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FDA panel recommends expanding indications for Medtronic CRT devices
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The FDA’s Circulatory System Devices Advisory Panel voted to recommend expanding the indications for Medtronic’s biventricular cardiac resynchronization therapy devices.
However, the panel requested modifications to Medtronic’s proposed indications, and its vote was contingent on the firm and the agency agreeing to those modifications and on appropriate wording. Medtronic is seeking FDA approval to allow doctors to implant its biventricular cardiac resynchronization pacemakers and cardiac resynchronization therapy defibrillators in patients with a lower NYHA class and a higher left ventricular ejection fraction than current indications.
A narrow decision
The panel voted 6-1 that the devices are safe for use in patients who meet the criteria for the proposed indication and 7-0 that they are effective for use in those patients. However, it split 3-3-1 over whether the devices’ benefits outweigh the risks for those patients. Panel chairman Richard L. Page, MD, broke the tie to make the final vote 4-3-1. The FDA is not required to follow the recommendations of its advisory panels, but it usually does.
“I feel comfortable with my vote,” Page said. “We are a split panel, but our members are confident in our recommendation in the context of the indications being modified.”
Medtronic is asking the agency to approve implantation of its biventricular pacemakers and CRT-Ds in patients who meet all of the following criteria:
- Class I or class IIa indication for pacemaker implantation in accordance with American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines.
- NYHA class I, II or III HF.
- LVEF ≤50%.
- Diagnosis of second or third degree AV block, first degree AV block with symptoms similar to pacemaker syndrome, or documented Wenckebach or PR interval >300 ms when paced at 100 ppm.
The panel requested the last criterion be modified to exclude those without any AV block and to include patients with first degree AV block only if there is “verifiable confidence that ventricular pacing is needed in this patient most of the time,” Page said.
For CRT-D eligibility, patients would also need to be deemed at risk for developing a life-threatening ventricular arrhythmia.
Currently, the biventricular pacemakers are indicated only for patients with NYHA class III or IV HF, LVEF ≤35% and a prolonged QRS duration. The biventricular CRT-Ds are indicated for patients with NYHA class III or IV HF, LVEF ≤35% and a prolonged QRS duration, or for patients with NYHA class II HF, left bundle branch block, LVEF ≤30% and a QRS duration ≥130 ms.
Medtronic is basing its request on the results of the BLOCK HF trial, which showed that patients assigned biventricular pacing had a lower incidence of the primary outcome of death, HF requiring IV therapy, or a ≥15% increase in LV end-systolic volume index (LVESVI) compared with patients assigned right ventricular pacing (45.8% vs. 55.6%; HR=0.74; 95% CI, 0.6-0.9).
Debate over endpoint
Much of the day’s debate concerned the validity of LVESVI as an endpoint. FDA staff and consultants said that BLOCK HF did not demonstrate that LVESVI was a predictor of death or urgent-care HF events, and that a large percentage of the primary endpoint coming from a ≥15% increase in LVESVI made the treatment seem more effective than it might be in real-world use.
“The clinical meaning of changes in LVESVI is unclear,” Erin Cutts, the lead reviewer of the application for FDA, told the panel.
Medtronic staff said that the data on LV end-systolic volume index showed a positive trend and that rates of death and urgent-care HF events at 1 year were much lower for patients assigned biventricular pacing than for patients assigned right ventricular pacing.
Page said he agreed that “LVESVI is a marker for deterioration” and that he was confident in the findings because “the data were so consistent” across all subgroups.
Panel members debated whether the positive 1-year data outweighed the risks of LV lead implantation, which produced a complication rate of 5.7% in the group assigned biventricular pacing.
“I’m not sure that, clinically, there’s all that much,” panel member Patricia A. Kelly, MD, who voted that the risks outweigh the benefits, said. “I agree that the data send a signal, but the main difference is in time to first urgent-care HF event, and there’s not much change after the first year.”
The panel also recommended to FDA staff that should the application be approved, a post-approval study should be required. The study should be larger than the 300 patients proposed by Medtronic, and it should include subgroups that were not well represented in BLOCK HF, including women, minorities and people with NYHA Class I HF. – by Erik Swain
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