American Journal of Cardiology
Volume 101, Issue 12 , Pages 1805-1807, 15 June 2008

The Deadly Double Standard (The Saga of Screening for Subclinical Atherosclerosis)

  • Harvey S. Hecht, MD

      Affiliations

    • Corresponding Author InformationCorresponding author: Tel: 212-434-2606; fax: 212-434-2205.

Received 19 January 2008; received in revised form 10 February 2008; accepted 10 February 2008. published online 14 April 2008.

Article Outline

 

Preventive cardiology has been on the verge of a major breakthrough for the past decade, only to be stymied by the application of a double standard that may have resulted in death and disability for hundreds of thousands of patients over this time span. There are 565,000 myocardial infarctions annually as the first symptom of coronary artery disease, and 50% of men and 64% of women who die suddenly of coronary disease have no previous symptoms.1 If the pool of patients at high risk from which 95% of these events emerge could be readily identified and treated, events would be reduced by ≥25% with aggressive statin therapy to reduce low-density lipoprotein (LDL) cholesterol and significantly more by the addition of niacin or fibrates to raise high-density lipoprotein cholesterol.2 Coronary artery calcium (CAC) scanning by computed tomography has provided this capability for ≥15 years, accumulating a massive database unequivocally establishing its superiority to conventional National Cholesterol Education Program and Framingham risk factor guided stratification.3, 4, 5, 6

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Scientific Statements 

The rapidly accumulating database resulted in 2 recent attempts at American College of Cardiology and American Heart Association (AHA) scientific statements to provide guidelines for the appropriate use of CAC assessment. The first was scheduled for publication in 2004 and recommended the assessment of CAC to measure plaque burden in physician-referred patients at intermediate risk to more effectively guide treatment. Several weeks before the scheduled publication in Circulation, the following was published in the Wall Street Journal7: “Heart scans, the popular but controversial tests that link heart-attack risk to an accumulation of calcium in the coronary arteries, are poised to win an endorsement from the American Heart Association, which has long been skeptical of their value. Within the next few weeks, the influential organization is planning to publish a scientific statement that will say the tests can help doctors predict which patients are at risk of future heart attacks and decide how aggressively to treat those in danger. The guidelines are expected to apply specifically to patients at ‘intermediate’ risk of a heart attack based on their cholesterol levels, blood pressure, age and health habits. Though it stops well short of supporting widespread screening, the document—expected to be published in the next few weeks in Circulation: Journal of the American Heart Association—is likely to spark wider use of the exams and, possibly, improved reimbursement by insurers.”

In response, the editor of Circulation canceled publication of the statement and offered the following explanation in a subsequent issue8: “Some would argue that the embargo did not apply here because the AHA's News Media staff had not yet delivered formal embargoed material to the press and because this was an official Scientific Statement of the Association and not an original scientific paper. The editors, however, believe that the spirit of the embargo is of utmost importance in maintaining the scientific integrity of the journal.”

After a further delay of 3 years, and the accrual of additional consistently powerful prognostic data in tens of thousands of patients,3 the next American College of Cardiology and AHA scientific statement was created in 2007 and read, “The Committee judged that it may be reasonable to consider use of CAC measurement in such patients based on available evidence that demonstrates incremental risk prediction information in this selected (intermediate risk) patient group. This conclusion is based on the possibility that such patients might be reclassified to a higher risk status based on high CAC score, and subsequent patient management may be modified.”4 If incremental risk prediction was clearly demonstrated, why was the recommendation only a lukewarm “may be reasonable” rather than a stronger statement appropriate to the extraordinary amount of positive evidence?

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Screening for Heart Attack Prevention and Education and the Texas Legislature 

Concurrently, a group of prominent cardiologists from the nonprofit Association for the Eradication of Heart Attacks published the Screening for Heart Attack Prevention and Education (SHAPE) guidelines, which recommended measuring CAC or carotid intima-media thickness as the initial step for asymptomatic men aged >45 years and women aged >55 years, except for the patients at lowest risk.9 On the basis of this premise, the Texas Legislature introduced a bill mandating insurance coverage of $200 for these tests in patients at intermediate risk.10

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The Reaction 

These events triggered a vociferous response, culminating in a statement from the president of the American College of Cardiology11: “We should not perform mass screening without any scientific data to support its appropriateness. This issue is not about the conservatism of the American College of Cardiology and American Heart Association, it's about the practice of evidence-based medicine. The Association for the Eradication of Heart Attacks is a group of shameless self-promoters who have no scientific basis for their assertions.” More recently, an attorney authored a commentary in JAMA, concluding, “Robust professional debate over the interpretation of ambiguous or limited scientific evidence is preferable to legislative mandates that disrupt the scientific process and foreclose alternative options. Over time, further debate and new evidence may yield optimal screening guidance. In the interim, physicians can weigh the SHAPE guidelines relative to other clinical evidence for treating individual patients. To ensure that the Texas legislation is an isolated event rather than the leading edge of transforming clinical practice guidelines into mandates, the medical community should encourage legislators to proceed with abundant caution.”12 An American College of Cardiology spokesman responded, “The American College of Cardiology, having already expressed its opposition to the SHAPE guidelines, did not expect legislation promoting the guidelines to pass in 2007.”13

Subsequently, critically important data have emerged from the National Institutes of Health–sponsored Multi-Ethnic Study of Atherosclerosis (MESA) that have confirmed, in a prospective, population-based study, the remarkable prognostic power of CAC and its superiority to the Framingham risk score.5, 6

