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Speaker 1:
[00:00] 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.

Speaker 2:
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Speaker 3:
[00:41] Hi, everyone. This is John Mandrola from theheart.org, Medscape Cardiology. And this is This Week in Cardiology for April 17th, 2026. This Week, Spirit HF, another spirinolectone trial and HEPPF. The Essence Imaging Study of the Treglyceride-Lowering Drug Olozarsin, SERPAD trial in Peripheral Artery Disease, and Ultrasign Guided Femoral Venous Access, a wonderful trial called Ulysses. So first, a quick thank you to all those who came up to me at the European Heart Rhythm Association meeting in Paris. It was really nice to hear that you listened to this podcast. I say sorry to the 5K organizers as I just woke up with a bit of a cold and could not answer the bell on Monday morning. Okay, first topic today is the Spirit HF Trial. Now, this is from the ACC meeting and I look forward to this trial, which was another test of sprinter lactone in patients with HEPF-PEPH. The goal, of course, was to retest the America's subgroup of the TopCat Trial, which was a 2014 RCT of sprinter lactone versus placebo in patients with HEPF-PEPH. To briefly recall, TopCat randomized nearly 3,500 patients to sprinter lactone or placebo. The top line New England Journal of Medicine results found an 11 percent non-significant reduction of CV death, cardiac arrest, or heart failure hospitalizations. However, huge regional differences in outcome spurred reviews of the trial and it came to be known that half of the trial patients, those from Russia and Georgia, did not receive the active drug and hence that explains why those patients garnered no benefit, while the patients enrolled from the Americas had a statistically significant 18 percent reduction in the composite primary. The thing was that this included only half the trial cohort, about 1,700 patients, not 3,500. The Russia-Georgia cohort had no difference in the P for interaction was low, but not significant at 0.12. This is really hard to translate to patients, right? Because number one, it's one trial. It's positive in the Americas, but the Americas is a subgroup. Yet, there's a good reason to believe the subgroup because the other subgroup did not even receive the drug. So when I read about the German-led four-country RCT of spirital lactone versus placebo in patients with half-breath, I was excited. The trial planned to enroll only 1,500 patients, and it was powered for a 25 percent reduction in the primary endpoint of CV deaths and heart failure hospitalization. So right off the bat, you're thinking, that's pretty optimistic expectations, because in the main TopCat trial, which was done 15 years ago, when event rates were likely higher, the America subgroup had a number of patients of 1,700, and the point estimate of the effect size was only 18 percent. So I think that the Spirit HF trial has a great risk to be underpowered, right? Planning fewer patients than the America subgroup of TopCat. Again, you'd expect more event rates 15 years ago than you would see now. The first patient enrolled in Spirit HF was in 2018, the last in 2024. Sadly, due to the COVID pandemic, they enrolled only half of their goal patients. So 750 patients were enrolled rather than 1,500. That's only 370 patients per group. The main result was a totally uninformative primary endpoint. The hazard ratio was 1.18, with 95 percent conference intervals going from 0.72 to 1.92, a 28 percent reduction versus a nearly two-fold increase. So again, very wide conference intervals. There was a near doubling of the rates of low blood pressure, high potassium and renal events in the sprenolactone arm, all of which were statistically significant. Now, the authors did many analyses such as as-treated, such as using total heart failure events. But honestly, none of these are worth mentioning because the trial did not recruit near enough patients nor record near enough events to sort out the signal from the noise. What we know from the America's subgroup of TopCat is not in any way altered by this study. SpiritHF is not published yet, but I doubt the publication will shed any light on what we already know and what we want to know. What we want is a confirmatory trial of spirtalectone in HEPF-PEPH. We have the Fine Arts trial of phenyranone versus placebo in patients with HEPF-PEPH. This was positive. It was a 16 percent reduction in CV death heart failure hospitalization primary endpoint. It was driven by heart failure hospitalizations, not CV death. Now, we don't know whether the $4 per month spirtalectone is as good as the many dollars per month phenyranone. This is sad, but I don't blame the German group. Trials are hard to do and they were surely hard during the pandemic. But what I've come