After the Shutes: Vitamin E Trials and Legacy

When Evan Shute and his colleague Dr. A. Vogelsang published their short letter on vitamin E and coronary heart disease in Nature in June 1946, they started an argument that outlived both Shute brothers. Over the next six decades, vitamin E was tested in small angina studies, in a Canadian double-blind trial, in an American crossover study, in two very large Harvard observational studies, and finally in some of the largest randomised trials ever run on a single nutrient, including one organised from Hamilton, Ontario, in the same province as the Shute Institute in London.

This page follows that research in order, describing what each study tested, the dose it used and what its authors reported, without adding a verdict of its own. It then sets out the argument made by the Shutes’ supporters — that the brothers’ individually adjusted, often higher-dose protocol was never itself put to the test — and closes with Linus Pauling’s view of the brothers, their induction into the Orthomolecular Medicine Hall of Fame in 2004, and the Institute’s record of more than 30,000 patients. The story of the 1946 claims themselves is told on Vitamin E and the Heart.

Table of Contents

  1. Early Angina Studies (1948–1949)
  2. Anderson’s Double-Blind Trial (1974)
  3. Gillilan’s Crossover Study (1977)
  4. The Antioxidant Revival: the 1993 Harvard Cohorts
  5. CHAOS (1996)
  6. HOPE and HOPE-TOO: A Canadian Trial
  7. The Women’s and Physicians’ Health Studies
  8. The 2005 High-Dose Meta-Analysis
  9. Dose, Protocol and the Advocates’ Argument
  10. Pauling, the Hall of Fame and the Shute Legacy
  11. Key Research Papers
  12. Connections

1. Early Angina Studies (1948–1949)

The Shutes’ early reports were clinical case series: patients treated in practice, with the physicians describing how they fared. Within two years of the Nature letter, other physicians began publishing on the question. In January 1948 the Lancet carried a short paper by D. H. Makinson, S. Oleesky and R. V. Stone titled “Vitamin E in angina pectoris”. Later that winter the same journal printed a one-page item under the same title by Wilfrid Shute, Evan Shute and Vogelsang.

In 1949 the New England Journal of Medicine published “Vitamin E in the treatment of angina pectoris” by I. S. Ravin and K. H. Katz. The PubMed records of these early papers carry titles only, with no abstracts, and their full texts could not be consulted, so their designs and results are not described here. What the titles show is the shape of the debate: from 1948 onward, the question had moved out of the Shute Institute and into other hospitals, and angina — chest pain from a heart muscle short of blood — had become the test case.

The brothers answered with papers of their own. In 1949 the Annals of Internal Medicine printed their account of “The physiological and biochemical basis for the use of vitamin E in cardiovascular disease”, setting out why they believed the vitamin worked. Their explanation — that vitamin E lowered the oxygen needs of heart muscle, encouraged new collateral vessels and might help to dissolve clots, as Maclean’s summarised it in 1953 — is described on Wheat Germ Oil and Alpha-Tocopherol.

By the early 1970s the question had been reviewed several times. In 1973 R. E. Hodges published a review titled “Vitamin E and coronary heart disease” in the Journal of the American Dietetic Association. According to Charles Marshall’s 1986 book Vitamins and Minerals: Help or Harm?, as cited by Wikipedia, Hodges noted that the Shute brothers’ studies were not controlled and concluded that “massive doses of vitamin E are useless in the prevention or treatment of coronary heart disease.” The review itself has no abstract in PubMed, so the wording here is Hodges’s as Marshall quoted it.

Back to Table of Contents

2. Anderson’s Double-Blind Trial (1974)

The trial most often cited from this period was run by T. W. Anderson and published in the Canadian Medical Association Journal in February 1974. It was a randomised, double-blind study: neither the patients nor the doctors assessing them knew who was receiving vitamin E and who was receiving a dummy capsule.

According to the paper’s abstract, forty patients with angina pectoris were given either 3,200 IU of vitamin E a day or a placebo for nine weeks. That dose was higher than most of the figures the Shutes themselves reported using. Fifteen further patients who were already taking vitamin E on their own, at 400 to 2,400 IU a day, were also studied.

