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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 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 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) 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 To demonstrate that SPECT MPI acquired during binodenoson-stress and adenosine-stress detect similar magnitudes of ischemia in the same patients 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 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: • 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 Eligible Patients Randomized to Sequence VISION 305 1st Scan “MPI #1” adenosine 2nd Scan “MPI #2” binodenoson binodenoson adenosine 2-7Days Days 2-7 adenosine 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 placebo 0.06 mL/kg in 30 secs adenosine, 140 g/kg/min x 6 min or binodenoson 1.5 g/kg in 30 secs -30 sec RP = radiopharmaceutical RP placebo, 0.047 mL/kg/min x 6 min 0 1 2 Time (min) 3 4 5 6 Demographics Gender (M / F) Age (Years, SD) BMI (kg/m2, SD) Reason for referral: Chest Pain Prior MI Prior CABG/PCI VISION 302 n=415 37% / 63% 63.3 (12.0) 31.4 (7.0) 94% 4% 9% VISION 305 n=427 46% / 54% 62.9 (11.9) 31.3 (6.5) 97% 7% 15% Demographics Gender (M / F) Age (Years, SD) BMI (kg/m2, SD) Reason for referral: Chest Pain Prior MI Prior CABG/PCI Low LK Intermed LK High LK Known CAD VISION 302 n=415 37% / 63% 63.3 (12.0) 31.4 (7.0) 94% 4% 9% Target 5% 45% 25% 25% Actual 6% 45% 24% 26% VISION 305 n=427 46% / 54% 62.9 (11.9) 31.3 (6.5) 97% 7% 15% Target 5% 45% 10% 40% Actual 5% 44% 10% 41% Data Analysis and Results Efficacy: SPECT image concordance • Methodology • Results Side effects • Methodology • Results 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 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 Stress Stress Rest Rest Binodenoson SDS = 9 Adenosine SDS = 8 Difference between studies = SDSbino – SDSadeno = 1 SDS unit 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) Primary Endpoint Analysis of SDS Difference Hypothesis: 95% CI of mean SDS Bino – Adeno difference is within +/- 1.5 SDS units Mean SDS Difference Bino - Adeno -3 VISION 302 -2 -1 0 1 2 3 VISION 305 -1.5 1.5 SDS units Data Analysis and Results Efficacy: SPECT image concordance • Methodology • Results Side effects • Methodology • Results 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 VISION 302 2-3o AVB Flushing Chest Pain Dyspnea Nausea Headache Abdm Discmft Dizziness *p<0.05 in sequential testing Bino N=402 0* 32* 38* 42* 18 43 25 19 Adeno N=404 3% 50 61 51 22 35 28 17 VISION 305 Bino N=419 0* 38* 38* 45* 16* 47 34 19 Adeno N=421 1% 58 61 54 22 42 28 19 Patient-Rated Intensity of Side Effects: 1-10 Visual Analog Scale VISION 302 Flushing Chest Pain Dyspnea Nausea Headache Abdm Discmft Dizziness *p<0.05 in sequential testing 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 VISION 305 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 Blinded Patient Responses to “Which Treatment Did You Prefer?” VISION 302 VISION 305 80 70 71% Percent 60 68% P=0.004 P=0.001 20% 21% 50 40 30 20 10 0 11% 9% Bino Adeno No Pref Bino Adeno No Pref Summary Efficacy In both trials, the extent and severity of SPECT MPI reversible perfusion defects (ischemia) were similar with binodenoson as with adenosine 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 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