January 20, 2010

Gilbert E. DAlonzo, Jr, DO
Editor in Chief
Journal of the American Osteopathic Association
142 Ontario St.
Chicago, IL 60611-2864

To the Editor:

     In How to avoid a heart attack: putting it all together",[1] Thomas A. Haffey D.O., does an admirable job of knitting together multiple threads into a coherent treatment approach. In his discussion of  Practical Evidence-Based Dietary Tips he recommends antioxidants, but goes on to say that vitamins B6, B9, B12 and Vitamin E may increase heart attack risk, but with no evidence based reference. He goes on to say that Vitamins C Vitamin E and a multivitamin have no place in a comprehensive CVD prevention strategy . We disagree with these conclusions and the interpretation of the papers on which they are based.

     In a science based paradigm we should look at the total weight of the evidence; one metaanalysis does not an unalterable conclusion make. Biological plausibility and a careful exploration of a given papers bias are also important factors.

     Haffey cites  the results of The Physicians Health Study II[2] which included the evaluation of four randomized groups of male physicians, who were told to take 400 IU of synthetic alpha-tocopherol every other day, 500 mg of Vitamin C every day and a multivitamin every day, and concluded that there was no effect on cardiovascular events when compared with placebo .

     In the Physicians Health Study II it is not plausible to believe that their study subjects would reduce their vascular risk by taking a modest dose, every other day, of a form of vitamin E with inferior antioxidant capacity. Nature often utilizes redundancy. Vitamin E is actually a group of six to eight closely related compounds that work better together as a group than individually. If one were to rely only on synthetic alpha-tocopherol, the minimum daily dose needed has been shown to exceed 800 IU, far greater than the 400 IU ingested every other day by subjects in this study.[3], [4] An increasing number of scientists are questioning the wisdom of administering alpha-tocopherol Vitamin E by itself.[5], [6], [7], [8], [9] One reason is that alpha-tocopherol displaces critically important gamma-tocopherol in the body.[10] It was admitted by the authors that the failure to include gamma tocopherol may have been a reason that no effect was seen in the alpha-tocopherol groups.[2]

     Published studies that document vascular benefits in response to Vitamin C typically use doses of 1000 to 6,000 mg each day.[11], [12], [13], [14], [15], [16] The authors of the Physicians Health Study II alluded to this when they stated, In a pooled analysis of nine cohorts, Vitamin C supplement use exceeding 700 m/day was significantly associated with a 25% reduction in coronary heart disease risk[2], [17] Since the doctors who designed this study knew that Vitamin C intakes exceeding 700  mg/day significantly reduced heart attack rates.[17], why did they limit their subjects daily dose to only 500 mg?[2]

     A widely reported study emanating from UCLA found that men who took 800 mg a day of vitamin C lived six years longer than those who consumed the recommended daily allowance of 60 mg/day. This study, which evaluated 11,348 participants over a 10 year period of time, found that higher vitamin C intake reduced cardiovascular disease mortality by 42%.[18] A study in 1,214 persons age 75-84 studied over a four year period found that those people with the lowest vitamin C plasma levels (<17 micromol/L) had the highest mortality, whereas those aging people  with the highest plasma levels (> 66 micromol/L) had a mortality risk nearly 50% less.[19]. The Established Populations for Epidemiologic Studies of the Elderly followed 11,178 persons aged 67-105 years from 1984-1993, examined Vitamin E and Vitamin C supplement use in relation to mortality risk. They found that Vitamin E reduced the risk of all cause mortality by 34%, reduced the risk of coronary disease mortality by 47%, and the simultaneous use of  vitamins E and C was associated with a 42% lower risk of total mortality and a 53% lower risk of coronary mortality.[20]

     Back in the Physician Health Study II, it turns out that a significant number of study subjects who were supposed to take the Vitamin C and/or E supplements did not take their entire study product as instructed. Yet when the calculations for heart attack or stroke incidence were made, those who took as little as 66% of their low-dose Vitamin C and/or E supplements were counted as having taken the entire dose. At the end of the study, 28% of the study participants admitted that they had not even taken 66% of their low-dose Vitamin C and/or E supplements. What do you suppose that does to significance?

     Even more troubling is the method used to track who was really taking their supplements. Participants were asked to remember and track supplement usage for over eight years time without any verification of actual pill counts, compliance by plasma antioxidant analysis, or in vivo surrogate markers of oxidative stress. Relying on participants memory and recollection over a lengthy period of many years is a rather poor way of ensuring adherence, and render the authors "sensitivity analysis" much less "significant" than it might otherwise be.

     If we begin the reading of any paper with an assessment of the bias of the authors and associated institutions, we can often save a lot of time in arriving what the practical value of a paper is. As our health care system continues to deteriorate, we will need to reassess the low tech low cost interventions that will allow our patients to remain well and reduce the utilization of our  high interventional medicine resources. Dr Haffey has made a good start, but this argument about orthomolecular medicine and vitamin use is far from over.

     It was Mark Twain who said, There are lies, there are damn lies, and there are statistics.

