The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of multidisciplinary experts in areas of cardiovascular epidemiology, coronary imaging, clinical trials, and clinical practice. After reviewing the state of the evidence for coronary artery imaging in risk assessment, working group members deliberated on considerations for potential designs of clinical trials to address current gaps in knowledge.
A large number of myocardial infarction, stroke, and heart failure events occur in the United States as the result of long term exposure to elevated atherogenic blood lipid levels. Many of these cardiovascular events occur in individuals without pre-existing clinical cardiovascular disease (CVD). Since atherogenic blood lipid levels can be lowered significantly with drugs in most individuals, recent guidelines have based treatment recommendations on identifying individuals with sufficient risk-to-benefit from drug treatment within a 10-year period (see the 2018 AHA/ACC Multisociety Guideline on the Management of Blood Cholesterol and 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease). These guidelines recommend statin treatment for high-risk individuals with 10-year CVD risk ≥20%. They also recommend consideration of, or the initiation of, statin treatment for those at intermediate risk (estimated CVD risk of 7.5% to 19.9%) and select individuals at borderline risk (5-7.5%) after a clinician-patient discussion and in the context of considering additional clinical risk-enhancing factors.
These guidelines have based their CVD risk assessment on the 2013 Pooled Cohort Equation (PCE). The PCE is based on a combination of data from five cohorts and is used to estimate the 10-year primary risk of atherosclerotic CVD among patients without pre-existing clinical CVD who are between 40 and 75 years of age (2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk). However, the guidelines acknowledge that in many cases, assessment of atherosclerotic CVD risk may still be uncertain even after assessment of PCE and consideration of risk-enhancing factors. In these cases, the guideline authors concluded that the use of coronary artery calcium (CAC) is reasonable as a shared-decision making tool to guide risk-based decisions for initiation of statin therapy for those at intermediate or selected borderline risk. Epidemiological research has concluded that CAC screening by non-contrast computed tomography (CT) improves the accuracy of the 2013 PCE and other similar risk assessment tools (Nasir K, et al., JACC 2015;66:1657-68;Valenti et al., Int J Cardiol. 2015 May 6; 187:534-540).
A wide range of CVD guidelines over the last decade have considered the role of CAC in risk assessment and in decision making about the use of statins in the primary prevention of CVD. When comparing the recent aforementioned AHA/ACC guidelines with recommendations from other major professional societies, there is no agreement in the role of CAC screening among these guidelines. This is largely because there is a lack of definitive randomized clinical trial evidence to show that CAC screening is a superior strategy for CVD risk assessment and prevention compared to traditional risk assessment without CAC. Barriers to the conduct of such trials have been the large sample size needed and the lack of consensus that this is a very high priority question. The recent enhancement of the state of the art of pragmatic trials by the NIH Collaboratory and the creation of larger networks and cohorts like PCORNET may make large scale prevention trials more feasible.
Discussions were centered around several areas. Workshop participants reviewed the role of CAC in the current CVD prevention guidelines from United States and selected other countries. Participants gleaned insights from findings from recent observational studies about the associations between CAC and coronary CT angiography and the occurrence of CVD in young, middle-aged and older populations without definite clinical CVD at baseline. There was a discussion of modeling studies that have estimated the cost effectiveness and net benefit of CAC screening in assisting in deciding which patients might have the greatest benefit from statins, and about the impact of the lack of a large outcome study on current prevention guidelines. There were detailed discussions of clinical trials relevant to the workshop objectives including: trials previously proposed, currently being planned, and trials currently underway – including the Risk Or Benefit IN Screening for CArdiovascular Diseases (ROBINSCA) trial, the Coronary Calcium (CorCal) Study, and the Computed Tomography Coronary Angiography for the Prevention of Myocardial Infarction (SCOT-HEART 2) Trial. The workshop concluded by identifying and carefully reviewing future research clinical trial opportunities.
