University of Minnesota

Report of the Ad Hoc Panel on Atherosclerotic Coronary Artery Disease 1969

Classification and diagnostic criteria for large clinical trials
National Heart Institute, October, 1969

(The institute changed its name to Heart & Lung Institute in December 1969).

In the late ‘60s, after much deliberation, officials at the National Heart Institute rejected expert proposals for a National Diet-Heart Study. If, as many insisted, knowledge was inadequate for authoritative public recommendations about lifestyle and prevention, then the magnitude of the atherosclerosis problem required that the knowledge be sought, namely through the gold standard of clinical trials. In this period I have characterized as “The Pause,” a major conference was called by the Institute to lay grounds for characterizing CVD in future epidemiological studies it was planning, particularly the methodological needs for clinical trials it was under great pressure to mount.

William Zukel, as associate director for clinical applications at the Institute, sponsored the panel, along with a strong staff including Jane Wilcox, acting chief of the cardiac disease branch of the Heart Institute. Campbell Moses was the liaison with American Heart, and participants were Charles Kossman, chairman (cardiologist and head of the department of medicine at the University of Tennessee in Memphis); Henry Blackburn and Robert Reese, Joseph Doyle, Richard Ebert, James Leonard, and Henry McGill.

The Panel, after three meetings and much work between, produced specific guidelines for the classifications and diagnostic criteria to be used in large clinical trials, unspecified, in the planning stage. We proceeded to lay out material on definitions and criteria for manifestations of CHD and their sensitivity, specificity, validity and reliability suitable for trials of primary and secondary prevention, along with specifics of exclusion and inclusion of trial participants (omitted from the report as going beyond its charge).

The resultant vision of this fairly sophisticated panel involving epidemiologists, clinicians, and pathologists was introduced with the following positive view: “In general, the risk factor hypotheses have received additional credence and have become increasingly tenable over the last several years. It now appears rational and prudent to identify and correct these risk factors in an attempt to influence the course of atherosclerotic coronary artery disease. Evidence concerning the efficacy of such intervention is suggestive, but indirect. It is apparent that there is an increasing need for unequivocal answers concerning the effects of intervention; direct and conclusive evidence can only be obtained from well-designed, carefully conducted clinical trials” (Report 1969, pg 1).

The Report indicated that plans for such undertakings were actively underway at the Heart Institute, during a period of active discussion following its 1968 rejection of the idea of a National Diet-Heart Study. It was under considerable pressure from the community to conduct other relevant experimental strategies to evaluate prevention, if diet were not to be tested. It soon became aware of major deficiencies of definition, nomenclature and criteria that needed to be worked out before embarking on large, costly, long-term, multi-centered interventions.

The Ad Hoc Committee, established by the Institute’s Advisory Heart Council, met in February, April and May, 1969 in Bethesda. In our first meeting, and in his final report, Kossman led off with a specialist’s negative and condescending view about epidemiological methods: “The clinical cardiologist will find the epidemiologically oriented criteria and classifications unsatisfactory for bedside use and not adequate in terms of the considerable skill he has acquired to making a precise diagnosis of disease of the coronary arteries. This Report is concerned with the methodologies of studying large populations over long periods of time often by personnel without the training or the advantage of direct patient observation and evaluation possessed by the clinical cardiologist. Under [such] circumstances the criteria for diagnostic must be more rigid, and classifications must be used which are necessarily restrictive in order to ensure the greater possible accuracy in the results and conclusions of an essentially epidemiologic type of study. Indications of atherosclerotic coronary artery disease will be eliminated from a study using these criteria but those accepted will very likely have the disease. To aid in keeping the former [false negatives] at a minimum and the latter, true positives, at a maximum at a large clinical trial involving the use of a primary or secondary intervention is the purpose of this report” (ibid. pg 1).

Kossman had clearly got the message of why and how consistency beat precision in surveys and trials but felt obliged to hold it gingerly by his fingertips and far away from his nose. This set the uncomfortable tone of our deliberations.

After a section on trial principles and the narrowness and precision of the questions being asked In trials, the lesson continued: “The clinical trial connotes a research effort that has immediate social and scientific consequences. Trial participant public participation is a unique feature and, in such circumstances, there is an added responsibility to ensure scientific excellence, precise design, and a high level of performance” (ibid. pg 3).

The Report then deals with details of nomenclature, with death rates, sudden death, and autopsy findings; with characterization of clinical manifestations of myocardial infarction including categories of probable and possible myocardial infarction, angina pectoris, and congestive heart failure. There is reference to WHO definitions, a section on electrocardiography concerned with validity, reliability, general use and limitations, with the positive panel conclusion that, “The ECG is clearly a valid, practical and objective method for measuring the prevalence and incidence of events relevant to coronary artery disease in large trials and population comparisons”(page 15). The panel recommended standard procedures, trained paramedical personnel, and the development of methods for detecting post-exercise electrocardiographic evidence of myocardial ischemia (predictability and significance and hazards), followed by a strong case for tape-recording or direct transmission of trial ECGs to a central computing facility, a crucial go-ahead to government to support computer electrocardiography that we were careful to interject as a base for future expansion of those modalities in mass surveys and trials. (Subsequent NIH-sponsored population studies and trials have incorporated both paper and tape recording, manual and automated analysis in electrocardiography, using standard classifications and central coding.)

The Report indicates that age- and sex-adjusted total death rate is an easier endpoint to measure and its rate reduction a convincing demonstration of efficacy of any intervention on CVD, since total death rate is closely related to the death rate from atherosclerotic coronary artery disease (ibid. pg. 19).

The Report’s Summary characterizes angina pectoris diagnosis as about 80% specific and 80% sensitive for coronary artery disease, when evidence is elicited by a well-trained person. It lays out a guiding chart for a medical history-physical combination with electrocardiographic findings and acute phase reactants (temperature, blood count, sedimentation rate, cardiac enzymes).

Appended statements on the electrocardiogram and clinical classifications advise that the electrocardiogram provides information relevant to coronary artery disease that confirms and adds to the clinical data because it has different and independent errors of classification; a central electrocardiographic facility is essential to quality control procedures and computerized electrocardiograms are feasible. A table of estimates is provided of sensitivity, specificity, validity, and risk ratios using the medical history, the electrocardiogram at rest and after exercise, and their combination, along with an extensive bibliography.

An Appendix contained material showing hard data on the validity, repeatability, sensitivity and specificity of all the methods studied by the hardworking panel. The Report summary by the Chairman inserted his private “asides”: strong on silent infarcts as a useful indicator for myocardial infarction but concluding that physical examination is non-contributory, serum enzyme changes are inconsistent and non-diagnostic, as are the acute phase reactants, and questioning the value of the electrocardiogram, ignoring detail provided by the panel on the validity and repeatability of each. The report closed as it had begun, with a clinician’s disdain for standard methods and procedures as undeserving of a cardiologist’s respect, but grudgingly conceded to be required for large and costly publicly supported events such as clinical trials. (Henry Blackburn)