Latest news with #JohnMandrola
Medscape
11-07-2025
- Health
- Medscape
Jul 11 2025 This Week in Cardiology
Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast , download the Medscape app or subscribe on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only. In This Week's Podcast For the week ending July 11, 2025, John Mandrola, MD, comments on the following topics: approval of first-generation devices, the ticagrelor controversy, ICD longevity, the PRAGUE-25 trial (one of the most important trials of the year), and some thoughts on the end of EP as a profession. Catalin Toma, MD, who is Director of Interventional Cardiology at the University of Pittsburgh Medical Center, writes regarding what I talked about on lack of data in the invasive pulmonary embolism (PE) field. I have been involved with PE interventions from very early on and could not agree more that we need randomized controlled trials (RCTs) to understand the role of interventional PE therapies in the high-intermediate risk and massive PE groups. However, until a few years ago the whole field of interventional PE was completely new, with virtually no expertise! Launching into RCT with the early devices, and with the lack of cumulative knowledge we have now would have led to predictable negative results. He says, 'Good thing we didn't send astronauts to the moon in Apollo1 or to Mars in the current generation of starships.' So now we are able to do major RCTs with both catheter-directed thrombolysis and thrombectomy (HI-PEITHO is almost complete, the ATTRACT PE is close to completion, PEERLESS 1 and 2 are underway). And to be honest, Toma adds, 'the fact that industry is engaging in these trials is commendable, especially given how popular and reimbursed things are already—this didn't happen out of goodwill, but because doctors pushed for getting data. At our center, we approach virtually every patient referred for intervention and enroll them in trials.' Toma concludes by saying, 'I think the ethos for obtaining good clinical evidence is still here. But I am happy I learned how to ride before bombing downhill.' I think this is a really important point. I highlight it because I recall last year having a conversation with Dr Bobby Yeh about early-generation devices and iteration. That is, if you study and then restrict first-generation devices, you might hurt innovation. So there is a balance needed. That said, I stand by my stance that the FDA should reform this extremely problematic 510k approval pathway where devices get approved by being similar to an already approved device. This is a really problematic and too lackadaisical approval pathway, I think. More Ticagrelor Controversy BMJ Investigation Finds More Concerns in Ticagrelor Trials Just before my last podcast, the BMJ published another concerning report from senior editor Peter Doshi regarding irregularities in two key platelet function studies of ticagrelor. I take the role here as a neutral journalist. As an EP, antiplatelet drugs are not something I use every day. Let's review some basics. Ticagrelor is a huge player in the post-stent antiplatelet market. In 2022, the United States spent more than $750 million on it. Despite representing only 7% of total P2Y12 inhibitor prescriptions among Medicare beneficiaries in 2020, ticagrelor accounted for nearly two thirds of total Medicare spending on these drugs in the same year. Globally, the makers of ticagrelor, AstraZeneca, brings in more than a billion dollars in annual ticagrelor sales. The seminal trial was a 2009 study called PLATO, comparing ticagrelor vs clopidogrel in 18,000 patients with acute coronary syndrome. The primary endpoint of CV death, myocardial infarction (MI), or stroke occurred in 9.8% of patients on ticagrelor vs 11.7% on clopidogrel. This was a 16% relative risk reduction (HR 0.84; 95% CI, 0.77-0.92). MI and CV death were reduced, as was all-cause death. PLATO also found no significant differences in major bleeding. Despite this 'big win,' ticagrelor failed at its first review at FDA. Mainly because a subgroup analysis found that, in the US, ticagrelor patients had poorer outcomes than those randomized to clopidogrel—a 27% higher risk of the primary endpoint Thomas Marciniak, who was an FDA medical officer, wrote a scathing review saying he had worries about the PLATO data quality. Marciniak called AstraZeneca's application 'the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests.' However, FDA leadership did not endorse these reservations. One explanation put forth by the authors was that US patients fared better with clopidogrel because US patients had higher doses of aspirin. Though you would not know it, because ticagrelor is so popular, there were multiple layers of controversy surrounding PLATO and ticagrelor. One association was this: in an analysis based on data monitoring by the sponsor vs independent contract research organization monitoring, the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the United States—ticagrelor fared worse. Here is another chapter: Eric Bates, a professor of medicine at the University of Michigan, wrote a concise but readable narrative review in Journal of the American Heart Association , and the striking finding is how scant few other observational or RCTs align with PLATO. Yet another layer in the controversy: Victor Serebruany and Dan Atar wrote an editorial in EHJ in 2010 titled, 'PLATO trial, do you believe in magic?' Their major point was the massive overall and CV death reduction. There were 107 more lives saved with ticagrelor than after conventional clopidogrel (399 vs 506), representing a highly significant absolute mortality reduction (HR = 0.78; 95% CI, 0.69–0.89; P < .001). This they felt was highly surprising because it was three times more than the COMMITT trial where clopidogrel beat placebo. What's more, the mortality reduction (107 deaths) numerically exceeds the MI prevention benefit (89 events), making it a 'hitherto unmatchable achievement.' Important to say is that PLATO authors have published multiple rebuttals, and the Department of Justice (DOJ) investigation was started but then terminated 11 months later. DOJ said: 'After an extensive investigation . . . we determined that the allegations lacked sufficient merit such that it was not in the best interests of the US to intervene in the suit.' In my December podcast, I also noted how the non-industry funded ISAR-REACT 5 trial, comparing prasugrel to ticagrelor, so strongly favored prasugrel over ticagrelor, by a statistically significant 36% for the primary endpoint of death, MI, and stroke — and trended toward lower bleeding as well. It still perplexes me how little effect that trial had on actual usage. Prasugrel is also once a day. The newest BMJ investigation that came out in June focused on two mechanistic studies supporting the rapid onset and potent antiplatelet effects of ticagrelor. One was called ONSET/OFFSET and the other study was called RESPOND. Both were published in Circulation . ONSET/OFFSET studied 120 patients who got either ticagrelor, clopidogrel, or placebo. Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation. RESPOND studied clopidogrel nonresponders and found that ticagrelor overcomes nonresponsiveness to clopidogrel, and its antiplatelet effect is the same in responders and nonresponders. Nearly all clopidogrel nonresponders and responders treated with ticagrelor will have platelet reactivity below the cut points associated with ischemic risk. You could see how these studies could be used in marketing pamphlets along with PLATO to help explain how PLATO came out positive. Norwegian researcher Dan Atar was quoted as saying: 'The ONSET/OFFSET study, when it came out, caused incredible interest,' I remember numerous discussion groups where people were asked to interpret these findings.' And AstraZeneca was also pressing the message that the platelet studies, which found faster and greater platelet inhibition, explained PLATO. FDA officer Thomas Marciniak, however, noted that early benefit (which would be expected with faster platelet inhibition) was not seen in PLATO. He wrote 'I would expect that patients with the very early invasive strategy would have the greatest need for good platelet inhibition, but ticagrelor fared worse [in PLATO] for short term outcomes in these patients.' But that was not all: Enter Victor Serebruany, a pharmacologist with expertise in platelet function tests. Serebruany thought the pharmacodynamic data were too good to be true. ONSET/OFFSET's study schedule, he reckoned, was almost impossibly intense, including a requirement for six blood tests in an 8-hour period. This would require 210 mL of blood drawn for the study. The company told Serebruany that it looked into his concerns and found nothing amiss. The BMJ sought to interview 15 investigators in the two platelet trials—and few, including the corresponding author, were responsive. One investigator that the The BMJ could reach was Tonny Nielsen, a co-author of RESPOND and principal investigator in Denmark, according to AstraZeneca documents. But Nielsen told The BMJ in a written response, 'I did not participate in the RESPOND study,' a statement further substantiated by two of his colleagues. And yet he was listed as an author of the Circulation paper despite not being involved. Meanwhile, The BMJ found that one investigator, Alberto Yataco, operated an active study site in Baltimore, but never became an author despite enrolling 12 patients and ordering extra test kits. Yataco could not be located for the story. The next chapter was that the platelet tests were finicky, prone to artifacts and most platelet tests were done in single centers. However, these studies were multicenter and Doshi writes that it not clear that training and standardization were done in the studies. Furthermore, Doshi found numerous other data integrity issues: more than 60 of 282 readings from platelet machines used in the trials were not present in FDA datasets. There were missing baseline measurements for patients who had blood drawn multiple times. Some study sites began recording data before equipment arrived. Finally, The BMJ 's review also found that the protocol-specified primary endpoint results for RESPOND were statistically nonsignificant ( P = .157) but were subsequently reported in Circulation as significant ( P = .005) because of an undeclared change in primary endpoint definition. I would encourage you to read Doshi's reports in BMJ from December 2024 and this year. See what you think. My questions go back to PLATO. Why does the drug do worse in geographies where there are independent research organizations? Is this a coincidence? Why, as Dr Bates, lays out, so little corroborating data supporting ticagrelor vs clopidogrel? Why did ticagrelor underperform so badly compared to prasugrel in ISAR-REACT? I worry that when you put these observations together, there is worry that an accepted drug may not be what we thought. Maybe there is nothing there, but gosh, if we are wrong about ticagrelor, that would be a big thing. Let me know what you think. I think this is a big story. Heart Rhythm has published a simple but important study on the battery life of cardiac defibrillators. My opinion on this issue has changed. I once thought that the difference of a few years was not clinically relevant. My mind works like this. Maybe yours does too. When I have a talk that is a month or so in the distance, I don't worry one bit about it. I never plan anything a year in advance because a year seems like forever from now. So, the difference in battery life between, say, 7 and 10 years was hard to sort out. But now that I am old enough to have dealt with nearly every possible device complication, I have come to hate generator changes—because this is where many of the complications start. If you meet an EP doctor not scared of generator changes, consider referring to a different one. Generator changes deserve your highest respect because these are hazardous interventions. Therefore, ICDs with longer battery lives mean fewer generator changes. And this is no small issue. Dr James Freeman and colleagues used a US remote monitoring dataset to study ICDs implanted from 2003 to 2023. They assessed the time from implant to replacement. I know; it's simple but the data are remarkable. And it turns out that device advertisements had some truth to them. The first finding was that battery longevity declined 2-3 years for each extra lead implanted. Pause there. This is exactly why primary prevention ICDs should be one lead unless there is a real need for atrial-based pacing. The second finding was that device manufacturer mattered. Estimated longevity could be 2-4 years longer based solely on who made it. Boston Scientific had long marketed their devices as having the longest battery life. And, indeed, this data corroborated their pitch. Boston Scientific devices outpaced their competitors in single, dual and biventricular devices. By a lot. I've seen this and I often use Boston Scientific devices for this very reason. The third finding was that programmed outputs and the percentage of pacing mattered. It's like my bike light. If I keep it on high, I struggle to finish the 2-hour ride. I continue to believe that device follow-up and attention to detail is as important as skillful implant. The fourth finding was that recent-generation devices have a little less of a longevity gap, though it still exists. For instance, the 'estimated' median longevity of a single-chamber Boston Scientific device implanted after 2022 was 180 months. It was only 110 months for an Abbott device. That's 5 years. You might quibble with this because it is estimated, but the authors would counter that they looked at estimated vs actual in older devices and found good agreement. This study almost seems too simple to report on. But it's not. The choice of device manufacturer is too often set by initial costs or