Sep 04 2026 This Week in Cardiology

0:00You're listening to this week in Cardiology from the Heart.org MedScape Cardiology. This podcast is intended for healthcare professionals only. Any views expressed are the presenters' own and do not necessarily reflect the views of WebMD or MedScape. When every decision matters, you need trusted medical intelligence. MedScape AI synthesizes peer-reviewed evidence and MedScape's expert validated content in seconds, delivering clinically verified answers you can trust. Even over 13 million MedScape members on the world's leading platform for clinicians start using MedScape AI on the web or in the MedScape app. MedScape AI trusted medical intelligence. Hi everyone, this is John Mandrola from the Heart.org MedScape Cardiology. And this is this week in Cardiology for September 4th, 2026. This week is the first of many ESC recap shows. I'll do the single AF trial, CMR guide trial, two ATTR cardiomyopathy studies, PVI

1:06sham AF, STARI, and I think an important observational study of ICD benefit over the past decades. First of all, it was great to see so many listeners. I met someone, my first person from Russia that I've ever met, and that was cool. Second, thank you times 1000 for listening and coming up to say hello. It means a lot to me. Third, I am so impressed by ESC. While the US meetings get smaller, the ESC just gets bigger and bigger. Just have to say, wow. And finally, this podcast will be a little bit longer than normal, and it is only going to be a fraction of what I will cover from ESC. So stay tuned in the coming weeks. And if you happen to be in Geshive Poland this weekend, come to the PQRST Congress. I am presenting on PFA and the Pendage Closure this coming Saturday. Okay, I'll start with a single AF trial to anti-quagulate or not an intermediate risk AF.

2:07And that's the question of this trial. And the question of anti-quagulation in patients with AFib who have one risk factor is one of the toughest in EP. Men with a Chads Vascore of 1 or females with a Chads Vasc 2, they have a pretty low yearly stroke risk. And of course, the net benefit of anti-quagulation turns on stroke risk, being at a level that the 60th percent reduction in ischemic stroke is more than the bleeding rate increase with anti-quagulants. Now I realize that guidelines say treat these patients with anti-quagulation. But that evidence was mostly obtained in higher risk patients. I would also add that most of these one stroke risk people are younger. So if you start an equagulation in a 50 or 60 year old, you're having to continue it for a long, long time. So it's a big decision. Single AF was conducted in South Korea and it was a pretty simple trial. Doe Act versus No Antequagulation in about 1800 patients, mean age 60, 76 percent male,

3:09and three quarters of these patients had paroxysmal AF. The primary outcome was a big composite of stroke systemic embolism, major bleeding, and CV death. And the results. After approximately two years of follow-up, the primary endpoint occurred in only four of 901 patients. That 0.5 percent in the Doe Act arm versus 13 patients of 902, 1.5 percent in the No Doe Act arm. That absolute risk difference was minus 1.0 percent. And the conference intervals were such that the p-value was 0.03. Stroke events drove the difference. It was three versus 10 events. Major bleeding was rare in both groups. Three versus four patients. Now I wrote about this trial. Now I'll link to my column. It's a technically positive trial, statistically significant p-value less than 0.05. The first message I see is that these patients have a very low risk of stroke. It actually calculates to 0.55 percent in the control arm per year.

4:14That 0.1 percent in the Doe Act arm is very low, especially since a third of these patients had persistent AFib. Daniel bleeding rates in the Doe Act arm were also similarly low. So therefore, doing nothing incurs little risk. And anti-coagulation also incurs little harm. Indeed, this is the main problem, I think, with translating this trial in the clinic. Namely, when we apply evidence, we ask, is the effect size clinically important? And is it statistically robust? And neither are really true here. They had three versus 10 strokes in 1,800 patients. And that could have been noise, of course. You can calculate a fragility index and a number of events occurring in the other arm that could turn the positive p-value to non-significant is either one to two events. So it's a very fragile result. Another complicating factor for translating this evidence is we now know, but we did

