study funded by molecular insight pharmaceuticals. all investigators
DESCRIPTION
Phase 2B Study of the Safety and Efficacy of [ 123 I]-BMIPP for Identification of Ischemic Myocardium Using SPECT in Adults Admitted to the ED for Evaluation of an Acute Coronary Syndrome. - PowerPoint PPT PresentationTRANSCRIPT
Phase 2B Study of the Safety and Efficacy of [123I]-BMIPP for Identification of Ischemic
Myocardium Using SPECT in Adults Admitted to the ED for Evaluation of an
Acute Coronary Syndrome
James E. Udelson MD, Timothy Bateman MD, Ethan Spiegler MD, Steven Bergmann MD, Ami Iskandrian MD, John Mahmarian MD,
Gary Heller MD PhD, Michael Kontos MD, Jack Ziffer MD,
Nicholas Borys MD, Norman LaFrance MD,
John Babich PhD, Ernest Garcia PhD
Study funded by Molecular Insight Pharmaceuticals. All investigatorsreceived research support from MIP. JEU and EG are consultants to MIP. JB, NL, NB are employees of MIP.
BackgroundBackground
Data suggest that BMIPP imaging of FA metabolism may have advantages in the dx of ACS compared with existing techniques:
• Better accuracy due to “Ischemic Memory”, identifying ischemia up to 30 hours after symptoms subside
• Reduced radiation exposure
• Possibly eliminating need for pharmacologic / exercise stress
Study ObjectivesStudy Objectives
• To evaluate the performance characteristics (sensitivity, specificity, positive and negative predictive value) of [¹²³I]-BMIPP imaging for detection / exclusion of ACS
• To evaluate the safety of [¹²³I]-BMIPP in patients with suspected ACS
Study DesignStudy Design
• Phase 2B, at 9 US sites• Pts w suspected ACS being initially
evaluated in the ED, to be stratified based on LK of ACS
• BMIPP SPECT imaging within 30 hrs of cessation of sx, after rest injection
• Safety evaluations during admission and up to 30 days post-discharge
Inclusion CriteriaInclusion Criteria
• > 30 years of age, to be admitted via ED for further evaluation of possible ACS
• If female, then not of childbearing potential or negative serum or urine ßHCG pregnancy test within 24 hours prior to receiving test drug
• Able to undergo BMIPP imaging beginning within 30 hrs of symptom cessation
Exclusion CriteriaExclusion Criteria
• History of LVEF < 40%
• Clinical hx of previous MI, Q-waves on ECG consistent with previous MI, or acute STEMI
• Left bundle branch block on ECG
• Known history of significant drug allergy or allergy to contrast media or iodine/iodides
• Formerly or currently on medication that targets fatty acid uptake or metabolism (e.g., etomoxir)
• Serum creatinine level > 2.0 mg per deciliter
Stratifying Likelihood of ACSStratifying Likelihood of ACS
Each pt must ALSO meet criteria for one of 3 LK strata:
Stratum A: HIGH LK FOR ACS
• Sx of ACS, accompanied by at least one of:
• New ST-segment depression
• T-wave inversion
• Elevated initial levels of troponin
Stratum B: INTERMEDIATE LK FOR ACS
• Known hx CAD, by cath or prior revasc, without hx of previous MI
• No stratum A criteria
Stratum C: LOW LK FOR ACS
• Pts who do not meet criteria for Stratum A or B and meet all the following:
• Sx possibly consistent with ACS
• ECG without findings diagnostic for acute ischemia
• Normal initial troponin
[¹²³I]-BMIPP Study Procedures[¹²³I]-BMIPP Study Procedures
Hospitalization Follow-Up
TIME (min) 0 10 20
Inject [¹²³I]-
BMIPP
BMIPP SPECT ~10 Min
IF INDICATED STRESS
MPI
STUDY
ENROLLMENT
IF INDICATED, CORONARY
ANGIOGRAPHY,
REVASCULARIZATION
30 day phone
follow-up for events
and safety
BMIPP SPECT Imaging BMIPP SPECT Imaging
• Dose of 2.5 – 5.4 mCi
• Rest SPECT imaging beginning ~10 mins following injection
• Imaging with double- or triple-headed cameras, LEHR collimators, centered on the 159 keV photopeak of 123I
• No attenuation or scatter correction
BMIPP SPECT Image AnalysisBMIPP SPECT Image Analysis
QA following development of gender-specific QA following development of gender-specific normal DBnormal DB
• 30 women and 30 men with < 5% LK CAD• 20 women and 20 men with known CAD of
varying extent (1-, 2-, and 3VD)• Imaging:
• Normals: rest BMIPP SPECT• CAD pts: rest BMIPP SPECT within 24
hours after inducing ischemia by treadmill exercise
• Subsequent optimization of QA thresholds for abnormality
Folks et al, Folks et al, ASNC 2007ASNC 2007
Mean NormalPatient ProfileMean - SD
0º 90º 180º 270º 360º
% C
ou
nts
Angle
“Risk Stratified” Criteria for BMIPP Defects
LLN
High 2 SD
Int 2.5 SD
Low 3 SD
Criteria for abnormality = 3% LV extent
LK ACSLK ACS
LLN
LLN
Mean NormalPatient Profile
0º 90º 180º 270º 360º
% C
ou
nts
Angle
“Risk Stratified” Criteria for BMIPP Defects
LLNLowLow 3 SD3 SD
Criteria for abnormality = 3% LV extent
