Circulation November 18, 2025 Issue

Welcome listeners to this week's Circulation on the Run podcast in the week of November 18, 2025. I am one of your co-hosts, Dr. Petter Mayre, professor from University of Oslo in Norway. And I'm your other co-host, Dr. Shirin Derudgar from University of Arizona College of Medicine, Phoenix. And Shirin, this week's feature is not from cardiology per se, but from vascular disease in the brain.

We're gonna talk about thrombectomy for acute large vessel occlusion. And that's the results from the Angel reboot trial coming up soon. But before we go there, we have a true... hardcore cardiology trial results coming up. And that is the results from the DAPA ACT-HF-TIMI68 trial that was published at ESC in Madrid in August this year.

And this trial sharing relates to the SGLT2 inhibitors. So that's sodium glucose co-transporter 2 inhibitors, which is now main treatment in patients with heart failure. And in this trial... They investigated the efficacy and safety of initiating one SGLT2 inhibitor called dapoglifosin in patients who were still hospitalized for acute heart failure.

And this trial comes to us from corresponding author David Berg and the TIMI study group at Brigham and Women's Hospital in Boston, MA. And they tested the effect of the apoglufosin. on the primary outcome which was a composite of time to cardiovascular death or worsening heart failure through just two months follow-up. Interesting.

So the first cardiovascular outcomes trial of SGLT2 inhibitors in patients hospitalized with a primary diagnosis of heart failure. How many patients did they enroll here and what did they find? Yes, it was actually quite a large study for acute heart failure and they randomized a total of 2,401 patients and the median age of these were 69 years. There were 34% women, 19% black race, and 72% had an ejection fraction below 40%. And also 45% had a newly diagnosed heart failure.

Now, share into the primary results. So, the primary outcome occurred in 10.9% in the dipoglossosin group and 12.7% in the placebo group. and that yield has a ratio of 0.86, which was not significant because the 95% conference intervals range from 0.68 to 1.08. In Sheeran, the rates of symptomatic hypotension were 3.6% and 2.2%, respectively, and the rates of worsening kidney function were 5.9% and 4.7%.

with dapogliflozin and placebo, respectively. So, in conclusion, an in-hospital initiation of dapogliflozin did not significantly reduce the risk of cardiovascular death or worsening heart failure through two months. in hospitalized heart failure patients. Now, Sharon, in addition to the main results of this trial, this paper also includes the meta analysis of patients hospitalized for heart failure.

So that includes data from the MPOLS trial and the SOLOIS-WHF trial. And in this meta-analysis, SGLT2 inhibitors did reduce the risk of cardiovascular death or worsening heart failure. with a hazard ratio of 0.71 and a p-value of 0.012 and also the risk of all-cost death with a hazard ratio of 0.57 and a p-value of 0.001. So two for one in this paper sharing, both new data from the trial and also from this meta-analysis.

Thanks, Peter. That was such a great discussion on SGLT2 inhibitors in acute heart failure. Now, for our next paper, we're switching gears to something mechanistic, but...

Clinically fascinating. What happens after a heart attack? We know that in some patients The infarct scar can develop fatty infiltration over time, which has been linked to worse function and arrhythmias. But why does this happen? That's right. I have seen those MRI scans showing fatty scar tissue, but I've never really understood how it forms. Exactly, Petter.

The team led by Dr. Nicholas Frangiojones at the Albert Einstein College of Medicine set out to answer that. Using mouse models and human heart tissue, they found that when TGF beta signaling A key pathway that keeps fibroblasts on task is disrupted. Those fibroblasts can actually turn into fat cells instead of forming stable scar tissue.

Oh wow, so the same fibroblasts that pill the scar after an infarct can transform into adipocytes. That's right. When TGF-beta signaling was lost, the scars were weaker. Some hearts even ruptured early on better, and later up to 40% of the scar tissue was replaced by fat. and then linear tracing conferred these new fat cells came directly from fibroblasts

Very interesting. So that could really explain why some post-MI scars remodel poorly and trigger arrhythmias. Exactly, Petter. And it highlights TGS beta's role in keeping fibroblasts. stable after injury. And disrupting that control might actually underlie the fatty metaplasia we see in ischemic cardiomyopathy and maybe point to new ways to present it. And with that, I think it's time to dive into our favorite segment, the mailbag. What else do you have for us this week? Yes, Sharon.

There is a letter by Dr. Deng et al regarding the article aspirin plus rivaroxaban versus rivaroxaban alone for the prevention of venous stent thrombosis among patients with post-thrombotic syndrome. And then there is another letter by Dr. Wang related to optimizing antithrombotic strategies for post-thrombotic syndrome. And we also have an in-depth piece by Dr. Michael Gibson.

titled Minimizing Missing Data in Clinical Trials, highlighting how missing data can distort clinical trial results and also providing a roadmap. for proactively minimizing and managing data loss to preserve trial integrity.