to understand as a user of the evidence, not a trialist, but a user of the evidence like you and everyone else who uses this evidence, is that you need enough events in the trial to make conclusions. I mean, one way to get enough events is to recruit more patients. That costs money, but another way is to run an event-driven trial and simply wait for more events. I'm not sure though that the latter situation we're just waiting for more events would work here because most of the heart failure trials go for two to three years, not five to six years. The thing is that Frank Harrell says, a statistician for Vanderbilt, says that if you're going to experiment on human beings, you should be fairly certain the trial has a chance to sort signal from noise. While this trial was optimistic in its power predictions, there was no earthly idea to have predicted a global pandemic. So again, it's not on them. Yes, I do think it is worthwhile currently, now, for government somewhere to fund a TopCat-like trial. Before we spend oodles on the brand name Phenerenone, we should have a proper comparison of spironolactone first. My friends, this is why you need tough regulators in positions at FDA and EMA, so that they demand such trials. Our next topic is a new class of lipid-lowering drug has a dubious debut at ACC. The journal Circulation has simultaneously published the Essence-TIMI-73B imaging study of the APO-C3 inhibition with the drug Olozarsin. This is the first trial of the intensive triglyceride lowering drug on coronary plaque progression. The idea is that apolipoprotein C3 inhibition will slow or reduce coronary plaque progression. Now, I learned a fair amount from the author's nicely written introduction, and let's do some basic background before I tell you the trial results with Olozarsin. The first thing to say is that triglyceride-rich lipoproteins are APO-B-contained particles that are considered atherogenic. The degree of the atherogenic effect of these TRLs relative to low-density lipoproteins or LDLs has been debated, with some studies supporting significantly greater atherogenic risk per particle of the TRL. However, unlike with LDL cholesterol-lowering drugs, the results of cardiovascular outcome trials targeting TRLs have been mixed and have not demonstrated that triglyceride-lowering in the absence of LDL cholesterol and APO-B-lowering results in a reduction in coronary heart disease risk. Now, of course, one of the headwinds for triglyceride-lowering drugs has been their weakness in reducing lipids. Fibrates, fish oil, niacin, and statins have only modest effects on triglycerides. That's different from statins and PCSK9, which markedly reduce LDL cholesterol. So triglyceride-lowering therapies also have variable effects on the LDL cholesterol and APO-B, which directly measures estrogenic particle count. This was not reduced in two CV outcomes trials with fibrates and fish oil. That's strength in the PMO-fibrate trials. Enter olisarsin, which began with the knowledge that naturally occurring loss of function mutations in the APO-C3 gene were associated with very low triglyceride levels and a lower risk of CAD. So olisarsin is an antisense oligonucleotide targeting apolipoprotein C3, which has been shown to lower triglycerides by approximately 60 percent, and it also lowers directly measured remnant cholesterol by approximately 70 percent. These numbers come from the main phase 3 Essence-TIMI-73B trial, which was published in 2025 in the New England Journal, and this trial randomized patients with moderate hypertriglyceridemia. The trial showed that the drug caused serious massively reductions in triglyceride levels. Like I said, 64 percent, which is a lot. Olisarsin, however, also lowers ABL-B, but only by about 15 percent, and it has no effect on LDL cholesterol. This imaging part of the study looked at the effects of the triglyceride-lowering drug on plaque progression using CCTA, of course. Patients had moderate hypertriglyceridemia, 150 to 500 plus an increased cardiovascular risk, or they could have severe hypertriglyceridemia with greater than 500. Two cohorts were randomized in the original trial. One was 50 milligrams of Olusarsin sub Q4 weeks versus placebo, and the other was 80 milligrams of sub Q4 week Olusarsin versus placebo. The primary endpoint of the main trial was changes in triglyceride levels. But for the imaging study, the primary endpoint was the placebo-adjusted percent change in coronary non-calcified plaque volume from baseline to months 12. They also looked at other endpoints with such things as low attenuation plaque volume, necrotic core, and other plaque components. For the main analysis of the imaging study, the authors pooled the two Olusarsin cohorts, the 80 and 50. Those combined, about 470 patients were studied, 350 on active drug, 120 on placebo, and nearly