Hi, my name is Professor Mamas Mamas from Keele University and I'd like to welcome you to this Medscape special event from the ACC (American College of Cardiology) in New Orleans.
Today, I'm going to talk about the three or four most interesting trials that I think, are really going to change practice.
Apple Heart Study
So the first thing I'd like to talk about is the Apple Heart Study. This is an important study, not because of the results, but rather in how we undertake clinical trials.
So the Apple Heart Study was a single arm prospective study that enrolled over 400,000 adult patients in the United States. And the primary focus of this was to evaluate irregular notifications but also to look at the association between the irregular notifications and documented AF from a patch.
So the way that these researchers undertook this trial was to use information derived from the Apple heart watch, and particularly the irregular notification facility of this.
In the patients that had irregular notifications, which were around 2500 out of 400,000 patients, these individuals were sent an ECG patch, and of the ones that had an ECG patch around 450 returned the ECG patch for further analysis. So that's 450 patients out of a total of 400,000 patients.
This was an interesting study because around close to 150 patients had documented AF. And in those where there was documented AF on the ECG patch, the positive predicted value for the abnormal pulse notification was around 80%. You may say, well, you know, why is this an important study, after all, several million pounds or dollars have been spent in 400,000 patients just to detect around 150 episodes of AF? Surely there's a better way of identifying AF?
I think this is an important study for a number of reasons. So first and foremost, I think it will change how we undertake studies. It took only 9 months to recruit 1 in 600 adult patients in the United States. This is amazing. No other study can have such a rapid and large recruitment of patients in such a short period of time.
I think cardiology and other medical specialties are moving towards e-health and so using information from wearable devices, I think is very much the way forward. Will this impact on clinical practice? I don't think so. I think it's more around thinking about how we structure trials and looking at the feasibility of using information from e-health, and also thinking about how this information will be actionable.
Transcatheter Aortic Valve Replacement (TAVR)
The next area that I think really will be practice-changing is around TAVR and its use in aortic stenosis. So randomised control trials have driven changes in practice, particularly in TAVR, and we've gone from non-surgical candidates, to high-risk surgical candidates, to intermediate-risk candidates. And all of these trials have shown at least equivalence compared to the gold standard, which is surgical aortic valve replacements.
PARTNER 3 Trial
So talking about the PARTNER 3 trial. This was a randomised controlled trial of 950 patients with severe aortic stenosis that were considered low-risk, and low-risk defined by the STS score with a predictive mortality of less than 4%.
These were randomised to surgical aortic valve replacements versus a balloon expandable SAPIEN 3 valve, and the patients were randomised in a one-to-one setting. The primary endpoint was death, stroke, or all-cause hospitalisation, and secondary endpoints were death, stroke, new AF at 30 days.
Associated with the TAVR or SAVR there were surgical or PCI revascularisation, and this was around 13% in the SAVR arm and 6.5% in the PCI arm.
The trial was initially structured around non-inferiority. And there was a secondary analysis of superiority. And interestingly, these were both met. So for the primary endpoint in the SAVR group, this was 15.1% in surgery, and in the TAVR group it was 8.5%. This was both non-inferior and superior.
There were other interesting factors. So for example, in length of stay, TAVR was much shorter. In terms of major bleeding complications, again, far less in TAVR. But pacemaker implantation, the rates were greater in TAVR, and also the degree of mild aortic valve paravalvular leak was also greater in the TAVR arm, so it’s about 1 in 3 patients had this.
So the second TAVR trial was the Evolut trial. This was a trial using a self-expanding Medtronic valve – either the CoreValve, the Evolut R, or the Evolut PRO. The primary endpoint was death or disabling stroke at 24 months. And there were a number of different secondary endpoints, which were various composites of either vascular complications, major bleeds, strokes, acute injury, prosthetic valve dysfunction, prosthetic valve thrombosis, and so forth.
A total of 1468 patients were randomised. Although interestingly 24-month follow-up was only available in 72 patients in the TAVR arm and 65 patients in the surgery arm. And the mean follow-up of this study was 12.2 months. The primary endpoint was met in 5.3% of patients in the TAVR arm and 6.7% of patients in the surgery arm. The new-onset AF at 30 days was 7.7% in the TAVR arm and 35.4% in the surgery arm.
So clearly this trial was non-inferior, and there was much less new onset AF. So we have two trials showing either equivalence or superiority of TAVR compared to SAVR.
