Letters to the Editor  |   May 2010
How to Avoid a Heart Attack: Putting It All Together
Author Affiliations
  • Steven P. Hirsh, RPh, DPM
    Touro College of Osteopathic Medicine New York, New York
    Ostrow Institute for Pain Management New York, New York
    Private practice New York, New York
    Firshein Center for Comprehensive Medicine New York, New York
    Integrative Medicine New York, New York
    Touro College of Osteopathic Medicine New York, New York
    Life Extension Foundation New York, New York
Article Information
Cardiovascular Disorders
Letters to the Editor   |   May 2010
How to Avoid a Heart Attack: Putting It All Together
The Journal of the American Osteopathic Association, May 2010, Vol. 110, 268-270. doi:10.7556/jaoa.2010.110.5.268
The Journal of the American Osteopathic Association, May 2010, Vol. 110, 268-270. doi:10.7556/jaoa.2010.110.5.268
To the editor:  
In his clinical review article published in the May 2009 supplement to JAOA—The Journal of the American Osteopathic Association,1 Thomas A. Haffey, DO, admirably knits together multiple threads of cardiovascular disease (CVD) management into a coherent treatment approach. In his list of practical evidence-based dietary tips, he recommends antioxidants but states that vitamins B6, B9, B12, and E may increase heart attack risk without providing an evidence-based reference. He later concludes that, based on findings from the Physician's Health Study II (PHS II), “vitamin E, vitamin C, 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. Physicians and researchers must consider the total weight of the evidence; one randomized controlled trial or meta-analysis does not an unalterable conclusion make. Biological plausibility and careful exploration of a given study's bias are also important factors. 
The PHS II2 was a randomized, placebo-controlled trial in which participants (male physicians) were directed to take 400 IU of vitamin E (synthetic α-tocopherol) every other day, 500 mg of vitamin C every day, or both supplements. (Beta carotene and a multivitamin were also randomly assigned but were not reported on in the study.) The researchers concluded that the vitamins had no effect on cardiovascular events when compared with placebo. 
It is implausible that the PHS II participants 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 thrives on redundancy. Vitamin E is actually a group of six to eight closely related compounds that work better together as a group than individually. Using synthetic α-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 In addition, an increasing number of scientists are questioning the wisdom of administering α-tocopherol vitamin E by itself.5-9 One reason is that α-tocopherol displaces critically important γ-tocopherol in the body.10 The PHS II authors admitted that the failure to include γ-tocopherol may have been a reason that no effect was seen in the α-tocopherol groups.2 
Vascular benefits from vitamin C have been reported using doses of 1000 mg to 6000 mg daily.11-16 In the introduction of their study, the PHS II authors alluded to the benefits of high-dose vitamin C when they stated, “In a pooled analysis of 9 cohorts, vitamin C supplement use exceeding 700 mg/d was significantly associated with a 25% reduction in coronary heart disease risk.”2 Considering that the researchers who designed the PHS II2 knew that vitamin C intakes exceeding 700 mg per day significantly reduced heart attack rates,17 why did they limit their subject's daily dose to only 500 mg? 
Various studies exist that dispute the PHS II findings. A widely reported study emanating from the University of California, Los Angeles found that men who took 800 mg per day of vitamin C lived 6 years longer than those who consumed the recommended daily allowance of 60 mg per day. The study, which evaluated 11,348 men for 10 years, found that higher vitamin C intake reduced cardiovascular disease mortality by 42%.17 
A 4-year study of 1214 people aged 75 to 84 years found that those with the lowest vitamin C plasma levels (<17 μmol/L) had the highest mortality, whereas those aging people with the highest plasma levels (>66 μmol/L) had a mortality risk nearly 50% lower.18 
The Established Populations for Epidemiologic Studies of the Elderly followed 11,178 older adults aged 67 to 105 years from 1984 to 1993 and 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% and reduced the risk of coronary disease mortality by 47%. In addition, 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.19 
Furthermore, in the PHS II, a clinically significant number of study participants who were supposed to take vitamin C, vitamin E, or both did not take the vitamin doses as instructed. Yet when the calculations for heart attack or stroke incidence were made, those who took as little as two-thirds of their low-dose vitamin C and 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 two-thirds of their low-dose vitamin C and E supplements. How might that lack of adherence affect the study's clinical and statistical significance? 
