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4 hours ago
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Sacituzumab or Chemo in First-Line TNBC: Which Is Better?
Treatment with pembrolizumab and the antibody-drug conjugate (ADC) sacituzumab govitecan improved progression-free survival (PFS) in patients with PD-L1-positive locally advanced or metastatic triple-negative breast cancer (TNBC) compared with treatment with pembrolizumab and chemotherapy, the results of ASCENT-04/KEYNOTE-D19 showed. Swapping in sacituzumab govitecan for chemotherapy led to a 3.4-month improvement in PFS and an almost twofold longer duration of response, with potentially fewer adverse events and a lower rate of discontinuations. Currently, pembrolizumab with chemotherapy is the standard of care for PD-L1-positive TNBC, but the 3-year survival rate remains low at about 36%. These findings support sacituzumab govitecan and pembrolizumab as the new standard for previously untreated patients in this setting, said lead investigator Sara Tolaney, MD, MPH, who presented the results at the American Society of Clinical Oncology (ASCO) 2025 annual meeting. Once the new combination with sacituzumab govitecan, which targets the Trop-2 protein on tumor cells, is approved, 'I would recommend it in the first-line setting,' said Tolaney, a breast medical oncologist at the Dana-Farber Cancer Institute, Boston, Massachusetts. 'I think this really does change the game for' PD-L1-positive metastatic TNBC, said study discussant Jane Meisel, MD, a breast medical oncologist at Emory University, Atlanta, Georgia. 'I look forward to seeing this potentially make its way into clinical practice.' The study included 443 women who had either de novo metastatic disease or were at least 6 months away from completing systemic therapy for early-stage disease. Patients had a combined positive PD-L1 score of 10 or higher, and about 40% of TNBC tumors expressed the Trop-2 protein. Half of the patients were randomly assigned to 10 mg/kg sacituzumab govitecan on day 1 and day 8, plus pembrolizumab 200 mg on day 1 of 21-day cycles for a maximum of 35 cycles (n = 221). The other half were randomly assigned to pembrolizumab on the same schedule plus investigators' choice of gemcitabine plus carboplatin or paclitaxel/nab-paclitaxel (n = 222). Approximately 5% of patients had received a prior checkpoint inhibitor for earlier-stage disease; 43% of women in the chemotherapy arm crossed over to sacituzumab govitecan monotherapy after progression. At a median follow-up of 14 months, median PFS was 11.2 months in the sacituzumab govitecan group vs 7.8 months in the chemotherapy group, which translated to a 35% lower risk of cancer progression during follow-up (hazard ratio [HR], 0.65; P = .0009). Tolaney noted that PFS in the ADC group increased with higher Trop-2 expression, but the ADC group also did better than the chemotherapy arm regardless of Trop-2 levels, suggesting that 'you didn't need to preselect patients for use of sacituzumab by Trop-2.' Median duration of response was 16.5 months with sacituzumab govitecan vs 9.2 months with chemotherapy. Although overall survival follow-up is ongoing, the trend favors the ADC group (HR, 0.89). Commenting on the study, Julie Gralow, MD, a breast medical oncologist at the University of Washington, Seattle, noted that sacituzumab govitecan is already indicated as monotherapy in the third or later lines for metastatic disease. The ASCENT-04 results 'will likely move this drug, this regimen, earlier in the metastatic setting' for TNBC, Gralow agreed. On the side effect front, the most common (≥10% of patients) grade 3 and 4 adverse events in the sacituzumab govitecan group were neutropenia (43%) and diarrhea (10%); in the chemotherapy group, the most common adverse events were neutropenia (45%), anemia (16%), and thrombocytopenia (14%). Serious adverse events were numerically more common in the ADC arm (38 vs 31), but there were fewer dose reductions and fewer treatment discontinuations than with chemotherapy. 'The nice thing is that many of us have used both of these agents, sacituzumab and pembrolizumab, quite a bit,' and with no new safety signals, breast oncologists will 'feel comfortable with [the combination] once it makes its way into the clinic,' Meisel said. The work was funded by Gilead Sciences, maker of sacituzumab govitecan. Tolaney disclosed research and travel funding from Gilead and is a Gilead advisor. Gralow and Meisel reported no relevant financial relationships.
