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Myocardial Perfusion Imaging:

How does it affect clinical


decisions?
Prof. Carlos D. Libhaber
Wits University
Johannesburg – South Africa
During the past decades, the most rapidly
growing areas of nuclear cardiology have
been in the application of stress
myocardial perfusion SPECT (MPI) and
lately stress myocardial perfusion PET
for prognostication in patients with known
or suspected CAD.
This growth has been stimulated by a
wealth of studies in large patient groups,
as well as a basic shift in the clinical
approach to patient management toward
strategies based on patient risk rather
than coronary anatomy as an endpoint.
The angina cascade
Myocardial oxygen demand

Angina

Ischemic ST depression

Global LV dysfunction

Significant perfusion defect

Regional myocardial dysfunction


Flow heterogeneity

Rest

Exercise treadmill time


Beller GA et al, Am J Cardiol 61; 1988
Symptomatic
Role of Exercise ECG

Meta-analysis: 19 exercise ECG studies,


3721 women, 1977 men

Gibbons RJ et al, Circulation 2002;106:1883-1892


Symptomatic
Role of Cardiac Radionuclide
4 Imaging

Santana-Boado C et al, J Nucl Med 1998;39:751-755


Risk-based approach to patient
care

A new paradigm in patient management is


that of a risk-based approach to patients
with suspected CAD without limiting
symptoms.

Berman DS et al: Hurst’s The Heart, 2004, pp 525-565


Risk-based approach to patient
care

With a risk-based approach, the focus is


not on predicting which patient has
anatomic CAD but on identifying patients
at risk for specific adverse events, ie:
cardiac death or nonfatal MI, and on post-
MPI management strategies that might
reduce the risk of these outcomes.

Berman DS et al: Hurst’s The Heart, 2004, pp 525-565


Risk-based approach to patient
care

Catheterization and revascularization can


be limited to those patients who may
benefit from these procedures using this
approach.

Berman DS et al: Hurst’s The Heart, 2004, pp 525-565


Incremental prognostic value

Given the constraints placed on physicians and


the health care system to practice clinically
effective and cost-effective medicine, it is
generally accepted that all diagnostic modalities
must be judged by the added or incremental
information they contribute over that provided
by the information known about the patient
before the test.

Berman DS et al: Hurst’s The Heart, 2004, pp 525-565


BAYESIAN THEORY
• The use of the Bayesian theory
incorporates the pretest risk of disease
and the sensitivity and specificity of the
test (likelihood ratio) to calculate the
posttest probability of coronary disease.

• The diagnostic power of the exercise test


is maximal when the pretest probability of
CAD is intermediate (30 – 70%)
BAYES THEOREM
Probability of CAD
Incremental prognostic value

Hence, the clinical value of MPI for prognostic


in CAD depends on the incremental or added
prognostic information yielded by this modality
over all data available before the test:
– clinical
– historical
– data from the nonimaging components of stress
testing

Berman DS et al: Hurst’s The Heart, 2004, pp 525-565


Incremental prognostic value

This analytic approach permits clinicians to


determine the true prognostic value of a test
and its actual contribution.

Berman DS et al: Hurst’s The Heart, 2004, pp 525-565


Incremental prognostic value

Several large studies reporting prognostic


analyses of MPI in cohorts using exercise,
vasodilator, or both types of stress and in
various clinical settings have highlighted its
added value.
Berman DS et al, J Am Coll Cardiol 27: 756, 1996
Hachamovitch R et al, Circulation 93: 905-914, 1996
Hachamovitch R et al, Circulation 97: 535-543, 1998
Hachamovitch R et al, Circulation 107: 2899-2906, 2003
Marwick TH et al, Am J Med 106: 172-178, 1999
Sharir T et al, Circulation 106: II-523, 2002 (abstr)
Vanzetto G et al, Circulation 100: 1521-1527, 1999
Zellweger MJ et al, J Am Coll Cardiol 37: 144-152, 2001
Added value of Gated-SPECT

• Left ventricular ejection fraction, when


measured by other modalities, has been shown
to risk-stratify patients for risk of subsequent
cardiac death.
Added value of Gated-SPECT

• Sharir and coworkers, demonstrated that that


post-stress LVEF, as measured by gated
SPECT, provided significant information over
the extend and severity of perfusion defect in
the prediction of cardiac death.

