Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis - Article Review - Dr. Anthony Hodsman
This article appraisal is part of the EMiNEM Bone and Mineral Metabolism Series. Click here to reach the EMiNEM homepage on UKidney
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR,
Objectives To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women's Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.
Design Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies. Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling postmenopausal women.
Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.
Results In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16 718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P=0.05 for clinical myocardial infarction or stroke, P=0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P=0.04), stroke (1.20(1.00 to 1.43), P=0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P=0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28,072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P=0.004) and the composite of myocardial infarction or stroke (1.15(1.03 to 1.27), P=0.009).
Conclusions Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.
In a recent meta-analysis, the authors determined that the use of calcium supplements significantly increased the risk of myocardial infarction1. They now explore the hypothesis that co-administration of calcium supplement with vitamin D might modify this effect. The original Women's Health Initiative (WHI) investigators reported that women enrolled in the sub-study that randomised them to calcium plus vitamin D supplements or placebo were not at increased risk for cardiovascular events 2. However, roughly half the participants were taking personal (additional, non-protocol) supplements of both micronutrients at the time of randomisation, effectively changing the WHI sub-study to an evaluation of lower vs. higher doses of supplementation when an ITT analysis was performed. Using the WHI limited access, clinical trials dataset, the authors re-analysed the trial sub-groups, stratified according to the presence or absence of additional non-protocol calcium/vitamin D supplements.
Study design and study population
1) The primary analysis of the WHI dataset was carried out on the sub-group who weren't taking non-protocol (i.e. personal) calcium supplements at randomisation (n=16,718, or 46% of the whole study population). They were well-matched to the sub-groups taking personal calcium supplements, although there was a slight excess of baseline cardiovascular risk. As expected half the patients were on study protocol HRT. An assessment of cardiovascular risk was performed in the calcium plus vitamin D vs placebo groups.
2) A meta-analysis of cardiovascular risk was performed using the WHI limited access dataset, and 2 additional RCT's of calcium plus vitamin D, (one of which was the large RECORD trial)
3) The magnitude of the risk of cardiovascular events with calcium plus vitamin D was similar to that previously reported by these authors in a meta-analysis of 11 trials of calcium supplements (without vitamin D)1. Thus the meta-analysis of the 3 calcium plus vitamin D trials was pooled with the calcium trials, providing patient-level data in 24,869 people in 6 trials (WHI and 5 RCT's of calcium supplements), and trial-level data in 28,072 people in 9 trials (WHI and 8 RCT's of calcium supplements).
Intervention or observation
For the WHI limited-access dataset, an assessment of cardiovascular risk (MI, stroke, coronary revascularisation, together with composite end-points including MI or stroke) was performed in the calcium plus vitamin D vs placebo groups, using Cox proportional hazards models adjusted for age, prevalent cardiovascular disease at baseline and randomisation status WHI Trial.
Meta-analytical methodology was otherwise similar to the author's previous report 1.
Primary endpoint, secondary endpoint
There were 4 pre-specified endpoints in the WHI dataset ( MI, coronary revascularisation, death from MI, and stroke) and their combinations. Serial ECG's allowed detection of silent MI's.
The endpoints in the meta-analyses were limited to MI, stroke, and the combined incidence of MI and stroke.
The hazard ratios with the WHI sub-group taking calcium plus vitamin D (but choosing not to take additional personal calcium supplements, were significant (p < 0.05) for many of the cardiovascular endpoints – see abstract. However there was no increased risk for any cardiovascular endpoint in the sub-groups taking additional personal calcium supplements.
Complete trial-level data for cardiovascular events were available for 20,090 people in the meta-analyses of the 3 trials of calcium plus vitamin D. The HR's for MI (1.21), Stroke (1.20) and the composite of MI or Stroke (1.16) were all significant (p ≤ 0.05).
When the results of the 3 trials of calcium plus vitamin D were pooled with those of the trials with calcium supplements, there was an increased risk of MI whether evaluating patient-level data (HR 1.26, p=0.005) or trial-level data (HR 1.24, p=0.004).
The authors have generated a great deal of discussion around the safety of routine calcium supplements in the management of osteoporosis in the non-uremic population. In their discussion the authors carefully address the limitations of their analysis of the WHI dataset, including their choice to include only those subjects not taking additional "personal" calcium/vitamin D supplement to "unmask" the excess cardiovascular risk in this post-hoc sub-group analysis, together with the risks of unknown confounding factors.
The authors point out that the excess of cardiovascular risk is very similar across the meta-analyses, lending plausibility to the findings. However, there are several anomalies, including;
i)the lack of a dose effect - an increase in the calcium intake from 500 to > 1000 mg/day in the sub-group taking additional personal calcium supplements, had no effect to modify the cardiovascular risk.
ii)Indeed, in the group taking personal (non-protocol) calcium supplements, the overall incidence of cardiovascular events were actually lower.
For a detailed review of the "calcium supplement debate", readers are referred to the position paper from the Professional Practice Committee of the American Society for Bone and Mineral Research 3. In this report the difficulties surrounding the conduct of RCT's involving single, readily available micronutrients are discussed. The benefits and harms are often small, and therefore difficult to document rigorously. Finally, there are other meta-analyses/RCT's in which no evidence of cardiovascular harm could be demonstrated. The debate continues!
Impact on practice
The use of nutritional calcium supplements, particularly in postmenopausal women, is widely used in the belief that they play a key role in prevention and treatment of osteoporosis. In the current report; the authors conclude in their discussion that..."in our analysis, treating 1000 patients with calcium or calcium and vitamin D for five years would cause an additional six myocardial infarctions or strokes (number needed to harm of 178) and prevent only three fractures (number needed to treat of 302)". If "these data justify a reassessment of the use of calcium supplements in older people", then the use of the much larger doses of calcium salts routinely used in dialysis patients as a dietary phosphate binder should also be reassessed in the dialysis population in whom the risk of cardiovascular complications is many-fold higher.
1. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. Bolland MJ, Avenell A, Baron JA et.al. BMJ 2010; 341:c3691
2. Calcium/vitamin D supplementation and cardiovascular events. Hsia J, Heiss G, Ren H et.al.. Circulation 2007; 115: 846
3. The challenges of the single micronutrient study; commentary on calcium supplements and cardiovascular events. (June 2011) Bockman RS, Zapapowski C, Kiel DP, Adler, RA. http://www.asbmr.org/Statements.aspx
Reviewed by Reviewed by Dr. Anthony Hodsman