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In This Week’s Podcast
For the week ending September 15, 2023, John Mandrola, MD comments on the following news and features stories.
Reader Feedback
I want to first address some nice reader feedback. Dr. Tim Balthazar, a cardiac intensivist, pushed back on my coverage of ECLS-SHOCK, which was venoarterial extracorporeal membrane oxygenation (VA ECMO) vs standard care and found no benefit and increased harm in the VA ECMO group. Dr. B made the point that ECLS did not recruit patients most likely too benefit. Specifically, that many resuscitated patients have a systemic inflammatory response (SIRS) -like syndrome and most often respond to IV fluids and not VA ECMO. Some of these points were made at the presentation at ESC.
My response is first to thank Dr. Balthazar for taking the time to listen and write. His point centers on patient selection. In short, they did not select the right patients for if they had the treatment may have worked. This is a common criticism of null trials. My general answer is that:
when we translate evidence, we must always consider for whom that evidence applies;
proponents of therapies shown ineffective bear the brunt of proof -- if, in the face of one or more nonsignificant trials, proponents believe something works, then the onus is on the proponents to show it does pass muster in a trial.
Dr. Evan Schreyer also took issue with my commentary on ECLS-Shock. Dr. S wrote:
“I believe you may have over-extrapolated by saying that all mechanical support may not work in MI related cardiogenic shock.”
He then described some of the weaknesses of VA ECMO relative to other forms of mechanical support.
My response is that I am not exactly sure what I said, but what I wrote in the script (which I don’t always follow exactly) was this:
“I also think [ECLS-SHOCK] puts a serious damper on mechanical support of any sort. Though we await the Impella trials before making any judgements based on observational data.”
One of the more important Impella in cardiogenic shock (CS) trials is called DanGerShock, which the authors write will be properly powered.
Another note to Evan – I hope all is well at Hartford Hospital. As a UCONN medical student I have fond memories of rotating there.
Final feedback: Dr. Aslannif Roslan inquired about my thoughts on chronic total occlusion percutaneous coronary intervention (CTO-PCI). I refer listeners to my coverage of a flawed meta-analysis on the August 11, 2023 podcast. I also wrote commentary on the first CTO-PCI trial called DECISION CTO in 2017. The link is in the notes. The short story is that CTO -PCI needs a lot more data.
Imaging in the Cath Lab
Two big trials, presented at the ESC meeting and published in the New England Journal of Medicine (NEJM), addressed the use of imaging to place stents in the cath lab.
I cover this as a neutral Martian looking at the data. There are corollaries in electrophysiology (EP), as we have a number of costly add-on tools to use in our labs that the profit-driven companies say will improve our procedural success.
One laudable fact that is that, at least in interventional cardiology, they are putting these add-on tools to the test of the randomized controlled trial (RCT). Good on them.
Brief background: PCI has come a long way from the days of the plain old balloon angioplasty. Stents have iterated a lot. But another way to improve PCI results is not just in the actual stent, but its placement in the coronary arteries, which are far from inert tubes.
The goal of imaging, and in the case of the OCTOBER and ILUMIEN IV trials, optical coherence tomography (OCT), is to better place the stent and this should lead to better clinical outcomes.
You know, like the use of intracardiac ultrasound should lead to better AF ablation outcomes.
ILUMIEN IV randomly assigned nearly 2500 patients who had diabetes or complex coronary lesions to PCI guided by OCT or plain old angiography.
There were too primary endpoints — one imaging (a surrogate) and one clinical.
The surrogate endpoint was minimum stent area, measured in millimeters.
The clinical endpoint was a composite called target-vessel failure at 2 years. This includes important things like cardiovascular (CV) death, myocardial infarction (MI) in the stented vessel, or revascularization due to ischemia in the treated vessel.
The first primary endpoint favored the OCT arm. Minimum Stent area was 0.36 mm2 more in the OCT arm. That was highly statistically significant.
The clinical endpoint however was not different statistically. Target-vessel failure within 2 years occurred in 88 patients (7.4%) in the OCT group and 99 patients (8.2%) in the angiography group; hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.67 to 1.19; P = 0.45.
OCT related events were not different.
One notable observation: Stent thrombosis within 2 years occurred in six patients (0.5%) in the OCT group and in 17 patients (1.4%) in the angiography group. The P-value listed is 0.02. but it’s one of many endpoints.
These are small numbers of events, and it could be statistical noise, but stent thrombosis is the most feared complication of PCI, because you go from 0% obstruction to 100% obstruction and patients do badly with this. Think MI and sudden death.