relationships with reps. These are both bad. Ugly even. Battery longevity matters and Boston Scientific does better than its competitors. I don't have any financial relationships with any company, but how long an ICD lasts is hugely relevant. It's hard to think a decade on, but I can tell you now, as an old dude, it matters. Even if a device costs a bit more, if it lasts 5 years longer, than it is a value. The problem is that in private systems in the US, payers may change often. So value from longer devices only accrues if the payer doesn't change. Atrial fibrillation (AF) ablation is undergoing a transformation I have not seen in 20 years of doing this procedure. The advent of pulsed-field ablation (PFA) is the tale of two stories: one story is that we have a way of ablating the left atrium which is super-fast and without the worry about killing patients from atrioesophageal fistula. This is good and it has lowered our bar of offering this procedure. But…But….PFA, I worry, is killing EP as a field. Every time I finish a PFA case, I shake my head in disbelief. Why? Because EP was once a profession where we cared about physiology. We diagnosed and treated arrhythmias based on a deep understanding of mechanisms. Pulmonary vein isolation (PVI) started to ruin that concept because we simply put electric fences around the PVs. The cryoballoon was worse because we simply put a balloon in the PV and froze. Now with PFA, we can destroy left atrial myocardium even faster. We isolate PVs in slightly more than 30 minutes. We can do 4 to 5 cases per day. The EP doctors, industry, and hospitals are making tons of money. But we have not learned a darn thing about AF pathophysiology. And, worse, PFA has made AF ablation so easy, that anyone who has catheter skills could do it. Anyone. I mean it. In the US and most of the Western world, except maybe Denmark, Norway and few other places, most patients with AF are obese. Obesity and its accompanying metabolic abnormalities surely promotes AF by creating structural and atrial disease. The Adelaide group has elegantly shown this over the past decade. No matter, US doctors ignore the pathophysiology and take these obese patients for PVI. We say weight loss and RF management is hard, and don't deny the patients with obesity the 'benefits' of PVI. Well, thank goodness our field has people like Pavel Osmancik, MD, in the Czech Republic to do a proper trial. PRAGUE-25, performed in 5 centers in the Czech Republic, bravely compared a weight loss intervention (with anti-arrhythmic drugs) to ablation in patients with obesity and AF. These patients had a mean BMI of 35. The lifestyle modification (LFM) arm included a weight management program with dietary and exercise specialists using tech support via mobile phone apps and regular in-person and telephone conversations. Also brave was Dr. Osmancik's choice of endpoint — freedom from AF. Thank goodness he and his team also measured secondary endpoints, because this is where the real story lies. His team convinced more than 200 patients to undergo randomization. This would be a fun study to recruit patients for. Imagine the explanation: You are obese. We could ablate your AF or put you on a program of weight loss and exercise. That would be a tough, tough conversation. As you would expect, AF ablation was better at reducing the surrogate endpoint of freedom from 30 seconds of AF. The percentage of patients with AF freedom at 12 months, 73% in the catheter ablation group vs 35% in the weight loss group. The HR was 2.8 times (95% CI, 1.9-4.0). (Please pause and note here that more than a third of patients with AF had freedom from AF without ablation). This led to topline conclusions that AF ablation was better than weight loss for AF. The real story is the nuanced secondary findings: Weight loss was significantly greater in the LFM group (6.4 kg vs 0.35 kg). Glycemic control was better in the LFM. A1c decreased by 1.4 ± 4.8 mmol/L in the LFM while it increased by 2.5 ± 10.5 mmol/L in the ablation arm. Fitness as measured by VO 2 max was also better in the LFM group. Reduction in AF burden, which is arguably a more relevant endpoint than freedom from a 30-second episode, was numerically larger in the ablation arm, but the between group difference did not reach statistical significance. Quality of life (QoL) improved equal degrees in both arms, which is surprising because you'd expect less AF and less AAD to associate with better QOL. Perhaps the weight loss and gain in fitness countered the less AF. The key limitation of PRAGUE-25 was the modest weight loss of only 6 kg, which is less than Adelaide's number of 10% body weight loss, where the real AF benefits kick in. The study came before GLP-1 agonists drugs were available and I would love to see this trial repeated with GLP-1 drugs. I hope your conclusion of PRAGUE-25 is similar to mine. LFM may have lost on the surrogate measure of freedom from 30 seconds of AF, but if overall health of our patients is the doctor's goal, LFM clearly won. It led to more weight loss, improved glycemic measures, better fitness and similar QoL improvements. I seriously think PRAGUE-25 argues for a conservative LFM-first approach to AF in patients with obesity. It also argues most persuasively for a larger, properly powered CABANA-like trial with LFM aided by GLP-1 drugs vs ablation. That's a trial that could change EP for the better. My friends, if you keep destroying the LA with PFA, instead of treating the patient's more serious metabolic problems, you may make a lot of money in the short term; you may gain status in the hospital because your relative value units (RVUs) are so high; the company may make you a key opinion leader, but you are destroying the once great field of EP. PRAGUE-25 should re-invigorate our drive to help patients improve their overall health. The patients in the lifestyle management group may have had more episodes of 30 seconds of AF, but they ended up with better health overall.
Medscape
27-06-2025
- Health
- Medscape
Jun 27 2025 This Week in Cardiology
Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast , download the Medscape app or subscribe on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only. In This Week's Podcast For the week ending June 27, 2025, John Mandrola, MD, comments on the following topics: FDA approves triple-drug polypill, a change of opinion, a deep dive into invasive pulmonary embolism therapies, heart disease trends, and diabetes care is on fire. I learned this week that fellow medical conservative, Andrew Flapan, MD, of Edinburgh, died suddenly. Andrew invited me twice to speak at the Royal College meeting. I enjoyed my time with him immensely. He was a force of nature, and a 'doctor's doctor.' To my colleagues in Edinburgh, I offer my condolences. FDA News in Hypertension The FDA this week approved the three-component polypill for hypertension. It's going to be called Widaplik, which is a silly name. It includes the angiotensin receptor blocker (ARB) telmisartan, the calcium-channel blocker amlodipine and the diuretic indapamide. There will be a polypill with standard doses of the three drugs, but also one with two lower doses. My feelings have changed about the polypill. I used to be dead set against it. I thought it was dumb, and it would be far better to just titrate does of selected drugs. But now I am more open to the whole simplicity thing. As I age, I grow more interested in minimally disruptive care — a concept began by Mayo Clinic endocrinologist Victor Montori, MD. The idea is that life is for living, not for being a patient. Getting prescriptions filled is a huge pain in the butt these days. So the idea of taking one pill that has a better chance of controlling blood pressure (BP) is absolutely minimally disruptive compared to titrating two or three pills, each requiring a prescription. The evidence for polypill efficacy is quite decent. The Lancet published an RCT comparing the triple polypill to three different two-drug combinations. And it fared well — the triple-drug polypill lowered the systolic blood pressure statistically more than any of the other combinations. It was a small efficacy trial but there were no significant differences in hypotension, though more patients in the triple therapy arm had out-of-range sodium or potassium values, but 'very few clinically significant electrolyte abnormalities occurred in any groups.' Also in 2024, JACC published an RCT of about 300 patients with mild to moderate hypertension. This trial randomized patients in a 2:2:1 ratio to polypill quarter-dose (telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg), polypill half-dose (telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg), or placebo. The BP reductions delta vs placebo was about 7-8 mm Hg. At Week 4, clinic BP control (<140/90 mm Hg) was 37% for placebo, 65% for quarter-dose and 70% for half-dose. Both doses had highly significant P-values. Adverse effects were similar. In 2023, JAMA Cardiology published a meta-analysis of seven trials with 1900 patients looking at 3- and 4-component polypills vs monotherapy or placebo. Again, the polypills were more effective BP-lowering drugs and there were very little adverse effect differences. A word of caution: These trials enrolled 59-year-old patients. They had run-in periods. And in trials, patients are motivated, clinicians are motivated, there are research nurses. IOW the trial environment is seriously protective. The practice of evidence-based medicine (EBM) requires us, the practitioners, to be mindful of the external validity of trials. Giving three drugs in a single pill is not for frail, elderly patients with serious comorbidity. Patients on these drugs should get follow-up. But, again, I stress, the sole point of preventive therapies, like treating hypertension in middle-aged people is so they become old-aged. When patients successfully make it to old age, there is reason for caution. Benefits are less and side effects come more frequently. The thing about the polypill is that it offers a single best chance of getting control of BP. Simple is better not only because it is less work for the patient, but in my experience, early success is more likely to lead to adherence and confidence in the clinician. I don't know how much this drug will cost. The three components are not at all costly but putting them together could be. That would be sad. I am upbeat about polypills. I have changed my mind. We need to talk about a new kid on the block — interventional pulmonary embolism (PE) care. Our two EP labs bookend the three cath labs. I visit our cath labs as a curious person and journalist. I often see the doctors treating PE. The pictures are impressive when a doctor literally sucks a clot out of the pulmonary artery. My former partner for decades, Tom Tu, MD, became the chief medical officer of Inari. I loved working with Tom. Our cubicles in clinic were close. (By the way in private practice, you only get a cubby. My diplomas are not on the way, they're in boxes.). Tom pushed me on evidence. And I once debated him in front of the entire medical staff about percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD). I had all the data; Tom had the stories. And I got crushed. Anyway, I liken endovascular clot aspiration in PE to clot aspiration in myocardial infarction (MI) and embolic protection devices in transcatheter aortic valve replacement (TAVR). Seeing a clot that was once in the body has huge persuasive properties. But scary pictures of clot are not evidence. The European Heart Journal Open has published an eye-opening review on the endovascular treatment of intermediate-risk PE. Now I know what you are thinking: review articles are terrible to read. And I would agree in most cases, but this review however by Arman Shahriar, MD, is superb. Sharp, short sentences; lots of subdivisions. I will link to it, and there are two reasons to read it: (1) if you are interested in PE care, which is increasingly common in cardiology practice; and (2) this is a shining example of the failure of evidence-based practice to determine best therapies. Advocates of EBM should read it for the many lessons. Here is a brief review: PE is obviously a leading cause of CV mortality and morbidity. But the hard part of PE treatment is that PE is not one thing. It's a bit like atrial fibrillation (AF) in that way. PE can be mild, even incidentally discovered on a CT done for other reasons, and it can be severe and devastating, causing shock and collapse. The extremes make for easy decisions. But most people with PE present with 'intermediate' levels of risk. Endovascular procedures have increasingly been used in the past decade. Interesting is that the increased use parallels almost exactly the rise of PE Response Teams (or PERT). Since so few patients present with extremely high-risk PE or extremely low risk, most endovascular therapies are deployed in intermediate risk patients. The problem is that there is little evidence for use of these procedures in intermediate risk. In fact, no guideline gives interventional therapy a Class 1 recommendation because there is not Class-1-level data. A word on risk stratification and basic management: Everyone agrees the first step in PE care is to risk-stratify using clinical, lab, and imaging parameters. The European Society of Cardiology (ESC) defines high-risk PE by hemodynamic instability, which is associated with a 30-day mortality risk exceeding 15%. These patients require immediate adjunctive intervention directed at reperfusion (medical, endovascular, or surgical) to prevent death. By contrast, low-risk PE — characterized by normal BP, low clinical severity, and no evidence of cardiac dysfunction — carries a low early-mortality risk of < 1% and can generally be safely managed with anticoagulation alone in the outpatient setting. Intermediate-risk patients, which encompass 25%-60% of hospitalized PE cases, have stable vital