Dec 05 2025 This Week in Cardiology

You're listening to This Week in Cardiology from TheHeart.org, Medscape Cardiology. This podcast is intended for healthcare professionals only. Any views expressed are the presenter's own and do not necessarily reflect the views of WebMD or Medscape. Hi, everyone. This is John Mandrola from the heart.org Medscape Cardiology. And this is This Week in Cardiology. We're back after a break from Thanksgiving.

This week, I'm talking about is less is more after PCI, the target first trial. I'll also talk about a negative trial that is actually really positive, aspirin versus anticoagulation. In terms of bleeding, AEDs and factor 11 inhibitors are not dead yet. So let's first start with some listener feedback and I'm going to have it short. I've received so much listener feedback that I just want to summarize.

Most of the feedback is on the issue of culprit-only PCI versus complete revascularization at the time of STEMI. I think it's time to let it rest for now. I see non-culprit lesions. as chronic and stable, and that's why the full revast trial was negative, but others don't. They see these lesions as less than stable because they're occurring in the setting of a STEMI.

Of course, the trials are mixed, but in my opinion, they lean more towards no benefit for complete revascularization on serious outcomes. So I guess the compromise could be just don't mandate routine anything in the guidelines. If I were the czar of these procedures, I would say you aren't compelled to do every non-culpirate lesion routinely, but if there were areas where you felt concerned, it's hard to argue against it.

Still, though, I lean on the notion that even in the best trials, like the complete trial, which are positive based on a reduction of MI rather than any hard outcomes like CV death or death, I think there's a lot of room for judgment here. And I don't think we have to have mandates about what to do post STEMI. Now, another listener wrote to me.

about the target-first trial of early discontinuation of aspirin after PCI in low-risk MI patients. This listener's astute concern was the choice of endpoint that had ischemic events and bleeding events, but they were in the same non-inferiority endpoint. And if I've said it once, I've said it a million times. You can't or you shouldn't have events expected to go in different directions in the non-inferiority endpoint because they cancel each other out.

And then they lead to no difference in net. And no difference is a positive result in a non-inferiority trial. The correct way to do non-inferiority is like it was done in the DOAC versus Warfarin trials. They tested non-inferiority for stroke and systemic embolism, efficacy. And then they tested bleeding, which was safety with superiority. So since the listener mentioned the target...

first trial, and I haven't done it yet, let's just review it. It's a pretty good trial. A European study, about 960 patients in each arm. One group gets dapped for a month. then stops the aspirin and continues the P2Y12 as sort of monotherapy. The other group gets dap for a year. These patients had to have a mild MI. What does that mean? STEMI or non-STEMI? And they had to have complete revascularization. The exclusion criteria were any high bleeding risk situations.

or any complex PCI, such as a CTO or left main, or if there was more than 80 millimeters of stent. The choice of P2Y12 was left to the doctors. Patients were about 61 years old. About a quarter of them were female, half STEMI, half non-STEMI. Ticagular 73%, prostagrel 22%, clopidogrel 5%. Now, about 82% of these patients had a single-vessel PCI during the MI, so most of these patients didn't have multivessel disease.

The overall results, the primary endpoint of death, MI, stent thrombosis, stroke, major bleeding, which was BARK 3 or 5, Occurred in 2.1% in the monotherapy arm versus 2.2% in the adapt group. The difference in absolute risk was tiny at 0.09%, and the 95% upper bound of the risk difference was 1.2%. which was less than the non-inferiority margin of 1.25%, which I thought was pretty strict, but only by a little. So the p-value for non-inferiority was equal to 0.02.

Now, here are the specific numbers with monotherapy versus death, 4 versus 2. MI, 7 versus 10. Stent thrombosis, 1 versus 0. Stroke, 3 versus 2. Bleeding, now this is bleeding 3 or 5, 7 versus 7, so not any different. When they looked at secondary outcomes, now this bleeding outcome had BARK 2, 3, and 5. Well, now there's 2.6 versus 5.6. So that's significant for superiority. So a lot less total overall bleeding. in the single monotherapy group cv death and mace were similar

So my comments, the first thing to say is that the bleeding events and the primary outcome were similar, and therefore it did not drive the primary outcome towards non-inferiority. In other words, we didn't have events going in both ways, which is good, but it could have. So my thoughts are to keep safety events away from MACE events when testing non-inferiority. Target First did show that if you include all bleeding, now that includes clinically relevant bleeding BARK 2,

The single arm, the one with the dropped aspirin, was superior to DAPT over the year. A target first is the first of many trials in this space, but to include only MI patients. The first to allow P2Y2... Y-12 choices, and most of the doctors went with ticagrelor or prosagrel. The authors do note that their results were in contrast to stop DAPT2 ACS, which was one month of DAPT was not non-inferior to 12 months of dual antiplatelet therapy.

but they note that in the STOP-DAP-2 ACS trial, the completeness of revascularization was unknown, and recurrent ischemic events were often linked to untreated lesions rather than to stent failure.

