Multiple Risk Factor Intervention Trial (MRFIT)

Background/Questions

When a 1969 blue-ribbon NIH committee quashed the proposed National Diet-Heart Study, its act set in motion a strong movement to test intervention on multiple CVD risk factors simultaneously. The profound implications of the world-wide evidence about risk factors from prospective epidemiological studies created pressure for preventive action. The risk factor paradigm itself provided the rationale: multiple risk factors (MRF) combined are synergistic, that is, more predictive than their summed individual parts; thus, their combined control should be the more efficacious strategy for CVD prevention.

Two agencies took over design and implementation of the MRF strategy, WHO for the European MRFIT in Industry in 1971 and NHLI for the U.S. Multiple Risk Factor Trial (MRFIT) in 1972. But programs begun in ambiguity are likely to end in ambiguity. The NIH design of the U.S. MRFIT was a problem in its definition of high risk by a multivariate score, rather than in well-defined subgroups in which factorial design would produce potentially more information (with a somewhat larger sample size; thus an economic decision was made). Moreover, MRFIT’s direction from the outset was distant and early on was inexperienced in trial operation. The design invested heavily in education for prevention among randomized individuals. In contrast, the WHO MRFIT among randomized industries was minimalist in its institutional intervention tactics.

Results

With the exception of suggestive effects in the Belgian industries study among the WHO groups, the MRF (Multivariate Risk Factor) trials produced reductions in attack rates commensurate with their reductions in risk factors, but with insufficient differences in event rates to attribute the change to interventions. Late follow-up of the U.S. MRFIT cohort appeared to show effectiveness of the intervention. But differences within the trial period would have required for significance the larger numbers recommended by the original MRF investigator team. Neither risk factor changes nor attack rates in MRFIT experimental subjects were as different from the control group’s as predicated in the design.

Conclusions/Discussion

Dubbed a failure, “vultures” spiraled down to pick at the fresh carcass of multi-factor 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 with ischemic ECG findings. And for a while, the multi-factor risk prevention strategy was widely pooh-poohed by those who never bought its theory in the first place.

In the end, in historic perspective, few 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, for whatever reasons, than the design anticipated, thus diluting the treatment differences.

Over the years, great value came out of the MRFIT cohort data and accessory 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 the U.S. 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. This happened in the U.S. and in Europe in the 1970s and ‘80s.

Follow-up

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 in public health strategies for reducing multiple risk factors, along with surveillance of trends in population risk factor levels and CVD attack rates. (HB)