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RESEARCH: Henrik Toft Sørensen, Steffen Christensen, Frank Mehnert, Lars Pedersen, Roland D Chapurlat, Steven R Cummings, and John A Baron Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study BMJ 2008; 336: 813-816 [Abstract] [Full text]

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Bisphoshonates and atrial fibrillation - Not yet a clean bill of health.

Bo Abrahamsen, Kim Brixen   (19 March 2008)

Bisphoshonates and atrial fibrillation

Henrik T. Sørensen, Steffen Christensen, Frank Mehnert   (16 May 2008)

Bisphoshonates and atrial fibrillation - Not yet a clean bill of health. 19 March 2008
Bo Abrahamsen, Consultant physician Copenhagen University Hospital Gentofte, DK-2900 Hellerup, Denmark, Kim Brixen Send response to journal: Re: Bisphoshonates and atrial fibrillation - Not yet a clean bill of health.	The authors' aim was to identify patients with incident (i.e. new) atrial fibrillation. Unfortunately, they diluted their potential effect sizes by not excluding patients with chronic atrial fibrillation who were known to be on daily cardiac glycosides prior to the date of hospitalisation. Despite this - and in contrast to their conclusion - the results in table 1 indicate a significantly higher proportion of current bisphosphonate users among patients with atrial fibrillation compared with the proportion among non-AF controls (431/13586 vs 1958/68054, p=0.04, OR 1.12, 95% CI: 1.01-1.24). This difference, which is not pointed out to readers, only disappears after adjustment for cardiovascular risk factors. As an additional limitation, the study does not outweigh by sample size the clinical trials that preceded it. Thus, in the alendronate FIT study comprising 6,459 patients randomized to oral alendronate or placebo, a trend towards higher incidence of serious AF(1) was seen in the alendronate group compared with the controls (47 versus 37 patients, p=0.07). The present observational study included 3,862 bisphosphonate exposed patients. At present we remain without firm evidence for or against the cardiovascular safety of oral bisphosphonates and larger observational studies are needed. 1) Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med 2007;356:1895-6 Competing interests: Dr Abrahamsen receives consultancy fees from Nycomed, research grants from Roche and speaker´s fees from Servier, Eli Lilly and MSD. Dr Brixen receives consultancy fees from Servier, Novartis, Eli Lilly, Nycomed and Osteologix as well as speaker's fees from Eli Lilly & Co., Novartis, Roche, MSD, and Nycomed.
Bisphoshonates and atrial fibrillation 16 May 2008
Henrik T. Sørensen, Professor Dept of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45, 8200 Aarhus N, DK, Steffen Christensen, Frank Mehnert Send response to journal: Re: Bisphoshonates and atrial fibrillation	Sir, We thank Abrahamsen and Brixen for their interest in our study on use of oral bisphosphonates and risk of atrial fibrillation.1 They suggest that the fact that we include patients treated with cardiac glycosides (a potential marker of atrial fibrillation/flutter) in our study may reduce our ability to detect an increased risk of atrial fibrillation/flutter. We therefore did a logistic regression analysis restricted to patients without previous cardiovascular hospitalisations and without previous use of cardiac glycosides. This analysis gave virtually the same estimates as the overall analysis with an unadjusted relative risk (RR) of atrial fibrillation of 1.09 (95% CI, 0.94 to 1.25) and an adjusted RR of 0.92 (95% CI, 0.79 to 1.07). Abrahamsen and Brixen state that the crude OR of atrial fibrillation in our study was 1.12 (95% CI, 1.01 to 1.24), whereas we found an unadjusted RR of 1.10 (0.98 to 1.23). Since we used a matched design, we did conditional logistic regression to compute the unadjusted relative risk,2 which may explain the small difference. Furthermore, it was stated that any difference in atrial fibrillation risk between bisphosphonate users and non-users only disappears after adjustment for cardiovascular diseases. However, controlling for previous cardiovascular disease had little impact on the relative risk estimate. The unadjusted RR was 1.10 (0.98 to 1.23), and, with adjustment for cardiovascular diseases, 1.05 (95% CI, 0.94 to 1.18). In our case-control study we included 435 (3.2%) cases of atrial fibrillation that used oral bisphosphonates and 1958 (2.9%) control patients without atrial fibrillation that used oral bisphosphonates. That is substantially more than the 47 cases of atrial fibrillation in the intervention group and 37 cases in the placebo group of the FIT trial.3 This illustrates the efficiency of a case-control design to examine rare adverse drug reactions.4 We found no evidence that use of the oral bisphosphonates included in our study increase the risk of atrial fibrillation/flutter. However, as mentioned in our paper, we were not able to examine the risk of atrial fibrillation/flutter in relation to use of zoledronic acid and risedronate. References 1. Sørensen HT, Christensen S, Mehnert F, Pedersen L, Chapurlat RD, Cummings SR, Baron JA. Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 2008;336:813-6. 2. Rothman KJ, Greenland S, Lash TL. Modern Epidemiology, 3 ed. Philadelphia. Lippincott Williams & Wilkins, 2008. 3. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med 2007;356:1895-6. 4. Vandenbroucke J. When are observational studies as credible as randomised trials? Lancet 2004;363:1728-31. Competing interests: None declared