Tobacco Documents Online

Re: Multiple Risk Factor Intervention Trial The results of the ten-year, $115 million Multiple Risk Factor Intervention Trial, known as MRFIT, were reported in the September 24, 1982 issue of the Journal of the American Medical Association.1 MRFIT was designed to test the hypothesis that reductions in cigarette smoking, high blood pressure and elevated serum cholesterol reduce the risk of dying from coronary heart disease (CHD). However, the trial failed to confirm this hypothesis. In the words of an editorial accompanying the report: "Unfortunately, the fundamental question facing the investigators at the beginning of the experiment remains unanswered."2 As discussed in Science: "Briefly, the results are inconclusive."3 An editorial in the British Medical Journal described the project as ending "with inconclusive results -- and leaving many questions unanswered.''4 Similarly, another major British medical publica- tion, The Lancet, editorialized that the MRFIT results "prove nothing."5 In short, MRFIT failed to show that reducing levels of smoking, cholesterol and blood pressure, reduces risk of death due to heart disease. The study involved over 12,000 men who were believed to be athigh risk for heart disease on the basis of their smoking histories, and blood pressure and serum cholesterol levels. TIMN 0019376

Measurements of these variables were made on three screening visits, after which the men were randomly assigned to one of two groups. Half of the men were assigned to a "special intervention" (SI) group and received intensive counseling to change smoking and dietary habits and were treated for high blood pressure. The other men were assigned to a "usual care" (UC) group, were told of their risk status and received annual medical assessments at MRFIT clinics. However, the investigators made no efforts to change their risk factor levels, and instead referred the UC men to their usual sources of health care. During several years of follow-up, men in the SI group showed a substantial reduction in their risk factor levels com- pared to the UC group. The largest changes occurred in cigarette For men who reported smoking at the first screening smoking. visit, the reported quit rates in the SI group were over 70% greater than in the UC group. However, the difference in the reported smoking quit rates was even larger when based on smoking "at baseline," defined by the investigators as the average reported smoking rates at the second and third screening visits. In this case, the SI group showed quit rates over 100% greater than the UC group. In fact, the investigators stated that the SI-UC difference in reported smoking "exceeded design goals by 122%." Compared to the UC group, men in tie SI group also showed reductions in blood pressure and serum cholesterol. TIMN 0019377

However, these reductions were more modest, and generally did not meet the expectations of the investigators. Despite this, MRFIT investigators noted that the .overall differences between the two groups were substantial. In fact, they computed that they had achieved "83% of the SI-UC risk factor difference initially assumed in the design." During the seven year follow-up period, men in the SI group sh~wed a CHD mortality rate of 17.9 deaths per 1,000 com- pared to 19 3 per 1 000 in t~e UC group, a small and "statis- tically nonsignificant difference." These results do not support the hypothesis that the risk factors studied in MRFIT, especially cigarette smoking, are causally related to coronary heart disease mortality. Thus, even though the study was successful in reducing risk factor levels, the investigators were forced to conclude that "the overall results do not show a beneficial effect on CHD or total mortality from this multifactor intervention." Despite reporting this lack of effect, MRFIT researchers did not discount the value of risk factor intervention in reducing CHD mortality. They justified their continued belief in the benefits of risk factor intervention by noting that the possi- bility that intervention was ineffective "seems inconsistent with most published scientific data." However, risk factor intervention TIMN 0019378

trials from both Norway6 and England7 have failed to demonstrate statistically significant effects on CHD mortality attributable to smoking reduction. Moreover, if previous data were sufficient to establish whether there are benefits of risk factor reduction, then MRFIT would never have been necessary. Even the authors emphasized that "the trial was of course initiated to test this question." ~So faced with findings that failed to support the ~ ~ intervention hypothesis, the investigators offered various ~~ ~ ~ explanations. They pointed to limitations of the statistical ~.~ ~ tests used in the study. In addition, they noted that the major ~ ~ reductions in risk factor levels and mortality rates in the UC ~. ~ ~ group were une.xpected. Finally, they suggested that there may have been certain subgroups of men in the SI group that were affected unfavorably by the therapeutic treatment for hypertension ~. ~ ~ used in the intervention. In regard to the UC group, the MRFIT researchers reported ~ ~ more than expected reductions in risk factor levels during the study and mortality rates lower than expected. However, it is questionable whether these developments led to the failure to demonstrate an overall beneficial effect of intervention. To illustrate, so long as a substantial difference in risk factor levels between the UC and SI groups was obtained, TIMN 0019379