signs but other concerning features, such as cardiac dysfunction. Short-term mortality rates in intermediate-risk PE range from 1%–3% in clinical trials; and 3%–5% in observational studies. According to the ESC, patients with both imaging and laboratory evidence of cardiac dysfunction are deemed intermediate-to- high risk. This is where controversy and uncertainty come in — because of the limited data. The rationale for endovascular therapy of PE stems from a seminal trial called PEITHO in 2014. NEJM published the RCT of systemic lytics + heparin vs heparin alone in 1000 patients with intermediate-risk PE. The study found a small benefit in its primary efficacy endpoint (composite of 7-day mortality and hemodynamic decompensation; 2.6% vs. 5.6%, P = .02) that was outweighed by risks of major extracranial (6.3% vs. 1.2%, P ≤ .001) and intracranial (2.4% vs. 0.2%, P = .003) hemorrhage. Thus, the rationale for endovascular therapies were born. Because systemic lytics worked but were far too dangerous. Lax FDA likely leads to dubious evidence: Five endovascular devices hold indications for PE in the US. In 2014, the EKOS ultrasound-assisted thrombolysis catheter (Boston Scientific) became the first FDA-authorized endovascular therapy in acute PE. This catheter was initially studied in one RCT of 59 intermediate-risk patients (ULTIMA) and a prospective cohort of 150 intermediate and high-risk patients (SEATTLE II), with both studies demonstrating short-term improvements in the right ventricular/left ventricular (RV/LV) ratio. Thereafter, four 'analogous' devices have passed muster in the FDA's 510k pathway, where a device only has to be shown similar to a previous device. These include clot extraction devices of one sort of another. The authors of the review paper in EHJ Open then discuss four important and yet unanswered clinical questions: One question is surrogate validity. Measures of right ventricular (RV) dysfunction, such as RV size > LV size were adopted in earlier studies because it is associated with early mortality. But experts, including the AHA guideline writers, acknowledge uncertainty as to whether rapid improvements in RV dysfunction is a reliable surrogate for outcomes. I would add that RV size is like LDL. No one cares about their echo image. They care about being alive and breathing well. Remaining question number 2 asks whether interventional therapy plus anticoagulation beats simple anticoagulation alone in the short and long term. Only three small trials have addressed this question and the results are mixed. Less than 200 patients have been studied in RCTs with these devices. I know; it's crazy. And again, I remind you FDA allowed these devices based on similarity to others — not evidence of benefit. Remaining question number 3 is whether endovascular therapy added to anticoagulation improves clinical outcomes for patients, including mortality, hemodynamic deterioration, symptom resolution, and sequalae that contribute to long-term mortality such as chronic thromboembolic pulmonary hypertension (CTEPH), post-PE impairment (PPEI), or recurrence of disease. For instance, in intermediate-high risk PE, short-term mortality ranges from 1%–3% and CTEPH develops in 2%–3% of patients, and PPEI in 10%–30%. Despite the rise in endovascular therapy, there have been no RCTs. The good news is that there are now at least three ongoing trials. My hospital participates in one of them and the problem is extremely strict entry criteria, which will limit external validity. The fourth remaining question is the safety of endovascular therapy. While all the devices limit systemic thrombolysis, some involved large-bore catheters. The authors cite a large, real-world, non-industry supported observational study published in the Journal of the Society for Cardiovascular Angiography & Interventions that found much higher rates of major bleeding with endovascular therapy than previously described (10%–15%). The authors devote another section to explaining the popularity of these devices in the absence of evidence. This is quite interesting. One cause is the rise of PERT teams — who are led by interventional-minded doctors. Another, and perhaps stronger, tailwind is reimbursement changes. I did not know this, but following an FDA 510k market approval, insurers independently determine if they will cover a device. The Centers for Medicare & Medicaid Services (CMS) is the largest insurer and its decision influence private insurers. But in 2021, CMS controversially ended its non-coverage policy for PE devices, which allowed local Medicare contractors to decide. This decision accelerated coverage and in turn accelerated use. CMS, the authors wrote, could have required ongoing evidence generation within its CED mechanism — that is, coverage with evidence development . But, alas, they did not. (By the way, a sidebar here, I feel like coverage with evidence—for everything new—could be the most important policy ever employed.) The third reason for rising popularity of these treatments is marketing of observational research. Industry sponsors registries, which of course are voluntary, and produce favorable results, and these get made into ads. Companies than spend money paying doctors to speak and travel. Here is a direct quote from the paper: Until its recent acquisition by Stryker, Inari Medical was a relatively young company that derived two-thirds of its revenue from FlowTriever sales. Since its initial public offering in 2020, the company had rapidly increased its volume and magnitude of general physician payments. In 2020, it made 3500 general payments to physicians amounting to nearly a million dollars. Over the next three calendar years (2021, 2022, and 2023), these figures increased to $2.49 million, $4.86 million, and $6.74 million, respectively, representing 0.9%, 1.2%, and 1.4% of top-line revenues. And it wasn't just physicians. Hospitals too benefited financially via higher diagnosis-related group (DRG) reimbursement rates. Get this: hospitals get paid on severity. Using a device bumps severity. So it's self-fulfilling. Here's another quote from the authors: ' Between 2021 and 2022, for example, the reimbursement for endovascular therapy for PE with major comorbidity or complications (MS-DRG 166) nearly tripled from $9040 to $24,550. Accordingly, an interventional PE service line can generate high revenues for a hospital system .' BOOM—there you go. PERT teams make money. I don't mean to beat up the PE treatment people. I highlight this topic because of its EBM lessons. In the heyday of cardiology, we were leaders in the generation of evidence. Post-MI care, HF care, and in arrhythmias we had CAST and AFFIRM. So, it's weird that that same evidence-generating ethos did not infect the PE world. Which of these devices, if any, is better is a knowable question. But it won't come from observational studies. It has to be via RCTs. And I realize PE patients come in different varieties, but nonetheless, these studies could have been done. And then we would know. And you might say, John, there are ongoing trials now. My counter is that it's largely too late. Equipoise has been injured. When you return from a clot-extracting course on a beach resort, do you think you are going to be energized to randomize a PE patient in a trial or do clot extraction? When reimbursement is favorable, do you think doctors will be keen to randomize or do the procedure? I have already sent multiple notes to my friend Vinay Prasad encouraging him and Marty Makary at the FDA to do something to tighten device regulation. I am not against approving early generation devices, but there must be strong post-marketing requirements for evidence. There currently is not. But, in truth, as professionals and scientists, we should not need FDA to help us. We should want evidence; we should require evidence before exposing our patients to unproven therapy. Sadly, though, the recent experiences with left atrial appendage occlusion, PE, and now tricuspid interventions don't shine a favorable light on the scientific aspects of our profession. The Journal of the American Heart Association published an interesting paper on trends in heart disease mortality. It makes you think. A Stanford-led team used the national vital statistics at the CDC to present data on heart disease mortality over the past 52 years — from 1970 to 2022. The findings: Some good news: Heart disease deaths are decreasing. In 1970, heart disease accounted for 41% of deaths; that has declined to 24% of all deaths. And life expectancy went from 71 years in 1970 to 77.5 in 2022. The proportions of types of heart disease deaths have changed dramatically. Over the past 50 years, overall age‐adjusted heart disease mortality decreased by 66% from 1970 to 2022 (from 761 to 258 per 100,000). In 1970, more than 90% of heart disease deaths were ischemic. Ischemic causes of cardiovascular (CV) death declined to 53% in 2022. One of the reasons may be this statistic: Since 1970, age-adjusted mortality from acute myocardial infarction (AMI) decreased by 89%, from 354 to 40 per 100,000. Since 1970, age-adjusted mortality from any ischemic disease decreased by 81%. But, conversely, since 1970, age-adjusted mortality from other heart disease subtypes increased by 81% with the greatest increases in HF (146%), hypertensive (106%) and arrhythmia (450%). For instance, in 1970, these other subtypes (HF, hypertensive, and arrhythmia) accounted for just 9% of heart disease deaths; now it is 47% of heart disease deaths. First is that the authors rightly acknowledge limitations in the use of coding. For instance, disease names have shifted somewhat. Arrhythmia-related deaths may in fact be related to underlying ischemic heart disease. But limitations aside, it's worth thinking about this data. The fall in deaths from AMI and ischemic heart disease represents a shining example of excellence in both cardiology and public health. The reduction in smoking stands out as a huge success in public policy. Surely this has enhanced the lives of millions of people. I would also laud my interventional colleagues. I spend a great deal of time criticizing the overuse of intervention in stable CAD, but the acute treatment of MI has been one of the most important medical achievements of a generation. Young people cannot appreciate where we were when I began medical school in 1985. MIs then were largely treated with morphine and Swan-Ganz catheters. Now, people come in with an anterior MI and leave with band-aid on their wrist and a normal ejection fraction. So impressive has been the trend in AMI care that it is hard to find an ischemic cardiomyopathy patient who qualifies for a primary prevention implantable cardioverter-defibrillator (ICD). Keep in mind too that this marked reduction in MI deaths bears on screening for heart disease. Namely, the better we get at treating a condition, the less value there is in finding it early. We don't screen for appendicitis or gallbladder disease or pneumonia because we can simply treat those problems when they occur. AMI isn't quite there but it's approaching that. By the way, if you are young and looking for a job that has meaning, I can't think of a better job than interventional cardiology. Nearly every day, you are saving or enhancing a life. The problem of course is that it is hard because like delivering babies, MIs happen at all hours. Another factor in the reduction of death from ischemic heart disease could be statins. Statin use has gone from none to up to 45% of adults over the time frame. Since we know that statins consistently reduce CV events by about 25%, not having an MI in the first place is a good way to not die of ischemic heart disease. I for one think statins play a consequential role in lower ischemic heart disease deaths but smoking and MI care are much larger causal factors. My final comment is the alarming language (both in the paper and online) regarding the rise in other forms of heart disease. Yes, the rise in obesity, which has led to more hypertension and more AF and more heart failure with preserved ejection fraction (HFpEF) is a big concern. I don't want to downplay it. Obesity is a public health crisis, and largely a public health failure. But on the other hand, it's important for doctors to understand that all people die. If you reduce MI deaths, and increase life expectancy, what do you think happens: people die of other diseases, such as heart failure, atrial fibrillation, dementia, cancer, and falls. It's normal. It's still a good thing to extend life, and enhance life, but it's also important to recognize that reducing ischemic heart disease deaths does not magically reduce healthcare costs, because eventually, aging people develop some sort of disease, and if is treated, money is spent. The reason to improve treatment of heart disease is not to save money — it is to extend quality of life. If our therapies do that, then it is worth the money spent. American Diabetes Association (ADA) 85th Scientific Sessions I won't get into specifics, but at the recent American Diabetes Association meeting in Chicago a trove of studies came out that should be on our radar. For instance, a study showed early data on once-weekly insulin. Think about that if you have type 1 diabetes: once-weekly insulin. There were early studies on other GLP-1 drugs as well as combinations of drugs. I think semaglutide and tirzepatide may become the simvastatin of GLP-1's soon. There was even some encouraging data on recombinant gene therapy for type 1 diabetes. The diabetes world is advancing fast. And I think it's only a matter of a short time that cardiologists will be prescribing GLP-1 drugs like we did for SGLT2 drugs. And finally, before I close, I'll say that there's been another BMJ investigation as reported on more potential — emphasis, potential — troubles in the ticagrelor evidence base. I will look into that and have a report on the next TWIC podcast.
