Virginia A. Moyer, MD, MPH; on behalf of the U.S. Preventive Services Task Force *
Disclaimer: Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Financial Support: The USPSTF is an independent, voluntary body. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF.
Disclosures: Dr. Moyer: Support for travel to meetings for the study or other purposes: Agency for Healthcare Research and Quality. Dr. Owens: Support for travel to meetings for the study or other purposes: U.S. Preventive Services Task Force. Dr. Pignone: Grants/grants pending (money to institution): multiple federal awards, American Cancer Society, Informed Medical Decisions Foundation; Royalties: textbook chapters on lipids, prevention; Travel/accommodations/meeting expenses unrelated to activities listed: travel to meetings on aspirin prevention, Partnership for Prevention. Authors not named here have disclosed no conflicts of interest. Authors followed the policy regarding conflicts of interest described at www.uspreventiveservicestaskforce.org/methods.htm. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0198.
Requests for Single Reprints: Reprints are available from the USPSTF Web site (www.uspreventiveservicestaskforce.org).
Update of the 2003 U.S. Preventive Services Task Force (USPSTF) recommendation on vitamin supplementation to prevent cardiovascular disease and cancer.
The USPSTF reviewed the evidence on the efficacy of multivitamin or mineral supplements in the general adult population for the prevention of cardiovascular disease and cancer.
This recommendation applies to healthy adults without special nutritional needs (typically aged 50 years or older). It does not apply to children, women who are pregnant or may become pregnant, or persons who are chronically ill or hospitalized or have a known nutritional deficiency.
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of multivitamins for the prevention of cardiovascular disease or cancer. (I statement)
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of single- or paired-nutrient supplements (except β-carotene and vitamin E) for the prevention of cardiovascular disease or cancer. (I statement)
The USPSTF recommends against β-carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer. (D recommendation)
Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: clinical summary of U.S. Preventive Services Task Force recommendation.
Appendix Table 1. What the USPSTF Grades Mean and Suggestions for Practice
Appendix Table 2. USPSTF Levels of Certainty Regarding Net Benefit
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David L. Keller, MD, MS, FACP
None
March 5, 2014
While awaiting definitive evidence....
The USPSTF guideline statement includes the following statements: Statement 1: “Two large trials, the Physicians' Health Study II (13) and the SU.VI.MAX (Supplementation in Vitamins and Mineral Antioxidants) study (14), showed a decrease in overall cancer incidence in men (pooled unadjusted relative risk, 0.93 [95% CI, 0.87 to 0.99])“ Statement 2: “Use of dietary supplements is common in the U.S. adult population. Forty-nine percent of adults used at least 1 dietary supplement between 2007 and 2010, and 32% reported using a multivitamin–multimineral supplement (1). Supplement use is more common among women and older adults than men and younger adults (2).” Statement 3: “The lack of effect in women and the use of different supplement formulations in the 2 trials make extrapolating these findings to the general population difficult.” Could the lack of benefit of multivitamins and mineral supplements (MVMS) in women be due to the fact that women have a higher background use MVMS than men (Statement 2)? Intention-to-treat analysis would count women in control groups who took MVMS in violation of experimental protocol as if they were not taking MVMS; this would tend to reduce the apparent benefit of MVMS in women, perhaps explaining Statement 3. Was a per-protocol analysis of these trials conducted, for hypothesis generation about the possible anti-cancer effects of MVMS in women? As a male physician, I will continue to take a MVMS, based on Statement 1, until evidence emerges which disproves the results of these 2 large trials. While awaiting definitive evidence, considering the costs and potential harms and benefits involved, I would take a MVMS if I were a woman, and I will so inform my female patients.
David L. Keller, MD, FACP
Internal Medicine Physician
March 24, 2014
Analyzing the results of disparate trials
The USPSTF guideline statement on multivitamins and cancer risk (1) includes the following statements:
Statement 1: “Two large trials, the Physicians' Health Study II (PHS II) and the SU.VI.MAX (Supplementation in Vitamins and Mineral Antioxidants) study, showed a decrease in overall cancer incidence in men (pooled unadjusted relative risk, 0.93 [95% CI, 0.87 to 0.99])“
Statement 2: “Use of dietary supplements is common in the U.S. adult population. Forty-nine percent of adults used at least 1 dietary supplement between 2007 and 2010, and 32% reported using a multivitamin–multimineral supplement. Supplement use is more common among women and older adults than men and younger adults.”
Statement 3: “The lack of effect in women and the use of different supplement formulations in the 2 trials make extrapolating these findings to the general population difficult.”
Could the lack of benefit of multivitamins and mineral supplements (MVMS) in women be due to the fact that women have a higher background use MVMS than men (Statement 2)? Intention-to-treat analysis would count women in control groups who took MVMS in violation of experimental protocol as if they were not taking MVMS; this would tend to reduce the apparent benefit of MVMS in women, perhaps explaining Statement 3. Was a per-protocol analysis of these trials conducted, for hypothesis generation about the possible anti-cancer effects of MVMS in women?
As a male physician, I will continue to take a MVMS, based on Statement 1, until evidence emerges which disproves the results of these 2 large trials. While awaiting further evidence, considering the costs and potential harms and benefits involved, and the higher likelihood of off-protocol MVMS supplementation by women in the control groups of the studies which showed decreased cancer rates for men, I see no reason to dissuade women from taking a MVMS at this time.