Anderson reported that the trial gave no statistically convincing evidence that vitamin E benefited angina. He was careful about what that meant: a small effect could not be ruled out with a study of this size, and he judged that further trials were justified. A companion report by Anderson and D. B. Reid, “A double-blind trial of vitamin E in angina pectoris”, appeared the same year in the American Journal of Clinical Nutrition; its PubMed record has no abstract.

The trial came two years after Evan Shute had written to the same journal under the title “Proposed study of vitamin E therapy” (1972), a one-page letter whose PubMed record carries the title only.

Back to Table of Contents

3. Gillilan’s Crossover Study (1977)

In 1977 Gillilan, Mondell and Warbasse published “Quantitative evaluation of vitamin E in the treatment of angina pectoris” in the American Heart Journal. Their study enrolled 48 patients with stable angina whose coronary artery disease had been confirmed.

The design was a double-blind crossover: each patient spent one period on vitamin E and another on a placebo, so that each person served as his or her own comparison. The vitamin E was given as 1,600 IU a day of d-alpha-tocopherol succinate, a natural-source form, for six months.

The study measured things that could be counted rather than only described: how long patients could exercise on a treadmill, how well the left ventricle (the heart’s main pumping chamber) worked, and how often chest pain occurred. According to the abstract, vitamin E produced no improvement in exercise capacity, left-ventricular function or the frequency of angina.

The dose, 1,600 IU, sat at the top of the range that later advocates attribute to the Shutes for angina and coronary disease (see section 9).

Back to Table of Contents

4. The Antioxidant Revival: the 1993 Harvard Cohorts

For a decade after Gillilan, vitamin E and the heart drew little attention. That changed when researchers came to think of heart disease partly in terms of oxidation — the idea that LDL cholesterol does its damage in artery walls after it has been chemically altered by free radicals. Vitamin E, a fat-soluble antioxidant carried in the same particles, became a natural candidate for protection. (Its chemistry is described on Vitamin E.)

In May 1993 the New England Journal of Medicine printed two papers side by side from Harvard researchers. These were observational cohort studies: they followed large groups of people over time and compared what they ate and took with what happened to them, without assigning anyone a treatment.

Both teams wrote that their findings did not prove that vitamin E caused the lower risk: people who choose to take supplements may differ from those who do not in many other ways. The supplement doses involved were mostly well below those the Shutes had reported giving, but the findings revived interest in a question many physicians had regarded as closed.

Back to Table of Contents

5. CHAOS (1996)

The first large randomised trial of vitamin E in patients with established coronary disease was the Cambridge Heart Antioxidant Study, known as CHAOS, published in the Lancet in 1996 by Stephens and colleagues in Cambridge, England. It enrolled 2,002 patients with coronary disease and gave them either alpha-tocopherol (400 IU or 800 IU a day) or a placebo, with a median follow-up of 510 days.

The trial reported two findings that pointed in different directions, and both belong in the record:

The CHAOS doses — 400 and 800 IU — were within the range the Shutes had described using, though fixed rather than adjusted patient by patient.

Back to Table of Contents

6. HOPE and HOPE-TOO: A Canadian Trial

The Heart Outcomes Prevention Evaluation (HOPE) was coordinated from Hamilton, Ontario, by Salim Yusuf and colleagues. It tested two treatments at once — a blood-pressure drug and vitamin E — and the vitamin E results were published in the New England Journal of Medicine in January 2000, in a paper separate from the drug results.

HOPE enrolled 9,541 people aged 55 or over who were at high risk of heart attack or stroke. Half received 400 IU a day of natural-source vitamin E and half a placebo, for an average of 4.5 years. The main outcome — heart attack, stroke or death from cardiovascular causes — occurred in 16.2% of the vitamin E group and 15.5% of the placebo group, a relative risk of 1.05 that was not statistically significant. The investigators found no effect on any of the three parts of that outcome, and reported no significant adverse effects of vitamin E.