Medscape
20-06-2025
- Health
- Medscape
Jun 20 2025 This Week in Cardiology
Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast , download the Medscape app or subscribe on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only. In This Week's Podcast For the week ending June 20, 2025, John Mandrola, MD, comments on the following topics: a big, deep dive into CTA and fractional flow reserve CT, and a sobering report on the new EVOQUE valve. Mark Petrie from the UK writes to correct my description of the CRAAFT-HF trial. I mistakenly said it was a surgical vs catheter ablation trial, but Dr Petrie said that they were actually randomizing to atrial fibrillation (AF) ablation plus heart failure with reduced ejection fraction (HFrEF) medical therapy vs HFrEF medical therapy alone in patients with left ventricular dysfunction. Saturday is the first day of summer. Where has the time gone? There is a spot at the halfway point of our 5 AM ride, about 20 miles out in the country that the sun rises over a farm on a hill. It's a hot spot on the ride but once a year I try to convince the crew to stop for a photo. Imaging and Behavior Change Five Reasons I Don't Believe an Imaging Test Improves Outcomes My friends in Edinburgh, who have been leaders in the use of coronary computed tomographic angiography (CCTA), report on a nested substudy within the SCOT-HEART 2 trial. Let's start with SCOT-HEART 1, which randomized symptomatic patients (stable CP) to receive CTA plus standard care vs standard care alone — which often included functional stress testing. CCTA-led care led to a significantly lower rate of death from cardiovascular (CV) death and nonfatal myocardial infarction (2.3 vs 3.9%). This seemed like a big win for CCTA, but the controversy centered on the fact that the small delta in statin use in the two groups (more in the CTA) was nowhere near enough to drive the large reduction in myocardial infarction (MI). For instance, I cited Andrew Foy, who calculated that to believe statin therapy drove SCOT-HEART, you'd have to believe statins have a number needed to treat (NNT) of 3, not its normal 50-100. Nonetheless, the use of CCTA is different in cost-constrained systems like Scotland. In Scotland, it is used to reduce coronary angiography and PCI. Knowledge of coronary artery disease (CAD) is used to guide medical therapy, and there is no incentive to do more angiography. In the United States, CCTA is used as a cash machine, because the nanosecond an American patient and American doctor see CAD, the patient gets a hotline to the cath lab and PCI. The problem, of course, with anatomical testing is that you can have twinge of chest pain from a cramp and if you have incidental CAD, boom, you now have lifelong dependence on antiplatelet. Now to the SCOT-HEART 2 trial, which is a randomized controlled trial (RCT) using CTA. The study question is this: Is screening with CTA more clinically effective than CV risk scoring with an equation? The plan is to enroll at least 6000 people (not patients, people ) in Scotland who are at risk of heart disease to CTA-guided management vs equation-guided management. They will use an equation called ASSIGN, which is like the pooled cohort equation (it only uses outcome data from Scotland) and includes the social deprivation score. Those in the equation (or standard care) arm get lifestyle advice and lipid-lowering therapy (LLT) for 10-year risk > 10%. Those in the CTA arm get lifestyle advice for normal CTA, lifestyle advice, plus LLT and aspiring for non-obstructive disease, and for those with obstructive disease, they get lifestyle advice, LLT, aspirin, ACE inhibitor plus review by a cardiologist. At 5 years, the primary outcome is coronary death or MI. There are lots of secondary outcomes. JAMA Cardiology has published a nested cohort study within SCOT-HEART 2 looking at a primary outcome of the proportion of participants who achieved the National Institute for Health and Care Excellence (NICE) recommendations for diet, BMI, smoking and exercise. Diet, smoking and exercise were self-reported, and weight, BMI, and step count were measured. The study population included 400 people enrolled over 4 years, which does not seem like a lot. At 6 months, those in the CTA screening were more likely to meet the primary composite endpoint of compliance with the NICE recommendations for diet, BMI, smoking and exercise — it was 17% vs 6%. These seem low but that's because people had to reach all four of the components. The relative risk increase was an odds ratio of 3.4 times more likely to achieve these four goals in the CTA group. Other secondary findings were that fewer participants in the CTA group were recommended for LLT (51% vs 75%). That's because the risk score placed more above 10% but with normal CTA, LLT was not given. Even though fewer LLTs were recommended with CTA, acceptance of LLT was higher in the CTA group, 77% vs 46%. In the end, statistically similar numbers of patients took LLT in both groups (44% vs 35%). Antiplatelet use was much higher in the CTA group, 40% vs 0.5%. The authors broke down secondary outcomes based on whether CTA showed disease, and this associated with slightly lower weight, BMI, waist circumference, blood pressure, total and LDL cholesterol concentrations, and greater improvements in daily step count. Another interesting twist was that 100 individuals in the CTA arm were given a verbal report of their CTA and the 100 were shown their images. No differences were seen in the two subgroups for the primary and secondary outcomes. The authors were pretty calm in their conclusions. They note these interesting observations, that CTA resulted in more accurate risk stratification where some patients with high equation risk had no disease and some patients with low equation risk had disease. CTA did increase acceptance of lipid-lowering therapy as well as increase the proportion of patients reaching lifestyle goals. The obvious take-home message here is that this data supports the seeing-is-believing idea. The editorialists wrote enthusiastically that: 'the results of this nested randomized clinical trial within the SCOT-HEART 2 study are striking. A preventive strategy incorporating CCTA appeared to be not only more precise but also more motivating to participants and clinicians. CCTA reclassified 1 in 3 individuals based on 10-year risk score, targeting therapy to those who were assumed to derive greatest benefit.' I laud the Edinburgh team for doing SCOT-HEART 2. But the differences in verbal acceptance of lifestyle, or LLT use, or aspirin use, or tiny blood pressure (BP) changes are not what we care about. The only outcome is MI or coronary death. When you submit a person with no disease to medical imaging, it ought not be for motivation. It should only be for their health benefit. The changes in lifestyle or drug use or more precise risk stratification are made up surrogate endpoints that have meaning only if there is a difference in outcomes. I strongly oppose the use of imaging to scare patients into taking statins or not eating chips. In Scotland, the downstream effects of CTA may be different than in the US. Here, it is highly likely that seeing disease will affect future interventions. Let's say there is mild disease noted on a screening CTA. Maybe the US patient is given statins and aspirin. Well, what do you think happens in the months or years to come the next time that patient has a twinge of CP? It's right to the ER and then the cath lab for stents or bypass. We need to celebrate the fact that SCOT-HEART 2 will be done, but until then, we need to resist the urge to image our patients based on minor differences in surrogate endpoints, some of which are self-reported. Heart disease treatment and prevention is simple: it's lifestyle (including diet and exercise), possibly lipid-lowering therapy. Imaging is not required and should not be done until there is evidence it improves outcomes. Symptoms Don't Always Indicate the Severity of Coronary Artery Disease JACC-CV Interventions has published a research letter looking at the association between cardiac symptoms and coronary plaque. I will call this a back-to-the-future study with modern imaging confirming a lesson that Dr Bernard Lown described a half-century ago Only now we get to toss around terms like fractional flow reserve, total plaque atheroma, and — sit down for this one — artificial intelligence–enabled quantitative coronary plaque analysis (AI-QCPA) tools. I will speak about the letter, which is modest, but the main thing that happened is that it caused me to look into the FFR-CT data. And OMG. The researchers used data from the ADVANCE registry, which was a 5000-patient registry from multiple centers done to assess how often FFR-CT changes management vs regular CT. The sample included about 4300 patients who referred for coronary CT and had a coronary lesion. Symptoms were characterized by a) squeezing chest or neck pain, b) pain precipitated by exertion, c) relieved by nitrates or rest. Typical angina had all three; atypical angina had 2 of 3, noncardiac had one, and there was also a group with dyspnea only. There were five groups of patients: 25% no symptoms 10% dyspnea only 6% noncardiac 37% atypical chest pain 22% typical angina Now pause. The authors had total plaque volume and FFR-CT on each of these patients. Then they just did correlations. And they found, with these correlations: Only typical angina had a positive correlation with plaque atheroma. Typical angina also correlated strongly with negative values of FFR-CT. The authors also noted, surprisingly, that atypical chest pain, noncardiac chest pain, and dyspnea each correlated with higher FFR-CT, greater than 0.8 suggestive of normal flow. The authors and imaging proponents seem excited about this. In a Medscape news article, one of the authors says: 'Even having no symptoms was not a reliable indicator of cardiovascular health in these patients. Just because a patient doesn't report any symptoms doesn't mean there is no atherosclerosis.' Also quoted in the news article, Matthew Budoff, MD, a cardiologist at UCLA said: 'cardiologists rely heavily on symptoms to determine how severe cardiovascular disease is, but the new research is beginning to dispel that idea.' Budoff also added that: 'the new findings support the idea CT angiography should be a bigger part of the diagnostic process, so clinicians can look not only at whether a patient has stenosis but also go beyond to see if they have any atherosclerosis or plaque that might be a target for medical therapy.' This letter seems so funny to me. One of the first lessons we were taught at Indiana University in the 1990s was that when a patient presented with typical angina and even a positive stress test, that catheterization would show left main or severe triple vessel disease about 10%, it would be normal in 10%, and somewhere in between in 80%. In other words, symptoms are a very unreliable marker of CAD. Now we have a study that uses have artificial intelligence (AI), CT, FFR, and multivariable regression to confirm something that's as old as the hills. I don't agree with Dr Budoff that cardiologists rely heavily on symptoms. At least not in many places in the US. The main requirement for a stress test in the US is insurance coverage and the main requirement for a cath is a wrist. We don't rely on symptoms. We rely on imaging and angiography. I have this saying that I don't say too much anymore but think often: If every stress imaging machine broke for a month, heart disease outcomes would not change. I wonder whether this also applies to CTA imaging and surely to FFR-CT. A colleague tells me that FFR-CT adds $1500 to basic CTA. I find that shocking. Now I want to go to the advance registry paper in 2018. The main value in this research letter was a kick in the butt to go back to the original evidence for this FFR-CT business, the