They said that their R trial, which is target, suggests that when complete revascularization was achieved with the use of the latest generation stent platform, The justification for extended dual antiplatelet therapy in low-risk patients may differ from current practice because of residual anatomic ischemic risk has already been addressed.

Though I would say, just looking at it as a neutral Martian, the numbers in the two trials were quite similar, and non-inferiority was just barely missed in stop-dap, so it was close. Now, one weakness to note in the target trial was that while the non-inferiority was met in the intention to treat arm, it was not met in the per-protocol analysis.

In the per-protocol analysis, the upper bound was 1.42. And in non-inferiority trials, actually, per-protocol and as-treated analyses are considered more rigorous. Because in a non-inferiority trial, you want to test the outcomes in the patients who actually stayed in their group and had their therapy. Whereas in superiority trials, the more rigorous test is the intention to treat because it preserves randomization.

Nonetheless, the patients with net adverse outcomes in the PERP protocol were 17 patients each. What made the non-inferiority miss is not the fact that there was a difference in events. There were both 17 patients had an event. It was that they had wider conference intervals. Therefore, I don't think it's that big of a deal. I don't think it changes the conclusions.

So my final conclusion would be that there are a lot of trials in this post-stent space looking at different levels of antiplatelet therapy. And there's oodles of different combinations of patient characteristics, such as the type and size of stents, the type and size of vessels, whether there's calcification. There's also different bleeding risks, so it's hard. to take one trial and say you have to do this yet this

Trial tells me that in a relatively low-risk MI situation where complete revascularization is achieved, 82% of the patients had just one vessel disease. The MACE endpoints... will be low with single month dap followed by P2Y12 monotherapy, and you're going to get less bleeding. Now, perhaps it's the iteration of stenting or the intensity of medical therapy.

But MACE events seem quite low after MI, and perhaps that is why shorter duration DAP seems to be working. Obviously, this isn't a space that I work in every day, so let me know if you have a different view of this trial.

All right, the second topic is really interesting. It's a negative trial, but it's really positive. This was the Retreat Frail study. Now this is a story about reduction of blood pressure medicines in frail elderly patients who live in a nursing home. And I know what you may be thinking. I don't go to nursing homes and this doesn't apply to me. I don't want to listen.

But I want to push back and I want to urge you to listen to this elegant trial because there are some good nuggets of wisdom, I think. Now, retreat frail was conducted in France. About 1,000 patients underwent randomization. Half the group got a step down in medicines, and the other half just had usual care. Patients had to be... older than 80, they had to be on more than one blood pressure drug, and they had the systolic blood pressure less than 130. The step-down...

approach appeared conservative and it was incremental. For instance, before randomization, a clinician reviewed a patient's med list and determined those that could be discontinued and those that could not be discontinued owing to medical necessity. Another example, only one medication could be discontinued at each visit. In the case of beta blockers, treatment was first reduced to half dose and then withdrawn one week later if the systolic blood pressure remained below 130.

The same approach was used with loop diuretics. The primary endpoint was death from any cause, and the trial went on for four years. Secondary endpoints included changes in the number of drugs being used from baseline to last trial visit. and the change in systolic blood pressure during the follow-up period. Now, while inclusion criteria mandated age greater than 80, the actual age of patients was 90 years and 80% were female.

The average systolic blood pressures were low, 113, and the average number of medications for blood pressure was 2.5 to 2.6. But this eye-opener... The average number of concomitant medicines was 6.6. So that's like nine medications for 90-year-old nursing home patients. More than 10,000 nursing home patients were screened to enroll 1,000 in the trial. That's important because obviously this is a pretty selected group.