Sharir T et al, J Nucl Med 42: 831-837, 2001


Risk of adverse events after a
normal scan

• Extensive literature examining risk after a


normal stress  most studies report rates of
hard events (cardiac death or nonfatal MI) of
<1% per year of follow-up

Berman DS et al: Hurst’s The Heart, 2004, pp 525-565


Klocke FJ et al, J Am Coll Cardiol 42, 1318-1333, 2003
Risk of adverse events after a
normal scan
The American Society of Nuclear Cardiology
published a position statement in 1997 stating that a
normal MPI study predicts a very low likelihood (<1%)
of adverse events such as cardiac death or myocardial
infarction for at least 12 months and that this level of
risk is independent of:
– gender
– age
– symptom status
– past history of CAD
– presence of anatomic CAD
– imaging technique or isotope (201Tl or 99mTc sestamibi)

Bateman TM et al, J Nucl Cardiol 4: 172-173, 1997


Risk of adverse events after a
normal scan
However, published prognostic studies performed in
patients undergoing pharmacologic stress,
considered a population at higher risk and with more
co-morbidity than patients undergoing exercise stress,
have reported hard event rates of 1.3% to 2.7% per
year, suggesting that underlying clinical risk and prior
CAD may influence event rates after a normal MPI

Heller GV et al, J Am Coll Cardiol 26: 1202-1208, 1995


Shaw L et al, J Am Coll Cardiol 19: 1390-1398, 1992
Stratmann HG et al, Am J Cardiol 73: 647-652, 1994
Calnon DA et al, J Am Coll Cardiol 38: 1511-1517, 2001
Kang X et al, Am Heart J 138: 1025-1032, 1999
Amanullah AM et al, J Am Coll Cardiol 27: 803-809, 1996
Risk of adverse events after a
normal scan
• Recently, an analysis of 7376 patients with normal
stress MPI addressed predictors of risk and its
temporal characteristics.

• Variables identified as markers of increased risk and


shortened time to risk:
– use of pharmacologic stress
– presence of known CAD
– DM (in particular, female diabetics)
– advanced age

Hachamovitch R et al, J Am Coll Cardiol 41: 1329-1340, 2003


Predicted events rates in the first and second
years after a normal stress MPI study

50 y.o. male, Ex, No 0.1


Hx CAD 0.1

80 y.o. male, Aden, 1.5


No Hx CAD 1.6
Year 1
Year 2
50 y.o. male, Hx 0.9
CAD 1.5

80 y.o. male, Hx 1.4


CAD 2.4

0 0.5 1 1.5 2 2.5 3

Predicted Hard Event Rate (%)


Hachamovitch R et al, J Am Coll Cardiol 41: 1329-1340, 2003
Risk of adverse events after a
normal scan
• The increased baseline risk of patients after
normal MPI is limited to a subset of patients.

• As a whole, patients with normal MPI are at


very low risk

• Patients with known CAD who had normal MPI,


the temporal component of risk increased
rapidly.

Hachamovitch R et al, J Am Coll Cardiol 41: 1329-1340,2003


Expressing the extent and severity
of perfusion results
17 and 20-segment models of the left ventricle

13
1 7
2 6 8 12 14 18
19

3 5 9 20
11 15 17
4
10 16

11
1 5
6 10 12 16
2 4 17
7 9 13 15
3
8 14

Berman DS et al, J Am Coll Cardiol 26: 639-647, 1995


Berman DS et al, J Nucl Cardiol 11: 414-423, 2004
Cerqueira MD et al. Circulation 105: 539-542, 2002
Expressing the extent and severity
of perfusion results

Each segment is scored from 0 to 4

0 = normal
1 = equivocal reduction
2 = definite but moderate reduction
3 = severe reduction of tracer uptake
4 = absent uptake of radioactivity

Berman DS et al, J Am Coll Cardiol 26: 639-647, 1995


Cerqueira MD et al. Circulation 105: 539-542, 2002
Expressing the extent and
severity of perfusion results

• SSS  summed stress score

• SRS  summed rest score

• SDS  summed difference score

Berman DS et al, J Am Coll Cardiol 26: 639-647, 1995


Cerqueira MD et al. Circulation 105: 539-542, 2002
Expressing the extent and
severity of perfusion results
• The SSS, yields the perfusion analog of the
peak ejection fraction  represents
ischaemic and infarcted tissue
• The SRS is analogous to the resting ejection
fraction  is related to the amount of infarcted
or hibernating myocardium
• The SDS  expresses the amount of perfusion
defect reversibility
Berman DS et al, J Am Coll Cardiol 26: 639-647, 1995
Cerqueira MD et al. Circulation 105: 539-542, 2002
Expressing the extent and
severity of perfusion results

