Medical Device Daily National Editor

The trial name, STILETTO, has the quality of a neon sign. And Martha Gulati, MD, laughs when she reports that some of the women thinking of enrolling ask if their participation will get them a pair of high heels.

She tells them they won't get any shoes, spiky heels or otherwise, but she hopes that they'll feel better as a result if they are selected for the study, designed to explore a potential treatment for Syndrome X.

STILLETO stands for "Syndrome X Trial: Identifying underLying Endothelial dysfunction and Testing Treatment Outcomes in women," with Syndrome X being a group of cardiovascular symptoms thought to lead to worse heart disease.

To be conducted by physicians at the Bluhm Cardiovascular Institute of Northwestern Memorial Hospital (Chicago), the trial specifically is designed to explore options for treating women shown to have, specifically, endothelial dysfunction, and if that treatment has a longer-term preventive effect.

Gulati, MD, associate medical director of the Center for Women's Cardiovascular Health and assistant professor of medicine at the Feinberg School of Medicine (Chicago) of Northwestern University, is the lead investigator of STILETTO.

She told Medical Device Daily that Syndrome X is defined by three primary symptoms, angina, an abnormal EKG and abnormalities of the microvasculature (and different from metabolic syndrome which consists of having a group of five other high-risk conditions for heart disease, diabetes, high blood pressure, obesity, decreased HDL cholesterol and elevated triglycerides).

Gulati notes that women experiencing chest pain – this very obviously and intuitively indicating a heart problem – often are put through a variety of diagnostics, such as stress testing and cardiac angiography, but with those tests frequently showing no other evidence of coronary artery disease.

So they are often sent home with little direction, but subsequently experience similar symptoms and go on to develop worse problems, or even heart attack and death.

As a result, Gulati says that there are no clear guidelines for treating these women, and STILETTO is an attempt to fill that therapeutic gap.

Endothelial dysfunction is defined as a condition in which the outer layers of vascular cells are not functioning properly, and she says there is a body of research indicating that this condition is the earliest stage of coronary artery disease in women.

While the research points to such a relationship, she says, "We're not 100% certain." Thus, STILETTO, the name constructed to underline its focus on women, will explore the possibility of a cause/effect relationship.

It will first identify the presence of endothelial dysfunction in a group of women presenting with Syndrome X and then provide a two-pronged approach to stave off follow-on heart disease: guidance in making behavioral changes, such as with diet and exercise, and medical treatment consisting of a combination of basic cardio drugs.

The trial directly addresses the well-publicized disparities between men and women in the treatment of heart disease, with women frequently being diagnosed with heart disease more slowly than men and slower to receive necessary therapies, and as a result, dying of heart disease more often than men, it is thought.

Clearly underlying the reports of these disparities are two, often unstated possibilities: that doctors are treating women suspected of having heart problems less aggressively, due to some bias, or that cardiovascular science medicine has been slow to identify the ways in which heart diseases impact women in different ways than in men.

Gulati says she favors "the latter" of these explanations and that STILLETO is an attempt to better understand what may be a sentinel precursor of more serious disease in women and provide preventive measures.

The women in the trial – which she describes as a pivotal study of only about 50 enrollees to begin with – will be selected from those who appear with chest pain and then are diagnosed as having endothelial dysfunction. The diagnosis will be made by an injection of acetylcholine, that drug serving to indicate vasoconstriction.

Once enrolled, the women will be guided in pursuing "aggressive" lifestyle changes and also receive treatment with what Gulati described as a "cocktail" of drugs developed by the trial investigators, primarily a combination of statins, beta blockers and aspirin, all cardio-therapeutic standards.

The enrollees will be followed for one year to determine if there is any improvement in symptoms, and Gulati acknowledges that a trial with a much greater number of women, followed for a much longer period, is necessary to offer the power robust enough to determine the endothelial dysfunction/more serious disease combination and the efficacy of the therapies used.

But she says the women in such a study would not have to be tracked out to 20 or 30 years, only a much shorter time, given how aggressive heart disease sometimes attacks these women.

She told MDD that STILETTO investigators are applying for additional grant monies to do an extension of the current trial.

Neil Stone, MD, medical director of the Center for Vascular Disease and professor of medicine at the Feinberg School of Medicine, underlined the importance of the study, saying that there "are currently no other randomized trials comparing the effectiveness of such therapy in women with cardiac symptoms, normal coronary arteries but evidence of coronary endothelial dysfunction."

STILETTO is supported by the Woman's Board of Northwestern Memorial Hospital.

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