5:16not know when the trial was started, that short duration intermittent AFib also confers a low stroke risk. The NOAA and Artigia trials both were randomized patients with subclinical AF. It's AF of a couple of hours to dole acroplocivo or aspirin in the Artigia trial. Both trials found that anti-coagulation did indeed lower the stroke risk, but it also increased the major bleeding by similar amounts. Notably, these trials enrolled patients with a chads mask of around four, yet stroke rates were about 1% per year. Now this leads me to consider two possible patients who could have been in single AF, but might have different approaches. Consider for a second a 50-year-old with hypertension in a little bit of AFib on her smartwatch that's symptomatic. This patient would do well on or off endic coagulation. The best strategy actually might be for her to use these alerts as a stimulus to improve her lifestyle, so as to normalize blood pressure and then remove that risk factor and likely

6:20reduce or eliminate RA-5. But on the other hand, consider a 64-year-old person with an upcoming birthday to age 65 who has serious insulin-dependent diabetes and persistent AFib. This patient would likely have a higher stroke risk and would benefit from oral endic coagulation. So I think within single AF, there are some subtle nuance for most patients in this trial. I think the results are truly the type that can be shared with patients. But I think maximizers will want the anti-coagulation. Minimizers may look at that 0.4% risk reduction and they might put pill-dissuitility higher than the stroke reduction and not take them at all. Overall, I think this is a great trial because now there is contemporary data where there was once little data. The small effect size and statistical fragility allow for people to choose, and in most cases, there's no obvious correct answer. And I think this is a problem with modern cardiology, isn't it? We are so good at treating people that have serious illness, but when we try and treat healthier

7:24and healthier people, the gains are going to be smaller. All right, speaking of small gains, let's talk about SCAR as an ICD risk stratifier. JAMA has published the CMR Guide trial which asked the question of whether a patient with mild to moderate left and trigger dysfunction, that is 36-50%, and substantial SCAR on a CMR scan will benefit from a primary prevention ICD. This is such a timely and relevant question. For three reasons, right? A, most people who have sudden cardiac death don't have an EF less than 35%, which is the current ICD eligibility threshold. B, most people in whom we place an ICD for low EF never have sudden cardiac death and therefore they get no benefit from it. And we know that the incidence of sudden death as a proportion of cause of death in people with heart failure is decreasing. And I'm going to discuss an important observational study from the ESC meaning that addresses the

8:26declining incidence of sudden death. Now we know that SCAR is a rhythmic and recall the three criteria for reentry. Two pathways, unidirectional block and slowed conduction and all three of these criteria for reentry can occur within a myocardial SCAR. So the idea of picking people with SCAR is that you may enrich the population most likely to benefit from the device. So an Australian team led the multinational CMR guide trial which was published in JAMA. I think it's a pretty cool study though it has some very big limitations. Now one clue about the limitations is that it enrolled only 350 patients and if you remember from SCUDHF one of the seminal trials that trial enrolled 2500 patients. So patients with a left ventricular injection fraction of 36 to 50% were randomized to have a primary prevention ICD or implantable loop recorder. That is they also had to have SCAR on CMR. The primary endpoint, sudden cardiac death or hemodynamically significant ventricular

9:30arrhythmia. The 353 enrolled patients were younger, 65 years, mostly male and were on decent baseline medical therapy. The trial was initiated before FDA approval of SGLT2 inhibitors. Demine injection fraction of enrolled patients was 40%, and the average percentage of late gadolinium enhancement was about 18 to 19%, and the Schemaectomyomyopathy was present in over 70% of patients. So the results. The immediate follow-up of 6.3 years, 6.3 years, a primary outcome event occurred in 14 patients in the ICD arm and 16 patients in the ILR arm that 7.8% versus 9.2% hazard ratio 0.76 but confidence intervals that went from 0.37 to 1.58 and a big old p-wave of 0.47. So obviously not statistically significant. The components of the primary outcome differed, sudden death occurred in 3 versus 10 patients

10:35respectively, but ventricular tachycardia occurred in 12 versus 6 patients. All cause mortality, which is an important endpoint occurred in 11% of patients in both arms. Quality of life scores was modestly worse in the ICD arm than the ILR arm. The minimally clinically important difference in the Minnesota living with heart failure questionnaire, which is a scale 0 to 105 is felt to be 5, and it was 5.8 points worse in the ICD arm. There was a subgroup analysis that suggested an ICD benefit in patients age less than 70 compared with those greater than 70, the hazard ratios were 0.28 and 2.3 respectively, and I would caution that there were only 4 versus 12 events in the under 70 arm. So my comments, now this trial was surely underpowered. The 24% reduction in the primary endpoint had a point estimate of 0.76, but the lower

