, %) African American Caucasian Asians Others

31 (8%)313 (85%)

4 (1%)20 (6%)

No. of risk factors (median, IQR) 2 (1)

TIMI Score (low/intermediate/high) in %

94.3/ 5.4/ 0.3

ACS during index hospitalization (%, n) Unstable angina pectoris (%, n) Myocardial infarction (%, n)

31 (8%)23 (74%)8 (26%)

MACE during six month follow- up (%, n):Recurrent chest pain:

Outpatient evaluation (PCP)Readmission without testingReadmission with testing

068 (18%)50 (74%)

5 (7%)13 (19%) Hoffmann et al. JACC

2009

Prevalence of Plaque and Stenosis in ACP

No CAD50.4% Significant stenosis

detected/ not excluded 18.4%

Non-obstructive Plaque 31.2%

CAD categories by CT with relevance for early triage of patients with ACP in the ED (n=368, 8%

ACS)

Hoffmann et al. JACC 2009

ROMICAT I – CAD and ACS

No CAD No ACS

Hoffmann et al. JACC 2009

ROMICAT I – CAD and ACS

No CAD

Nonobstructive Plaque

No ACS

7 ACS• non-stenotic ACS• small vessel disease

Hoffmann et al. JACC 2009

Challenges – small coronary branches

59-year old female with typical chest pain, non-diagnostic ECG and negative serial Troponin

ROMICAT I – CAD and ACS

No CAD

Nonobstructive Plaque

Significant stenosis detected or not excluded

No ACS

7 ACS• non-stenotic ACS• small vessel disease

24 ACS

Hoffmann et al. JACC 2009

ROMICAT I – Diagnostic Accuracy

Sens: 100% (0.88-1.00)

NPV: 100% (0.98-1.00)

Spec: 54% (0.49-0.60)

PPV: 17% (0.12-0.23)

ACSNo

ACS

Plaque

No Plaque

31 154

0 183

Sens: 77% (0.59-0.90)

NPV: 98% (0.95-0.99)

Spec: 87% (0.82-0.90)

PPV: 35% (0.24-0.48)

ACSNo

ACS

Sign. Stenosi

sNo Stenosi

s

24 44

7 293

1. Triage Criterion: Presence of Plaque

2. Triage Criterion: Presence of Stenosis (>50%)

Hoffmann et al. JACC 2009

Efficacy of CT - Age and Gender

AgePreProb

RiskProb - neg.

Test Risk

Prob - pos. Test

Risk

Women

<45 0%Very low

- - - -

45-55 2% Low 0% (2%) Very low 18% (16%) High

55-65 4% Low 0% (4%) Very low 27% (23%) High

>65 21% High 13% (8%) Intermed 38% (17%) High

Men<45 5% Low 0% (5%) Very low 57% (51%) High

45-55 4% Low 1% (3%) Very low 22% (18%) High

55-65 23% High 12% (11%) Intermed 46% (23%) High

>65 28% High 12% (16%) Intermed 35% (7%) Intermed

Bamberg et al. AJC 2009

What to do with stenotic lesions?

severe RCA lesion

Hoffmann JACC 2006, Motoyama JACC 2007, Kitagawa AHJ 2008

Non-calcified plaque

Positive remodeling

Spotty calcification

Culprit Lesions Features

A CT-based Score to Identify Culprit Coronary Lesions Among Patients With Acute Chest Pain and Low to Intermediate Likelihood of ACS

Maros Ferencik, Christopher L. Schlett, Khuram A. Nasir, Brian B. Ghoshhajra,

Mathias F. Kriegel, Subodh B. Joshi, Ian S. Rogers, Quynh A. Truong, Dahlia Banerji, Fabian Bamberg, Thomas J. Brady, John T.

