Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial

Abstract

Objective To determine the effect of calcium supplementation on myocardial infarction, stroke, and sudden death in healthy postmenopausal women. Design Randomised, placebo controlled trial. Setting Academic medical centre in an urban setting in New Zealand. Participants 1471 postmenopausal women (mean age 74): 732 were randomised to calcium supplementation and 739 to placebo. Main outcome measures Adverse cardiovascular events over five years: death, sudden death, myocardial infarction, angina, other chest pain, stroke, transient ischaemic attack, and a composite end point of myocardial infarction, stroke, or sudden death. Results Myocardial infarction was more commonly reported in the calcium group than in the placebo group (45 events in 31 women v 19 events in 14 women, P=0.01). The composite end point of myocardial infarction, stroke, or sudden death was also more common in the calcium group (101 events in 69 women v 54 events in 42 women, P=0.008). After adjudication myocardial infarction remained more common in the calcium group (24 events in 21 women v 10 events in 10 women, relative risk 2.12, 95% confidence interval 1.01 to 4.47). For the composite end point 61 events were verified in 51 women in the calcium group and 36 events in 35 women in the placebo group (relative risk 1.47, 0.97 to 2.23). When unreported events were added from the national database of hospital admissions in New Zealand the relative risk of myocardial infarction was 1.49 (0.86 to 2.57) and that of the composite end point was 1.21 (0.84 to 1.74). The respective rate ratios were 1.67 (95% confidence intervals 0.98 to 2.87) and 1.43 (1.01 to 2.04); event rates: placebo 16.3/1000 person years, calcium 23.3/1000 person years. For stroke (including unreported events) the relative risk was 1.37 (0.83 to 2.28) and the rate ratio was 1.45 (0.88 to 2.49). Conclusion Calcium supplementation in healthy postmenopausal women is associated with upward trends in cardiovascular event rates. This potentially detrimental effect should be balanced against the likely benefits of calcium on bone.Trial registration Australian Clinical Trials Registry ACTRN 012605000242628.

Calcium supplementation and the risks of atherosclerotic vascular disease in older women: Results of a 5-year RCT and a 4.5-year follow-up

“…We addressed this by preplanning a per-protocol analysis, setting the compliance level at 80% or more of the medication. Bolland and colleagues (1) also report a per-protocol analysis of those consuming 60% or more of the medication, and the rate ratio for adverse events increased and the confidence interval increased, but the results again were nonsignificant.…”

“…First, misclassification of myocardial infarction and stroke and poor concordance between selfreported events and adjudicated or validated events, particularly with angina, congestive heart failure, and peripheral arterial disease, have been reported in other studies. (1,13,14) As is done in pharmaceutical trials, our analysis chose to analyze serious adverse events, that is, verified hospitalization and death data attributed to ASVD, to provide a more robust analytical endpoint. It should be noted that the validity of Western Australian Hospital Morbidity Data System (HMDS) data has been verified exhaustively with over 250 publications, (3) whereas cardiovascular endpoints have been assessed against self-reported and adjudicated medical records and found to be as accurate as adjudicated medical records.…”

Relationships between vascular calcification, calcium metabolism, bone density, and fractures

“…The study design and results of both trials have been published previously. (10,14,15) The women were over 55 years of age, were not taking agents for osteoporosis (including hormone-replacement therapy or vitamin D supplements in doses > 1000 IU/day), and were free from major ongoing illnesses, including hepatic, renal, or thyroid dysfunction, malignancy, metabolic bone disease, or serum 25-hydroxyvitamin D concentration of less than 25 nmol/L and had normal spine BMD for their age (Z-score > -2). The men were over 40 years of age, free from major ongoing illness (including coronary heart disease, hypertension, diabetes, renal or thyroid dysfunction, liver disease, malignancy, or metabolic bone disease), had an estimated 5-year cardiovascular risk of greater than 15% and a serum 25-hydroxyvitamin D concentration of less than 25 nmol/L, had normal spine and hip BMD for their age (Z-score > -2), and were not using lipid-lowering therapy or agents that might have an impact on calcium metabolism.…”

“…(5,6) In patients with renal failure, calcium supplements accelerate vascular calcification and increase mortality in both dialysis and predialysis populations. (7)(8)(9) Calcium supplements also have been associated with increased cardiovascular event rates in a randomized, controlled trial in older women (10) and subsequent meta-analysis. (11) The mechanism of the association between calcium metabolism and vascular disease is unknown.…”

Update in Women’s Health for the General Internist

“…17 A previous randomized controlled trial in healthy older women with prespecified CVD outcomes showed possible increases in MI and cardiovascular events in women who took calcium. 18 What this Study Adds This meta-analysis included 15 RCTs that had at least 100 participants aged 40 and older and had a study duration of at least 1 year. Among a total of 15 eligible trials, 5 provided patient level data on 8,151 participants and 11 provided trial level data on 11,921 participants.…”