11:40bound of the confidence interval goes all the way down to 0.37 and the upper bound all way up to 1.58, so that's a lot of uncertainty. What's more, the first component of the primary outcome, sudden cardiac death, only occurred in 3 versus 10 patients, and that's over 6 years of follow-up. The second component of the primary endpoint, VTVF, was higher in the ICD arm, but that's likely because the ICD treats VTF, so you will likely have more of it because people don't die of the VTVF. Now overall mortality was essentially identical, and as I wrote in my column on medscape in the heart.org, all cause mortality is the only proper endpoint for an ICD trial. You expose people to the risk of a device only if it increases the odds that that person lives longer. A rhythmic or sudden cardiac death does not count because we have numerous ICD trials that have shown that an ICD can reduce sudden death and not increase survival.

12:41The latest one of course is Danish. Danish showed a reduction in rhythmic death, but no difference in mortality. The authors admit the power issue, but I have to tell you they tend towards spin by suggesting that their result extends the evidence base from low EF to moderate EF patients for an ICD, and I don't think it does extend the ICD evidence to this population. Now perhaps they feel the subgroup of younger patients is persuasive, but I don't agree with that either. First of all, the little power that this trial had was for the entire population, not one subgroup. Secondly, there were only 13 events, primary outcome events, in that subgroup. Now, one thing we did learn I think, and it is a likely explanation of the no results, is that this group of patients have an extremely low rate of sudden death. At 1% per year, it was fourfold less than predicted during trial design and substantially less than what was seen in the seminal trials of the ICD.

13:42In the positive, made it two trial, the sudden death rate and the control arm was approximately 6% per year. In the non-significant Danish trial, it was only 1.5% per year. And remember, my friends, an ICD cannot extend survival unless the rate of sudden rhythmic death is substantial. So CMR guide is a nice trial. I law the authors for trying to test this widely held theory about scar and ICDs, but it should definitely not change our practice. And I think it begins to disprove the theory about scar and ICD benefit. We definitely need more studies to test this theory that a scar identifies people that an ICD will be useful for. Next topic is a single versus dual therapy in ATTR cardiomyopathy. Now two studies for me, as seen, formed a curious question of using two agents in these patients with ATTR cardiomyopathy.

14:43Now we know that the transthyretin stabilizers, such as tephamidus, came first and RCT showed benefit, though it did take years to see curve separations in those seminal trials. Well now there are TTR silencers, which inhibit the hepatic production of the precursors. Combining these two different drugs is sort of mechanistically appealing, isn't it? Because one stabilizes it and one drug stops production of it and both might reduce the emaloid deposition. The thing is, the whole combining these drugs is not like combining Lycena Peril and Spurinal Actone. That is did a brief search and put the cost of both these drugs in the hundreds of thousands per year each each. So at ESC, the Helios B investigators presented a pre-specified subgroup analysis of the effect of utisaran as a single agent or when added to patients who took tephamidus at baseline. New England Journal of Medicine published the Helios B trial last summer.

15:46It had 665 patients with ATTR, Chronoomyopathy and they were randomized to utisaran versus placebo. And the primary endpoint was a composite of death and recurrent CV and events and that includes hospitalization for any CV cause or an urgent heart failure visit. The curious thing was that about 40% of patients in Helios B were using tephamidus at baseline. So utisaran treatment led to a lower risk of death from any cause and recurrent cardiovascular events compared with placebo that hazard ratio overall in the population was .72 and conference intervals were significant at .56 to 0.93 to p value 0.01. The hazard ratio in the monotherapy population was 0.67 with conference intervals that stayed below 1 that was 0.49 to 0.93 and a lower risk of death for many cause through 42 months and that hazard ratio was also positive.