Nagurney, Udo Hoffmann

Cardiology Division, Dept. of Radiology and Dept. of Emergency MedicineCardiac MR PET CT Program

Massachusetts General Hospital and Harvard Medical School

Background

• Retrospective studies suggest that lesion culprit lesions in ACS patients can be identified by CT and are characterized by– Positive remodeling index– Spotty calcifications– Larger plaque areas– Low CT attenuation of the plaque

• However, whether these criteria enable appropriate risk stratification among patients who have significant stenosis is unknown

Motoyama S et al. JACC. 2009;54:49Motoyama S et al. JACC. 2007;50:319Hoffmann U et al. JACC. 2006;47:1655

Methods – Subject Selection

• CT performed in 368 subjects with acute chest pain but without objective evidence of ACS

• In 34/368 subjects (9%) at least one >50% stenosis was detected by CT – 21 subjects with ACS– 13 subjects without ACS

• culprit vessels/lesions were determined based on combination of available clinical data (nuclear stress test, invasive coronary angiography)

Methods – Characterization of stenotic lesions by Coronary CTA

• CT images were analyzed on a dedicated workstation (Vitrea, Vital Images)

• Two independent readers analyzed the data, blinded to the clinical information

• Measurements– Degree of stenosis– Stenosis length– Remodeling index– Plaque area at the site of the stenosis– Plaque volume

• Plaque composition: non-calcified, spotty calcifications, heavy calcification

Results – Subject Characteristics

ACS(n=21)

No ACS(n=13) 

p-value

Age (years) 61 (51-67) 58 (49-65) 0.97

Gender (male) 18 (86%) 11 (85%) 1.00

BMI 27 (25-30) 31 (28-33) 0.05

HTN 14 (67%) 11 (85%) 0.43

HLP 11 (52%) 8 (62%) 0.73

Diabetes 3 (14%) 6 (46%) 0.06

Results - Coronary Plaque Characteristics

ACS(n=21)

No ACS(n=13)

P

Degree of Stenosis (%) 73 (65-83) 66 (56-85) 0.64

Length of Stenosis (mm) 5 (4-8) 4 (3-5) 0.02

Positive Remodeling (RI >1.05)

13 (62%) 2 (15%) 0.01

Plaque Length (mm) 15 (11-22) 14 (12-19) 0.67

Plaque Area (mm2) 14 (11-17) 10 (7-18) 0.11

Plaque Volume (mm3) 212 (126-264) 171 (78-223) 0.24

<90 HU Plaque Volume (mm3)

91 (51-109) 49 (40-75) 0.03

Spotty Calcification 10 (48%) 2 (15% ) 0.08

Results – CT-based Score and Prediction of ACS

Score A Score B Score C Score D

Spotty Calcification X X X X

Positive Remodeling X X X X

Length of Stenosis (>4.5 mm)

X X X

<90HU Plaque Vol. (>80 mm3)

X X

Plaque Area (>10 mm2) X

OR for predicting ACS 4.1 5.4 4.0 3.7

(95% CI) (1.3-12.8)

(1.8-16.3)

(1.6-10.2)

(1.5-8.8)

p-value 0.01 0.003 0.004 0.004

AUC 0.76 0.85 0.86 0.88

Results – ROC Analysis

Score DCutoff = 2Sens 90%Spec 85%PPV 90%NPV 85%

Limitations

• Small sample size• Invasive coronary angiography not

available for all subjects• IVUS not available for the verification

of plaque characteristics• Findings need further validation in a

larger sample

Conclusions

• Confirmed earlier studies that culprit lesions in ACS are characterized by – positive remodeling, spotty calcifications, larger

plaque areas, and low CT attenuation of the plaque• Identified length of stenosis as additional

characteristics• Demonstrate high accuracy of a CT-based score for

ACS within the subgroup of patients with significant stenosis on coronary CTA

• May serve as a triage criterion to decide whether patients with significant stenosis but absence of objective signs of ischemia should be referred to invasive coronary angiography

What to do with stenotic lesions?

severe RCA lesion

14/34 patients with a significant stenosis in CT had no ACS or MACE after 6 months

Stenosis w/o ACS

Incremental Value of LV function

severe RCA lesionno regional LV dysfunctionnormal stress SPECT studyDischarge diagnosis of ‘non cardiac chest pain’No MACE after 6 months

Incremental value of LV Function

Sensitivity Specificity PPV NPV

Subjects with non-obstructive plaque (n=112)

Regional LV dysfunction 3/743% (17 –

73)

97/10592% (90 –

94)

3/1127% (11 -

46)

97/10196% (94 -

98)

Subjects with non-diagnostic CT scan (n=32)

Regional LV dysfunction 3/560% (25 -

87)

23/2785% (79 –

90)

3/743% (18 –

62)

23/2592% (85 -

97)

Subjects with significant stenosis (n=32)