As a single overall prognostic variable, the SSS


(summed stress score) has been shown to be
the single most important predictor of hard
events

Hachamovitch R et al, Circulation 97: 535-543, 1998


Event risk with abnormal scans
• Berman DS et al, Hurst’s The • Travin MI et al, J Nucl Cardiol
Heart, 2004, pp 525-565 11: 253-262, 2004

• Ladenheim ML et al, Am J • Thomas GS et al, J Am Coll


Cardiol 59: 270-277, 1987 Cardiol 43: 213-224, 2004

• Hachamovich R et al, • Heller GV et al, J Am Coll


Circulation 93: 905-914, 1996 Cardiol 26: 1202-1208, 1995

• Hachamovich R et al, • Kang X et al, Am Heart J 138:


Circulation 97: 535-543, 1998 1025-1032, 1999

• Marwick TH et al, Am J Med • Giri S et al, Circulation 105: 32-


106: 172-178, 1999 40, 2002

• Sharir T et al, J Nucl Med 42 : • Hachamovich R et al,


831-837, 2001 Circulation 105: 823-829, 2002
Event risk with abnormal scans
Risk

Extent/Severity of stress perfusion defects


Event risk with abnormal scans

• This relationship has been shown to be present


irrespective of:
– the type of stress performed
– the patient cohort examined
• clinical characteristics
• history of CAD
– the type of isotope used
Event risk with abnormal scans

• Variation in the relationship found in patients


with DM

– Risk was greater for patients with IDDM than


NIDDM

– and NIDDM greater than non-diabetic patients

Berman DS et al, J Am Coll Cardiol 41: 1125-1133, 2003


Event risk with abnormal scans
Relationship between log relative hazard for predicted cardiac mortality
and SSS in IDDM, NIDDM and non-diabetic patients

IDDM

P<0.001
2.0

NIDDM
Log Relative Hazard
1.5

Non-diabetic
1.0
0.5
0.0
-0.5
-1.0

0 10 20 30 40 50

Summed Stress Score


Berman DS et al, J Am Coll Cardiol 41: 1125-1133, 2003
Event risk with abnormal scans
P<0.001
4.5
4.2
4
3.5
P<0.01
3 2.9 2.9
2.7
2.5 2.3
CD
2
MI
1.5
1 0.8
0.6
0.5 0.3
0
Normal Mildly Abnl Mod Abnl Sev Abnl
2946 884 445 898
Hachamovitch R et al, Circulation 97: 535-543, 1998
Mildly abnormal perfusion scan
Not only do scan data provide incremental
prognostic information over prescan
information, but also:
– advanced age
– prior CAD
– DM
– atrial fibrillation
– pharmacological stress
Hachamovich R et al, Circulation 93: 905-915, 1996
Hachamovich R et al, Circulation 107: 2899-2906, 2003
Hachamovitch R et al, Circulation 105: 1329-1340, 2003
Berman DS et al, J Am Coll Cardiol 41: 1125-1133, 2003
Moderately to severely abnormal
perfusion scan
Although both reversible and fixed stress
perfusion defects are predictors of prognosis,
those at highest risk of cardiac events are
patients with extensive stress-induced
abnormalities with:
– 201Tl
– 99mTc sestamibi
Ladenheim ML et al, Am J Cardiol 59: 270-277, 1987
– 99mTc tetrofosmin Vanzeto G et al, Circulation 100: 1521-1527, 1999
Travin MI et al, J Nucl Cardiol 11: 253-262, 2004

– dual-isotope Heller GV et al, J Am Coll Cardiol 26: 1202-1208, 1995


Berman DS et al, J Am Coll Cardiol 26: 639-647, 1995
Hachamovitch R et al, Circulation 93: 905-914, 1996
Hachamovitich R et al, Circulation 97: 535-543, 1998
Zellweger MJ et al, J Am Coll Cardiol 37: 144-152, 2001
Kang X et al, Am Heart J 138: 1025-1032, 1999
Hachamovitch R et al, Circulation 105: 823-829
Shaw LJ et al, J Nucl Med 44: 134-139, 2003
Nonperfusion MPI markers of risk
Transient ischemic dilatation (TID) of the LV

• TID is considered present when the LV cavity


appears to be significantly larger in the
poststress images than at rest.

