“It Isn’t Always Fun.” – MRFIT, Multiple Risk Factor Intervention Trial
Though all too often irresponsible and self-indulgent myself, I have found it easy to be censorious about others. Malcolm Muggeridge, in The Infernal Grove.
MRFIT became a “defining moment” for the field of cardiovascular disease epidemiology and prevention and for many of us personally. I early became involved in the idea when invited by Gordon Stewart in the spring of 1970 to write a chapter for his series, Trends in Epidemiology. I proposed to deal with the new and attractive concept of a prevention trial that would simultaneously reduce multiple cardiovascular risk factors. Here are the conclusions of that chapter, published in 1971:
A Multifactor Preventive Trial (MPT) marks a trend in cardiovascular epidemiology 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 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 probably provides the best likelihood of demonstrating soon and with greatest efficiency any possibility of a major reduction in the incidence of CHD.
‘Pure’ preventive trials on single risk factors are not possible when the treatment involves health advice in the open population; other changes occur that confound the 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.
My thinking then was conditioned by several critical exposures. The more important was my close involvement with the ideas of master prevention strategists Richard Remington, Jeremiah Stamler, and Henry Taylor, and the submission in 1969 of a grant proposal to NIH on just such a trial, called, incredibly, The National Cooperative Trial on Multifactorial Prevention of First Heart Attacks and Coronary Mortality in Free-living, High-Risk, Middle-Aged American Men; “JUMBO,” for short. Signatories to JUMBO included the ring leaders above, me, and enough other experts to cover all bases (e.g. Benson, Keys, McGandy, Nichaman, Sheffield, McFate Smith, Stare, and Syme).
I had also been influenced in fall, 1968, by our deliberations at the Makarska Conference on Mass Field Trials in Prevention of Coronary Disease, which involved many expert colleagues. There, a major international strategy of preventive studies and trials was outlined (See The Makarska Conference in Volume I of these memoirs). I was also fortunate to participate in November, 1970, in the Report of the WHO Working Group on Multifactor Preventive Trials in Ischemic Heart Disease, in Rome, which also involved a bevy of distinguished clinicians and early preventionists. It provided the strategy for subsequent British, Belgian, and Scandinavian efforts at multiple risk factor trials.
*Insert foto of Makarska Conferees with names (e.g. Chalmers, Epstein, Fox, Glasunov, Greene, Heady, Karvonen, Keys, Morris, Remington, Rose, Stamler, Taylor, Tibblin, and Whyte, among others)
*Insert Photo of Rome WHO Multifactor Trial Expert Group and their names
In further background of this intense activism for a major U.S. multiple-risk-factor trial was the final recommendation, right or wrong, of the so-called Ahrens Committee of the NHLI, which came out in 1969 against a national diet-heart trial on grounds of feasibility and cost. After a long and acrimonious debate, and several years of NIH indecision about a diet-heart prevention effort, both the scientific community and NIH were anxious to move ahead. If diet modification was not to be, they sought urgently to implement an alternative prevention research strategy that would respond to all the strong recommendations, including new and compelling ones from the NHLI Task Force on Atherosclerosis and from a weighty conglomerate called The Joint Commission on Heart Disease Resources.
Cumulative experience at that time indicated that intervention on diet alone, or on any single risk characteristic that involves lifestyle and behavior, would simultaneously and inevitably modify other risk behaviors, thus confounding and rendering “impure” any single-factor trial of causality. Moreover, cost and statistical power considerations (adequate sample size and event rates) pointed to the need for involving the highest risk population available within any reasonable rubric of primary prevention, that is, among those without overt coronary disease. Moreover, in theory, a multifactor approach would have a multiplicative (more than additive) impact over any single-factor therapy, thus giving a greater chance of, and a more efficient approach to achieving a solid conclusion about preventability, whether positive or otherwise.
All these practical and theoretical considerations resulted in proposals that, within an ideal multiple-risk-factor design accounting for elevated individual and combined risk factors, should answer efficiently the major questions about multifactor risk reduction and primary prevention of coronary disease (CHD). With the lagniappe of a factorial design, recommended in JUMBO, suggestive information would also be obtained on the effect of reduction in individual components of risk, specifically diet and cholesterol level, blood pressure level, physical activity, and smoking habit.
But it was not to be.
