Framingham, MA - One of the principal investigators for the pivotal ENDURANCE trial testing HeartWare International’s ventricular-assist device (VAD) as destination therapy says he still plans to present the full results late next year.
Moreover, Dr Joseph Rogers (Duke University, Durham, NC) said his preference would be to compare the primary ENDURANCE results against those of a 360-patient "supplemental cohort," enrolled in a continued-access fashion with the same inclusion/exclusion criteria, but with "enhanced blood-pressure management."
Those aims, however, seems at odds with recent remarks made by the Heartware CEO Doug Godshall on calls with financial analysts.
On an August 8 earnings call, Godshall said that the current plan is to have the ENDURANCE data set "comingled" with the supplemental cohort study that was approved by the FDA in June [1], before presenting the final numbers. That’s despite the fact that patients in the latter will be tracked for just one year instead of two, will be followed for a different primary end point, and will undergo more intensive blood-pressure management over the course of the trial than patients did in ENDURANCE.
"Given that this trial is now an aggregated original cohort, additional cohort, with the submission of the data being comingled and sort of contingent on one another, it is not our expectation that we are going to be presenting any [destination-therapy] data next year," Godshall said on the call. He also declined to say whether the company would release top-line "pass/fail" data on the ENDURANCE primary end point next year, "because the performance in this additional cohort could influence the interpretation of that primary-end-point area."
Speaking with heartwire today, however, Rogers stressed that the original ENDURANCE cohort is still planned exactly as outlined in the beginning of the trial" and "when the trial gets presented it will be the original cohort of patients that we originally asked for, and that should be available toward the end of "14."
ENDURING results
As previously noted by heartwire, ENDURANCE is a 450-patient, multicenter randomized comparison of the Heartware HVAD with the HeartMate II LVAD in the setting of destination therapy for patients with end-stage heart failure. The primary end point in ENDURANCE is stroke-free survival at two years. Enrollment has completed.
The "supplemental cohort" is enrolling up to 360 patients (240 to the Heartware VAD and 120 to a control device) for only one year, and according to remarks made by Godshall in a June financial call, the end point will be "stroke incidents or reduction in stroke at 12 months."
Asked about company comments regarding plans to combine the data sets, Rogers said, "If that’s true, I don’t know that. . . . I haven’t spoken to co-PI Dr Francis Pagani (University of Michigan Hospital, Ann Arbor)] about this, but I’m sure both of us would make a strong case to analyze this data as scientifically accurately as we possibly can."
Adding that he hasn’t spoken with the FDA or the company about this either, Rogers said, "I think the most scientifically valid way to approach that would be to compare rates from the original cohort with the extended population."
Neurological events and BP control
At issue is a signal of higher adverse neurological events among Heartware patients in ENDURANCE. In an unusual move, the FDA actually asked to see interim results on a subset of patients in ENDURANCE as part of its review of the device as a bridge-to-transplant therapy in 2012. Those interim results are included in the instructions for use for the Heartware VAD in the approved bridge-to-transplant setting and indicate a numerically higher rate of ischemic and hemorrhagic strokes for the Heartware device (6.7% and 5.1% respectively) as compared with the control LVAD (with ischemic and hemorrhagic stroke rates of 4.3% and 0%, respectively).
"It was a very unusual request from the FDA [to look at the ongoing ENDURANCE data], I thought, but it is what it is," Rogers said. "There was a question of whether the adverse-event rate for neurological events was higher with Heartware, so that’s what prompted the company to go back into the data set and identify factors that may be associated with that, and one of the factors that came out was high blood pressure."
Godshall made similar statements on the August 8 earnings call, noting that sites in ENDURANCE that had done a better job monitoring and managing patients’ blood pressure "witnessed a notably lower incidence of neurologic events." Thus, in the supplemental cohort, patients with the same inclusion/exclusion criteria at the same 50 ENDURANCE sites will be enrolled in the same way but subject to more rigorous blood-pressure management during the trial.
Combining data sets
As often noted by heartwire, combination of data sets from populations managed according to a different protocol is unusual, typically frowned upon, and likely to complicate interpretation of results.
But, Godshall said, "We are confident that the results from this enhanced pressure-management strategy will have a positive impact on outcomes and further support [destination-therapy] approval."
Rogers, however, was clearly unaware of any discussions to fully "integrate" the data sets and acknowledged doing so would open the door to criticism that combining the two could potentially dilute the adverse-event rates acknowledged so far in ENDURANCE.
"I can"t argue with that: whenever you change trial design in the middle of a study, you run that risk," he said. "On the other hand, it seems unwise to expose human subjects to potentially serious adverse events. If you think that that’s an issue—that blood-pressure management is an important issue to prevent strokes—you have to implement that change to protect the safety of human subjects participating in a clinical trial."
He continued: "This field is still in its relative youth, and there are things we don’t know about the pumps. . . . We were assuming that those two pumps we were testing in ENDURANCE are the same, and they are not, they are very different pumps. So it may be that BP management is more important with one than the other."
Rogers reiterated that his hope would be to compare the supplemental cohort with the original ENDURANCE cohort. "So you have the same trial design, the same pumps, and a background signal with neurological event rates, and then, in that new cohort, where you"ve hopefully got the blood pressure down, you can look at the delta for stroke rate."
Roger’s intention, he told heartwire today, is to submit the ENDURANCE results for the AHA 2014 meeting, or possibly the following ACC meeting.
HeartWare spokesperson Christopher Taylor, speaking with heartwire last week, confirmed the information as stated in the earnings calls but said company officers declined to be interviewed for this story, pending what it anticipates to be the FDA’s final go-ahead on the supplemental cohort.
The HVAD approval for bridge-to-transplantation was based primarily on the ADVANCE trial, which compared patients with the HVAD with those with other pumps who were in the Interagency Registry for Mechanical Assisted Circulatory Support.
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