And we have a cardiovascular case series by Dr. Justin Grodin titled Twin Diseases in Different Organs, A Cautionary Tale of Anchoring on a Positive Scan. And this is about... a 72-year-old with atrial fibrillation and worsening heart failure, and it illustrates the dangers of anchoring on one positive scan. Great, Shirin. And now let's move to the feature to dig into a very interesting trial in the field of stroke. Okay, let's do it better.

Thank you so much, Petter and Sharon, for that wonderful discussion of several of the articles. And listeners, now we're going to transfer to our feature discussion today. And I am one of your co-hosts. Dr. Greg Hunley, Associate Editor here at Circulation. And we have with us today, Dr. Graham Hanke. And he is from the University of Western Australia and involved heavily.

in the field of neuroscience. And listeners, today our feature discussion relates to bailout intracranial angioplasty and stenting. and a very fascinating randomized clinical trial that was performed in China. Well, Graham, maybe can you help orient our listening audience to... really the process of bailout intracranial angioplasty and studying. When is it used? Well, it's used, Greg, thank you, in patients with acute ischemic stroke who have a large vessel occlusion.

and who have unsuccessful thrombectomy. So as you know, when people have an acute ischemic stroke, the reperfusion strategies are chemical thrombolysis. plasminogen activators like alteplase and tenecteplase, and mechanical thrombectomy by endovascular contact aspiration or stent retrieval of the thrombus. And this is the mechanical thrombectomy is a successful procedure in at least 80% of patients with acute ischemic stroke due to large vessel occlusion.

in recanalising the artery, restoring perfusion and improving survival free of disability from about 30% to about 50%. And it's particularly successful in patients who embolise from a proximal source like the heart into the brain, into a large artery that has been patent and hitherto was normal. And so it's quite easy to get the clot out.

But in about 20% of cases, thrombectomy is not successful in recanalising the artery and restoring perfusion and improving outcome. And that's particularly in patients who have... inherent vessel pathology intracranially. And so the thrombus forms on a ruptured atherosclerotic plaque. So there's already a stenotic lesion there.

Then there's thrombotic occlusion and trying to get a catheter in there and suck it out or pull out the clot. You can dissect the artery or it can be very difficult to have a successful procedure. The strategies in that situation to perhaps give intraarterial fibrinolysis or to give intravenous antiplatins like tyrofibin. So Graham, it sounds like there are medical therapies to manage the situation in which there's incomplete restoration of flow or we have perhaps a complication.

But Graham, are there also procedural therapies? Yes, and there's bailout or rescue intracranial angioplasty or stenting. And that was the subject of this study because... Observational studies have reported that rescue adjunct intracranial artery angioplasty or stenting following unsuccessful endovascular therapy for acute ischemic stroke.

due to ICAD-related or intracranial atherosclerotic disease-related large artery disease is associated with improved functional outcomes compared to endovascular therapy alone.

but the assignments were not randomized and comparisons between them are therefore prone to systematic bias and so we've been awaiting a randomized controlled trial to minimize systematic bias and That's what Beng Goh and colleagues from Beijing, Tiantian Hospital and Capital Medical University in Beijing, China, have achieved in designing and undertaking the Angel Reboot trial.

Very nice, Graham. And so maybe for our listeners, can you describe more in detail about this trial? It appears that it was conducted across 36 tertiary care centers in China. But who did they include in the study population? And then how did they conduct the randomization? Yes, well, they recruited a total of 348 patients. with acute ischemic stroke within the previous 24 hours caused by an occlusion of an anterior or posterior circulation large artery and who had undergone

unsuccessful endovascular therapy and that was defined as incomplete reperfusion after three passes. In other words, less than 50% of the affected tissue area. was reperfused an e-ticky score of zero to 2a in about a third of patients or they had residual stenosis of more than 70 percent of the intracranial large artery after one to three passes in about two-thirds of the patients. And those patients were randomly assigned to the open-label balloon angioplasty or stenting or to standard therapy.

And the standard therapy was just to continue or terminate the thrombectomy procedure at the discretion of the interventionalist. Now, the baseline characteristics were reasonably balanced between the treatment groups, and they included that. The cause of the stroke in 94% of the cases was intracranial atherosclerotic disease. And the stroke onset time to puncture was about a median of about eight and a half hours.

there was a periprocedural use of tyrofiban post-thrombectomy in 96% of patients. So the baseline characteristics were reasonably well balanced. And Graham, just for a listening audience... In terms of the age of these participants? Yes, the mean age was 62 and 63 in their respective treatment groups, and they had their usual profile of vascular risk factors.