At the conclusion of the workshop, there was general agreement that when planning new large outcomes trial in the United States, several questions should be addressed in order to ensure that the trial will have the largest scientific and public health impact. Any new proposed trial should focus on the most important questions that are not being adequately addressed by any currently ongoing trials, including the three trials mentioned above (ROBINSCA, CorCal Study, and SCOT-HEART 2). Past clinical trials have tended to focus on individuals who were middle-aged and typically at intermediate risk; future trials might consider other age groups in which the utility of pharmacological prevention strategies is less certain. New trials should also carefully consider the use of pragmatic trial design features because of the large samples sizes that will likely be required and to help ensure the cost of obtaining CAC scores can be done very efficiently and at lower cost.
The meeting participants will develop a workshop report, highlighting key points in the discussion and key research opportunities. This report will be submitted for publication in a peer reviewed journal.
Philip Greenland, MD (Workshop Co-chair)
Harry W. Dingman Professor of Cardiology and Professor of Preventive Medicine (Epidemiology), Northwestern Feinberg School of Medicine
Erin D. Michos, MD, MHS (Workshop Co-chair)
Associate Director of Preventive Cardiology and Associate Professor of Medicine, Johns Hopkins School of Medicine and Associate Professor of Epidemiology, Johns Hopkins Bloomberg School of Public Health
Lawrence J. Fine, MD, DrPH
Branch Chief, Clinical Applications and Prevention Branch, Division of Cardiovascular Sciences, NHLBI
Nicole Redmond, MD, PhD, MPH
Physician, Clinical Applications and Prevention Branch, Division of Cardiovascular Sciences, NHLBI
Karen P. Alexander, MD
Professor of Medicine, Duke University School of Medicine
Walter T. Ambrosius, PhD
Professor of Biostatistics and Data Science, Wake Forest School of Medicine
Kirsten Bibbins-Domingo, PhD, MD, MAS
Lee Goldman, MD Endowed Chair in Medicine, Professor and Chair of the Department of Epidemiology and Biostatistics, and Vice Dean for Population Health and Health Equity, University of California-San Francisco (UCSF) School of Medicine
Michael J. Blaha MD, MPH
Associate Professor of Cardiology and Epidemiology and Director, Clinical Research, Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University
Ron Blankstein, MD
Director of Cardiac Computed Tomography, Associate Director, Cardiovascular Imaging Program, Brigham and Women’s Hospital; and Associate Professor of Medicine and Radiology, Harvard Medical School
Stephen P. Fortmann, MD
Distinguished Investigator and Senior Director, Science Programs, Kaiser Permanente Center for Health Research
David C. Goff, MD, PhD
Director, Division of Cardiovascular Sciences, NHLBI
Amit Khera, MD
Director, Preventive Cardiology Program and Dallas Heart Ball Chair in Hypertension and Heart Disease, University of Texas-Southwestern Medical Center
Donald M Lloyd-Jones, MD, ScM
Senior Associate Dean for Clinical and Translational Research
Chair, Department of Preventive Medicine and Eileen M. Foell Professor of Heart Research and Professor of Preventive Medicine (Epidemiology), Medicine (Cardiology) and Pediatrics
David J. Maron, MD
Chief, Stanford Prevention Research Center; and Director, Preventive Cardiology
Clinical Professor of Medicine (Cardiology), Stanford University School of Medicine
James K. Min, MD
Professor of Radiology, Weill Cornell Medical College
Director, Dalio Institute of Cardiovascular Imaging at New York Presbyterian Hospital/Weill-Cornell Medical Center.
J. Brent Muhlestein, MD
Cardiologist, Intermountain Health Care and Professor of Cardiology, University of Utah School of Medicine
Khurram Nasir, MD, MPH
Chief, Division of Cardiovascular Prevention and Wellness, Houston Methodist DeBakey Heart and Vascular Center
Madeline R. Sterling, MD, MPH, MS
Assistant Professor of Medicine, Weill Cornell Medicine
George Thanassoulis, MD, MSc
Director, Preventive and Genomic Cardiology, McGill University Health Center and Assistant Professor of Medicine, McGill University