Heartmate II Continuous-Flow VAD Sets New Benchmark in Destination-Therapy Trial

Reed Miller

November 18, 2009

November 17, 2009 (Orlando, Florida) — Advanced heart-failure transplant-ineligible patients with Thoratec's HeartMate II continuous-flow left-ventricular assist device (LVAD) have better-than-even odds of surviving two years on the device [1].

The results of the 200-patient HeartMate II study comparing HeartMate II with HeartMate XVE were presented today at the American Heart Association (AHA) 2009 Scientific Sessions by Dr Joseph Rogers (Duke University Medical Center, Durham, NC), and the paper, by first author Dr Mark Slaughter (Advocate Christ Medical Center, Oak Lawn, IL) and colleagues, was simultaneously published online in the New England Journal of Medicine.

Unlike older pulsatile devices such as the HeartMate XVE, the HeartMate II supports the failing left ventricle with continuous flow that reduces the pulsatility of the heart. "We haven't had a clear idea up to this point what kind of impact that different kind of blood flow was going to have on long-term quality of life and performance," Rogers said.

Heartmate II Trounces Its Forerunner in Trial

As previously reported by heartwire, the HeartMate II destination-therapy trial randomized 200 transplant-ineligible patients--the so-called "destination-therapy" indication--in a 2:1 ratio to either HeartMate II or the first-generation HeartMate XVE pulsatile pump. The patients had NYHA class 3B or 4 heart-failure symptoms with a mean left-ventricular ejection fraction of 17%, and 80% were on intravenous inotropes.

The actuarial survival rates at two years were 58% and 24% for the HeartMate II and HeartMate XVE, respectively (p=0.008).

Of the 134 patients randomized to HeartMate II, 62 survived at least two years without suffering a stroke or requiring their device to be repaired or replaced. Only seven of the 66 patients randomized to the HeartMate XVE survived two years without a reintervention or stroke (hazard ratio 0.38, p<0.001).

The difference in stroke- or surgery-free survival, the primary end point of the study, was driven primarily by a difference in the need to reoperate to repair or replace HeartMate XVEs, Rogers explained at a press conference announcing the results at the AHA meeting. Only 10% of HeartMate II devices required repair or replacement vs 36% of the HeartMate XVE LVADs. "Each of these devices can pump 10 L of blood per minute. But one of the real challenges with the XVE device is that it had a fairly reliable failure mode between 12 and 18 months, and that was primarily related to wear of the bearing or dysfunction of the valves. The continuous-flow device doesn't have valves."

Also, 17 patients in the HeartMate II group and nine patients in the HeartMate XVE group were eventually given a heart transplant after their previous contraindications for transplant were resolved by the mechanical support.

HeartMate II was associated with statistically significant lower rates of several "clinically meaningful" adverse events, including hospitalizations, sepsis, non–device- and device-related infection, right-heart failure, and arrhythmias, Rogers pointed out.

The rates of disabling stroke were about the same in both groups, 11% for the HeartMate II vs 12% for the XVE.

"The persistent stroke risk that we've seen in all mechanical circulatory support trials [is] an area that we're still working hard to understand." Hemorrhaging stroke was the most common cause of death in both groups in the trial. With the pulsatile device, a single antiplatelet agent is sufficient, whereas the anticoagulation protocol in the HeartMate II trial included perioperative heparin followed by dual antiplatelet therapy and warfarin. During the study, the investigators saw a lot more bleeding events than thrombotic events, so the investigators cut back on the anticoagulation and antiplatelet therapies, Rogers said. "There may be interesting and important impacts of [anticoagulation therapy] that we have not yet explored.

Ready to Bring Vads to Less Sick Patients?

Dr Georg Wieselthaler (University of Vienna, Austria) noted that reports subsequent to the completion of the REMATCH trial, the 2001 seminal destination-therapy trial of an earlier version of HeartMate XVE, showed that some centers can consistently achieve better outcomes with HeartMate XVE than those shown in REMATCH; however, the survival rate of patients on HeartMate XVE in the HeartMate II trial is similar to that shown in REMATCH. "There's been no change in the outcomes of patients in past decade with the pulsatile-flow device," Rogers pointed out. He told heartwire that he believes the outcomes with HeartMate XVE in both REMATCH and the HeartMate II trial are representative of the typical experience with the device.

Commenting on the results, Dr Lynne Warner Stevenson (Harvard Medical School, Boston, MA) the director of the cardiomyopathy and heart-failure program at Brigham and Women's Hospital, told heartwire , "The important thing in this trial, unlike most trials, is not the difference between these two therapies, because we already knew that the XVE device is not good enough for durable therapy. We knew [HeartMate II] would be better than that.

"The important thing in this trial is the absolute outcomes," she said. "In a clinical sense, we've been waiting for a device that gives us a better-than-50% survival at two years."

Although two-year survival better than 50% marks a major milestone in the development of ventricular-assist technology, "the one-year survival of 68% was slightly lower than we had hoped," Stevenson said.

"Basically, that means that we'll want to identify a population with one-year mortality of more than 30% before we'd consider this device. So when you look at making these decisions, you have to look at up-front risk as well as long-term outcome, because for most people, the immediate time is more valuable than the delayed time."

Stevenson pointed out that, in the trial, both devices produced sustained improvements in functional outcomes. About 80% of patients on HeartMate II improved to NYHA class 1 or 2, with a doubling of the mean six-minute-walk distance and similar improvements in other quality-of-life metrics.

"This is a very sick patient population. . . . This is a group of patients that is quite compromised, just sitting still. So it's encouraging that we got such a good outcome in such a sick population. What we're anxious to see is what kind of outcomes we will get in patients who are less sick to start out with," she explained. "So we're hoping to move into an era where we can use devices in patients who are walking around, who are not sick enough to use inotropes. Move it earlier in the disease. This trial helps us do that, but we still have a long way to go."

Wieselthaler also suggested that the device came too late to help many of the patients in the trial. "The largest percentage of patients died within the first six months after implantation, whereas after this period, the death rate--at least in the HeartMate II cohort--flattens," he observed. "Now, we can speculate that maybe some of these patients were already too sick and therefore did not survive the first six months after the implant, and the patients who get the devices earlier will have better outcomes."

"The mortality rates in the trial early on are very high, not because the devices are failing but because the patients fail at those early time points, [because] the people we're implanting are in cardiogenic shock, debilitated, or malnourished, or they have end-organ dysfunction," Rogers said. "Would patients have even better outcomes if they weren't quite as sick as the individuals we keep enrolling in these trials? Many of us believe the answer is yes."

He pointed out that the National Institutes of Health is soliciting proposals for a trial of ventricular assist devices in "less sick" heart-failure patients. "Once that trial is completed, we'll have a clearer idea about the potential benefits to people who aren't quite as morbidly ill as the people we've been putting in the trials."

Stevenson said that once FDA approves HeartMate II for transplant-ineligible patients, physicians will be able to begin implanting it in patients less ill than the population in the HeartMate II trial, and their outcomes will be tracked in the Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS]. "For the same reasons as in this trial, it's not so important to compare those data with something else, just what they are on their own."

Thoratec filed a premarket approval supplement with the FDA for the destination-therapy indication for HeartMate II in April, a year after the FDA approved it as a bridge to transplant. It has had a CE Mark approval in Europe since November 2005.