Using a frailty scale, almost 40% of the patients were described as having severe or very severe frailty. Only 10% were labeled as fit well or managing well. So over the follow-up period, just over three years, the primary endpoint of death was similar in both groups. in the step-down group, 60.2, and the usual care arm hazard ratio right at 1, 1.02. The death from cardiovascular causes was also similar, and all other outcomes were similar, including heart failure events.

and a composite of major adverse cardiac events and a measure of cognition or strength. Between baseline and last trial visit, the mean number of blood pressure drugs... use decreased from 2.6 to 1.5 in the step-down group, but it also decreased from 2.5 to 2.0 in the usual care group, and that's probably pretty important.

The actual systolic blood pressure changed only by about 4 millimeters mercury in the two groups. The trial is concluded. Now, this is what sits in the New England Journal of Medicine, which is interesting. Among older nursing home residents with frailty who were receiving treatment with antihypertensive agents and antisystolic blood pressure below 130, an antihypertensive treatment step-down strategy did not lead to...

lower all-cause mortality than usual care, period. That's it. Okay, my comments. So in the New England Journal, it looks like the retreat frail study was negative. In other words... the intervention did not help the patient, so perhaps we don't do the intervention. Yet I think this is absolutely the wrong conclusion. It seems that words and statistical rules got in the way of making proper clinical conclusions from this study.

I mean, what I mean is that all trials have to begin with a hypothesis of power calculation and estimates of effect. I get that. But in the case of 90-year-olds, it's not really feasible to think you can control mortality with one intervention because in a 90-year-old, competing causes of death approach infinity, right?

The matter of finding no difference in the primary outcome in this trial should not be considered a negative finding. I can see it a different way. First, the author showed you that you can reduce meds and not harm people. You can reduce meds and barely bludge. blood pressure measures. You can reduce meds and not change cardiovascular deaths.

Had I been a consultant to the trial organizers, I might have suggested a non-inferiority design, where the step-down arm did not have to be superior, only non-inferior, since it is clearly less burdensome to take fewer pills. Non-interiority was felt to be not acceptable, I would have suggested a win-ratio analysis where death could be on the top and on the bottom could be the number of pills a person had to swallow. And that endpoint was less than the step-down group.

You might also push back on this trial because they screened 10,000 to enroll 1,000. And I would agree that it is a select population. However, I think there are enough patients with polypharmacy and soft blood pressure in this age group to apply these results to. Of all the drugs I stop in the elderly, aspirin is number one, but blood pressure medicines are number two.

In fact, I think the main reason to see older patients with frailty in clinic, these are patients who have difficulty getting to your office, but it's probably worth coming to your office once a year or twice a year because those are opportunities to stop the medicines. I would say not every week, but most weeks, I explain to people when I stop their blood pressure medicines that these sorts of drugs, these preventive things like blood pressure meds and statins,

They're designed to be given to 50 and 60 year olds so that these patients become 90. And once you get to 90, you've graduated from benefiting from these drugs and you may get harm. So Reject Frail tells me that less is more. We reduce the burden of being a patient and have no negative effect on death. It's a win. And if any of the New England Journal of Medicine people are listening to this podcast by accident, I say kudos to them for publishing this important trial.

All right, third topic is major bleeding with either aspirin or apixaban. JAMA Cardiology has published a very nice sub-study of the Artesia trial. Looking at rates of major bleeding in the aspirin and apixaban arms, recall that in artesia, patients with devices... With device detected subclinical AF, the average duration of AF was 1.5 hours. These patients were randomized to either aspirin or apixaban. Notable was that these patients had a high CHADS-VASc score.

a mean of 4, 3.9 to 4, CHADS-VASC. And to review, the main results of artesia was that apixaban was associated with a statistically significant... 37% lower rate of stroke or systemic embolism. However, the absolute risk reduction was tiny at 0.5% per year. Well, that's because the annual stroke risk was so low. And I think that's one of the main findings of the main trial, was that despite having a CHADS-VASc score of 4, these patients with short-duration AFib...

had annual stroke rates of 1% or less, which is like they would have a CHADS-VASc of 1 or something. In other words, subclinical AF really looks like a low stroke risk. pattern and was seen in the NOAA trial as well. So for the main safety endpoint in artesia, this was bleeding in the on-treatment arm and it was 80% higher in the apixaban arm. The hazard ratio was 1.80. The 95% conference intervals were 1.26 to 2.57. But again...