publication of the ADVANCE registry in the European Heart Journal in 2018. First author Fairbairn. This will be a trigger warning because this is one of those things you can't unsee or unhear. ADVANCE registry included about 5000 patients with symptoms concerning for CAD and atherosclerosis on CCTA. The authors recorded the basic info, symptoms, CCTA and FFR-CT findings were recorded along with treatment plans. They also had 90-day outcomes. For each enrolled patient, a clinical management review committee used data from coronary CTA to determine the management plan using the following criteria: (a) optimal medical therapy, (b) percutaneous coronary intervention (PCI), (c) coronary artery bypass graft surgery (CABG), or (d) more information required. The primary endpoint of the registry is the reclassification rate between the management plan based on coronary CTA alone vs CTA plus FFR-CT. Two teams came up with the original plan based only on CTA. A site team and a blinded core team from Duke. The primary endpoint was the reclassification of the treatment plan from the CT-FFR results. The primary results were that it changed management in about two-thirds of the cases. It was hard for me to see a pattern in the reclassification. The authors tell us later that the majority of subjects were safely deferred to medical management alone, and only a minority required 'further testing.' A second finding was that rate of no significant disease at angiography was significantly lower in patients who had a positive FFR < 0.8 (about 15%) vs > 0.8 (44%). Odds ratio for no significant disease was 0.19 for a positive FFR (that is < 0.8) A third finding was that 19 MACE events happened in the 90 days after the study, 10 of them were death, and all happened in the FFR < 0.8 category — 19 vs 0. The authors concluded that FFR-CT was great. It guided management, helped predict no disease, and even had a strong association with MACE events. They noted this: 'FFR-CT led to a recommendation of invasive coronary angiography (ICA) in only 40% of subjects in a cohort with an anatomic obstructive disease rate of 72%, and subjects referred for ICA downstream were significantly more likely to have obstructive disease at ICA if they had a positive FFR-CT.' And this: 'Importantly, a negative FFR-CT was associated with an excellent short-term prognosis, as none of the 1600 subjects with negative FFR-CT experienced death, MI, or unplanned hospitalization for ACS and urgent revascularization.' A colleague in imaging advises me that this was one of the major studies cited to establish FFR-CT. My gosh, this is terrible. What a mess. First of all, the study was sponsored by HeartFlow. It was a late-breaker at ESC in 2018. I must have had jet lag because I missed it. Much of my criticism follows a Twitter thread from my friend Venk Murthy at University of Michigan. A primary endpoint in change in management in a voluntary registry sponsored by the company is about as weak an endpoint as you can get. Why isn't this a measurement of clinical psychology? What if you chose, say, in a non-industry-funded study, a doctor team skeptical of FFR-CT. I bet few would be swayed by the CT-FFR results. Another problem was that most of the FFR-CT values were abnormal in the left anterior descending artery (LAD) and were between 0.7-0.85. We know this from the IQR values. But now I will cite a study from Christopher Cook in Darrell Francis' group published in JAMA Cardiology 2017. What this London group found is that when doing a systematic review of all studies measuring the diagnostic accuracy of FFR-CT, they found that values just under the cutoff of 0.8 (that is, between 0.7 and 0.8) had the lowest accuracy — only 46% accurate. Pause there. That's like a coin flip. Cook et al report that if you want accuracy from FFR-CT, say 82% overall accuracy threshold, you needed values lower than 0.63 or above 0.83. And if you wanted more stringent 95% and 98% diagnostic accuracy thresholds from FFR-CT, you needed values lower than 0.53 or above 0.93, and lower than 0.47 or above 0.99, respectively. A third issue is that most of the patients (77%) were nontypical angina — either atypical or non-cardiac pain. But we know from the Manesh Patel seminal NEJM paper from 2010 that when patients with atypical symptoms go to cath, the chance of obstructive disease is low — regardless of the results of stress testing. In fact, a positive stress test only changed the likelihood of having CAD from 35% to 41%; hence, my stance that if every stress imaging machine broke, CV outcomes would hardly change. The point in citing this seminal paper is that most patients in the ADVANCE registry study — the 77% with atypical symptoms — should not have had a change in management. A fourth issue is that the MACE events are 100% noise — 19 vs 0. And 10 deaths in the first 90 days. I can't even believe they mentioned MACE events. The CI for the odds ratio goes from 1.2 to 326. The P-value, however, was calculated to be significant at .039, which is crazy. So, in sum, this is one of the weakest, late-breaking, practicing-changing trials I have seen. It's a psychology experiment and we have no idea a) which treatment strategy was best, and b) what meaning is there in changing a treatment strategy without knowing which one is correct. If we wanted to know about FFR-CT, it's simple: you randomize people to care with the HeartFlow FFR-CT vs those without. Then you measure outcomes — MI, CV deaths, even urgent revascularization. But this was not done. Instead, FDA approves the HeartFlow, proponents and key opinion leaders speak highly of it, these studies are not highly criticized, and CT scans get $1500 added to them. HeartFlow was approved de novo in 2014 but received a 2019 clearance for 'virtual modeling.' When I asked my AI friend Claude to explain the difference between the two designations — 2014 and 2019 — one of the 'significant' points was a business model expansion wherein the original FFR-CT was a one-time diagnostic test, but the 'planner (the virtual modeling) creates additional revenue opportunities for each patient who needs intervention.' And then this: the 2019 decision Expands HeartFlow's market from diagnosis into treatment planning. My AI program Claude must not know I am a critical appraiser because it then wrote: Physicians can now use HeartFlow for the entire patient journey: diagnosis → treatment planning → post-intervention assessment. This creates much stronger physician adoption and stickiness. And it makes the cost–benefit analysis more favorable since one CT scan can support multiple clinical decisions. The 2019 Planner approval was huge for HeartFlow because it transformed them from a diagnostic company into a comprehensive coronary care platform. Instead of just answering "Does this patient need a catheterization?", they can now answer: "Exactly how should we treat this patient's disease?" This is why HeartFlow's valuation and market penetration accelerated significantly after 2019. They weren't just competing with stress tests anymore; they were competing with the entire invasive workup process. I had no idea this stuff was happening. What a tragic waste of money. This may be one of the lowest value medical interventions I have seen. And you think I am wrong to be hopeful about FDA new leadership. Regulators should have required an RCT. Since they did not require and RCT, physicians should. Companies are not nefarious. They simply jump over the bar we hold for them. In this case the bar was ridiculously low. Speaking about lax FDA regulation, JACC has published a sobering research letter on the transcatheter tricuspid valve replacement called the EVOQUE valve. This one is also really scary. On this I hardly need commentary; I can just tell you the data. First author was Lior Lupu. FDA approved the valve in February 2024. This was based on the pivotal TRISCEND II trial, which was driven quality-of-life measures, not hard outcomes, and was not blinded. Thus, placebo effects were surely present. The group of authors from Washington, DC used the MAUDE database at FDA, which stands for Manufacturer and User Facility Device Experience. It contains information about device malfunctions, injuries, and deaths associated with medical devices that have been reported by manufacturers, healthcare facilities, and users. The main weakness of MAUDE is that there is no denominator and it's voluntary. In the year since approval, the research team found 150 reports on EVOQUE that describe 158 events. 1. Bradycardia or high degree atrioventricular (AV) block was most common (n = 70 or 44%) and there were 2 deaths. 66 of the 70 required pacemakers. Most were detected at the implant however a third were seen later between days 3 and 90. 2. Device malposition, migration, or embolization occurred in 33 patients (20.9%), causing 6 deaths. Most events were diagnosed within 3 months: 76% intraprocedurally, 14% within 2 days, and 7% between 3 days and 3 months. Management included transcatheter valve-in-valve implantation in 10 cases (eg, SAPIEN-in-Evoque), with 2 requiring a second valve for optimization. Two patients underwent transcatheter treatment for paravalvular leak, while 16 required surgery. 3. EVOQUE leaflet thickening or thrombus was identified in 20 patients (12.7%), with clinical or hemodynamic consequences reported in 16 of the 20. Cases were detected within the first month (56.3%), between months 2 and 6 (25.1%), and after 1 year (18.8%). Management included thrombolysis (n = 4), transcatheter valve-in-valve implantation (n = 2; 1 also had device migration), and surgery (1 patient with severe postprocedural thrombosis with hemodynamic instability). 4. Cardiac tamponade was reported in 8 patients (5.1%), with 5 patients undergoing surgery and 4 deaths. 5. Venous injury or bleeding occurred in 8 patients (5.1%), with 2 deaths. 6. Five cases of ventricular tachycardia, fibrillation, or cardiac arrest were reported: 2 intraprocedurally and 3 postprocedurally (days 0, 4, and 7). 7. Mechanical failure of the delivery catheter was reported in 4 patients (2.5%), all due to nose cone separation. The authors write that while bradycardia, tamponade, valve injury, and valve thrombosis had been reported in the trial, valve malposition, migration, or embolization — the second most frequently reported adverse event in this research letter — were not reported in the trial. So, they were new discoveries. Also, additionally, 3 cases of ventricular arrhythmia or cardiac arrest were reported within the first postprocedural week without a definite etiology. Nose cone separation wherein the nose can go missing into the PA also occurred. Like I said, I hardly need comment because the list of complications is so sobering. Of course, MAUDE has no denominator, but on the other hand it is also voluntary, so this is likely underreporting. I would note that only 237 patients received a valve in the TRISCEND II pivotal trial. There were substantial complications noted. To me, this was quite lax regulation. First, there should have been a trial with a sham procedure. Quality-of-life metrics are meaningless when one group gets a procedure and the other group gets bland white tablets. Second, there should have been more patients in the trial. And third, the approval should have been contingent on a required database, such as that with TAVR. This report is really scary given the number of deaths. In fact, mortality from tricuspid valve surgery is the main reason transcatheter techniques were designed. In the transcript, I highlighted in orange font the number of deaths. I counted 14 deaths and 5 cases of ventricular tachycardia/cardiac arrest. Proponents may cite the learning curve, but I doubt it because I read that the company did a slow rollout where centers who were part of the trial were first. And you wonder why I am a medical conservative and slow adopter.