all patients were on background lipid lowering therapy, and these were mostly statins. The results are interesting. The drug worked impressively on some but not all lipids. Triglycerides, like I said, down by 64 percent, remnant cholesterol by 72 percent, ELDL by 61 percent, but ApoB only 16 percent, LDL, no change. The effect on the primary endpoint of non-calcified plaque volume was minimal. There were no significant differences between Olus-Arsin and placebo in non-calcified plaque volume. They also did not see any differences in other features of the plaque, such as low attenuation, plaque calcified plaque, fibrous plaque, total plaque volume, etc. And all of these results were consistent across subgroups. So on the surface, you might consider this sobering. Here you get massive reductions in triglyceride and remnant cholesterol and VLDL, but not even a small change in plaque characteristics. But, but, I'm not so sure I would close the book on this drug, right? Because first of all, plaque images are not outcomes. MI, stroke, and CV death are outcomes. We most care about the latter. Now, it's also only a 12-month study. And I went looking and I found an IVAS-based regression studies. And this shows that statins reduced plaque, but it took 24 months. So maybe the 12-month timeline is too short. Also, maybe the drug just can't do much incrementally over statins. Nearly all patients were on statins, like 97 percent. The authors draw a parallel to the azitamide story, which had also had neutral imaging results, but ultimately had some very modest cardiovascular benefits. So don't get me going about improve it, trial weaknesses, hint. Improve it, which was the azitamide, simvastatin study had 18,000 patients. It was simvastatin alone versus simvastatin plus azitamide, and the effect size was a minuscule 7 percent relative risk reduction, not absolute risk reduction, relative risk reduction. Because there were 18,000 patients, there was a statistically significant result, but again, a very tiny effect size with azitamide. So the drug olisarsin is FDA approved, it turns out, for familial chylomicronemia syndrome, which is a rare genetic disorder, with very high triglycerides and a high pancreatitis risk. The FDA has though accepted a supplemental new drug application for olisarsin for severe hypertriglyceridemia, and in fact is granted a priority review, and the target action date is this summer. The FDA also granted breakthrough therapy designation for the severe hypertriglyceride indication last winter. But this paper, and this paper, this Essence-Timmy 73 study is looking at patients with moderate triglyceride levels which is by far the largest potential market. But there is no approved indication pending here. I would hope that this would require large outcomes trials before even considering that. Indeed. Finally, my take of this whole approach, and really many approaches of statin add-ons, is it seems like it's going to be really tough to add a lot of added value to the $4 per month 80 of a Vatorvastat. I'll keep an open mind, but the question is going to be, for the cost, how much more value are we going to get by adding subsequent expensive drugs to simple generic statins? All right. Next topic is drug-coded balloons looked quite good in peripheral artery disease interventions. Now, I'm not a vascular surgeon, but I watched the intervention field of vascular surgery from a distance, and I think we can learn a lot from our colleagues there. At ACC, Swiss investigators presented in the Journal of Medicine published a SERPAD RCT of a serolimus-coated balloon interventions in inferegulinal PAD. I present the trial as an example of a well-conducted, minimally biased industry-funded trial that tried to answer a reasonably good question of whether the serolimus-coated balloon performed as well as an uncoated balloon. In other words, my friends, not all industry-funded trials are bad, and here's an example I think of a pretty good one, and let me show you. First, some background. The background is that pachyletaxil-coated balloons improve patency, but previous studies have found really benefits in radiological or surrogate outcomes mainly in patients with claudication. Pachyletaxil balloons have not been used for below the knee PAD, and of course, there were those mortality signals which I think have largely been allayed, but were somewhat concerning. Cirulimus, of course, is a different drug coding than pachyletaxil. It's similar in effect, but it's different. Patients in this trial were screened at any of 44 vascular centers in Switzerland and referred to one of two trial sites for the actual procedure. Inclusion required symptomatic PAD in the femoral popliteal arteries or arteries below the knee, and the disease warranted endovascular intervention. A few notables on inclusion is that even