***
Bethesda on my mind.
By late 1971, still on Sabbatical leave in Geneva, I was in active negotiations with William Zukel at NHLI about joining the staff of the NHLI in Bethesda. At that juncture, the future of The Lab at Minnesota, and my relationship to that future, were uncertain. We discussed my involvement with a new branch of the Institute to implement the extensive NIH plans for preventive studies and trials (that eventually became DECA, the Division of Epidemiology and Clinical Applications). We went so far as to establish that my reserve commission in the U.S. Public Health Service could be activated easily and at a competitive salary level, and we discussed mutual time lines. We also discussed future activities of such a new division, which would include the prompt design and implementation of a multiple-risk-factor intervention trial. These negotiations were carried out quietly but enthusiastically on both sides.
*Insert Bethesda correspondence
A Defining Moment
This was a defining moment, an opportunity for renewal of my professional and my personal life: the fate of the LPH at Minnesota was uncertain, my marriage was failing, and my children were close to completion of high school. In contrast, my status in the community of my peers was strongest. I was involved in European happenings and in WHO and had just been elected chair of our principal professional group, the Council on Epidemiology of the American Heart Association. Choices were clear: to take on a new leadership role, whether at NIH or at Minnesota, or to continue a comfortable, yeoman-like supportive role in a research team at Minnesota or elsewhere; satisfying work but hardly challenging. I felt ready for a major challenge, a “sea change.”
During this prehistory of the MRFIT, I always carried in mind Jerry Stamler as the model of a multicenter trial leader, having worked profitably and joyfully with him in the Coronary Drug Project. I felt that the MRFIT leader should be nothing less. Could I meet the model? At that critical moment, returning from Sabbatical, I was laid low by a painful, chronic, and disabling malady that quite destroyed my ability to respond to the opportunities of a new life. A leading position in Bethesda, or direction of a national trial, were suddenly out of the picture, and for an indefinite time.
Because the NIH need was immediate, Bill Zukel was the first to hear from me about my physical inability to carry out our plan that I move to the Institute. Typically unflappable, Bill asked: “But you’ll be able to chair the MRFIT, won’t you, Henry?”
I replied that such a role was also not possible, but, without thinking, I suggested that I should be able to organize committees and act effectively as an officer or perhaps as vice-chair of the trial. Zukel and I then discussed potential national chairpersons for MRFIT and he moved ahead with the necessary decisions. NHLI statistical staff, entirely in-house, went on to prepare the fateful MRFIT design and requests for proposals (RFP) were promptly issued for a coordinating center and a few core units to pretest the protocol. Minnesota responded successfully to both requests.
Minnesota was aboard. By 1973, MRFIT was underway. But it was much differently configured and directed than JUMBO or the Minnesota Mafia had earlier proposed, or than I had ever envisioned.
MRFIT in Practice
A program begun in ambiguity is likely to end in ambiguity, and the NIH in-house design of that trial was ambiguous to the point of bizarre. Moreover, MRFIT’s direction from the outset was distant, formal, and, if you will, insistently, excessively democratic. Leadership of such a complex project, of 20 centers and multiple disciplines and thousands of subjects, can be democratic to a fault. Mass meetings were called of all delegates to address all issues, eschewing a core working group able early on to make interim decisions and to move things forward with dispatch. The organization seemed often directionless for months between cumbersome, “democratic,” sometimes fractious, steering meetings. Moreover, quality control was only what could be administered rote by a statistical center, when the trial, in fact, needed a skilled and persistent and involved central gadfly. Partnerships among disciplines and experts and teams were not established early, nor were working groups early formed to plan, nor was there, as mentioned, a rapid-response management. As Vice-Chairperson, I had a few pedestrian functions assigned in methodology and in the clinical and electrocardiographic aspects of the study; otherwise I was a classically castrate VP.
Fairly soon, the major disciplines of the study, clinical, methodological, analytical, sociological-behavioral, and interventional were at odds, oft-times at war.
The model I had in mind for such a large and complex project was that of the Coronary Drug Project with Jeremiah Stamler in the chair, a trial-experienced Steering Committee, and the savvy University of Maryland Coordinating Center. Few participants will forget the effective, harmonious, and truly delightful pursuits of that study, with its knowledgeable national leadership working side by side with a strong steering group and an out-going and involved coordinating center. Seeing these happy parts not falling together for MRFIT, I became frustrated and impatient.
