Meet MRFIT

Who’s he? He, or, rather, it, was the Multiple Risk Factor Intervention Trial, an all too often forgotten landmark study. Although conducted before the age of EBM this trial, its registry and its derivative works are among the most important in all of medicine. So it’s “fitting” that, as we approach the 22nd anniversary of its publication, JAMA ran a commentary and a free link to the original article. In this commentary JAMA reported the 25 year follow up data on the MRFIT cohort. This follow up analysis verified the findings of the original study:

The main finding of our report was that the relationship between serum cholesterol and CHD mortality is continuous, graded, and strong; ie, CHD risk is progressively higher at every cholesterol level from 160 mg/dL and higher levels, with no threshold. This finding prevails with 5-, 10-, 15-, 20-, and 25-year follow-up and for the first, second, third, fourth, and fifth 5-year follow-up periods. These robust results, controlled for age, systolic blood pressure, number of cigarettes smoked per day, diabetes status, race and ethnicity, and study geographic site, prevailed over the 25-year follow-up with only modest attenuation in quantitative strength of relative risk from higher serum cholesterol levels and with increase over time in absolute excess risk from higher serum cholesterol levels as the CHD death rate increased annually.

The commentary points out that MRFIT debunked some myths which, unfortunately, remain popular today. One such myth is that there is a threshold value of serum cholesterol for cardiovascular risk. In the 60’s and 70’s it was 300. Later it was 200 + age, then 200. Today, the idea that lower and lower targets are better is dismissed as “disease mongering.” Yet, as MRFIT makes clear there’s no threshold. Or if there is it’s lower than anything we’ve accomplished in the Western world. The Framingham study showed the same thing. Now those were observational studies, but innumerable diet and drug trials, lowering cholesterol by various means, also showed it.

Another debunked myth, recently resurrected by the Vitorin study (a finding that needs more nuanced understanding) and the pleiotropic effects of statins (yes, they do exist) is that “cholesterol lowering doesn’t matter.”

Why don’t we get it? Because it isn’t that simple and because the people who are leading the popular debate don’t have a clue about the notions of relative risk, absolute risk and population attributable risk. I tried my best to do some debunking last year.

One of the derivative works of MRFIT I mentioned was an analysis of hypertension treatment which demonstrated an increased risk of death in patients treated with thiazides who had electrocardiographic abnormalities. It was probably this concern rather than pharmaceutical company marketing of newer drugs that led to a decline in thiazide prescribing beginning in the 1980’s.