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Bisphosphonates unlikely to slow progression of aortic stenosis

Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) – Bisphosphonate therapy doesn’t slow progression of aortic stenosis, according to the largest study to date to assess the effect of bisphosphonates on valvular disease progression.

“It is unlikely that bisphopshonates will modulate valvular calcification or other pathophysiological mechanisms sufficiently to affect progression of aortic stenosis at least once this has become established,” Dr. Brian P. Griffin of the Cleveland Clinic in Ohio who worked on the study told Reuters Health by email.

“Pharmacological modulation of the progression of aortic stenosis has been disappointing in practice though experimental models suggest it may be feasible,” he added. “We may be addressing the valve too late in the course of disease to allow modulation as the pathophysiological process in humans likely occurs over a long period unlike the acute lesions produced in experimental models.”

In the Journal of the American College of Cardiology April 17, available online now, the study team notes that aortic stenosis, or AS, is an active process of chronic inflammation, involving the renin-angiotensin system, lipid accumulation and calcium deposition. As a result, it’s been targeted by several drugs in an effort to slow its progression. Trials testing statins in nonhyperlipidemic patients with AS have yielded disappointing results, with no clear benefit on AS progression. There are conflicting results from retrospective studies on the value of angiotensin-converting enzyme inhibitors in AS.

Bisphosphonates potentially could affect the pathophysiology in AS via their ability to inhibit vascular calcification. In several small observational retrospective case series provide support for this. However, only 234 patients were included in these studies, with only 54 taking a bisphosphonate.

This prompted Dr. Griffin and his colleagues at the Cleveland Clinic to conduct a much larger analysis involving 801 women with mild to moderate AS at baseline defined as an aortic valve area (AVA) between 1.0 and 2.0 cm². Altogether, 323 of the women, or 38%, were on a bisphosphonate at the time of their initial echocardiogram and had been taking it for an average of about three years.

During follow up lasting five years on average, the use of bisphosphonates did not affect the hemodynamic progression of valve stenosis, the researchers report.

They didn’t see any differences in the rate of change in AVA or peak and mean valvular gradients when the women were stratified based on their use of bisphosphonates.

Bisphosphonate therapy also had no impact on survival and did not delay aortic valve replacement surgery or slow the rate of narrowing of the valve in patients who eventually had valve surgery.

These data argue against the use of bisphosphonates in older women to prevent the progression of AS, they say.

Dr. Griffin noted that “smaller studies often over estimate the effect of a treatment. This large study failed to demonstrate a significant effect. However, by lumping individual bisphosphonates together, we may have failed to detect the beneficial effect of a specific single bisphosphonate. This was not apparent in our analysis but is a possibility,” he added.

“Bisphosphonates are a large group of drugs, each with its own specific characteristics and affinities to distinct pathways in the calcification and inflammatory process. As such, categorizing all these drugs as 1 group might have prevented us from identifying positive signals in the data,” the researchers note in their paper. The retrospective nature of the study is another limitation, one which might have led to observations of reduced efficacy of bisphosphonate therapy, although the researchers tried to circumvent this problem with propensity matching.

“Our study is novel in that it incorporated multiple echocardiograms in individual patients over a longer period,” the researchers add. And, in contrast to prior studies, it suggests that the rate of progression of AS, at least in the population studied, is not linear but tends to lessen over time.

“Many previous studies that have examined the progression of AS showed that the rate of change tends to be relatively constant over time; however, these studies evaluated the progression over a relatively short time frame and used linear analysis, often using the annualized change in valve area or pressure gradients as the mode of expression of progression,” the investigators note.

“We believe that further studies are necessary to better understand the mechanisms of calcification and inflammation in AS to identify appropriate therapeutic targets and drugs to modify the natural course of disease,” they conclude.

The authors have no relevant disclosures related to this study.

SOURCE: J Am Coll Cardiol 2012;59:1452-1459.