The absolute risk increase was quite small, 0.8% higher in the apixaban arm versus aspirin. Overall, there were 28 more bleeds in the apixaban arm versus aspirin in a trial of 4,000 patients. The point of the sub-study in JAMA cardiology was to characterize the bleeding events because not all bleeding is the same. The categories of bleeding were such as ISTH major bleeding, critical site bleeding in the brain eye or pericardium, non-critical site bleeding, intracranial bleeding, GI bleeding.

And then the authors would characterize the bleeding. Category one was bleeding that wasn't an emergency. Category two, not an emergency, but need for some attention. Category three, hemodynamic stability, and category 4, fatal bleeding. So now the results, and this was apixivan versus aspirin. For critical site bleeding in the brain, eye, or pericardium or joint, the rates were 25 and 22 respectively, so no different.

For intracranial bleeding, it was 17 versus 20, so no different, but numerically lower with apixaban. For non-critical sites like GI, urine, bruising, surgical site, nosebleeds, it was 62 versus 25 events, and that was statistically higher for apixaban. For fatal bleeding... It was 5 versus 8, so not significantly different and quite low for both groups, but numerically lower in the apixaban arm.

For bleeding that required transfusion, it was 28 versus 18. That was higher in a pixel band arm, but it did not reach statistical significance. Now for the bleeding categories. The higher rates of bleeding with apixaban were primarily in Category 2. This was bleeding that was not emergency but required some attention. That was 54 versus 27.

there were little differences in very minor, category 1, or very serious bleeding, category 3 or 4. Now, my comments. I hope you didn't phase out with all these data points because I think this is quite remarkable data. Yes, the overall results show more total bleeding with apixaban. It's true. That's the main trial results. But, but the details are important. The first lesson here, I think that...

Apixaban is an extremely safe oral anticoagulants. Rates of major bleeding were only 1.7% per 100 patient years with most of the bleeding that occurred. at non-critical sites was not fatal nor intracranial. Recall also that these were 77-year-old patients. The Artesia authors rightly, I think, ask us to balance the bleeding harm.

against the 37% reduction in stroke in the trial. And given that most of the bleeding was non-major bleeding, I think this is a reasonable argument. Now, the only caveat in that argument is that I wonder how... Artesia would have come out with placebo instead of aspirin, right? At the time of Artesia planning, it was not widely appreciated how useless aspirin was in chronic vascular disease or even for AFib.

An apixaban versus nothing comparison may have made apixaban look worse in terms of bleeding. The second lesson, I think, from this sub-study is that aspirin also causes major bleeding in older patients. The rate of major bleeding was slightly less than apixaban, but it approached 1% per year.

And aspirin did not seem to protect patients from major or fatal bleeds. In fact, for intracranial bleeds, which are the most feared, rates of bleeding were actually numerically higher in the aspirin arm, 20 versus 17. Same for fatal bleeding, 8 in aspirin versus 5 in apixaban. Now the third lesson I think in this is for the left atrial appendage proponents.

Of course, we know that left atrial appendage closure requires aspirin. So what we see here is that it does not reduce major bleeding in critical sites, such as the brain. Indeed, this was confirmed in the closure AFib trial that I recently covered where bleeding rates were... Higher, 7.4% versus 6.23% in the LLA closure versus best medical therapy arm. Best medical therapy was mostly included oral anticoagulation.

Now, we should just pause there and think about that. Bleeding rates in the appendage closure arm were higher than the anticoagulation arm. This is the whole thing, the whole... package for left atrial appendage closure it probably doesn't reduce stroke so the advantage is that it can reduce bleeding but it didn't reduce bleeding and i think it doesn't reduce bleeding at least in closure af because aspirin

It's a serious antithrombotic. Now, the other reason why bleeding rates in the closure AF trial were higher is because the trialists properly included periprocedural bleeding. Some of the seminal trials with appendage closure excluded the procedure time, but no patient can exclude the procedure time. So, okay, you think I'm full of beans. You're like, get out of here, Mandrola. There's no way that apixaban and aspirin are even in the same ball field when it comes to bleeding.

Well, now I want you to go look up one of the best trials ever done in atrial fibrillation and stroke prevention. 2011, it was led by the late Stuart Connolly. 5,500 patients with AFib who were felt unsuitable for warfarin. This is the Averroes trial. Now these patients who are unsuitable for warfarin, these might be the ones that get...

left atrial appendage closure in our modern time now. The trial was apixaban versus aspirin, and everybody knows that apixaban crushed aspirin for stroke events. We know that. That was the primary outcome of the trial. But little known from the Averos trial was that in the intention to treat ARM of the bleeding analysis, the bleeding rates were 1.4% apixaban, 1.2% aspirin, which was not statistically significant. No difference in bleeding. Now the purist will say all, John, in the as-treated.

analysis of avaros the rates were 1.4 percent versus 0.9 percent and that hazard ratio was 1.54 but still those 95 conference intervals were not statistically significant I think the bottom line is the new DOACs are pretty darn tough to beat. Their stroke prevention properties are strong, their bleeding rates are low, and especially critical site bleeding.