Regional LV dysfunction 15/1883% (69 –

91)

12/1486% (67 –

95)

15/1788% (73 –

96)

12/1580% (63 –

88)

Seneviratne et al. submitted

- cardiac CT vs. nuclear stress perfusion imaging in patients at very low risk for ACS (serial negative Troponin measurements)- Outcomes: ACS during index hospitalization and 6 month FU

Gold Standard

UAP

More Interventions in very low risk population

Outcomes

Time to Diagnosis and LOS

Shorten LOS and minimize cost

• presumptive diagnosis and management after standard ED triage with cardiology consultation (n=58)

• CCTA was performed and results presented to caregivers who adjusted their recommendations– revised ACS diagnosis in 18 of 41 patients– canceled hospitalizations in 21 of 47– altered early invasive treatment in 25 of 58

• no MACE events were recorded in the 32 patients discharged from the ED

Cardiac CT- Changing Management

Rubinshtein Circulation 2007

CT will be highly effective because..

1. Fast, robust, and available – unique direct visualization of CAD

2. Strength of CT – high NPV - high Prevalence of negative CT exams (50%) in patients in whom traditional risk assessment does not allow triage

3. Combined assessment of CAD and regional LVF - Incremental Value of LV function to guide management if CT is positive (modest PPV of CAD findings)

4. Prognostic benefits – warranty period, preventive therapy

Questions

1. Absence of CAD justifies discharge without serial Troponin?

2. Incremental benefit of LV function justifies additional radiation exposure?

3. CT appropriate for very low, low or intermediate risk ED patients?

4. CT saves invasive angiograms – i.e. in patients with minimal troponin increase (exclusion of significant CAD in myocarditis)

5. Change of CT indication by introduction of hs troponin

6. TRO

Additional Promises of CT - Prognostic Benefits

1. negative CT – “clean bill” for several years - decrease of subsequent testing in repeated presenters

2. CT - new non-obstructive disease – initiation of secondary prevention

Lehman et al. American Journal of Medicine 2009

Incidental findings by CT

Definite alternative diagnosis: 1.3% pneumonia (n=3), pneumothorax (n=1), and gallstones in a patient with cholecystitis (n 1).

Possible alternative diagnosis: 4.1%No PE, ADhiatus hernia (n=12), thoracic aortic aneurysm (n=3), sinus of Valsalva aneurysm (n=1)

Subsequent diagnostic testing in 20.5% of patients, with 65/81 for noncalcified nodules

Within 6 months, 3 patients underwent biopsies with 2 of the lesions diagnosed as cancer.

Lehman et al. American Journal of Medicine 2009

ROMICAT I – Incidental Findings by CT

- CT STAT (16 centers, 700 patients, PI Gil Raff)- CT vs. MPI in low risk patients- sponsor: Bayer Healthcare

- ACRIN (4 centers, 1300 patients, PI Harold Litt)- CT vs. SOC in low risk patients- sponsor: ACRIN

- ROMICAT II (7 centers, 1000 patients, PI Udo Hoffmann)- CT vs. SOC in intermediate risk patients- sponsor: NHLBIOutcomes: low health effect size, cost driven, potentially MACE over two years in intermediate risk

Randomized Trials

James Goldstein, M.D., Kavitha Chinnaiyan, M.D., Daniel Berman, M.D., Udo Hoffmann, M.D., Stephan Achenbach, M.D., Leslee Shaw, Ph.D., Aiden

Abidov, M.D., Ph.D., Brian O'Neill, M.D., John Lesser, M.D., Issam Mikati, M.D., Uma Valeti, M.D., Michael Shen, M.D., and Gilbert Raff, M.D., for the

CT-STAT investigators

CT –STAT

Multi-center Prospective Randomized design 15 sites experienced with CCTA

750 “Low-risk” acute CP patients (TIMI Risk score<4, Initial ECG & Enzymes Normal)

CT STAT - OBJECTIVES

• Primary outcome: Diagnostic efficiency - Time-to-diagnosis & cost-to-diagnosis

• Secondary outcome: Safety - MACE over 6-months

CLINICAL DECISION ALGORITHM

CCTA Arm

• Stenoses 0-25% D/C

• Stenoses >70% ICA

• Stenosis 26-70%, CAC >100 Agatston units, or uninterp scans MPI

SOC ARM

• Nl serial ECGs cardiac biomarkers and MPI D/C

• Abnormal ECG, biomarkers and/or MPI ICA

CLINICAL OUTCOMES: CCTA

• No stenosis 297/361 (82.3%) pts• significant stenosis in 27 (7.5%) pts• Moderate stenosis in 23 (7%) pts• CTA uninterpretable in 14 (3.9%) pts

