WomenHeart (Washington), a patient activist group representing the interests of women who have suffered heart attack, recently challenged the clinical trial protocol of the AbioCor replacement heart made by Abiomed (Danvers, Massachusetts), with that group targeting the fact that all of those in the trial thus far have been men. In letters sent to Abiomed and the FDA, Nancy Loving, the organization's executive director, questioned the design of the trial and asked the agency to conduct an investigation of the protocol and the absence of female patients. That absence, she told Cardiovascular Device Update, "reinforces the public misperception that only men get heart disease," while also reinforcing another perception – "that only men get access to the good stuff" in receiving cardiovascular treatment. The specific target of WomenHeart's challenge is the possibility of discrimination against women in the trial.
In answer, Ed Berger, Abiomed's vice president of strategic policy and planning, said that there is no flaw in the trial but more likely something going on "very deep-rooted in aspects of the health care delivery system." Rather than launch a counterattack, Berger told Cardiovascular Device Update that Abiomed was "extraordinarily sympathetic and supportive of WomenHeart's position, and we in fact find that their interest is absolutely and totally aligned with ours."
Berger expressed the hope that women will be represented in the total population of participants before the full 15-patient clinical trial is completed. But he said such decisions are not in Abiomed's hands but rather in the hands of the clinical trial sites and their selection processes. Abiomed has communicated to all of the clinical sites its desire to see women included in the trial, he said, "and we're working with our clinical sites on that issue."
Berger pointed to key aspects of the heart's design which tend to limit participation to larger individuals, whether male or female, and likely to favor men. For instance, the establishment of the initial device parameters – allowing it to fit just 20% of women vs. 50% of men – was the product of specification "deliverables," established by the National Institute of Health (Bethesda, Maryland), he said. Those parameters covered the operational output to produce the necessary liters per minute, in part for testing purposes, and established the size of the heart. Secondly, Berger pointed to the company's goal "to test the technology in the shortest possible time period to bring it to market and start to save lives."
Thus, he noted that Abiomed already has launched a "vigorous initiative designed to bring a smaller device to virtually all adults to market" as its next-generation product. And Berger said he had seen no discrimination by the company's clinical trial sites. Rather, he hypothesized "something much more fundamental and structural going on than these sites exercising discriminatory judgment." That "something" might also be demonstrated by looking at recent national heart transplant statistics that he cited: slightly more than 26% of recipients were women in 1999, a figure only slightly more than the 21.4% women reported in 1990, with the 1999 total being the highest over a 10-year span. "That's on a population base where at least as many women are dying of heart failure and congestive heart failure than men," he noted. Calling the 3-to-1 heart transplant statistic a "maldistribution," Berger said it would be interesting "to know more about that, but again, it points to some underlying structural element" at work in the transplant centers' method of selection.
Berger expressed the hope that the AbioCor trial would serve to encourage a heightened awareness concerning heart disease in women. "If women who are sick enough to need heart replacement aren't moving through the health care system in a way that makes them appear as candidates than our position is diminished in the future, let alone the position of social equity."
Thus far, two patients in the trial remain supported by the AbioCor. Four patients have died, one in the process of implanting the heart. The Texas Heart Institute (Houston, Texas) on Feb. 16 reported the most recent death in the trial, that of Bobby Harrison, who succumbed from complications of a stroke. He had been the third person implanted and survived 140 days on the heart. Overall, four patients in the trial have been supported on it beyond the 60-day end-point seen as demonstrating positive results in the trial.
Can drugs fill cardiovascular's unmet need?
The largest unmet need in cardiovascular health is a therapy that will effect a cure, not just treat symptoms. And not surprisingly a panel of drug makers meeting at last month's Biotechnology Industry Organization (Washington) CEO & Investor Conference in New York argued that pharmaceuticals are on the way to satisfying that need. The panel itself was sponsored by the investment banking firm of Adams, Harkness & Hill (Boston, Massachusetts), with Carol Werther, a company managing director and biotech analyst, downplaying the future role, on the device side, of drug-coated stents. In-stent restenosis remains a large problem yet to be solved with a proven, and commercialized, drug-coated stent product, she noted.