Medscape
12 hours ago
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Fast Five Quiz: Multiple Sclerosis and Depression
Depression is among the most common comorbidities of multiple sclerosis (MS), leading to psychological quality-of-life issues that can further exacerbate a patient's functional capacity. The significant burden of depression in patients with MS is typically associated with neuroinflammatory processes which are directly correlated to depression severity. Understanding the relationship between depression and MS is crucial for healthcare providers, to develop effective treatment strategies that address both the neurologic and psychological aspects of the disease. What do you know about the interplay of MS and depression? Check your knowledge with this quick quiz. The prevalence of depression in the general population is approximately 13%, according to the Centers for Disease Control and Prevention (CDC). Other data indicate that it falls between 25% and 54% in patients with MS. Depression, along with other disorders such as anxiety and fatigue, are among the most common comorbidities of MS. These comorbidities further degrade quality of life in patients who are already affected by the functional disabilities caused by the diseases. A multidisciplinary approach can help to holistically manage MS to ensure that quality of life is optimized across specific healthcare needs. Learn more about guidelines for MS. A recent systematic review reported that depression symptoms do not significantly improve after smoking cessation in patients with MS, although these patients do see improvements in anxiety. The same review noted that depression is associated with a 1.3- to 2.3-fold increased prevalence in patients with MS who also smoke tobacco. Although smoking cessation is known to cause short-term mood changes, a recent cross-sectional analysis of the NHANES study found that longer duration of cessation is associated with lower risk for depression. However, the persistence of depression in former smokers with MS might be due to depression's strong association with MS, and clinicians should not assume that depression symptoms will improve when a patient quits smoking. Learn more about tobacco product use and depression. Though depression and anxiety can occur in any subtype of MS, an extensive review and meta-analysis found that both were more prevalent in progressive MS (defined by the researchers as PPMS and SPMS) compared with RRMS. In contrast, the same meta-analysis reported that patients with MS and an Expanded Disability Status Scale (EDSS) score of less than 3 had higher rates of depression compared with patients with an EDSS score of greater than 3, while the prevalence of anxiety was higher in patients with an EDSS score greater than 3 compared with an EDSS score below 3. Proinflammatory cytokines in MS have been shown to disrupt the monoaminergic system, which is a component of the pathogenesis of depression. As such, treatments that enhance monoamine neurotransmission (such as SSRIs, SNRIs, and dopaminergic psychostimulants) are indicated for use in depression and MS-associated depression. Learn more about the pathophysiology of MS. Although comorbid depression in MS often presents similarly to fatigue, several characteristics can help clinicians distinguish between the two and guide appropriate treatment. According to a recent review, patients with depression typically have better functioning in the evening while those with fatigue typically have better functioning in the morning. Other characteristics of depression tend to include hypersomnia and hopelessness; patients with fatigue usually experience insomnia and strong hopefulness for recovery. Learn more about symptom management of depression and fatigue in MS. According to a systematic review and meta-analysis assessing exercise best practices for depression in MS, programs implementing ergometer training protocols had the largest effect size. The data reviewed indicated immediate improvements in depression scores with exercise, and depression symptoms were found to improve regardless of exercise frequency, duration, or activity. This is consistent with another review that cited a range of nonpharmacologic interventions for improving depression in MS, including exercise as well as cognitive-behavioral therapy, yoga, dietary habits, and sleep hygiene. Further, data on Hatha yoga, circuit training at moderate intensity, and resistance training with active rest periods in patients with MS and depression are limited. Learn more about exercise for depression. Editor's Note: This article was created using several editorial tools, including generative AI models, as part of the process. Human review and editing of this content were performed prior to publication.
Medscape
a day ago
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CDC Drops Guidance for COVID Vaccines for Pregnancy
The US Centers for Disease Control and Prevention (CDC) has just updated its child and adolescent immunization schedule in a way that states that parents who want to vaccinate healthy children could do so, based on shared decision making with a clinician. The agency also updated the adult immunization schedule to say there is 'no guidance' on use in pregnancy. The update for children and adolescents seems to contradict the May 27 announcement on COVID vaccines by Health and Human Services (HHS) Secretary Robert F. Kennedy, Jr. In a 58-sec video posted to X, Kennedy said the COVID vaccine was 'being removed from the CDC-recommended immunization schedule' for healthy pregnant women and also for healthy children. US Food and Drug Administration Commissioner Marty Makary, MD, said on the video that 'there's no evidence healthy kids need it today,' while National Institutes of Health Director Jay Bhattacharya, MD, called the move 'good science.' As of press time, HHS had not issued a formal proposal or written policy to further detail the announcement, but the CDC had change its online immunization schedules. The see-sawing of the policy announcements — without any public meetings or input — have left clinicians perplexed and fearful about availability of the COVID-19 vaccine for healthy pregnant women and healthy children in advance of what is typically a surge of infections during the summer and fall months in the US. Linda Eckert, MD, a professor of obstetrics and gynecology at the University of Washington in Seattle, said she was 'horrified' when she heard the announcement. 