reductions in risk factor levels in the UC group should not matter, unless it was assumed that such decreases led to decreased mortality for the UC group. Even the authors were hesitant to entertain, seriously this suggestion, since it assumed what MRFIT was designed to prove. On the other hand, they did imply that the lower than expected mortality in the UC group made possible effects of risk factor reductions in the SI group more difficult to observe. It should be noted in this context that expected death rates were calculated using "risk functions" which were based on data from. the well-~own Framingham Heart Study and which attribute major roles to smoking, cholesterol and hypertension in CHD. That the predicted death rates in the UC group based on these functions ~ ~were~ inaccurate seems to call into question the validity of Framingham data. In other words, the failure of MRFIT to demon- strata an effect of intervention may have been because initial assumptions about the relation of risk factors to coronary heart disease were wrong. As noted earlier, MRFIT investigators also focused on possible "unfavorable" effects of intervention on certain sub- groups of men in the SI group. It was suggested that these effects may have offset an overall beneficial effect of interven- tion on mortality. 5 TIMN 0019380

However, due to the complex subject selection pro- cedures, analyses of data from subgroups are not scientifically valid. This was recognized by the authors who noted that "it must be remembered that subgroups defined by the presence or absence of one of the three major risk factors are not otherwise comparable." Editorial comments regarding MRFIT in other scientific and medical journals have also noted that such subgroup analyses shaky" 3 are "statistically and are "worrying features''4 of the trial report. Nevertheless, the MRFIT investigators made extensive ~comparisons using such data. They focused on one particular ~subgroup, namely hypertensive men who had electrocardiographic ~ ;~abnormalities. Such men in the SI group were reported to be at increased risk of death from CHD compared to those in the UC group. However, as noted in an editorial in the British Medical "~Journal, "it seems unlikely that the small numbers with such an adverse response, less than a tenth of the total study, could ,,4 ~.;~ have diluted any important positive overall effect. Putting aside questions of validity, the various reasons offered by the MRFIT investigators to explain away their findings are peripheral to the central purpose and results of MRFIT. Thus, they serve merely to divert attention from the study's overall failure to observe a favorable effect of risk factor reduction on mortality. In general, therefore, the MRFIT investigators have TIMN 0019381

apparently refused to believe their own findings. They justify this disbelief through the use of assumptions which the trial was designed to test and by using admittedly invalid reanalyses of their data. Nevertheless, an objective view of the study shows that it was highly successful in meeting its projected intervention goals, in that there was a substantial difference in risk factor levels between the SI and UC groups. Yet, it failed to demonstrate a favorable effect of such intervention on CHD mortality. Shook, Hardy & Bacon December, 1982 TIMN 0019382

References i. Multiple Risk Factor Intervention Trial Research Group, "Multiple Risk Factor Intervention Trial: Risk Factor Changes and Mortality Results," JAMA 248(12): 1465-1477, September 24, 1982. 2. Lundberg, G., "MRFIT and the Goals of The Journal," JAMA 248(12): 1501, September 24, 1982. 3. Kolata, G., "Heart Study Produces a Surprise Result," Science 218: 31-32, October i, 1982. 4. Oliver, M., "Does Control of Risk Factors Prevent Coronary Heart Disease?," Br Med J II: 1065-1066, October 16, 1982. 5. Editorial, "Trials of Coronary Heart Disease Prevention," Lancet II: 803-804, October 9, 1982. 6. Bjermann, I., et al., "Effect of Diet and Smoking Intervention on the Incidence of Coronary Heart Disease: Report from the Oslo Study Group of a Randomised Trial in Healthy Men," Lancet II: 1303-1310, December 12, 1981. 7. Rose, G., et al., "A Randomised Controlled Trial of Anti- Smoking Advice: 10-Year Results," J Epidemiol Community Health 36: 102-108, 1982. 8 TIMN 0019383