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In This Week’s Podcast
For the week ending April 11, 2025, John Mandrola, MD, comments on the following topics: The TAP-IT, STRIDE, FreshUP, and SINGLE SHOT CHAMPION trials.
I have some really fun trials to discuss today. Let's start with one of my favorite trials then do some more recap of ACC and EHRA.
The TAP-IT Trial
PhD candidate Signe Glargaard from Copenhagen led the TAP-IT trial, a simple elegant RCT comparing thoracentesis plus medical therapy vs medical therapy alone in patients with heart failure (HF) and pleural effusion.
If you take care of patients with acute congestion due to HF, you know the dilemma. The patient has obvious congestion; there is dyspnea, edema, neck veins, rales, and decreased breath sounds. There is known left ventricular (LV) dysfunction and an elevated BNP. Now the chest x-ray (CXR) shows a large pleural effusion—in addition to the acute congestion.
For decades, I have recommended draining that effusion through a catheter. Back in the old days, we did it ourselves, with a needle and a vacuum bottle. Now patients go to radiology for ultrasound-guided drainage.
My idea — perhaps yours too — was that thoracentesis is a simple procedure that speeds the decongestion, expands the lung and patients come back feeling better.
Our pulmonologists admonished me a few years ago that there was scant little evidence for the extra procedure, and I should consider just using diuretics. I said no way. Thoracentesis helps. You can see the darn fluid in a bottle that was once in the body squishing the lung. Plus, patients say they feel better.
Well, Dr Glargaard and her colleagues set up and ran an RCT. 135 patients with acute HF and effusion. 1-1 randomization to thoracentesis plus meds vs meds alone.
The primary outcome was one of my new favorites—days alive out of the hospital. More on that later. They also looked at quality of life, length of stay (LOS), and mortality.
The median LVEF was 25%. Average age 80-82 years. More than half were considered frail. They screened only 255 and enrolled 135 patients.
And the results. Before I say the results, I should add, there was a BOOM. There was no difference in days alive out of the hospital (84 compared with 82). There was no diff in LOS of the index hospital stay. No diff in 90-day mortality and most important, no difference in quality-of-life scores.
Diuretic dosing was not different. Weight loss—not different. Nothing was different. Except there were 5 pneumothoraxes in the thoracentesis group and one had to be drained with a chest tube. 20 out of the 80 thoracenteses (25%), participants experienced minor complications or discomfort during or after the procedure, resulting in an overall complication rate of 26% (21 out of 80).
Comments
Circulation published the trial, but it should have been in NEJM because it is simple elegant trial that reversed a common practice—at least in my zip code.
I love the trial because it proved me wrong. I had been fooled. Sure, I knew acute heart failure required intense diuresis, but I had also thought when there was substantial effusion, thoracentesis aids the process.
The big bottle of yellow fluid that gets pulled out looks impressive. The post-CXR without the fluid does too. Patients come back feeling better. It all made perfect sense.
But, as it turns out so often in medicine, what makes sense does not always pass muster in an RCT.
TAP-IT wins the week not only because it informs (and reverses) a common practice of thoracentesis for HF, but more so because it teaches crucial evidence-based medicine lessons. That is, you have to submit common practices to proper trials.
No, we don't need to study empathy, compassion, or taking the time to sit down and listen to patients, but surely when we propose sticking needles into people, this should pass an RCT test. It hadn't been done, until now.
A few caveats: There were important exclusion criteria to TAP-IT. Effusions that could have been due to other causes, such as cancer or infection were excluded. And there is still a role in “diagnostic” thoracentesis. Also, massive effusions, more than two thirds of the pleural space, were excluded, so the neutral results of TAP-IT should not be applied to these patients.
But my practice changes, today. No more routine upfront thoracentesis. Thanks to the team in Denmark.
One final comment: one of the most important first questions I like to ask when looking at a study manuscript is this: Was the study science or marketing? TAP-IT was clearly science. Now I will show you a marketing study.
STRIDE Trial
There aren't many great options for patients with claudication and diabetes. The drugs are old, modestly effective, and revascularization is a bad idea in most cases.
