For CVD prevention, evidence on vitamins inconclusive at best

Those looking for good news about the benefits of vitamins, multivitamins and minerals for CVD prevention have been disappointed recently.

A recommendation statement issued by the US Preventive Services Task Force (USPSTF) in February declared that current evidence on almost all supplements is insufficient to assess the balance of benefits and harms for the prevention of CVD and cancer. This is the first update since a 2003 recommendation.

There is, however, sufficient evidence to determine that beta carotene and vitamin E do not reduce the risk for CVD or cancer, and there is adequate evidence that beta carotene increases the risk for lung cancer in high-risk individuals, Virginia A. Moyer, MD, MPH, chair of the task force, and colleagues wrote in the statement published in Annals of Internal Medicine.

Other studies, reviews and meta-analyses on vitamins for CVD prevention released in the past year have been mostly negative, leading some to question whether any future research is warranted.

However, dietary supplement use remains common. Many supplements are advertised to prevent CVD and cancer. According to the USPSTF report, 49% of US adults used at least one dietary supplement from 2007 to 2010, and more than $28 billion was spent on dietary supplements in 2010.

Cardiologists should not necessarily assume the book is closed on the topic and should remain vigilant about keeping up with the latest research as their patients ask about the benefits of supplementation.

Effects, outcomes of supplementation

The negative effects of insufficient nutrition, such as adverse CVD outcomes for vitamin D-deficient individuals, are well recognized. However, the new USPSTF recommendation statement acknowledges that supplementation may not be the answer.

“Our recommendation is not that people stop taking supplements; rather, it is that people recognize that taking supplements is not going to benefit them in terms of preventing heart disease or cancer,” Moyer, who is vice president of maintenance, certification and quality for the American Board of Pediatrics, Chapel Hill, N.C., told Cardiology Today. The most important message from the report is that “while good nutrition is essential to overall health, the best way to get that is through a balanced diet rich in fruits and vegetables and whole grains. All of those things have been associated with reduced risk for CVD and cancer, whereas taking vitamin supplements has not been demonstrated to get that result.”

Similarly, the American Heart Association’s position is that nutritional deficiencies should be addressed via diet, not supplementation, Linda V. Van Horn, PhD, RD, an AHA spokeswoman and professor of preventive medicine at Northwestern University Feinberg School of Medicine, said in an interview.

“Because some studies have shown adverse events and outcomes from taking certain vitamin/mineral supplements, general encouragement to take supplements is unwarranted and potentially harmful,” she said. “For so many other reasons, including prevention of other chronic diseases, weight management and role modeling a healthy lifestyle for the family, dietary sources of nutrients, including dietary fiber, fatty acids and so on, are recommended over single- or dual-supplement use.”

This does not necessarily mean that there will be never be evidence for supplementation, said Keith C. Ferdinand, MD, FACC, FAHA, professor of clinical medicine at Tulane University, New Orleans, and chair of the National Forum for Heart Disease and Stroke Prevention.

“The lack of evidence in any review of present data does not mean a lack of a true association,” he told Cardiology Today. “Clinical studies have always had difficulty trying to define the relationship between vitamins, either as single or multivitamins, and their effects on CVD. There is biological plausibility, for instance, that still remains for the effects of vitamin D in CVD, especially in African Americans.”

Also compounding the issue, it is inherently difficult to conduct clinical trials with vitamins, especially studies large enough to come to definitive conclusions, according to Nanette K. Wenger, MD, MACC, MACP, FAHA, emeritus professor of medicine at Emory University School of Medicine, consultant for Emory Heart and Vascular Center, and a Cardiology Today Editorial Board member.

“The major challenge to that kind of trial is that they require large populations,” she said. “So many patients have already made up their mind that either they don’t have any interest in enrolling or they don’t have interest in stopping a medication or supplement that they like to take.” Another challenge is that “for some of the vitamins, there is even disagreement about what normal levels are and what normal requirements are.”

Trend of negative research

Results from other research and analyses published in the past year covered by Cardiology Today, many related to vitamin D, have been mixed at best.

There was bad news for multivitamin supplementation in the TACT trial, which reported no difference in CV events, death or hospitalization between patients assigned an oral 28-component high-dose multivitamin and multimineral mixture and those assigned placebo.