Medscape
13-06-2025
- Health
- Medscape
Jun 13 2025 This Week in Cardiology
Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast , download the Medscape app or subscribe on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only. In This Week's Podcast For the week ending June 13, 2025, John Mandrola, MD, comments on the following topics: Listener feedback on cardiac sarcoidosis, SA node ablation, surgical AF ablation, chronic kidney disease protection, and recruiting for clinical trials. One of the best parts of this podcast is the listener feedback I receive. This week, David Birnie, MD, the division chief of cardiology at the University of Ottawa and an academic electrophysiologist, active in cardiac sarcoid research, sent me feedback on a paper from Dutch and American authors that I covered 2 weeks ago on May 30. The Mostly Dutch paper studied ~1500 patients with biopsy-proved established sarcoidosis, most of which were non-cardiac. The question was how to risk stratify for an implantable cardioverter-defibrillator (ICD). The two ways were using either professional society recommendations or cardiac magnetic resonance imaging (CMR). CMR was grouped into 4 categories: one high-risk category and three low-risk categories. High-risk category was 'pathology-frequent LGE.' The three main findings were that if either professional society criteria or CMR indicated a high risk, the rate of ventricular tachycardia (VT) at 5 years was high — about 1 in 3 patients had VT. The second finding was that CMR had the better C-statistic compared with risk criteria from professional societies. The C-statistic was quite good at 0.86. The third and most sobering finding was that ICDs treat sudden death and being wrong is fatal. And yet the prediction missed some patients. And this is what Dr Birnie writes about. That is…the nuance of risk stratifying for an ICD in patients with suspected or documented cardiac sarcoidosis (CS). One of the most common ways that CS presents is with atrioventricular (AV) block at surprisingly young ages. When a 75-year-old presents with AV block it's surely due to aging. But when a 50-year-old presents with AV block, you should think about CS. Birnie writes, in an email: Specifically in CS, patients who present with advanced conduction system disease and metabolically active disease seem to be at very significant subsequent risk of VT and VF, even with normal EF. He cited a study from Circulation EP 2018, which showed that AV block, even with a normal EF, had 5-year VT rates of nearly 10%. It is not clear why that is, and research is ongoing and Birnie says it may partly actually be related to steroids. He cited one of his papers in JCE . And the title of that paper was: 'Treatment with corticosteroids was associated with an increase in ventricular arrhythmia burden in patients with clinically manifest cardiac sarcoidosis: Insights from implantable cardioverter-defibrillator diagnostics.' He adds that most of us in the field regard this subgroup as an exception to any sort of late gadolinium enhancement (LGE) cutoff or pattern 'rule.' Indeed, due to increased awareness and CMR and PET, we are increasingly diagnosing these patients earlier and earlier and there are reports where the PET scan is positive and the MRI is actually negative (Eur J Nucl Med Mol Imaging. 2016 Feb;43(2):259-269). That is, the disease is picked up so early in the process that scar has not yet formed. These findings led Dr Birnie to strongly recommend that all patients in this sub-group are recommended to have an ICD regardless of LGE. He and colleagues are currently updating the Heart Rhythm Society guidelines on all of this, hoping to be published early in 2026, co-chaired by myself and Jordana Kron. He also wanted me to plug a cardiac sarcoid conference that he's hosting Aug 24-25 in Ottawa. Thanks to Dr Birnie for updating me and TWIC listeners. Pulsed field ablation (PFA) is white hot in the EP world, So it had to happen. Heart Rhythm Case Reports , which is a really great journal, has published a case report of a group who failed to resist the urge to mess with the sinus node. Yes, a group of ablation doctors report the first case of using PFA to ablate the sinus node in a patient with purported inappropriate sinus tachycardia (IST). I don't usually cover case reports, but I want to mention this report because of the seriousness and danger involved. First some background on IST. IST has been around since I was training. I know this because we tried ablating sinus nodes in the 1990s and it went terribly. It either did not work, or injured the phrenic nerve or it caused symptomatic junctional rhythm. I tried it a handful of times earlier in my practice — and it still did not work. Many of my colleagues think ablation of the sinus node doesn't work because of the difficult anatomy of the sinus node, which is a) not in one place, b) often epicardial, and c) in close proximity to the phrenic nerve. And anatomy may indeed be problematic, but the far more important reason that ablation is a bad idea for IST is that the cause of IST is unknown and likely not cardiac. And this is a problem. If the sinus node is normal but receiving disordered neural input, then ablating the normal structure is not going to work. It's sort of the atrial fibrillation (AF) ablation problem on steroids. Yes, there are a few variants of AF clearly a forme fruste of atrial tachycardia from the pulmonary veins (PVs), as was described by the Bordeaux group 25 years ago, most AF occurs because of a mixture of triggers and substrate. We ablate the PVs and sometimes it works. Ablating the sinus node (SN) for IST is even worse, because IST is surely caused by something extracardiac. Perhaps an autoimmune condition, more often seen in women, and surprisingly, women who work in the health field. Anyways, the case report involved using PFA to ablate the SN. The patient already had a pacer because of an overzealous previous SN ablation attempt. The pacer was no longer pacing because the IST had recurred, which is often the case. The authors tell us that it worked, heart rate (HR) was reduced, and the 34-year-old women felt better with atrial pacing and had persistent junctional rhythm at 90 days — 90 days. If I had reviewed this case, I would have strongly urged the editors to not publish it. One reason is that the women had morbid obesity, so I question the diagnosis of IST. Morbid obesity can surely cause regular sinus tachycardia (ST) due to a combination of deconditioning and genetic causes. In other words, the ST may not have been inappropriate. Second issue is that we only get 90 days of follow-up. Who knows whether the HR will come back. We also get no discussion of the long-term risks of a 34-year-old with a pacemaker. This, my friends, should be avoided in the most strenuous ways. When she is my age, she will have 30-year-old leads. Then what happens when she gets infection at a generator change. Or there is lead failure. I want to also mention some of those who are advocating a combined surgical–hybrid thorascopic ablation approach wherein a surgeon does epicardial linear ablation to isolate the SN. I will cite a non-random comparison study from 2022 where the surgical approach compared favorably to the endocardial ablation approach — that we know does not work. This study included authors who were employees of AtriCure, the company that makes the linear ablation device. It was not randomized, not blinded, and included no sham procedures. The control arm of endocardial ablation we know does not work. My take of this space and condition is that research should be focused on the causes of IST. I warn my colleagues not to run amok with PFA. I understand the urge to do something aggressive for these patients, because IST causes a lot of symptoms. Care of these patients requires tons of empathy, honesty about uncertainty, patience, and reassurance that it will likely improve with time. IST is similar in some ways to postural orthostatic tachycardia syndrome (POTS) and things like supine exercise often works. But not right away. PFA makes it easier to destroy cardiac tissue, that's good in the left atrium (LA) because we can avoid atrioesophageal fistula. But IST should infuse us with great caution. To be honest, I am not even sure there is enough equipoise to even propose a randomized controlled trial (RCT) including ablation as an arm. The first thing to say is that surgical AF ablation, especially concomitant ablation, holds great promise. The patient is already being operated on, so the extra risks are minimized, plus these patients often have significant structural heart disease. The problem in this space is the limited data, multiple approaches, and varied patient presentation. We simply don't have CABANA-like data for surgical AF ablation. Probably the best compilation of the data is a meta-analysis from the group of Richard Whitlock, first author, Graham McClure in EP Europace in 2018 — yes 7 years ago. They meta-analyzed 23 RCTs and found that surgical AF ablation did reduce AF compared to no ablation, but did not affect stroke or mortality. The key finding though was that only one of the trials was considered low risk of bias. So we need data on surgical AF ablation. Not only because it's potentially very helpful, but also because it can be incomplete, or, what I call willy-nilly ablation to add an extra CPT code. This is especially bad because it can lead to LA flutters or poor atrial transport function. A recent retrospective, observational comparison study published by a number of academic surgeons in the Annals of Thoracic Surgery has stirred some conversation online. It's stirred conversation because the group who received surgical ablation had a significant survival advantage. The data source came from Medicare. Patients who had ablation at the time of coronary artery bypass grafting (CABG), which also includes hospital and surgeon volume as well as the surgeon's preference for doing ablation. Some do it a lot; others do it very little. That is a hint. The primary endpoint was all-cause mortality, which I often like because it is free of ascertainment bias — alive or dead. But it is not a great AF ablation endpoint because exactly zero non-HF trials of AF ablation show mortality reduction. That's because reducing AF burden is unlikely to reduce death, because of competing causes of death. That too is a hint. This study had a twist, though, in the comparison, which is necessary, because literally everyone knows that healthier patients are more likely to get concomitant ablation. The authors did something else to try and sort out the obvious confounding. They did an instrument variable analysis wherein the authors used surgeon preference for ablation as the "instrumental variable" (IV variable). Here's how it works: Some surgeons frequently perform ablation (> 40% of their cases) Some surgeons rarely perform ablation (< 5% of their cases) A patient's treatment depends partly on which surgeon they happen to see, and this creates — from a patient perspective — a "quasi-randomization." Then the authors do two parallel analyses: both require propensity matching techniques. As-treated analysis, which is a direct comparison of patients who got ablation vs. those who didn't. This is the traditional and highly biased approach. Surgeon-preference analysis: a patient with AF is sort of randomized in which surgeon operates on them. And if surgical AF ablation reduces mortality, surgeons who do more often should have lower mortality. This approach is interesting because if both analyses show similar results, it somewhat strengthens confidence that the findings are real rather than due to selection bias. And that's exactly what they found: As-treated analysis : 4.40 months survival advantage Surgeon-preference analysis: 4.96 months survival advantage The concordance between led the authors to conclude: 'Our findings support current guidelines recommending for surgical ablation during CABG in patients with atrial fibrillation and it highlights that ablation is currently underused in contemporary practice.' I am very warm to the possibility that concomitant surgical AF ablation may be a good thing to do for some patients with coronary artery disease (CAD) and CABG and AF. But this study does not support anything, nor does it suggest AF ablation is underused. Despite doing an IV analysis, which sounds great, this is still a non-randomized comparison. There is likely selection bias that cannot be overcome by matching. For instance, surgeons who do more AF ablation may see different types of patients, they may work at a better hospital and do better follow-up. These are things that randomization takes care of. That's not the main reason I don't put any weight on this study: the main reason is that the authors found no difference in the incidence of stroke in the two groups with either the as-treated or surgeon preference analysis. So, I ask, if the ablation of AF is not good enough to reduce stroke, how does it reduce death? I don't see a mechanism for reducing death — especially given all the other competing risks. What's more, the Whitlock meta-analysis of 23 RCTs showed no reduction in death with surgical ablation. So, your prior belief has to be extremely pessimistic and therefore it would take strong evidence to change. About 100 times stronger data than this. What's more, the mortality curves separate (by only 4 months) after 5 years. That seems a) like a minimal difference and b) separation over that long a time seems more related to healthier patients getting surgical ablation or better health systems. I want to continue my friendships with the cardiac surgeons. They do important work. But I would also suggest as humbly as possible that they need to improve when it comes to evidence generation. To me, there seems a huge need for proper RCTs of standardized AF ablation techniques. Endpoints should not be