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31 May 2011
Re-analysis of data from a large randomised controlled trial has found a modest increase in the risk of some cardiovascular events in postmenopausal women using calcium and vitamin D supplements to prevent osteoporotic fractures. This is in contrast to the conclusions of the original study authors, who found no increased risk. The finding appears to be supported by inclusion of previously unpublished data from other studies in a meta-analysis. However, there are limitations to the data which make its implications unclear.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Action
We have been advised that regulatory agencies including the MHRA have considered the relevant data, and no change to prescribing practice is currently recommended. Unless and until they publish advice on this matter, prescribers should consider these data in discussions with patients and weigh the potential benefits and risks of using calcium and vitamin D on an individual basis. They should do so in line with NICE guidance on primary and secondary prevention of osteoporotic fracture, which recommends prescribers to consider offering these supplements to postmenopausal women who receive treatment (e.g. with bisphosphonates) unless they are confident that the patient has an adequate calcium intake and is vitamin D replete. Prescribers may also consider offering calcium (at least 1g/day depending on nutritional calcium intake) plus vitamin D (700-800 units/day) to people not receiving pharmaceutical treatment or prophylaxis, but who are at high risk of falls or fractures such as frail elderly people living in care homes.
What is the background to this?
As discussed in MeReC Rapid Review 1772, an earlier meta-analysis by this research group concluded that calcium supplements without vitamin D increased the risk of myocardial infarction (MI) versus control by about 30% in relative terms, but did not find a statistically significant effect on risk of stroke or death. However, the analysis did not include studies of calcium plus vitamin D versus control. This limited the relevance of those data in the light of UK practice, which is usually to prescribe both together.
The Women’s Health Initiative (WHI) CaD study was a placebo-controlled, double blind randomised controlled trial (RCT) designed to test the effects of calcium and vitamin D supplements on fracture risk, especially hip fractures, in post menopausal women. It recruited 36,282 postmenopausal women, 50 to 79 years of age, (mean 62 years), and randomly assigned them to receive 1g of elemental calcium (as calcium carbonate) with 400 units of vitamin D daily, or placebo. Fractures were ascertained for an average follow-up period of 7 years. Although not the primary outcome examined, it reported no statistically significant adverse effect of calcium and vitamin D on any cardiovascular (CV) end point. However, 54% of the participants were taking personal (i.e. non-study) calcium supplements at randomisation and 47% were taking personal vitamin D supplements. The authors of the study discussed here hypothesised that the common personal use of calcium supplements might have obscured an adverse effect of calcium and vitamin D on CV risk. They therefore analysed the dataset to examine this possibility. They also included data from other trials in two meta-analyses: one considering the risks of calcium plus vitamin D on CV outcomes, and one considering the CV risks of calcium with or without vitamin D.
What does this study claim?
Full results are given below. In the re-analysis of the WHI data, calcium and vitamin D supplementation in women not using non-study supplements (n=16,718) was associated with an increased risk of clinical MI which just reached conventional limits of statistical significance (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.00 to 1.50, P=0.05). Applying this HR to the rate of clinical MI in the control group (2.03% over 7 years) suggests an NNH of 224 over 7 years. There was an observed increase in the risks of revascularisation, stroke, and total MI (i.e. including MI diagnosed on routine ECG) but none of these was statistically significant. There was a very slight observed reduction in all-cause mortality but again this was not statistically significant. There was a significant increase in the risks of the composites of clinical MI or revascularisation, and of clinical MI or stroke; but not in the risks of total MI or CHD death, or of total MI, coronary heart disease (CHD) death or revascularisation (HR 1.13, 95%CI 0.99 to 1.29, P=0.07). When previously unpublished data from two other trials (an extra 3,372 participants) were added in a meta-analysis, similar results were obtained.
