CD&D
and DON LONG
CD&D Executive Editor

Last month's approval of the advanced generation ventricular assist device (VAD) from Thoratec (Pleasanton, California) — the HeartMate II Left Ventricular Assist System (LVAS) — is leading the way in heart pump devices that are smaller, and touted as more efficient, and thus more available for implantation in smaller bodies: women, smaller men and younger people.

The term "leading" is important here, since Thoratec heads a small confluence of device makers working to provide smaller ventricular-assist devices (VADs) and related heart-assist systems. These include Ventracor (Sydney, Australia/Foster City, California), Circulite (Saddlebrook, New Jersey), Heartware (Framingham, Massachusetts) and Berlin Heart (Berlin, Germany), all likely to benefit from the continuing efforts of Thoratec.

Thoratec's smaller device — 3 inches in length and weighing about one pound — is being bannered as opening the therapeutic door for implantation in the sickest women and smaller men, overcoming a limitation that has been seen as a barrier and downside for the VAD sector (as well as the totally implanted AbioCor artificial heart from Abiomed [Danvers, Massachusetts]). The smaller size is "where this type of mechanical heart technology is going now," FDA spokeswoman Karen Riley told Cardiovascular Devices & Drugs, in commenting on the HeartMate II okay.

HeartMate II uses a continuous-flow pump that constantly moves blood with a single moving part, a spinning rotor, enabling the device to be smaller. And because there's only one moving part, the potential for breakage is reduced, Riley said.

And Daniel Schultz, MD, director of FDA's Center for Devices and Radiological Health, underlined the reduced size of the device: "The HeartMate II is an important advance in mechanical heart technology," he said in an agency statement. "Until now, some heart transplant candidates have been under-served due to the large size of previously approved heart-assist devices."

With the approval, Thoratec said it would work quickly to roll out the product, while continuing its effort to seek improvements, and applications, for broader groups of heart failure patients. The new approval is for bridge-to-transplantation (BTT), for New York Heart Association (NYHA) Class IV patients.

"Typical patients who come to mind are those who need some sort of support as a BTT," David Smith, executive VP and CFO of Thoratec, told CD&D. "Not just women, but men who are smaller. In the past, certainly smaller body sizes have been under-served. Predecessor devices have been too large. We're pleased the label allows the physician to make the determination on which device and size to use."

Moving forward for DT okay

Now, Thoratec forges ahead with Part 2 of the same study, for patients who were not candidates for heart transplant and meet specific inclusion and exclusion criteria. The company said that this is the first time the FDA has approved a clinical trial with both indications in one protocol. Dubbed the Destination Therapy (DT) study, the criteria of this second-part, 479-patient trial includes patients who are not yet as ill as those in the company's original REMATCH trial, and allows for inclusion of some late NYHA Class IIIB heart failure patients.

The DT application targets "a larger patient population," Smith said. "One of our devices [Heartmate XVE] is currently approved for this indication. But it hasn't seen much uptake because of durability of the device, which is 18 to 24 months. We believe HeartMate II has much greater durability ... out to 10 years."

From 2,000 and 2,500 Americans receive a heart transplant each year, but another 25,000 to 50,000 die waiting for a donor heart.

The primary outcome measure for the 439-patient HeartMate II BTT trial was the rate of survival to transplantation, or 180 days. The primary endpoint of the HeartMate II DT trial will be patient survival, rate of neurological events and device reliability at two years.

With a price tag of $80,000, Smith said the HeartMate is covered by virtually all payers, public or private. For Medicare, implantation of VADs has been covered since the late-1990s under a National Coverage Determination for VADs used as BTT.

"CMS over last couple of years has recognized the value of mechanical support, and ventricular devices in particular," Smith said. "Last October, the DRGs that would be associated went up 25%. So that was a strong endorsement for these types of devices."

He said roll-out of HeartMate will begin immediately. "We have pumps on the shelf and we are working to get the labels printed. We've been supplying these throughout the clinical trail and have the stock ready to ship."

The HeartMate II can pump up to 10 liters of blood per minute, the full output of a healthy heart. It is implanted alongside a patient's native heart and takes over the pumping ability of the weakened heart's left ventricle.

