Third-Generation LVAD Shows Good Efficacy, Safety

CHICAGO – A third-generation, investigational left ventricular assist device performed at least as well as current devices on the market, and also showed signs of important benefits like reduced infections and bleeding during 6 months of follow-up as a bridge to heart transplant in 140 patients in a pivotal, multicenter study.

Based on results from the ADVANCE (Evaluation of the HeartWare Ventricular Assist System for the Treatment of Advanced Heart Failure) study, HeartWare – the company developing the new device – said that it would seek marketing approval from the Food and Drug Administration for the HeartWare ventricular assist device (VAD) as a bridge to transplant before the year’s end. A small, continuous-flow pump, the HeartWare VAD is implanted in the pericardium with no need for a pocket. Experts who heard the new data cautioned that although the results so far look fine, the long-term durability and performance of the new VAD need assessment compared with the current standard, the HeartMate II.

"Implantation of the HeartWare VAD pump in the pericardial space was associated with a very high probability of success at 180 days," said Dr. Keith D. Aaronson at the annual scientific sessions of the American Heart Association. The 92% of patients who received the HeartWare VAD and were either alive with their device or had received a heart transplant during the 180 days after device placement was "the highest rate ever reported in any left VAD [LVAD] study," said Dr. Aaronson, medical director of the heart failure program at the University of Michigan in Ann Arbor.

"The survival and the success of the HeartWare VAD are excellent outcomes," Dr. Aaronson said. The question of which VAD works better – the HeartWare model or the HeartMate II – "comes down to the adverse event profile for the two devices. The only way to know for sure [which device is better] is to compare them head to head." A trial now underway compares the two VADs as destination therapy for patients who are unable to get a heart transplant, he noted.

"The HeartMate II has been a good workhorse. People know how to use it and are comfortable with it. When the HeartWare device comes out, people will want to use it, and surgeons seem to like the idea of implanting the device directly in the heart. But [questions like] which is the best kind of VAD, where do you put it, and what’s the best way to anticoagulate patients [are] not clear. The HeartMate VAD advances one piece of the puzzle, but the upcoming trials that will compare the VADs head to head will give us a lot more answers," commented Dr. Mariell L. Jessup, professor of medicine and medical director of the heart and vascular center at the University of Pennsylvania in Philadelphia.

"This is the first successful completion of a bridge-to-transplant trial with a control" group of patients, noted Dr. Lynne Warner Stevenson, professor of medicine and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital in Boston. "We all know that the bridge results are not the same as the destination results."

The HeartWare VAD arm of the study ran at 30 U.S. sites during August 2008–February 2010. The researchers screened 157 patients to find 140 who met the enrollment criteria, including having New York Heart Association class IV heart failure and being listed for a heart transplant. Surgeons ultimately placed the HeartWare VAD in 137 patients. The control arm included 499 U.S. patients who received a commercially available LVAD during the same period and were registered in the INTERMACS (Interagency Registry for Mechanical Assisted Circulatory Support) system. By the first half of 2009, 94% of these INTERMACS control patients received a HeartMate II as their LVAD, and throughout the 18 months of the study Dr. Aaronson estimated that all but 3%-4% of the control patients received a HeartMate II. The average age of the VAD recipients was 53 years, and about a quarter were women.

After 180 days, 63% of the HeartWare VAD recipients remained alive with their device in place, and 29% had received a heart transplant, 4% had their device switched for another VAD, and 4% had died. The overall 92% success rate in this group was comparable with a 90% overall success rate among the control patients in the INTERMACS registry. The similar rates in the two arms met the prespecified criteria for noninferiority of the new device. But the HeartWare VAD did not show statistically significant superiority to the control devices, either in an unadjusted analysis or after adjustment in a propensity analysis, Dr. Aaronson said.

Mortality during the first 30 days following device placement ran 1.4% in the HeartWare group and 3.4% in the control patients. The 1.4% perioperative rate in the HeartWare recipients was "remarkable," Dr. Aaronson said, and was "comparable to the rate in patients electively receiving an aortic valve replacement."

