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NHLBI/AATS Symposium and Workshop on Cardiothoracic Surgery - Exploring Collaborative Clinical Research: Opportunities and Gaps
The National Heart, Lung, Blood Institute (NHLBI) and the American Association for Thoracic Surgery (AATS) hosted a symposium on April 26 and workshop which followed on April 27, 2011, in Bethesda, Maryland, to identify major research opportunities and gaps in collaborative clinical research for cardiothoracic surgery. In attendance were cardiac surgeons, cardiologists, academicians, clinical trialists, and representatives from government and industry. The symposium consisted of 24 invited presentations where key research opportunities and gaps were articulated, discussed, and expanded upon in the topic areas of:
- Structural Valve Disease,
- Ischemic Heart Disease,
- Therapies for Advanced Heart Failure,
- Operative Strategies,
- Aortic Disease/Management,
- Arrhythmias, and
- Aging Populations and Co-morbidities.
The workshop participants included symposium speakers, NHLBI staff and FDA guests. Following presentations by the FDA and Cardiothoracic Surgical Trials Network, major opportunities and gaps that were identified in the preceding symposium were further discussed and organized into the broad categories of technology development and application; new treatments and operative strategies; and randomized clinical trials and comparative effectiveness research. Recommendations from the workshop participants to address these opportunities and gaps will serve to inform the NHLBI on new research directions and priorities in cardiothoracic surgery. Symposium and workshop materials are available at http://aats.org/CME/NHLBI.
The 2010 AATS Survey of Topics in Cardiothoracic Surgery Research helped to define the 7 topic areas of the symposium. Invited presenters were asked to identify their perception of the most significant research opportunities and gaps, and a summary of the symposium deliberations is presented below.
- Structural Valve Disease
Presenter ideas and public discussion included: mechanisms to track the occurrences, treatments and outcomes of aortic valve disease; benefits of a national registry to link Society of Thoracic Surgeon (STS) registry and administration databases, as well as an extension to European databases; surgical blueprints that fuse 3D imaging and computational models to guide valve repair; as well as challenges for creating durable tissue engineered valves and valves using autologous tissue on biologic scaffolds. There was also broad consensus for a need to follow-up patients for 10+ years in surgical trials.
- Ischemic Heart Disease
The major themes from this session included: strategies to revitalize/regenerate aging or dysfunctional cardiac tissue, including the use of stem cells, particularly in patients with comorbidities; clinical trial opportunities involving revascularization approaches such as hybrid coronary revascularization, CABG and percutaneous coronary intervention; and the concept of the emerging “Heart Team,” which has the potential to change the paradigm of how cardiac patients are managed through a integrated clinical approach.
- Therapies for Advanced Heart Failure
Discussion included: engineering challenges for the next generation of VADs; the issue of partial vs. complete circulatory support; ;the need to understand the mechanisms associated with cardiac remodeling (positive and negative) when functional MR is treated; better understanding of RV function and failure; and the physiologic differences observed from pulsatile and continuous flow devices. Also discussed was how to use mechanistic investigations to optimize the timing and effectiveness of cell-based therapies to repair and regenerate damaged portions of the heart and enhance multidisciplinary collaborations to address research challenges.
- Operative Strategies
Opportunities and gaps discussed included: the need for mechanistic understanding of neuro-, cardio-, and renal injury and protection from ischemia and reperfusion injury; identification and testing of potential protective agents and approaches including conditioning; and intraoperative monitoring strategies for early identification of injury. There was broad agreement for investigation into markers for pre-operative screening and risk stratification for vulnerability to neurocognitive deficit, especially in aged populations.
- Aortic Disease/Management
Areas identified included prediction modeling for aneurysm development, growth and rupture, and aortic dissection, which could incorporate advances in plaque imaging, genomics, and new technologies. New strategies should be sought for stroke prevention during aortic manipulations including transcatheter aortic valve implantation. Design and development of ascending aortic stent-grafts are needed to improve upon current off-label use of aneurysm grafts. Opportunities exist to pool clinical outcomes for aortic aneurysm and dissection with endograft device registry data with a consideration for banking of clinical specimens.
