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Vitamin-D deficiency linked to fatal stroke in whites but not blacks

Racial differences did not explain the excess risk in blacks compared with whites, said lead author Dr Erin Michos


The Heart.org, Susan Jeffrey, Nov 15, 2010

Although blacks had higher rates of both fatal stroke and vitamin-D deficiency, racial differences did not explain the excess risk in blacks compared with whites, said lead author Dr Erin Michos (Johns Hopkins University School of Medicine, Baltimore, MD).

In whites, vitamin-D deficiency was associated with a twofold increase in fatal stroke after adjustment for other risk factors.

A randomized placebo-controlled trial, the Vitamin D and Omega-3 Trial (VITAL), funded by the National Institutes of Health and run by Harvard Medical School and Brigham and Women's Hospital, is currently investigating whether 2000-IU daily vitamin D or fish oil containing about 1 g of omega-3 fatty acids reduces incident cancer, heart disease, or stroke. Investigators plan to enroll 25% black subjects in that trial.

"We certainly await those results before we can strongly endorse widespread screening and treatment programs for vitamin-D deficiency," Michos concluded. "But while we're waiting for the clinical-trial data, I think there are compelling enough data that I do recommend screening for vitamin-D deficiency. It's very common, and doses of 1000 to 2000 IU a day appear safe with little downside, and we know it has good benefit for the bone."

The findings are being presented Monday here at the American Heart Association 2010 Scientific Sessions but were discussed Sunday at a press conference here.


Independent risk factor

Previously, the Johns Hopkins group and others have shown vitamin-D deficiency to be a risk factor for cardiovascular disease, MI, and all-cause and cardiovascular mortality, independent of traditional cardiovascular risk factors, Michos said. Vitamin-D deficiency can be easily screened for through 25-hydroxyvitamin D [25(OH)D] testing and treated by vitamin-D supplementation and modest sunlight exposure, she said.

Previous work has also noted racial differences in 25(OH)D vitamin-D levels, which were thought perhaps to explain some of the excess cardiovascular risk seen in blacks compared with whites, Michos noted. Vitamin-D deficiency is highly prevalent in the US, but particularly so for black populations, since melanin in the skin blocks the UVB synthesis of vitamin D, acting as a natural sunscreen, she said. It's estimated that 80% of blacks in the US have insufficient vitamin-D levels.

Prior studies looking at the relationship of vitamin D to stroke have been done only in white populations to date. "Because vitamin-D deficiency is more common in blacks and stroke is more common in blacks, we decided to examine whether low vitamin-D levels contribute to the excess risk of stroke in blacks compared with whites," she said.

For this analysis, they used the third National Health and Nutrition Examination Survey (NHANES III), a nationally representative cross-sectional sample of US adults. Included were 7981 white and black adults with no history of cardiovascular disease and stroke. Between 1988 and 1994, they answered medical questionnaires and underwent physical exam and 25(OH)D testing.

NHANES III was linked to the National Death Index in 2006, which was used to identify participants who had died with stroke listed as the cause of death. Over an average of 14 years of follow-up, there were 176 total stroke deaths in 116 whites and 60 blacks.

"At baseline, as we anticipated that we'd see, blacks had much lower 25(OH)D levels than whites," Michos said. Vitamin-D deficiency, defined as a 25(OH)D of <15 ng/mL, was seen in 6.6% of whites vs 32.3% of blacks.

"We confirmed prior work that among whites, those who were vitamin-D deficient had a twofold increased risk of dying of a fatal stroke compared with whites who had optimal vitamin-D levels," she said. "However, to our surprise, we actually saw no association of vitamin-D levels with fatal stroke among blacks."

Risk of fatal stroke associated with vitamin-D deficiency (25[OH]D <15 ng/mL) in white vs black participants

Group
Hazard ratio
95% CI
p
Whites
2.16
1.04-4.49
<0.05
Blacks
0.94
0.50-1.79
NS

Still, blacks had a higher rate of fatal stroke compared with whites, a 65% increase after adjustment for a variety of risk factors, including age, sex, education, income, body-mass index, smoking, physical activity, and C-reactive protein, among others.

Rate of fatal stroke for blacks vs whites

End point
Hazard ratio
95% CI
Fatal stroke
1.65
1.07-2.54

She pointed to limitations of their study, including that vitamin D was measured only once at baseline, which may not capture lifetime patterns of vitamin-D status. They had only 60 fatal stroke events among blacks, so they may have been underpowered to detect a difference.

