1. AATS Grant Writing Workshop Developing a Clinical Research Program, Trial Design, Patient Enrollment Timothy J. Gardner MD Christiana Care Health System Wilmington Delaware Clinical Professor of Surgery University of Pennsylvania Bethesda March 4, 2011

2. Why should I develop a Clinical Research Program? Importance of research in the triad of excellence as a surgeon (skilled surgeon, effective teacher, thoughtful and productive researcher) Primary importance of our clinical work mandates attention to surgical methods and outcomes Clinical research is achievable by virtually all cardiac and thoracic surgeons Clinical research has become even more relevant in this current environment

7. Traditional progression of clinical research activities Case Reports of small number of patients. Provides anecdotal evidence of efficacy Case Series, usually retrospective reports from a single center: Suggestive evidence Observational Reports, larger number of cases, even from multiple centers, including non-audited Registries: Supportive evidence Prospective studies, open trials performed with standardization: Convincing evidence Randomized Controlled Trials: comparative clinical research: Forms evidence base

8. Limitations to case reports and follow-up studies Retrospective reviews are limited to medical record data Series are usually surgeon- or site-specific Outcome-specific information is usually quite limited, focusing on deaths and major complications There are no “control” patients or groups Treasure, Eur J Cardiothorac Surg 2009; 35:474-78

9. Randomized clinical trials in surgery Goal of any trial is to generate rigorous scientific evidence of safety and efficacy RCTs aim to eliminate selection bias Distribute confounding factors among study groups to mitigate potential biasing influences on interpretation of outcomes

11. Requirements for Developing a Clinical Research Program Motivated surgeon-leader with Division and Department support (dedicated time and initial funding assistance) Dedicated research team with committed research coordinator Supportive and facilitating academic and clinical environment Clinical collaborators (cardiologists, oncologists, biostatisticians, etc.)

12. Usual Questions for Trial Design Clear and relevant hypothesis Primary and secondary endpoints Appropriate patient populations Well defined comparators Power – sample size Statistical design Sites and recruitment expectations

13. Ann Thorac Surg 2007; 83: 1934-9

14. Observational Report Ann Thorac Surg 2008; 86: 1139-46 12,812 patients from 1997 – 2006, 44% OPCAB Propensity matched between CPB- and OP-CABG “OPCAB provides significant mortality & morbidity advantages, especially in women Similar outcomes at 10 years

15. RCT, but small sample size Single surgeon trial 100 patients in each arm Similar outcomes at 30 days and 1 year Reduced costs with OPCAB Adequate for non- inferiority conclusion? JAMA 2004: 291: 1841-49

16. RCT, with Level A evidence 2203 patients, 18 centers, qualified surgeons Composite 30-day and 1-year clinical end points OPCAB patients had worse outcomes including graft patency N Engl J Med 2009; 361: 1827-37

17. Observational data, Registry-based

18. EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 18 Optimal revascularization strategy in patients with three-vessel disease and/or left main disease The 3-year Outcomes of the SYNTAX Trial A. Pieter Kappetein, MD PhD Erasmus Medical Center, Rotterdam, The Netherlands On behalf of the SYNTAX investigators 12 September 2010 Conflicts of Interest: None

19. EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 19 The 3-year SYNTAX results suggest that CABG remains the standard of care for patients with complex disease (intermediate or high SYNTAX Scores); however, PCI may be an acceptable alternative revascularization method to CABG when treating patients with less complex (lower SYNTAX Score) disease. The 3-year MACCE rates for the CABG and PCI registry were 16.4% and 38.0% respectively SYNTAX patients will continue to be followed for 5 years. Summary: II

20. http://www.ctsurgerynet.org/

21. Evaluation of Outcomes Following Mitral Valve Repair/Replacement in Severe Chronic Ischemic Mitral Regurgitation OBJECTIVES: The objective of this study is to evaluate the safety and efficacy of mitral valve repair and mitral valve replacement for patients with severe ischemic mitral regurgitation (MR). Specifically, this study compares mitral valve repair with annuloplasty and a sub-valvular procedure for severe tethering to mitral valve replacement and complete preservation of the sub-valvular apparatus. o The primary aim of this trial is to evaluate the impact of these two surgical approaches on left ventricular remodeling. o 250 subjects; 90% power to detect an absolute difference of 15 ml/m2 in LVESVI based on a 35% (replacement) v. 20% (repair) reduction in LVESVI. o Secondary aims of this trial include assessment of the impact of these two surgical interventions on cardiac performance, mortality, adverse events, quality of life, functional status, severity of MR, and health resource use. Enrollment as of Feb 23, 2011 = 165/250 (66%) 21

22. 22 Note: Mitral valve replacement will include complete preservation of the subvalvar apparatus. The technique of preservation, choice of prosthetic valve, and technique of suture placement will be dependent on the surgeon’s preference. The prosthetic valve will be tested for paravalvular leaks using the left ventricular saline infusion test Note: The annuloplasty ring will be chosen by the surgeon. The ring is sized to the anterior leaflet and intertrigonal distane. A semi-rigid or rigid annuloplasty ring will be used and. If tethering is present, a subvalvar procedure may be performed.

23. Patient enrollment issues Patients are often uncomfortable when there is uncertainty expressed by the surgeon about effectiveness of the proposed treatment Referring physicians may expect their treatment preferences to be honored “Doctor, you do what you think is best” Program marketing may confound the patient enrollment challenges

24. Equipoise – mandatory concept for RCTs, but often lacking among surgeons Uncertainty about comparative merits of 2 different diagnostic or treatment options Ethically, the investigator should have no significant preference For most RCTs, “clinical equipoise” refers to genuine uncertainty within the expert medical community about the treatment options Freedman B, N Engl J Med 1987; 317: 141-5

25. Why should I develop or participate in a Clinical Research Program? Supports and defines academic mission Provides evidence-basis for surgical practice Helps clarify best clinical practices Associated with surgical leadership