Washington Editor

Robert Jarvik, MD, is a name known to many, for his development of the Jarvik 7 and the drama that was the life — and death — of retired dentist Barney Clark, the person first implanted with that first artificial heart in 1982.

Despite the high hopes surrounding the first human use of this device, Clark passed away 112 days later. From implant to death, Clark was plagued by infections and other complications, with the intense pubicity concerning his last days casting a pall over hopes for this technology and greatly reducing public interest in its real clinical potential.

Others, besides Jarvik, played important roles in the development of the artificial heart (see sidebar). But whatever its exact genesis and development, Jarvik brought the device to fruition for its first use in humans. And later advancements in device technology, primarily by Abiomed and SynCardia, have reviewed hopes for the technology, as well as its cousin, the ventricular assist device (VAD).

Jarvik is today probably better known as the TV spokesman for the cholesterol drug Lipotor. Currently, Jarvik and Pfizer (New York), the maker of Lipitor, are the subjects of a U.S. congressional inquiry questioning the use of celebrity endorsements in pharmaceutical advertisements. (Jarvik declined to address this controversy for this interview.)

Critics of the ads say that it is misleading for Jarvik to appear in the ads, inasmuch as he has never practiced medicine, despite obtaining an MD. Others make the case that Jarvik does have substantial knowledge of heart disease and that using actors to portray doctors is much more misleading.

Whatever the merits, Jarvik’s appearance in the ads seem to be effective. It was reported in March 2007 that Jarvik’s work for Pfizer coincided with a 15% increase in sales of the drug. Jarvik’s name also is attached to a new VAD, the left ventricular assist device (LVAD), the Jarvik 2000, under development by his company, Jarvik Heart (New York). The device is a rotary pump that can run for up to 10 hours on a single charge of its external lithium-ion batter. The 2000 runs automatically, but the operation of the unit can be overridden by the wearer for periods of exercise or other sources of higher demand.

The Jarvik 2000 is a lighter and quieter unit than most of the competition, weighing only 90 grams, or about 15 ounces. The HeartMate II, a competitor LVAD made by Thoratec that received a nod from an FDA advisory panel but is not yet on the market, weighs roughly the same. Both are much smaller and lighter than currently available units, including Thoratec’s 1200-gram HeartMate. Jarvik said the Flowmaker operates without generating any noise.

The Jarvik 2000 is a booster pump, which means that the patient’s heart continues to beat, providing the pulsatile flow associated with normal cardiac function. Because the unit is not designed to completely replace left ventricular function, the pivotal trial cannot enroll patients with New York Heart Association stage IV heart failure.

The Jarvik 2000 is a lighter and quieter unit than most of the competition, weighing only 90 grams, or about 15 ounces.

The HeartMate II, a competitor LVAD made by Thoratec that received a nod from an FDA advisory panel in December but is not yet on the market, weighs roughly the same. Both are much smaller and lighter than currently available units, including Thoratec’s 1200-gram HeartMate. Jarvik said the Flowmaker operates without generating any noise.

In a recent interview with Cardiovascular Device Update, Jarvik provided an update on the Jarvik 2000 and other issues in the cardiovascular device industry.

Q. What is the regulatory status of the Jarvik 2000?

“We have completed the first 75 patients” in the pivotal trial for an interim analysis of theJarvik 2000 Flowmaker, Jarvik said, and that “the six-month follow-up will be complete for all 75 patients” sometime in the spring.

Jarvik said FDA gave the nod for enrollment in the pivotal trial for the Flowmaker, in March 2005. European Union officials granted the device a CE mark two months later.

As for when Jarvik Heart will attempt to file the final paperwork on the Flowmaker PMA, Jarvik said,”if the results of the interim analysis support an application — or with a group of [63] pilot study patients we’ve had — we could submit an application sometime next summer,” meaning the summer of 2008. “That would be the earliest reasonable date.”

If not by then, the company might have to enroll another 75 patients and put another two years into the effort.

Whether the application will go to an advisory panel remains to be seen, but given the recent history of high-risk cardiovascular devices, this seems likely. If so, Jarvik said “we’re quite confident we’ll meet the primary endpoint.”

As is the case with many devices for which a control is either impossible or impractical, the Flowmaker trial consists of “a pre-stated performance goal, defined as either transplant or listed for transplant status 1A or 1B at 180 days,” Jarvik said. As is commonly the case for such devices, secondary endpoints include measures of quality of life, neuro-cognitive function, and rates of serious adverse events.

Q. Is there any risk to damage to the heart with the Flowmaker?

“It’s a fair expectation that if you left a pump with a crossing [of the aortic valve] that you’d have some damage” sooner or later, Jarvik said, but he pointed out that the unit is inserted into the left ventricle and does not straddle the aortic valve, sending blood through the fixation cannula and around the outside of the heart to the aorta.

Unlike the Jarvik Flowmaker, the Impella 2.5, made by Abiomed, crosses the aortic valve. However, Jarvik noted that the Impella is for short-term use and hence is not necessarily going to create problems with the aortic valve when used appropriately.

Regarding other safety features, Jarvik said that when a pump causes blood flow to completely bypass the aortic valve, the valve leaflets can fuse. The Flowmaker occasionally goes into low flow mode, but even at this state of affairs, it forces the left ventricle to pump, keeping the aortic valve leaflets from sealing.