The company that makes the GLP-1 semaglutide had an idea: perhaps it would work for claudication in patients with diabetes. It's a decent idea, actually.
The problem is not the idea; it was how the idea was tested.
STRIDE investigators screened more than 1300 patients in numerous centers and countries, to enroll 790 in an RCT comparing semaglutide to placebo for the treatment of claudication.
Inclusion criteria were strict: Patients had to be able to walk pain-free for 200 m on a flat surface at a fixed speed of 3.2 km/h (2 mph) but also had to be symptom limited by 600 m and a fixed incline of 12%.
The chosen primary endpoint was the ratio to baseline of the maximum walking distance at week 52 measured by the constant load treadmill with fixed speed and fixed incline (as above). There were many secondary endpoints, including physical function questionnaires.
Patient were average age 68 years, 27% were female, and the median BMI was 28 kg/m2. About a third of patients were on SGLT-2 inhibitors.
The primary endpoint was positive for semaglutide. The estimated median ratio to baseline in maximum walking distance at week 52 was significantly greater in the semaglutide group than the placebo group.
The semaglutide arm had a 21% increase in maximum walking distance vs an 8% increase in the placebo arm. That is about 26 m or 87 ft more distance with semaglutide. Semaglutide also improved the pain-free walking distance (median of 14 meters extra). Quality-of-life scores improved more with semaglutide though the differences were modest. Participants in both treatment groups lost weight between baseline and week 52: There was a mean difference of 4.1 kg in the semaglutide vs placebo arm.
The authors concluded that semaglutide increased walking distance and called for more research on the mechanisms of benefit as well as further trials in patients without diabetes.
Comments
The two problems with STRIDE were a) unblinding of treatment arms and likely placebo effect and b) an extremely modest increase in exercise time.
It's nobody's fault but the GI symptoms and weight loss that comes with GLP-1 drugs leads to patients knowing their treatment assignment. Given the tiny improvements (meters) increase in exercise time, you could easily say this was placebo effect.
What I can fault the trial authors is why they did not do a blinding index or treatment guess questionnaire or some measure of blinding.
The second issue was that the increase in exercise time over placebo was modest and similar to cilostazol. Thus, it's hard to get excited about using a very expensive agent for claudication.
GLP-1 makers don't have a shortage of cash. They could design and conduct a more robust study. One that measures hard endpoints and quality of life as secondary endpoints. I have thought about the issue of blinding in placebo controlled GLP drugs. I have not come up with an easy answer.
The SUMMIT HF trial of tirzepatide in HFpEF also had a quality-of-life primary endpoint that was positive. But, again, there is the matter or placebo effect.
Perhaps we simply cannot rely on subjective endpoints for GLP-1a. Therefore, I don't think STRIDE rises to the level of expanding the indication for GLP-1 in PAD.
And…STRIDE is a good example of a trial destined to be positive by design.
FRESH UP
The next trial challenges yet another dogma in cardiology: fluid restriction in patients with HF.
Two years ago, Justin Ezekowitz presented and published results of the SODIUM HF, which busted the dogma of sodium restriction for HF.
This year at ACC, we learned results of the Dutch-led FRESH UP RCT, first author, Job Herrmann, which tested fluid restriction in HF
Nature Medicine published the paper. This was an investigator-initiated trial conducted in 7 Dutch sites.
The intervention was a 1500 mL/day fluid restriction vs standardized lifestyle advice. Any patient with Class 2 HF was eligible; there was no EF restriction. The primary endpoint was KCCQ at 3 months. The key secondary endpoint was thirst distress, which I did not know existed as an outcome measure.
There were 504 patients randomized. These were 67-year-old patients, two thirds male, and nearly 90% had Class 2 HF symptoms. About half had HFrEF and half had HFpEF. Importantly, the mean KCCQ was 77, which is pretty good at baseline—with minimal limitations.
Self-reported fluid intake was about 300 mL higher in the liberal intake arm — 1800 vs 1500.
The KCCQ-OSS after 3 months was 74.0 in the liberal fluid intake group versus 72.2 in the fluid restriction group, with a mean difference after adjustment for baseline scores of 2.17 (95%CI -0.06–4.39; P = .06).
