Null Series — Vitamins and wholegrains for heart disease prevention

[Null Series Part One here.]

Beliefs and ideologies can be stronger than the science, especially when it comes to our diets. Sadly, so can our fears. Millions of Americans take vitamins and worry about what they eat, fearing that if they fail to eat loads of antioxidants, free radicals will lead to heart disease, cancers and other chronic diseases of aging. Yet, the strongest studies continue to show these concerns to be unsupported.

Remember, science can never prove something beyond all doubt, but it can disprove an hypothesis or scary claim. That’s why sound clinical trials, designed to be fair tests of hypotheses, that fail to support a belief, and show us there is nothing to worry about, are the most important of all. But for those null studies to help us, we first have to hear about them.

Vitamin C and E

Vitamins E has been popularly believed for decades to hold special antioxidant properties and many Americans fear they don’t get enough in their foods to protect them from age-related diseases. [See Vitamin E deficiency, below.] Millions more take mega-doses of vitamin C. The small amounts of essential vitamins needed by our bodies to prevent deficiencies, as are readily obtained by most people from an unrestrictive diet, do lots of good things for us. That doesn’t mean, though, that more is better or will help us live longer and prevent cancers or heart disease.

The latest results of the Physician’s Health Study II*, testing vitamin C and vitamin E for the prevention of cardiovascular disease among men, were just published. It exemplified a null study with news men can use.

This was a randomized, placebo-controlled, double-blind clinical trial that had enrolled 14,641 male physicians, aged 50 years or older, between July 1999 and 2001. The participants included healthy men (to test the vitamins for primary prevention) and 754 men with a history of heart attack, stroke or cancer (to test the vitamins for secondary prevention).

The men were randomized into four groups to receive the equivalent of 200 IU of a-tocopherol and 500 mg vitamin C daily, or one of the vitamins with a placebo, or just a placebo. The intervention and control groups were evenly matched in all characteristics evaluated, including age, BMI, smoking, minimal physical activity, alcohol, aspirin use, hypertension, high cholesterol, diabetes, and parental history of heart attacks.

The men were followed through August 2007 by way of questionnaires. Their cardiovascular events were confirmed using medical records and reviewed by a blinded physician committee, and deaths were confirmed by death certificates or autopsy reports. After 8-10 years later, about 70% of the men were still taking their study pills, but with similar compliance among all groups.

After about 8 years of follow-up, 841 (11.5%) of the men in the vitamin E group had died compared to 820 (11.1%) in the placebo group; and 857 (11.6%) men in the vitamin C group had died compared to 804 (11%) in the placebo group. No statistical difference in deaths between any of the groups.

There was also no difference in overall cardiovascular events among those taking the vitamins and those taking a placebo (the lines appear as one):

The risks for individual events varied slightly. Vitamin E was associated with 8 fewer deaths from heart attacks and 16 more from hemorrhagic stroke. Vitamin C use was associated with 13 fewer stroke deaths and 8 more from heart attacks.

Among just the men with a history of heart disease or strokes, there was also no difference with either vitamin for the secondary prevention of cardiovascular events. There was no reduction in risks among the men assigned to both vitamins. The authors were also unable to find any statistical association between any of the individual confounding factors and cardiovascular events among any arm of the trial.

The authors noted that this is one of the longest trials on record of vitamin E and vitamin C for cardiovascular disease. It provided no evidence for concerns that men who don’t take these antioxidant vitamins might increase their risks for any bad cardiovascular outcome or for dying early. And, as you can see by the findings, there’s not even a hint to suggest that results would suddenly change to show a benefit for those who take extra vitamins for even longer. They concluded:

These data provide no support for the use of these supplements in the prevention of cardiovascular disease in middle-aged and older men.

Correlations are not causations

We’ll now switch gears and look at a study that didn’t make the news as a null study, but should have.

Epidemiological studies — that observe correlations among groups of people — are the source for the vast majority of food fears and beliefs in the near magical merits or perils of certain foods or nutrients. Epidemiological studies with untenable findings also aren’t always reported in the news as null studies, and correlations are often reported as causal, leading us to believe there’s a lot more evidence than there really is. So, when the premise is later put to test in randomized clinical trials, the gold standard of evidence, and fails to hold up, it can come as a surprise if we haven’t been paying close attention all along.

Remember, epidemiological studies are used to look for links to begin formulating hypotheses to be tested in intervention studies. Without even a strong, credible link between a food and a disease or premature death, it’s not where scientists will continue to look in their search for a cause or preventative. They move on, looking for other links to formulate a better hypothesis. Null well-conducted epidemiological studies can help us move on, too.

