Author + information
- aEmory University School of Medicine, Atlanta, Georgia
- bIcahn School of Medicine at Mount Sinai, New York, New York
- cUniversity of Minnesota/VA Medical Center, Minneapolis, Minnesota
- ↵∗Address for correspondence:
Dr. Y. Chandrashekhar, Division of Cardiology, University of Minnesota/VA Medical Center, Cardiology (111C), 1 Veterans Drive, Minneapolis, Minnesota 55417.
Detecting unrecognized coronary artery disease (CAD) and estimating its risk of adverse events is a major responsibility for clinicians, and differentiating asymptomatic subjects at risk for atherosclerosis from those not at risk accounts for a significant part of their work load. This is often done from a risk factor–based perspective (multiple risk factors incorporated into risk equations or calculators such as the pooled cohort equation or Framingham risk score), because detecting CAD itself is difficult, and the importance of CAD is predicated on its probability of causing adverse events. It is now abundantly clear that coronary artery calcification (CAC) can both reliably detect the presence of asymptomatic atherosclerosis and predict risk for future events, and it does this far better than any other combination of risk factors available. It remains doubtful that there is any other area in cardiovascular imaging in which the clinical evidence is sufficiently robust as it is for CAC. Nevertheless, CAC has not found acceptance in major guidelines. In this special issue of iJACC, we bring together and highlight additional data for CAC, including long-term prognosis associated with low risk scores, the varying relationship between calcified plaque density and cardiovascular events, and the cost implications of asymptomatic screening and targeted preventive treatment. This special issue is emblematic of the state of the evidence that has been amassed on CAC scanning over the past several decades and is testimony to the many researchers who have worked in this field.
CAC scanning meets many of the criteria we are looking for in a contemporary imaging procedure. It is repeatable across equipment vendors, it is easy to measure, it encapsulates tremendous information on cardiovascular risk, and, importantly, it is low cost. What more could we want! Moreover, there is more information coming from studies looking at extent of vessel involvement, plaque density, lesion size and number, and plaque location that could further refine and improve the effectiveness of risk stratification. We are currently on the cusp of a much more expanded delineation of atherosclerotic plaque that is calcified than what had been previously realized by using the Agatston score alone.
CAC is challenged, however, in that it is a test performed as a screening tool or for risk stratification purposes in asymptomatic patients. This does make for a rather unique and challenging procedure, as our health care system is more focused on testing of symptomatic subjects and does not primarily involve the concept of wellness. Currently, our accepted standard for the evaluation of asymptomatic subjects and guided preventive care includes calculation of a global risk score, such as the pooled cohort equation, despite its being less predictive of outcomes than CAC (1,2). CAC scanning overcomes many of the limitations of the pooled cohort equation in that it improves risk detection in young subjects, women, and subjects of diverse race and ethnicity. CAC also has an additional advantage in that it is both a visualization of CAD (thus allowing targeted secondary prevention) and a predictor of risk (being a marker of the extent of atherosclerotic burden in the coronary arteries), while strategies based on risk factors estimate risk alone, although not as accurately, and guess the presence of CAD.
Despite the abundance of evidence, CAC has not been successful in garnering sufficient support for a class I indication in relevant clinical practice guidelines, nor has it been successful in receiving appropriate high-level recommendations from the U.S. Preventive Services Task Force, for which, a high-level recommendation would be grade A or B, meaning that the service is recommended and the net benefit is at least moderate. An updated task force recommendation for all nontraditional cardiac risk factors is ongoing and should be available in 2018. For this and other technology assessment reviews, there is generally a call for randomized trial evidence demonstrating that the use of CAC saves lives.
Of course, this has been the gold standard for establishing the value of any procedure or strategy in cardiovascular medicine. However, should this standard be written in stone and not be revisited again, even if there are data that randomized trials are not infallible (3) and certain tests might need a more practical and forward-thinking standard that is not dependent on the vagaries of almost infinite funding for very large trials. CAC scanning has several important and unique considerations, including that asymptomatic populations are at decidedly low risk and require very large sample sizes and lengthy follow-up for documentation of meaningful differences in clinical outcomes between a CAC-guided and a non-CAC-guided treatment strategy. The total cost of such a trial could easily exceed $100 million, which is likely not fundable given the limited resources available for clinical research. Such a trial is undoubtedly the standard for the highest quality evidence, but in our current era, it seems more of a luxury that we cannot afford.
Given that funding such a trial is improbable, how do we move the science to the next level? Should we change our standards? One may take a very hardline approach and state unequivocally “no,” but we are then left with current screening approaches that also do not have randomized trial evidence and fail to accurately identify risk in a sizable proportion of screened subjects. So how do we progress to improve on the CAC evidence, especially as it relates to guiding preventive strategies of care? Can we begin to engage the community in alternative forms of evidence? Perhaps by developing clinical trials using intermediate outcomes or even patient-reported outcomes such as their preferences, diagnostic certainty, or compliance with therapeutic management or lifestyle recommendations.
It may be time for the imaging community to set standards or acceptable alternatives and novel pathways for high-quality indications and recommendations without the need for a definitive and albeit expensive randomized trial. There may be opportunities to fund smaller trials but also to integrate assessment of implementation as a core part of the research design. Recent negative trials suggest that the answer is not necessarily to fund a large trial but to create alternative approaches or research designs to demonstrate superiority or risk reduction for an imaging procedure. Thus, this special issue on CAC scanning should also be viewed as a call to action to the community to think strategically and develop novel but acceptable standards to move evidence beyond effective risk stratification. Certainly, the imaging community has decades of experience demonstrating that many imaging modalities can risk-stratify, but there has to be more!
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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