Analyses Find Calcium Plus Vitamin D Increases MI Risk



A year after publishing a meta-analysis finding a link between calcium supplements and cardiac event risk, a New Zealand–based research team says calcium supplements containing vitamin D are also linked to elevated cardiac risk.

The new findings, published online April 20 in the journal BMJ (doi:10.1136/bmj.d2040), come from two new analyses: an update of a recent meta-analysis and a re-analysis of data from a randomized, placebo-controlled 2007 trial of calcium and vitamin D supplementation enrolling 36,282 postmenopausal women.

The research team, led by Dr. Mark J. Bolland of the University of Auckland (New Zealand) had in July 2010 published a meta-analysis of data on nearly 12,000 participants from 11 randomized controlled trials (n = 11,921) that found calcium supplements without vitamin D associated with a 27% increased incidence of myocardial infarction (BMJ 2010;341:c3691).

Those findings appeared in some contrast to those from the 2007 trial, in which women were randomized to receive 1 g calcium and 400 IU vitamin D daily, and where no elevated cardiovascular risk was found (Circulation 2007;115:846-54).

For their current analysis, Dr. Bolland and colleagues revisited the dataset from that trial and isolated women known to have been taking personal supplements at the start of the trial (about 54%), evaluating their results separately from those of the women not taking personal calcium and/or vitamin D supplements at randomization. The original researchers’ inclusion of women taking personal supplements, Dr. Bolland and colleagues argued, may have masked any harmful effect from the supplements used in the trial.

Dr. Bolland and colleagues found that the hazard ratios for four cardiovascular events – myocardial infarction, coronary revascularization, death from coronary heart disease, and stroke – among nonsupplementing women assigned to calcium and vitamin D, ranged from 1.13 to 1.22, and all reached statistical significance. For the women who had been taking personal supplements at enrollment, by contrast, cardiovascular risk was unchanged with allocation to the study calcium and vitamin D.

Finally, the researchers pooled the data with previously unpublished data from two other placebo controlled trials of calcium and vitamin D and found increases in the risk of myocardial infarction similar to that observed in studies of calcium-only supplements.

Adding results for calcium and vitamin D trials to those from trials of calcium alone, Dr. Bolland and colleagues found "consistent evidence from 13 randomized, placebo controlled trials involving about 29,000 participants with about 1,400 incident myocardial infarctions and strokes that calcium supplements with or without vitamin D increase the risk of cardiovascular events," Dr. Bolland and colleagues wrote, putting the pooled increased risk at 25%-30% for myocardial infarction and 15%-20% for stroke.

The researchers acknowledged that there is much to be learned about how calcium and vitamin D supplementation might affect cardiac risk, and that more research was necessary, but hypothesized that an "abrupt change in plasma calcium concentration after supplement ingestion" may cause an adverse cardiac effect. The findings, they concluded, "justify a reassessment of the use of calcium supplements in older people."

In an editorial accompanying the current article, Dr. Bo Abrahamsen of Gentofte Hospital in Copenhagen, and Dr. Opinder Sahota of Nottingham (England) University Hospitals voiced concerns about the post hoc analysis used by Dr. Bolland and colleagues in reevaluating data from the 2007 trial, and emphasized that "insufficient evidence is available to support or refute the association" (BMJ 2011 April 20 [doi:10.1136/bmj.d2040]).

While as a whole, "randomization can be assumed to have been equal across the two arms in terms of confounders, measured and unmeasured, this may not have been true for the additional strata created in the post hoc analysis," they wrote. "Although it is straightforward to remove those who were taking their own supplements from the cohort when they make up uneven parts of the randomised arms, interpreting the results is difficult because of the loss of equal randomisation."

The current study was funded by the Health Research Council of New Zealand and the University of Auckland School of Medicine Foundation. Three authors, including Dr. Bolland, declared that they had no competing interests. Dr. Alison Avenell has had calcium used in studies supplied by Shire and Nycomed, and Dr. Ian R. Ried is a consultant to Fonterra, and has used calcium supplements provided by Mission Pharmacal in clinical trials.

Dr. Abrahemsen acknowledged receiving consultancy fees from Novartis, serving on advisory boards for Amgen and Nycomed, and receiving lecture fees from Eli Lilly and Proctor and Gamble. Dr. Sahota acknowledged receiving consultancy fees from Shire, serving on advisory boards for Amgen and Medtronic, and receiving lecture fees from Eli Lilly and Amgen.

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