“Every pump out there has some risk of damage,” Jarvik said, including seemingly innocuous incidents.

For instance, it would not be difficult to accidentally shut a car door on an electrical line of such a device, and Jarvik said he was aware of an incident in which a purse-snatcher mistook the external battery component for a purse and attempted to make off with it. The unit’s alarm went off, though, and the would-be felon dropped the bag, allowing the patient to recover the equipment.

Q. What is the essential difference between bridge-to-transplant and destination therapy for VADs?

“There’s a sea change in the world of heart assist devices where experts will tell you that there should be no distinction between bridge-to-transplant and destination therapy,” Jarvik said.

As is often the case for patients with late-stage heart failure, the lack of available transplants makes the VAD a destination device by default.

“There are nowhere near enough donor hearts,” so “the result is that quite a few patients will have long-term support,” Jarvik said.

The implant procedure is probably fairly routine for surgeons experienced with such equipment. Jarvik that the procedure requires a left thoracotomy, usually entailing no removal of portions of a rib to facilitate access. The fact that the Flowmaker can be installed without stopping the heart “avoids the effect of the heart-lung machine, which is the thing that’s linked to cognitive derangement,” he said.

Q. Are you concerned about competition from the growing pipeline of VADs under development?

“Not at all,” Jarvik said. “I think that the market [for devices dealing with other than end-stage heart failure] is going to get something near a real market,” he said.The HeartMate is the only device that has achieved rapid clinical acceptance in this space, and Thoratec’s HeartMate II “is on the verge of approval”

Still, development can be impeded by the competition. Jarvik said he does see some indications of crowding at centers of excellence that get the bulk of clinical trials.

“There are many centers that have a variety of VADs,” he said, with some of the crowding is due to the fact that some sponsors make their devices available free of charge.

Jarvik said he expects that the Flowmaker “will do better than anything prior,” but that FDA offers a potential bottleneck to commericalization.

“I feel the regulatory process is so slow,” and that some worthwhile devices are hindered as a consequence.

Q. What is a realistic outer limit for destination therapy for the Flowmaker and for VADs in general?

Jarvik said that a a number of patients have been on the Jarvik 2000 for up to seven years, and that this is not utterly unique.

“There are several [heart assist] devices that are potentially reliable up to 10 years,” he said, and this fact gives clinicians and FDA breathing room to expand the use of VADs into earlier-stage disease, providing relief and possible recovery before patients move into the end-stages of heart failure.

“The real difference is the success of rotary blood pumps versus pusher plates,” Jarvik said. “All these [modern] pumps are one moving part.” While he noted still some reports of infections, these devices are “so much better” than early systems.

Considering the entire field of ventricular assist, Jarvik said that the question of the physiological effects of pulsatile [producing a sort of simulated beating, and beating sound] versus non-pulsatile pumping “was a debate in the field for years.”

Blood flow to capillaries is not pulsed even with a normal heart because of the buffering effects of intervening tissue, but Jarvik acknowledged that “the kidneys are quite sensitive, and pulsatile pressure is thought to be beneficial to kidney function.”

The Flowmaker seems to step around this problem, but whether it will crop up in another device remains to be seen.

Q. You were at the FDA advisory panel for the HeartMate II (HM II) and saw how much discussion there was concerning bleeding. Did you find the incidence of bleeding events in connection with the HM II conspicuous?

“It appears higher than ours, but bleeding is our most common complication,” Jarvik said. “Some of these patients are really compromised ... but they’re not bleeding to death” as a result of the operation.

Still, he pointed out that bleeding creates several severe problems, including amplified suppresion of the immune system that can complicate efforts to transplant a heart.

If VADs make their way into patients with less severe diseases, he said, the incidence — and the severity of the consequences — of bleeds will likely fall because these patients are generally healthier.

Jarvik is not actively pursuing a new design for the artificial heart, partly because, he said, “I would not choose to excise a natural heart” if bi-ventricular pumping is available. “We think that the use of two rotary pumps is practical for total support” in lieu of removing a heart and replacing it with an artificial mechanism.

O. Howard Frazier, MD, the director of transplant services at the Texas Heart Institute has tried this, he said, “and has shown that balancing the flow between the right and left side is easy. There is some auto-regulation that occurs in the vascular system,” so it can be done.

Q. What do you see in the near future that you think is exciting for heart failure patients?

“Some have proved that myocytes can be viable” for reversing the remodeling process that leads to heart failure, Jarvik said.

He noted that the use of clenbuterol, the anabolic steroid that is not yet legal for medical use in the U.S., is “apparently effective in the redevelopment of myocardial function” when used in conjunction with a VAD. He said that the current protocol being pursued by Magdi Yacoub, MD, and others at Harefield Hospital (London) “is very promising.”

Jarvik said that one of the more interesting developments that may come into play is the use of genetically altered pig hearts as transplants. Acute rejection can be handled in such a situation, he said, but chronic rejection is tougher to overcome.

“I think it would be great if people succeed in these efforts,” Jarvik said.

He added that whatever the pace of non-mechanical advances, there will always be a place on the medical shelf for devices that serve as bridge to recovery.

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