Apr 17, 2026 This Week in Cardiology Podcast

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In This Week’s Podcast

For the week ending April 17, 2026, John Mandrola, MD, comments on the following topics: SPIRIT-HF, another spironolactone trial in HFpEF; the ESSENCE imaging study of the drug olezarsen; the SirPAD trial in peripheral artery disease; and ultrasound-guided femoral venous access.

A quick thank you to all those of you who came up to me at the European Heart Rhythm Association meeting in Paris. It’s really nice to hear that you listen to this podcast. Sorry to the 5K organizers as I had to miss the race for a bit of cold.

ACC: SPIRIT-HF Trial

I had looked forward to the SPIRIT HF trial, which was another test of spironolactone in patients with heart failure with preserved ejection fraction (HFpEF). The goal was to retest the Americas subgroup of TOPCAT — a 2014 RCT of spironolactone vs placebo in patients with HFpEF.

To briefly recall, TOPCAT randomized nearly 3500 patients to spironolactone or placebo. The topline NEJM results found an 11% nonsignificant reduction of cardiovascular death, cardiac arrest, or heart failure hospitalization (HHF). However, huge regional differences in outcomes spurred reviews and it came to be known that half the trial patients 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. However, this included only half the trial cohort (about 1700 patients, not 3500). The Russia/Georgia cohort had no difference and the P-value for interaction was low but not significant (P = .12)

This is super hard to translate. It’s one trial — positive in Americas, but it’s a subgroup, yet 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 spironolactone vs placebo in patients with HFpEF, I was excited. The trial planned to enroll 1500 patients and was powered for a 25% reduction in the primary endpoint of CV death and HHF.  This is quite optimistic because in TOPCAT, a trial done 15 years ago, the reduction in the Americas subgroup of 1700 patients was only 18%.

So right off the bat, the trial had a great risk to be underpowered: it’s planning fewer patients than the Americas subgroup of TOPCAT (which was 1700) and you would expect fewer events in 2026 than in 2010, because patients with HF have fewer events.

The first patient enrolled in SPIRIT-HF was in 2018, the last in 2024. And, sadly, due to COVID, they enrolled half of their goal. A total of 750 patients were enrolled rather than 1500. That’s only 370 per group.

The main result was a totally uninformative primary endpoint — the hazard ratio was 1.18 with 95% confidence intervals going from 0.72 to 1.92. A 28% reduction vs a nearly twofold increase.

There was a near doubling of the rates of low blood pressure, high potassium, and renal events in the spironolactone arm — all of which was statistically significant.

The authors did many analyses, such as “as treated”, using total heart failure (HF) events — but none of these are worth mentioning because the trial did not recruit near enough patients nor record near event events to sort out signal from noise.

What we knew from the Americas subgroup is not in any way altered by this study. SPIRIT-HF is not published yet, but I doubt the publication will shed any light on what we want to know.

Namely, the FINEARTS trial of finerenone vs placebo in patients with HFpEF was positive at a 16% reduction in the CV death/HHF primary endpoint — driven by HHF not CV death. Now we don’t whether the $4-per-month spironolactone is as good.

This is sad. I don’t blame the German group. Trials are hard, and they were surely hard during the pandemic.

But what I have come to understand — as a user of the evidence — is that you need enough events to make conclusions. One way to get enough events is to recruit more patients but another way is to run an event-driven trial and simply wait for more events. I am not sure the latter would work here because most HF trials go for 2-3 years.

The thing is that if you are going to experiment on humans 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.

And, yes, I do think it worthwhile for a government somewhere to fund a TOPCAT-like trial. Before we spend oodles on the brand name finerenone we should have a proper comparison of spironolactone first. And my friends, this is why you need tough regulators in positions at FDA and European Medicines Agency (EMA).

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 APOC3 inhibition with the drug olezarsen. This is the first trial of intensive triglyceride-lowering on coronary plaque progression. The idea is that apolipoprotein C3 (APOC3) inhibition will slow or reduce coronary plaque progression.