In retrospect, I suspect that the tone of my communications became gradually more strident. The result was that I was consulted less and less. Eventually suggestions from my quarter I suspect were heard little at all. From meeting to meeting my position at the oval table was progressively farther from Grand Central. Then, I made a stupid mistake and at the same time became victim of another beyond my control.
Goof — Big Time.
Some are born stupid, some achieve stupidity, and some have stupidity thrust upon them.” Richard Armour in The Natural Science of Stupidity by Paul Tabori
In March, 1974, at the American Heart Association’s Public Affairs meeting on Marco Island, Florida, in the course of another presentation, I dropped the name of the upcoming MRFIT and hadn’t the presence of mind to parry reporters’ aggressive questions about it, resulting in a premature and quite incomplete announcement of the study in the national press. It was unintended, naive, and stupid of me.
A short while later, the headline writer for a medical opinion journal, which had done a series of articles on risk factors for heart attack, labeled me “Mr. Fit” in the publication’s editorial, to my complete surprise and mortification.
Bad.
*INSERT “MRFIT HEADLINE”
Though uncomfortable and embarrassed with the unsought label “Mr. Fit,” I assumed that everyone knew headlines were quite beyond the control of the author of any article. I sent all MRFIT colleagues copies of the journal bearing the offensive headline; the article was otherwise a good summary of our common intervention issues. Several of these colleagues became convinced, thereupon, that I was attempting to acquire the entire national identity of the trial; to be “Mr. Fit” personified. Roy Dawber of Boston, speaking for them, chastised me in a quite tough impersonal letter. No one tried to assess directly the reality. And I called no one to ventilate or seek advice. Embarrassed, chagrined, already marginalized, I offered to resign from the trial leadership.
But before resigning from MRFIT, I composed a letter summarizing what I saw as the major problems in that unhappy trial and sent it to Bob Levy, the Director of NHLBI. He was astounded, apparently having no suspicion that any problem existed in this prevention juggernaut under his jurisdiction. He did not know, for example, that his staff had ignored or rejected the early MRFIT planning groups’ strong advice to modify the Institute’s in-house design to a factorial one, and to boost the study numbers and power to correct major weaknesses we found in the plan. Nor did he know of most of the issues about governance that I described. With grave concern, Dr. Levy called an urgent Bethesda meeting of the trial leadership.
Just at that moment, I blossomed in a florid, weeping reaction to my dermatologist’s massive 5-alpha fluorouracil-treatment of long-term actinic damage to my face and arms. I was a leper, clearly unable to appear in public, travel on a plane, or participate in a national meeting. My critical letter of resignation, followed by my failure to appear and confront those accused, were interpreted as sniping rather than my intent to evoke, with my immolation, serious consideration about the direction of MRFIT.
In the letter I made several positive suggestions for MRFIT: that W. McFate Smith (“Mack”), who was long experienced in clinical trials and who was a fair and diplomatic person, take my vice-chairman’s role, and that Jeremiah Stamler, the most experienced trialist in town, be drafted into active and on-going central aspects of analysis and governance of the MRFIT. For complex reasons, Jerry had till then been very retiring in the MRFIT. In the end, rather than consulting with Stamler and Smith and other colleagues as I should have, I packaged all these concerns into one powder wad of resignation and fired the gun — in the form of my letter to our NHLBI boss, Bob Levy — thus lighting my immolatory blaze.
The Chair organized an effective defense. Soon I resigned and was quite out of the picture in MRFIT nationally, not to return. But in the end, what I felt was most needed for the trial did occur. I consoled myself that the denouement for me had positive consequences for the trial in which I and others had invested so much time and energy: Mack Smith and Jeremiah Stamler were duly appointed and thereafter assumed active roles in core management of the study.
The Chairman, passing me in the hall after the final steering meeting in which these issues were put to rest, hissed, sotto voce, “Good hunting, Henry!”
Hunting was not my intent. I had CDP as a model. I wanted MRFIT to be similarly fruitful. I had been there from its conception and had invested years of activity and thought in the trial. And I very much wanted it to be collegial — to be fun! My credo was already, “If it isn’t fun, it isn’t epidemiology!”