According to a review by Vijay Kunadian, MBBS, MD, FRCP, from Newcastle University in the United Kingdom, and colleagues, although a number of longitudinal studies have demonstrated a link between low levels of vitamin D and increased CV adverse events, randomized controlled trials have mostly failed to confirm that vitamin D supplementation led to improved CV outcomes. Kunadian and colleagues found only six randomized controlled trials investigating vitamin D supplementation on CV events or surrogate markers of CAD. Of those, only one, a study by Forman and colleagues investigating the effect of vitamin D supplementation on BP in black adults, was positive. Forman and colleagues found that for each 1,000 units per day of vitamin D3 (cholecalciferol), there was a 1.4-mm reduction in systolic BP (P=.04). The study shows that “perhaps the story is not complete for vitamin D, and we need to ensure that the trials which are ongoing continue,” Ferdinand said.

Among the trials with less favorable outcomes for vitamin D was VitDISH, which investigated the effect of vitamin D supplementation on isolated systolic hypertension in older adults. At 3 months, results showed no difference in mean BP between the vitamin D supplementation and placebo groups.

Ferdinand noted that VitDISH may have produced negative results because the supplements provided increased vitamin D levels to 28 ng/mL, which may not be adequate to affect BP and other CV outcomes, whereas in the study by Forman, many patients exceeded vitamin D levels of 30 ng/mL, “where you may start to see a BP effect.”

At the AHA’s 2013 Scientific Sessions, Thomas J. Wang, MD, of Vanderbilt University, reported that he and colleagues had stopped DAYLIGHT, a study of people with prehypertension or stage 1 hypertension and vitamin D deficiency, early because no BP-lowering benefit was found for vitamin D supplementation.

A series of analyses published in The Lancet by Mark J. Bolland, PhD, from the University of Auckland, New Zealand, and colleagues concluded that vitamin D supplementation does not prevent MI, stroke, cancer or bone fractures and that results of future trials were unlikely to yield different conclusions. Bolland and colleagues also performed a trial sequential analysis and found no evidence that vitamin D supplementation altered the RR of any CV endpoint by 15% or more, and concluded that adding future positive trials to a trial sequential analysis would be unlikely to change the results.

There have also been two recent analyses casting doubt on the ability of fatty acid supplementation to reduce coronary risk. Rajiv Chowdhury, MD, PhD, from the University of Cambridge, and colleagues analyzed 27 randomized controlled trials on fatty acid supplementation and coronary disease, and they found no evidence that fatty acid supplementation was associated with risk reduction. In the Age-Related Eye Disease Study 2 (AREDS2), Denise E. Bonds, MD, MPH, of the NHLBI, and colleagues found no reduction in the risk for CVD or secondary CVD outcomes associated with supplementation with two long-chain omega-3 fatty acids or two macular xanthophylls in older people.

Continued investigations

Several large-scale studies are currently in progress.

Most notable is VITAL, for which JoAnn E. Manson, MD, DrPH, of Brigham and Women’s Hospital, and colleagues have enrolled 25,000 men aged at least 50 years and women aged at least 55 years without history of CVD and cancer. The randomized, double blind, placebo-controlled 2x2 factorial trial will examine vitamin D (in the form of cholecalciferol) and omega-3 fatty acid (in the form of fish oil [combined eicosapentaenoic acid and docosahexaenoic acid]) for the prevention of CVD and cancer.

There are also large-scale trials of vitamin D for the primary prevention of CVD underway in Australia, Europe, Finland and New Zealand, according to the review by Kunadian and colleagues.

Questions have been raised about whether such research should continue. After the TACT trial and the preliminary findings of the USPSTF recommendation statement were reported in December, Eliseo Guallar, MD, DrPH, from the Welch Center for Prevention, Epidemiology and Clinical Research in Baltimore, and colleagues wrote an Annals of Internal Medicine editorial calling for an end to the use of and research on vitamins for chronic disease prevention.

“Beta carotene, vitamin E and possibly high doses of vitamin A supplements are harmful,” they wrote. “Other antioxidants, folic acid and B vitamins, and multivitamin and mineral supplements are ineffective for preventing mortality or morbidity due to major chronic diseases. … These vitamins should not be used for chronic disease prevention. Enough is enough.”

Duffy Mackay, ND, senior vice president for scientific and regulatory affairs for the Council for Responsible Nutrition, a trade association representing the dietary supplement industry, responded that lack of research is not the same as lack of positive results. “We strongly support both the need for more research and the need for the scientific community to come to terms with a rigorous approach to studying nutrition that may not reflect the current model of studying drugs,” he said in a press release.