all-cause death. It should be AF burden and stroke incidence. Given the increasing prevenance of AF and CAD, I would think this would be a fantastic place for the new NIH leadership to invest money in. I realize that TWIC is a cardiology podcast, but we have yet another big randomized controlled trial of finerenone, the newest mineralocorticoid receptor antagonist, or MRA. As an EP doctor in the Southeastern United States, are unhealthiest geography, I see many patients for AF who also have type 2 diabetes (T2D) and chronic kidney disease (CKD). It goes with the territory. If you are an AF patient obese enough to have T2D, you likely have some CKD. I scratch my head these days, because in T2D there are so many drug classes available. Which one should we use, or should we use both—as if the drugs were generic $4 per month tablets. New England Journal of Medicine published the CONFIDENCE trial last week. I discuss it because it provokes me to think about science questions vs marketing efforts. Here is the deal. Patients with T2D who were taking an ACE inhibitor or ARB and had CKD as defined by an increased urinary albumin-to-creatinine ratio. I know, cardiologists don't use this number. Just think about it as enough CKD to spill protein, which is bad, and correlates with CV outcomes. The study treatment arms were finerenone alone, empagliflozin alone, or the combination of the two. The primary outcome was change in the urine albumin-to-creatinine (UACR) ratio. About 800 patients were randomized in the three arms. The main result was expressed in relative risk reduction: At day 180, the UACR ratio results were: Finerenone alone had a 32% reduction Empagliflozin alone: 29% reduction And the combination therapy had a 52% reduction from baseline So, the reduction with combination therapy was 29% greater than that with finerenone alone and 32% greater than that with empagliflozin alone; both were highly statistically significant. Adverse events and drug discontinuation were similar, though there was a decrease in the estimated glomerular filtration rate (eGFR) of greater than 30% at day 30 in two times more patients in the combination group, though GFR improved at study end when the drugs were stopped. In addition: 'the frequency of hyperkalemia, was relatively lower by approximately 15 to 20% with combination therapy.' For the optimistic or maximizer-docs, the previous model was sequential initiation of these two drug classes. This trial shows that simultaneous initiation worked better. But there were many critical appraisal issues — so many in fact, that it makes me wonder whether this was a marketing exercise. The most obvious issue is the endpoint. While we can say that cholesterol levels, or blood pressure (BP), or creatinine, these are surrogate markers that most patients don't care about. The UACR ratio is even more esoteric and likely even less of a surrogate marker than LDL or BP. The point of kidney protection strategies is to lower kidney outcomes — new dialysis, even doubling of the creatinine, or CV events. I realize UACR ratio is easier and may be an earlier sign, but I will quote the authors own words to underscore the uncertainty: Quote: 'We speculate that, taken together, these data suggest that the reductions observed with combination therapy with empagliflozin and finerenone will probably correlate with meaningful reductions in the risk of progression of chronic kidney disease.' I mean, that is truly remarkable in the NEJM. We speculate, probably . Wow. Then there is the matter of a 6-month trial. These were 67-year-old patients How long are we supposed to use these two classes of meds? Forever? Really? Then there is the matter of the 44-day screening period before randomization. They screened 1600 patients and excluded half. Why? They don't say. Highly selected patients, though, is not nefarious — lots of trials pick the perfect patient. But I mention the screen to randomized information because it speaks to the generalizability of this data. Finally, and I sound like a broken record, whenever finerenone is used in a trial, there should be an arm for spironolactone or eplerenone. That way, we would have an idea of the incremental value, if any, of the new nonsteroidal finerenone. In the end, I think CONFIDENCE was a marketing exercise. It does not change practice, and 6-month data of a very surrogate endpoint hardly meets any regulatory standard. Two UK Cardiology Trials Struggle to Recruit Patients Journalist Sara Freeman reports from the meeting of the British Cardiovascular Society meeting in Manchester, which I was lucky enough to be asked to speak last year, on a session describing difficulty in recruiting patients for two important clinical trials. This is an important topic. I can add a third trial that is also noting slow enrollment. In the UK, the CRAAFT-HF trial compares surgical vs catheter ablation in patients with HF. This is a hugely important question. For multiple reasons: the first is that despite my friendship with Nassir Marrouche, Christian Sohns, and Philipp Sommer, the principal investigators of CASTLE and CASTLE HTx, the numbers of HF patients in trials of AF ablation are few. The event rates are low, and the evidence for AF ablation in HF is limited. CRAAFT-HF would add to that evidence base. What's more, patients with HF often have atrial structural disease making them less likely to be pulmonary vein isolation (PVI) responders. And surgical AF ablation could also remove the left atrial appendage epicardially, a maneuver proven effective in the LAAOS III trial. I think surgical AF ablation could beat catheter-based ablation. The main problem with recruitment is the strict entry criteria. Indeed, this is a problem in HF and AF, as the chief weakness of the CASTLE trials was the highly selective entry criteria. The second UK trial having problems is the BRITISH trial of using scar on CMR to determine ICD implantation in patients with non-ischemic cardiomyopathy (NICM). BRITISH has a really brave trial protocol. Patients with NICM LVEF < 35% who have a scar on CMR would be randomized to either ICD or CRT-D vs implantable loop recorder (ILR) or CRT-P. (Basically no backup ICD). This is exactly what we want to know. It's a beautiful study question. The third trial that I traveled to Berlin to speak about this winter is the bravest of them all: The PROFID trial, which seeks to replicate the MADIT-II trial 20 years after. MADIT-II was ischemic CM with ejection fraction < 30% and the ICD reduced mortality with a number needed to treat of < 25. The idea behind PROFID is that sudden death rates in HF have fallen, medical therapy has improved, and the delta between the ICD arm and medical therapy arm is surely less. Well, PROFID also has had slow enrollment, for a couple of reasons: one is that there aren't that many terrible ischemic CM patients out there anymore, thanks to the IC community and rapid percutaneous coronary intervention (PCI) during ST-elevation myocardial infarction (STEMI). The second issue is that, at least in Germany, if you are a doc who randomizes a patient to PROFID and they are randomized to the medical arm, you lose reimbursement for the ICD. I highlight this topic mostly for my EP colleagues. While PFA holds all the excitement, we have stalled in terms of new major evidence development. PFA is nice, especially for patients, but if we are to maintain are stature as a profession, we need to support those who seek to answer important questions, like CRAAFT-HF, BRITISH, and PROFID.
Medscape
06-06-2025
- Health
- Medscape
Jun 06 2025 This Week in Cardiology
Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast , download the Medscape app or subscribe on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only. In This Week's Podcast For the week ending June 6, 2025, John Mandrola, MD, comments on the following topics: Listener feedback on cardiac sarcoidosis, out-of-hospital cardiac arrest, less is more when it comes to post-stent antiplatelets, lipoprotein(a), and atrial fibrillation in HFpEF. Dr Riina Kandolin from Helsinki, Finland, writes via email that I should clarify some of my comments on the cardiac sarcoidosis (CS) paper I made last week. The paper I spoke about last week from a primarily Dutch and Minnesota group compared societal recommendations for an ICD vs cardiovascular magnetic resonance imaging (CMR) phenotyping in patients with suspected CS. The key word was 'suspected' CS. In that study, in the European Heart Journal , CMR phenotyping by (1) no late gadolinium enhancement (LGE) and normal EF, (2) no LGE and abnormal EF, (3) pathology-frequent LGE, and (4) pathology-rare LGE, performed better than professional society recommendations for ventricular tachycardia (VT). Dr Kandolin pointed me to an incredible Circulation EP paper from their group in Helsinki on 305 patients with either biopsy-proven CS (just under half) or highly suggestive by criteria. Right away, this is a different population because the first study looked at patients with distant sarcoidosis (say the lungs) and were evaluating for cardiac sarcoidosis while the second study, in Circulation EP this year, studied patients with proven CS. Two main points of difference arise. In patients with true CS, all have pathology-frequent LGE. So it does not distinguish risk. Rather, the Finnish group showed that it was the degree (and somewhat the distribution) of LGE that predicts sudden death and VT. They found that myocardial LGE making up >9.9% of left ventricular (LV) mass or affecting >6 LV segments may suggest prognostically significant LV involvement and a high risk of sudden cardiac death (SCD). This analysis and its implications bear similarities to what we do for hypertrophic cardiomyopathy (HCM). Namely, in HCM, there is a risk score that corresponds to a yearly risk of VT. If th 5-year threshold reaches >6% for sudden cardiac death, then an ICD is recommended. ESC recommends a similar risk score prediction for laminopathies as well. ICDs for criteria above a risk threshold. The Finnish authors therefore suggest in their discussion that their CMR findings could have clinical relevance. Quote: In patients who have no other guideline-based class I or IIa indications, implantation could be considered if LGE mass is >9.9% by the full-width at half-maximum method or the LGE involves >6 LV segments. Less extensive LGE predicted a 5-year SCD/VT rate <7% with an SCD risk of 0.6 per 100 patient-years, and in these patients other EP studies or close surveillance with repeated risk assessments could be discussed at shared decision-making . If you care about CS and risk stratification, this is an excellent paper. It's worthy of a bookmark. I appreciate the feedback because I learned a lot. My one comment — and this is not at all a criticism of the paper (or papers) — but as a doctor I struggle with these risk thresholds. Say in HCM, what if the 5 year-risk is 5% not 6%. Or in this case of CS, the LGE mass is 7% not 9.9%? The dichotomization of implantable cardioverter-defibrillator (ICD) or no ICD of continuous variables makes me nervous when the outcome is surviving sudden death because you have an ICD. I realize it would be unwise to place ICDs in all patients, including low-risk people, because of ICD harm, but not having an ICD is also a risk. I don't know the answer and perhaps there never will be an answer to finding the ideal patient for an ICD, but HCM and CS are clearly different from RCT-based heart failure (HF) criteria. In HF, we have entry criteria from trials — albeit old trials. Sort of. We used to be able to say that if you are like a MADIT-2 patient, you have a 30% lower mortality with an ICD compared to no ICD. The modern problem is that medical therapy is a lot better, and that 30% benefit may be a lot less. By the way — that is why if you practice in Europe, you should be participating in PROFID EHRA trial of ICD vs no ICD in ICM. One practical comment from my experience is that if a CS patient has heart block and you are implanting hardware, it seems wise to strongly consider an ICD if the LGE is even close to the threshold. The listener feedback is great. I learn a ton from it. Thank you. The American Heart Association sent me two emails yesterday regarding their efforts to increase awareness of bystander CPR. One was a National Football League player named Justin Reid who is leading an effort; the other email said the Atlanta Falcons are teaming up with the AHA to equip players and coaches with the lifesaving CPR (cardiopulmonary) skills during National CPR and AED (automated external defibrillator) Week. The second note is that Circulation: Outcomes published a paper today from a group at Mid-America finding that resuscitation practices for out-of-hospital cardiac arrest (OHCA) differ by geographies. Namely, compared to White catchment areas, communities serving Black and Hispanic have lower rates of OHCA survival. Of course, the causes could be a lot of things, but the research team noted that in Black/Hispanic areas, first responders were less likely to recognize cardiac arrest, police were less likely to respond to a cardiac arrest, and patients were less likely to be defibrillated. Basically, community-level quality of OHCA was less than what it is White catchment areas. And this may explain the differences in survival. I think it explains some of the differences. But OHCA survival rates are complicated, and differences could also be due to severity of disease. My point in highlighting OHCA is that it's one of the highest value interventions in all of medicine. I have spent many hours on this podcast discussing new treatments with marginal benefit. Bystander CPR and an adequate EMS system is hugely valuable. Why? Because only 10% of patients with OHCA in the US survive. Ventricular fibrillation (VF) without CPR or an automated external defibrillator (AED) occurring out of the hospital is nearly 100% deadly. A VF patient