Osteoporosis Drug Promotes Atrial Fibrillation in Population-Based Study  CME

News Author: Steve Stiles
CME Author: Hien T. Nghiem, MD
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From Heartwire — a professional news service of WebMD

April 30, 2008 — Women who have ever taken alendronate (Fosamax, Merck), the bisphosphonate widely prescribed for preservation of bone density that recently went off patent, have an increased risk of developing atrial fibrillation (AF), according to a population-based, case-control study in the April 28, 2008 Archives of Internal Medicine [1].

In multivariate analyses, the odds ratio (95% CI) for incident AF associated with current or past alendronate use among nearly 1700 women in a clinical practice setting was 1.86 (1.09 - 3.15), with a disproportionate share of the risk concentrated among those who were previously but are no longer on the drug.

"Bisphosphonates have been proven to prevent fractures in people at very high risk of fracture," lead author Dr Susan R Heckbert (University of Washington, Seattle) observed for heartwire, and for those people, "the benefits in fracture prevention from taking alendronate will outweigh the possible risk of atrial fibrillation."

For others, including patients "maybe at only moderate risk of fractures or for patients who are at particularly high risk of atrial fibrillation, such as those with coronary disease, heart failure, or diabetes," she said, "they and their physicians need to do the best they can with the available evidence to weigh the benefits and risks."

Heckbert et al observe that their work supports two prior studies that had suggested bisphosphonates might promote AF; published last year and reported then by heartwire, they were the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial of zoledronic acid (Zometa, Novartis) [2] and the Fracture Intervention Trial (FIT) using alendronate [3]. In contrast to those studies, according to the group, the current analysis shows increased risk of AF overall and also specifically in the acute-care setting.

An accompanying editorial [4] lists several notes of caution regarding the group's findings, including some related to the study's observational nature (such as the possible presence of uncontrolled confounders, like hyperthyroidism) and the fact that "the association [between alendronate and AF] has not been consistently reported and the biological plausibility of the finding is uncertain." Conclude the authors, Drs Jane A Cauley and Kristine E Ensrud (University of Pittsburgh, PA), "At this time, it seems that the benefits of bisphosphonate treatment in patients with osteoporosis outweigh the risk of AF."

Heckbert studied 719 patients with AF, classifying them according to duration of the arrhythmia and whether the diagnosis had been made in an outpatient or acute-care setting. They were matched with 966 non-AF controls according to age, treated hypertension, and calendar year of diagnosis.

Hazard ratio* for atrial fibrillation for users of alendronate compared to those who had never used alendronate

The AF risk didn't vary by history of cardiovascular disease, treated hypertension, or age. Significantly increased AF risks were observed among patients who used statins and among diabetics, but there were so few patients involved, little can be made of the observations, according to Heckbert.

The bisphosphonate-AF link observed in the current analysis and the HORIZON and FIT studies, she said, "was and still is a completely unexpected effect," whose mechanism, if the effect is real, remains undefined. Speculating, Heckbert said infusions of the drugs could cause an inflammatory response, "and inflammation is known to be related to the development of atrial fibrillation." Or, she said, the treatment may affect the metabolism of calcium or other ions to which the atrium may be sensitive.

Heckbert said she knows no reason why their findings wouldn't apply to men. "We would have liked to study this in men," she said, but in their database, "you could count on one hand the number of men who had atrial fibrillation and were taking a bisphosphonate."

Dr. Heckbert and colleagues and coauthor Dr Steven R Cummings (University of California, San Francisco) have disclosed receiving research support from Amgen, Novartis, Eli Lilly, Pfizer, and Zelos and consulting fees and honoraria from Amgen, Novartis, Lilly, Zelos, Merck, and P&G-Aventis. The study was entirely supported by grants from the National Heart, Lung, and Blood Institute. Dr. Cauley has disclosed receiving research support from Merck, Eli Lilly, Pfizer, and Novartis; consulting fees from Lilly and Novartis; and being on the speaker’s bureau for Merck.

Sources

1. Heckbert SR, Li G, Cummings SR, et al. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med. 2008;168:826-831.
2. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822.
3. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med 2007;356:1895-1896.
4. Cauley JA, Ensrud KE. Considering competing risks. . . Not all black and white. Arch Intern Med. 2008;168:793-795.

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals

Clinical Context

Bisphosphonates reduce the risk for fracture; in particular, alendronate has been shown to reduce the risk for vertebral, hip, and nonspinal fractures in women with osteoporosis.

A recent publication from the HORIZON trial in women with postmenopausal osteoporosis reported a higher risk for serious AF in those receiving zoledronic acid vs those receiving placebo. This adverse effect was unexpected and had not been recognized previously. Bisphosphonates accumulate in bone and are detectable in body fluids for at least several months after administration. An acute syndrome of fever and elevation of tumor necrosis factor and interleukin 6 levels for 1 to 2 days commonly occur after intravenous administration of bisphosphonates. Several authors have hypothesized that inflammation is related to atrial remodeling and fibrosis and may be involved in the pathogenesis of AF.

The aim of this study was to examine whether alendronate use was associated with the risk for incident AF in women in a clinical practice setting.

Study Highlights

• In this population-based, case-control study conducted at Group Health, a large integrated healthcare delivery system in Washington State, a total of 719 women with confirmed incident AF between October 1, 2001, and December 31, 2004, and a total of 966 female control subjects without AF were identified.
• They were selected at random from the Group Health enrollment and frequency matched on age, the presence or absence of treated hypertension, and calendar year.
• The prevalence of osteoporosis was similar in patients with AF and control subjects (10.4% vs 9.6%).
• Ever-use of alendronate was defined as the receipt of at least 2 alendronate prescriptions.
• More patients with AF than control subjects had ever used alendronate (6.5% [n = 47] vs 4.1% [n = 40]; P = .03).
• Results revealed that compared with never-use of any bisphosphonate, ever-use of alendronate was associated with a higher risk for incident AF (odds ratio, 1.86; 95% confidence interval, 1.09 - 3.15) after adjustment for matching variables, a diagnosis of osteoporosis, and a history of cardiovascular disease.
• There was no evidence of a difference in AF risk according to the total cumulative grams of alendronate dispensed or according to the interval since the first prescription of alendronate.
• Based on the population-attributable fraction, we estimated that 3% of incident AF in this population might be explained by alendronate use.
• Of the 719 patients with AF, 299 (41.6%) had transitory AF, 328 (45.6%) had persistent/intermittent AF, and 83 (11.5%) had sustained AF during the first 6 months after presentation. The risk for sustained AF associated with alendronate ever-use was higher than the risk for transitory or persistent/intermittent AF.
• The risk for AF associated with alendronate use was higher in patients with diabetes mellitus vs those without diabetes (P = .03) and in those who were currently taking statins vs those who were not (P = .02).
• Limitations of this study include the following: it was an observational study, patients were not randomly assigned alendronate use, there may have been unknown or unmeasured confounding factors, ascertainment of AF may not have been complete, the results could not be applied to men, and the number of alendronate users in the subgroup was small.

Pearls for Practice

• After the administration of intravenous bisphosphonates, an acute syndrome of fever and elevation of tumor necrosis factor and interleukin 6 levels occur for 1 to 2 days, and, subsequently, the bisphosphonates accumulate in the bone.
• Ever-use of alendronate was associated with an increased risk for incident AF in clinical practice.

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