1. Clinical Trial Design for Second Generation TAVI - Academic View
William S. Weintraub, MD
John H. Ammon Chair in Cardiology
Christiana Care Health System
Professor of Medicine
Thomas Jefferson University
Disclosures: Grants or Consulting from Sanofi-Aventis, Merck, Pfizer,
Otsuka, Gilead, Abbott, GSK, Astra-Zeneca, Lilly, BMS, Bayer, Shionogi

2. TAVI Works!
TAVI reduced mortality and repeat hospitalizations compared to medical therapy in PARTNER B cohort
However, stroke, vascular complications and bleeding were increased with TAVI
These results cannot be generalized to other patient groups
RCT comparison to medical therapy no longer possible

3. Usual Questions For the next trial: Primary and secondary endpoints
Appropriate patient populations
Comparator selection
Power – sample size
Statistical design
Sites and recruitment

4. Primary and Secondary Endpoints
All cause mortality seems to be the endpoint for the moment
Comparisons between devices may require different endpoints
Consider hospitalizations for heart failure, syncope, symptoms
Durability
Paravalvular leak
Health status – may need new instruments
Cost-effectiveness should be part of all trials

5. What are the Potentially Appropriate Populations?
Non-surgical candidates
Borderline surgical candidates
Current surgical candidates

6. The Comparator
For patients not appropriate for surgery, historical controls or first generation device
Expanded indications, perhaps standard surgery

7. Power and Sample Size
For similar devices to the current, similar populations, studies compared to historical controls will be relatively small, similar to PARTNERS
Expanded indications will require larger sample sizes

8. Statistical Design
Comparison to historical controls will be simple superiority
Comparison of new devices to current or surgery will most probably be non-inferiority, will require large sample sizes and will be a considerable challenge.

9. Sites and Recruitment
The number of centers performing TAVI is still small
This will increase considerably over the next several years
As the trials become more complex, more sites will be needed to achieve adequate sample size, especially for non-inferiority compared to active control

10. Call for a National Registry
Only a national registry will provide sufficient numbers to fully describe efficacy, safety and cost
A national registry will permit detailed assessment of outcomes in subgroups
This may be an approach for comparative effectiveness studies between different devices, approaches
A registry will permit benchmarking of outcomes
Properly constructed, a registry in an institution permits data collection to be incorporated in workflow

11. Conclusions
It is unusual for a comparison to medical therapy to offer such a straightforward outcome
Comparing new devices may be or become more difficult
Defining the population will be a challenge
A national registry is a high priority