FDA Panel Backs HeartWare VAS Despite Safety Concerns

GAITHERBURG, MD. – Despite problems with the quality of the safety data in the pivotal trial, the majority of a Food and Drug Administration advisory panel supported approval of the HeartWare left ventricular assist device as a bridge-to-transplant in people with end-stage heart failure at an April 25 meeting of the FDA’s Circulatory System Devices Panel.

At the meeting, the panel voted 9-2 that the benefits of the HeartWare Ventricular Assist System (VAS) outweighed its risks for use as a bridge to cardiac transplantation in patients at risk of death from refractory end-stage heart failure, the indication proposed for approval by the manufacturer, HeartWare.

The HeartWare VAS is a small, lightweight, continuous-flow pump that is implanted entirely in the pericardial space via a median sternotomy; it is the first magnetically levitated left ventricular assist device (LVAD) pump, providing flows of up to 10 L/min; it is connected to an external controller via a 4.2 diameter percutaneous driveline. It is intended for use inside and outside of the hospital and is contraindicated in patients with a body surface area (BSA) of less than 1.2 m², in patients who cannot tolerate anticoagulation therapy, and in pregnant women.

If approved, it would be the first LVAD that does not require an abdominal incision and creation of an abdominal pump pocket.

The panel voted unanimously that based on the available data, there was "reasonable assurance" that the device was effective for this group of patients, and voted 8-3 that there was "reasonable assurance" that it was safe.

The panelists raised issues about the quality of the safety data, which were described as a "mess" and having "more holes ... than Swiss cheese."

But the majority agreed the data supported its effectiveness, particularly when considering the alternatives for this group of patients with end-stage heart failure. The panel chair, Dr. Richard Page, chair of the department of medicine at the University of Wisconsin, Madison, said that despite the safety issues, the bar for efficacy had been met and that the device "represents a real advance in technology" that will make a difference for many patients. Panelist Dr. David Slotwiner, of Long Island Jewish Medical Center, New Hyde Park, N.Y., said that despite flaws in the safety data, he described it as "a novel device for a desperate population."

In the pivotal trial, the ADVANCE (Evaluation of the HeartWare LVAD System for the Treatment of Advanced Heart Failure) trial, a U.S. prospective, multicenter, nonrandomized study, 140 patients with New York Heart Association class IV heart failure, who were on a list for a transplant, received the HeartWare VAS as a bridge to transplant. Their outcomes were compared with 499 patients in a National Institute of Health–sponsored U.S. registry tracking outcomes in recipients of commercially available LVADs, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). More than 90% of those in INTERMACS have received Thoratec’s HeartMate II LVAD. This was the first LVAD study where data from INTERMACS have been used as a contemporaneous control.

The study met the primary end point, which was a success rate at 180 days (defined as remaining on the original device, transplanted, or explanted for recovery) at 180 days among the HeartWare VAD recipients (90.7%) that was noninferior to the success rate in the INTERMACs control group (90.1%).

Safety data from INTERMACS were not available for the safety analysis, so safety data on LVADs from the literature were used for comparison.

Although the trial met the prespecified primary end point, FDA reviewers raised concerns about the comparability of the two groups, and the thrombosis rates, the need to exchange devices, and ischemic strokes in recipients of the HeartWare VAS. Within 180 days, the observed ischemic stroke rate was 8% (11 patients), and the observed hemorrhagic stroke rate was 3% (4 patients). Of the ischemic stroke patients, 27% died or were considered ineligible for transplant because of the stroke; all of the hemorrhagic stroke patients died or became ineligible for transplant.

The panel agreed that while the strokes are a concern, the rates seen in the study did not appear to be substantially different than the rates reported in the literature, although they all agreed that better safety data were needed.

Within 180 days of implantation, seven HVAD pumps were exchanged in seven patients, all of which were associated with signs and symptoms of intraventricular/pump thrombosis, according to the FDA’s analysis. Panelists said that while these cases raised some concerns, it was difficult to make any conclusions without a control group, and one panelist said that in his view, the risks of pump thrombosis were outweighed by the potential benefits.