• MPI in 37 patients• ICA in 24, revasc in 13 (9 PCI, 4 CABG)• No ACS in patients in whom CCTA

excluded stenoses

CLINICAL OUTCOMES: SOC

• CCTA in 8 patients• ICA in 21 patients (8 PCI, no CABG)

CLINICAL OUTCOMES: CCTA vs SOC

• ICA during index visit (CCTA = 5.1%, SOC = 4.6%, p = NS).

• ACS (CCTA = 3.2%, SOC = 3%, p = NS).

TIME-TO-DIAGNOSIS

0

1

2

3

4

5

6

7

Ho

urs

Time to diagnosis

CCTA

SOC

CCTA Reduced Time by 54%, p=0.0001

COSTS-TO-DIAGNOSIS

$0

$500

$1,000

$1,500

$2,000

$2,500

$3,000

$3,500

Cost to diagnosis

CCTA

SOC

CCTA Reduced Costs by 38%, p=0.0001

CONCLUSIONS

• Low risk population – 3% ACS, 86% without significant CAD

• Time-to-diagnosis decreased by half, due to more rapid facilitation in testing

• Cost-to-diagnosis decreased by one-third, primarily due to expedited time-to-diagnosis and reduced length of stay

50

Overview of ROMICAT II

• Randomized controlled diagnostic multi center (n=7) trial, including 1000 subjects with acute chest pain and low to intermediate likelihood of ACS

• Primary Aim: To demonstrate that including cardiac CT into the early assessment of patients with ACP improves the efficiency of patient management.

51

Study Design

* Defined as chest pain suspicious for ACS + inconclusive ECG.** Hospital Length of Stay in discharged subjects is equal to time spent in the ED.

52

Study Organization

53

Timeline

09/09-01/10 Pre-enrollment period

01/10-05/11 Enrollment period

06/11-01/12 Follow-up and final database

02/12-12/12 Data analysis

01/13-09/13 Cost and cost effectiveness

Ancillary Studies Funded by ACRIN

• serial hs- troponin measurements – correlation with diagnostic testing and clinical outcomes*

• One and two year phone call follow-up to determine occurrence of MACE and health care utilization

54*As part of the site survey, biomarker storage and handling capability information will be collected.

PROMISE

Intervention

Primary Endpoint

TimeScreening

AndConsent

Patients with Chest Pain Suspected of CADLow to Intermediate Risk, Required NoinInvasive Testing

Intervention Arm:Anatomic testing

64 slice CTA

Usual Care Arm:Functional testing

Test selection: Ex ECG, Stress echo, Stress MPI

MIDeath Unstable Angina Hospitalization Peri-Procedural Comp

Secondary Endpoints

Follow-Up

Individual Components of Primary Endpoint

Cost and Cost-Effectiveness

Telephone Interviews at 6,12, 24, 30, 36, 42 48 Months;Additional Data Collection from Practice/Hospital

RandomizationX

Quality of Life; Patient Satisfaction

Core Lab

PROMISE

• Cardiac CT researched in very low to low risk patient populations

• Benefits through high sensitivity but adverse effects in patients who may not need CT not sufficiently clarified

• Major change of ED setup and organization necessary to use CT optimally

Conclusions

Thank you!

MGH Cardiac MR PET CT ProgramFabian Moselewski, Ian Rogers, Quynh Truong, Michael Shapiro, Sujith Seneviratne, John Nichols, Christopher Schlett, Sam Lehman, Maros Ferencik, Suhny Abbara, Ricardo C. Cury, Thomas J. Brady, Javed Butler, Nina Dannemann, Ron Blankstein, Khuram Nasir Department of Emergency Medicine John T. Nagurney, David F.M. Brown, Blair ParryCardiology Division Claudia U. Chae, Ik Kyung Jang, Rob GersztenHarvard Public School of Health Scott Gazelle, Joseph Ladapo, Milton Weinstein