I learned a fair amount from the authors’ nicely written introduction. Let’s do some basic background before I tell you the trial results:

Triglyceride-rich lipoproteins (TRLs) are (apoB)-containing particles that are considered atherogenic. The degree of the atherogenic effect of TRLs relative to low-density lipoprotein (LDL) particles has been debated, with some studies supporting significantly greater atherogenic risk per particle of the TRL.

However, unlike with LDL-C lowering drugs, the results of cardiovascular outcomes trials targeting TRLs have been mixed and have not demonstrated that triglyceride (TG) lowering in the absence of LDL-C and apoB lowering results in a reduction in coronary heart disease risk.

One of the headwinds for TG-lowering drugs has been their weakness in reducing lipids. Fibrates, fish oil, niacin, and statins have only modest effects on TG. That’s different from statins and PCSK9 inhibitors, which markedly reduce LDL-C.

TG-lowering therapies also have variable effects on LDC-C and ApoB, which directly measures atherogenic particle count — and this was not reduced in two CV outcomes trials with fibrates and fish oil (the STRENGTH trial and the PROMINENT trial of pemafibrate).

Enter olezarsen, which began with the knowledge that naturally occurring loss of function mutations in the APOC3 gene were associated with very low TG levels and a lower risk of coronary artery disease (CAD).

Olezarsen is an antisense oligonucleotide targeting APOC3, which has been shown to lower triglycerides by approximately 60% and lowers directly measured remnant cholesterol by approximately 70% in patients with largely moderate hypertriglyceridemia in the main phase 3 Essence–TIMI 73b trial  — published in 2025 in NEJM. This trial showed that the drug caused massive reductions in TG levels. Olezarsen also lowers apoB by about 15% but has a neutral effect on LDL-C.

This imaging study looked at the effects of the TG-lowering drug on plaque progression using coronary computed tomography angiography (CCTA).

Patients had moderate hypertriglyceridemia (150-500) plus an increased cardiovascular risk or severe hypertriglyceridemia (>500)

Two cohorts were randomized. One was 50 mg olezarsen subcutaneous (SQ) every 4 weeks vs placebo and the other was 80 mg olezarsen SQ every 4 weeks vs placebo.

The primary endpoint of the main trials was changes in TG levels but for the imaging study the primary endpoint was the placebo-adjusted percent change in coronary noncalcified plaque volume (NCPV) from baseline to month 12. Other endpoints were low-attenuation plaque volume (LAPV), necrotic core and other plaque components.

For the main analysis, the authors pooled the two olezarsen cohorts (80 mg and 50 mg combined). About 470 patients were studied (350 on olezarsen vs 120 on placebo). Nearly all these patients were on background lipid-lowering therapy mostly statins.

Results

The drug worked impressively on some but not all lipids. TG cut by 64%, remnant cholesterol by 72%, very low-density lipoprotein (VLDL) by 61%, apoB more modestly by 16%. LDL-C unchanged.

The effect on the primary endpoint of noncalcified plaque was minimal. There was no significant difference between olezarsen and placebo in noncalcified plaque volume, low-attenuation plaque, calcified plaque, fibrous plaque, or total plaque volume at 12 months. Results were consistent across all subgroups.

My Comments

On the surface, you might consider this sobering. You get massive reductions in TG, remnant cholesterol, and VLDL but not even a small signal of change in plaque characteristics. But...but....I am not so sure I would close the book on the drug.

• Plaque images are not outcomes. Myocardial infarction (MI), stroke, and CV death are outcomes. We most care about the latter.

• It’s only a 12-month study and I went looking and found IVUS-based regression studies showing that statins reduced plaque over 24 months, so maybe 12 months is too short.

• Also, maybe the drug just can’t do much incrementally over statins. Nearly all patients were on statins.

• The authors draw a parallel to ezetimibe, which had neutral imaging results but ultimately had some very modest CV benefits. Though don’t get me going about IMPROVE-IT trial weaknesses. Hint: IMPROVE-IT had 18,000 patients studied on simvastatin alone vs simvastatin plus ezetimibe and the effect size was a miniscule 7% relative risk reduction.

