October 15, 2014

1. SAFE STEMI for Seniors: a PASSION proof of concept studyPredictable And SuStainable Implementation Of National CardioVascular Registries Thinktank(PASSION CV Registries Thinktank) October 15, 2014

2. Proof of Concept vs. Leap of Faith?

3. NCRI Data Infrastructure • Internal Randomization • Integrated EMR->NCDR->EDC data • EDC data collection for supplemental research data (e.g. study drug admin, efficacy details) • Consistent application of data validation rules • Data output using CDISC SDTM • 21CFR11 Compliant

4. NCRI Workflow

5. Data Standards Harmonization

6. Initial Proof of Concept

7. Initial Proof-of-Concept: TREATT / SAFE-PCI • Randomized open-label trial of women undergoing PCI • Hypothesis: Compared with femoral, the radial approach is: • Superior with respect to bleeding and vascular complications • Non-inferior with respect to procedural failure • Protocol standardized “Best” background medical therapy to minimize bleeding risk and ischemic complications • Bivalirudin • Prasugrel for ACS patients < 75 years old, no prior stroke, body weight > 60 kg; clopidogrel otherwise • GP IIb/IIIa inhibitors at operators’ discretion, intention specified prior to randomization • Arteriotomy management • Patent hemostasis mandated for radial patients • Femoral closure devices allowed at operator discretion

8. SAFE-PCI Study design Female patient undergoing PCI or cardiac cath w/poss. PCI Best background medical therapy Bivalirudin, P2Y12 inhibitors 2b3a at investigator’s discretion N=3000 pts randomized for 1800 PCI pts Patent hemostasis required Vascular closure devices allowed Femoral Radial Primary Efficacy Endpoint (72 hrs or hospital discharge): BARC Types 2, 3, or 5 bleeding or Vascular Complications requiring intervention Primary Feasibility Endpoint: Access site crossover Secondary endpoints: Procedure duration, total radiation dose, total contrast volume, 30-day death/vascular complications/unplanned revascularization

9. NCRI and TREATT / SAFE-PCI • As the first registry-based randomized trial in the US, the SAFE-PCI for Women trial demonstrated a new paradigm for conducting efficient pragmatic clinical trials using a National Cardiovascular Research Infrastructure • 1787 women randomized at 60 US sites • 96.7% of sites enrolled ≥ 1 subject • 70.9% of sites enrolled ≥ 10 subjects • High quality data; Adjudication possible • CFR Part 11 compliant – IND and IDE applications • Faster enrollment, Reduced site workload by ~ 30% • Reduced costs (total budget ~ $5 million)

10. Proof of Concept

11. Study of Access site For Enhancing PCI in STEMI for Seniors(SAFE-STEMI for Seniors) • Next stage in proofs-of-concept • Public health focus: Senior population (both genders, age >= 65 years) • NCDR registry prospectively linked with claims data for long term (1-year) follow up • Randomization with factorial design • radial vs. femoral access • Single IRA only vs. IFR guided multivessel intervention

12. SAFE-STEMI for Seniors • Data to evaluate therapeutic strategy and support two independent IDEs • Hypotheses: • Superior bleeding and clinical outcome (NACE) at 1 year associated with radial vs. femoral vascular access • Superior death, re-MI & refractory angina associated with iFR guided multi-vessel PCI vs. IRA-only • 1 year MACE performance goal for second generation DES

13. SAFE-STEMI for SeniorsStudy Design (n=~1650)

14. Key Challenges • Data Specifications • Atomic definitions • Timing • Qualifiers • Observed vs explicit response • Parallel Workflows • Patient Care • Clinical Research • QI Registry • Systems Interfaces • More interfaces • Validation purpose

15. Opportunity: Reusability

16. Beyond the horizon • Reusable infrastructure may facilitate opportunities for informative registry-based studies and simultaneous evaluation of treatment strategies • Consistent data standards and workflows create downstream efficiencies for future investigations • Integration with EHR initiatives will evaporate the distinction between source documents and CRFs