Michael J. Reardon, MD: The TAVR Study for Low-Risk Mortality

News broke at the American College of Cardiology (ACC) 2019 Annual Scientific Sessions in New Orleans, LA, that transcatheter aortic valve replacement (TAVR) in severe aortic stenosis patients with a low risk of death from surgery is actually more than just a viable alternative to surgery.

As study author Michael J. Reardon, MD, noted: it’s likely the superior treatment. In an interview with MD Magazine® while at the American College of Cardiology (ACC) 2019 Annual Meeting in New Orleans, CA, Reardon, a professor of Cardiothoracic Surgery and Allison Chair of Cardiovascular Research at Houston Methodist Hospital, laid out all the details of the breaking TAVR trial that continue to boost the biologic valve procedure’s ascent into clinical prominence.

MD Mag: What is the significance of the low-risk mortality TAVR trial?

Reardon: So, aortic stenosis, of course, is a disease when, you have severe symptomatic aortic stenosis, it kills you. There is no medical therapy. The only therapy is to replace your aortic valve. Until recently, the only option was surgery. Now, we have transcatheter aortic valve replacement (TAVR). We tested it in people that were high-risk for surgery, and it was as good as surgery. That's 8% of the population currently being operated on by us.

We tested intermediate-risk patients—that's 12% of the population. It's been approved there. This trial is testing TAVR against surgery in a low-risk population that is the remaining 80% of population that you'll see in your office with severe aortic stenosis. So, the outcome of this trial is not just going to shift us a little bit, but if it's positive, it would be a seismic shift of what we can offer our patients.

What were some of the most significant or surprising findings?

So, what we did is we tested the self-expanding supra-annular valve, which is the core valve in the Evolut family of valves, against surgery. Surgeons were allowed to choose any valve they wanted, as long as it was a biologic valve. Some tried a few first-generation valves—CoreValve 31—and about three-quarters used second-generation valve Evolut R, and 22.3% used third-generation Evolut Pro. Now that's important because the other trial that we saw today, which was a stunningly good trial, was all third-generation valves, and we're just getting there with this.

What the primary endpoint of the trial was all-cause mortality or disabling stroke at 2 years. We did this with a Bayesian analysis. Bayesian analysis lets us, when we have 850 people at 1 year, actually have a predictive model that moves everybody forward to 2 years. I don't want to get into Bayesian models unless you're interested, but it gives us a good endpoint—it's been validated over and over again.

So, the endpoint of all-cause mortality or disabling stroke for surgery was 6.7% percent. For TAVRs: 5.3%. That gives us a difference of 1.4% percent. We used an absolute 6% non-inferiority margin, which gives us a posterior probability curve that's greater than .999. Now, for those of you that need P values, subtract that from 1, you get a P value of > .001 as a good approximation.

We do a lot of sensitivity analysis, and in every sensitivity analysis, TAVR maintained its non-inferiority. We had 7 powered hierarchical endpoints. For 1 year, it was effective orifice area, mean gradient, change of NYHA (New York Heart Association) classification, and change of KCCQ (Kansas City Cardiomyopathy Questionnaire) quality of life (QOL) score. If all those paths are hierarchical, we then go down to superiority, and we have effective orifice area, mean gradient at 1 year, and KCCQ at 1 month. All those passed, which meant that at 1 year, TAVR was significantly better than surgery for effective orifice area, for mean gradient, and for return of QOL at 30 days.

Now we had a variety of other endpoints that we looked at. One was a composite safety, which included mortality, stroke, atrial fibrillation, bleeding, and kidney injury. And at 30 days TAVR was superior for that. And it was also superior for subcomponents of stroke, bleeding, and kidney injury. It was superior for atrial fibrillation, and it was superior for hospitalization. The only thing that surgery won at 30 days was for pacemakers. There were more pacemakers in the TAVR group than the surgical group.

If you go to 1 year, TAVR is now superior for disabling stroke and for hospitalization. So what that the other thing we could do is, we have enough patients—that was 1400 patients that we analyzed there—we have over 800 at 1 year. So we can do standard frequent-sense Kaplan-Meier curves. So at 1 year, the mortality for TAVR was 2.3%, and surgery was 3%—really low. At 30 days, in fact, it was 0.7% for TAVR and 1.2% for surgery. We're very good in both groups, amazingly low.

Then, if you moved to disabling stroke, doing a Kaplan-Meier, it was .7 for TAVR, and I think 2.1 for surgery. That was significantly in favor of TAVR—statistically significant. We also looked at hospitalization, and at 1 year, 3.1% of the TAVR patients got hospitalized, and 6.3% of the surgical patients. Again, this was significant for TAVR, another win.

So the other trial we saw—the PARTNER trial, which is a stunningly good trial with a really good result—used an endpoint of all-cause mortality, disabling stroke, or hospitalization. If we use our endpoint of all-cause mortality, disabling stroke, or hospitalization, we actually turn out significant for TAVR to a rank level .002. It’s 10.4 at 1 year for surgery, 5.3 for TAVR.

The conclusion of this trial is that we meet our primary endpoint of 2 years of all-cause mortality, disabling stroke of non-inferiority, we're safer at 30 day—less death, less stroke, and by the way you’ll get out of the hospital in half the time as surgery—and your QOL improves faster. Whereas, surgery had a little bit fewer pacemakers, and a little less alert regurgitation, but we only had 22.3% of our third-generation valves, which was actually designed to reduce that. I think we’ll do better as we move forward. And the pacemakers are already coming down. My trial site’s personal pacemaker rate was 5.6%. There are tricks to keep it down at 1 year.

Both of them had excellent survival, but TAVR had less strokes and less hospitalization, and it also had at every single time point superior hemodynamics than surgery. We've seen this in every trial of the self-expanding valve: they perform better than surgical valves. The effective orifice area, how big the valve gets is bigger than surgery at every time. For the mean gradient, lower than surgery, every single time point.

Now, we think this is important as we move into the lower-risk population, because they're going to be more active. And we know from flow dynamics—until you get an effective orifice share of 2, it's hard to increase your flow without increasing your gradient significantly. And TAVR had an effective orifice area of 2.2. What that means is that you're now in my low-risk group, and you get a TAVR, and you want to go out and run, you can do that.

You can be more active, and we think that that's going to have an impact in your functional recovery, maybe your QOL, and maybe even your longevity. So this is a very positive trial. It used to be, as we were going through this, we thought that maybe TAVR would be an alternative to surgery and low-risk care.

This data tells us that TAVR is probably the preferred therapy in the group of patients we tested. And when I talk to patients in my office now, when they come in with aortic stenosis and they're a candidate for a biologic surgical valve because of age and other criteria—if I don't talk to them about TAVR, I have not given them really true informed consent, and we're not doing true shared decision-making.

The study, “Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-Risk Patients,” was published online in The New England Journal of Medicine.