Clarifying the evidence: vitamin E, vitamin A, and folate.

VOL 5: NOVEMBER • NOVEMBRE 2005d Canadian Family Physician • Le Médecin de famille canadien 1471

Letters

Corresp ondance

Clarifying the evidence:

vitamin E, vitamin A, and folate

A

fter reading the article “Health benefits of selected vitamins,”¹ we would like to clarify the evidence regarding the effect of supplementation with vitamin E, vitamin A, and folate on cardiovas- cular disease (CVD) and mortality. Th e theory that antioxidant vitamins prevent CVD is well known but not supported by higher-level evidence (ran- domized controlled trials, systematic reviews, and meta-analyses).

As possible evidence of benefi t, the authors point to the Cambridge trial,² in which patients taking 400 to 800 IU of vitamin E had a signifi cant reduc- tion in non-fatal myocardial infarction. It did not, however, show a reduction in cardiovascular death as the authors suggest, but rather a non-signifi- cant increase in cardiovascular death and all-cause mortality.² As well, these patients had proven cor- onary artery stenosis, and the authors previously acknowledged that clinical trials had not demon- strated benefi t in patients at increased risk. More to the point, a number of randomized controlled trials and meta-analyses, including secondary- and primary-prevention patients with and without risk factors, have failed to show benefi t of vitamin E on CVD.^3-10 In fact, a recent meta-analysis¹¹ dem- onstrated that doses of ≥400 IU of vitamin E are associated with a signifi cant increase in all-cause mortality (number needed to harm [NNH] 257, confi dence interval [CI] 136-3334). Unless future evidence suggests benefit, patients should be advised that vitamin E does not prevent CVD and is potentially harmful in high doses (≥400 IU).

In Table 1, the authors indicate that “possible health benefits” of vitamin A include “General health, including immunity” and then in the text indicate that caution is “recommended because of some evidence that high intake of carotenoids might be harmful to some groups, such as smokers.”

The evidence indicates, however, that all-cause mortality is increased not only in smokers⁵ but also in primary- and secondary-prevention patients in a variety of populations (NNH 326, CI 140-∞).¹⁰

The observed link between increased homo- cysteine levels and better cardiac outcomes¹² has led to the hypothesis that, by reducing the surro- gate marker of homocysteine through folate and B₁₂ supplementation, cardiac outcomes will be improved. In the high-risk population of patients who have had percutaneous coronary interven- tion, one trial has shown benefi t¹³ while another has demonstrated harm¹⁴ from folate supplemen- tation. Secondary prevention trials of folate sup- plementation used by stroke¹⁵ and stable coronary artery disease¹⁶ patients have failed to show benefi t.

At present, the assumption that “folic acid supple- mentation greatly aff ects homocysteine levels, and hence, coronary artery disease” is an exaggeration beyond the available evidence.

Th ere are examples throughout medicine where theory, extrapolation of effects through surro- gate markers, and weaker levels of evidence have led to harmful consequences for our patients. We should focus on proven preventive therapies, such as blood pressure control, before advocating poten- tially harmful therapies.

—G. Michael Allan, MD, CCFP

—Wendy Payne, MD Edmonton, Alta by e-mail References

1. Ryan-Harshman M, Aldoori W. Health benefi ts of selected vitamins [Food for Th ought]. Can Fam Physician 2005;51:965-8.

2. Stephens NG, Parsons A, Schofi eld PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-6.

3. De Gaetano G, Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: randomised trial in general practice [published erratum appears in Lancet 2001;357:1134]. Lancet 2001;357:89-95.

4. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:23-33.

5. Tornwall ME, Virtamo J, Korhonen PA, Virtanen MJ, Taylor PR, Albanes D, et al. Eff ect of alpha-tocopherol and beta-carotene supplementation on coronary heart disease during the 6- year post-trial follow-up in the ATBC study. Eur Heart J 2004;25:1171-8.

6. Lonn E, Yusuf S, Hoogwerf B, Pogue J, Yi Q, Zinman B, et al. Eff ects of vitamin E on cardio- vascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care 2002;25:1919-27.

7. Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nicolucci A. Primary preven- tion of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients:

results of the Primary Prevention Project (PPP) trial. Diabetes Care 2003;26:3264-72.

1472 Canadian Family Physician • Le Médecin de famille canadien dVOL 5: NOVEMBER • NOVEMBRE 2005

Letters Correspondance

8. Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al. Vitamin E in the pri- mary prevention of cardiovascular disease and cancer: the Women’s Health Study: a random- ized controlled trial. JAMA 2005;294:56-65.

9. Eidelman RS, Hollar D, Hebert PR, Lamas GA, Hennekens CH. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med 2004;164:1552-6.

10. Vivekananthan DP, Pen MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003;361:2017-23.

11. Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analy- sis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.

12. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-22.

13. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Eff ect of homocysteine-lowering therapy with folic acid, vitamin B₁₂ and vitamin B₆ on clinical outcomes after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002;288:973-9.

14. Lange H, Suryapranata H, De Luca G, Borner C, Dille J, Kallmayer K, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004;350:2673-81.

15. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75.

16. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ.

Secondary prevention with folic acid: eff ects on clinical outcomes. J Am Coll Cardiol 2003;41:2105-13.

Sexual consequences of prostate cancer treatment

Y

our July 2005 issue seems mislabelled. Th ere are indeed sexual consequences of advanced and aggressive prostate cancer, but the tragedy is that the

largest part of the epidemic of male sexual depreda- tion is a result of treatment, not disease.

Your issue would better be titled “Severe Sexual Consequences of Aggressive Treatment of Prostate Cancer.”

Off ering editorial comment¹ from a urologist is like inviting a logger to discuss the preservation of old-growth forests. Th e surgeon advises family physicians to explain to patients that they “might experience changes in ejaculation.”

Might? What truthful family physicians will tell their patients is, “Th is means the end of sex as you know it for almost all men treated. And by the way, as many as four in 10 of you will end up wearing a diaper at least some of the time.”

Th en, truthful family physicians will make sure their patients understand that aggressive screening and treatment of prostate cancer might, at best, prolong their lives a few months. (See Tom Pickles’s review of the lack of proven benefi t with current therapies.²)

Surely avoiding prostate-specifi c antigen screen- ing in asymptomatic patients and restricting surgi- cal and radiation interventions to clinically obvious cancers is the plan family physicians providing evidence-based care should follow.

—John B. Hoehn, MD, CCFP Walla Walla, Wash by mail References

1. Pommerville PJ. From bedside to bed. Recovery of sexual function after prostate cancer [editorial]. Can Fam Physician 2005;51:941-3 [Eng], 948-50 [Fr].

2. Pickles T. Current status of PSA screening. Early detection of prostate cancer. Can Fam Physician 2004;50:57-63.

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