And they had an average National Institute of Health Stroke Scale score of 12, so reasonably severe strokes. And about a quarter of them had intravenous alteplase as pretreatment. Very nice.

So now I think a unique feature that you mentioned earlier is to have long-term follow-up. And so what were the study results? Firstly, just at the end of the procedure, Those with standard therapy, 77% of them had residual stenosis, whereas those randomized to angioplasty or stenting as a rescue therapy, only 6% had residual stenosis, more than 70%. the intervention seemed to open up the artery at the end of the procedure now the primary outcome and primary analysis of this study was the

at the functional outcome as measured by the modified Rankin score at 90 days. And that was published in the Lancet Neurology last year and showed there was no benefit of... balead antiplasty or stenting on functional outcome and survival at 90 days. And that was probably because there were complications. There was dissection in 14% of patients.

arterial dissection who got stented versus only 3% who didn't. And symptomatic intracranial hemorrhage in 5% who got bailout angioplasty or stent versus only 1%. So there were early periprocedural complications that perhaps contributed to no short-term benefit on the primary analysis at 90 days. But to the credit of the investigators, they...

adapted the trial and obtained ethics and consent to continue follow up up to one year. And that's what this paper is reporting. Having previously reported no early benefit at 90 days, they... completed the follow-up in 94 percent of the patients initially randomized so 326 of the 348 originally recruited completed follow-up to one year and it was pretty balanced 166 had

bailout angioplasty or stenting and 160 got standard therapy and so the primary outcome at the end of one year in those people was there was a significant improvement in survival and functional independence with the modified rank and score ordinal scale showing an odds ratio of 1.34. So about a 30% greater odds of having a shift.

in your functional outcome from severe to moderately severe to mildly severe and if one thinks about it in a categorical sense of modified rank and score zero to two that is survival and being independent and not needing help for anyone, it was 47% if you were assigned standard therapy or 67% if you had balad antiplasty or stenting.

Now, why would people do better at one year? Well, the recurrent stroke rate was less. In the standard therapy group, 13% went on to have another stroke, whereas having stented that. intracranial atherosclerotic lesion and restoring perfusion it also removed the source of subsequent thromboembolism so recurrent ischemic stroke was reduced from 13 to 4 so a hazard ratio of

0.3 confidence intervals 0.13 to 0.71. But the numbers were small. It was really only seven events versus 21, but still quite statistically significant. So that's the... message here was despite an early periprocedural complication rate, the longer-term benefits of stenting that atherosclerotic lesion realized less subsequent. recurrent ischemic strokes. And the plausibility of that is that we see that when we stent an extracranial carotid artery.

like carotid endarterectomy or stents for people who come in with a TIN or ischemic stroke and want to prevent a recurrence. And when we use submaximal balloon angioplasty of symptomatic intracranial arteries. there's again an early complication rate but there's a longer term benefit in preventing recurrence so the results are plausible but are they valid and that was the question for the editors

Very nice. And so that leads us to the next question, Graham. And for our listeners, Graham is the Perrin Institute Chair in Stroke Research at the University of Western Australia. And so... Graham, you know, I know there are many papers that come across your desk as an associate editor here at Circulation. What do you see now? as the next series of studies that need to be performed in this sphere of research? Well, one swallow doesn't make a summer. We need replication in science.

A reasonably small study with a reasonably small number of outcome events. And although we think the results are valid and sources of bias, performance detection and attrition bias were minimised. to the credit of the investigators. There's still concern about random error here and chance due to small numbers, and there's also a concern about generalizability.

Can we generalize these results from Chinese centers and expert operators and Chinese patients with intracranial arterial disease to other centers and operators to other causes of large artery occlusion? So we need more randomised trials to see if we can confirm these results in other populations and other centres. And we need longer follow-up. I mean, it was only one year. There might even be greater benefits longer term.

or that the relative risk reduction and absolute risks might be different in the longer term. So we need replication in additional trials, and hopefully this paper will reignite. the initial lack of enthusiasm from the initial short-term results and inspire other investigators to consider long-term benefits as well as short-term risks.

Very nice. Well, listeners, we want to thank Dr. Graham Hanke from the University of Western Australia, the associate editor that reviewed this manuscript and also the editorialist. that highlighted in this paper from Huang Guo from China that among Chinese individuals with large vessel occlusion that patients with unsuccessful re-canalization or high-grade residual stenosis following thrombectomy, that bailout angioplasty or stenting was associated with reduced disability.

and stroke recurrence after one year compared to standard therapy. Well, on behalf of Petr, Shirin, and myself, we want to wish you a great week, and we will catch you next week on The Run. This program is copyright of the American Heart Association 2025. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more... please visit ehijournals.org.