The USPSTF report also states that "the use of different supplement formulations in the 2 trials makes extrapolating these findings to the general population difficult", which refers to the fact that the Physician's Health Study tested "a commercially available multivitamin that contained 30 ingredients" (which was Centrum Silver), while the SU.VI.MAX Study tested a supplement which "included nutritional doses of vitamins C and E plus β-carotene, selenium, and zinc". If we wish to determine which nutrients led to the significant decrease in cancers seen in both studies,
it would most likely be the list of nutrients common to both multivitamin preparations, which is essentially the SU.VI.MAX blend. Where significant differences exist between the doses (e.g. vitamin C at 60 mg in Centrum Silver versus 120 mg in SU.VI.MAX), I would lean toward the latter due to the more robust drop in relative risk for cancer in the latter study.
1: Moyer VA. Vitamin, Mineral, and Multivitamin Supplements for the PrimaryPrevention of Cardiovascular Disease and Cancer: U.S. Preventive Services TaskForce Recommendation Statement. Ann Intern Med. 2014 Feb 25. doi:10.7326/M14-0198. [Epub ahead of print] PubMed PMID: 24566474.
Dose-Response Effect of Multi-Vitamins on Cancer Reduction
In comparing the multivitamin doses taken and the respective average reductions in relative risk for cancer in the Physicians' Health Study II versus the SU.VI.MAX study, a dose-response effect is evident. The presence of a dose-response effect tends to corroborate the mild but significant reductions in risk of cancer observed in theses studies. Follow-up studies need to be done to determine how much further the relative risk of cancer can be reduced by means of increasing the doses of these vitamins.Dose-Response Table:---------------------------------------------------------------------------------------------------------------------------Centrum Silver 50+ SU.VI.MAX multivitamin-----------------------------------------------------------------------------------------------------------------------------Beta-Carotene 1000 IU Beta-Carotene 6mg = 6000 mcg = 9960 IUVitamin C 60 mg Vitamin C 120 mgVitamin E 50 IU as DL-alpha-tocopherol Vitamin E 30 mg = 67 IU of DL-alpha-tocopherolZinc 11 mg Zinc 20 mgSelenium 55 mcg Selenium 100 mcg---------------------------------------------------------------------------------------------------------------------------------Avg. RR = 0.93 Avg RR = 0.69
Independent physician
April 19, 2014
Multivitamins reduced mortality in men in SU.VI.MAX
Dr. Moyer failed to mention the fact that men randomized to receive multivitamin supplements in the SU.VI.MAX trial had significantly lower overall mortality than men randomized to placebo. In the SU.VI.MAX trial, a significant decrease in cancer incidence was observed in men randomized to antioxidant supplements compared to those taking placebo (91 vs. 125 cancers, RR, 0.71; 95% CI, 0.53–0.93). Significantly decreased mortality was observed for antioxidant recipients during the supplementation period (41 vs. 63 deaths; RR, 0.64; 95% CI, 0.43–0.95) compared to men taking placebo. These facts should be considered, along with the apparent dose-response effect of the 5 antioxidant micronutrients given in both the SU.VI.MAX and PHS II studies, with respect to reduction in cancer incidence in men (as detailed in my additional comments here and on PubMed Commons).
David L. Keller, MD
Independent Internist
April 23, 2014
The evidence consistently demonstrates that multivitamins benefit older men
The United States Preventative Services Task Force (USPSTF) recently updated their report on multi-vitamin supplements, and again found "insufficient evidence" to recommend their general use. The USPSTF report dismissed the significant reduction in cancers seen in men in both the SU.VI.MAX and Physicians' Health Study (PHS II), partly because the lack of benefit in women caused them to doubt the results found in men. However, they failed to address the reasonable explanation offered by the SU.VI.MAX authors, which is that women have a higher baseline nutritional status than men, and thus have less to gain by adding a multivitamin supplement.The second reason USPSTF gave for not being able to interpret the results of the PHS II and SU.VI.MAX studies was that they tested different multivitamin supplement formulations. However, the 5 antioxidants used in the SU.VI.MAX supplement are a sub-set of the micronutrients in the Centrum Silver administered in PHS II. I have pointed out elsewhere in PubMed Commons that there is a rudimentary dose-response effect evident when one compares the effects of the low-dose Centrum Silver supplement, versus the higher-dose SU.VI.MAX supplement, with regard to the significant reduction in cancer seen in men in both studies. A dose-response effect tends to corroborate the findings of the individual studies, and it also suggests the need for a dose-ranging study of the SU.VI.MAX supplement. Would increasing the doses of these 5 antioxidant nutrients reduce cancer rates and mortality even further in men? Would a significant effect in women become evident?Lastly, the updated USPSTF report completely omitted any mention of the significant reduction in all-cause mortality seen while men were taking the SU.VI.MAX supplement.At this time, there is consistent evidence from 2 large, prospective, randomized, placebo-controlled trials that the low-dose multivitamin supplement used in PHS II significantly reduces the incidence of cancer in men, and that the higher-dose SU.VI.MAX supplement (consisting of 5 antioxidant nutrients in higher doses than in Centrum Silver) reduces cancer rates even more in men, and adds a significant reduction in all-cause mortality. How many more studies must be done to convince the USPSTF that the results of PHS II and SU.VI.MAX are true? How many men will get cancer or die while we wait for those studies?I propose that the USPSTF change their assessment of multivitamin supplements to reflect the significant dose-related benefits multivitamins have demonstrated for men over the age of 50, who can benefit from reduced cancer rates and overall mortality, according to the best evidence we have. The USPSTF should call for dose-ranging studies to determine whether the benefits of the five antioxidants administered in SU.VI.MAX can be increased by increasing their doses.At the very least, the USPSTF report should be amended to state that overall mortality was significantly decreased in men taking the SU.VI.MAX supplement. The absence of that fact from their report seems inexcusable.
Moyer VA, on behalf of the U.S. Preventive Services Task Force. Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. ;160:558–564. doi: 10.7326/M14-0198
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Published: Ann Intern Med. 2014;160(8):558-564.
DOI: 10.7326/M14-0198
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