Among women in WHICaD using non-study calcium supplements, there was no statistically significant effect on any outcome except all-cause mortality, which was decreased in the women randomised to calcium and vitamin D (HR 0.84, 95%CI 0.73 to 0.97, P=0.01). Applying this HR to the rate of death in the control group (4.36% over 7 years) suggests an NNT of 143 over 7 years).
Finally, the authors carried out a meta-analysis of patient-level data (six trials, n=24,869) and trial-level data (nine trials, n=28,072) of calcium supplements with or without vitamin D. Both found statistically significant increases in the risks of MI, stroke and the composite of MI or stroke, but not all-cause mortality.
So what?
As the authors say, the apparent increased risk is ‘modest’ (sic) but because of the widespread use of calcium and vitamin D supplements, the effect at a population level could be substantial. However, there are several reasons for prescribers to be cautious before changing their policy on prescribing calcium and vitamin D on the basis of this study.
Firstly, as the related editorial points out
“Although for the WHI study as a whole, randomisation 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. This could have contributed to the surprising findings of a 16% increased risk of clinical myocardial infarction or stroke in women allocated to calcium plus vitamin D supplements who did not use personal supplements and a 16% reduction in mortality in women given the same intervention who did use such supplements”.
The study authors note that the women using personal supplements differed from those who did not with regard to a number of factors that might influence CV risk but say that there is evidence that a significant interaction between these factors and risk of death from MI or CHD is unlikely. However, this does not consider the interaction with other outcomes, the effects of unmeasured confounders, and also assumes that all confounders (measured and unmeasured) were equally distributed between intervention and control groups within the subsets of users or non-users of personal supplements.
Secondly, in the WHI CaD study re-analysis the observed increased risks of clinical MI, and the composite of clinical MI or stroke, in women not taking non-study supplements were at the limit of conventional levels of statistically significance. In other words, the possibility that these findings were a result of chance is just about at the level beyond which the possibility is conventionally judged too high to accept the finding ‘beyond reasonable doubt’. The P value was lower (lower probability of a chance effect) in the meta-analysis but we should note that the WHI CaD re-analysis contributed about 75% to 80% of the weighting to this, and so the problems from inadequate randomisation may still have been material; and also information about the reliability of the additional data is not presented. Interpretation and application of the additional meta-analyses of calcium with or without vitamin D are more difficult because usual UK practice is to prescribe both substances together. In addition, the dose of vitamin D used in WHI CaD was about half that that usually recommended in the UK. The possible protective effect of vitamin D on possible cardiovascular adverse effects from calcium supplements is discussed further in MeReC Rapid Review 1772.
Finally, notwithstanding these questions, if there is an increased risk of CV events, this must be weighed against the beneficial effects of calcium and vitamin D supplementation. The authors suggest that treating 1000 women with calcium or calcium plus vitamin D for five years would prevent three fractures and cause an additional six MIs or strokes. However, the women in WHI CaD were at lower risk of falls and fractures than those usually recommended to receive calcium and vitamin D supplementation in the UK (see study details, below), so the absolute benefit in such women is likely to be less than in people at high risk. The Cochrane review found a significant benefit from calcium and vitamin D (at a daily dose of 1.2g calcium plus 800 units vitamin D) in higher risk, institutionalised people but not in lower risk, community dwelling people. The NNT to prevent hip fracture in higher risk people was 37 over 2 to 3 years. It should also be noted that people at higher baseline risk of CV events would have a higher absolute risk of possible harms from calcium and vitamin D supplements.
The major trials of pharmaceutical treatments for osteoporosis (such as bisphosphonates) included calcium and vitamin supplements. NICE guidance on use of such drugs for primary or secondary prevention of osteoporotic fracture advises prescribers to consider using supplements unless they are confident that patients have an adequate calcium intake and are vitamin D replete. The editorial associated with this meta-analysis notes that in a Finnish retrospective cohort study of 23,615 patients, calcium plus vitamin D or vitamin D supplements used in combination with anti-osteoporotic drugs reduced mortality in men by 28% (HR 0.72, 95%CI 0.50 to 1.03) and women by 38% (HR 0.62, 95%CI 0.50 to 0.76). This provides some reassurance and underlines the need to weigh carefully the possible risks and benefits in each individual patient’s circumstances.