OCTOBER randomly assigned 1200 patients who had a complex bifurcation lesion to OCT-guided PCI vs angiography alone.
They had only one primary endpoint – major adverse cardiac events (MACE) defined as a composite of CV death, target lesion MI, or revascularization due to ischemia at 2 years.
The results favored OCT. At 2 years, 10.1% of pts in the OCT arm had a primary outcome vs 14.1% in the angiography alone arm. HR 0.70; CI ranged from 0.50-0.98. And the P-value snuck in at 0.035.
All components of the primary outcome contributed. And definite or probable stent thrombosis here were low and similar in both arms.
Procedure-related complications were 6.8% vs 5.7%, so 1.1% higher in the OCT arm.
Steve Stiles covered these sessions. His report is excellent. He also covered a network meta-analysis that was presented at the session.
The meta-analysis presented by Dr Gregg Stone included ILUMIEN-4, OCTOBER, and 18 earlier outcomes trials comparing PCI guided by intravascular imaging (IVI), either OCT or IV ultrasound, and angiography-only PCI.
It covered 12,428 patients with chronic or acute coronary disease and followed them a mean of 26 months; the longest follow-up was 5 years. They were assigned to IVI-guided or angiography-only PCI, with 7038 and 5390 patients, respectively.
I have not seen a publication of this yet, so I will keep the report brief. In general, image-guided PCI did better on major clinical outcomes. Especially stent thrombosis.
Comments. Steve covered the debate in his piece. That is, proponents of imaging, specifically, OCT, think it should be used more often. They believe the extra costs — contrast, x-ray exposure, and maybe slight increase in risk — justify its use.
I say, at least there is data to debate. Unlike in EP.
OCTOBER finds a clear signal of better outcomes. ILUMIEN IV did not. I discount ILUMIEN’s imaging primary endpoint as a surrogate.
Both trials list as limitations that you cannot control for performance bias. Inteventional cardiologists are not blinded. Many may be proponents of OCT. They may use super-extra caution in the OCT arm. But they also may be super cautious in the control arm.
The positive OCTOBER trial has a whopper of a limitation. “Patient eligibility was verified by on-site investigators and not by a centralized core laboratory” That should alert you to the possibility of selection bias, meaning doctors including or excluding patients based not on randomization but other specific characteristics.
In sum, I am not sure the imaging data are strong enough to warrant solid recommendations in the guidelines, because this could lead to a change in the standard of care. And if you don’t use imaging and the patient has a bad outcome, you are liable.
However, there surely seems enough signal in these trials to warrant use of imaging in difficult lesions.
How about this: we rely on super-skilled operators to choose the most effective and safest way to perform PCI. In an ideal world, such things as cost constraints would not affect these decisions. It would only be about outcomes. But we do not live in this ideal world.
I would also add the caveat that I trust these patients undergoing PCI are not patients with stable coronary artery disease who could have been as well treated with optimal medical therapy.
Final comment: I’d love to see the EP community do a similar study looking at hard outcomes of intracardiac echocardiography (ICE) for AF ablation. I wonder what the results would be? In many cost-constrained systems, ICE imaging is not used. In the United States, it has become the standard of care, and if you don’t do it, and a bad outcome occurs, you can be sure an American colleague will testify against in a malpractice suit.
REMEDIAL
The crazy thing about atrial fibrillation (AF) is that it causes so many different kinds of symptoms. Some patients have no symptoms. Some can be totally disabled. Those with heart failure may decompensate rapidly. Most patients are somewhere in the middle between zero symptoms and disabled.
But it gets even more complicated than that. Because AF not only reduces cardiac output, induces funny sensations in the chest, and reduces vigor, that pesky rhythm can also mess with your psyche.
I know this firsthand. Even as an electrophysiologist, AF messed with my head. I was anxious and down. Had you formally assessed my anxiety and depression scores during the year or so I had AF, I would have scored poorly. And I see this often in the AF clinic. Multiple times per day I tell patients that I am a cardiologist but I am also a psychologist.
EP docs who care for patients with AF spend oodles of time reassuring, educating and counseling patients. The take-home of all this is that we will help them.
The psychologic disruptions of AF are underplayed in cardiology circles. Good health is surely more than physical things like your heart rhythm.
A group of famous researchers from Australia decided to formally study the psychological aspects of AF, including the effects of ablation.
Empirical study is something I always favor. Sadly, though, their study, called REMEDIAL, and published in JAMA, could not answer the question.
