Multiple Risk Factor Intervention: The Concept and Consequences

When the recommendations of Ed Ahren’s 1969 blue ribbon committee to move ahead with a definitive diet-heart trial were rejected by the NHLI, this act set in motion a strong movement to test intervention on multiple CVD risk factors. The profound implications of the risk factor evidence from prospective epidemiological studies world-wide created intellectual pressure for preventive action; if no diet-heart trial, something else had to be done. The risk factor paradigm itself provided the rationale: multiple risk factors (MRF) combined were synergistic; more predictive than their summed individual parts.

Other events soon burnished the MRF concept, particularly the so-called Jumbo Proposal and the Makarska Conference on Preventive Trials. Two major agencies then took over design and implementation of the MRF strategy, WHO for the European Multiple Risk Factor Intervention Trial (MRFIT) in Industry and NHLBI for the U.S. MRFIT.

The arguments for a MRF trial were outlined in summary form in a 1971 epidemiological thinkpiece (1):

• A Multifactor Preventive Trial (MPT) marks a trend in epidemiological thinking that merits critical attention.
• The MPT concept is highly appropriate to chronic diseases often associated with multiple risk factors.
• The MPT allows tailoring of the treatment to the need, thereby following precepts widely acceptable in clinical medicine.
• The MPT tests the most fundamental and urgent hypothesis, whether primary prevention of coronary disease (CHD), with an associated reduction in total mortality, is indeed possible.
• The MPT provides the best likelihood of demonstrating soon and with greatest efficiency the possibility of a major reduction in CHD incidence.
• ‘Pure’ preventive trials with single risk factors are not feasible when the treatment involves health advice in the open population; other changes occur that confound the causal conclusions.
• MPT design, organization, and execution are more complex than in a single factor trial and require greater staff experience.
• More precise information on the contribution of individual treatments to prevention can be determined by parallel single-factor trials and by multifactor trials using factorial design.
• The knowledge obtained and the conclusions allowed from single-factor and multifactor trials are complementary.

Long and sometimes acrimonious debate, and several years of NIH indecision about the course for a CVD prevention effort, followed the Ahrens Report, with abrupt arrest of definitive research on that central issue of the time: diet, blood lipids, and heart attack. Both the scientific community and NIH central were anxious to move ahead. If a trial of diet modification was not to be, they sought to implement an alternative research strategy, one responding to the many strong recommendations for action from epidemiologists and clinicians. These included new and compelling recommendations from the 1971 NHLI Task Force on Arteriosclerosis and from a weighty North American conglomerate called The Joint Commission on Heart Disease Resources.

All these practical and theoretical considerations converged into proposals that, within an ideal multiple-risk-factor design, it was thought should answer efficiently the major questions about risk reduction and primary prevention of coronary disease.

MRFIT in Practice

Programs begun in ambiguity are likely to end in ambiguity. The NIH design of the U.S. MRFIT was ambiguous to the point of bizarre. Moreover, MRFIT’s direction from the outset was distant, formal, and inexperienced in trials. It invested heavily, however, in education for prevention among randomized individuals. The WHO MRFIT among randomized industries was, on the contrary, minimalist in its institutional intervention tactics. With the exception of suggestive effects in the Belgian industries study, the MRF trials produced reductions in attack rates commensurate with their reductions in risk factors but insufficient differences in events to attribute the change to the interventions.

Long-term follow-up of the U.S. MRFIT appeared to show effectiveness of the intervention overall, but with differences that would have required at least the larger numbers recommended by the investigator team. During the trial period, however, the level of risk factor changes in MRFIT were not as different from the control group’s as predicated. Disease rates similarly were not significantly influenced during the design period.

Dubbed a failure, the vultures spiraled down to pick at the fresh carcass of CVD prevention. The dairy, beef, and egg industries and their advertisers soon made much copy on MRFIT’s purportedly negative results. The tobacco industry made nefarious use of them. The hypertension community suffered for decades from the bad name given thiazide diuretics by the MRFIT results among a small vulnerable subgroup. And for a while, the multi-factor risk prevention strategy was widely pooh-poohed by those who never bought it in the first place.

In the end, in historic perspective, several MRFIT centers had positive intervention results in risk-factor lowering. Thus, intervention inadequacy must have occurred in the trial overall. And the control group did much better than anticipated, thus diluting the differences.

Over the years, great value came out of the MRFIT cohort data and methodological studies. National reports emanated on predictive power of diet, nutrients, the ECG and exercise habits, and from new data on biomarkers and behaviors. A sizable coterie of young medical investigators acquired competence in the operation of population surveys and randomized clinical trials. And the mortality findings among the 370,000 MRFIT screening recruits put to rest the long controversy over whether there is a threshold effect or whether blood cholesterol or blood pressure level are smoothly and continuously related to heart attack risk throughout their distributions. They are.

But MRFIT, overall, as a trial of multiple-risk-factor reduction, was not the certain winner it had been sanguinely hypothesized. It proved nearly impossible to accelerate mass lifestyle changes therapeutically, and to detect changes over and above those going on in the broader community, just at a time when both the people at risk and the community-at-large became increasingly conscious of and highly activated over their health, as happened in the U.S. and Europe in the 1970s and ‘80s.

The 16-year follow-up in MRFIT, showing that the attack rates among Special Intervention participants were substantially reduced over those of controls on Usual Care, suggested to the cognoscenti that the trial had probably worked. But in the annals of cardiovascular science, MRFIT has gone down as a “boondoggle of prevention.”

Today, nevertheless, the concept of reducing multiple risk factors to prevent heart attack and stroke persists intact, both for the individual and for the public health. This is because of incontrovertible evidence from single factor trials about the effects of reducing elevated levels of blood cholesterol and blood pressure and from overwhelming observational evidence of their combined causal influence. Developments forge ahead in preventive practice and public health strategies for reducing multiple risk factors, along with surveillance of trends in population risk factor levels and attack rates.

As we will analyze in the segment on “Decline,” favorable national trends in health behaviors and multiple risk-factor levels were accompanied by a steady and brisk decline in coronary and stroke death rates among many industrial nations from the late 1960s until the mid-1990s, at which time the rate of fall appeared to diminish. This apparent setback was associated with backsliding in average risk factor levels and a failure of health promotion to reach under-served populations among the poor, youth, the elderly, and women.

Prevention and health promotion strategies are now being recommended not only for the highest multi-factor risk segment of industrial societies but among whole countries and cultures at excess risk. They are also being addressed at professional and policy levels for the prevention of elevated risk factors in the first place — primordial prevention. (Henry Blackburn)

References

Blackburn, H. Multifactor preventive trials (MPT) in coronary heart disease. Trends in Epidemiology. American Lectures in Epidemiology, Community Health and Tropical Medicine ed. G.T. Stewart and Charles C. Thomas, Springfield, 1972.

Report of the Markarska Conference on Preventive Trials in Coronary Disease. International Society of Cardiology, 1968.