" I'm Brian Lindman, I'm the medical director of the Structural Heart and Valve Centre at Vanderbilt University Medical Centre in Nashville, Tennessee.

The EARLY TAVR trial was presented at the end of last year and that trial was designed to address the question among patients with asymptomatic severe high gradient aortic stenosis, is an early TAVR approach better than clinical surveillance with deferred valve replacement when symptoms occur?

So there have been a number of studies with respect to biomarkers in aortic stenosis that have shown that biomarkers, natriuretic peptides and high sensitivity troponin specifically are associated with maladaptive left ventricular remodelling dysfunction symptom onset and worse outcomes after valve replacement.

So the thought here was that perhaps biomarkers could identify perhaps a subpopulation from that study that may derive greater relative benefit from an early TAVR strategy compared to clinical surveillance. And this this assumption is is reflected in the guidelines which where there's a two way indication for among asymptomatic patients you may preferentially consider intervention when BNP is greater than three times normal. So the thought there is that it reflects perhaps a sicker heart and patients that may benefit more from unloading the heart earlier.

So what we observed was that indeed higher biomarker levels were associated with worse outcomes in the early TAVR trials, but there was no differential treatment effect with respect to the benefits of of an early approach. Said differently, regardless of baseline biomarkers, there was a benefit to early TAVR compared to clinical surveillance and there was no interaction between biomarker subgroup and treatment allocation with respect to endpoints. In fact, counter to our hypothesis, in some scenarios those with lower or normal biomarkers derived greater relative benefit from an early intervention strategy compared to clinical surveillance. Again, this was not what we expected.
We also looked at whether or not biomarkers were associated with timing of conversion to valve replacement in those in the clinical surveillance population and found that although there was a modest trend significance with baseline NT pro BNP tertiles and timing of conversion for those in the clinical surveillance arm, driven mostly by the lowest tertile of NT probnp, which had a slightly longer time to conversion, it was a fairly modest association. There was no association with troponin and timing of conversion.

We also looked at whether or not the biomarkers were related to the mode of presentation and we found that a higher proportion of patients with higher BNPs had a more acute or severe presentation at the time of conversion, but this association was modest. And still among those with the lowest tertile of biomarkers, one third still presented with acute valve syndrome or a more acute or severe presentation. So it didn't rule that out for those patients with low biomarkers.

So overall, we did not see a treatment effect, which was the biggest thing we were looking at. The benefit of early TAVR was consistent across biomarker subgroups.
Well, I think as expected, we saw that biomarkers were associated with higher event rates. But there's been this thought that, okay, the early TAVR trial among all comers, it showed a benefit to earlier intervention. But maybe are there specific subgroups that we might select out that really derive the benefit versus those who it might be safe to wait. And I think the thought was that maybe those with normal biomarkers it would be safe and you could just watch those, but act on those with a higher biomarker level.
And these results show that's not true, that in fact greater relative benefit is derived from those with lower or normal biomarker levels than those with higher biomarker levels. And although there was a slightly in some cases greater absolute risk reduction from early TAVR among those with higher biomarker levels, across the board there was improvement and better outcomes with an early intervention approach. And really when you're looking at absolute benefit reduction and the number needed to treat, it's not number needed to treat or not treat, its number needed to treat now versus on average in the early TAVR trial 11 months later. So, you know, you're not gaining a whole lot by waiting.

So I think overall the take home there would be that a single biomarker measurement in asymptomatic patients is not particularly helpful in tailoring or guiding timing of intervention. And so I think one implication from that would be that the guidelines suggesting that that be considered. You know, this is the first randomised data to actually test that guideline and it shows that it's not particularly useful.

Well, I think just because we had these findings in patients with asymptomatic severe high gradient, AS still leaves open the fact that at earlier stages of as, perhaps like the progress trial, for example, as the follow up to early TAVR is testing timing of intervention in patients with moderate as, perhaps with some increased risk factor symptoms or other markers of risk, and we also have a biobank in that trial, and so in that patient population which is much more heterogeneous than the early TAVR population, it may well be that biomarkers actually are helpful in that population to identify patients who derive particular benefit from an early intervention strategy.
So we'll be able to test that, and that'll be forthcoming.”