Apr 17 2026 This Week in Cardiology

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Hi everyone, this is John Mandrola from the Heart.org MedScape Cardiology.

And this is this week in Cardiology for April 17th, 2026.

This week, SpiritHF, another Spirin Electone trial and HEPF.

The Essence Imaging Study of the Triglyceride Lowering Drug Olozarsin, Surpad Trial and

Peripheral Artery Disease, and Ultraside Guided Femoral Venus 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 SpiritHF trial.

Now, this is from the ACC meeting, and I look forward to this trial, which was another

test of Spirin Electone in patients with HEPF.

The goal, of course, was to retest the America's subgroup of the TopCat trial, which was

a 2014 RCT of Spirin Electone versus placebo in patients with HEPF.

To briefly recall, TopCat randomized nearly 3,500 patients to Spirin Electone or placebo.

The top-line New England Journal of Medicine results found an 11% non-significant reduction

of CV death, cardiac arrest, or heart failure hospitalizations.

However, huge regional differences in outcomes 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% 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 Peefer Interaction was low, but not significant

at 0.12.

This is really hard to translate the 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 Spirin Electone versus placebo in patients

with HEPF, I was excited.

The trial planned to enroll only 1,500 patients, and it was powered for a 25% reduction in the

primary endpoint of CV deaths and heart failure hospitalization.

So right off the bat, you're thinking, that's pre-optimistic expectations, because in

the main top-cat trial, which was done 15 years ago, when event rates were likely higher,

the Americas subgroup had a number of patients of 1,700, and the point estimate of the

effect size was only 18%.

So I think that the Spirit HEP trial has a great risk to be underpowered, right?

It's planning fewer patients than the Americas subgroup of top-cat, and again, you'd expect

more event rates 15 years ago than you would see now.

The first patient enrolled in Spirit HEPF was in 2018, the last in 2024, and 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% conference intervals going from 0.72 to 1.92, 28% reduction,

versus a nearly two-fold increase.

So again, very wide conference intervals.

Now, there was a near doubling of the rates of low blood pressure, high potassium, and

renal events in the Sprennel Actone Arm, all of which were statistically significant.

Now, the authors did many analyses, such as as treated, such as using total heartfire

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 subgroup of TopCat is not in any way altered by this study.

Spirit HEPF is not published yet, but a 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 Sprennel Actone in HEPF.

We have the fine arts trial of Fenerinoin versus placebo in patients with HEPF.

This was positive, it was a 16% reduction in CV death, heartfire hospitalization primary

endpoint, it was driven by heartfire hospitalizations, not CV death.

Now we don't know whether the $4 per month Sprennel Actone is as good as the many dollars

per month Fenerinoin.

This is sad, but I don't blame the German group, I mean trials are hard to do and they

were surely hard during the pandemic.

What I have 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 a 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 which is waiting for more events would work

here because most of the heartfire trials go for two to three years, not five to six years.

The thing is that Frank Harrell says, a statistician for Vanderbilt, is 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.

And yes, I do think it is worthwhile currently now for governments somewhere to fund a top

cat like trial.

I mean before we spend oodles on the brand name Fenerinone, we should have a proper comparison

of Spirinal Actone first.

In 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 Timmy 73B Imaging Study

of the APO C3 inhibition with the drug alizarcin.

This is the first trial of the intensive triglyceride lowering drug on coronary plaque progression.

The idea is that APO lipoprotein C3 inhibition will slow or reduce coronary plaque progression.

Now I learned to fair amount from the author's nicely written introduction and let's do

some basic background before I tell you the trial results with oloz arcin.

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 in PCSK9, which markedly reduce LDL cholesterol.

So triglyceride lowering therapies also have variable effects on the LDL cholesterol

and APO B, which directly measures atherogenic particle count.

And this was not reduced in two CV outcomes trials with fibrates and fish oil.

That's strength in the PEMO Fibrate Trials.

Enter Olazarsin, 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 Olazarsin is an anti-sense oligoneucleotide targeting APO lipoprotein C3, which has been

shown to lower triglycerides by approximately 60%, and it also lowers directly measured

remnant cholesterol by approximately 70%.

These numbers come from the main phase III essence, Timmy 73, the trial, which was published

in 2025 in New England Journal, and this trial randomized patients with moderate hyperglyceride

emia.

The trial showed that the drug caused serious massively reductions in triglyceride levels,

like I said, 64%, which is a lot.

Olazarsin, however, also lowers APO B, but only by about 15%, and it has no effect on LDL

cholesterol.

So 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 hyperglycerideemia, 150 to 500, plus an increased cardiovascular

risk, or they could have severe hyperglycerideemia with greater than 500.

Two cohorts were randomized in the original trial.

One was 50 milligrams of Olazarsin sub-Q4 weeks versus placebo, and the other was 80

milligrams of sub-Q4 week Olazarsin 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, and they also looked at other

endpoints with such things as low attenuation, plaque volume, the chronic core, and other

plaque components.

And for the main analysis of the imaging study, the authors pooled the two Olazarsin

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.

So the results are interesting.

The drug worked impressively on some, but not all lipids, triglycerides, like I said,

down by 64 percent, redundant cholesterol by 72 percent, ELDL by 61 percent, but APOB

only 16 percent, LDL no change.