'I was just like, why did this happen?' she told Medscape Medical News . COVID during pregnancy 'is dangerous to my patients, and when my patients don't do well, their pregnancies don't do well,' Eckert said. The virus is also very dangerous to infants during the first 6 months of life, 'and maternal antibody transfer is the way that those infants are protected,' said Eckert, a member of the American College of Obstetricians and Gynecologists (ACOG) immunization committee. The announcement prompts questions, but not many answers, she said. 'What are we going to do with our patients? How are we going to have these conversations now?' said Eckert. 'We're all trying to read the tea leaves as to what [Kennedy] really means,' said Paul Offit, MD, director of the Vaccine Education Center at Children's Hospital of Philadelphia, Leaving clinicians, insurers, and patients to guess is 'a wholly irresponsible way to do business,' Offit told Medscape . Offit said that Kennedy has made no secret of his intent to focus on chronic disease while reducing resources for infectious disease. The Secretary 'has for 20 years been an anti-vaccine activist and science denialist,' said Offit. 'He's basically doing what he can to tear down the vaccine infrastructure in this country,' he said. Alarms Sounded Many professional organizations expressed alarm at Kennedy's announcement. The HHS Secretary bypassed the traditional process for vaccine recommendations, which includes discussion of evidence for safety and effectiveness at open public meetings held by the CDC's Advisory Committee on Immunization Practices (ACIP). ACIP then makes a recommendation, which the CDC director approves or disapproves. 'It is concerning that such a significant policy change was made unilaterally outside an open, evidence-based process with no regard for the negative impact this will have on millions of Americans,' said Tina Tan, MD, president of the Infectious Diseases Society of America, in a statement. 'By removing the recommendation, the decision could strip families of choice,' said Sean O'Leary, MD, chair of the American Academy of Pediatrics' Committee on Infectious Diseases, in a statement. 'Those who want to vaccinate may no longer be able to, as the implications for insurance coverage remain unclear,' he said. 'It's also unclear whether healthcare workers would be eligible to be vaccinated.' O'Leary said that the evidence shows that pregnant women, infants, and young children are at higher risk of hospitalization from COVID and that the vaccine's safety 'has been widely demonstrated.' 'Despite the change in recommendations from HHS, the science has not changed,' said ACOG President Steven J. Fleischman, MD, in a statement. Most infants under the age of 6 months who are hospitalized for COVID are born to unvaccinated mothers, said Fleschman. Kennedy's announcement may mean pregnant people are less likely to choose to vaccinate, he said. 'We are very concerned about the potential deterioration of vaccine confidence in the future,' said Fleischman. Jason M. Goldman, MD, president of the American College of Physicians, agreed. 'The HHS announcement will likely further erode public confidence in the safety of these vaccines, despite the evidence demonstrating their benefits,' he said, in a statement. Goldman also said the policy change has 'the potential to threaten insurance coverage for COVID vaccines and boosters, increasing the cost and placing them out-of-reach of individuals who do still want to be vaccinated.' Who Will Get the COVID Vaccine? Uptake of the vaccine has been waning, even with insurance coverage. According to CDC's COVID-19 Vaccination Dashboard, 14% of pregnant women had received the 2024-25 vaccine. As of late March, just under 13% of children 6 months-to-17 years had received the vaccine, the CDC reported at the ACIP's last meeting in April. Children under 6 months have the second highest COVID-related hospitalization rates, comparable to those of adults aged 64-75; only adults aged 75 or older have higher rates, the CDC has reported. A fifth of 1000 hospitalized infants with COVID-19 during a 2-year period were admitted to an intensive care unit; nine died while hospitalized. Vaccination of mothers has led to a decline in hospitalizations, however, said the agency. Even so, 96 children under age 4 and 56 aged 5-17 died from COVID from September 2023 to August 2024, said CDC officials at the last ACIP meeting. COVID's dangers during pregnancy have been documented in many studies. Researchers from George Washington University in Washington, DC, reported in a 2023 paper that pregnant women with COVID-19 experienced 7 times greater risk of dying during pregnancy or childbirth, 3 times greater risk of being admitted to the ICU, 23 times greater risk of developing pneumonia, and 5 times greater risk of thromboembolic disease. Eckert said that, despite the dangers, fewer patients have been opting for vaccination over the last few years 'because people view COVID as less of a threat.' She still talks to patients about protection. The new recommendation is going to make it more difficult to help patients stay safe, she said. Meanwhile, as reported by Medscape , the FDA announced earlier in May that it would be calling for more studies