Among those promoting their new pharmaceutical approaches were Michael Goldberg, chairman and CEO of Emisphere Technologies (San Francisco, California), which is developing an oral form of heparin; Bill Freytag, PhD, president and CEO of Myogen (Westminster, Colorado), with its lead product enoximone, an oral formulation delivered intravenously to combat congestive heart failure; and Russell Medford, president and CEO of AtheroGenics (Alpharetta, Georgia), which is developing AGI 1067, a small molecule therapeutic addressing atherosclerosis.
Besides describing these new drug treatments, all three noted their companies pursuit of the underlying sources of heart disease. Goldberg said that Emisphere's strategy is to examine arterial injury using gene array analysis and the way arterial inflammation can be turned on or off. Heparin, he said, "can down-regulate, cool down the inflammatory condition, and anti-inflammatory cytokines can be up-regulated." The company's current studies are in the process of addressing these approaches, with dosing amounts being a key control factor, he said.
Myogen is exploring the genetic risk factors behind congestive heart failure "at the molecular level," Freytag said. Myogen's search has resulted in "three important discoveries to develop therapeutics," he said, including the discovery that congestive heart failure could originate as early as birth, with certain genes turned off and later turned on, resulting in interference with the heart's function. The company also found pathways for intervening in this switching on/off process and finally had "targeted the ability to move in and develop drugs that can reverse this fetal gene expression program."
AtheroGenics' AGI 1067 product also works below the tissue level, operating as a molecular agent to reduce the inflammatory condition which leads to atherosclerosis, according to Medford. This product addresses the fundamental process of intracellular signaling within the vasculature. Medford noted that angioplasty treats only a specific area of the vasculature, while GI 1067 provides a systemic approach to what Metzger termed "a very diffuse disease."
Bringing the discussion back to drug-coated stents was noted cardiologist Martin Leon, MD, clinical professor of medicine at Georgetown University Medical Center (Washington) and director and CEO of the Cardiovascular Research Foundation, who described what he considered to be key endpoints for potential commercialization of these products. The rate of restenosis has to be reduced from double digits to single digits, and those treatments are likely to be accomplished only by "a very aggressive site-specific therapy, not a systemic approach," Leon said.
Besides requiring a good stent and a strongly therapeutic drug, the critical factor will be their combined ability to achieve very specific drug delivery. "The dynamics of delivering a drug at a certain concentration over a specific time period is fundamental to this process," he said, adding that this requires "the proper integration of device and drug."
Despite his cautionary note concerning the difficulty of achieving this, Leon said that, based on proof-of-concept studies, this drug/device combination "could really work – it has the potential."
Diabetes, heart disease link not understood
A survey released last month by the American College of Cardiology (Bethesda, Maryland) and the American Diabetes Association (Alexandria, Virginia) indicates that a majority of people suffering diabetes do not understand their increased risk for heart disease and stroke. More than two-thirds, or 68%, reported having risk factors associated with cardiovascular disease – such as high blood pressure or high cholesterol – but failed to relate these problems to their diabetes. That lack of information and connection is particular important since an estimated 65% of those with diabetes die of heart attack or stroke. More than half of people with diabetes polled said they did not feel at risk for a heart condition (52%) or stroke (53%), and 60% said they did not feel at risk for either high blood pressure or cholesterol. Other studies have shown that most people with diabetes show these risk factors.
Joining with the two organizations to promote increased awareness of the connection was Tommy Thompson, secretary of Health and Human Services. He noted there are more than 16 million Americans with diabetes, and added, "that figure is growing at an alarming rate." Christopher Saudek, MD, president of the American Diabetes Association, pointed to what he called "the harsh reality" of diabetes. Those with the disease "have a two to four times greater likelihood of having a heart attack than if you do not have diabetes," he said. "Education is vital. While noting that all those with diabetes should understand the need for lowered cholesterol, reduced weight, increased physical activity and the appropriate use of medications." He said this was important, "especially [for] older adults and high-risk groups such as African Americans and Hispanics."
The study also yielded some good news. In their visits with health care providers, 75% of people with diabetes say they ask questions about managing their diabetes. On the other hand, about half of those surveyed said their health care provider never discussed ways in which they could reduce their risks for heart disease and stroke, such as lowering their blood pressure. And one-third of the smokers in the survey said quitting smoking was not discussed.