MRFIT Study – What did it tell us?

The Australian Broadcaster ABC televised the program Heart of the Matter Part 1 – Dietary Villains on Thursday, 24 October 2013. This program listed the MRFIT study as more evidence that cholesterol is not implicated in heart disease.

The Multiple Risk Factor Intervention Trial (MRFIT) was a coronary heart disease prevention trial that was conducted at 22 US clinical centres (18 cities) from 1973 to 1982. The multiple risks evaluated were:

  • elevated serum cholesterol
  • elevated blood pressure
  • cigarette smoking
A number of popular commentators use this trial as proof that cholesterol is not implicated in heart disease.

The tobacco industry also used the results of the MRFIT study to argue that smoking is not harmful.

MRFIT Results

12,866 men between the ages of 35-57 with one or more of these risk factors were randomly assigned to the Special Intervention (SI) or Usual Care (UC) group and followed for 6-8 years.

UC men were given information on risk factors, referred to their usual sources of care, and re-examined annually.

SI participants received group and individual counselling on a fat-modified diet, a stepped-care drug treatment program for diastolic hypertension (after an initial attempt at blood pressure control by weight reduction, if indicated), and, for cigarette smokers, counselling aimed at cessation. 1

In Special Intervention group, serum cholesterol was only 3– 2% lower than in Usual Care group. There was a 30% reduction of smokers in the Special Intervention group. CHD deaths were 7% lower in Special Intervention group.

So the results are not spectacular.

Note that the Usual Care group was not a No Treatment group. They were making changes that resulted in lowering their risk factors. CHD mortality was declining in the USA, Canada and Australia but not in the United Kingdom.

Initially, the drug hydrochlorothiazide was used in the trial to lower blood pressure. However, this drug:

  • raises cholesterol 2
  • causes left ventricular hypertrophy 3
  • increases mortality 4

The use of this drug did distort results.

The results after 16 years are more impressive. After 16 years, those who had been in the intervention group, CHD deaths were 11.4% lower and total mortality was 5.7% lower than the Usual Care group

Serum Cholesterol and Risk of Premature Death

There were 356 222 men aged 35 to 57 years, who were free of a history of hospitalization for myocardial infarction, that were initially screened by the MRFIT program in its recruitment program.

This provided researchers with a group that had standardised serum cholesterol measurements and long-term (6 years) mortality follow-up. 5

For the entire group aged 35 to 57 years at entry, the age-adjusted risks of CHD death in cholesterol quintiles are shown below.

QuintileCholesterol
(mg/dL)
Cholesterol
(mmol/L)
Age-Adjusted
Risk
1< 182< 4.711
2182-2024.71-5.221.29
3203-2205.23-5.701.73
4221-2445.71-6.312.21
5> 244> 6.313.42

The conclusion from this paper is that:

These data of high precision show that the relationship between serum cholesterol and CHD is not a threshold one, with increased risk confined to the two highest quintiles, but rather is a continuously graded one that powerfully affects risk for the great majority of middle-aged American men.
For these men that were initially screen for the MRFIT cohort and without a history of myocardial infarction, low risk was defined as:

  • optimal level of serum cholesterol
  • optimal systolic and diastolic blood pressure
  • non-smoking
  • no history of treatment for diabetes.

Only 2% of the men in the MRFIT cohort met these criteria. Only 6 of these men died from CHD during the 6-year follow-up, and the CHD death rate was 87% lower than for the rest of the cohort. 6

Significance of Dietary Fats

Results from the MRFIT were used to determine the effects of polyunsaturated fat acids on coronary heart disease. 7

  • No significant associations with mortality were detected for linolenic acid, the predominant dietary omega-6 fatty acid.
  • Significant inverse associations observed for omega-3 fatty acids on mortality from coronary heart disease, all cardiovascular diseases and all cause mortality
  • Omega-3 to omega-6 ratio was also significant for cancer mortality.

WHO Trial in Belgium, Italy, Poland and UK

Another study was the WHO Collaborative Trial of Multifactorial Prevention of CHD which involved over 60,000 middle aged men in a total of 80 factories in Belgium, Italy, Poland and the UK 8. The interventions were:

  • cholesterol-lowering diet
  • advice to stop smoking
  • reduce overweight
  • treat raised blood pressure
  • take regular exercise
Belgium had the greatest reduction in the risk factors with corresponding reductions in outcomes in the intervention group for:
  • total mortality -17.5%
  • coronary mortality – 20%
  • CHD incidence – 24.5%

Footnotes

  1. Kjelsberg, M. O. et al. (1997) Brief description of the Multiple Risk Factor Intervention Trial. American Journal of Clinical Nutrition. 65191S–5S.
  2. van Brummelen, P. et al. (1979) Influence of hydrochlorothiazide on the plasma levels of triglycerides, total cholesterol and HDL-cholesterol in patients with essential hypertension. Current Medical Research and Opinion. 6 (1), 24–29.
  3. Ernst, M. E. et al. (2011) Long-term effects of chlorthalidone versus hydrochlorothiazide on electrocardiographic left ventricular hypertrophy in the Multiple Risk Factor Intervention Trial. Hypertension. 58 (6), 1001–1007.
  4. Multiple Risk Factor Intervention Trial Research Group (1982) Multiple Risk Factor Intervention Trial: risk factor changes and mortality results. Journal of American Medical Association. 2481465–1477.
  5. Stamler, J. et al. (2008) The Multiple Risk Factor Intervention Trial (MRFIT)—Importance Then and Now. Journal of American Medical Association. 300 (11), 1343–1345.
  6. Stamler, J. et al. (2008) The Multiple Risk Factor Intervention Trial (MRFIT)—Importance Then and Now. Journal of American Medical Association. 300 (11), 1343–1345.
  7. Dolecek, T. A. (1992) Epidemiological Evidence of Relationships between Dietary Polyunsaturated Fatty Acids and Mortality in the Multiple Risk Factor Intervention Trial. Experimental Biology and Medicine. 200 (2), 177–182.
  8. Truswell, A. S. (2010) Cholesterol and Beyond: The Research on Diet and Coronary Heart Disease 1900-2000. Springer Netherlands.

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