CDU Contributing Writer

It is beginning to sink in. Women die of heart disease as often as men. Ad attempts are being made to emphasize that it is a greater cause of fatality than the more publicized threat of breast cancer. Unfortunately, women’s cardiovascular concerns frequently have gone under-addressed, even quite often in the cardiovascular sector itself. The reasons for this are numerous. Heart disease often manifests itself in women quite differently than in men, and women may allow their multiple responsibilities to delay seeking medical consultation, it is often said. Additionally, there is a suspicion that gender bias may result in more aggressive treatment of men’s symptoms than on those of women.

Increasingly, however, the cardiovascular device industry is responding by providing more information concerning women’s heart disease, attempting to include more women in clinical trials (the under-representation of women in studies recognized as a problem across most disease sectors) and designing products that address the unique cardiovascular needs of women.

Barb Reindl, vice president at Guidant (Indianapolis), has been involved in the company’s women’s heart health initiatives for several years. She notes that Guidant, now a unit of Boston Scientific (Natick, Massachusetts), has been actively engaged in a variety of efforts to increase awareness of women’s heart health issues. “We recognized about seven or eight years ago that this was a significant concern in women’s health that had not received adequate attention from the device industry,” she says. “We decided to place more emphasis on our education and outreach to women, and also to our internal efforts to address these issues with our products.”

Guidant created its Women’s Health Initiative in 2000 with the inception of GROW (Guidant Reaches Out to Women). To help create awareness and encourage women to take action by talking to their healthcare providers, GROW designed a leadership campaign to disseminate clinical data across healthcare disciplines and improve healthcare professional education. Materials and tools, including brochures, risk assessment tools, educational presentations, gender-specific cardiovascular health seminars and women’s heart health web content were developed as part of the campaign.

Since 2003, GROW has supported professional women’s educational programs, reaching an estimated 12,000 healthcare providers, according to the company, and that GROW representatives have participated in more than 250 community outreach events, reaching up to 250,000 individuals, primarily women. The events have ranged from supporting large-scale American Heart Association (AHA; Dallas) Go Red Luncheons, AHA Walkathons, silent auctions, women’s organizations and smaller community-based events. Additionally, the company offers expert speakers to address women and community groups on the topic of women’s heart health and has placed women’s heart health-themed advertisements and participated in several editorial features in magazines and newspapers.

“Ultimately, reaching out to healthcare professionals will result in more women at-risk being identified to receive appropriate cardiovascular care,” according to Reindl. She says Guidant is embracing the idea that significant clinical benefit could be delivered to women by lowering the morbidity and mortality of cardiovascular disease through earlier diagnosis and treatment. In addition to the company’s awareness and education initiatives, Guidant supports the efforts of the Society for Women’s Health Research (Washington) to enhance the enrollment of women in ongoing clinical trials. The Steering Committee of a large Guidant-sponsored clinical trial recently included in its formal agenda the discussion of how to involve and attract more women to the trial.

“We are actively working to increase the representation of women in clinical trials related to cardiovascular devices and therapies,” Reindl says. “If you look at clinical trials involving medical devices, you will see that there traditionally has been a very low percentage of participation by women.”

Additionally, experts in the field say that it is often difficult to keep women in trials because of their multiple responsibilities, not the least of which being child-bearing and child-rearing.

COMPANION study involves women

Countering this trend, in the recently completed Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial, about 30% of the participants were women. Reindl says that is the highest female participation in a cardiac trial ever for Guidant and among the highest for any manufacturer. COMPANION was a prospective, multi-center, randomized study of patients with advanced heart failure (New York Heart Association Class III or IV). The patients studied in this trial had a poorly functioning left ventricle, the heart’s main pumping chamber. Enrollling more than 1,600 patients at 130 centers in the U.S., COMPANION used Guidant’s Contak TR cardiac resynchronization therapy (CRT-P) and Contak CD cardiac resynchronization therapy defibrillator (CRT-D) in the device treatment arms.

