v asodilator i nduced s tress i n c on cordance with adenosine binodenoson pivotal clinical trial...
TRANSCRIPT
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Vasodilator Induced Stress In CONcordance with Adenosine
Binodenoson Pivotal Clinical Trial Program
James E. Udelson, Bruce Iteld, Fred Weiland, Jack Foster, Robert Bonow, Edward Ficaro,
Raymond Gibbons, Gary Heller, Frans Wackers, Richard Barrett, Glenn Pixton
for the VISION 302 and 305 Investigators
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Disclosures
Drs. Udelson, Iteld, Weiland, Foster, Bonow, Ficaro, Gibbons, Heller and Wackers received research grant support and/or consulting honoraria from King Pharmaceuticals R&D
All investigators and/or their institutions received research grant support from King Pharmaceuticals R&D
Drs. Barrett and Pixton are employees of King Pharmaceuticals R&D
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Background
Vasodilator stress is widely used in lieu of exercise for SPECT MPI
Mechanism: stimulation of adenosine A2a receptors coronary arteriolar dilation, decreased resistance and increased CBF
Stimulation of other adenosine receptors (A1, A2b, A3) high incidence of side effects (>80%), including 2o/3o AVB, CP, SOB, flushing
More selective A2a receptor stimulation desirable
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Background (con’t)
Binodenoson is a highly selective A2a agonist
In Phase 2 cath lab studies, CBFR with I.V. binodenoson was similar to that seen with I.C. adenosine
Phase 2 studies suggested SPECT image concordance with adenosine, and fewer/less severe side effects than adenosine in single-blind studies
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VISION Pivotal Trial Program:Primary Objective
To demonstrate that SPECT MPI acquired during binodenoson-stress and adenosine-stress detect similar magnitudes of ischemia in the same patients
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Secondary Objectives
To evaluate and compare side effects between binodenoson and adenosine:• Incidence of 2nd or 3rd degree AV block
• Incidence, intensity of reported side effects, patient preference
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Study Design
Two multi-center trials: VISION 302 (40 sites), VISION 305 (39 sites)
Randomized, active-controlled (adenosine), crossover design
Double-blind, double-dummy drug dosing
Enrolled pts were risk-stratified by ACC pre-test LK for CAD, to ensure broad pt representation
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Inclusion/Exclusion Criteria
Inclusion:• Referred for clinical pharm stress MPI• Age ≥ 30 years• Typical or atypical anginal pain• Provide informed consent
Exclusion:• Pregnancy• Very low pre-test LK for CAD• MI within 30 days, PCI or CABG within 3 years,
unless new angina• Contraindications for adenosine• LVEF < 0.35, or NYHA HF Class IV
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2-7 Days2-7 Days
Study Design: VISION 302 and 305
Eligible Patients Randomized to Sequence
adenosineadenosine
adenosineadenosine binodenosonbinodenoson
binodenosonbinodenoson
1st Scan1st Scan““MPI #1”MPI #1”
2nd Scan2nd Scan““MPI #2”MPI #2”
2-7 Days
Identical image protocols, camera, isotope, doses, acquisition times and image Identical image protocols, camera, isotope, doses, acquisition times and image time post-dose, time of day, background anti-anginal meds heldtime post-dose, time of day, background anti-anginal meds held
adenosineadenosineadenosineadenosine
adenosineadenosineadenosineadenosine
VISION 305
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Double-Blind, Double-Dummy Drug Administration
placeboplacebo0.06 mL/kg0.06 mL/kgin 30 secsin 30 secs
binodenosonbinodenoson1.5 1.5 g/kgg/kgin 30 secsin 30 secs
adenosine, 140 adenosine, 140 g/kg/min x 6 ming/kg/min x 6 min
placebo, 0.047 mL/kg/min x 6 minplacebo, 0.047 mL/kg/min x 6 min
-30 sec 0 1 2 3 4 5 6Time (min)
RPor
RP = radiopharmaceutical
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Demographics
Gender (M / F) 37% / 63% 46% / 54%Age (Years, SD) 63.3 (12.0) 62.9 (11.9)BMI (kg/m2, SD) 31.4 (7.0) 31.3 (6.5)Reason for referral:Chest Pain 94% 97%Prior MI 4% 7%Prior CABG/PCI 9% 15%
VISION 302 VISION 305n=415 n=427
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Demographics
Gender (M / F) 37% / 63% 46% / 54%Age (Years, SD) 63.3 (12.0) 62.9 (11.9)BMI (kg/m2, SD) 31.4 (7.0) 31.3 (6.5)
n=415 n=427