The perceived thirst distress was lower in patients randomized to liberal fluid intake (TDS-HF: 16.9 vs 18.6, with a mean difference after adjustment for baseline scores of -2.29 (95% CI. 1.09–3.49; P < .001)
As for clinical outcomes, the trial was not powered to assess these. There were small numbers of events. And no substantial differences.
The authors discussed previous studies, of which there were a handful, but very small numbers and heterogenous populations. These small studies provided mixed results.
Comments
At first look, the mean difference of only 2 patients on the KCCQ is small. The scale goes from 0-100 and clinically important gains are around 5 points. The mean diff in FRESH UP is only 2.1 but the CI go from 0–4.4. Previous studies have found that when the mean difference is 2 there can be many patients who have > 5-point increase.
Yet they concede that since the result is nonsignificant, it would be inappropriate to state that liberal fluid intake leads to a higher health status. However, the observed difference does make it very unlikely that fluid restriction results in better health status. What's more, they argue that there was no signal of harm.
I like the study and effort to sort this out. But I don't think FRESH UP reaches the level of busting a dogma. For the following reasons.
They enrolled patients with very mild HF. Most with class 2 symptoms, very high KCCQ scores, and relatively young age.
Second issue, the difference in intake was minimal—only 300 cc. About one small bottle of water. You would not expect much difference in quality of life.
As for safety, there were very few events, as you'd expect in a trial enrolling a healthy group, so it is hard to conclude much.
In sum, I think we can say there was no worsening of quality of life; there was a trend to better QOL, and nothing bad happened in these mild HF patients who had liberal fluid intake.
You'd really want to repeat such a study in patients with a bit more HF, perhaps with a mildly low sodium level. These patients are often put on a strict, and I'll say miserable, fluid restriction. I wonder if it is necessary.
Nonetheless, limitations aside, congratulations to the authors.
More on the New Kid on the Block — PFA for AF ablation
Two studies came out recently looking at the value of PFA — pulsed field ablation. Even though this is an electrophysiology topic, it's worth talking about here on a general cardiology podcast.
I know PFA is a big deal, because nearly every week, I have a patient ask about it.
At the EHRA meeting, Dr. Tobias Reichlin presented results of the SINGLE SHOT CHAMPION trial. NEJM published the RCT comparing PFA ablation with cryoballoon for patients with AF.
It's important to set out that PFA is not one thing. Numerous companies are developing different PFA systems. Many but not all PFA systems include catheters that offer multipolar catheters that ablate large areas. This differs from point-to-point RF ablation w small-tipped catheter.
The system used in the trial was the Boston Scientific penta-spline system vs the standard old-school cryo-balloon (CB).
This was a relatively simple (and elegant) trial of 105 patients who had PFA vs 105 who had CB in two Swiss centers. These were expert ablators who had long experience with both systems—an important difference from some of the early regulatory trials of PFA, for instance ADVENT, where PFA was compared to thermal ablation, but the American operators were completely new to PFA.
Another important point with SINGLE SHOT CHAMPION was that it was investigator-initiated and controlled study. Boston gave funds but had no say in the trial procedures.
Mean age was 64 and mean CHADVASC score of 2. The primary endpoint was first recurrence of atrial tachyarrhythmia (AT) or atrial fibrillation (AF) between 90-365 days. So there was a blanking period for the primary endpoint. All patients had loop recorders.
Curiously they used a non-inferiority design and allowed a margin of 20 percentage points for primary endpoint. More on why I call this curious later.
Results
A recurrence of atrial tachyarrhythmia was observed in 39 patients in the PFA group and in 53 patients in the cryoablation group That is 37.1% and 50.7%, The between-group difference was −13.6 percentage points; 95% confidence interval, −26.9 to −0.3; P < .001 for non-inferiority, P = .046 for superiority)
The HR was 0.66 with CI from 0.43-1.01. I think the P for superiority right at 0.05, the threshold, relates to the upper bound hitting 1.
Since I have been on a kick lately to stop reporting blanking period, I will link again to my editorial co-authored with Drs. Foy and Ruzieh. The Swiss team did report results from day 1 after the procedure.