Grundy14 eloquently summarized the concepts that have been validated by the data: “Imaging has at least 3 virtues. It individualizes risk assessment beyond use of age, which is a less reliable surrogate for atherosclerosis burden; it provides an integrated assessment of the lifetime exposure to risk factors; and it identifies individuals who are susceptible to developing atherosclerosis beyond established risk factors. Also of importance, in the absence of detectable atherosclerosis, short-term risk appears to be very low. Thus, for primary prevention, a recommendation could be established that detection of significant plaque burden is a preferred strategy for initiation of LDL-lowering drugs. With such a recommendation, major risk factors and emerging risk factors could be used as a guide for selecting subjects for imaging more than as a primary guide for therapy. Once subclinical atherosclerosis is detected, intensity of drug therapy could be adjusted for plaque burden.”

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Double Standard 

The overriding issue that has been used to delay the implementation of CAC measurement is the lack of studies demonstrating the impact of CAC on outcomes; the prognostic value of CAC is no longer doubted. As Lauer15 wrote in criticism of the SHAPE guidelines, “randomized trials of coronary artery disease screening have not been performed. We simply do not know whether screening prevents premature death or major cardiac events.” He recommended the use of “Global Risk Scores, such as those put out by the Framingham Heart Study or the European Score Group.” The authors of the SHAPE guidelines responded as follows16:

1. The traditional approach that Lauer strongly advocates, which is based on risk factors and the Framingham Risk Score, has also never been shown in randomized controlled trials to improve clinical outcomes.

2. The 2 measures of atherosclerosis that SHAPE proposes be used in risk assessment, the CAC score and the carotid intima media thickness, have been consistently shown to have prognostic power superior to that of the Framingham Risk Score by fulfilling the unequivocal epidemiologic requirement of having a significantly greater area under the receiver operating characteristic (ROC) curve. If neither the CAC score nor the Framingham Risk Score has outcome data to support it, why not use the one with the greater prognostic power?

3. The CAC score and carotid intima media thickness are precise tools that measure subclinical atherosclerosis in much the same way that the universally accepted tools of echocardiography, myocardial perfusion imaging, magnetic resonance imaging, and coronary arteriography provide information in their respective domains. Contrary to what most cardiologists would assume, none of these tests has ever been shown to affect outcomes in the manner called for by Lauer, in whatever area they have been applied. Nonetheless, they are rightly endorsed by all cardiac societies because of the invaluable information they provide. Although these tools have not been proposed for screening, the logic is still the same. In a medical arena in which the most commonly used technologies totally lack evidence that they improve outcomes, why hold screening for subclinical atherosclerosis to a different standard?

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Costs 

In response to this question, in an era of increasing medical imaging costs, the implementation of a test used for screening a large segment of the population must be accompanied by demonstration of cost effectiveness. CAC screening has been subjected to several analyses, the most recent of which showed that CAC screening using the SHAPE guidelines was less cost effective than treating everyone and more cost effective than using National Cholesterol Education Program guidelines, on the basis of a cost of $400 for CAC screening.17 As with mammography, the cost of CAC screening will be much lower when implemented in guidelines (i.e., in the $100 range). With this change, the SHAPE guidelines become the most cost effective modality.

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Randomized Clinical Trials 

Randomized clinical trials are of fundamental importance to the development of sound practice guidelines. Yet they have not been applied to any of the currently used technologies. For instance, there has never been a randomized trial demonstrating that stress testing of any kind improves outcomes in patients with suspected coronary disease compared with decision making without stress testing, and it would be impossible at this point to roll back the clock and demand such trials. Moreover, the need for such a trial would be severely questioned in view of the high risk attributable to patients with abnormal test results.

The same can be said for CAC screening; the identification of high risk in previously unidentified patients will make them eligible for aggressive medical therapy. There is now universal agreement that CAC identifies high-risk patients3, 4, 5, 6 and that aggressive medical therapy reduces risk by ≥25% in the primary and secondary prevention populations.2 A randomized controlled trial, although desirable, should not be necessary to prove that the aggressive treatment of patients at high risk identified by CAC screening will improve outcomes, especially in view of its clearly superior prognostic value compared with the Framingham risk score. Such a trial would require ≥5 years, 10,000 patients, and tens of millions of dollars, and ethical concerns would be raised by withholding treatment from patients with high CAC scores and low Framingham risk scores. All attempts to obtain funding have failed.

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Conclusions 

Thus, there is a double standard that demands randomized controlled trials for CAC screening while ignoring their necessity for every other technology. The death and disability inherent in relying on the Framingham risk score are perpetuated by the double standard, in combination with specific steps taken to either prevent the dissemination of guidelines as they were written by the experts or play down the significance of the data, as well as condemnation of the only state that has had the courage to mandate the best level of prevention for the biggest killer of its residents. It is incumbent on the cardiology community to temper the inflexible need for randomized trials with the reality of 565,000 patients presenting with myocardial infarctions annually as their first symptoms, 95% of whom could be identified as at high risk by CAC screening18, 19 and aggressively treated to significantly reduce events.2

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References 

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PII: S0002-9149(08)00387-1

doi:10.1016/j.amjcard.2008.02.086

American Journal of Cardiology
Volume 101, Issue 12 , Pages 1805-1807, 15 June 2008