Whole grains, high-fat dairy and eggs

Earlier this month, media reported that eating more wholegrains and less eggs and high-fat dairy foods can reduce our risks of developing heart failure. We heard that a large study of more than 14,000 people that ran for 13 years had shown people lowered their risk for heart failure by 7% for each one serving increase of wholegrains in their diet; and that their risks were 8% higher for every serving increase in high-fat dairy. This new study was said to add further support for the healthy eating recommendations by the American Heart Association. The source of these news stories was a press release from the American Dietetic Association.

Let’s take a closer look. The news was reporting on an epidemiological study just published in the November issue of the Journal of the American Dietetic Association. The authors, led by Jennifer A. Nettleton, Ph.D., at the Division of Epidemiology and Community Health at the University of Minnesota in Minneapolis, used the database of the Atherosclerosis Risk in Communities Study (ARIC).

The ARIC recruited 15,792 middle-age people from four communities in 1987 and is sponsored by the National Heart, Lung and Blood Institute (NHLBI). The participants were given exams on enrollment, in 1990-2, 1993-5, and finally in 1996-8 and followed with annual phone calls. The 1987 and 1993 interviews included a modified 66-item food frequency questionnaires, and nutrients were estimated using Harvard’s Nutrient Database. The surveillance part of the ARIC is ongoing and has been monitoring inpatient heart failures since 2005, using local hospital discharge records and county death certificate. The quality ARIC database has been used to cull out hundreds of correlations, published in more than 525 epidemiological studies to date.

For this paper, the authors used the data on 14,153 people in the ARIC database, excluding those with incomplete information, underrepresented racial groups, and those who already had heart failure at enrollment. They used computer modeling to look for correlations between specific food groups and the cases of heart failure identified during the following 13.3 years.

The diets among the 1,140 people who developed heart failure during the study period and the 13,813 without heart failure were remarkably similar. Their calculated caloric intakes, protein, carbohydrate, total fats, saturated fats and trans fats, monounsaturated fats, polyunsaturated fats, dietary fiber, cholesterol, and sodium were comparable, as were the specific foods they consumed each day. Among the healthy versus heart failure groups, wholegrain were 1.3 (±0.01) versus 1.1 (±0.04) servings per day; fruits and vegetables were both 4 servings/day; high-fat dairy was 0.82 and 0.87 servings/day; eggs 0.29 versus 0.36 (±0.01); red meat or processed meat 1 serving/day in both groups; fish 0.32 serving/day; and nuts 0.37 versus 0.36/day. No real-life difference at all.

So, not surprisingly, the authors’ computer Cox proportional hazards regression model was unable to derive a single tenable odds ratio for heart failure associated with any dietary factor. They adjusted for energy intake; age; sex; race group; study center; education level; smoking; physical activity level; alcohol consumption; history of coronary heart disease, stroke, diabetes, and hypertension. All of the odds ratios hugged either side of null (1) — 0.93 to 1.23 — none beyond chance, statistical error or confounding factors.

It was a null study, finding no tenable correlation between any dietary factor and the onset of heart failure.

To split hairs among untenable findings and try to give them meaning has no merit, of course. Nuts, for example, were associated with an untenable 9% higher risk — more than the risk associated with high-fat dairy (8%) or the risk associated with red meat or processed meats (7%). Yet, we didn’t hear that nuts raised risks. Fruits and vegetables were associated with an untenable 2% higher risk — 9% higher than wholegrains. Of course, we didn’t hear that fruits and vegetables were associated with higher risks, either. None of these odds ratios are tenable, though, so it really didn't matter to scientists.

Instead, media reported the authors’ conclusion:

In this large, population-based sample of African-American and white adults, whole-grain intake was associated with lower HF risk, whereas intake of eggs and high-fat dairy were associated with greater HF risk after adjustment for several confounders… Overall, these data are consistent with traditional diet – CVD hypotheses and support recent findings suggesting greater whole-grain intake reduces HF risk and greater egg intake increases HF risk.

While focused on diet, the much more significant differences between the healthy and heart failure groups went unexplored and unreported. The most notable differences between those who developed heart failure compared to the healthy controls:

● hypertension was nearly twice as prevalent;

● coronary artery disease was 5 times as prevalent,

● diabetes was 3.5 times as prevalent; and

● a history of strokes was more than twice as prevalent.

