Risk of Ischemic Stroke Associated with Calcium Supplements and Interaction with Oral Bisphosphonates: A Nested Case-Control Study.

Conflicting results about the association of calcium supplements (CS) with ischemic stroke (IS) have been reported. We tested this hypothesis by differentiating between CS alone (CaM) and CS with vitamin D (CaD) and between cardioembolic and non-cardioembolic IS. We examined the potential interaction with oral bisphosphonates (oBs). A nested case-control study was carried out. We identified incident IS cases aged 40-90 and randomly sampled five controls per case matched by age, sex, and index date. Current users were compared to non-users. An adjusted odds ratios (AOR) and 95% CI were computed through conditional logistic regression. Only new users were considered. We included 13,267 cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls (20,147 and 41,231, respectively). CaM use was associated with an increased risk of cardioembolic IS (AOR = 1.88; 95% CI: 1.21-2.90) in a duration-dependent manner, while it showed no association with non-cardioembolic IS (AOR = 1.05; 95% CI: 0.74-1.50); its combination with oBs increased the risk of cardioembolic IS considerably (AOR = 2.54; 95% CI: 1.28-5.04), showing no effect on non-cardioembolic. CaD use was not associated with either cardioembolic (AOR = 1.08; 95% CI: 0.88-1.31) or non-cardioembolic IS (AOR = 0.98; 95% CI: 0.84-1.13) but showed a small association with cardioembolic IS when combined with oBs (AOR = 1.35; 95% CI: 1.03-1.76). The results support the hypothesis that CS increases the risk of cardioembolic IS, primarily when used concomitantly with oBs.

Association of oral bisphosphonates with cardioembolic ischemic stroke: a nested case-control study.

Background: Bisphosphonates have been reported to increase the risk of atrial fibrillation. Therefore, it is conceivable that they may increase the risk of cardioembolic ischemic stroke (IS). However, most epidemiological studies carried out thus far have not shown an increased risk of IS, though none separated by the main pathophysiologic IS subtype (cardioembolic and non-cardioembolic) which may be crucial. In this study, we tested the hypothesis that the use of oral bisphosphonates increases specifically the risk of cardioembolic IS, and explored the effect of treatment duration, as well as the potential interaction between oral bisphosphonates and calcium supplements and anticoagulants. Methods: We performed a case-control study nested in a cohort of patients aged 40-99 years, using the Spanish primary healthcare database BIFAP, over the period 2002-2015. Incident cases of IS were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, matched for age, sex, and index date (first recording of IS) using an incidence-density sampling. The association of IS (overall and by subtype) with the use of oral bisphosphonates within the last year before index date was assessed by computing the adjusted odds ratios (AOR) and their 95% CI using a conditional logistic regression. Only initiators of oral bisphosphonates were considered. Results: A total of 13,781 incident cases of IS and 65,909 controls were included. The mean age was 74.5 (SD ± 12.4) years and 51.6% were male. Among cases, 3.15% were current users of oral bisphosphonates, while among controls they were 2.62%, yielding an AOR of 1.15 (95% CI:1.01-1.30). Of all cases, 4,568 (33.1%) were classified as cardioembolic IS (matched with 21,697 controls) and 9,213 (66.9%) as non-cardioembolic IS (matched with 44,212 controls) yielding an AOR of 1.35 (95% CI:1.10-1.66) and 1.03 (95% CI: 0.88-1.21), respectively. The association with cardioembolic IS was clearly duration-dependent (AOR≤1 year = 1.10; 95% CI:0.82-1.49; AOR>1-3 years = 1.41; 95% CI:1.01-1.97; AOR>3 years = 1.81; 95% CI:1.25-2.62; p for trend = 0.001) and completely blunted by anticoagulants, even in long-term users (AOR>1 year = 0.59; 0.30-1.16). An interaction between oral bisphosphonates and calcium supplements was suggested. Conclusion: The use of oral bisphosphonates increases specifically the odds of cardioembolic IS, in a duration-dependent manner, while leaves materially unaffected the odds of non-cardioembolic IS.

Risk of Myocardial Infarction Among New Users of Calcium Supplements Alone or Combined With Vitamin D: A Population-Based Case-Control Study.

A population-based case-control study was conducted to evaluate the risk of acute myocardial infarction among new users of calcium supplements either in monotherapy (CaM) or in combination with vitamin D (CaD). A total of 23,025 cases and 114,851 controls randomly sampled from the underlying cohort and matched with cases by age, sex, and index date were included. New users of CaM and CaD were categorized as current users, recent users, past users, and nonusers. We computed adjusted odds ratios (AORs) and their 95% confidence intervals (CIs) among current users as compared with nonusers through a conditional logistic regression. No increased risk was associated with CaM overall (59 cases (0.26%) and 273 controls (0.24%); AOR = 0.80; 95% CI 0.59-1.09), nor was it found in any of the conditions examined. Instead, the use of CaD was associated with a decreased risk (275 cases (1.19%) and 1,160 controls (1.45%); AOR = 0.78; 95% CI 0.67-0.90), dose and duration-dependent, and particularly evident in patients with a high cardiovascular risk (AOR = 0.59; 95% CI 0.43-0.81).

Risk of Ischemic Stroke Associated With Calcium Supplements With or Without Vitamin D: A Nested Case-Control Study.

BACKGROUND: There is controversy surrounding the risk of ischemic stroke associated with the use of calcium supplements either in monotherapy or in combination with vitamin D. METHODS AND RESULTS: A nested case-control study was performed with patients aged 40 to 89 years old, among whom a total of 2690 patients had a first episode of nonfatal ischemic stroke and for which 19 538 controls were randomly selected from the source population and frequency-matched with cases for age, sex, and calendar year. Logistic regression provided the odds ratios while adjusting for confounding factors. A sensitivity analysis was performed by restricting to patients who were new users of calcium supplements as either monotherapy or with vitamin D. Calcium supplementation with vitamin D was not associated with an increased risk of ischemic stroke (odds ratio 0.85; 95% confidence interval, 0.67-1.08) in the population as a whole or under any of the conditions examined (dose, duration, background cardiovascular risk, sex, or age). Calcium supplement monotherapy was not associated with an increased risk in the population as a whole (odds ratio 1.18; 95% confidence interval, 0.86-1.61), although a significant increased risk at high doses (≥1000 mg/day: odds ratio 2.09; 95% confidence interval, 1.25-3.49; <1000 mg: odds ratio 0.76; 95% confidence interval, 0.45-1.26) compared with nonuse was observed. The sensitivity analysis did not affect the inferences, with similar results observed among new users as to the overall study population. CONCLUSIONS: This study suggests that calcium supplements given as monotherapy at high doses may increase the risk of ischemic stroke, whereas their combination with vitamin D seems to offset this hazard.