The HeartWare recipients also showed statistically significant and clinically meaningful improvements in their quality of life. Their average scores on the Kansas City Cardiomyopathy Questionnaire for clinical summary and overall summary rose from a level consistent with severe heart failure at baseline to a level indicating mild heart failure 3 months after device placement. Their average EuroQol 5D self-rating showed an increase after 3 months that was comparable with "what is usually reported for heart transplant recipients," Dr. Aaronson said.

As Dr. Aaronson noted, much attention focused on adverse events. His analysis compared the rates seen in the 140 HeartWare VAD recipients vs. 281 patients who received the HeartMate II VAD in a multicenter study done during 2005-2008 that led to HeartMate II’s approval (J. Am. Coll. Cardiol. 2009;54:312-21). In the HeartWare series, bleeding at gastrointestinal sites occurred at a rate of 25% per patient-year, and bleeds requiring surgery occurred in 27% per patient-year. In the HeartMate II series, bleeds needing surgery occurred in 45% per patient-year, with no report on gastrointestinal bleeds. The 25% per patient-year gastrointestinal-bleeding rate in the HeartWare patients was "relatively low, about one-third the rate that’s been reported" by individual centers for patients who received the HeartMate II, he said.

"We need to know if there is a meaningful difference in the gastrointestinal bleeding, a key issue for all the nonpulsatile VADs," Dr. Jessup said.

Infection rates with the HeartWare VAD (39% per patient-year) also ran "substantially lower" than the 85% rate reported from the HeartMate II multicenter series. Ventricular arrhythmias also showed a substantial reduction with the HeartWare VAD (13% per patient-year vs. 40% per patient-year in the HeartMate II series).

Ischemic stroke rates with the HeartWare VAD ran 11% per patient-year, similar to the 9% rate seen in the multicenter HeartMate II series. Hemorrhagic stroke occurred at the same rate (5% per patient-year) with both devices. Half of the 10 ischemic strokes in the HeartWare VAD recipients occurred during the first 48 hours following device placement. "We believe they were surgically related; there is a clear learning curve" for placing the HeartWare VAD, Dr. Aaronson said. In addition, he noted that 8 of the 10 patients who had ischemic strokes later recovered to "moderate disability."

Another "key issue" that experience with the HeartWare VAD has so far not addressed is aortic valve insufficiency, Dr. Jessup said. "No one talks about it in these short-term trials, but you really see aortic insufficiency in destination-treatment trials. The longer you see patients [with LVADs], the more you see them developing hypertension and aortic insufficiency. Will there be a difference in the VADs for aortic insufficiency?"

The study was sponsored by HeartWare, the device developer. Dr. Aaronson said that he has received research support from HeartWare, Thoratec, and Terumo. Dr. Jessup is a consultant to Medtronic and a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Stevenson has been a consultant to Medtronic.

CHICAGO – A third-generation, investigational left ventricular assist device performed at least as well as current devices on the market, and also showed signs of important benefits like reduced infections and bleeding during 6 months of follow-up as a bridge to heart transplant in 140 patients in a pivotal, multicenter study.

Based on results from the ADVANCE (Evaluation of the HeartWare Ventricular Assist System for the Treatment of Advanced Heart Failure) study, HeartWare – the company developing the new device – said that it would seek marketing approval from the Food and Drug Administration for the HeartWare ventricular assist device (VAD) as a bridge to transplant before the year’s end. A small, continuous-flow pump, the HeartWare VAD is implanted in the pericardium with no need for a pocket. Experts who heard the new data cautioned that although the results so far look fine, the long-term durability and performance of the new VAD need assessment compared with the current standard, the HeartMate II.

"Implantation of the HeartWare VAD pump in the pericardial space was associated with a very high probability of success at 180 days," said Dr. Keith D. Aaronson at the annual scientific sessions of the American Heart Association. The 92% of patients who received the HeartWare VAD and were either alive with their device or had received a heart transplant during the 180 days after device placement was "the highest rate ever reported in any left VAD [LVAD] study," said Dr. Aaronson, medical director of the heart failure program at the University of Michigan in Ann Arbor.