Far more significant correlations, and more biologically plausible, than trying to derive meaning from two-tenths of a serving difference in wholegrains or a single egg every two weeks.

We also didn’t hear in the news that the authors had reported: “There were no significant interactions between dietary intake variables and BMI, sex, race, or baseline disease status (CVD, diabetes, or hypertension).”

The bottom line, again, is that this population study was unable to find any tenable correlation between any examined dietary factor and the development of heart failure. The hypothesis that diet plays a causal role in heart failure, and hence a preventative intervention, was unsupported in this study. Without even a solid link, food can’t possibly be the cause.

It’s another null study that can help us put our fears to rest.

© 2008 Sandy Szwarc

Vitamin E deficiency

How often do we hear that most of us are deficient in vitamin E because we eat so poorly?

When nutritional experts with the National Academy of Sciences, Institutes of Medicine, Food and Nutrition Board reviewed the evidence on vitamin E and levels among the U.S. population, to establish the government’s latest daily reference intakes (DRI), they reported: “Vitamin E deficiency occurs only rarely in humans, and overt deficiency symptoms in normal individuals consuming diets low in vitamin E have never been described. Vitamin E deficiency occurs only as a result of a genetic abnormality, as a result of fat malabsorption syndromes or protein-energy malnutrition.” Only a handful of families with a clinically evident vitamin E deficiency due to a genetic mutation have ever been described. Cystic fibrosis is one of the syndromes that can cause vitamin E deficiency. In underdeveloped countries, it is, of course, most related to starvation.

The term vitamin E actually refers to a family of eight structures: four tocopherols (alpha-, beta-, gamma-, and delta-) and four tocotrienols (alpha-, beta-, gamma-, and delta-). Alpha-tocopherol is the only form maintained in the human body and is found in the largest amounts in blood and tissues. It is also the form that appears to have the greatest biological significance and is used to establish dietary recommendations. Vitamin E is found in a wide range of foods — nuts, vegetable oils (safflower, cottonseed, olive, canola), grains, fruits, vegetables and fatty meats — which is why deficiencies among our general population and other developed countries are rare, according to these experts. They also found that most dietary surveys underestimate actual intakes.

The primary clinical sign of vitamin E deficiency is peripheral neuropathy, and if deficiency is severe and prolonged, it can lead to blindness and dementia. Deficiency symptoms are halted with vitamin E supplements. The hypothesis was proposed in 1989 that vitamin E might affect atherosclerosis in humans, since it appeared to inhibit LDL-oxidation in in-vitro laboratory studies. And the scientific process began. Three epidemiological studies subsequently reported inverse correlations between estimated intakes of vitamin E and heart disease, said the NAS review. To test the hypothesis, four large randomized, double-blind intervention trials using various dosages and forms of vitamin E alone have been conducted to evaluate it for secondary prevention among high risk populations most likely to show a benefit. They’ve failed to support the hypothesis of vitamin E as preventing heart disease and reducing mortality.

● The Cambridge Heart Antioxidant Study on coronary artery disease patients found a nonstatistical increase in fatal heart attacks but no decrease in overall mortality.

● The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study of male smokers in Finland found a 50% higher mortality from hemorrhagic strokes, a 16% lower mortality from ischemic stroke and 5% lower mortality from heart disease.

● The GISSI Prevenzione study of Italian heart attack patients found no benefit in reducing mortality or heart attacks or strokes after 3.5 years.

● The Heart Outcomes Prevention Evaluation Study (HOPE) of heart disease, stroke and peripheral artery disease patients also found no effect on reducing overall mortality, heart attacks or strokes.

The expert committee concluded: “As of this date, there are insufficient data on which to base a recommendation of supplemental vitamin E as a heart disease preventative for the general population.” The evidence for an effect on cancer risk is even weaker than that for cardiovascular disease, they noted. While various clinical trials are underway to see if vitamin E can reduce risks for certain diseases, even these trials may not lead to information applicable for the general population, they cautioned, as “these trials generally are targeting groups at high risk for particular diseases.”

Even more clinical trials have been conducted on various other antioxidant vitamins, alone and in combinations. As Cochrane Collaborative’s latest systematic review of every clinical trial of antioxidants (including vitamin C, vitamin E, beta-carotene, vitamin A and selenium) conducted since 1945 found: there is no sound evidence that antioxidants decrease mortality, nor any evidence to support a role of antioxidants for primary or secondary prevention. [Reviewed here.]

* Physicians Health Study II [Clinicaltrials.gov ID: NCT00270647] — the fine print: