The risks of risk reduction

If a little is good more is better.  Right?  Not so.  Two recent medical articles imply exactly the opposite.  The first one should be taken with  large grains of salt based on past experience.  It  says that women taking multivitamins were 2.4% more likely to die during the 19 years of the study.  The study was large (about 39,000) and since the age at entry was 62 there were plenty of deaths (about 16,000) over the years of the study, so a bizarre effect involving small numbers is very unlikely.  So the effect is real.   Why should you take this with salt?  Because the study is a naturalistic one.  They just asked if the women were taking vitamins and watched what happened (e.g. I’m assuming that this was an observational study — N. B. I haven’t been able to get my hands on the paper yet, so I may have to eat my words).  We have the horrible example of similar studies leading up to the Heart and Estrogen/Progestin Replacement Study (HERS).

      [ Science vol. 297 pp. 325 – 326 ’02 ] During the planning study for the Women’s Health Initiative, some argued that it was unethical to deny some women the benefit of hormones and give them a placebo.  The reason the HERS study was funded was that Wyeth couldn’t get the FDA to approve hormone replacement therapy as a treatment to prevent cardiovascular disease.  So Wyeth funded HERS to prove their case.

        [ J. Am. Med. Assoc. vol. 280 pp. 605 – 613, 650 – 652 ’98 ] The HERS study is in.  There was no benefit of estrogen + progestin in 2763 women with coronary disease younger than 80 in a 4.1 year followup.  However, only 75% of those assigned to hormone treatment were taking it at the end of 3 years.  The patients weren’t worse, however, the number of venous thrombotic events was significantly higher in the estrogen/progestin group 34 vs. 12.  

        Of interest is that 3 different meta-analyses concluded that estrogen replacement therapy decreases the risk of coronary heart disease by 35 – 50% — these were all meta-analyses of observational studies and not prospective and randomized.

        Actually patients on hormone replacement therapy did WORSE in the first 2 years and had an INCREASED risk of heart disease.

       More work from the Women’s Health Initiative trial in 16,608 women showed increased risk of stroke, dementia, global cognitive decline.  In addition there was no benefit against mild cognitive impairment.  This was published in the 28 May ’03 JAMA.   The present work extends the initial early findings to followup to 5.6 years.  The rate of stroke was 31% higher.  80% were ischemic.   The increased risk was seen in all categories of baseline stroke risk.  40/61 women diagnosed with dementia were in the hormone (prempro) group.  This is in a subgroup of 4,532/16,608 women in the study.  The references are all JAMA vol. 289 pp. 2663 – 2672, 2651 – 2662, 2673 – 2684, 2717 – 2719 ’03.

        So what was the problem.  Why were the results so different from what was expected?   The women taking hormones in the 50 observational studies were (1) thinner (2) better educated (3) concerned enough about their health and vigor to take hormones — it is well known that compliers with mediation — even placebo medication — have a better outcome than noncompliers — believe it or not  (4) smoked less.  


        The second study is much better.  It was prospective, involved large numbers (35,000 men) and was randomized, so that subjects either received extra vitamin E or extra selenium (or both or nothing) in the hopes of preventing prostate cancer.  620 of the men in the extra vitamin E group alone developed prostate cancer as opposed to 529 in those receiving a placebo.   So the extra vitamin E was actually bad.  The numbers are large and unlikely to be a statistical fluke.   
        Oxidants are widely held (or worried about) to cause cancer.  Vitamin E (with its tons of conjugated double bonds) is a free radical scrounger (had to put something in for the chemists), hence an antioxidant.  Here’s a study showing it increased the risk of lung cancer.  It’s old but good.  The last paragraph shows how horribly illogical the practice of medicine and the ‘scientists’ working in clinical medicine were back then. Note that this stuff was published in Science (in the unrefereed Letters section).

       [ New England J. Med. vol. 330 pp. 1029 – 1035 ’94 ] The Alpha-Tocopherol, Beta-Carotene Trial (ATBC trial)  randomized double blind placebo controlled of daily supplementation with alpha-tocopherol (a form of vitamin E), beta carotene or both to see if it reduced the incidence of lung cancer was done in 29000 Finnish male smokers ages 50 – 69 (when most of the damage had been done).  They received either alpha tocopherol 50 mg/day, beta carotene 20 mg/day or both.   There was a high incidence of lung cancer (876/29000) during the 5 – 8 year period of followup.  Alpha tocopherol didn’t decrease the incidence of lung cancer, and there was a higher incidence among the men receiving beta carotene (by 18%).    Alpha tocopherol had no benefit on mortality (although there were more deaths from hemorrhagic stroke among the men receiving the supplement).   Total mortality was 8% higher among the participants on beta carotene (more deaths from lung cancer and ischemic heart disease).  It is unlikely that the dose was too low, since it was much higher than the estimated intake thought to be protective in the uncontrolled dietaryt studies.   The trial organizers were so baffled by the results that they even wondered whether the beta-carotene pills used in the study had become contaminated with some known carcinogen during the manufacturing process.  However, tests have ruled out that possibility.

      Needless to say investigators in other beta carotene clinical trials (the Women’s Health Study, the Carotene and Retinoid Efficacy Trial) are upset.  [ Science vol. 264 pp. 501 – 502 ’94 ]  “In our heart of hearts, we don’t believe [ beta carotene is ] toxic”  says one researcher.  Touching isn’t it.  Such faith in a secular age, particularly where other people’s lives are at stake.  I love it when ecology, natural vitamins and pseudoscience take it in the ear.   

Caveat Reador
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