• May often represent apparent cavity dilation


due to diffuse subendocardial ischemia

Weiss AT et al, J Am Coll Cardiol 9: 752-759, 1987


Mazzanti M et al, J Am Coll Cardiol 27: 1612-1620, 1996
Nonperfusion MPI markers of risk
Transient ischemic dilatation (TID) of the LV

• TID is considered to represent severe and


extensive ischemia and has been shown to be
highly specific for critical stenosis (> 90%
narrowing) in vessels that supply a large portion
of the myocardium (ie: proximal LAD or
multivessel lesions 90%)

Weiss AT et al, J Am Coll Cardiol 9: 752-759, 1987


Mazzanti M et al, J Am Coll Cardiol 27: 1612-1620, 1996
Nonperfusion MPI markers of risk
Transient ischemic dilatation (TID) of the LV

• TID in the setting of vasodilator stress has been


found to have similar implications as that
associated with exercise.

Chouraqui P et al, Am J Cardiol 66: 689-694, 1990


Nonperfusion MPI markers of risk
Transient ischemic dilatation (TID) of the LV

The prognostic value of TID as observed on


MPI has been reported by Abidov and
coworkers, who evaluated 1560 patients with
normal stress MPI with no LV enlargement who
were followed up for 2.3 years for hard and soft
cardiac events.

Abidov A et al, J Am Coll Cardiol 42: 1818-1825, 2003


Nonperfusion MPI markers of risk
Transient ischemic dilatation (TID) of the LV

They demonstrated that in patients with


otherwise normal MPI, TID is an independent
prognostic marker of total events even after
significant clinical variables, i.e. age, typical
angina and DM, are factored.

Abidov A et al, J Am Coll Cardiol 42: 1818-1825, 2003


Nonperfusion MPI markers of risk
Increased lung uptake of perfusion tracers

• It is generally accepted that the finding of increased


pulmonary uptake of 201Tl reflects increased
pulmonary capillary wedge pressure because of
either ischemia or nonischemic etiologies.

• Increased thallium lung uptake after exercise has


been shown to have incremental prognostic
information over myocardial perfusion defect
assessment.

Gill JB et al, N Engl J Med 317: 1486-1489, 1987


Nonperfusion markers in the setting
of pharmacological stress
The role of ST segment change

Marshall and colleagues found that although ST


depression was infrequent  only 17% of
patients had at least 1 mm ST depression and
5.3% had at least 2 mm ST depression, it was
both a univariate and multivarible predictor of
adverse outcomes, hence providing incremental
value over perfusion data alone
Marshall ES et al, Am Heart J 130: 58-66, 1995
Nonperfusion markers in the setting
of pharmacological stress
The role of ST segment change

Subsequent studies in larger populations


confirmed both the independent value of ST
depression and its incremental value over
perfusion variables for prediction of cardiac
death and MI

Hachamovitch R et al, Am J Cardiol 80: 426-433, 1997


Nonperfusion markers in the setting
of pharmacological stress
The role of ST segment change

Some studies, including larger studies using


cardiac death as solitary endpoint, have not
found ST depression during adenosine stress
to be predictive of outcome, whereas other
studies have.
Berman DS et al, J Am Coll Cardiol 41: 1125-1133, 2003
Heller GV et al, J Am Coll Cardiol 26: 1202-1208, 1995
Stratmann HG et al, Am J Cardiol 73: 647-652, 1994
Lette J et al, Am Heart J 129: 880-886, 1995
Amanullah AM et al, Am J Cardiol 82: 725-730, 1998
Stratmann HG et al, Am Heart J 123: 317-323, 1992
Chikamori T et al, Jpn Circ J 57: 851-861, 1993
Nonperfusion markers in the setting
of pharmacological stress
Clinical and hemodynamic responses to vasodilator stress

Normally, there is a mild rise in heart rate and


fall in blood pressure, particularly systolic blood
pressure, with adenosine or dipyridamole
infusion.
Nonperfusion markers in the setting
of pharmacological stress
Clinical and hemodynamic responses to vasodilator stress

Ammanullah and colleagues found both a


higher heart rate at rest and a blunted heart
rate increase during adenosine infusion to be
univariate predictors of severe or extensive
CAD in women.