Reason for referral:Chest Pain 94% 97%Prior MI 4% 7%Prior CABG/PCI 9% 15%
VISION 302 VISION 305
Actual6%
45%24%26%
Target5%
45%25%25%
Low LKIntermed LK
High LKKnown CAD
Actual5%
44%10%41%
Target5%
45%10%40%
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Data Analysis and Results
Efficacy: SPECT image concordance
• Methodology
• Results
Side effects
• Methodology
• Results
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Methods: SPECT Image Reviews
Compliant: with FDA Guidelines Independent Readers: No other
involvement with studies or development program, no knowledge of other readers’ interpretations
Blinded: to all treatment data Separated: Reader reviews of both MPI
studies from same patient were separated by 2 weeks or ≥ 50 studies
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Methods: Segmental Scoring of MPI
Each segment at stress/rest from 0=NL, to 4=severe defectDerived global scores: SSS: sum of stress scores = total abn myocardium at stressSRS: sum of rest scores = extent of infarctSDS = SSS - SRS = extent/severity of ischemia
Circulation 2002
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Analysis of SDS
Binodenoson Adenosine SDS = 9 SDS = 8
Stress
Rest
Difference between studies =
SDSbino – SDSadeno = 1 SDS unit
Stress
Rest
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Primary Efficacy Endpoint Hypothesis
Mean paired difference between SDS (extent/severity of ischemia) of binodenoson images and adenosine images is within 1.5 SDS units in either direction,
and Fewer than 10% pts with highly
discordant results (severe ischemia on one, no ischemia on alternate image)
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Primary Endpoint Analysis of SDS Difference
-3 -2 -1 0 1 2 3
Mean SDS Difference Bino - Adeno
Hypothesis: 95% CI of mean SDS Bino – Adeno difference is within +/- 1.5 SDS units
VISION 302
VISION 305
-1.5 1.5SDS units
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Data Analysis and Results
Efficacy: SPECT image concordance
• Methodology
• Results
Side effects
• Methodology
• Results
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Assessment of Side Effects: Methodology
When side effects occurred, pts were asked to rate severity on a 1 – 10 point VAS scale
At follow-up, while still blinded, pts were asked which study they preferred
Order of analysis of individual side effects was pre-specified for sequential testing, to account for multiplicity
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Frequency (%) of Pre-Specified Side Effects
2-3o AVB
Flushing
Chest Pain
Dyspnea
Nausea
Headache
Abdm Discmft
Dizziness
BinoBino
N=402N=402
0*
32*
38*
42*
18
43
25
19
AdenoAdeno
N=404N=404
3%
50
61
51
22
35
28
17
BinoBino
N=419N=419
0*
38*
38*
45*
16*
47
34
19
AdenoAdeno
N=421N=421
1%
58
61
54
22
42
28
19
VISION 305VISION 302
*p<0.05 in sequential testing
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Patient-Rated Intensity of Side Effects: 1-10 Visual Analog Scale
Flushing
Chest Pain
Dyspnea
Nausea
Headache
Abdm Discmft
Dizziness
BinoBino
N=402N=402
1.4*
1.7*
2.0*
0.8
1.9
0.9
0.7
AdenoAdeno
N=404N=404
2.8
3.6
2.9
1.1
1.8
1.3
0.8
BinoBino
N=419N=419
1.4*
1.5*
2.0*
0.7*
2.0
1.4
0.7
AdenoAdeno
N=421N=421
2.8
3.3
2.9
1.2
2.0
1.4
0.9
VISION 305VISION 302
*p<0.05 in sequential testing
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Blinded Patient Responses to“Which Treatment Did You Prefer?”
71%71%
20%20%
9%9%0
10
20
30
40
50
60
70
80
Bino Adeno No Pref
Per
cen
t
68%68%
21%21%
11%11%
P=0.001P=0.004
VISION 302 VISION 305
Bino Adeno No Pref
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Summary
Efficacy In both trials, the extent and
severity of SPECT MPI reversible perfusion defects (ischemia) were similar with binodenoson as with adenosine
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Summary
Side effects The incidence and intensity of
flushing, chest pain and dyspnea were significantly reduced with binodenoson
Patients preferred binodenoson in a blinded analysis
AV block was not observed with binodenoson
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Conclusions
Selective adenosine A2a receptor stimulation with binodenoson for pharmacologic stress MPI:• Can be performed safely with 30 sec
bolus dosing• Provides similar clinical information
on the extent/severity of ischemia as adenosine• Is associated with a significant
reduction in the incidence and intensity of many side effects