16:48In the overall population treatment with utisaran resulted in less of a decline in the distance covered on the 6 minute walk test in placebo and less of a decline in the KCCQ quality of life summary. So in the subgroup of patients on tephamidus at baseline utisaran therapy reduced the primary endpoint by less. The reduction was not 33% but 21% on those patients who took the stabilizer. So hazard ratios were 0.67 alone and 0.79 if they were already on a stabilizer. The study that was presented as a late breaking clinical trial at ESC and published in JACs specifically reported on the subgroups getting vatisaran who were on tephamidus and those not on tephamidus. Now patients on tephamidus were slightly younger and had higher baseline 6 minute walk distance in a higher KCCQ in short they were a little bit healthier. The effect sizes were the same as in the main paper 0.79 versus 0.67 the p value for

17:54interaction however was negative. Now similar patterns were observed for all caused death, CV events and worsening heart fire but none of those had a significant p for interaction. Utisaran preserved the 6 minute walk distance in both baseline tephamidus strata whereas improvement in KCCQ appeared attenuated among patients receiving tephamidus at baseline. Basically what this paper added was formal interaction testing which were all non-significant meaning that there did not appear to be a heterogeneous treatment effect though I will have more to say on this in my comments. Now also presented as a hotline and published in a new and journal of medicine was a trial called cardio transform trial and this is a drug that I have never really heard of before this and it is called eplontursin, which is a new TTR silencer or reducer of hepatic TTR in patients who have the attr cardiomyopathy. The primary endpoint of this placebo control trial was CV death recurred clinical events

18:57up to 140 weeks and we know from a press release from July that the trial failed to meet its primary endpoint. The primary endpoint occurred in 29.4% receiving the eplontursin versus 32.2% of those receiving placebo and that relative risk or rate ratio was 0.89 with confidence interval 0.73 to 1.09 in that p value 0.28 so non-significant. The key difference here is that more than three fours of participants got ended up on background stabilizer or started a stabilizer during the trial. Thus the proportion of patients who are on stabilizers was much higher compared with Helios B. In the cardio transform trial there did appear to be a little bit more of a subgroup difference. In the patients on the stabilizer the hazard ratio versus placebo was as high as 1.14 but as monotherapy it was as low as 0.71.

20:00This is interesting isn't it? Now I come on on this as a neutral observer looking at the evidence. I don't take care of patients with cardiac amyladosis unless they need a pacemaker, defibrillator or ablation. In both trials though there seems to be a qualitatively similar effect. It is the effect of the silencer or the TTR reducer it seems to be most effective as monotherapy. In Helios the effect size versus placebo was 21% and the confidence intervals crossed one. That is with those patients on stabilizers. In the Eplonturcent trial the hazard ratio was as high as 1.14 when patients were on a stabilizer but as monotherapy both drugs looked pretty good. But of course when we talk about this we are talking about subgroups which includes about half the patients so like most subgroups it is underpowered. Now another headwind for newer ATTR chromaopathy therapies is that heart failure therapy is better these days.

21:01There is more use of SGLT2 inhibitors, more use of MRAs. There is also earlier diagnosis because of an awareness campaigns. Any newer trial for these drugs is going to enroll patients earlier in their disease course. They are going to be a little bit healthier and these patients are going to have fewer events which is good for them but not as easy for the drug makers who will have to enroll more patients or follow them longer to show differences. Next topic is a stunning result of another sham controlled AF ablation trial. At ESC we heard the surprising results of the German Ledge PVI sham AF trial and LANDSET published the results. The team led by Dr. Ralph Vokter and Nikolas Douglas screened 1200 patients with symptomatic AFib. They enrolled 262 patients in a 2-to-1 fashion to AF ablation with whatever ablation system that Dr. wanted to use or a sham procedure where the patient got heavy sedation, two

22:03venous shees and cardioversion if there was atrial for relation. The primary endpoint is what it's supposed to be. This was a proper endpoint and it was quality of life as measured by the AF EQT questionnaire which is a 0-100 scale and it is a device that measures multiple different quality of life domains. So cardioversion was performed often 54% in the ablation arm and 36% of the sham arm had cardioversion. So for the results, the first thing to say is the blinding index was very good. Patients could not easily guess their treatment assignment and this is a strong credit to the trial list. The AF EQT score improved in the ablation group from 61 points at baseline to 81.1 points at 6 months. But it also improved in the sham arm from 58.2 points to 74.9 points in the between group