The drug olezarsen is FDA-approved for familial chylomicronemia syndrome, a rare genetic disorder with super high pancreatitis risk due to high TG. 

The FDA has, though, accepted a supplemental New Drug Application for olezarsen for severe hypertriglyceridemia (sHTG) and granted it Priority Review, with a PDUFA target action date of June 30, 2026. The FDA also granted Breakthrough Therapy designation for the severe hypertriglyceridemia (sHTG) indication in December 2025.

This paper enrolled those with moderate TG levels, which is by far the largest potential market, but there is no approved indication pending here. I would hope this would require a large outcomes trial before even considering that.

My take of this approach — and really many approaches of statin add-ons — is it’s going to be tough to add a lot of added value to $4 per month 80 mg of atorvastatin. But I will keep an open mind.

Drug-Coated Balloons Looked Quite Good in PAD Interventions

• Sirolimus-Coated Balloon Reduces Amputation Risk in Peripheral Artery Disease

I am not a vascular surgeon but I watch the interventional field from a distance. At ACC, Swiss investigators presented and NEJM published the SirPAD RCT of sirolimus-coated balloon interventions in infra-inguinal peripheral artery disease (PAD).

I present the trial as an example of a well-conducted, minimally biased, industry-funded trial that tried to answer a good question of whether the sirolimus-coated balloon performed as well as an uncoated balloon. In other words…not all industry-funded trials are bad.

The background is that paclitaxel-coated balloons improve patency, but previous studies have found only benefits in radiological or surrogate outcomes mainly in patients with claudication. Paclitaxel balloons have not been used for below-the-knee PAD and of course there were those mortality signals, which have largely been allayed.

Sirolimus, of course, is a different drug coating than paclitaxel.

Patients were screened at any of 44 vascular care centers in Switzerland, then referred to one of two trial sites for the actual procedure. Inclusion required symptomatic peripheral artery disease in the femoropopliteal arteries or arteries below the knee. And the disease warranted endovascular intervention. A few notables on inclusion is that even those requiring emergency intervention were enrolled. And the target lesion definition was broad enough to include fem-pop disease and below-the-knee disease, as well as previously treated lesions.

The broad inclusion I see as a plus.

The 1250 patients were 75 years old on average. About 35% were women. As you would expect, many patients had established atherosclerotic cardiovascular disease (ASCVD) and multiple risk factors as well as one third with chronic kidney disease (CKD) greater than stage 3.

The PAD was a mix: about one third had critical limb ischemia, 10% with acute limb ischemia, and two thirds with severe claudication. About 40% of the lesions were previously treated. And 1 in 3 lesions was below the knee. Surprisingly, only 66% were on lipid-lowering therapy.

The results:

• A primary-outcome event of unplanned major amputation affecting the target limb or endovascular or surgical intervention for the target lesion for critical ischemia within 1 year occurred in 8.8% in the sirolimus-coated–balloon group vs 15.0% in the uncoated-balloon group [risk difference, −4.9 percentage points; 95% CI, −8.5 to −1.3; P < .001 for non-inferiority; P = .009 for superiority).

• A key secondary-outcome event of any unplanned amputation affecting the target limb or revascularization of the target lesion for critical or noncritical limb ischemia within 1 year after randomization occurred in 23% and 30.8%, respectively (risk difference, −7.8 percentage points; 95% CI, −12.7 to −2.9; P = .002).

• Death rates occurred in 11.8% vs 12.8% and was not statistically different

• The incidence of adverse events were similar in the two groups.

• Components of the endpoint — amputations and the choice to re-intervene — were both reduced, albeit the greater reductions came in the choice to re-intervene. Unplanned major amputation was 1.3 vs 2.7% in favor of the drug-coated balloon. Re-intervention at the lesion for critical ischemia was 8.3 vs 13.3% in favor of the drug coated balloon.