If approved, the manufacturer’s postmarketing plans include a study that will continue to evaluate patients in the ADVANCE trial. The HeartWare VAS was approved in the European Union in 2009. It is also being studied as destination therapy, comparing it to the HeartMate II.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

GAITHERBURG, MD. – Despite problems with the quality of the safety data in the pivotal trial, the majority of a Food and Drug Administration advisory panel supported approval of the HeartWare left ventricular assist device as a bridge-to-transplant in people with end-stage heart failure at an April 25 meeting of the FDA’s Circulatory System Devices Panel.

At the meeting, the panel voted 9-2 that the benefits of the HeartWare Ventricular Assist System (VAS) outweighed its risks for use as a bridge to cardiac transplantation in patients at risk of death from refractory end-stage heart failure, the indication proposed for approval by the manufacturer, HeartWare.

The HeartWare VAS is a small, lightweight, continuous-flow pump that is implanted entirely in the pericardial space via a median sternotomy; it is the first magnetically levitated left ventricular assist device (LVAD) pump, providing flows of up to 10 L/min; it is connected to an external controller via a 4.2 diameter percutaneous driveline. It is intended for use inside and outside of the hospital and is contraindicated in patients with a body surface area (BSA) of less than 1.2 m², in patients who cannot tolerate anticoagulation therapy, and in pregnant women.

If approved, it would be the first LVAD that does not require an abdominal incision and creation of an abdominal pump pocket.

The panel voted unanimously that based on the available data, there was "reasonable assurance" that the device was effective for this group of patients, and voted 8-3 that there was "reasonable assurance" that it was safe.

The panelists raised issues about the quality of the safety data, which were described as a "mess" and having "more holes ... than Swiss cheese."

But the majority agreed the data supported its effectiveness, particularly when considering the alternatives for this group of patients with end-stage heart failure. The panel chair, Dr. Richard Page, chair of the department of medicine at the University of Wisconsin, Madison, said that despite the safety issues, the bar for efficacy had been met and that the device "represents a real advance in technology" that will make a difference for many patients. Panelist Dr. David Slotwiner, of Long Island Jewish Medical Center, New Hyde Park, N.Y., said that despite flaws in the safety data, he described it as "a novel device for a desperate population."

In the pivotal trial, the ADVANCE (Evaluation of the HeartWare LVAD System for the Treatment of Advanced Heart Failure) trial, a U.S. prospective, multicenter, nonrandomized study, 140 patients with New York Heart Association class IV heart failure, who were on a list for a transplant, received the HeartWare VAS as a bridge to transplant. Their outcomes were compared with 499 patients in a National Institute of Health–sponsored U.S. registry tracking outcomes in recipients of commercially available LVADs, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). More than 90% of those in INTERMACS have received Thoratec’s HeartMate II LVAD. This was the first LVAD study where data from INTERMACS have been used as a contemporaneous control.

The study met the primary end point, which was a success rate at 180 days (defined as remaining on the original device, transplanted, or explanted for recovery) at 180 days among the HeartWare VAD recipients (90.7%) that was noninferior to the success rate in the INTERMACs control group (90.1%).

Safety data from INTERMACS were not available for the safety analysis, so safety data on LVADs from the literature were used for comparison.

Although the trial met the prespecified primary end point, FDA reviewers raised concerns about the comparability of the two groups, and the thrombosis rates, the need to exchange devices, and ischemic strokes in recipients of the HeartWare VAS. Within 180 days, the observed ischemic stroke rate was 8% (11 patients), and the observed hemorrhagic stroke rate was 3% (4 patients). Of the ischemic stroke patients, 27% died or were considered ineligible for transplant because of the stroke; all of the hemorrhagic stroke patients died or became ineligible for transplant.

The panel agreed that while the strokes are a concern, the rates seen in the study did not appear to be substantially different than the rates reported in the literature, although they all agreed that better safety data were needed.

Within 180 days of implantation, seven HVAD pumps were exchanged in seven patients, all of which were associated with signs and symptoms of intraventricular/pump thrombosis, according to the FDA’s analysis. Panelists said that while these cases raised some concerns, it was difficult to make any conclusions without a control group, and one panelist said that in his view, the risks of pump thrombosis were outweighed by the potential benefits.