Approval not easy

Approval of the HeartMate II didn't come easily. Following FDA approval of a pivotal study in early 2005, Thoratec completed enrollment of the agreed-upon total of 133 patients in May 2006. In April 2007, the FDA sent a major deficiency letter to Thoratec regarding the trial, noting implantation of the device in patients in a continuous access trial.

Thoratec presented all its data both to FDA and to the panel in support of its application, but the panel appeared to put its primary focus on pivotal trial data, in which the device missed the prescribed objective performance criteria by one percentage point. During that panel meeting, bleeding events were another focus of discussions, with 59 of the adverse events reported consisting of hemorrhage, a level that some panelists saw as higher than expected.

The HeartMate II includes an electrical cable to power the blood pump which passes through the patient's skin to an external controller that the patient wears on his or her waist. The controller is powered either by batteries or connected to an electrical power outlet. Blood flow is set through the pump based on the patient's need, and the controller monitors pump performance, sounding alarms if it detects dangerous conditions or a possible malfunction.

The system can operate on two external batteries, allowing the patient to move freely for up to three hours.

In a clinical study of 126 patients at 26 transplant centers, 57% of patients with the HeartMate II survived to heart transplant, which is comparable to the survival of patients treated with currently approved heart-assist devices.

The FDA reported that Thoratec is required to conduct a post-approval study to further evaluate the HeartMate II's performance.

The HeartMate II received the CE mark in late 2005.

'Nipping' at Thoratec's heels?

Riding the sector wave for smaller heart-assist devices is Ventracor, and Peter Crosby, company CEO, told CD&D that with the progress his company is making with its LVAS, "We expect we'll be nipping at [Thoratec's] heels."

He added: "We've grown so quickly over the last couple of years, we've shot up out of nothing and kind of surprised people."

The company's VentrAssist LVAS measures 3.5" in diameter (60 mm) and weighs in at just 10 ounces (298 grams) — making it implantable not only in smaller men and women, but also children — but with the power to push five to nine liters per minute of blood, which Crosby said is enough in one year "to fill Yankee Stadium."

He said that Ventracor's pump uses "a different fundamental design, a centrifugal pump" that he compared to the water pump of a car. It "comes in on an axis, gets ejected at a tangent to the periphery and is accelerated from inside and outside" by a single moving part, called an impeller.

He said that the Heartmate is an axial flow pump that he compared to a jet engine, "blood flowing in at one end of the pump, a turbine accelerates the blood flow along the access of the pump," with bearings at both ends, offering some potential for clotting.

Crosby put the VentrAssist at half the size of the HeartMate II, and he said the HeartMate's configuration is unlikely to shrink much "without going to a completely different design."

Predicting that Ventracor will be a "major player in the [VAD] field," Crosby told CD&D the heart pump field "is not a zero-sum game. There's room in this market for at least two players and maybe three [and] it's much better to compete in a large market than a small one."

He puts the patient pool for this arena at 5,000 "new" heart failure patients each year, about half of them looking at only one additional year of life. And he described this as a large and important need, given that heart failure is "worse than most cancers, worse than mortality from a first heart attack."

Working on the FDA 'mating dance'

Referring to the process of winning regulatory approval in the U.S. as the "FDA mating dance," Crosby said that Ventracor is halfway through its BTT trial enrollment and that it hopes to win PMA approval for that indication by 2010.

It also is developing a DT trial, but with less experience in the enrollment for that application, he said the company is making no precise estimates for that approval or, if that approval is finally won, what product uptake might turn out to be.

"It is difficult to project that — historical data is not a very good guide to future performance [for this application]. We will have to see how well the Heartmate II goes."

Overall, Crosby finds great hopefulness in the field with Thoratec's entry of its advanced-generation device, the progress that Ventracor is making and the development of other heart-assist devices, noting that end-stage heart failure treatments have been, heretofore, very limited, despite the size of the patient pool.

To a certain extent, he said, the problem has been a sense of futility that not much can be done for these patients — a futility driven in part by the hope of a heart transplant but an insufficient, and shrinking, supply of donor hearts.