How will this change our practice? Well, I think very much the data is now limited to 1 year for the PARTNER 3 trial and 2 years for the Evolut trial. I think in the longer-term, you know, we don't know how these valves will function. You know, we don't have 10-year follow-up data in this low-risk population. And so, this is often going to be a very difficult and challenging choice for the interventional cardiologist or the surgeon. You know, do you go with a technology that has very good short-term results, or do you consider using the gold standard which is surgical aortic valve replacement?
I think the other thing to think about is the average age of the patients. In both trials, the average age was 75 years old. I think, you know, in much younger patients in their 60s, in my opinion, I would probably refer them for surgery rather than a TAVR trial.
In both of these trials there's going to be follow-up for 10 years. And I think it's going to be really interesting to see whether there's late catch-up, whether SAVR has better outcomes in the longer-terms, or whether the equivalence of TAVR persists over time. So watch this space.
The last trial I'd like to talk about is the AUGUSTUS trial. So the AUGUSTUS trial was a 2 by 2 factorial design which was a randomised control trial in patients with atrial fibrillation, either having acute coronary syndrome or undergoing PCI.
Why is this trial important? Well, it's important because about 1 in 10 patients undergoing PCI will have atrial fibrillation, and about 1 in 10 to 1 in 8 patients with acute coronary syndrome have atrial fibrillation. And it's very challenging in these patients to manage them. Why? Because these patients have increased risk of thrombotic complications, but treating them because of their requirements for anticoagulation has meant that they also have increased risk of bleeding complications. And so the challenge is how do we manage these patients?
So the AUGUSTUS trial aimed to answer this. This was a 2 by 2 factorial design and it was comparing apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) with a vitamin K antagonist, and also comparing aspirin versus placebo.
This was in patients with AF undergoing PCI, or patients with acute coronary syndrome. The primary outcome was major or clinically relevant non-major bleeding, and there were a number of secondary outcomes, including bleeding complications, as well as safety endpoints around the ischaemic perspective.
This trial recruited over 4600 patients into it. And clopidogrel was used as the antiplatelet in over 92% of patients.
So, in terms of the primary endpoint, for apixaban this was 10.5% of major bleeding complications compared to 14.7% of major bleeding complications with the vitamin K antagonist. So certainly there was superiority of the apixaban arm.
In terms of aspirin, the major bleeding complications were 16% in the aspirin arm versus 9% in those patients receiving placebo. And the highest rate of bleeding was in those patients receiving a vitamin K antagonist, warfarin and aspirin, in close to 19% of patients - or 1 in 5 patients had a bleed. And the lowest risk was apixaban versus placebo, which was 7.3%.
So, many of the news outlets have reported that, you know, this is great, patients don't need aspirin and so forth. But I think we need to delve a bit deeper into the trial. So for a start, safety endpoints for ischaemic complications were really underpowered to detect small but relevant outcomes. And certainly, if you look at things like stent thrombosis, then you'll see that there is a very big trend, but not significant, towards worse outcomes in the placebo arm compared to the aspirin arm.
I think the second point to bear in mind is that these patients were recruited between a week and 2 weeks after their index events. So that means that these patients would have received aspirin for that week or 2 weeks. I mean, the average time to recruitment was around a week. And don't forget that many of the adverse outcomes in these patient groups occur early on. So for example, stent thrombosis will occur early on and so you're removing the highest-risk population.
I think this is an important trial however, because certainly it is going towards the direction of travel in that 'less is more'. So overburdening these patients with dual antiplatelet therapy and anticoagulation is associated with worse outcomes from the bleeding perspective. And I think we have to bear in mind - and now that we're seeing more and more elderly patients - this will certainly impact on our practice.
Final thoughts about the ACC - I think this has been a really superb meeting. I think that we have a number of really key, important, practice-changing trials that inform us how the future of clinical trial design is going to be, but also trials that will change how we treat elderly patients with AF with aortic stenosis.
I think it's been very interesting from a social perspective. You know, now the ACC have introduced childcare facilities, which I think is a good thing, it increases the ability of individuals to attend these meetings. And there've been some really fantastic women-in-cardiology sessions as well highlighting the challenges faced by women in cardiology and discrimination.
Unfortunately, many of these interesting sessions have been at the periphery and it would be nice to see them more ingrained centrally within the main programme.
So I'd like to thank you for joining us on Medscape UK and I hope that you will be able to comment on what your favourite trials have been in the ACC. Thank you.
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Cite this: Mamas A. Mamas. ACC: What Could Change UK Cardiology Practice? - Medscape - Mar 20, 2019.