Here, PFA stood out even more. With a difference of -20% percentage points better on the time to recurrence, with CI ranging from -33 to -7%. That's because the PFA has far fewer recurrences in the blanking period. More on that later.
The mean AF burden in the two groups from day 1 to 365 was 1.6% vs 2.5%.
Procedure times were shorted with PFA (55 vs 73 minutes). Serious safety events were infrequent, but they did occur. One patient in the PFA had a stroke, and there were 2 patients who had tamponade leading to drainage in the CB arm.
Repeat ablation procedures were done in 16 patients in the PFA group and in 10 patients in the cryoablation group (rate ratio, 1.60; 95% CI, 0.76 to 3.37).
Comments
First, we have to congratulate the Swiss teams. They did the trial—on their own. They were curious and instead of reporting retrospective data, did a proper prospective trial. They got some funds for loop recorders but did the work on their own. In the science vs marketing dichotomy, this counts as science, in my opinion.
They asked an important question—that is, we really do want to nail down the efficacy of PFA. We should have more of this in the cardiology community. That is, people doing trials without much industry support.
This is also a better comparison than previous PFA vs thermal trials because a) all patients had loop recorders which make assessment of AF recurrence much more accurate than intermittent holters, and b) the operators were experienced in both PFA and CB.
On the results, I think it's fine to say PFA was non-inferiority to CB. I would be far less excited to say PFA was superior.
The majority of the benefit seems to occur in the blanking period. PFA has less recurrence. After 90 days the Kaplan-Meier (KM) curves for AF recurrence are parallel. This fits with prior PFA data, which seems to have less early recurrence. Some suggested future PFA trials could be shorter because there were so little differences after 3 months in the KM curves.
While time to AF recurrence was better with PFA, the better measure of AF burden was low in both groups and not substantially different — 1.6 vs 2.5%.
Here are few other reasons to be doubtful that this trial establishes superiority. The CB results in this trial are the lowest reported. The authors suggest that this was bad luck, as 1 in 5 patients in the CB had a common ostia left pulmonary vein (PV), which makes CB difficult.
Also, 2 of the CB patients had their implantable loop recorder (ILR) removed, and the data censored as an endpoint. It doesn't sound like a lot, but the margin for superiority was very close.
I am also curious why 6 more patients in the PFA arm had re-ablation? With better results in the PFA arm, you'd expect re-ablations would be less.
I am also curious about the decision to use non-inferiority. The indication for NI design is not super strong. Recall that for something to be tested for non-inferiority, you'd want the new treatment to be less expensive (not the case for PFA) or less invasive or convenient (not the case for PFA).
I bet the non-inferiority choice had to do with pragmatism. As, you'd have to have more patients to study superiority.
Overall, this trial shows results largely similar to ADVENT, which found PFA and thermal ablation performed quite similarly. The remaining questions I think are whether different PFA systems do better. The BSX system used in the trial is a first-generation device.
Different companies with different catheters and different electrical algorithms may be better. The answer of course is to it the Swiss way. Don't report retrospective nonrandom comparisons. Do prospective randomized trials.
A quick note on a PFA study I missed when it came out in January this year. It's relevant to the trial I just discussed. I can do it briefly.
First author Daniel Scherr, along with many big European operators reported 427 patients who had repeat ablation due to clinical recurrences after a PFA ablation with the Boston Scientific pentaspline system used in the SINGLE SHOT CHAMPION.
The key finding:
Only 45% of patients had all pulmonary veins durably isolated at the beginning of the repeat procedure — more than half had reconnection.
Use of mapping procedure was associated with durable pulmonary vein isolation (PVI). No one vein stood out as difficult. Recurrences were equally distributed among the 4 veins.
Also notable was similar durability of posterior wall (PW) isolation. 45% of patients who had PW isolation as part of the initial procedure had reconnection of the PW.
Comments
This data looks quite similar to thermal ablation. I was going to do FAME 3 five-year results, which made headlines because in the primary analysis of the CABG vs FFR-PCI trial, PCI did not even reach non-inferiority against CABG, but now, at 5 years, the headlines have PCI as catching up and being just as good as CABG. Well, I am not sure that is right. There was some serious nuance involved. I will have more on that next week.
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