Part of the group was then followed further in an extension called HOPE-TOO, reported in JAMA in 2005 by Lonn and colleagues. After a median of about seven years, the investigators reported no benefit of vitamin E for cancer or for major cardiovascular events. They also reported a higher risk of heart failure in the vitamin E group (relative risk 1.13).

For the Shute story, HOPE carries a geographical echo: it was a Canadian trial, run from a city in the same province as the Shute Institute, testing the nutrient the brothers had championed there half a century earlier.

Back to Table of Contents

7. The Women’s and Physicians’ Health Studies

Two further American trials tested vitamin E in healthy people, asking whether it could prevent a first heart attack or stroke rather than treat existing disease.

The Women’s Health Study (2005)

Led by Lee and colleagues and published in JAMA in July 2005, the Women’s Health Study gave 39,876 women either 600 IU of vitamin E or a placebo every other day, and followed them for an average of 10.1 years. Major cardiovascular events — heart attack, stroke or cardiovascular death — were not significantly reduced (relative risk 0.93). Cardiovascular deaths alone were lower in the vitamin E group (relative risk 0.76), and total mortality was essentially unchanged (relative risk 1.04).

The Physicians’ Health Study II (2008)

Published in JAMA in November 2008 by Sesso and colleagues, the Physicians’ Health Study II gave 14,641 male physicians 400 IU of vitamin E every other day (and, in a separate comparison, vitamin C) or placebo, for a mean of eight years. Vitamin E had no effect on major cardiovascular events (hazard ratio 1.01). The trial reported a higher rate of haemorrhagic stroke — stroke caused by bleeding in the brain — in the vitamin E group (hazard ratio 1.74).

Taken over a day, the doses in both trials averaged less than 400 IU, because the capsules were taken on alternate days.

Back to Table of Contents

8. The 2005 High-Dose Meta-Analysis

In January 2005 the Annals of Internal Medicine published a meta-analysis by Miller and colleagues, which pooled the results of 19 randomised trials of vitamin E involving 135,967 participants. The question was not heart disease specifically but death from any cause.

The authors divided the trials by dose. In the trials using high doses — 400 IU a day or more — they calculated that all-cause mortality was higher in the vitamin E groups, by 39 deaths per 10,000 people (P = 0.035). Their dose–response analysis suggested that risk began to rise above about 150 IU a day.

The authors concluded that high-dosage vitamin E supplements may increase all-cause mortality, as the paper’s title states. They also set out the analysis’s limits: the high-dose trials were often small, and many were carried out in people with chronic diseases, so the findings might not apply to healthy adults. The safety side of vitamin E is covered on the site’s Vitamin E toxicity page.

Back to Table of Contents

9. Dose, Protocol and the Advocates’ Argument

Supporters of the Shutes’ work have answered the trial record with one central argument: the brothers’ method was never tested as they practised it. The fullest modern statement of this view is Andrew W. Saul’s 2003 paper “Vitamin E: A Cure in Search of Recognition”, published in the Journal of Orthomolecular Medicine, the journal of the International Society for Orthomolecular Medicine.

Saul’s argument, in summary, runs as follows:

The two higher-dose trials of the 1970s complicate the picture in both directions. Anderson used 3,200 IU a day, well above the Shutes’ usual figures, and Gillilan used 1,600 IU of a natural-source form for six months; both reported no measurable benefit for angina, though both were small. The advocates’ reply is that these were short trials of one condition at a fixed dose. These positions are reported here as their holders state them; the dose figures are historical, not instructions.

Back to Table of Contents

10. Pauling, the Hall of Fame and the Shute Legacy

The Shutes found their strongest scientific ally in Linus Pauling, the two-time Nobel laureate whose own campaign for vitamin C followed a similar path of public enthusiasm and professional resistance. In his 1986 book How to Live Longer and Feel Better, as quoted by Wikipedia, Pauling wrote that “there is no doubt that Wilfrid Shute and Evan Shute were convinced that vitamin E is the most important substance in the world. I confess to having the same feeling about vitamin C.” Pauling’s own story is told on his page.

