Overall 1471 healthy postmenopausal women were randomised: 732 to calcium and 739 to placebo. Three hundred and thirty six women in the calcium group and 296 women in the placebo group stopped the study drug before the five year end point. Baseline characteristics were similar between the groups (table 1). Between baseline and five years significant changes were found in weight (−0.9 kg), systolic blood pressure (10 mm Hg), high density lipoprotein cholesterol levels (0.19 mmol/l), and low density lipoprotein cholesterol levels (−0.76 mmol/l); these did not differ between the groups. The flow chart of study participants has been presented previously.15
Overall, 90% of participants had complete follow-up. Among those still taking the study drugs at five years, tablet compliance was 85% in both groups in each six month period. When participants who discontinued the study drugs were included, compliance over the study was 58% in the placebo group and 55% in the calcium group (P=0.13).
Table 1 Descriptive and biochemical characteristics of healthy, postmenopausal women assigned to calcium supplementation or to placebo. Values are means (standard deviations) unless stated otherwise
Table 2 shows the numbers of women with possible cardiovascular events that were self reported or reported by family members. Although no difference was found between groups in the number of women with any cardiovascular event (angina, chest pain, myocardial infarction, or sudden death), a statistically significant increase was found in the number of women who had a myocardial infarction (P=0.01). Similar trends were found in the calcium group compared with the placebo group for stroke, transient ischaemic attack, and sudden death. The composite end point of myocardial infarction, stroke, or sudden death was higher in the calcium group (P=0.008).
Table 2 Potential vascular events self reported by healthy postmenopausal women assigned to calcium supplementation or to placebo or reported by family members. Values are numbers of women (numbers of events) unless stated otherwise
Table 3 shows the number of women with cardiovascular events that were self reported or reported by family members and were confirmed by the adjudication process. A statistically significant increase was found in myocardial infarction in the calcium group, but there was not a significant increase in stroke or the composite end point (P=0.076).
Table 3 Verified vascular events self reported by healthy postmenopausal women assigned to calcium supplementation or to placebo or reported by family members. Values are numbers of women (numbers of events) unless stated otherwise
Table 4 shows adjudicated data, including events not reported by participants. A statistically significant increase in the number of women with any of the end points in the calcium group was no longer found. When the data were expressed as event rates, however, the rate ratios for both myocardial infarction and the composite end point were of borderline significance. When these data for myocardial infarction were plotted over time the groups began to diverge at about 24 months, and thereafter continued to separate (figure), although statistical significance was not achieved (P=0.14). Time course analyses of the proportion of women with a verified stroke or a verified composite end point showed a similar temporal pattern (P=0.2-0.3 for both analyses, data not shown).
Table 4 Verified vascular events self reported by healthy postmenopausal women assigned to calcium supplementation or to placebo, reported by family members, and from the national database of hospital admissions in New Zealand.* Values are numbers of (more ...)
Kaplan-Meier survival plot showing proportion of healthy postmenopausal women assigned to calcium supplementation or to placebo that had a verified myocardial infarction during the study. Included are events self reported by participants and those from (more ...)
When the analyses in table 4 were restricted to events occurring in participants with more than 60% compliance since the start of the study no sudden deaths were found. For myocardial infarction, stroke, and myocardial infarction or stroke, event rates were little changed in the placebo group from those for the cohort shown in table 4 (6.6, 11.6, and 18.2), but event rates tended to be higher in the compliant members of the calcium group (15.5, 22.6, and 38.1). This was reflected in the respective rate ratios (2.4, 0.8 to 8.5, P=0.14; 2.0, 0.8 to 5.1, P=0.14; and 2.1, 1.1 to 4.4, P=0.03).
Poisson regression analysis was used to determine whether the effect of treatment on number of events per participant was independent of age and glomerular filtration rate (above or below median for each); history of ischaemic heart disease, stroke, hypertension, dyslipidaemia, and diabetes; and compliance with the study drug. The P values for the effect of treatment allocation were not significantly attenuated by adjustment for any of these potential confounders (table 5), but previous ischaemic heart disease and high compliance were identified as independent risk factors.
Table 5 Poisson regression models of effects of calcium supplementation or placebo and other variables on composite end point (myocardial infarction, stroke, or sudden death) in healthy postmenopausal women
No differences were found between groups in the number of women who had a verified ST segment elevation myocardial infarction or a verified non-ST segment elevation myocardial infarction, or in the number of women in whom the diagnosis of myocardial infarction was made by an elevated troponin level in the context of a recent operation or other important medical illness. Also, no differences were found between groups in the number of women with different clinical categories of stroke (partial anterior circulation infarct, total anterior circulation infarct, lacunar infarct, or posterior circulation infarct).19
The number of women needed to treat for five years to cause one myocardial infarction was 44, to cause one stroke was 56, and to cause one cardiovascular event was 29. By comparison the number needed to treat to prevent one symptomatic fracture was 50.