If approved, the manufacturer’s postmarketing plans include a study that will continue to evaluate patients in the ADVANCE trial. The HeartWare VAS was approved in the European Union in 2009. It is also being studied as destination therapy, comparing it to the HeartMate II.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

GAITHERBURG, MD. – Despite problems with the quality of the safety data in the pivotal trial, the majority of a Food and Drug Administration advisory panel supported approval of the HeartWare left ventricular assist device as a bridge-to-transplant in people with end-stage heart failure at an April 25 meeting of the FDA’s Circulatory System Devices Panel.

At the meeting, the panel voted 9-2 that the benefits of the HeartWare Ventricular Assist System (VAS) outweighed its risks for use as a bridge to cardiac transplantation in patients at risk of death from refractory end-stage heart failure, the indication proposed for approval by the manufacturer, HeartWare.

The HeartWare VAS is a small, lightweight, continuous-flow pump that is implanted entirely in the pericardial space via a median sternotomy; it is the first magnetically levitated left ventricular assist device (LVAD) pump, providing flows of up to 10 L/min; it is connected to an external controller via a 4.2 diameter percutaneous driveline. It is intended for use inside and outside of the hospital and is contraindicated in patients with a body surface area (BSA) of less than 1.2 m², in patients who cannot tolerate anticoagulation therapy, and in pregnant women.

If approved, it would be the first LVAD that does not require an abdominal incision and creation of an abdominal pump pocket.

The panel voted unanimously that based on the available data, there was "reasonable assurance" that the device was effective for this group of patients, and voted 8-3 that there was "reasonable assurance" that it was safe.

The panelists raised issues about the quality of the safety data, which were described as a "mess" and having "more holes ... than Swiss cheese."

But the majority agreed the data supported its effectiveness, particularly when considering the alternatives for this group of patients with end-stage heart failure. The panel chair, Dr. Richard Page, chair of the department of medicine at the University of Wisconsin, Madison, said that despite the safety issues, the bar for efficacy had been met and that the device "represents a real advance in technology" that will make a difference for many patients. Panelist Dr. David Slotwiner, of Long Island Jewish Medical Center, New Hyde Park, N.Y., said that despite flaws in the safety data, he described it as "a novel device for a desperate population."

In the pivotal trial, the ADVANCE (Evaluation of the HeartWare LVAD System for the Treatment of Advanced Heart Failure) trial, a U.S. prospective, multicenter, nonrandomized study, 140 patients with New York Heart Association class IV heart failure, who were on a list for a transplant, received the HeartWare VAS as a bridge to transplant. Their outcomes were compared with 499 patients in a National Institute of Health–sponsored U.S. registry tracking outcomes in recipients of commercially available LVADs, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). More than 90% of those in INTERMACS have received Thoratec’s HeartMate II LVAD. This was the first LVAD study where data from INTERMACS have been used as a contemporaneous control.

The study met the primary end point, which was a success rate at 180 days (defined as remaining on the original device, transplanted, or explanted for recovery) at 180 days among the HeartWare VAD recipients (90.7%) that was noninferior to the success rate in the INTERMACs control group (90.1%).

Safety data from INTERMACS were not available for the safety analysis, so safety data on LVADs from the literature were used for comparison.

Although the trial met the prespecified primary end point, FDA reviewers raised concerns about the comparability of the two groups, and the thrombosis rates, the need to exchange devices, and ischemic strokes in recipients of the HeartWare VAS. Within 180 days, the observed ischemic stroke rate was 8% (11 patients), and the observed hemorrhagic stroke rate was 3% (4 patients). Of the ischemic stroke patients, 27% died or were considered ineligible for transplant because of the stroke; all of the hemorrhagic stroke patients died or became ineligible for transplant.

The panel agreed that while the strokes are a concern, the rates seen in the study did not appear to be substantially different than the rates reported in the literature, although they all agreed that better safety data were needed.

Within 180 days of implantation, seven HVAD pumps were exchanged in seven patients, all of which were associated with signs and symptoms of intraventricular/pump thrombosis, according to the FDA’s analysis. Panelists said that while these cases raised some concerns, it was difficult to make any conclusions without a control group, and one panelist said that in his view, the risks of pump thrombosis were outweighed by the potential benefits.

If approved, the manufacturer’s postmarketing plans include a study that will continue to evaluate patients in the ADVANCE trial. The HeartWare VAS was approved in the European Union in 2009. It is also being studied as destination therapy, comparing it to the HeartMate II.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.