So the effect on the primary endpoint of non-calcified plaque volume was minimal.

There were no significant differences between Olazarsin and placebo and 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, 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 redundant cholesterol and VLDL, but not

even a small change in plaque characteristics.

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 IVIS-based regression

studies, and this shows that statins reduced plaque, but it took 24 months, so maybe the

12-month timeline is too short.

So maybe the drug just can't do much incrementally over statins.

Nearly all patients were on statins, like 97%.

The authors draw a parallel to the zidimib story, which also had neutral imaging results,

but ultimately had some very modest cardiovascular benefits, though don't get me going about

improve it, trial weaknesses, hint, improve it, which was the zidimib symbastatin study,

18,000 patients, it was symbastatin alone versus symbastatin plus a zidimib, and the

effect size was a minuscule 7% 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 a zidimib.

So the drug olazarcin is FDA-approved, it turns out, for familio, chylo-micronemia 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 olazarcin for severe

hyperglyceridemia, 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 hyperglycerid

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 addons,

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 tour of a stat?

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?

Alright, 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 interventional 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 Newland Journal of Medicine published a SERPAD

RCT of a serolimus-coded balloon interventions in inferringonal PAD.

I presented 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-coded balloon performed

as well as an un-coded 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.

Background is that packletaxle-coded balloons improve PAD and C, but previous studies have

found really benefits in radiological or surrogate outcomes mainly in patients with clotication.

Packletaxle balloons have not been used for below the NEPAD, and of course there were

those mortality signals which I think have largely been elayed, but were somewhat concerning.

Serolimus, of course, is a different drug coating than packletaxle.

It's similar in effect, but it's different.

In this trial, we're screened at any of 44 vascular centers in Switzerland, then referred

to one of two trial sites for the actual procedure.

Inclusion required symptomatic PAD in the femoral papalteal arteries or arteries below the

knee, and the disease warranted endovascular intervention.

Now, a few notables on inclusion is that even those requiring emergency interventions

were enrolled, which is good.

In a target lesion definition was broad enough to include fem popped disease and below

the knee disease as well as previously treated lesions, and 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 factors,

as well as a third was CKD greater than stage 3.

And the PAD was also a mix.

About a third had critical limouschemia, 10 percent acute limouschemia, and two thirds

was 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 a criticalist game year within one year, occurred in 8.8 percent in the serolimus

coded balloon group versus 15 percent in the uncoded balloon group, that risk differences

4.9 percentage points and 95 percent conference intervals were from minus 0.8 to 1.3,

highly significant p-value for both non inferiority and superiority.

A key secondary endpoint of any unplanned amputation affect the target limb,

or revascularization of the target limb for either critical or non-critical schemia,

was also positive to a high degree 23 percent versus 30.8 percent, and again,

highly significantly better for the drug coded balloons.

That 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 reintervene,

these were both reduced, albeit the greater reduction came in the choice to reintervene.

Unplanned major amputations were 1.3 versus 2 percent in favor of the drug coded balloon,

but re-intervention at the lesion for criticalist schemia 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,

and the surpath trial is duplanned to follow the patients for longer, which is good.

I am also reassured by the fact that Cyrillymus has a long track record in coronary sense,

and I would doubt we'd see any packletaxle-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 coded 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 equipois to a serious and 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.

All right, let me finish with another vascular story from the European Heart Rhythm Association,

and I did not misspeak. This is actually a vascular study from a heart rhythm meeting.

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 a fib 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 occurrence of venous excess site

complications in the month after the procedure, and we all know what they are. AV fished to the

pseudoanurism 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 excess or a blind stick. And the trial was stopped for efficacy

following the first interim analysis after enrollment of half of the planned patients.

The composite primary outcome occurred in three patients, 0.6% in the intervention group,

in 16 patients, 3.3% in the control group, that's a risk ratio of 0.19 or an 81% risk reduction

that was highly statistically significant. Additionally, ultrasound guided venous puncture

significantly reduced the rate of an unintended arterial puncture two versus 16%

and the rate of unsuccessful venous excess attempts requiring crossover to the other group,

0.2 versus 8.2%. 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 excess was used in only 71%

of laps, meaning, nearly one in three laps in Europe still did not use it.

I remind listeners that AF-oblation 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 re-artery access during coronary

underography, 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 I've 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 micro-puncture needles as well. That said, before this trial, if I were to have told you

that the labs that do blind sticks 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% reduction in serious excess complications. The absolute risk reduction was 2.7%

and the number needed to treat, it's 37%. The number needed to treat of 37 might not be as impressive

as a 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

of looking at intercardiac echo to guide routine AF-oblation. Again, another imaging guided

add-on. Nearly every AF-oblation in the United States is done with ice guidance, which requires

an extra-central venous excess. 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-oblation. 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 to fix some of

for an AF-oblation, 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 mappy catheter, they just cut their profit margin,

then such a trial could be done. My prediction or my two senses on the use of ice or imaging for

AF-oblation is that we've gone now to 30-minute PFA-PVI 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, and I give first author Dr. David Shock a huge credit for doing this trial

as well as his team. Congratulations. So that's it for this week in cardiology. As always, I'm

grateful that you listen. 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.