While Guidant does not currently have device applications and technologies that are gender-specific, Reindl says the company is continually working to make its devices smaller and more physiologically compatible to better meet the needs of a wide variety of anatomies. Likewise, additional features have increased the physician’s ability to program each device, she says, to best meet the needs of the individual patient’s disease state, anatomy and lifestyle.

For instance, when the first programmable pacemaker was introduced to the U.S. market in 1978, it was 37 cc in volume. Today Guidant’s Insignia Ultra weighs just 10.8 cc, with a physiological shape designed to improve patient comfort – which usually means thinner. The Vitality family of implantable defibrillators are among the smallest ICDs in the world, designed with a size and shape that address the needs of patients who are concerned with body image, Reindl explains. In addition, a range of lead sizes allows the physician to select the product best suited to the individual patient’s anatomy. An increased number of programming options and device features gives the physician the opportunity to tailor treatment to each patient’s needs.

“We don’t think there has to be a gender-specific implantable device, a different one for women vs. men, but we do believe that it is important to make our devices implantable and as comfortable as possible for a wide variety of people with different anatomies,” Reindl says. “Efforts to make devices smaller and thinner, with shapes that are more physiologically compatible, are a major concern for us now and will be in the future.”

Reindl says Boston Scientific also is very focused on developing advanced scanning technologies intended to improve the diagnosis and treatment of heart disease in women, by more accurately assessing their unique symptoms. These advanced generation scanning symptoms will play a key role in saving women’s lives, she says.

256-slice scan shows promise

Some of the scanning advances are coming from Toshiba America Medical Systems (Tustin, California), where the 64-slice scan may soon be bested by the 256-slice scan. The currently available Aquilion 64 CFX from Toshiba delivers high-speed, high-resolution images, enabling physicians to capture precise images of any area of the body, including the rapidly moving heart and lungs, which frequently appear blurry when scanned by a traditional CT scanner. This fast-scanning capability allows important diagnostic information concerning the heart to be obtained within a single breath-hold as short as 10 seconds, while a CT angiogram can be imaged within 15 seconds.

Robb Young, senior manager for cardiology CT at Toshiba, says the 64-slice CT was a huge step forward for women’s cardio health. “64-slice CT is a fantastic test for women because it can address the phenomenon of positive remodeling,” he says. Positive remodeling refers to a condition in which the lumen remains the same but the vessel wall gets fatter and fatter, a problem seen often in women. The 64-slice CT makes it possible to see the size of the vessel wall itself.

“Women who had a negative stress test or cath lab are getting a 64-slice CT scan and seeing soft plaque in their coronaries,” he says. “The other issue is that women’s coronary vessels are smaller, and having more thin slices helps you visualize those vessels better.”

However, achieving complete coverage of the heart or other organs within a single rotation requires a system capable of covering at least 120 mm of anatomy, with no table movement. Toward this end, Toshiba, in cooperation with the New Energy and Industrial Technology Development Organization (NED; Kawasaki City, Japan), has developed two prototype 256-slice CT systems based on the Aquilion platform’s core technology.

Utilizing Toshiba’s proven gantry design and high-efficiency detector material, these systems cover 128 mm of anatomy with 0.5 mm slices, producing fine, isotropic resolution of the heart during a single gantry rotation. Young says the 256-slice technology could be on the market within three years.

Toshiba also is making a concerted effort to include more women in clinical trials, Young says.

AbioCor II could be used in women

Abiomed (Danvers, Massachusetts) recently has emphasized the development of a range of heart support products, but it is best known for its pioneering work in the development of the AbioCor fully implantable artificial heart, just approved by the FDA under its humanitarian exemption protocol.

In the company’s 15-patient clinical trial, the patients enrolled – 12 implanted successfully — were men. The absence of any women in the trial drew criticism from at least one activist women’s group, but there was obviously no gender bias in the selection of those enrolled. Given the very specific and narrow specifications for the patients who could benefit from implantation of the AbioCor, the potential pool of enrollees is very narrow, and the size of the AbioCor – approximately that of a grapefruit – doesn’t allow its implantation even in all men, and thus even a much smaller number of women.