Even more troubling in the PHS II is the method used to track supplement intake. Participants were asked to remember and track supplement intake for more than 8 years. The researchers did not verify actual pill counts, compliance by plasma antioxidant analysis, or in vivo surrogate markers of oxidative stress. Relying on participants' memory and recollection for such a long period is a rather poor way of ensuring adherence and renders the authors' “sensitivity analysis” much less “significant” than it might otherwise be. 
If we as physicians and researchers begin the critical analysis of any article with an assessment of the bias of the authors and associated institutions, we can save time in determining the practical value of an article. As our healthcare system continues to deteriorate, we will need to reassess the low tech, low cost interventions that will allow our patients to remain healthy and reduce the utilization of our high interventional medicine resources. Dr Haffey has made a good start, but the 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.” 
 Editor's Note: A response letter from Thomas A. Haffey, DO, will appear in the June issue of the JAOA.
Haffey TA. How to avoid a heart attack: putting it all together. J Am Osteopath Assoc. 2009;109(5 suppl 1):S14-S20. Accessed May 11, 2010.
Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFaden J, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physician's Health Study II randomized controlled trial [published online ahead of print November 9, 2008]. JAMA. 2008;300 (18):2123-2133. Accessed May 11, 2010.
Devaraj S, Tang R, Adams-Huet B, Harris A, Seenivasan T, de Lemos JA, 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;86 (5):1392-1398. Accessed May 11, 2010.
Kivose C, Muramatsu R, Kameyama Y, Ueda T, Igarashi O. Biodiscrimination of alpha-tocopherol stereoisomers in humans after oral administration. Am J Clin Nutr. 1997;65(3):785-789. Accessed May 11, 2010.
Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Association between alpha-tocopherol, gamma-tocopherol, selenium and subsequent prostate cancer. J Natl Cancer Inst. 2000;92(24):2018-2023. Accessed May 11, 2010.
Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci USA. 1997;94(7):3217-3222. Accessed May 11, 2010.
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 [published online ahead of print December 23, 2007]. Free Radic Biol Med. 2008;44(6):1203-1208. Accessed May 11, 2010.
Reiter E, Jiang Q, Christen S. Anti-inflammatory properties of alpha- and gamma-tocopherol [published online ahead of print January 11, 2007]. Mol Aspects Med. 2007; 28 (5-6):668-691. Accessed May 11, 2010.
Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. Gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Natl Acad Sci USA. 2000;97(21):11494-11499. Accessed May 11, 2010.
Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. J Nutr. 1985;115 (6):807-813. Accessed May 11, 2010.
Nappo F, De Rosa N, Marfella R, De Lucia D, Ingrosso D, Perna AF, et al. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA. 1999;281(22):2103-2112. Accessed May 11, 2010.
Valkonen MM, Kuusi T. Vitamin C prevents the acute atherogenic effects of passive smoking. Free Radic Biol Med. 2000;28(3):428-436.
Jeserich M, Schindler T, Olschewski M, Unmüssig M, Just H, Solzbach U. 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;20(22):1676-1680. Accessed May 11, 2010.
Wilkinson IB, Megson IL, MacCallum H, Sogo N, Cockcroft JR, Webb DJ. Oral vitamin C reduces arterial stiffness and platelet aggregation in humans. J Cardiovasc Pharmacol. 1999;34(5):690-693.
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;103(5):1715-1721. Accessed May 11, 2010.
Hernández M, García-Pagán JC, Turnes J, Bellot P, Deulofeu R, Abraldes JG, et al. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology. 2006;43(3):485-491.
Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992;3(3):194-202.
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;78(5):999-1010. Accessed May 11, 2010.
Losonczy KG, Harris TB, Havlik RJ. Vitamin E and Vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: The Established populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr. 1996;64(2):190-196. Accessed May 11, 2010.