slide1
Download
Skip this Video
Download Presentation
Disclosures

Loading in 2 Seconds...

play fullscreen
1 / 29

Disclosures - PowerPoint PPT Presentation


  • 48 Views
  • Uploaded on

V asodilator I nduced S tress I n C ON cordance with Adenosine Binodenoson Pivotal Clinical Trial Program.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Disclosures' - ron


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

Vasodilator Induced Stress In CONcordance with AdenosineBinodenoson 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 Pixtonfor the VISION 302 and 305 Investigators

disclosures
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
background
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
background con t
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
vision pivotal trial program primary objective
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
secondary objectives
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
study design
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
inclusion exclusion criteria
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
study design vision 302 and 305
Study Design: VISION 302 and 305

VISION 305

adenosine

adenosine

Eligible Patients Randomized to Sequence

1st Scan

“MPI #1”

adenosine

binodenoson

2-7 Days

2-7 Days

2nd Scan

“MPI #2”

binodenoson

adenosine

Identical image protocols, camera, isotope, doses, acquisition times and image time post-dose, time of day, background anti-anginal meds held

double blind double dummy drug administration
Double-Blind, Double-Dummy Drug Administration

adenosine, 140 g/kg/min x 6 min

placebo, 0.047 mL/kg/min x 6 min

placebo

0.06 mL/kg

in 30 secs

RP

or

binodenoson

1.5 g/kg

in 30 secs

-30 sec 0 1 2 3 4 5 6

Time (min)

RP = radiopharmaceutical

demographics
Demographics

VISION 302 VISION 305

n=415 n=427

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%

demographics1
Demographics

VISION 302 VISION 305

n=415 n=427

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%

Target

5%

45%

25%

25%

Actual

6%

45%

24%

26%

Target

5%

45%

10%

40%

Actual

5%

44%

10%

41%

Low LK

Intermed LK

High LK

Known CAD

data analysis and results
Data Analysis and Results
  • Efficacy: SPECT image concordance
    • Methodology
    • Results
  • Side effects
    • Methodology
    • Results
methods spect image reviews
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
methods segmental scoring of mpi
Methods: Segmental Scoring of MPI

Each segment at stress/rest from 0=NL, to 4=severe defect

Derived global scores:

SSS: sum of stress scores = total abn myocardium at stress

SRS: sum of rest scores = extent of infarct

SDS = SSS - SRS = extent/severity of ischemia

Circulation 2002

analysis of sds
Analysis of SDS

Stress

Stress

Rest

Rest

Binodenoson Adenosine

SDS = 9 SDS = 8

Difference between studies =

SDSbino – SDSadeno = 1 SDS unit

primary efficacy endpoint hypothesis
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)
paired difference vision 302 binodenoson adenosine sds
Paired Difference VISION 302Binodenoson-Adenosine SDS

Mean SDS difference = -0.09

140

N=374

120

100

80

Number of patients

60

40

20

0

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10

12

SDS Difference Bino - Adeno

paired difference vision 305 binodenoson adenosine sds
Paired Difference VISION 305Binodenoson-Adenosine SDS

160

140

120

100

80

60

40

20

Mean SDS difference = -0.68

N=391

Number of patients

0

-16

-14

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10

12

14

16

SDS Difference Bino - Adeno

primary endpoint analysis of sds difference
Primary Endpoint Analysis of SDS Difference

VISION 302

VISION 305

-1.5

1.5

Hypothesis: 95% CI of mean SDS Bino – Adeno difference

is within +/- 1.5 SDS units

Mean SDS

Difference

Bino - Adeno

-3 -2 -1 0 1 2 3

SDS units

slide21

197

38

14

6

38

13

7

2

9

8

9

5

5

7

6

10

Binodenoson vs. Adenosine AgreementPer-Patient Basis, Reader-Defined SDS VISION 302

Adenosine

Binodenoson

Normal(SDS: 0-1)

Mild(SDS: 2-4)

Moderate(SDS: 5-8)

Severe(SDS: >8)

Normal (SDS: 0-1)

Mild(SDS: 2-4)

Moderate(SDS: 5-8)

Severe(SDS: >8)

Patients in Extreme Off-Diagonal Cells: 11/374 (3%)

Exact categoricalagreement: 229/374 (61%)

data analysis and results1
Data Analysis and Results
  • Efficacy: SPECT image concordance
    • Methodology
    • Results
  • Side effects
    • Methodology
    • Results
assessment of side effects methodology
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
frequency of pre specified side effects
Frequency (%) of Pre-Specified Side Effects

VISION 302

VISION 305

Bino

N=402

0*

32*

38*

42*

18

43

25

19

Adeno

N=404

3%

50

61

51

22

35

28

17

Bino

N=419

0*

38*

38*

45*

16*

47

34

19

Adeno

N=421

1%

58

61

54

22

42

28

19

2-3o AVB

Flushing

Chest Pain

Dyspnea

Nausea

Headache

Abdm Discmft

Dizziness

*p<0.05 in sequential testing

patient rated intensity of side effects 1 10 visual analog scale
Patient-Rated Intensity of Side Effects: 1-10 Visual Analog Scale

VISION 302

VISION 305

Bino

N=402

1.4*

1.7*

2.0*

0.8

1.9

0.9

0.7

Adeno

N=404

2.8

3.6

2.9

1.1

1.8

1.3

0.8

Bino

N=419

1.4*

1.5*

2.0*

0.7*

2.0

1.4

0.7

Adeno

N=421

2.8

3.3

2.9

1.2

2.0

1.4

0.9

Flushing

Chest Pain

Dyspnea

Nausea

Headache

Abdm Discmft

Dizziness

*p<0.05 in sequential testing

blinded patient responses to which treatment did you prefer
Blinded Patient Responses to“Which Treatment Did You Prefer?”

VISION 302

VISION 305

80

71%

70

68%

60

P=0.004

P=0.001

50

Percent

40

30

20

21%

20%

10

11%

9%

0

Adeno

No Pref

Bino

Adeno

No Pref

Bino

summary
Summary

Efficacy

  • In both trials, the extent and severity of SPECT MPI reversible perfusion defects (ischemia) were similar with binodenoson as with adenosine
summary1
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
conclusions
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
ad