"Once a patient gets very sick, the therapeutic options really decline," he said. "So in some senses, there has been a fatalistic approach."

Additionally, he said that the U.S. regulatory pathway and tech uptake has been to wait until a patient gets very sick before considering a heart-assist pump. This, he said, contrasts with the European approach of using a VAD earlier in the heart disease development, providing it as a "bridge-to-decision" concerning longer-term therapies.

Earlier heart failure the target

Another player in the heart assist sector is CircuLite, though Paul Southworth, company president/CEO, told CD&D that it is targeting a different heart failure sector — earlier disease development, before patients have reached that "fatalistic" end-stage period.

Before reaching the Class IV stage, heart failure patients, Southworth said, "continue to have a physiologic response. The heart still does everything it's intended to do. We're supplementing the heart with three liters of blood."

CircuLite's device is the Synergy Endovascular system, which Southworth described as the size of a double-A battery and "one-sixth the size of the next smallest device in the world." Implanted, he said, in a "finger-like pocket beneath the skin," it is used to "supplement the heart, give it a break, increase the cardiac index, increase CO₂." An impella in the device spins at 26,000 RPMs and there is "no room for homolosis, blood shearing, thrombosis or clotting because of no surface-to-surface contact with blood."

Developed by the Helmoholtz Institute (Aachen, Germany), from which Circulite has an exclusive license, the device is implanted by means of a "mini-thoracotomy" (and not requiring it to be an adjunct to bypass surgery), and the company is particularly focused on moving its implantation to an even more minimal strategy.

"We believe that we're able to do this with an endosurgical approach," Southworth said. And given the emergence of other new percutaneous approaches in the field, he added, "What looked like a daunting task three-and-a-half years ago is now pretty fundamental."

He said that the company is projecting receipt of a CE mark for its technology and completing a submission to the FDA for a U.S. clinical trial by the end of this year; European commercialization by early 2009; and completion of the U.S. study by the end of 2009.

Heartware and Berlin Heart

Glad to see Thoratec's HeartMate II approval and the company's progress in the sector, Heartware also is developing a smaller VAD, calling it an HVAD.

The company in early May received Investigational Device Exemption approval from the FDA and said it would immediately launch a clinical trial of the device for the BTT indication in up to 150 patients suffering from end-stage heart failure, at up to 28 centers.

In March of last year, the first HVAD implant was performed in a 48-year-old man at the Vienna General Hospital (Vienna, Austria). The company said the device's small size "facilitated fast implant." It describes the HVAD as a "full-output pump implantable in the pericardial space and the only centrifugal pump implantable above the diaphragm."

The company in April presented initial clinical results from 23 patients at the meeting of the International Society for Heart and Lung Transplantation (Addison, Texas), with 21 of these enrollees meeting the primary endpoint of survival to 180 days or transplantation and two receiving transplants.

Gearing up for its U.S. trial, the company in April signed a lease on a new manufacturing facility in Miami Lakes, Florida, previously used by Cordis Neurovascular.

In a recent report to investors, CEO Doug Godshall said that Heartware was "very pleased by the positive momentum in our industry" and "optimistic that Thoratec's market development activities will help drive a shift in referral patterns and ... increase in implant numbers."

He added: "The greater the success that Thoratec enjoys and the broader the adoption of the HeartMate II, the greater the market opportunity will be when HeartWare becomes commercially available in the U.S. two to three years from now. In the interim, U.S. clinicians participating in our U.S. clinical trial will be able to see first-hand the meaningful clinical advantages presented by the HeartWare System.

Berlin Heart, which describes its business as the making of pumps, cannulas, and external components for internal and external use to stabilize cardiac activity, has had success focused on the development of heart assist devices for children, with its miniaturized device.

This past December it reported the first patient enrollment in the prospective IDE study for its Excor Pediatric VAD as a BTT device, a mechanical cardiac support system for critically ill pediatric patients suffering from severe heart failure.

The shares of Berlin Heart in late 2006 were purchased by Syscore, a company belonging to the family office of German billionaire Sylvia Stroher, the company calling Syscore "a long-term investor" that will support its position in the U.S. market.