"The survival and the success of the HeartWare VAD are excellent outcomes," Dr. Aaronson said. The question of which VAD works better – the HeartWare model or the HeartMate II – "comes down to the adverse event profile for the two devices. The only way to know for sure [which device is better] is to compare them head to head." A trial now underway compares the two VADs as destination therapy for patients who are unable to get a heart transplant, he noted.

"The HeartMate II has been a good workhorse. People know how to use it and are comfortable with it. When the HeartWare device comes out, people will want to use it, and surgeons seem to like the idea of implanting the device directly in the heart. But [questions like] which is the best kind of VAD, where do you put it, and what’s the best way to anticoagulate patients [are] not clear. The HeartMate VAD advances one piece of the puzzle, but the upcoming trials that will compare the VADs head to head will give us a lot more answers," commented Dr. Mariell L. Jessup, professor of medicine and medical director of the heart and vascular center at the University of Pennsylvania in Philadelphia.

"This is the first successful completion of a bridge-to-transplant trial with a control" group of patients, noted Dr. Lynne Warner Stevenson, professor of medicine and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital in Boston. "We all know that the bridge results are not the same as the destination results."

The HeartWare VAD arm of the study ran at 30 U.S. sites during August 2008–February 2010. The researchers screened 157 patients to find 140 who met the enrollment criteria, including having New York Heart Association class IV heart failure and being listed for a heart transplant. Surgeons ultimately placed the HeartWare VAD in 137 patients. The control arm included 499 U.S. patients who received a commercially available LVAD during the same period and were registered in the INTERMACS (Interagency Registry for Mechanical Assisted Circulatory Support) system. By the first half of 2009, 94% of these INTERMACS control patients received a HeartMate II as their LVAD, and throughout the 18 months of the study Dr. Aaronson estimated that all but 3%-4% of the control patients received a HeartMate II. The average age of the VAD recipients was 53 years, and about a quarter were women.

After 180 days, 63% of the HeartWare VAD recipients remained alive with their device in place, and 29% had received a heart transplant, 4% had their device switched for another VAD, and 4% had died. The overall 92% success rate in this group was comparable with a 90% overall success rate among the control patients in the INTERMACS registry. The similar rates in the two arms met the prespecified criteria for noninferiority of the new device. But the HeartWare VAD did not show statistically significant superiority to the control devices, either in an unadjusted analysis or after adjustment in a propensity analysis, Dr. Aaronson said.

Mortality during the first 30 days following device placement ran 1.4% in the HeartWare group and 3.4% in the control patients. The 1.4% perioperative rate in the HeartWare recipients was "remarkable," Dr. Aaronson said, and was "comparable to the rate in patients electively receiving an aortic valve replacement."

The HeartWare recipients also showed statistically significant and clinically meaningful improvements in their quality of life. Their average scores on the Kansas City Cardiomyopathy Questionnaire for clinical summary and overall summary rose from a level consistent with severe heart failure at baseline to a level indicating mild heart failure 3 months after device placement. Their average EuroQol 5D self-rating showed an increase after 3 months that was comparable with "what is usually reported for heart transplant recipients," Dr. Aaronson said.

As Dr. Aaronson noted, much attention focused on adverse events. His analysis compared the rates seen in the 140 HeartWare VAD recipients vs. 281 patients who received the HeartMate II VAD in a multicenter study done during 2005-2008 that led to HeartMate II’s approval (J. Am. Coll. Cardiol. 2009;54:312-21). In the HeartWare series, bleeding at gastrointestinal sites occurred at a rate of 25% per patient-year, and bleeds requiring surgery occurred in 27% per patient-year. In the HeartMate II series, bleeds needing surgery occurred in 45% per patient-year, with no report on gastrointestinal bleeds. The 25% per patient-year gastrointestinal-bleeding rate in the HeartWare patients was "relatively low, about one-third the rate that’s been reported" by individual centers for patients who received the HeartMate II, he said.

"We need to know if there is a meaningful difference in the gastrointestinal bleeding, a key issue for all the nonpulsatile VADs," Dr. Jessup said.

