CoreValve Beats High-Risk Surgery for AV Stenosis in Pivotal Trial

Shelley Wood

March 29, 2014

WASHINGTON, DC (updated) — Patients with severe aortic stenosis at high surgical risk had significantly higher one-year survival when treated with the CoreValve (Medtronic) self-expanding transcatheter aortic valve than with surgery, the pivotal trial studying the device in this patient population has found[1].

Dr David H Adams (Mount Sinai Medical Center, New York, NY) presented the results of the CoreValve High-Risk Study here during the first late-breaking clinical-trial session of the American College of Cardiology 2014 Scientific Sessions . They were published simultaneously in the New England Journal of Medicine.

The study was designed with the primary hypothesis that the one-year death rate would be noninferior in the transcatheter-aortic-valve-replacement (TAVR) group to the surgical group, using the as-treated population. Provided the noninferiority margin was met, a subsequent test for superiority was also planned.

In all, 795 patients were randomized at one of 45 US centers to either surgical valve replacement or the CoreValve transcatheter valve. In the TAVR group, the valve was delivered via the iliofemoral route in 323 patients and via "noniliofemoral access" in 67. Mean STS PROM and EuroSCORE scores, indicating degree of surgical risk, were roughly 7.5% and 18%, respectively, in both treatment groups (with the intention-to-treat and as-treated populations being very similar). Of note, this is lower than the surgical risk level of patients treated in the comparable (high-risk surgical patients) trial for the Edwards Sapien device in the PARTNER A trial, which was 10%.

Dr David Adams

Asked about this point in the discussion following his presentation, Adams noted that both the PARTNER A trial, as well as the CoreValve High-Risk Study, had set out to use a cutoff of STS score >15, and both trials had ended up enrolling lower-risk patients.

This suggests that contemporary risk-assessment tools "are not very good at picking patients that actually have a 15% mortality," Adams observed. "On the other hand, maybe that means surgery is really outperforming what we had historically looked at. We are convinced that we identified patients that were at increased risk."

One-Year Outcomes

At one year in the CoreValve study, the primary end point of death from any cause was significantly lower in the TAVR group than in the surgical group (14.2% vs 19.1%, p=0.04), an absolute difference of 4.9 percentage points. Similar results were seen in analyses of both intention-to-treat and as-treated populations. Of note, PARTNER A, the comparable trial using the Sapien valve, demonstrated noninferiority, but not superiority to surgery.

For secondary end points, major vascular complications were higher in the TAVR group, but bleeding events and acute kidney injury were lower. Risk of stroke at 30 days was not statistically different between the two treatment arms: 4.9% for TAVR and 6.2% for surgery.

As expected, permanent pacemaker implantation was higher in the CoreValve-treated patients (more than one in five patients treated with the transcatheter valve needed a pacemaker postimplantation, as compared with one in 10 in the surgery group). Between 20% and 23% of patients in both groups already had a pacemaker at the time of their procedures. New-onset AF or worsening AF was more common in the surgical group, affecting more than 30% of patients treated.

Moderate or severe paravalvular leak was 6.1% at one year in the TAVR group, compared with 0.5% in the surgical-valve-replacement group (p<0.001).

Nine subgroup analyses of the primary end point at one year showed that in all subgroups, the survival advantage with TAVR was preserved, including patients with an STS score less than or greater than 7. "In all groups we saw an approximate 30% reduction in risk of mortality," Adams said.

Experts Respond

Panelists discussing the results after Adam's presentations were complimentary. Dr Valentin Fuster (Mount Sinai Medical School, New York, NY) called the findings "absolutely fantastic results," with others echoing the sentiment. But almost all of the assembled experts zeroed in on ways that the CoreValve High-Risk Study differed from PARTNER A with the Sapien.

Dr Anthony DeMaria (University of California, San Diego) zeroed in on strokes: there were no significant differences between TAVR and surgery in the CoreValve study, whereas PARNTER A had shown major and minor strokes to be significantly higher in the transcatheter-valve–treated subjects.

Adams responded by noting that strokes were adjudicated after the fact in PARTNER A but prospectively planned for in the CoreValve study. "Our stroke rate during surgery was actually higher in this trial than in PARTNER A," but the stroke rate for the CoreValve device was actually similar to that seen with the Sapien in PARTNER A, although the rates for devices were similar. "I think the difference may be that we picked up more strokes for the surgery arm, because we looked for them more carefully," he said.

Dr Sanjay Kaul

Dr Sanjay Kaul (Cedars-Sinai, Los Angeles) queried the superiority claim, asking whether analyses had also been done of the "worst-case scenario," wherein all patients lost to follow-up ended up dying—would the superiority claim held up? By his calculation, Kaul said just one more mortality in the TAVR arm would have pushed the superiority finding into nonsignificance.

Responding, Adams begged off, saying he was not a statistician but reminded the audience that the FDA, the ACC, and the New England Journal of Medicine had reviewed all the numbers. Later, in the press conference, Adams said his email inbox had been buzzing with answers from statisticians at Medronic and other "expert friends" since Kaul's questions.

"The bottom line is that in the worst-case scenario, our inferiority margin is still met and our superiority margin is still close to being met—it creeps up to 0.05 or 0.06. We're going to try to get some answers to that in the next few days." A deep-dive sessions is scheduled for Monday.

Adams added that he did not believe the death of one additional patient would have changed the outcome of the trial, or the various reviewers would have picked this up.

Dr Anthony DeMaria

The CoreValve already holds US FDA approval for use in patients who cannot be treated surgically. The FDA will use these latest pivotal trial findings to decide whether to expand indications for use to high-risk surgical patients. Medtronic announced today that the FDA will not be requiring its advisory panel to review the evidence before the agency makes its decision on expanding the indications for use.

If approved, the CoreValve will join the Sapien as the only two transcatheter valves approved in the US for both high-risk surgical and nonsurgical patients. A glimpse into how these two devices might fare head-to-head is coming later in the meeting: Sunday morning, German investigators present the results of the CHOICE trial, a randomized comparison of the two transcatheter valves.

Medtronic sponsored the CoreValve High-Risk Study. Adams disclosed receiving royalties through his institution from Medtronic for a patent related to a tricuspid-valve annuloplasty ring and from Edwards for a patent related to degenerative-valve-disease–specific annuloplasty rings. Disclosures for the coauthors are listed in the paper.

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