23:03difference in change from baseline to 6 months was only 2.6 and it was not statistically significant. Ablation did reduce episodes in burden of AFib, clinically detected recurrence of AFib, detected during seven day halters occurred in 27% of patients in the ablation arm versus 48% of patients in the sham procedure group. AF burden on seven day halter monitoring of six months was lower with ablation than with sham 11.6% versus 23.6%. Both those differences were statistically significant and the authors made the only conclusion that they could possibly make was that despite a reduction in AF episodes and burden catheter ablation did not demonstrate superiority over a sham procedure for improving AF related quality of life at 6 months. So my comments, I also wrote about this trial I saw multiple lessons. The first is humility no matter how sure we are about things we must have the humility

24:05to test our beliefs and I thank the German authors for having that humility. The second lesson centers on a placebo effect and it is so embedded in nearly everything that we do is clinicians that it is easy not to notice it. As I wrote it is like fish who don't notice the water we can forget that our words and our actions create a caring signal that can then influence how patients subjectively feel. Performing a fibablation generates a huge caring signal. Not only is it a major invasive procedure but for the patients are then seen post procedure in the weeks and months after and really a patient becomes connected to many of their ablation doctors. AF is a complex illness and it has both physical and mental effects. The electrical AF episode is only part of the problem for many patients, right? A caring clinician who provides not only therapy but education and empathy and support that's bound to help alleviate symptoms.

25:07The AF eQT score is an ideal measure because it encompasses more than just arrhythmia symptoms like palpitations. But it also includes expectations. I am not surprised that mild to moderately symptomatic patients felt better without undergoing ablation. They had a caring physician. Many of them had cardioneversion. They got to see their patients. They didn't know whether they got the procedure or the sham and they felt better. A third lesson from this trial is that a single trial or multiple small trials is not enough to answer such crucial questions. The authors of PVI sham AF write that the reason their trial produced no results while the two previous smaller trials, sham PVI in the UK and PFA sham in the Czech Republic, had positive results is uncertain. I would agree but I would also argue that uncertain explanations in medical practice are the norm and that is why we lean on evidence to guide our therapy. That is why we must have multiple trials for important questions.

26:09Now I want to address some of the criticisms that I read online which has been robust actually. People are not happy about this. Many have said that this was not AF ablation versus sham because cardioneversion is actually active rhythm control and I understand that point. But my counter would be A, the other sham controlled trials used cardioneversion in the sham procedure but nobody seemed to have a problem with that because those trials were positive and everybody could just rest easy that AF ablation worked. My second reason that I'm okay with the cardioneversion is you have to be pragmatic. You cannot not convert someone when they're sedated. Well I realize that a true do nothing trial would be cleaner. But if we're going to ask a patient to be randomized, to possible sham procedure, the least we can do is something therapeutic. And a cardioneversion I think enhances the external validity and then it tests the AF relations effect on quality of life over a very basic rhythm control therapy and that's cardioneversion.

27:10So in some, if we are truthful ourselves, all of us have to admit there is a placebo effect from ablation. This trial just confirms what we already know. The question is not placebo effect yes or no. It is to what degree the quality of life is due to placebo. What is the percent placebo of resistant effect? This trial suggests it is far more than the two previous smaller trials. And I say good on the PVI, shame AF team. You all should be proud. Heck I can't speak German but I am extremely proud of you all. This is a great trial and is really important to test our beliefs. All right, next topic is should older adults take statins the star E trial. One of the most evidence based facts in all of menace and is that statins reduce cardiovascular events by about 25% in relative terms. If the baseline risk is high that's a big absolute reduction. If the baseline risk is low, that reduction is smaller.

28:13What we did not know before star E was whether this risk reduction applied to older adults. There was sparse evidence as most of the people in statin trials were younger. The Australian team randomized nearly 10,000 older adults to 40 milligrams of a torvastatin or placebo. They chose two co-primary endpoints, a typical mace endpoint and a disability free survival endpoint. That included death, dementia and permanent disability. The mean age of patients was 75 years, nearly 40% were older than that and half were female. The average baseline lipid numbers were hardly that terrible LDL was 126 HDL 62 and triglycerides only 113. The first result was that adherence to the study medication was poor. After five years, 45% of individuals in the statin arm and 53% in the placebo arm were not taken to study drug.