C. Noel Bairey Merz, MD, FACC, FAHA, director of the Barbra Streisand Women’s Heart Center, the Linda Joy Pollin Women’s Heart Health Program and the Preventive Cardiac Center at Cedars-Sinai Medical Center, questioned whether that will happen.

The studies that were conclusive enough for the USPSTF to make recommendations from “were large and expensive studies, so I do not think it is likely that they will be replicated,” said Bairey Merz, a member of the Cardiology Today Editorial Board. “There is little to no industry support to conduct large trials due to lack of regulation and high profit margin.”

Patients must be counseled

As uncertainty remains on the safety and efficacy of vitamins and other supplements for CVD and cancer prevention, experts Cardiology Today interviewed encouraged frank discussion with patients about which supplements they are taking and why.

For instance, patients must pay attention to whether any supplements they are taking may interact with drugs prescribed them, Jacintha Cauffield, PharmD, BCPS, associate professor of pharmacy practice at the Lloyd L. Gregory School of Pharmacy at Palm Beach Atlantic University, West Palm Beach, Fla., said in an interview.

For example, “there is concern about coenzyme Q10 interacting with warfarin, and if a patient is taking both, he should be monitored. Also, omega-3 fatty acids, especially when taken at doses used in cardiovascular trials, can increase the risk for bruising and bleeding,” she said.

Some supplements taken for non-CV reasons can interfere with CV drugs, she noted. “The big one is St. John’s wort, which is still fairly popular. It can interact with cytochrome P450 3A4 and can decrease the levels of drugs, like statins and calcium channel blockers such as amlodipine.”

Patients with no known nutritional deficiencies who want to take supplements should be counseled on diet, Van Horn said.

“[Cardiologists] should encourage adherence to a healthy diet as recommended by the 2010 US Dietary Guidelines and/or the DASH studies that have shown favorable reductions in cardiovascular risk factors and did not include a vitamin/mineral supplement,” she said.

Ferdinand agreed that “in the general population, it’s probably at this particular point wasting money and resources using vitamin D supplementation if their purpose is to prevent CVD,” but it may make sense to investigate further in certain circumstances. “If a patient is at increased risk and has obvious hypertension, especially if dark-skinned or African American, it may make sense to give one check of vitamin D levels and give them appropriate supplementation if the patient is deficient,” he said.

If a cardiologist has a patient with a nutritional deficiency, it is best to conduct a thorough nutritional assessment and refer the patient to a registered dietitian if necessary, Van Horn said. “If it is determined that the diet is inadequate in specific nutrients, it will become apparent what the missing foods might be that have contributed to this problem,” she said. “This would trigger discussion regarding the missing foods and why they are avoided.”

If a conclusion is drawn that supplementation is necessary, the patient should be counseled on how to select the right supplement, Cauffield said.

“For example, with calcium supplements, there was concern about the lead content of some,” she said. “It’s not just a matter of counseling patients on what’s appropriate to take, but also what’s appropriate to avoid. The processes to make the vitamins aren’t as strong or as consistent as they are to make drugs, and I think that is often overlooked.”

Wenger said it is important to frame the discussion in a way that patients can easily understand. “For example, physicians who are trying to persuade their patients not to be taking all these preparations would be well served by having a one-page document that they could print out and hand to patients that had the imprimatur of the [USPSTF].”

Lack of good answers

Although there is now enough evidence to dissuade patients from taking vitamin E or beta carotene for CVD prevention, evidence on all other supplements is insufficient. Because of the inherent difficulties of performing randomized controlled trials of supplements, it may always be, except possibly in the case of vitamin D and fatty acids.

“The important point in terms of management is that if patients ask whether they should be taking these things, the data we found suggests we don’t have a good answer to that, but there certainly weren’t any strong data suggesting benefit,” Moyer said.

Given the lack of definitive conclusions on the issue and the popularity of vitamins among Americans, it is up to cardiologists to find out which supplements their patients are taking and why, and to suggest alternatives if necessary.

“The good news is that other than beta carotene, there does not appear to be harm. The bad news is that there does also not appear to be benefit,” Bairey Merz said. “So the old saying that Americans have the most expensive urine in the world due to our relatively high consumption of vitamins appears to remain true.” – by Erik Swain

Disclosure: Bairey Merz, Cauffield, Ferdinand, Moyer and Van Horn report no relevant financial disclosures. Wenger is chair of the Data and Safety Monitoring Board for the VITAL trial.