Response to Annals Hysteria

Aside from the recent Times article that once again spread a message of fear and misinformation, three articles were published in the Annals of Internal Medicine that were accompanied by an editorial verging on hysteria that proclaimed in stentorious tones: DON’T TAKE THEM!

Is that a justifiable conclusion? Well, when you look at the studies undertaken, I don’t believe the answer is that clearcut.  However, there also may be evidence here that clarifies who may and may not benefit from a simple micronutrient supplement.  At the end of the article are links to other analyses that rebut the claims made.

Let’s take a little closer look at each of these three negative studies. First, one relatively large study, using a low dose combination of often synthetic vitamin constituents (Centrum Silver) among older individuals (1). Using these modest doses, the upshot of the study, which was otherwise well-controlled and randomized, found no benefit of the use of the supplement in offsetting or mitigating cognitive decline over about 10-14 years. This was part of the large physician’s study and the study was limited by the potential that the doses may have been too low for an otherwise well-nourished population. Is this generalizable to older individuals who are well-nourished?

Perhaps so and taking a Centrum is therefore quite probably a waste of money if maintaining cognitive function is the goal. However, this is the same study that had previously reported that even this simple intervention modestly reduced the risk of cancer. Is that a useful endpoint? And indeed, the authors note that the study may need to be up to 20 years or longer to adequately detect any significant differences.

The third study was a meta-analysis or review of the literature that has pre-specified criteria for the selection of studies to be reviewed and then applies stastical analytic techniques to combine the results into a conclusion (3). They sought to assess the use of multivitamins in the primary prevention of cancer or cardiovascular disease. (Drug studies indeed more commonly look at the use of a drug in preventing a second heart attack, for example: secondary prevention.) Having done these, I know there is a certain degree of judgment in what gets selected and the method used for analysis. In this case, the authors note that the primary limitations are as they note is 1) they only assessed four RCTs and one cohort study that used radically different multivitamin/mineral formulas; one of these was a study that used a multi with only 5 ingredients another only 3 vitamins; 2) these were ONLY among otherwise healthy adults (not secondary prevention studies). The PHS-II study, discussed above, and another the SU.VI.MAX study were the two largest studies. So what can we conclude from this? That the extant data do not robustly support the use of a multi for these indications? Possibly, though they also note that the large PHS-II study that found a benefit for reducing cancer risk also detected a benefit for fatal myocardial infarction (adjusted hazard ratio, 0.61 [95% CI, 0.38 to 0.995]; P < 0.048). It may again be that these interventions are not up to the rather daunting task of achieving the endpoint of primary prevention—such studies probably need to be larger and a lot longer to come up with definitive conclusions.

They also reviewed single and paired studies. They noted that calcium alone is ineffective overall and possibly dangerous as a single supplement, but you throw in vitamin D, and gosh–lower mortality, though just barely (unadjusted RR 0.94, 95%? CI 0.87,1.01). It begins to beggar the imagination however to think these extremely disparate trials can be combined in any meaningful way when the populations, interventions and even primary outcomes were so significantly different.

The third study, however, did assess the effects of chelation therapy, with or without a multivitamin/mineral combination as secondary prevention for a heart attack (myocardial infarction) (3). It was a relatively short study with a median follow-up of 31 months in the vitamin group. The article notes that there was a huge dropout rate. Of the 853 in the vitamin arm and the 855 in the placebo arm, 584 and 547 were lost to follow up, respectively but the analysis was done “intent-to-treat” and all were included in the final analysis. Further, the study was not powered to see a difference with the few that were finally enrolled and completed the study—i.e., the initial proposal was to enroll 2,372 patients. And there was a small difference: while the primary and secondary outcomes did not achieve statistical significance, one can see in the Kaplan-Meier curves that there is a lower rate of events in the multi arm compared to the control by about 11% and that appears to improve as the study progresses: had it lasted longer or been better powered, might this trend have improved over time? We don’t know. The effect is relatively modest but the study wasn’t powered to detect this difference.

It seems to me that the latter study reflects reality and should calm the anxieties about people using supplements expressed by the editors (4). The upshot: Most people don’t want to take vitamins as suggested by the Lamas study. If THAT conclusion is generalizable, they have little to fear—but is that wise public policy?

The other important fact to note was that all the studies showed no evidence of adverse events. For the most part, side effects of the use of supplements are exceedingly rare and generally arise with the use of single agents (e.g., vitamin E or beta-carotene alone). Probably not the wisest way to use interventions designed to work in a biological way or in a system that is severely oxidatively stressed.

I would suggest several caveats. First, this is irrelevant to people living with HIV. Even a fairly simple formula can have a significant impact in slowing disease progression and reducing mortality (modestly) with the use of a multivitamin/mineral. The results of our meta-analysis will, we hope, be published soon. (This of course does NOT mean they are a replacement for antiretroviral therapy! Absolutely not.)

Second, these are SUPPLEMENTS – diet and access to clean water need to be the first consideration and far too many people have limited access to these basics while millions of others are forced to consume what is available on the market, which is often poor quality, processed, loaded with chemicals, preservatives, antibiotics, hormones and potentially dangerously genetically modified.

And finally, supplements are NOT drugs in key ways. They are supporting the body’s ability to fight disease while retaining an optimal level of health, especially when we are discussing the use of vitamins and minerals (as opposed to botanicals). Whether the optimal dosages have been determined, whether the findings are generalizable to everyone, whether there are groups, like people with HIV, for whom they are demonstrably beneficial—these are questions hardly answered to the point of declaring no one should ever use them as these editors have done.

Links:

Harvard rebuts the Annals of Internal Drugs.

http://www.hsph.harvard.edu/nutritionsource/multivitamin/

Linus Pauling Institute of Oregon State University.

http://lpi.oregonstate.edu/news/enoughisenough-response.html

Michael Mooney’s overview:

http://www.michaelmooney.net/Erroneous_Annals_Of_Internal_Medicine_Study_Says_Vitamins_Don%27t_Work.html

Industry’s Council for Responsible Nutrition:

http://www.nutraceuticalsworld.com/contents/view_blog/2013-12-18/enough-is-enough/?email_uid=dee72d271a/list_id=396c189146/

Michael Murray, ND:

http://doctormurray.com/?utm_source=WOW+-+Editorial+in+Medical+Journal+Promotes+Propaganda+Against+Multiple+Vitamin+&utm_campaign=CCmailing6-12-13&utm_medium=email

References:

1. Grodstein F, O’Brien J, Kang JH, et al. Long-Term Multivitamin Supplementation and Cognitive Function in Men: The Physicians’ Health Study II. Annals of Internal Medicine. 2013;159(12) :806-814-814. doi: 10.7326/0003-4819-159-12-201312170-00006.

2. Fortmann SP, Burda BU, Senger CA, Lin JS, Whitlock EP. Vitamin and Mineral Supplements in the Primary Prevention of Cardiovascular Disease and Cancer: An Updated Systematic Evidence Review for the U.S. Preventive Services Task Force. Ann Intern Med. Nov 12 2013;159(12):824-834-834. doi: 10.7326/0003-4819-159-12-201312170-00729.

3. Lamas GA, Boineau R, Goertz C, et al. Oral High-Dose Multivitamins and Minerals After Myocardial Infarction. Annals of Internal Medicine. 2013;159(12):797-805-805. doi: 10.7326/0003-4819-159-12-201312170-00004.

4. Guallar E, et al. Enough Is Enough: Stop Wasting Money on Vitamin and Mineral Supplements. Ann Intern Med. 2013;159(12): 850. Retrieved 19 Dec 2013 from http://annals.org/article.aspx?articleid=1789253

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