those requiring emergency interventions were enrolled, which is good. The target lesion definition was broad enough to include fem pop disease and below the knee disease, as well as previously treated lesions. I see this broad inclusion as a plus. There were 1,250 patients, 75 years old on average, about 35 percent women, and as you would expect, many patients had established ASCVD and multiple risk vectors, as well as a third was CKD greater than stage 3. The PAD was also a mix. About a third had critical limb ischemia, 10 percent acute limb ischemia, and two-thirds with severe claudication. About 40 percent of the lesions were previously treated, and one in three lesions was below the knee. Surprisingly, I don't know why this is, only 66 percent of these patients were on lipid-lowering therapy. So a few of the results. A primary outcome event of unplanned major amputation affecting the target limb, or endovascular surgical intervention for the target lesion for critical ischemia within one year occurred in 8.8 percent in the serolimus coded balloon group versus 15 percent in the uncoated balloon group. That risk difference is 4.9 percentage points, and 95 percent conference intervals were from minus 8.5 to 1.3, highly significant p-value for both non-inferiority and superiority. A key secondary endpoint of any unplanned amputation effect to targeting limb or revascularization of the target limb for either critical or non-critical ischemia was also positive to a high degree, 23 percent versus 30.8 percent, and again, highly significantly better for the drug-coded balloons. Death rates were 11.8 and 12.8, and this was not statistically different. Adverse events were similar in the two groups. And the components of the endpoint, which is the amputations and the choice to re-intervene, these were both reduced, albeit the greater reduction came in the choice to re-intervene. Unplanned major amputations were 1.3 versus 2 percent in favor of the drug-coded balloon, but re-intervention at the lesion for critical ischemia was 8.3 versus 13.3 percent in favor of the drug-coded balloon. So my comments, this is a pretty darn strong trial. I mean, they enrolled a broad population of patients with few exclusions. The results are clinically meaningful and statistically robust. While the trial was open label and one component of the primary endpoint was a decision to intervene, the harder outcome of amputations also favored the drug-coded balloon. The results are at one year and one wonders about longer-term follow-up in the SIRPAD trial as due plan to follow the patients for longer, which is good. I am also reassured by the fact that sirelimus has a long track record in coronary sense and I would doubt we'd see any pachlotaxel-like mortality signals. There surely weren't any significant mortality or safety signals in this trial. I'm just looking at it from a neutral martian, but if I was having a peripheral invention, I'd certainly choose the drug-coated balloon. Would I like a confirmatory trial? Yes, of course. Hopefully, there will be one. Though I have to say, this result does seem to diminish equipoise to a serious degree. Finally, and maybe I'm wrong here, experts can weigh in. I see this as a good example of an industry-funded trial that was designed and done well. So I guess it's possible. You don't have to choose biased endpoints that guarantee a positive result. Let me finish with another vascular story from the European Heart Rhythm Association. I did not misspeak this is actually a vascular study from a heart rhythm meeting. And in my opinion, the best trial coming out of the era meeting was a vascular story. And that is that the Frankfurt Germany Group randomized patients having AFib or left atrial flutter ablations to ultrasound-guided venous puncture to conventional palpation-guided or blind femoral puncture. And the research team told me that yes, John, many centers in Europe still stick the femoral veins blind. The composite primary outcome was the occurrence of venous access site complications in the month after the procedure. And we all know what they are, AV, facetelous pseudoaneurysm or bleeding requiring intervention or bleeding that prolongs the hospitalization. This Ulysses trial was conducted in six centers. Nearly a thousand patients were randomized to either the ultrasound-guided access or a blind stick. And the trial was stopped for efficacy following first interim analysis after enrollment of half of the planned patients. The composite primary outcome occurred in three patients, 0.6 percent in the intervention group and 16 patients, 3.3 percent in the control group. That's a risk ratio of 0.19 or an 81 percent risk reduction that was highly statistically significant. Additionally, ultrasound-guided venous puncture significantly reduced the rate of an unintended arterial