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

Abstract

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

“…The suggested interaction of calcium supplements with oral bisphosphonates is an interesting finding that may provide some clues. Our group recently reported a specific increased risk of cardioembolic IS with oral bisphosphonates [ 15 ], which was clearly duration-dependent. Based on the model proposed by Kamel et al [ 28 ] for cardioembolism of atrial origin, we postulated that the long-term use of bisphosphonates might induce an atrial cardiopathy, associated or not with atrial fibrillation, which ultimately could be the primary biological substrate for thrombogenesis.…”

“…However, few distinguished between ischemic and hemorrhagic stroke, and among those focusing on ischemic stroke (IS), none distinguished between the two main pathophysiological subtypes (cardioembolic vs. non-cardioembolic), which may be critical as the biological mechanisms underlying the potential association of calcium supplements with each subtype may substantially differ. Recently, our group reported a specific increased risk of cardioembolic IS associated with the use of oral bisphosphonates [ 15 ], suggesting an interaction between oral bisphosphonates and calcium supplements, while there was hardly any effect on non-cardioembolic IS. Bearing this in mind, we carried out the present study with a twofold aim: (1) to assess the association of calcium supplements, distinguishing between CaM and CaD, with IS overall and its two main pathophysiological subtypes, and (2) to examine the potential interaction of calcium supplements and oral bisphosphonates on IS (and its subtypes), from the perspective of calcium-supplement users.…”