Fundamental areas of investigation were identified including whether surgical treatment of atrial fibrillation (AF) improves outcomes in patients; whether surgical- vs. catheter-based (or combination) treatments are superior; and identification of the key mechanistic determinants of outcome. A proposed approach was to develop diagnostic modalities to uncover patient-specific mechanisms of AF, which could ultimately lead to predictive models to evaluate the efficacy of treatment strategies.
- Aging Populations and Co-morbidities
Common themes throughout the first day were the importance of improving representation of the elderly in clinical trials, improving the applicability of trials to the aged, and to optimize long-term cognitive and functional outcomes of the elderly during and after CT surgery. There continues to be a need for evidence-based clinical evaluation tools to assess operative risk and post-operative recovery in the elderly, from biomarkers of physiologic age to a simple/reliable clinical evaluation scheme to determine frailty as a risk factor for poor surgical outcomes. The prevalence of diabetes in the population motivates clinical trials of insulin sensitizing strategies combined with CABG, and the development of risk scores to identify diabetics who may benefit from early CABG in spite of mild/moderate/no symptoms of myocardial ischemia. Gender differences were also raised relating to the observation that women, like diabetics, typically fare worse in cardiac surgery than men.
To address the challenges identified, the workshop participants identified a series of national needs and priorities for collaborative clinical research in cardiothoracic surgery, which are summarized below:
Technology Development and Application
- Improve the understanding and engineering of de-cellularization / re-cellularization of native valves to produce robust constructs for use in clinical trials
- Develop a network and tissue bank to study myocardial recovery and its enhancement by drugs and/or cells in an LVAD population, and to assess the import of loading conditions on recovery
- Develop predictive models for the onset, evolution and treatment of aortic aneurysms involving multi-modal imaging, genetics, and tissue analysis
- Investigate the pathophysiology of right heart failure and its consequences following LVAD support including identification of risk factors and treatment strategies
- Develop patient-specific, image-based modeling capabilities for guiding CT surgery
- Develop integrative models (including molecular/cellular analysis of tissues) of AF mechanisms to allow design of patient specific therapy
New Treatment and Operative Strategies
- Identify simple, objective clinical evaluation tools and biomarkers to assess frailty and physiologic age
- Explore mechanisms of neurologic injury associated with heart surgery, and develop neuroprotective agents and novel management strategies for high-risk procedures and patient populations. Validate the accuracy and reproducibility of existing modalities for assessing neurological injury and function.
- Identify and test candidate drugs and other therapeutic approaches that mitigate ischemia and reperfusion injury in high-risk patients.
- Determine best approaches to regulate insulin peri-operatively, mitigate surgery-associated injury in diabetic patients and systematically track outcomes in diabetics who undergo heart surgery
Randomized Controlled Trials and Comparative Effectiveness Research
- Continue trials underway and launch next phase of CTSN trials and studies in pipeline, optimizing long-term follow up of surgical patients for clinical outcomes
- RCT of asymptomatic AS comparing surgical AVR vs. optimal medical management
- RCT of Tricuspid annuloplasty vs. no annuloplasty in the context of patients undergoing mitral valve surgery
- Either observational study or trial of peri-operative anticoagulation management in cardiac surgical patients
- Comparative effectiveness trial of surgical- vs. catheter-based (or combination) ablative strategies for AF, and an observational registry of new-onset post-operative AF to inform future investigations
- Focused trial of On-pump vs. Off-pump CABG in high-risk patients
The conferees plan to write a detailed summary of the symposium and complete workshop recommendations for publication in an appropriate peer-reviewed journal. The presentation slides are on the Symposium public site at http://aats.org/CME/NHLBI.
Participating Institute and Organizations
- Division of Cardiovascular Sciences, NHLBI
- American Association for Thoracic Surgery
- Eugene Braunwald, Professor, Cardiovascular Medicine, Harvard Medical School
- Andrew Wechsler, Professor, Cardiothoracic Surgery, Drexel University
Invited Speakers & Workshop Participants (http://aats.org/CME/NHLBI)
- Catherine Burke, MA
- Patrice Desvigne-Nickens, MD
- Albert Lee, PhD
- Ashley Lewis
- Marissa Miller, DVM, MPH
- Lisa Schwartz-Longacre, PhD
- Monica Shah, MD
- George Sopko, MD, MPH
Last Updated July 2011