puncture, 2 versus 16 percent, and the rate of unsuccessful venous access attempts requiring crossover to the other group, 0.2 versus 8.2 percent. So my comments, while I nor many of you would be surprised about this finding, it turns out that there was very little data to support the use of ultrasound guidance. I did find from the citations in the introduction of the paper, a 2018 study from Prague-led group, and they found lower rates of ultrasound guided complications, but the rates were so low that there was not enough power to show a statistically significant difference. I also noted again from their introduction that guidelines have said very little about the matter. A 2025 European survey found that ultrasound access was used in only 71 percent of labs, meaning clearly one in three labs in Europe still do not use it. I remind listeners that AF ablation is done under uninterrupted anticoagulation. So the patient's fully anticoagulated and an arterial stick is quite a serious flub. So this study could not have been done in our center, nor in many American centers because we have had a culture of image guided access for nearly a decade. And I have to give credit to our interventional cardiologists. To their credit, they drove this first with their move to radio artery access during coronary angiography, which is clearly safer than femoral artery cannulation, and then to mandating ultrasound imaging for any central venous access. Imaging guided access was also being done in parallel by the ICU physicians as well during this time. So I'm old enough that I began my career with blind sticks. There were no ultrasound machines at that time, and I did attempt early adoption of ultrasound many, many years ago, but I had trouble with it, and then I abandoned it. But shortly thereafter, I've re-adopted ultrasound imaging and have been doing it for the past 10 years and I can't imagine not doing it. I also use ultrasound access for axillary vein access for cardiac pacing. I also use micropuncture needles as well. That said, before this trial, if I were to have told you that the labs that do blind stacks were doing it wrong, they were inferior, I would be practicing a form of eminence-based medicine. I would say ultrasound is safe, it's inexpensive because the machine is already paid for, and it's obviously beneficial because you can see puncture of the vein, not the artery. But, but, as this podcast has said time and time again, that which makes sense does not equate to benefit. What the German team has done is to show that ultrasound guided access is clearly superior and should now come with a class 1A recommendation that we should all do this. There was a 79 percent reduction in serious access complications, the absolute risk reduction was 2.7 percent, and the number needed to treat is 37. The number needed to treat of 37 might not be as impressive as the number needed to treat of 10 or 12, but you have to remember that ultrasound guided access is non-invasive, it's inexpensive, and it doesn't even increase the amount of time it takes to get access. It's a clear win. Now, one huge lesson we can take from this bold trial is the permission to study other things people take as beneficial. For instance, I'd love to see a similar study looking at intracardiac echo to guide routine AF ablation. Again, another imaging guided add-on. Nearly every AF ablation in the United States is done with ice guidance, which requires an extra central venous access, it requires putting an extra catheter inside the heart. But yet far fewer labs in Europe and Canada use ice, of course, because of cost constraints. I'd love to see an RCT of ice guidance versus no ice guidance for AF ablation. You could look at efficacy or safety outcomes. At current reimbursement levels in the US, this trial would never happen because doctors here get paid extra to place the catheter whether they look at it or not. But if payers in the US ever went to a European model where you get a fixed sum for an AF ablation and it's up to the operators to spend money on whatever catheters they want, and if they open an ultrasound catheter or a fancy mapping catheter, they just cut their profit margin, then such a trial could be done. My prediction or my two sense is on the use of ICE or imaging for AF ablation is that we've gone now to 30-minute PFA, PDI procedures, and it's hard for me to believe that ICE would add anything to efficacy and safety. But again, that's just a guess. Trials are the way to answer questions, I give first author Dr. David Schock huge credit for doing this trial as well as his team. Congratulations. That's it for This Week in Cardiology. As always, I'm grateful that you listen. Until next week, this is John Mandrola from theheart.org Medscape Cardiology.

Speaker 1:
[27:56] 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.