ADVANCE: New LVAD Equivalent to HeartMate II, Nonrandomized Study Shows

November 14, 2010

November 14, 2010 (Chicago, Illinois) — A novel left ventricular assist device (LVAD) developed by a small company called HeartWare (Framingham, MA) is a viable alternative to the only other widely used LVAD, Thoratec's HeartMate II, as a bridge to heart transplant, according to a new study reported at the American Heart Association (AHA) 2010 Scientific Sessions.

Dr Keith Aaronson

The success rate was "quite high" and the survival "quite good" with the new device, which showed noninferiority when compared with patients in a national registry, most of whom had gotten the HeartMate II, said Dr Keith Aaronson (University of Michigan, Ann Arbor), who reported the results during a late-breaking clinical-trials session. "This provides a new opportunity for patients who require ventricular support as a means to get to a heart transplant," he noted.

ADVANCE, a multicenter trial carried out in the US, enrolled 140 patients who received the new HeartWare ventricular assist device (VAD) and compared the results at 180 days with patients in the Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS). This trial represents a first, said Aaronson, because it is the only such study to have used a contemporaneous control group: previous bridge-to-transplant trials of LVADs have all been single-arm studies, he noted.

Sir Magdi Yacoub

Discussant of the trial, Sir Magdi Yacoub (Harefield Hospital, Middlesex, UK), said: "The early results show this is at least as good as the other available devices, and we hope this will translate into clinical benefit, but this is only the beginning. Adverse reactions have been a major problem that has dogged the application of LVADs," he noted, so although ADVANCE can be considered a "landmark trial in the long road of optimizing LVAD usage, we await the long-term results with interest."

Dr Clyde Yancy

Asked to comment on the findings, immediate past president of the AHA Dr Clyde Yancy (Baylor College of medicine, Houston, TX) told heartwire : "The ADVANCE data are very provocative. We've gone from the pulsatile VADs to the continuous-flow VADs, now to the axial-flow VADs that restore some pulsatility. Certainly the noninferiority data are persuasive and demonstrate that we may have yet another platform we can use."

HeartWare VAD Smaller, With Less Bleeding and Infection, But Stroke Is a Concern

Aaronson said that the HeartWare VAD was implanted in 140 people listed for heart transplantation in ADVANCE, and the outcomes were compared with those of 499 people enrolled in INTERMACS who received an LVAD as a bridge to transplantation, the majority of whom got a HeartMate II.

This provides a new opportunity for patients who require ventricular support as a means to get to a heart transplant.

The primary outcome was success, defined as survival on the originally implanted device, transplant, or explant for ventricular recovery (with a requirement that people must survive 60 days postexplant) at 180 days. Secondary outcomes were a comparison of survival between treatment and control groups, and functional and quality-of-life outcomes, as well as adverse events, in the treatment group.

The HeartWare VAD (Source: HeartWare, Inc)

The treatment-group success was 92.0%, "which is the highest reported success with any VAD in a bridge-to-transplant study at 180 days," said Aaronson. Control-group success was 90.1%, so the HeartWare VAD met the criterion of noninferiority to the control (p<0.001) but not superiority, he noted.

Acknowledging the difficulty of comparing clinical-trial outcomes with those of a national registry, Aaronson said there nevertheless appears to be less bleeding and infection with the new device, which might be expected because it is smaller.

We need to be really critical and look at the results as we go along and not just say, 'Hurrah.'

Yacoub agrees. "One of the main attractions of this device, a major advantage, is that it's smaller, allowing it to be implanted in the pericardium, so you don't have to make a pocket in the abdomen with it," making the surgery easier and significantly shorter, he told heartwire . Also the driveline--which comes out of the device and is run down into the abdomen, exiting through the skin--is thinner, which results in less trauma, he said. These two things likely explain the lower rates of bleeding and infection seen with the HeartWare VAD in ADVANCE compared with the INTERMACS controls, he said. The smaller size of the HeartWare VAD also means it might be more appropriate for certain patient groups, he says: "Women, who have a lower body weight, children, someone who is extremely sick and you don't want to be dissecting, the elderly. It is pushing the frontiers, definitely."

But the incidence of stroke seen was higher than might have been expected with the smaller size of the device, both Aaronson and Yacoub said, and this is something that will require watching.

"The trial is only 180 days: we await the longer-term results with extreme interest because if there is major advantage it's going to be seen later. We need to be really critical and look at the results as we go along and not just say 'Hurrah,' " says Yacoub. There are other issues, too, he added, "such as evidence of GI bleeding due to malformations in the gut, and they got that already by 180 days. Also you get changes in the blood itself, the von Willebrand factor, and that is because of the lack of pulsatility. But that doesn't prevent me from concluding that this is a landmark trial and this device is extremely promising."

In the next two or three years . . . there is going to be a clinical trial of a factor Xa or thrombin inhibitor in the presence of a VAD compared with warfarin.

Dr Alfred A Bove (Temple University, Philadelphia, PA) says he is not surprised by the stroke data. "I don't think there was any doubt this was going to show effectiveness; the question is, how small can you get and still get benefit? It's a challenge. It's something we are going to have to deal with. We've learned that a high-speed axial VAD will work but it needs anticoagulation. One of the things that I think is going to happen in the next two or three years is that there is going to be a clinical trial of a factor Xa or thrombin inhibitor in the presence of a VAD compared with warfarin."

Head-to-Head Trial of HeartWare VAD and HeartMate II Ongoing

ADVANCE is the first US trial to look at the HeartWare VAD, but the device has been implanted in considerably more patients in Europe, around 1500 in total, HeartWare spokesperson Christopher Taylor told heartwire .

Aaronson commented: "The results in terms of survival and success with the HeartWare VAD stand on their own; they were excellent outcomes. I think the question really comes down to the adverse-event profile for the two devices. The only way we are going to know for sure is when we have a head-to-head comparison in the context of a randomized clinical trial," he says.

That trial, named ENDURANCE, is under way, and is a study of the HeartWare VAD against the HeartMate II for indefinite use in patients who aren't candidates for transplantation, so-called destination therapy; the trial is ongoing, although in the early stages. "Until then, physicians will have to look at these [ADVANCE results] and other results to draw their own conclusions as to which device to use for individual patients," says Aaronson.

Bove says that destination therapy is the ultimate goal for these devices: "The population that we need to deal with is the older population. They are not eligible for transplant--we draw the line at around 70. So you have all these 70- and 80-year-olds with heart failure and we run out of drugs, we run out of electrical devices; they need assist pumps."

He acknowledges, however, that cost-effectiveness will have to be proven. The cost of the HeartWare VAD, at around $86 000, is comparable to the HeartMate II; the latter was approved as destination therapy for end-stage heart failure in the US earlier this year, but the company is still awaiting changes to the Medicare coverage policy.

Bove predicts: "People will see a market in this older population who requires some assistance, but not full assistance; we're going to see more development. I don't think we'll end up with generic VADs for $4 a month in Wal-Mart, but the price will come down and the technology will get better based on competition." In fact, a HeartMate III is already under development, Yacoub told heartwire .

Yancy agrees and is eagerly awaiting the ENDURANCE data. "If this benefit can be realized in a destination-therapy group, it would really allow us to have more opportunities for patients who have truly advanced disease with no other options."

Aaronson has received financial support from HeartWare, Thoratec, and Terumo and is on the clinical steering committee for HeartWare but has received no personal remuneration.