In addition, the methodology didn't allow them to assess nonfatal or silent strokes or transient ischemic attacks, she said, "but this is an area that our group is going to be actively working on."

She speculated that it is possible that blacks may have a relative adaptive resistance to the adverse effects of low vitamin-D levels; for example, despite lower vitamin-D levels, blacks have lower fracture and osteoporosis rates than whites.


Association is not causation

During discussion here, Michos said that while information from the VITAL trial will be valuable, providing evidence-based data to help guide patient management, she is concerned that with a single dose of vitamin D, the trial will not answer the question it has set out to answer.

"I'm a big believer that what matters biologically is having adequate levels of vitamin D as measured by 25-hydroxy vitamin-D levels," she said. "So I'm not sure there's one fixed dose that everybody should take, because your blood levels vary in response to a given dose based on your sun exposure, your genetics, your body-mass index. That dose may be too low for someone who's too vitamin-D deficient; on the other hand, someone who has adequate vitamin-D levels may not need that dose."

Dr Michelle A Albert (Brigham and Women's Hospital, Boston, MA) is a coinvestigator on the VITAL trial and is responsible for the enrollment component for African Americans in the study.

At the press conference here, she agreed that it is difficult to use a single dose of vitamin D to ensure all subjects get to adequate levels. "However, I can tell you the dose was chosen to be one that would be as high as possible and not be toxic, to at least be powered to see an effect in the black population."

Michos acknowledged that it is the highest dose that's been used to date in a clinical trial. "By comparison, the Women's Health Initiative only used 400 IU, so they are to be commended," she said.

Albert was more cautious, though, about recommending vitamin-D supplements at this time after negative experience with antioxidant vitamins in the Women's Health Study. Vitamin D is promising, but she doesn't advocate vitamin D for her patients, she said, "because we don't have any evidence, any clinical-trial evidence that says that giving vitamin D will reduce your risk.

"We have a lot of epidemiologic data, observational data that suggest that higher levels are associated with lower risk, but we have been up that tree before, and we have to be very careful because we've failed up that tree before."

Dr Russell Luepker (University of Minnesota School of Public Health, Minneapolis) was moderator of the press conference. In an interview, he said that in his view, the data connecting vitamin-D levels and cardiovascular disease are too preliminary to have much impact on practice.

"We all got on the vitamin-E bandwagon a few years ago until finally somebody did some studies, including Drs Julie Buring and JoAnn Manson and the Brigham group, and they couldn't find anything, the HOPE trial couldn't find anything, and I think we need good studies before saying that, at least for cardiovascular disease," Luepker said.

Bone health in adults and bone growth in children is a "good enough reason to put [vitamin D] in the milk," he added, but they tend not to measure vitamin D for their patients at his institution. "As Michelle pointed out, we've been led down the pathway where epidemiologists say, 'Well, there's an association here, so obviously doing something about it must be the answer.' "

An epidemiologist himself, he still would like to see the results of VITAL and perhaps a confirmatory trial before changing clinical practice based on epidemiologic evidence.


Accumulating evidence

Other studies that will be presented here this week focus on other aspects of the connection between vitamin D and cardiovascular disease:

  • Researchers again used data from NHANES III and found serum vitamin-D levels were related to prehypertension. Dr Charumathi Sabanayagam (West Virginia University, Morgantown) and colleagues conclude that future randomized intervention trials should look at whether supplementation at that stage could prevent or delay onset of hypertension.
  • Dr Charles B Eaton (Brown University, Providence, RI) and colleagues looked at 25(OH) levels in 1829 postmenopausal women in the Women's Health Initiative observational study and control groups followed over 10 years for cardiovascular and all-cause death. They found low vitamin-D levels were associated with both mortality measures, but the association was attenuated after adjustment for other traditional risk factors; waist circumference was most prominent.
  • On Tuesday, researchers with lead author Dr Mathew Good (University of Kansas Medical Center, Kansas City) will report results of an observational study using a database of more than 10 000 male and female patients, which found that vitamin-D deficiency was associated with hypertension, coronary heart disease, cardiomyopathy, diabetes, and mortality (odds ratio 2.64, 95% CI 1.901-3.662; p<0.0001). Vitamin-D supplementation in this cohort was associated with a "substantial survival benefit," the researchers note, with a hazard ratio of 0.39 (95% CI 0.277-0.534; p<0.0001). The benefit was particularly evident in those who were deficient and was independent of aspirin or statin use, they note.

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