The kind of bleeding that people care about is low. This is good for our patients. And as closure AFib tells us, DOACs make a tough comparison for left atrial appendage closure. All right.

Next topic is an easy one. This is about a high-value intervention, the AED. The Canadian Journal of Cardiology has published a review paper on in-flight sudden cardiac death and AED use. It's a great topic, and I've recently had an encounter with this situation. And of course, as more and more people fly, and more and more older people fly, cardiac arrest in the air is surely going to increase.

And we can say that the sky is blue and everyone knows that survival of VF outside the hospital turns on rapid defibrillation and CPR, but mostly defibrillation. The authors reviewed the literature and found that in-flight cardiac arrest is rare, but it accounts for... 86% of all deaths that occur in the air. I also learned from the paper that the U.S. leads the field here, as AEDs are required on all flights, with one flight attendant and 7,500 pounds of payload in the U.S.

In Europe, Canada, and Australia, AED use is actually lower. The authors, of course, argue for higher AED availability, and this seems like a no-brainer. Honestly, out of hospital AED... availability may be one of the highest value interventions that exist in public health. I'm quite surprised that the U.S. leads the world in this, actually. Perhaps only driverless cars will surpass the public health benefit of having available AEDs.

All right, final topic is that the factor 11 inhibitors got a small breath of air this month with the Oceanic Stroke Trial. A year or two ago, we heard early promise from the factor XI inhibitors. They were supposed to be the perfect anticoagulant. They were effective and they had less bleeding. Well, two years ago, in November, our group was notified of sudden termination of the Oceanic AF trial, which we were randomizing for. This was a Sundoxian versus Apixaban in patients with AF.

It was terminated early for efficacy. There were more strokes in knee factor 11 arm. That's the thing. Preliminary trials with the first factor 11 drug had shown lower rates of bleeding. And lower rates of bleeding are a positive, but you need stroke prevention and clot prevention as well. Now, some have said that Oceanic AF failed because it was the wrong dose, and we also know that there are other factor XI drugs being tested. So the story, I think, on factor XI...

is far from done in atrial fibrillation. I mean, there's ableasimab, which is a sub-Q monoclonal antibody. There's milvexian, and there's two novel factor XI antibodies being studied by Regeneron. The Factor XI story in AFib is still ongoing. Last month, however, in a press release, Bayer announced that a Sundaxian met both its primary efficacy and safety endpoints in a trial called the Oceanic Stroke Trial.

And this was a big one that enrolled 12,300 patients. We didn't get any numbers, just general words like sundoxy and 50 milligrams daily significantly reduced the risk of ischemic stroke compared to placebo. both in combination with antiplatelet therapy in patients after a non-cardioembolic ischemic stroke or high-risk transient ischemic attack, and there was no increase in the risk of ISTH major bleeding.

in patients treated with a syndexion compared to placebo. So I went to clinicaltrials.gov, and it looks like it was a very big trial, but also non-cardioembolic stroke on standard antiplatelet therapy. The primary endpoint was first occurrence of ischemic stroke. Safety was the major bleeding endpoint. I don't know about you all, but with 12,000 patients, it might be easy to reach a statistically significant result without much of a clinically meaningful effect.

You know, one of those situations where the p-value is 0.04 and the absolute risk reduction is something like 1% or less. Yet, at least it's not a negative trial. Like I said earlier today, though, the DOAC drugs are going to be hard to beat. And so we'll see what happens with factor 11 drugs. That's it for this week in cardiology. As always, I'm grateful that you listened. Thank you.

And remember, if you like this podcast, please take the time to give us a rating, write us a review. If you have something you disagree with, please let me know. Until next week, this is John Mandrola from the heart.org Medscape Cardiology. You're listening to This Week in Cardiology from TheHeart.org, Medscape Cardiology. This podcast is intended for healthcare professionals only. Any views expressed are the presenter's own and do not necessarily reflect the views of WebMD or Medscape.