In REMEDIAL, which was done at two centers in Australia, 100 patients with symptomatic AF were randomly assigned to have AF ablation or take antiarrhythmic drugs (AADs).
The primary outcome was scores on the Hospital Anxiety and Depression Scale (HADS) at 12 months. This is a validated multi-question assessment.
Pause there for a moment. Stop and think. REMEDIAL will measure a subjective endpoint. One group gets an invasive procedure. One group does not.
The combined HADS score was lower in the ablation group vs the medical group at 6 months and at 12 months. The between group differences were highly statistically significant.
Other secondary measures that measured psychological distress also favored ablation. And, of course, as has been shown in many studies, AF ablation reduced the amount of AF episodes vs AAD.
The median AF burden in the ablation arm vs AAD was 0% vs 15%.
The authors conclusion:
In this trial of participants with symptomatic AF, improvement in psychological symptoms of anxiety and depression was observed with catheter ablation, but not medical therapy.
Their first two sentences in the Limitations section:
First, participants were not blinded to treatment assignment. Therefore, the possibility of a differential procedure-related placebo effect on study outcomes could not be ruled out. A larger multicenter study with a sham group would more completely answer this question and further clarify the mechanisms associated with the improvement in mental health.
Comments. I think the world of these researchers. They are some of the smartest people in our field. They have done practice-changing research. But this is not that. I agree 100% with their limitation statement in saying you need a sham group.
The only way to assess a subjective endpoint, such as anxiety or depression, is with a proper control, and that would mean a true sham procedure.
I’ve spent many hours delving into the literature on placebos and nocebos. Something as simple as the color of a pill can affect subjective outcomes. Clearly an invasive procedure puts out a much larger caring signal than pills. This is faith healing and subtraction anxiety on steroids.
What’s more, having done AF ablation now for 20 years, I can tell you of many cases of people who still have the same amount of AF — -sometimes more AF— after ablation, who have much better psychological health.
What’s surprising to me is that the accompanying editorial did not mention this major limitation.
In the care of patients with AF, attention to mental well-being is critically important. AF doctors must be teachers and psychologists. Addressing the anxiety and depression that often comes with AF is a core tenet of what we do.
Catheter ablation has its role. While I remain highly suspicious of quality of life data post ablation, I do AF ablation regularly because I believe it has a some amount of placebo-resistant effect. What that percentage is remains a mystery. I also do cardiac resynchronization therapy, and I would have thought the placebo-resistant effect would have been much larger than 16%, as shown by a extremely well done meta-analysis by Afzal Sohaib and Darrel Francis.
Finally, I worry a lot about the overuse of AF ablation. Positive media coverage of this paper, its publication in JAMA, could only worsen that. Relief of anxiety and depression is important. If we want to say ablation does that, we need a proper comparison and control arm. Procedure vs meds is not that.
New Anti-hypertensive Drugs
This will be brief because it was a phase 2 dose-finding study. Phase 3 trials studying clinical outcomes are what I usually cover on TWIC. But JAMA’s publication of the TARGET-HTN RCT deserves mention because a) hypertension (HTN) is a huge problem, b) it studies a novel drug that blocks aldosterone synthesis.
A couple of notes on aldosterone.
I often refer to spironolactone as my secret weapon for heart failure with preserved ejection fraction (HFpEF) and HTN.
The role of high levels of aldosterone in HTN, especially resistant HTN and HTN in obesity, is underappreciated.
Back in the 1990s when I started, I remember a Monday encounter with one of my senior partners. Dr. Richard Allen, who we called the general, because he was group leader. Allen took me aside and said John, that older lady with tough BPs and vascular congestion that you all were struggling with. You should have started her on a mineralocorticoid receptor antagonist (MRA). From then on, I never forget to think about spironolactone.
Well, TARGET HTN studied perhaps a better way to deal with aldosterone’s role in HTN. Instead of blocking the mineralocorticoid receptor, the drug lorundrostat inhibits aldosterone synthase.
The drug looked promising. In patients with HTN despite two background BP meds, the mean reductions in systolic BP were in the range of 10 mmHg.
A handful of patients had potassium levels above 6 mmol/L.
The conclusion is that lorundrostat looks promising enough to move on to phase 3 trials. A news column on theHeart.org|Medscape Cardiology from Megan Brooks also tells of another promising aldosterone synthase inhibitor called baxdrostat.
Both agents are a good way from clinical use, but both look to have larger BP reductions than the sadly modest and short-term drops seen with renal denervation.
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