MRFIT was not, and, sadly, would not become, “fun,” until the intervention was over and done. The useful long-term results of MRFIT appeared only years later and were due to the powerful collaboration of Jerry Stamler, a group of enterprising MRFIT investigators, and Jim Neaton with the fine analysis crew who stayed with the project at the Minnesota Coordinating Center. The level of risk factor changes in MRFIT had moved in a favorable direction during the trial period but were not as different from the control groups’ as predicated. Disease rates similarly were not significantly different.
The vultures spiralled down to pick at the carcass.
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 from the bad name given the thiazide diuretics by the MRFIT results among a small high-risk subgroup. For a while, the multi-factor prevention strategy was widely pooh-poohed by those who never bought it in the first place.
In the end, several MRFIT centers had quite positive intervention results in risk-factor lowering. We admired and envied them, but Minnesota and most other centers were not among them. Over the years, great value came out of the cohort and methodological studies and national reports on diet, nutrition, the ECG, and exercise, and from new data on biomarkers and behaviors emanating from the study. A sizable coterie of young medical investigators acquired competence in the operation of randomized clinical trials. And the mortality findings among the 370,000 MRFIT screening recruits put to rest the long controversy over whether blood cholesterol level is smoothly and continuously related throughout its distribution to the heart attack risk among individuals. It is.
But MRFIT, overall, as a trial of multiple-risk-factor reduction, was not the certain winner we had sanguinely hypothesized. And, as we were to find again and again in preventive trials, it is nearly impossible to accelerate lifestyle changes therapeutically, and to detect changes over and above those on-going in the broader community, just at a time when both the people at risk and the community-at-large become increasingly conscious of and highly activated over their health.
It was only after an 11-year follow-up in MRFIT that the attack rates among Special Intervention participants were found to be substantially improved over those of controls on Usual Care. In the minds of the cognoscenti, and over the long run, the darn thing had probably worked. But in the annals of cardiovascular science, MRFIT has gone down as “another large and costly boondoggle of prevention.” Its useful lessons in trial design, methods, interventions, and training were, alone, hardly worth the price tag.
The investigators concluded, finally, that the risk factor trends and attack rates in MRFIT were in a favorable direction, within a study design too weak to reach significance, and occurred during population-wide changes that resulted overall in lower than predicted risk; meanwhile treated hypertensive subgroups had sufficiently bad experience to reduce differences between treated and control groups. Long-term follow-up of the U.S. MRFIT cohort, as well as the Belgian MRFIT cohort in industry, detected lower heart attack rates among the treated groups.
[Not a few MRFIT investigators might disagree with the substance and direction of my evaluation here of the study and its early management. It is admittedly a personal and particular view from an originator of the study, who had great hopes for it and many disappointments over it. I suspect it is common for folks to share the same events and times and yet make quite different interpretations of history. So I look forward to hearing others’ views and perhaps reading others’ memoirs about MRFIT. Perhaps archives of MRFIT deliberations available in Bethesda would provide a more objective picture for the true historian.
At any rate, I felt neither rancor nor shame after leaving MRFIT and, in fact, was delighted to be free of an unhappy burden and to turn energies to home-grown matters of our new department in Minnesota. The MRFIT Chairperson with whom I had so strongly disagreed sent me a kind letter upon the death of my son John in 1980. I subsequently let him know how much I admired greatly his superb biography of Paul Dudley White. Our issues are long closed.]
Sequel
Today the concept of reducing multiple risk factors to prevent heart attack and stroke remains intact, both for the individual and for the public health. This is because of effective single factor trials on elevated blood cholesterol and blood pressure and the overwhelming observational evidence of their combined causal role. Development forges ahead nowadays with preventive practice and public health strategies for reducing risk levels, along with on-going surveillance of population attack rates.
Favorable national trends in health behaviors and multiple risk factor levels were accompanied by a steady and brisk decline in coronary death rates among many industrial nations from the late 1960s until the mid-1990s, at which time the rate of fall diminished. This setback was associated, in turn, with backsliding in some average risk factor levels and a failure of health promotion to reach under-served populations among the poor, youth, the elderly, and women. Strategies are now needed not only at the highest multi-factor risk segment of industrial societies but among whole countries at excess risk, as well as for the prevention of elevated risk factors in the first place — primordial prevention.