The orthomolecular movement — the school, named by Pauling, that treats illness with substances normally present in the body, often in large amounts — counts the Shutes among its pioneers. In 2004 both brothers were inducted into the Orthomolecular Medicine Hall of Fame.

The institution the brothers founded outlived them both. The Shute Institute at 10 Grand Avenue in London, Ontario, opened in 1948, published its own journal, The Summary, from 1949, and continued after Evan’s death in 1978 and Wilfrid’s in 1982. In 1953 Maclean’s reported the brothers’ own figure of about 10,000 patients treated in seven years. According to the finding aid for Evan Shute’s papers at the University of Chicago Library, the Institute closed in 2010 after treating more than 30,000 patients. Its building, an 1882 house called Waverly, is a designated heritage property.

The brothers’ wider legacy is visible in the way vitamin E is discussed today. The idea that a nutrient could be given in doses far above dietary levels to treat disease, rather than only to prevent deficiency, passed from the Shutes to Pauling and the orthomolecular physicians who followed. The large trials of the 1990s and 2000s, whatever their results, were in part a long answer to a question first put by two brothers from a Bruce Peninsula farm. Their lives are told on Life and Times.

Back to Table of Contents

Key Research Papers

  1. Vogelsang A, Shute EV. Effect of vitamin E in coronary heart disease. Nature. 1946;157:772. PubMed PMID: 21064771
  2. Makinson DH, Oleesky S, Stone RV. Vitamin E in angina pectoris. Lancet. 1948;1(6490):102. PubMed PMID: 18919158
  3. Shute WE, Shute EV, Vogelsang AB. Vitamin E in angina pectoris. Lancet. 1948;1(6495):301. PubMed PMID: 18933887
  4. Ravin IS, Katz KH. Vitamin E in the treatment of angina pectoris. N Engl J Med. 1949;240(9):331-3. PubMed PMID: 18123946
  5. Shute WE, Shute EV, Vogelsang A. The physiological and biochemical basis for the use of vitamin E in cardiovascular disease. Ann Intern Med. 1949;30(5):1004-8. PubMed PMID: 18126739
  6. Hodges RE. Vitamin E and coronary heart disease. J Am Diet Assoc. 1973;62(6):638-42. PubMed PMID: 4576935
  7. Shute EV. Proposed study of vitamin E therapy. Can Med Assoc J. 1972;106(10):1057. PubMed PMID: 5032131
  8. Anderson TW. Vitamin E in angina pectoris. Can Med Assoc J. 1974;110(4):401-6. PubMed PMID: 4204790
  9. Anderson TW, Reid DB. A double-blind trial of vitamin E in angina pectoris. Am J Clin Nutr. 1974;27(10):1174-8. PubMed PMID: 4214473
  10. Gillilan RE, Mondell B, Warbasse JR. Quantitative evaluation of vitamin E in the treatment of angina pectoris. Am Heart J. 1977;93(4):444-9. PubMed PMID: 320856
  11. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328(20):1444-9. PubMed PMID: 8479463
  12. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993;328(20):1450-6. PubMed PMID: 8479464
  13. Stephens NG, Parsons A, Schofield 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(9004):781-6. PubMed PMID: 8622332
  14. Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):154-60. PubMed PMID: 10639540
  15. Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J, Dagenais GR; HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293(11):1338-47. PubMed PMID: 15769967
  16. Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005;294(1):56-65. PubMed PMID: 15998891
  17. Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Glynn RJ, Gaziano JM. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2008;300(18):2123-33. PubMed PMID: 18997197
  18. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37-46. PubMed PMID: 15537682

PubMed Topic Searches

  1. Vitamin E and angina pectoris
  2. Vitamin E supplementation and cardiovascular disease (randomised trials)
  3. Papers by Evan V. Shute
  4. Papers by Wilfrid E. Shute

Further Reading

Back to Table of Contents

Connections