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Enough Is Enough

Eliseo Guallar, MD, DrPH; Saverio Stranges, MD, PhD; Cynthia Mulrow, MD, MSc; Lawrence J. Appel, MD, MPH; and Edgar R. Miller III, MD, PhD
[+] Article, Author, and Disclosure Information

From Johns Hopkins University, Baltimore, Maryland; University of Warwick, Coventry, England, United Kingdom; and Annals of Internal Medicine, American College of Physicians, Philadelphia, Pennsylvania.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2593.


Ann Intern Med. 2014;160(11):809-810. doi:10.7326/L14-5011-6
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Believe the data: multivitamins reduce cancer risk in men
Posted on June 3, 2014
David L Keller MD
none
Conflict of Interest: None Declared
Guallar and colleagues dismiss the clinical trial data demonstrating that multivitamin and mineral supplements (MVM’s) reduce cancer risk in men, stating: “ Because the observed possible benefits were limited to men, were modest (as in PHS II), or were evident only in subgroup analyses (as in the SU.VI.MAX study) and did not consistently extend to reductions in mortality, these findings are only weak signals compatible with small or no benefit.” (1)

I will challenge each clause of their compound statement separately, but first, for the record, I quote the abstract of the Su.Vi.Max study (2):

"However, a significant interaction between sex and group effects on cancer incidence was found (P = .004). Sex-stratified analysis showed a protective effect of antioxidants in men (relative risk, 0.69 [95% confidence interval {CI}, 0.53-0.91]) but not in women (relative risk, 1.04 [95% CI, 0.85-1.29]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, 0.42-0.93] in men vs 1.03 [95% CI, 0.64-1.63] in women; P = .11 for interaction)."

Simply stated: Men who took multivitamins had significantly fewer cancers and a lower overall death rate than men who did not. These were not small effects: the cancer rate for men was reduced by 31% and the overall death rate by 37%.

First, let us discuss the fact that these benefits “were evident only in subgroup analyses”. That would be a valid criticism if, for example, as a result of multiple post-hoc analyses, it was discovered that MVM’s only benefited persons born under a certain astrological sign, or some other biologically implausible subgroup. A subgroup analysis should be based on a rational indication, it should be predefined in the experimental protocol, one of a small number of such analyses, and be based on pre-randomization patient characteristics. The subgroup should be large enough to retain statistical power. The subgroup effect should be evident in other studies (3)(4). The Su.vi.max subgroup analysis was conducted on men, a large, natural subgroup which showed benefits in another study and was pre-specified in the study protocol. The bottom line is that the subgroup analysis yielded impressive results with convincing confidence intervals. So, how, precisely, does the fact that subgroup analysis was performed cast doubt on the results?

Guallar and colleagues also cast doubt on the data because the benefits of MVM’s were limited to men. The Su.vi.max investigators explained this by noting that women generally have better nutritional status than men; they are both more likely to eat fruits and vegetables, and also more likely to take MVM’s at baseline. Women, with good baseline nutrition, have less to gain by taking MVM’s and therefore exhibit no benefit in these studies. There are many differences between men and women, both biological and cultural, which result, for one thing, in the fact that women outlive men by several years on average. Do our future widows want to maintain this actuarial status quo?

As I have noted before (5), the 5 antioxidants included in the Su.vi.max supplement were a subset of the 30 nutrients in Centrum Silver, but at significantly higher doses. Thus, there was a dose-response effect evident for these antioxidants, with the PHS-II men who took MVM’s displaying a small but significant reduction in cancer rates, and the Su.vi.max men exhibiting a larger reduction in cancer rates, plus a decrease in all-cause mortality, consistent with the higher nutrient levels in the Su.vi.max supplement. This dose-response effect addresses Guallar’s complaint that the reduction in mortality was “not consistent”.

The USPSTF gave MVM supplements a grade of “I” for insufficient evidence to make a recommendation. Given the quality of the data supporting MVM use for men, it would seem prudent to change that to a “C” level recommendation - meaning that men should discuss MVM supplements with their doctors in the context of their individual diet quality and vegetable intake. Men with diets which do not match those of well-nourished women should consider adding a standard multivitamin & mineral supplement to reduce cancer risk while they work on improving their vegetable intake. To potentially reduce their overall risk of death, men with poor nutrition could increase the dose to twice a day to approximate the Su.vi.max supplement, at least until their eating habits improve.

References:

1. Guallar E. Enough Is Enough, Annals of Int Med. June 3 2014; Vol 160, No. 9

2. Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D, et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004; 164:2335-42.

3. Wittes J. On Looking at Subgroups. Circulation.2009; 119: 912-915
doi: 10.1161/​CIRCULATIONAHA.108.836601

4. Dijkman B, et al. How to work with a subgroup analysis. Can J Surg. Dec 2009; 52(6): 515–522. PMCID: PMC2792383

5. Keller DL. Open letter to the USPSTF: the evidence shows multivitamins reduce cancers in men, PubMed Commons, accessed on 6/3/2014
http://www.ncbi.nlm.nih.gov/pubmed/24566474#cm24566474_4093
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