depends on the knowledge and availability of his or her neighbors. Since survival is so bad, any tick up is likely highly cost effective. Bystander CPR and public AEDs are nearly free of risk — it's all benefit. I know OHCA care isn't as exciting as the newest ablation catheter, or stent, or new drug, but it's surely a lot higher in value than either of these things. A new tricuspid valve clip or more AEDs in your city? I'd go with the latter every time. So good on the AHA — and the NFL. The other thing I love about promoting OHCA is that it brings communities together for an obviously great and totally uncontroversial cause. Is a Year of Dual Antiplatelet Therapy Magical Thinking? I hesitate to delve into this topic because it is perhaps the most confusing in all of cardiology. But I will, because yet another study finds that 'less is more.' This seems too simple to state, but the idea is that having a metal cage propping open a coronary lesion is neither a fix nor is it free. Metal in the coronary attracts platelets and then clots can form. Stent thrombosis is a medicalized jargon, but it's a terrible outcome because you go from 0% blockage to 100% blockage. The good news is that the body eventually (and usually) forms a layer around the stent protecting it from the circulating platelets. This we call, and, jargon-wise it is a whopper, endothelialization. The problem of course is that antiplatelet drugs are also not free — blocking platelets increases the risk of major bleeding in the gut, kidneys, and brain. So, the quest — and it is a quest — is to find the Goldilocks recipe for preventing thrombotic or clotting events (such as myocardial infarction) with the lowest rate of bleeding. The usual regimen is to use two antiplatelet drugs (aspirin and either clopidogrel or ticagrelor or prasugrel) for a period before switching to single antiplatelet. Perhaps you can see the complexity already. There are four antiplatelet drugs of varying intensity; and there are near-infinite ways to break up time after the stent, and different types of patients. There's acute coronary syndrome (ACS) vs stable coronary artery disease (CAD) patients; there's high-bleeding risk and not-high-bleeding risk patients; and then there are different stents. You start multiplying and you get about a quadrillion different ways to do antiplatelet drugs. Today I will tell you about one recent trial — but know that there are many. The South Korean trial was called 4D-ACS. It was a comparison of two prasugrel-based strategies in about 650 patients who had PCI and stent during an ACS: one group gets one-month of dual antiplatelet therapy (DAPT) (aspirin 100 mg + prasugrel 10 mg, except the prasugrel dose is adjusted to 5 mg for age>75 or body weight < 60 kg vs the control arm: 12 month of DAPT with aspiring 100 mg and prasugrel 5 mg. The primary endpoint is called NACE. Not MACE , but NACE — or net adverse clinical events: death, myocardial infarction (MI), stroke, ischemia-driven revascularization and bleeding. Bleeding also has 5 different grades. This trial measured types 2-5, so minor bleeding was not included. The results: NACE occurred in 4.9% of the 1-month DAPT group and 8.8% of the 12-month DAPT group. The trial was a non-inferiority comparison. This is a good use of non-inferiority. Why? Because the short duration is very much less intense than the standard 12-month DAPT regimen. If it was just as good, it would be a win. Indeed the 4.9% vs 8.8% easily made non-inferiority and in fact with a hazard ratio [HR] of 0.51; 95% CI: 0.27-0.95; P = .034), it also made superiority. The driver of the lower NACE was a 77% lower rate of bleeding in the short duration DAPT arm: 1.2% vs 5.5%. There were almost no differences in thrombotic events such as MI, stroke, ischemia-driven revascularization. I cover this study because it is such a clear result. If using prasugrel, a one-month DAPT regimen is surely better than 12-month DAPT. You would think it's clear now, but it is surely not. First of all, all patients were Korean, and Asians may respond differently to antiplatelets. Second, the study used a type of stent that is not used in the US. Third, what about 1-month DAPT vs 3 months? What about combos of different antiplatelets. Like aspirin/clopidogrel vs clopidogrel. In general, the trend of late is for shorter courses of DAPT. But my solution in real life is to use one of the most important tools in all of medicine: phone-a-friend. I call my interventional cardiology colleague and ask what they think. They've done the stent and a bifurcation stent in the proximal LAD is going to be different from a mid-circumflex lesion. Perhaps I can make these general statements: ACS patients generally require longer DAPT duration (12 months) due to higher thrombotic risk Non-ACS patients most likely can safely use shorter DAPT durations (6 months for DES. Patients with high bleeding risk may benefit from abbreviated DAPT (1-3 months) regardless of presentation P2Y12 monotherapy after initial DAPT period shows promise for reducing bleeding while maintaining efficacy An individual risk assessment may prove helpful in guiding duration and intensity of DAPT. Final comment: if you are having an ST-elevation myocardial infarction (STEMI), you want a stent done fast. If you have chronic CAD, medical therapy first avoids the entire issue of deciding on the combination of antiplatelets. Sadly, this doesn't happen often enough in many places in the US. JAMA Cardiology has published an interesting study looking at the value (or lack of value) in adding Lp(a) into the new PREVENT equation. The first thing to say is that I covered the AHA's PREVENT equation in August of last year. Proponents of PREVENT say it's better than the standard PCE — which outputs 10-year risk of atherosclerotic events. Of course, the proponents of PREVENT don't just say it's better. PREVENT has been validated in observational datasets. PREVENT differs from the pooled cohort equation because it incorporates kidney function, statin use, social determinants of health and removes the race category. It also starts at a younger age. The most provocative aspect of PREVENT is that it simultaneously is felt to be more accurate, but it lowers estimates of CV risk and lowers the number of statin-eligible people. Gulp. Double gulp. Anyways, the question of the JAMA Cardiology study was whether the PREVENT equation can be made better by adding Lp(a) — which as you probably know is mostly genetically determined and, when elevated, is strongly associated with higher risk of CV events. Since race is removed from PREVENT and race can bear on Lp(a), adding it could be very important. Here is that they did. Two databases — UK biobank and MESA. This was big, big data. Both databases have long-term follow-up. Individuals in the database were put into 4 categories: low risk (5%), borderline (5%-7.5%), intermediate (7.5%-20%), and high risk (> 20%) Then they measured 10-year event rates and correlated it with Lp(a) levels overall and by risk category. Of course they do adjustments for age and sex. The main endpoint is the net reclassification improvement or NRI, which is complicated. Let me try to explain: NRI measures how well a new risk prediction model reclassifies people compared to an old model, but it does this by tracking movements in both directions and netting them out. The NRI splits reclassification into events (people who actually had the outcome) and non-events (people who didn't). For each group, it calculates: Proportion who moved up in risk categories minus the proportion who moved down This gives you a net movement figure for each group. The problem comes in relative vs absolute differences. You see this in the NRI studies of coronary artery calcium (CAC) where, when you consider absolute numbers, more people don't have events and are actually misclassified using NRI. I asked the AI tool Claude about this — because Claude helps — and Claude calls this 'The Conceptual Trap,' and I think it's worth talking about. Claude says that people often interpret NRI as "20% improvement in classification" when it's really "20% net improvement after accounting for movements in both directions." The absolute amount of reclassification — which tells you how much the models actually disagree — gets hidden in this netting process. In this study, they measured NRI both categorically — that is, how many moved into a different risk category based on Lp(a) (ie, going from borderline risk to intermediate risk) — and they also measured the NRI category-free (which is simply whether the patient moved up or down in risk at all). They differed — a lot. The category-free NRI for atherosclerotic events using Lp(a) was about .06 (or 6%). Now, the categorical NRI was 10 times lower — at 0.6% The way I would try to translate that is to say that adding Lp(a) reclassifies about 6% of people on a net basis for CV risk, but it is far less valuable for moving people between low, borderline, intermediate and high-risk categories. Here it was less than 1%. Now, the study did something else that is perhaps somewhat useful. They looked at subgroups of people who may get more reclassification. They found that adding Lp(a) resulted in slightly more reclassification for borderline risk and low risk people. But I have to say the differences are quite modest. For instance, the NRI for low-risk CHD prediction was 10% vs 7.5% for intermediate risk. 10% vs 7.5% — it doesn't seem like a big difference. This is a nice effort. Adding Lp(a) helps a little with prediction. A low-risk person who has an Lp(a) may want to take statins. A borderline person with a low Lp(a) may pass. But here's the thing, and I feel it's the same with CAC. I've seen patients for nearly 30 years in middle America, and the vast majority, perhaps 90% of people cannot conceptualize the difference between 7% and 9% vs 13% risk of 10-year events. I've had lipids done recently and I am borderline risk. And I can't really conceptualize 10-year risk of a nonfatal event. Maybe you can. Two reasons I struggle. One is that philosophically, I think much of disease and health is good and bad luck. As in…stuff happens. The second reason I struggle with 10-year risk prediction is relative to Ukraine attacking Russia's planes and the threat of World War III: how much worry should I place in whether my nonfatal CV risk is 7% without Lp(a) vs 9% with Lp(a)? I come back to my bottom-line when it comes to prevention: there are maximizers who want to do everything. For them, Lp(a) seems useless because they are already on aggressive lipid lowering. There are minimizers who aren't taking pills regardless. And for these patients, Lp(a) is also useless. So, for the few who sweat the details, fine — add Lp(a) to the mix. Publishing in EuroPace , a group of prominent researchers re-analyzed the TOPCAT Americas trial looking at the role of AF in predicting bad outcomes in patients with heart failure with preserved ejection fraction (HFpEF). Recall that TOPCAT is one of the most important trials in cardiology. Sadly, it was marred by data irregularities from Russia and Georgia. TOPCAT was spironolactone vs placebo in HFpEF. The hazard ratio (HR) was 0.89 for the composite primary of death, cardiac arrest, or heart failure hospitalization (HHF). The 11% reduction did not reach statistical significance. But all-cause death was 22% in the Americas and only 8% in Russia/Georgia, and the drug had little effect in that region. Further metabolic studies found that a third of patients supposedly randomized to spironolactone had undetectable metabolites. Excluding Russia and Georgia, TOPCAT was positive with a HR of 0.82 and a confidence interval of 0.69-0.98. I think this is a really important point. Ok, now to the EuroPace paper. The problem with studying HFpEF is it is diverse condition — unlike HFrEF. The authors, mostly EP docs, were interested in AF effects in HFpEF. Specifically, whether AF is simply a marker for advanced CV disease or is it an independent risk factor. They made two groups: Study patients who had AF before or at study entry. This was the 'any AF' group. Study patients with ongoing AF who had it at entry. Then they propensity-matched patients with no AF and looked at outcomes. I know, it's pretty easy to predict what will happen. Before I tell you the results, I hope you are thinking: small, hyperdynamic, noncompliant left ventricles are not going to do well with losing the atrial kick when AF occurs. The primary outcome of these comparisons was CV mortality. About 580 patients in TOPCAT who had any AF and 400 had ongoing AF. And they found that: Any AF was associated with a statistically significant increase in CV hospitalization, HHF, and progression of HF. Any AF, however, was not associated with an increased risk of sudden death. Ongoing AF was associated significantly with CVD, pump failure death, CV hospitalizations, and HHF. It was interesting to me that neither any AF or ongoing AF was not strongly associated with sudden death. AF seemed to associate mostly with progression of HF or pump failure. This paper has a lot of complicated comparisons, but I think it can be summarized as AF is a bad thing to have with underlying HFpEF. The question of course, the clinical question, is how to modify this problem with therapy. My first recommendation is to phone-a-friend: your EP colleague. I can't give you a generic right answer because there isn't one. HFpEF patients often have serious comorbidities that have to be considered, things like polypharmacy and CKD and valvular HD and frailty. Maybe antiarrhythmic drugs are the right answer. Maybe ablation. And underused in some places is the 'pace and ablate' strategy. We see a lot more HFpEF these days, because people live longer and with more chronic illness. When AF occurs, it's serious. Take Mr. Rogers' advice and realize that we all need helpers in our lives, and please: call your EP friends.
