Mar 28, 2025 This Week in Cardiology Podcast

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In This Week’s Podcast

For the week ending March 28, 2025, John Mandrola, MD, comments on the following topics: Stopping oral anticoagulation after AF ablation, the core problem with paradoxes like the smoker’s paradox, chronic total occlusion PCI, and an ACC/EHRA preview.

OAC After AF Ablation

A listener left me a comment and suggested I look at a study of stopping oral anticoagulation (OAC) after successful atrial fibrillation (AF) ablation. I had passed on the study earlier, but I have thought more about it and I will make some brief remarks today.

The reason to mention the issue of OAC after AF ablation is that it is one of the most difficult questions in all of EP today. Think about it: we use OAC when patients have AF and risk factors. Strong evidence backs this decision.

Then we do ablation and the patient no longer has AF, or more precisely, they no longer have AF symptoms. Knowing whether post-ablation patients have AF is another matter, because a not-small number of patients still have AF but post-ablation, they no longer feel AF. It’s weird; but ablation can reduce or eliminate symptoms from AF.

The advent of watches and mobile ECG devices has lessened the problem of detecting AF.  But still, correlation of AF episodes and symptoms after ablation is imperfect.

Yet the OAC decision after ablation is not as simple as the presence or absence of AF. When you ablate in the left atrium (LA), especially when you do more than just pulmonary vein isolation, there is a possibility of creating a prothrombotic state—from LA scar.

Recommendations now for OAC after ablation is use the CHADSVASC. If a pt was AC eligible before the procedure, then you should continue the OAC post-procedure. But that is a pure expert opinion. There is no data. And it seems crazy to continue OAC for years, decades even in someone you have ablated and has AF no more.

Well, JAMA Network Open has published an attempt at creating evidence to inform this decision. Japanese authors performed an observational retrospective cohort study — 1800 patients without AF after an ablation from a single center.

The authors made two groups: those who had OAC continued and those who had it stopped. This was up to the discretion of a clinician. AF was excluded by holter monitors and intermittent ECGs, not loop monitors.

The primary outcomes were stroke/systemic embolism and major bleeding.

As it turned out, about half had OAC continued, and the other half had it stopped.

There were substantial differences in baseline characteristics. OAC stopping group was younger, had more paroxysmal AF vs persistent AF, more symptoms and a lower CHA₂DS₂VASc, for instance. Conversely, the OAC continuation group had considerably higher rates of warfarin use, antiplatelet drug use, and medications for heart failure than the discontinuation group.

You know what happens next. The authors had to do adjustments to try and balance these baseline differences. They used an inverse probability of treatment-weighting technique. They also did propensity matching as well. More on this later.

They found that, after adjustment, the OAC discontinuation group had a significantly higher incidence of thromboembolism and lower rate of major bleeding.

The incidence rates were very low, which is the problem with studying this question, by the way.

For stroke events, it was 0.86 events per 100 person-years in the discontinued group vs 0.37 events per 100 person-years in the OAC continued group. That difference had a P value of 0.04.

It was the opposite for major bleeding. In the OAC continuation vs discontinuation arm it was 0.65 vs 0.10 events per 100 person-years. That P value was stronger at < 0.001.

The subgroups were kind of interesting. After adjustment, there was a very significant interaction in the rate of clotting events between symptomatic and asymptomatic AF. In patients with symptomatic AF the hazard ratio (HR) for discontinuation was 0.64 but confidence interval (CI) ranged from 0.25-1.64. Basically, wide and non-informative. However, the HR for discontinuation in patients with asymptomatic AF was 6x with CI that went from 2.5 to 15. That P for interaction was super low. An interaction p-value was also less than 0.05 also for left ventricular ejection fraction (LVEF) and LA dilatation and no LA dilatation.

Another interesting observation was that when they used propensity matching in 1100 of the 1800 patients, they found no difference in thrombo-embolic events between the OAC continuation vs discontinuation groups. They did find lower rates of major bleeding in the discontinuation arm w PS matching. They also found an interaction in propensity matching for symptomatic vs asymptomatic AF, LVEF, and LA dilatation.

The authors made the normal conclusions, restating the associations and the notable subgroups. They said they await future RCTs.

Comments

I am glad that Dr Denis Hart pushed me to look more closely at this study. I think the team of authors did a nice job. We learned some things.

One is that the rate of thromboembolic events in patients with purported successful ablation is very low. Less than one per 100-person years. Essentially less than 1% no matter the decision. The mean CHA₂DS₂VASc score in this study was low at 1.45. These were also not obese patients – BMI was 24 on average. Less than half had hypertension, only 10% had diabetes.

