New Data Linking Bisphosphonates and Atrial Fib: Should FDA Revisit?

Marlene Busko

March 20, 2014

BROOKLYN, NY — Authors of a new analysis say the US Food and Drug Administration (FDA) should consider revisiting its investigation of the atrial-fibrillation (AF) risk with certain osteoporosis drugs, in the wake of new studies[1]. Their analysis, which pools data from nine studies, including several since the agency first addressed the issue, showed that both oral and IV bisphosphates were associated with a significantly increased risk of new-onset AF. The risk was greater with the IV drugs.

"Bisphosphonates have been shown to reduce morbidity and mortality," lead author Dr Abhishek Sharma (Maimonides Medical Center, Brooklyn, NY) told heartwire . And this meta-analysis suggests that they should be continued as a first-line therapy for osteoporosis and osteopenia, "but we should be very careful in selecting our patients." In particular, patients at high risk for AF—those who are older or have a history of cardiac events—should be closely monitored.

"Bisphosphonates are very commonly used medications, and more and more indications are coming up, and these patients tend to have concomitant cardiac conditions," Sharma pointed out. "Bisphosphates are usually started by the patient's general physician or oncologist. I strongly suggest that my cardiology colleagues should be aware of this association, and apart from close patient surveillance, they should work with oncologists."

The meta-analysis was published online March 15, 2014, in the American Journal of Cardiology.

2008 FDA Statement: No Link to AF Risk

To treat osteoporosis and osteopenia, which affect more than 40 million Americans, bisphosphonates are typically first-line therapies, the researchers write. However, after concerns were raised about a potential risk of AF with bisphosphonate use, in 2008 the FDA reviewed data from clinical trials of 19 687 patients receiving bisphosphonates (alendronate [Fosamax, Merck), ibandronate [Boniva, Genentech], risedronate [Actonel,Sanofi], and zoledronic acid) and 18 358 patients receiving placebo. It concluded that there was no significant risk of AF associated with the use of these drugs and the absolute incidence of AF was low, but it would continue to monitor the data.

I strongly suggest that my cardiology colleagues should be aware of this association.

However, more studies have been published since then, Sharma explained. Last year, the group published a meta-analysis including newer studies, which showed that the use of bisphosphonates was linked with a greater risk of AF requiring hospitalization[2]. However, this finding may have been due to the IV bisphosphonates, since that route of administration is associated with a stronger release of inflammatory cytokines. Previous studies that examined oral and IV bisphosphonates separately have reported contradictory findings.

Therefore, the researchers performed a systematic review and meta-analysis of published studies to evaluate this.

They identified five randomized controlled trials, which compared IV zoledronic acid and oral alendronate and risedronate vs placebo. They also identified four observational studies that examined IV zoledronate and pamidronate, as well as oral alendronate, clodronate, etidronate, ibandronate, and risedronate. There were a total of 135 347 patients.

They found an increased relative risk of AF with both types of bisphosphonates, although the risk was greater with the IV format.

Relative Risk of AF With Bisphosphonate Therapy vs Nonbisphosphonate Therapy*

Bisphosphonate type RR (95%CI )
Oral and IV 1.28 (1.18–1.38)
IV 1.40 (1.32–1.49)
Oral 1.22 (1.14–1.31)

*Data pooled from 9 studies

The absolute risk for developing AF was low: 1.1% and 0.4% for IV and oral bisphosphonates, respectively, vs placebo.

Since five of the studies were published after the 2008 FDA review and the results suggest that AF is associated with oral and IV bisphosphonates, "it may be useful for FDA to revisit this association," Sharma and colleagues write.

Although this meta-analysis was large enough to capture rare events, it has several limitations, they acknowledge. They did not have detailed information about baseline cardiovascular risk factors and concomitant medication use, and the original studies were too small to see effects from individual drugs.

As well, the randomized trials used in the analysis were not specifically designed to determine risk of AF with bisphosphonates.

"Thus, prospective randomized data are needed to further evaluate the risk of AF with bisphosphonate therapy and to determine whether the association is a 'class' effect or is dependent on specific drugs," they conclude.

The researchers report no conflicts of interest.

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