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. 2009;4(3):e4720.
doi: 10.1371/journal.pone.0004720. Epub 2009 Mar 6.

Oral bisphosphonates and risk of atrial fibrillation and flutter in women: a self-controlled case-series safety analysis

Anthony Grosso  1 , Ian Douglas, Aroon Hingorani, Raymond MacAllister, Liam Smeeth
Affiliations

Oral bisphosphonates and risk of atrial fibrillation and flutter in women: a self-controlled case-series safety analysis

Anthony Grosso et al. PLoS One. 2009.

Abstract

Background: A recent trial unexpectedly reported that atrial fibrillation, when defined as serious, occurred more often in participants randomized to an annual infusion of the relatively new parenteral bisphosphonate, zoledronic acid, than among those given placebo, but had limited power. Two subsequent population-based case-control studies of patients receiving a more established oral bisphosphonate, alendronic acid, reported conflicting results, possibly due to uncontrolled confounding factors.

Methodology/principal findings: We used the United Kingdom General Practice Research Database to assess the risk of atrial fibrillation and flutter in women exposed to the oral bisphosphonates, alendronic acid and risedronate sodium. The self-controlled case-series method was used to minimise the potential for confounding. The age-adjusted incidence rate ratio for atrial fibrillation or flutter in individuals during their exposure to these oral bisphosphonates (n = 2195) was 1.07 (95% CI 0.94-1.21). The age-adjusted incidence rate ratio for alendronic acid (n = 1489) and risedronate sodium (n = 649) exposed individuals were 1.09 (95% CI 0.93-1.26) and 0.99 (95% CI 0.78-1.26) respectively. In post-hoc analyses, an increased risk of incident atrial fibrillation or flutter was detected for patients during their first few months of alendronic acid therapy.

Conclusions/significance: We found no robust evidence of an overall long-term increased risk of atrial fibrillation or flutter associated with continued exposure to the oral bisphosphonates, alendronic acid and risedronate sodium. A possible signal for an increase in risk during the first few months of therapy with alendronic acid needs to be re-assessed in additional studies.

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Conflict of interest statement

Competing Interests: Anthony Grosso has received an unrestricted research grant from Servier Laboratories for a separate safety study.

Figures

Figure 1
Figure 1. Pictorial representation of the self-controlled case-series method using total exposure time to define the ‘risk’ period.
Figure 2
Figure 2. Flow-diagram indicating derivation of bisphosphonate study population.
Figure 3
Figure 3. Time-to-event analysis using pre-defined ‘risk’ periods after commencement of therapy.
Figure 4
Figure 4. Risk estimates of incident atrial fibrillation or flutter after initiation of alendronic acid.
Figure 5
Figure 5. Risk estimates of incident atrial fibrillation or flutter after initiation of risedronate sodium.
See this image and copyright information in PMC

References

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