Early Enzyme Treatment Best in Fabry's Disease

September 17, 2008

September 17, 2008 (Munich, Germany) — A new study has found that early enzyme-replacement therapy brings the most benefit in patients with Fabry's disease. Dr Frank Weidemann (University Hospital Wurzburg, Germany) presented the results of his prospective study at the European Society of Cardiology Congress 2008 earlier this month.

Specifically, Weidemann and his colleagues found that only patients with no myocardial fibrosis at baseline improved in cardiac morphology, function, and exercise capacity following enzyme-replacement therapy. Those with mild or severe fibrosis stayed stable but saw no improvement in these parameters with the treatment, he noted.

"The results indicate that the extent of fibrosis at baseline is crucial," Weidemann told heartwire . "No fibrosis equals better outcome. Early treatment is desirable in order to achieve long-term cardiac improvement." He stressed, however, that this does not mean that those with fibrosis should not be treated. "They do need treatment because at least you will stabilize them--otherwise they will die--but you cannot bring them 'back' if they already have fibrosis, it's too late."

Prospective, Three-Year Study

Fabry's disease, an inherited fat-storage disorder, is caused by an X-linked deficiency of the enzyme galactosidase A, which is involved in the biodegradation of lipids. It results in the lipid globotriaosylceramide accumulating in the vascular epithelium, heart, kidneys, cornea, and other tissues, causing a range of related problems and increasing the risk of early heart attacks and stroke.

Men with the classic form of the disease typically die in early middle age, while those with the cardiac variant of Fabry's--in which residual galactosidase A exists in the system, but at levels less than 10% that of normal people--frequently experience myocardial dysfunction during middle age. Seven years ago came the first glimmer of hope that supplementing this deficient enzyme in people stricken with this progressive disease might have some impact.

In their Fabry's center at the University of Wurzburg, Weidemann explained to heartwire : "We had observed that sometimes people responded to enzyme-replacement therapy and sometimes they didn't. It was also known that sometimes people had myocardial fibrosis [around 50% of Fabry's patients have some fibrosis] and sometimes they didn't, but no one knew if this had any impact for the patient. We hypothesized that patients at an earlier stage of the disease--without any fibrosis--would have a better outcome compared with patients at a later stage of disease."

They prospectively followed 32 Fabry's patients on enzyme-replacement therapy--1.0 mg/kg recombinant agalsidase beta (Fabrazyme, Genzyme) every two weeks--for three years, grouping them according to the amount of fibrosis at baseline, detected by cardiac MRI using the late enhancement technique.

Weidemann explained that it is very easy to detect fibrosis in Fabry's patients, as "it is always found in one particular segment of the left ventricle, the posterolateral segment, which is unique to Fabry's disease." The patients were grouped into those with no fibrosis at baseline (n=12), those with mild fibrosis (n=11), and those with severe fibrosis (n=9).

In those with no fibrosis at baseline, the treatment resulted in a significant reduction in left ventricular mass (238 g at baseline vs 202 g at three years; p<0.001). In those with mild or severe fibrosis there was only a minor reduction in LV hypertrophy at three years.

And in the "much more important" area of myocardial function--as assessed by strain-rate imaging, an ultrasound technique to measure myocardial function very precisely--"only those with no fibrosis at baseline improved," Weidemann said. The same was true of the bicycle stress test--improvement was seen only in those with no fibrosis at baseline, "while the other two groups stayed stable," he noted.

Message Is to Treat Early

Weidemann said the message for clinicians treating these patients is that myocardial fibrosis should be assessed at baseline in Fabry's disease patients, using MRI with late enhancement, because early treatment is superior to late treatment for long-term improvement of cardiac morphology, function, and exercise capacity.

Weidemann said patients with Fabry's disease present at different ages. Some come in later life, because they are discovered, by screening or by accident, to already have a problem with some organs, whereas others are younger, discovered via family screening following a diagnosis of Fabry's in another family member. Currently, treatment with enzyme-replacement therapy begins whenever a patient begins to show signs of organ damage, whether in the heart or other organs, such as the kidney, he explained.

But an ongoing study--FIELD--is examining whether younger, asymptomatic patients may benefit from prophylactic treatment with a lower dose of the enzyme than is currently used for therapy, he noted.

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.


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