While the P value in the inverse probability of treatment-weighting (IPTW) group made significance for OAC continuation, it did not differ in the propensity matched group and even if it did, the absolute difference was tiny—less than 1%.

Lesson number 1: in relatively low risk patients without AF after ablation, the rates of thromboembolism are very low no matter the decision on OAC.

Lesson 2: When you stop OAC, rates of major bleeding decline.

We can move to Lesson 3: in the subgroup of asymptomatic AF, or those with impaired EF or large LA, there may be more risk with OAC discontinuation.

Due to the nonrandom nature of these comparisons, despite the matching there is no way to make clinical decision based on this data. Obviously, the baseline differences in these two groups were massive and confounding biases are likely.

But the three lessons stand out. And it makes me worry about the all-important OCEAN trial, which is scheduled to finish this year. OCEAN is going to be huge. An RCT comparing 15 mg rivaroxaban vs aspirin in patients with successful AF ablation. The primary outcome is a composite of stroke, systemic embolism, or covert stroke detected on MRI. Major bleeding will be a secondary outcome.

On the surface, having an RCT for this question is going to be great. And good on Atul Verma and colleagues for doing it. The challenge I think will come in interpretation. They estimate an annual primary outcome event of 3.5% and they are powering the trial for a 40% relative risk reduction w rivaroxaban.

This observational study, with its event rates well below 1%, makes we worry that OCEAN will be way underpowered for its primary outcome. And if that happens, we will have a non-informative primary outcome and likely higher rates of bleeding in the rivaroxaban arm, though that is not 100% guaranteed because recall that a-ban and asa had similar rates of bleeding in AVERROES.

One hope is that OCEAN will enroll much sicker patients than the Japanese study. Another hope is that we might see subgroup effects in OCEAN, like we did in this paper.

But, still, we are talking about patients with successful AF ablation. They will likely have low, low, low stroke event rates. The confusion could come in people saying, oh well, in OCEAN there was no significant difference in stroke and more bleeding, so let’s stop the OAC after ablation. That would be an incorrect interpretation if the confidence intervals of the primary are wide.

I am quite surprised we learned this much from an observational non-random comparison study.

Smoking Paradox

JACC Interventions has a paper, first author, Antonia Presch, looking at smoking status and 10-year outcomes after drug-eluting stent (DES) using something called the DECADE cooperation wherein individual patient data from 5 trials can be pooled. These were all trials testing different stents and stent techniques.

The point of this paper was to look at outcomes based on baseline smoking status. You might ask why do such a thing? We already know smoking is one of the most important risks for poor outcomes. We don’t need any more data.

Well, little did I know, the cardiovascular literature is full of papers purporting a smoker’s paradox, first reported in 1968 and perpetuated by numerous observational studies that compare outcomes of smokers and nonsmokers who present with myocardial infarction (MI).

One such "paradox" paper is Gupta et al, from Journal of the American Heart Association in 2016, which I will link to. They used an Inpatient sample database to look at nearly a million patients who presented with STEMI and had PCI. They compared outcomes based on smoking status and lo and behold, smokers had a 68% lower inpatient mortality then non-smokers. After adjustment it was still 40% better than non-smokers. The title of their paper was "Smoker’s Paradox in Patients with STEMI undergoing PCI."

I could cite oodles of these sorts of papers. There are also similar papers for obesity in HF, which gets called the obesity paradox. Let’s come back later to why this is utterly wrong. For now, let’s go to the DECADE cooperation meta-review of 5 trials with 10-year follow-up to see what smoking status reveals.

Presch et al report that after adjustment, smoking was bad. A 45% higher risk of death, 59% higher risk of CVD, a 60% higher rate of MI, and a doubling of the risk of stent thrombosis.

All of this, despite the fact that patients in the smoking group were 10 years younger and presented more often with less complex disease at the time of primary PCI.

Comments

These results are obvious. Everyone knows smoking is bad and confers a bad CV prognosis. I highlight the study because it shows how silly the idea is of the smoker's paradox. Or the obesity paradox, for that matter.

Here is the clue, and once I show it to you, I hope you won’t be able to unsee it. The papers that purport to show a smoker’s paradox have one thing in common. They look only at patients having a STEMI who had PCI.

Now think of causal pathways. Smoking causes MI (exposure causes disease). Age strongly causes MI (confounder which causes a disease). Age also causes death (confounder causes outcome).

The study from JAHA by Gupta et al includes only people who have a STEMI. They condition on the collider. STEMI is the collider because multiple causal pathways lead to it. (Age, other risk factors besides smoking)

The artificial relationship leading to smokers having lower in-hospital mortality stems from the fact that smokers having an MI are younger and less likely to have other risk factors. They often have less complex CAD.

Nonsmokers who have an MI are likely sicker and have other factors which lead to higher mortality.