My Comments

This looks pretty darn strong. They enrolled a broad population 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 the decision to intervene, the harder outcome of amputations also favored the drug-coated balloon.

The results are at 1 year, and one wonders about longer term follow-up. The SirPAD trialists do plan to follow the patients for longer, which is good.

I am also reassured by the fact that sirolimus has a long track record in coronary stents, and I would doubt we’d see any paclitaxel-like mortality signals. There surely weren’t any mortality or safety concerns in this trial.

If I were having a peripheral intervention, I’d 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 diminish equipoise to a dangerous degree.

Finally — and maybe I am wrong here, experts can weigh in — I see this trial as a good example of an industry-funded trial designed and done well. It’s possible. You don’t have to choose biased endpoints to guarantee a positive result.

Another Vascular Story from the European Heart Rhythm Association

I did not misspeak. In my opinion, the best trial coming out of the EHRA meeting was a vascular story. Namely, the Frankfort, Germany-led team randomized patients having atrial fibrillation (AF) or left atrial flutter ablations to ultrasound-guided venous puncture to conventional palpation guided or blind femoral puncture.

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 access site complications in the month after the procedure; this includes arteriovenous fistula, pseudoaneurysm, or bleeding requiring intervention or prolonged hospitalization.

The ULYSSES trial was conducted in six centers, nearly 1000 patients were randomized 1:1 to the ultrasound-guided access or a blind stick.

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 3 patients (0.6%) in the intervention group and 16 patients (3.3%) in the control group (risk ratio 0.19; 95% CI, 0.05–0.63; P = .002). 

Additionally, ultrasound-guided venous puncture significantly reduced the rate of an unintended arterial puncture (2% vs 16%, P < .0001) and the rate of unsuccessful venous access attempts requiring crossover to the other group (0.2% vs 8.2%, P < .0001).

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 use of ultrasound guidance.

I found a 2018 study from a Prague-led group that found lower rates of ultrasound-guided complications, but the rate was so low that there was not enough power to show a difference. What’s more, guidelines have said very little about the matter.

A 2025 European survey found that ultrasound access was used in only 71% of labs. Meaning nearly 1 in 3 labs in Europe still do not use it.

I remind listeners that AF ablation is done under uninterrupted anticoagulation. So an arterial stick is quite a serious flub.

This study could not have been done in our center because we have had a culture of image-guided access for nearly a decade. The interventional cardiologists, to their credit, drove this, first with their move to radial artery access during coronary angiography, and then to mandating ultrasound imaging for any central access.

I began my career with blind sticks — there were no ultrasound machines at that time. I attempted early adoption of ultrasound but had trouble with it and abandoned it, but have since re-adopted ultrasound-imaging for the past 10 years. I also use ultrasound for axillary vein access for pacing. As well as micropuncture needles.

That said, before this trial, if I were tell the labs that their blind stick was inferior, I would be practicing a form of eminence-based medicine. I would say ultrasound is safe, inexpensive (because the machine is paid for), and is 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 come with a Class 1 A recommendation that we should all do this. There was a 79% reduction in serious access complications. The absolute risk reduction was 2.7% and the number need to treat (NNT) was 37. Given the non-invasive and inexpensive nature, this is a clear win.

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 trial studying intracardiac echocardiography (ICE) to guide routine AF ablation.

Nearly every AF ablation in the United States is done with ICE guidance, which requires an extra central venous access and an extra catheter in the heart. But yet, far fewer labs in Europe and Canada use ICE (because of cost constraints). I’d love to see an RCT of ICE guidance vs no ICE guidance for AF ablation.

At current reimbursement levels, this trial could never happen in the US, because doctors 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 extra catheters (thereby cutting profit margin), then such a trial could be done.

My 2 cents is that now that we’ve gone to 30-minute pulsed field ablation (PFA) pulmonary vein isolation procedures, ICE would add very little 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 Schaack huge credit for doing this trial as well as his team. Congratulations.

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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: Apr 17, 2026 This Week in Cardiology Podcast - Medscape - Apr 17, 2026.