Design Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with up to eight other studies.
Patients The WHI CaD study included 36,282 postmenopausal women, 50 to 79 years of age, (mean 62 years). Fractures were ascertained for an average follow-up period of 7.0 years. At baseline, their mean BMI was 29kg/m2, 11% had had a fracture at age of 55 years or older, but 62% had not fallen in the previous 12 months. 68% were previous or current users of HRT, and in 60% of those where a baseline hip T-score was available, this was greater than –1.0.
Intervention and comparison The WHI CaD study randomised women to receive 1g of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily, or placebo
Outcomes and results (these analyses)
WHI CaD reanalysis
Results which are not statistically significant (P>0.05) are marked ‘NS’
| CV endpoint | No non-study calcium | Non-study calcium | ||
| HR (95%CI) | P value | HR (95%CI) | P value | |
| Clinical MI | 1.22 (1.00 to 1.50) | 0.05 | 0.92 (0.75 to 1.13) | 0.4 (NS) |
| Total MI* | 1.20 (0.99 to 1.47) | 0.07 (NS) | 0.94 (0.77 to 1.14) | 0.5 (NS) |
| Revascularisation | 1.15 (0.98 to 1.34) | 0.09 (NS) | 1.08 (0.93 to 1.27) | 0.3 (NS) |
| Stroke | 1.17 (0.95 to 1.44) | 0.1 (NS) | 0.83 (0.67 to 1.02) | 0.08 (NS) |
| Total MI or CHD death | 1.15 (0.97 to 1.38) | 0.1 (NS) | 0.97 (0.81 to 1.16) | 0.7 (NS) |
| Clinical MI or revascularisation | 1.16 (1.01 to 1.34) | 0.04 | 1.06 (0.92 to 1.23) | 0.4 (NS) |
| Clinical MI or stroke | 1.16 (1.00 to 1.35) | 0.05 | 0.88 (0.76 to 1.02) | 0.09 (NS) |
| Total MI, CHD death or revascularisation | 1.13 (0.99 to 1.29) | 0.07 (NS) | 1.08 (0.94 to 1.23) | 0.3 (NS) |
| Death from all causes | 0.99 (0.86 to 1.14) | 0.9 (NS) | 0.84 (0.73 to 0.97) | 0.01 |
*includes clinically silent MI diagnosed from changes in routine serial ECGs
Meta-analysis of data from WHI CaD plus previously unpublished data from two other trials (n=20,090), Calcium and vitamin D versus placebo:
| CV endpoint | Relative risk [RR] (95%CI) | P value |
| MI | 1.21 (1.01 to 1.44) | 0.04 |
| Stroke | 1.20 (1.00 to 1.43) | 0.05 |
| MI or stroke | 1.16 (1.02 to 1.32 | 0.02 |
Meta-analysis of calcium with or without vitamin D
Patient level data from six trials including WHI CaD, n=24,869, trial-level data from nine trials including WHI CaD, n=28,072
| CV endpoint | Patient level data | Trial-level data | ||
| HR (95%CI) | P value | RR (95%CI) | P value | |
| MI | 1.26 (1.07 to 1.47) | 0.005 | 1.24 (1.07 to 1.45) | 0.004 |
| Stroke | 1.19 (1.02 to 1.39) | 0.03 | 1.15 (1.00 to 1.32) | 0.06 |
| MI or stroke | 1.17 (1.05 to 1.31) | 0.005 | 1.15 (1.03 to 1.27) | 0.009 |
| Death from all causes | 1.04 (0.95 to 1.14) | 0.4 | 1.04 (0.95 to 1.13) | 0.5 |
Sponsorship Funded by the Health Research Council of New Zealand, and the University of Auckland School of Medicine Foundation. The authors are independent from the funders
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