Liza Heapes, a spokeswoman for Abiomed , says the company’s next generation of implantable devices will address the smaller size of most women. The initial AbioCor has been designed with the goal of providing 18 to 24 months of life to end-stage heart failure patients. With the clinical and design experience gained from its use, the AbioCor II is being designed to provide five years of additional life, and in a smaller package.

“The AbioCor II is 30% smaller, so it should fit more women,” Heapes says. “It’s a next generation device, and we think the advances in technology that allow us to make devices smaller will help address the needs of women.”

Women testing BTT device

Thoratec (Pleasanton, California), a company focused primarily on the development of ventricular assist devices (VADs), also reports attempts to respond to the heart-health needs of women with next-generation systems. Jeff Nelson, president of the cardiovascular division at Thoratec, explains that the HeartMate II is in clinical trials and is significantly smaller in size than the initial HeartMate.

“The first-generation device was very large, and because of the smaller body cavity of women we saw much less implantation of the device in women,” Nelson says. “When we went forward with the new technology, our pilot phase had a substantial increase in enrollment of females in the trial.” He says that Thoratec expects to file for the bridge-to-transplantation (BTT) indication sometime in the third or fourth quarter. “We’re projecting approval in the first quarter of next year.”

The company recently announced that it had it had completed enrollment in the BTT arm of its HeartMate II pivotal trial by implanting 133 patients. Gary Burbach, president and CEO of Thoratec, says that completion of enrollment marks an important milestone in the HeartMate II program, as the company has now enrolled the number of patients called for in the original trial design, achieving this goal within 15 months of the trial’s initiation.

BTT patients will be able to continue to receive the device under the Continued Access Protocol (CAP). Thoratec on May 16 reported that the FDA had approved an Investigational Device Exemption supplement that allows enrollment of up to an additional 90 patients in the BTT arm of the trial. BTT enrollment under the CAP allows continued enrollment in the 40 centers participating in the trial, subject to IRB approvals at the centers. The CAP patients will be enrolled and followed under the original protocol of the pivotal trial.

The addition of these patients will not impact the timing for the company’s planned submission of a premarket approval application (PMA) seeking a BTT application for the HeartMate II. In addition, the company continues to enroll patients in the Destination Therapy (DT) arm of the pivotal trial, which involves 200 total patients randomized to the company’s HeartMate XVE on a 2-to-1 basis.

In the initial phase of the study, 42% of those participating were women, compared to only 9% to 16% in previous trials for the first-generation HeartMate. The Phase I trial for the HeartMate II involved 38 patients in NYHA Class IV heart failure, implanted with the HeartMate II as a bridge to cardiac transplantation at 10 U.S. centers. The median BSA of the women was 1.65 m2, significantly smaller than the BSA of the men.

The initial outcomes were encouraging in both groups, Nelson says. Among females, eight received a transplant and two are ongoing after a median support period of 72.5 days. Five males have been transplanted and 11 are ongoing after a median support period of 208 days. Eight women and 10 men were discharged from the hospital supported by the device with good quality of life.

The investigators concluded that the HeartMate II provides a new long-term device option for women as well as men with advanced heart failure. The HeartMate II size is appropriate to meet the needs of most women, Nelson says, and the initial pilot trial results in women are comparable to those in men.

Thoratec, like other manufacturers, is devoting more resources to investigating women’s needs and responding to them, according to Nelson. The first step for any company, he says, is including women in any clinical trials for cardiovascular devices, as Thoratec has done with the HeartMate II. He says that another important goal is to educate physicians about how Thoratec is responding to the needs of female patients. From a business standpoint, women represent a huge market for a product like the HeartMate II, but Nelson says the referring physicians are the gatekeepers that ultimately determine access to Thoratec’s product and other advanced therapies.

“One of our biggest challenges is getting the word out to the referral community that the device is available and appropriate for a female patient population. There may be this preconception that the device is big and not suitable for a smaller woman,” he says. “Changing that idea is a very prominent focus of our education to the referral community.”