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Alendronate and Atrial Fibrillation
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NEJM
May 3, 2007
To the Editor: In this issue of the Journal, Black et al.1 report on a significant increase in the risk of serious atrial-fibrillation adverse events (defined as events resulting in hospitalization or disability or judged to be life-threatening) associated with once-yearly infusions of intravenous zoledronic acid for the treatment of osteoporosis in postmenopausal women. However, there was no increased risk of all adverse events of atrial fibrillation with such infusions.
We reviewed the results of the Fracture Intervention Trial (FIT), a randomized study of alendronate sponsored by Merck, which involved 6459 postmenopausal women (mean age, 69 years).2,3 The University of California at San Francisco coordinating center collected the data, created the data set, and provided reports to the data and safety monitoring board. At the board's request, a physician at the coordinating center who was unaware of study-group assignments confirmed potential atrial-fibrillation adverse events. The final 1997 analysis that was reported to the Food and Drug Administration showed 47 serious atrial-fibrillation adverse events (1.5%) among patients receiving alendronate versus 31 (1.0%) among those receiving placebo during an average of 4 years (relative hazard, 1.51; 95% confidence interval [CI], 0.97 to 2.40; P=0.07) (Figure 1). There was no increased risk of all atrial-fibrillation adverse events: 81 events (2.5%) versus 71 events (2.2%) (relative hazard, 1.14; 95% CI, 0.83 to 1.57; P=0.42). At that time, a true association between atrial fibrillation and the administration of alendronate was considered to be very unlikely in view of numerous comparisons of potential adverse events, no association for all atrial-fibrillation adverse events, and no apparent biologic plausibility.
The trend toward an increased risk of serious but not atrial-fibrillation adverse events in the FIT trial resembles the pattern observed in the study of zoledronic acid by Black et al.1 How potent bisphosphonates might increase the risk of serious atrial fibrillation is unclear. However, parenteral administration of bisphosphonates stimulates the release of inflammatory cytokines,4 and increased levels of inflammatory cytokines have been associated with an increased risk of atrial fibrillation.5 It is not known whether oral bisphosphonates also increase cytokine levels. Shifts of calcium within atrial cells can predispose patients to atrial fibrillation.6 Potent bisphosphonates cause a very small decrease in serum calcium levels,7 but the relevance of this finding to atrial electrophysiology is uncertain. Explanations must account for an increased risk of only serious atrial fibrillation.
The possibility of an increased risk of atrial fibrillation should be examined in other studies of bisphosphonates and assessed in trials of potent inhibitors of bone resorption. This potential risk must be weighed against the reduction in fracture risk.
Steven R. Cummings, M.D.
California Pacific Medical Center Research Institute
San Francisco, CA 94105
Ann V. Schwartz, Ph.D.
Dennis M. Black, Ph.D.
University of California, San Francisco
San Francisco, CA 94107
Dr. Cummings reports receiving consulting and advisory-board fees from Amgen and Organon, lecture fees from Merck and Lilly, and grant support from Amgen, Novartis, Lilly, and Pfizer. Dr. Black reports receiving grant support and honoraria from Novartis and Merck. No other potential conflict of interest relevant to this letter was reported.
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