Infection rates with the HeartWare VAD (39% per patient-year) also ran "substantially lower" than the 85% rate reported from the HeartMate II multicenter series. Ventricular arrhythmias also showed a substantial reduction with the HeartWare VAD (13% per patient-year vs. 40% per patient-year in the HeartMate II series).

Ischemic stroke rates with the HeartWare VAD ran 11% per patient-year, similar to the 9% rate seen in the multicenter HeartMate II series. Hemorrhagic stroke occurred at the same rate (5% per patient-year) with both devices. Half of the 10 ischemic strokes in the HeartWare VAD recipients occurred during the first 48 hours following device placement. "We believe they were surgically related; there is a clear learning curve" for placing the HeartWare VAD, Dr. Aaronson said. In addition, he noted that 8 of the 10 patients who had ischemic strokes later recovered to "moderate disability."

Another "key issue" that experience with the HeartWare VAD has so far not addressed is aortic valve insufficiency, Dr. Jessup said. "No one talks about it in these short-term trials, but you really see aortic insufficiency in destination-treatment trials. The longer you see patients [with LVADs], the more you see them developing hypertension and aortic insufficiency. Will there be a difference in the VADs for aortic insufficiency?"

The study was sponsored by HeartWare, the device developer. Dr. Aaronson said that he has received research support from HeartWare, Thoratec, and Terumo. Dr. Jessup is a consultant to Medtronic and a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Stevenson has been a consultant to Medtronic.

CHICAGO – A third-generation, investigational left ventricular assist device performed at least as well as current devices on the market, and also showed signs of important benefits like reduced infections and bleeding during 6 months of follow-up as a bridge to heart transplant in 140 patients in a pivotal, multicenter study.

Based on results from the ADVANCE (Evaluation of the HeartWare Ventricular Assist System for the Treatment of Advanced Heart Failure) study, HeartWare – the company developing the new device – said that it would seek marketing approval from the Food and Drug Administration for the HeartWare ventricular assist device (VAD) as a bridge to transplant before the year’s end. A small, continuous-flow pump, the HeartWare VAD is implanted in the pericardium with no need for a pocket. Experts who heard the new data cautioned that although the results so far look fine, the long-term durability and performance of the new VAD need assessment compared with the current standard, the HeartMate II.

"Implantation of the HeartWare VAD pump in the pericardial space was associated with a very high probability of success at 180 days," said Dr. Keith D. Aaronson at the annual scientific sessions of the American Heart Association. The 92% of patients who received the HeartWare VAD and were either alive with their device or had received a heart transplant during the 180 days after device placement was "the highest rate ever reported in any left VAD [LVAD] study," said Dr. Aaronson, medical director of the heart failure program at the University of Michigan in Ann Arbor.

"The survival and the success of the HeartWare VAD are excellent outcomes," Dr. Aaronson said. The question of which VAD works better – the HeartWare model or the HeartMate II – "comes down to the adverse event profile for the two devices. The only way to know for sure [which device is better] is to compare them head to head." A trial now underway compares the two VADs as destination therapy for patients who are unable to get a heart transplant, he noted.

"The HeartMate II has been a good workhorse. People know how to use it and are comfortable with it. When the HeartWare device comes out, people will want to use it, and surgeons seem to like the idea of implanting the device directly in the heart. But [questions like] which is the best kind of VAD, where do you put it, and what’s the best way to anticoagulate patients [are] not clear. The HeartMate VAD advances one piece of the puzzle, but the upcoming trials that will compare the VADs head to head will give us a lot more answers," commented Dr. Mariell L. Jessup, professor of medicine and medical director of the heart and vascular center at the University of Pennsylvania in Philadelphia.

"This is the first successful completion of a bridge-to-transplant trial with a control" group of patients, noted Dr. Lynne Warner Stevenson, professor of medicine and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital in Boston. "We all know that the bridge results are not the same as the destination results."