Amanullah AM et al, Am J Cardiol 79: 1319-1322, 1997


Nonperfusion markers in the setting
of pharmacological stress
Clinical and hemodynamic responses to vasodilator stress

• Abidov and colleagues investigated 3444


patients (54% women, mean age 74.0 ± 8.4
years) who underwent adenosine MPI with no
additional exercise as an adjunct and were
followed up for 2.0 years.

• During this follow-up 224 cardiac deaths


occurred (6.5%)
Abidov A et al, Circulation 107: 2894-2899, 2003
Nonperfusion markers in the setting of
pharmacological stress
Clinical and hemodynamic responses to vasodilator stress

7
6
Predicted CD, %/yr

SSS=0-3
5
SSS=4-8
4
SSS=9-13
3 SSS>13
SSS>13
2 SSS=9-13
1 SSS=4-8
SSS=0-3
0
High Medium Low
Tercile Tercile Tercile
N=1146, N=1153, N=1145,
Range 1.28-3.13 Range 1.12-1.28 Range 0.67-1.12
Ratio Peak/Rest HR
Abidov A et al, Circulation 107: 2894-2899, 2003
Post-MPI patient management and
its prognostic implications
Scan results and physician action

Multiple studies to date have examined post-


MPI resource utilization using referral rates to
early cath and revascularization as measures of
physician action (early = first 60 – 90 days post-
MPI)

Staniloff HM et al, J Nucl Med 27: 1842-1848, 1984


Pryor DB et al, Am J Cardiol 53: 18-22, 1984
Post-MPI patient management and
its prognostic implications
Scan results and physician action

Clinical
symptoms

Normal scan

Cardiac cath Medical therapy

Berman DS et al, J Am Coll Cardiol 26: 639-647, 1995


Post-MPI patient management and
its prognostic implications
Scan results and physician action

Subsequent results demonstrated that the


extent and severity of reversible defects shown
by the MPI result are the dominant factor
driving subsequent resource utilization

Hachamovitch R et al, Circulation 93: 905-914, 1996


Post-MPI patient management and
its prognostic implications
Scan results and physician action

For any amount of ischemia present, the


presence of anginal symptoms results in the
highest referral rates, while asymptomatic
patients have the lowest referral rates

Hachamovitch R et al, Circulation 107: 2899-2906, 2003


Post-MPI patient management
and its prognostic implications
Survival with medical therapy versus revascularization after stress MPI
6
5

Medical Rx
Lo Hazard Ratio
4

Revascularization
3
2
1
0

0 12.5% 25% 37.5% 50%


% Total Myocardium Ischemic
Hachamovitch R et al, Circulation 107: 2900-2907, 2003
Post-MPI patient management and
its prognostic implications
Survival with medical therapy versus revascularization after stress MPI

8 7.5
7
6
5
Lives saved
per 100 4 3.9 <60 yrs
treated with 3.4
3 60 - 80 yrs
Revasc vs.
Medical RX 2 >80 yrs
2
1.1
1 0.7
0.4
0.1
0
-1 -0.7
5 - 10% 10 - 20% >20%

% myocardium ischemic
Hachamovitch R et al, Circulation 107: 2900-2907, 2003
Post-MPI patient management and
its prognostic implications
Survival with medical therapy versus revascularization after stress MPI

Gated SPECT EF and ischemia add


incrementally to each other for prediction
of cardiac death and assessing potential
benefit from revascularization

Hachamovitch R et al, Circulation 106, 2002, (abstr)


Post-MPI patient management and
its prognostic implications
Survival with medical therapy versus revascularization after stress MPI

Although EF was found to be a superior


predictor of cardiac death, only inducible
ischemia identified which patients
experienced a short-term benefit from
revascularization.

Hachamovitch R et al, Circulation 106, 2002, (abstr)


Post-MPI patient management
and its prognostic implications
Survival with medical therapy versus revascularization after stress MPI

For any degree of ischemia, the survival


benefit associated with revascularization
was greater for patients with reduced EF.

Hachamovitch R et al, Circulation 106, 2002, (abstr)


Post-MPI patient management and
its prognostic implications
Treatment algorithms based on risk and potential benefits

Stress Gated SPECT

Mild/Moderate
No Ischemia
Ischemia
Ischemia >10%
(<10%)

Symptoms
controlled?
Medical Y N Catheterization
Therapy  Revasc.
TID
Lung uptake
ST changes
Motion abnorm

Hachamovitch R et al, Circulation 107: 2900-2907, 2003


Thank you!