Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study
BMJ 2008; 336 doi: https://doi.org/10.1136/bmj.39507.551644.BE (Published 10 April 2008) Cite this as: BMJ 2008;336:813
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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.
Competing interests: No competing interests
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
Competing interests: No competing interests