29:14Open label statin was used was reported in 19% of patients in the placebo arm by year five. Now, not surprising was that a torvastatin reduced LDL cluster by about 35 milligrams for deaths of liter more on average than placebo. The main result, over nearly six years, primary endpoint occurred at a rate of 10.9 per 1,000 person years in the statin arm versus 15.5 per 1,000 person years in the placebo arm. The hazard ratio was 0.7095% conference intervals went from 0.61 to 0.82, but a highly significant p-value. The drivers of the lower rate were MI stroke and re-vascularization. Rates of all cause and cardiovascular death were similar in both arms. Now the second co-primary endpoint of death dementia, our persistent physical disability, was only 6% lower in the statin arm and that did not reach statistical significance.

30:16Rates of dementia were almost identical. Persistent physical disability rates were very low and also similar. Medically important adverse events occurred in 8.8% of patients in the statin arm versus 6.7% in the placebo arm. Musculoskeletal and connective tissue disorders were just a little higher in the statin arm and hepato-billionary disorders were 3.3 versus 0.9%, both slightly higher in the statin arm. So my comments on this trial is that the interpretation is obvious and easy and it is that in this older but seemingly healthy population, a torvostatine reduces the risk for nonfatal cardiac events but does not extend lifespan or lower dementia and physical disability rates. The adverse effects is what you would expect. They were neither worrisome nor much different from previous statin trials. The absolute risk reduction was fall.

31:17The authors report a number needed to treat to prevent one major adverse cardiovascular event as 37 but that is over nearly 6 years. The NNT per year is more than 200. I'm not surprised by the results because statins have shown remarkably consistent results in both primary and secondary prevention trials. The 30% relative reduction in starry is consistent with the known benefits of statins. Now some people may posit a larger risk reduction if there was better adherence and I think this is a mistake because statin adherence is what it is. Other people would say that the crossover to open label statin use is also maybe a headwind to benefit but this is also not unexpected because surely patients who have events were started on statins over 6 years. I would have one major caution about translating this data in the clinic and that is that patients with serious disability or frailty were not included.

32:19I would not assume this effect applies to patients who have substantial comorbidity. Notable also is that only 4% of individuals in this trial were older than age 85. So this applies to 70 and 75 years old patients but not 90 year olds. So this trial reinforces my long held view that doctors need hardly be involved in statin decision making. These drugs should be over the counter where patients can decide with their own money if they want to take more than 2,000 tablets over 6 years to reduce cardiac events by a few percent. People take supplements to improve their health and it has nowhere near the level of this evidence. Patients could consider a torvastatin well studied beneficial heart supplement. In Stari the small absolute risk reduction in MI stroke and coronary vascularization was not large enough to improve survival or lead to less overall disability. And older people can have different preferences right.

33:21Minimizers who want to do everything to reduce the chance of having a heart attack or stroke they can take the pill. Minimizers will look at this and say I'm not going to do it. So I law the Australian team for providing evidence where there was little. Older adults similar to those enrolled in this trial can now make an informed decision about statin use. I'm happy to help them but it's 100% their choice and this data are so clear that my opinion on it is hardly more relevant than theirs. Final topic today is the declining ICD benefit after MI. I wanted to tell you about a really interesting study presented and you might not have heard about it or seen press coverage of it. At one of the young investigator sessions at ESC we heard results of this important observational analysis of the Profit database looking specifically at ICD mortality reduction over three different time periods. The idea is that the seminal trials of ICD's recruited patients in the 1990's and trials

34:22around the turn of the century found that the primary prevention ICD provided a mortality benefit. The thing is that the care of post-MI patients has greatly improved over the decades, right? Medical therapy of heart failure is better, re-vascularization is better and the other thing is likely happening is that more and more patients are getting ICD's who have competing causes of death older patients with other conditions. These are important clinical features because the way an ICD delivers its mortality benefit was by reducing arrhythmic death and arrhythmic death has to represent a large fraction or proportion of death. It was in relatively young patients with mostly a Scheme-Cart disease and they had not much else for diseases. Now, before this observational study I would highlight two clues, two big clues that primary prevention ICD benefit may be a lot less in this era than it was 30 years ago. One clue was that the Danish trial of non-eschemic patients with heart failure was utterly totally