Therefore, when you compare the two outcomes over the short-term you get a false impression where smokers appear to have better outcomes. Evidence for this comes in the fact that adjustment for simple things like age lessened the risk, from 60% better for smokers to 40% better.

The classic example of collider bias is the birth weight paradox. Among all infants, maternal smoking during pregnancy is associated with increased infant mortality (as expected). But when analyses are restricted to only low-birth-weight babies, maternal smoking appears to be associated with decreased infant mortality.

Why? Maternal smoking causes low birth weight. Congenital abnormalities and other really bad things also cause low birth weight. When you only look at low-birth-weight babies, you see that maternal smoking seems protective, because the non-maternal smokers who have low-birth-weight babies have much worse problems.

The reason why the JACC-IV paper does not show the paradox is most likely due to the fact that there was long-term follow-up as time allows smoking risk to accumulate.

Final Comment

Beware of "paradoxes" where something is known to be bad, like smoking or obesity, associates with better outcomes. They don’t exist, or at least I have not found one.

The most remarkable thing about these paradoxes is how often published papers purport to find them. I searched and found well more than 200 studies for the obesity paradox. It’s crazy.

There was even a smoker’s paradox noted for COVID-19 pneumonia wherein smokers seemed to do better. Of course, this too, was collider bias wherein when you compared only patients with pneumonia, smokers had fewer risk factors for death than non-smokers who had infection.

Chronic Total Occlusion PCI

Ischemia investigators have published in JACC a subanalysis of the ISCHEMIA trial. ISCHEMIA was an RCT of an invasive vs conservative strategy of patients with moderate-to-severe ischemia on stress testing. The current subanalysis studied patients with a chronic total occlusion, or CTO.

It’s an important question because to be a so-called CHIP operator, (complex, high-risk, indicated procedure) one should be able to do a CTO. CTO is pretty common. Technology has improved. Opening these lesions is increasingly possible.

Background

When I speak to patients about CTO, they often have trouble understanding how they are alive and have an occluded vessel? Of course, we understand that collaterals often grow and provide blood to that area.

The indication to open chronic total occlusions can be a) symptoms or b) a large area of ischemia — both due to inadequate collateral flow. I also think some doctors think doing so might improve ventricular function.

Here is the problem with CTO intervention: the evidentiary support is not only weak, but nearly nonexistent. In 2019, the DECISION-CTO trial studied PCI or no-PCI of CTO in more than 800 patients. There were nearly identical rates of major adverse cardiovascular events (MACE). Absolutely no difference. Three patients had serious complications from the procedure. In 2023, the smaller (n = 380 patients) the 3-year follow-up of the EURO CTO trial of PCI vs optimal medical therapy (OMT) of patients with CTO found no significant difference in CV death or MI. And in 2016, the even smaller EXPLORE trial of STEMI patients with a non-infarct CTO vs non CTO PCI found no difference in LVEF in follow-up.

As for symptomatic improvement from CTO PCI, perhaps the strongest evidence came from the main results of the EURO CTO trial. In 2018, in the European Heart Journal, the authors reported that PCI vs OMT led to an improvement in angina frequency, quality of life and physical functioning. However, as you all know, from the ORBITA trial, unblinded PCI trials that measure subjective measures are fraught. One group gets a big procedure and one group gets tablets. That’s not an ideal comparison because of placebo effects.

The ISCHEMIA Trial Substudy

About 3000 of the 5000 total patients had cardiac computed tomography-available (CCTA) studies. Recall that CCTA was used in ISCHEMIA to screen for left main disease and no CAD. Recall also that CCTA is not ideal for identifying total occlusions. Sometimes the CTA shows the a total occlusion but it is a subtotal occlusion which would make PCI seem better.

Of these 3000, nearly half had at least one CTO. 750 in the invasive arm and 718 in the conservative arm. The first data point is that patients with a CTO compared with no-CTO group were sicker; they had higher rates of CVD or MI, CVD and death. However, in the CTO patients, the invasive vs conservative strategies did not reduce outcomes.

• The composite of CVD or MI – no difference

• CV death – no difference

• All-cause death – no difference

• There were more procedural MIs in the invasive arm and more non-procedural MIs in the conservative arm, but total MIs were no different. (One note here, I suspect, that CTO-related procedural MIs are more serious than procedural MIs in regular, high-grade stenosis. I say this because if you cause an MI from trying to open a CTO, you may have harmed another vessel whereas a procedural MI from a standard lesion could just be a troponin leak from debris. This is only a Mandrola theory, though.

The authors also did an analysis of the 3000 patients with available CCTA scans and looked at outcomes based on the presence or absence of a CTO (This is like a subgroup analysis of the main trial). Here, CTO status had no significant effect on any of the MACE outcomes.