The HeartWare VAD arm of the study ran at 30 U.S. sites during August 2008–February 2010. The researchers screened 157 patients to find 140 who met the enrollment criteria, including having New York Heart Association class IV heart failure and being listed for a heart transplant. Surgeons ultimately placed the HeartWare VAD in 137 patients. The control arm included 499 U.S. patients who received a commercially available LVAD during the same period and were registered in the INTERMACS (Interagency Registry for Mechanical Assisted Circulatory Support) system. By the first half of 2009, 94% of these INTERMACS control patients received a HeartMate II as their LVAD, and throughout the 18 months of the study Dr. Aaronson estimated that all but 3%-4% of the control patients received a HeartMate II. The average age of the VAD recipients was 53 years, and about a quarter were women.

After 180 days, 63% of the HeartWare VAD recipients remained alive with their device in place, and 29% had received a heart transplant, 4% had their device switched for another VAD, and 4% had died. The overall 92% success rate in this group was comparable with a 90% overall success rate among the control patients in the INTERMACS registry. The similar rates in the two arms met the prespecified criteria for noninferiority of the new device. But the HeartWare VAD did not show statistically significant superiority to the control devices, either in an unadjusted analysis or after adjustment in a propensity analysis, Dr. Aaronson said.

Mortality during the first 30 days following device placement ran 1.4% in the HeartWare group and 3.4% in the control patients. The 1.4% perioperative rate in the HeartWare recipients was "remarkable," Dr. Aaronson said, and was "comparable to the rate in patients electively receiving an aortic valve replacement."

The HeartWare recipients also showed statistically significant and clinically meaningful improvements in their quality of life. Their average scores on the Kansas City Cardiomyopathy Questionnaire for clinical summary and overall summary rose from a level consistent with severe heart failure at baseline to a level indicating mild heart failure 3 months after device placement. Their average EuroQol 5D self-rating showed an increase after 3 months that was comparable with "what is usually reported for heart transplant recipients," Dr. Aaronson said.

As Dr. Aaronson noted, much attention focused on adverse events. His analysis compared the rates seen in the 140 HeartWare VAD recipients vs. 281 patients who received the HeartMate II VAD in a multicenter study done during 2005-2008 that led to HeartMate II’s approval (J. Am. Coll. Cardiol. 2009;54:312-21). In the HeartWare series, bleeding at gastrointestinal sites occurred at a rate of 25% per patient-year, and bleeds requiring surgery occurred in 27% per patient-year. In the HeartMate II series, bleeds needing surgery occurred in 45% per patient-year, with no report on gastrointestinal bleeds. The 25% per patient-year gastrointestinal-bleeding rate in the HeartWare patients was "relatively low, about one-third the rate that’s been reported" by individual centers for patients who received the HeartMate II, he said.

"We need to know if there is a meaningful difference in the gastrointestinal bleeding, a key issue for all the nonpulsatile VADs," Dr. Jessup said.

Infection rates with the HeartWare VAD (39% per patient-year) also ran "substantially lower" than the 85% rate reported from the HeartMate II multicenter series. Ventricular arrhythmias also showed a substantial reduction with the HeartWare VAD (13% per patient-year vs. 40% per patient-year in the HeartMate II series).

Ischemic stroke rates with the HeartWare VAD ran 11% per patient-year, similar to the 9% rate seen in the multicenter HeartMate II series. Hemorrhagic stroke occurred at the same rate (5% per patient-year) with both devices. Half of the 10 ischemic strokes in the HeartWare VAD recipients occurred during the first 48 hours following device placement. "We believe they were surgically related; there is a clear learning curve" for placing the HeartWare VAD, Dr. Aaronson said. In addition, he noted that 8 of the 10 patients who had ischemic strokes later recovered to "moderate disability."

Another "key issue" that experience with the HeartWare VAD has so far not addressed is aortic valve insufficiency, Dr. Jessup said. "No one talks about it in these short-term trials, but you really see aortic insufficiency in destination-treatment trials. The longer you see patients [with LVADs], the more you see them developing hypertension and aortic insufficiency. Will there be a difference in the VADs for aortic insufficiency?"

The study was sponsored by HeartWare, the device developer. Dr. Aaronson said that he has received research support from HeartWare, Thoratec, and Terumo. Dr. Jessup is a consultant to Medtronic and a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Stevenson has been a consultant to Medtronic.