35:25negative for the ICD. That was in 2016. The second clue was a paper by Shen et al in 2017 in the Newland Journal of Medicine where heart failure trialist reported arrhythmic mortality in heart failure trials over time. And they found a temporally over time decreasing risk of dying from arrhythmia over the decades in the trials. So in old heart failure trials arrhythmic death was a lot higher than newer heart failure trials. So this was the question asked by the team charity hospital in Berlin. They used a very large database of patients who had ICD's. These were multiple databases actually they included observational data and trials for multiple countries. The total number of patients in these databases was about 32,000 patients who had an EF less than 35% after an MI. Approximately 7.7000 of these had a primary prevention ICD and these were considered the ICD patients.

36:26About 25,000 patients without an ICD they were the non-ICD comparator group. Now this study was observational. It's not randomized and they're going to be substantial baseline differences so the authors had to do pretty extensive matching techniques. Their primary endpoint was all caused mortality and the analysis crucially looked at three different time periods and the advantage of the ICD declined by time period. So the hazard ratio for the ICD versus non-ICD patients was 0.54 in the time period 1995 to 2004. In the time period 2005 to 2014 the hazard ratio was increased to 0.67 and in the most recent time period 2015 to 2020 the hazard ratio had increased to 0.89 and was no longer statistically significant. There was negligible separation of the weighted cumulative mortality curves in this later

37:27time period and this test for interaction was highly significant. They also did a yearly analysis and found that the ICD benefit versus no ICD turned non-significant at around 2014 in onward. So my comments of course you have to start with this is observational and non-randomized and the authors are quite fair about listing the limitations not only about confounding but also the pooled use of multiple data sets. There was also an intention to treat analysis where if a patient received an ICD later after being enrolled they remained in the non-ICD group which could have biased towards the null but of course they do say that these crossovers were not more common in later years. Now the limitations preclude making clinical actions such as we should not say that ICDs are no longer indicated in a scheme at cardiomyopathy patients with low EF because of this study but I think these observations strongly suggest that ICD benefit may be decreasing over time

38:35and this is what we thought pre-study and so if you're just thinking like a Bayesian if you believe that pre-study and then you observe data like this it only strengthens the case. Now while non-random association studies should not be used for clinically denying an ICD to an eligible patient I think they do strengthen the case for equipoids for trials. Now I've spoken previously about the Profit ARA trial which will renomize patients post a My with a low EF to an ICD or no ICD. This is a bold trial and the Charity Hospital team tells me it's about half recruited and if you are a doctor in Europe I would highly encourage getting such patients randomized. Profit stands to be one of the most important trials in cardiology and it should be supported period end of story support profit. Now there is also a US trial which is similar called the contempt ICD led by a team at the University of Rochester. This is a similarly designed trial but a few of the Profit authors at ESC told me it is unhold due to enrollment

39:42issues. Now while I'm not surprised that American EP doctors struggle with the concept of trials having an expiration date I find it sad that we have become so soft in our thinking that we would not randomized to such an important trial. I would also hate to think that enrollment would be affected by compensation. Namely if you enroll a patient in a trial like this and half of them don't get the ICD your productivity goes down. This is sad sad sad we all have to now depend on our European colleagues to conduct this crucial trial and tell us the results and I would be not one bit surprised if modern day therapy has precluded benefit from a primary prevention ICD. But again that's just a prediction we have to do the trial to know. All right so that's it for this week in cardiology. I went longer than I normally did next week I'll have five more ESC trials in the week after that probably five more. So thanks for listening and remember if

40:47you liked this podcast please take the time to give us a rating write us a review if you don't agree with something I said let me know I'm always happy to have listener feedback. Until next week and next week I'll be in Louisville Kentucky at home this is John Mandrola from the Heart.org Medscape cardiology. You're listening to this week in cardiology from the Heart.org Medscape cardiology. This podcast is intended for healthcare professionals only any views expressed are the presenters own and do not necessarily reflect the views of WebMD or Medscape.