The authors then did something curious: they took the 137 patients who had successful revascularization with PCI and 216 with coronary artery bypass grafting (CABG) and did a Bayesian analysis of outcomes in those who had a successful CTO revascularization. And, with absolutely no surprise, those who had successful CTO revascularization vs the conservative had lower rates of all outcomes. But they did have a higher rate of procedural MI. Now the probability difference in all-cause death was low, but CV death was lower, MI was lower, unstable angina was lower.

I will talk more about this in the comments, but I want to interject how problematic such an analysis is. You can’t compare only patients who had a good outcome with the invasive approach to the conservative patients. That’s not how medical practice works. You don’t know before you start if you are going to be successful. What doctors want to know is whether having a CTO makes the invasive arm better than conservative arm.

The authors also did a QOL assessment and of course the invasive arm does better when there is a CTO. They also did an analysis of those with successful CTO revascularization and again these patients felt better.

Comments

I think this is a worthy area to look into. The presence of a CTO definitely indicates a higher-risk patient with more severe coronary artery disease (CAD). As evidenced by the higher rates of events vs the no-CTO patients.

So, it is conceivable that an invasive approach might be better.

But that was not shown. And the fact that an invasive approach did not lower outcomes is similar to previous data. Like, for instance, the many substudies of COURAGE and ISCHEMIA, which all found results similar to the main study — no benefit of adding PCI (in Courage) or the invasive arm (in ISCHEMIA). I would also add that the REVIVED BCIS trial of severe ischemic CM found no benefit of PCI vs medical therapy, which is remarkable because these patients had severe CAD and LV dysfunction. REVIVED authors have also searched for subgroups of patients with more severe disease who might benefit and again, they have not found any degree of severity that renders revascularization better.

The findings of this study strengthen the idea that no matter the degree of CAD, absent left main disease, if the CAD is stable, medical therapy initially is the best choice.

As for CTO PCI, I would not be distracted by the authors’ emphasis on reduction in spontaneous MI. Why? Because total MI was not reduced and no other outcomes were reduced with the invasive approach, and surely, we should not put much weight looking only at successful CTO procedures. That is a totally utterly unfair comparison because medical care does not have the benefit of knowing the future. I am surprised the authors added it.

Overall, I remain really worried about CTO procedures. I cannot find a shred of evidence that this invasive, potentially risky and costly procedure benefits patients in terms of outcomes.  But like many procedures with weak evidence, there may be a small subset of patients who benefit, but that is where trials come in.

There is an ongoing big trial now called ISCHEMIA-CTO but is not expected to report for 7 more years. Imagine how many of these procedures will be done in the interim.

Editorialists tell us that there are two ongoing sham-controlled CTO trials, which are also super relevant because to date, the only evidence to support CTO PCI is quality of life.

ACC and EHRA Preview

• Mandrola’s 5 Trials to Look for at the 2025 American College of Cardiology Scientific Sessions

I wrote a column on 5 picks of mine for trials to look for at ACC. WARRIOR will study intensive medical therapy for ischemia and no obstructive coronary artery disease, or INOCA, in women. Good on the authors and NIH for funding such a study. This is what we need more of from NIH. Money well spent.

I felt like the STRIDE trial of GLP1 agonists in peripheral artery disease (PAD) is a marketing trial designed to carve out another niche for an expensive drug. My colleague Pavel Osmancik spent years doing PRAGUE-25 trial comparing AF ablation to intensive weight loss. I bet ablation wins, but maybe not.

PROTECT TAVI will be yet another test for embolic stroke prevention during TAVI. Sadly, this trial is likely to be underpowered.

Speaking of marketing vs science. The DAPA-TAVI trial will compare dapa to placebo after TAVI. The thing about this trial that makes me think of marketing is that you could test the same question for any cardiac procedure. That is, take a procedure and then add an SGLT2 inhibitor vs placebo after a procedure and you will likely get fewer HHF, because SGLT2 inhibitors are diuretics after all. We will see what it shows, but it’s likely to be driven only by HHF. One big question will be if the investigators tell us about all-cause hospitalizations.

The European Heart Rhythm Association (EHRA) meeting is in Vienna. There will be lots of news about the hot new kid on the block— pulsed field ablation (PFA). A Swiss led team will report on a PFA vs cryo-balloon trial. I will report after all that I learn about PFA. I actually have to give a contra-debate lecture arguing against PFA, but I have not done a thermal AF ablation in like 8 months. I am a PFA evangelist, but I think I can put together a lecture on why we need to be careful with new AF technology.

Finally, I will say it again: ACC and EHRA people, get together. Let’s get these meetings on different weeks.