     Respectfully submitted,

John H. Juhl, D.O.
Touro-COM, Harlem

Gary L. Ostrow, D.O.
Ostrow Institute for Pain Management

Mikhail Gleyzer, D.O., M.D.
private practice, NYC

Richard Firshein, D.O.
Firshein Center for Comprehensive Medicine

Alexander Kulick, M.D.
Integrative Medicine, NYC

Barbara Gordon-Cohen, D.O.
Touro-COM, Harlem

Amy Davison, D.O.
Touro-COM, Harlem

William Faloon
Life Extension Foundation

Steven V. Joyal, M.D.
Life Extension Foundation

Steven P. Hirsh, R.Ph., D.P.M.
Life Extension Foundation

Contact person: John H. Juhl, D.O.
625 Madison Ave., 10A
New York, NY 10022
W: (212) 838-8265

[1] Haffey TA, How to avoid a heart attack: putting it all together, JAOA, 2009, May;109(5 suppl):S14-20.

[2] Sesso HD, Buring JE, Christen WG, et.al., Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians Health Study II randomized controlled trial, JAMA,2008 Nov 12;300(18):2123-33.

[3] Devaraj S, Tang R, Adams-Huet B, et.al., Effect of high dose alpha-tocopherol supplementation on biomarkers of oxidative stress and inflammation and carotid atherosclerosis in patients with coronary artery disease, Am J Clin Nutr, 2007 Nov;86(5):1392-8.

[4] Kivose C, Muramatsu R, Kameyama Y, Ueda T, Igarashi O, Biodiscrimination of alpha-tocopherol sterioisomers in humans after oral administration, Am J Clin Nutr, 1997 Mar;65(3):785-9.

[5] Helzlsouer KJ, Huang HY, Alberg AJ, et.al., Association between alpha-tocopherol, gamma-tocopherol, selenium and subsequent prostate cancer, J Natl Cancer Inst, 2000 Dec 20;92(24): 2018-23.

[6] Christen S, Woodall AA, Shigenaga MK, et.al., Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications, Proc Natl Acad  Sci USA, 1997 Apr 1;94(7):3217-22.

[7] Devaraj S, Leonard S, Traber MG, Jialal I, Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome, Free Radic Biol Med, 2008 Mar15;44(6):1203-8.

[8] Reiter E, Jiang Q, Christen S, Anti-inflammatory properties of alpha- and gamma-tocopherol, Mol Aspects Med, 2007 Oct; 28(5-6):668-91.

[9] Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN, Gamma-tocopherol and its major metabolite, in contrast to alp[ha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells, Proc Natl Acad Sci USA, 2000 Oct 10;97(21):11494-9.

[10] Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA, Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans, J Nutr, 1985 Jun; 115(6):807-13.

[11] Nappo F, De RN, Marfella R, et.al., Impairment of endothelial functions by acute hyperhomocystenemia and reversal by antioxidant vitamins, JAMA, 1999 Jun 9;281(22):2103-12.

[12] Valkonen MM, Kuusi T, Vitamin C prevents the acute atherogenic effects of passive smoking, Free Radic Biol Med, 2000 Feb 1;28(3): 428-36.

[13] Jeserich M, Schindler T, Olschewski M, et.al., Vitamin C improves endothelial function of epicardial coronary arties in patients with hypercholesterolemia or essential hypertension- assessed by cold pressor testing, Eur Heart J, 1999 Nov;20(22)1676-80.

[14] Wilkinson IB, Megson IL, MacCallum H, et.al., Oral vitamin C reduces arterial stiffness and platelet aggregation in humans, J Cardiovasc Pharmacol, 1999 Nov;34(5):690-3.

[15] Jablonski KL, Seals DR, Eskurza I, Monahan KD, Donato AJ, High-dose ascorbic acid infusion abolishes chronic vasoconstriction and restores resting leg blood flow in healthy older men, J Appl Physiol, 2007 Nov;103(5): 1715-21.

[16] Hernandez-Guerra M, Garcia-Pagan JC, Turnes J, et.al., Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension, Hepatology, 2006 Mar;43(3):485-91.

[17] Knekt P, Ritz J,Pereira MA, et.al., Antioxidant vitamins and  coronary heart disease risk: a pooled analysis of  9 cohorts, Am J Clin Nutr, 2004 Dec;80(6):1508-20.

[18] Enstrom JE, Kanim LE, Klein MA, Vitamin C intake and mortality among a sample of the United States population, Epidemiology, 1992 May;3(3): 194-202.

[19] Shetty PS, Breeze E, Fletcher AE, Antioxidant vitamins and mortality in older persons: findings from the nutrition add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community, Am J Clin Nutr, 2003 Nov;78(5): 999-1010.

[20] Losonczy KG, Harris TB, Havlik RJ, Vitamin E and Vitamin C upplement use and rsik of all-cause and coronary heart disease mortality in oloder persons: The Established  populations for Epidemiologic Studies of the Elderly, Am J Clin Nutr, 1996 Aug;64(2):190-6.