LK ACSLK ACS
Low LK ACSLow LK ACSPatient => Patient =>
NormalNormal
Mean NormalPatient ProfileMean - SD
0º 90º 180º 270º 360º
% C
ou
nts
Angle
“Risk Stratified” Criteria for BMIPP Defects
LLN
Low 3 SD
Criteria for abnormality = 3% LV extent
High LKHigh LKACS pt =>ACS pt =>
Abnormal by Abnormal by High LK criteriaHigh LK criteria
High 2 SD
LK ACSLK ACS
Study Population SampleStudy Population Sample
Dosed/Complete data for final dx (n) 105 / 97Age (yrs, SD) 56 (13)Women (%) 45Prior MI (%) 0Known CAD / CABG / PCI (%) 36 / 8 / 21Race (%)
Caucasian 52AA 31Hispanic 11
Relation of Sx to BMIPP imagingSx ongoing (% of pts) 32Cessation of sx prior to imaging (%)
0-9 hrs 239-30 hrs 45
Mean time from Sx cessation (hrs) 14 (9)
Final Diagnosis of ACSFinal Diagnosis of ACS
97 pts w complete study data
Low LK ACS
n = 49
Int LK ACS
n = 20
High LK ACS
n = 28
ACS +
n = 3
(prev = 6%)
ACS +
n = 4
(prev = 20%)
ACS +
n = 19
(prev = 68%)
Adjudicated Final Diagnosis
0102030405060708090
100
%
Sens Spec NPV PPV Sens fortrop+ MI
Performance Characteristics of BMIPP Imaging for Detecting ACSPerformance Characteristics of BMIPP Imaging for Detecting ACS
For ACS Dx
85
0102030405060708090
100
%
Sens Spec NPV PPV Sens fortrop+ MI
Performance Characteristics of BMIPP Imaging for Detecting ACSPerformance Characteristics of BMIPP Imaging for Detecting ACS
For ACS Dx
95%% CI: 69,94
85
59
0102030405060708090
100
%
Sens Spec NPV PPV Sens fortrop+ MI
Performance Characteristics of BMIPP Imaging for Detecting ACSPerformance Characteristics of BMIPP Imaging for Detecting ACS
For ACS Dx
95%% CI: 69,94 54,62
85
59
91
0102030405060708090
100
%
Sens Spec NPV PPV Sens fortrop+ MI
Performance Characteristics of BMIPP Imaging for Detecting ACSPerformance Characteristics of BMIPP Imaging for Detecting ACS
For ACS Dx
95%% CI: 69,94 54,62 83,96
85
59
91
43
0102030405060708090
100
%
Sens Spec NPV PPV Sens fortrop+ MI
Performance Characteristics of BMIPP Imaging for Detecting ACSPerformance Characteristics of BMIPP Imaging for Detecting ACS
For ACS Dx
95%% CI: 69,94 54,62 83,96 35,48
85
59
91
43
100
0102030405060708090
100
%
Sens Spec NPV PPV Sens fortrop+ MI
Performance Characteristics of BMIPP Imaging for Detecting ACSPerformance Characteristics of BMIPP Imaging for Detecting ACS
For ACS Dx
95%% CI: 69,94 54,62 83,96 35,48 85,100
BMIPP Imaging in Suspected ACSBMIPP Imaging in Suspected ACS
Pt 310
• 45 yo woman w sx suspicious for ACS (CP x 20 mins)• Initial troponin mildly positive• Peak trop 0.63 ng/mL (ULN 0.2)• BMIPP injected 26 hrs after sx subsided• Cath: LAD 70%, LCx 50%, RCA NL => PCI of LAD
Rest BMIPP SPECTRest BMIPP SPECT
• 48 yo man w sx suspicious for ACS (CP x 30 mins), no prior hx CAD• No ECG changes, initial troponin -• Int LK for ACS• All troponins -• BMIPP injected 8 hrs after sx subsided• Follow-up SPECT: partially reversible lateral wall defect
Pt 403
BMIPP Imaging in Suspected ACSBMIPP Imaging in Suspected ACS
Rest BMIPP SPECTRest BMIPP SPECT
• 68 yo man w sx suspicious for ACS, prior hx angina, no prior MI• T wave inversions• Initial trop 0.66 ng/mL (ULN 0.1)• Peak trop 1.52 ng/mL• BMIPP injected 20 hrs after sx subsided• Cath: RCA 99%, LAD 95%, LM 75% =>CABG
Pt 508
BMIPP Imaging in Suspected ACSBMIPP Imaging in Suspected ACS
Rest BMIPP SPECTRest BMIPP SPECT
Quantitative BMIPP DefectsQuantitative BMIPP Defects
16.5
1
20.5
6
0
5
10
15
20
25
Med
ian
BM
IPP
Def
ect
Siz
e (%
LV
Ab
nl
by
QA
)
ACS + ACS - True Pos False Pos
25th, 75th%ile: 6,31 0,5 8,32 4,14
p < 0.0001 p = 0.005
Safety DataSafety Data
• No pt discontinued from study due to adverse event
• 1 SAE – considered by PI as not related to study drug
• No pre- to post-dose changes in lab parameters considered clinically significant
SummarySummary
• In ED pts with suspected ACS, using a novel gender-specific, risk-stratified QA approach, BMIPP imaging demonstrated sensitivity and NPV for ACS similar to that reported for rest MPI
• However, these data were seen even though BMIPP was performed up to 30 hrs after cessation of sx, at mean 14 hrs
• Sensitivity for troponin+ MI is higher in this sample than previously reported for MIBI
• Safe and well-tolerated, consistent with Japanese experience
ConclusionsConclusions
• BMIPP imaging, even many hrs after cessation of symptoms, can detect or rule-out ACS / MI in ED pts with suspected ACS with clinically relevant performance
• The ability to image prolonged post-ischemic abnormalities in FA metabolism (“ischemic memory”), allowing imaging long after symptoms subside, is unique in this setting
• These data support the performance of larger pivotal trials, now ongoing, in this population