of COVID vaccines in healthy Americans and that it would recommend against approval except for individuals with a long list of conditions that put them at risk for more severe disease. One of those conditions is pregnancy or recent pregnancy. The COVID vaccine announcements are 'at the least, confusing for patients,' Eckert said. Will Policy Be Challenged? It is not clear whether anyone can or will challenge the HHS policy announcement. Normally, not even a CDC director would circumvent the ACIP's process, said Dorit Reiss, professor of law at UC Law San Francisco. Currently, there is no acting CDC director, she said, adding that it appears that Kennedy has stepped into the role, as he reportedly approved an ACIP recommendation on a chikungunya vaccine. While Kennedy is not violating a statute or regulation with his COVID vaccine announcement, a court could find that the decision is 'arbitrary and capricious' because it was offered without evidence or a rationale, said Reiss. 'These decisions are generally written out with references and a lot of data. They didn't do that,' Reiss told Medscape . Eventually, someone might legally challenge the policy, but it could take a while, said Reiss. The policy 'will have to hurt someone' for someone to make a case, she said. Reiss and Offit pointed out that vaccines could be prescribed off-label for groups that are not covered by any of the HHS recommendations. 'Probably 70% of the drugs on our formulary are not necessarily approved for pediatrics,' said Offit. But off-label use comes with its own set of headaches, he said. Clinicians might have to seek prior authorization from insurers, for instance. When asked whether the administration might just remove approvals altogether for COVID vaccines, Offit responded that with Kennedy in charge, 'anything is possible.' Offit reports no relevant financial relationships. Eckert disclosed that she is the author of 'Enough,' a book that calls for greater cervical cancer screening.
Medscape
a day ago
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NHS Gets £750m Boost to Fix Crumbling Buildings
The government has allocated £750 million to the NHS in England for tackling long-term maintenance problems. The Department of Health and Social Care (DHSC) said the money could be used by hospitals, mental health units, and ambulance services to mend leaky pipes, improve ventilation, and solve electrical issues. The investment aims to prevent operations and appointments being cancelled because of crumbling infrastructure. However, healthcare leaders said the cash injection is a 'drop in the ocean' and just a fraction of the estimated £14 billion maintenance backlog across the health service estate. More than £100 million will be put aside for maternity units to replace outdated ventilation systems in neonatal intensive care units and create better environmental conditions for vulnerable babies and their families. Scale of NHS Disrepair Hospital services were disrupted more than 4000 times in 2023-2024 due to poor quality buildings, according to England's Health Secretary Wes Streeting. Streeting highlighted the severity of the problem, noting that burst pipes had flooded emergency departments, faulty electrical systems had shut down operating theatres, and mothers had been forced to give birth in substandard facilities. A recent UNISON survey revealed NHS hospitals were plagued by rats, cockroaches, and sewage leaks. The survey also flagged problems with leaky roofs and out-of-order toilets. Simon Corben, director for NHS estates and facilities at NHS England, said repairs were overdue. 'Fixing the backlog of maintenance at NHS hospitals will help prevent cancellations,' he stated. Earlier this month, the DHSC pledged £102 million this financial year for GP surgeries to upgrade outdated premises. It followed an independent report by Lord Ara Darzi last year which concluded that outdated, inefficient buildings were unfit for purpose, created barriers to delivering high-quality patient care, and reduced productivity. 'Small Downpayment' Welcomed Daniel Elkeles, chief executive of NHS Providers, welcomed the latest announcement, particularly noting support for the 'often overlooked' mental health and ambulance sectors. However, he pointed out that 'an eye-watering near £14 billion is needed just to patch up buildings and equipment,' with mental health services alone facing a maintenance backlog exceeding £1 billion. Tim Mitchell, president of the Royal College of Surgeons of England, said NHS facilities had fallen into a 'dire state of disrepair' that was hampering efforts to reduce waiting lists. "With the NHS maintenance backlog currently standing at £13.8 billion, this really is just a drop in the ocean," he said. Matthew Taylor, chief executive of the NHS Confederation, described the spending boost as a 'small down payment' on the maintenance backlog. 'At £750 million a year, it would take almost 20 years to clear the backlog, assuming it does not continue to grow,' he warned. Healthcare leaders called for new investment models, including private sector involvement, to address the funding shortfall more rapidly. Projects are due to be delivered during the 2025-2026 financial year, with the first upgrades expected to begin this summer, the DHSC said.
Medscape
a day ago
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May 30 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 May 30, 2025, John Mandrola, MD, comments on the following topics: listener feedback, CRT vs CSP, important clues on the ECG, beta-blocker interruption after myocardial infarction, novel approaches to LDL-C lowering, and ICD decisions in cardiac sarcoidosis. Dr Steve Dickson, a heart failure cardiologist from Kansas City, writes via email to push back on my skepticism about rapid initiation of guideline-directed medical therapy (GDMT) in heart failure (HF). Dr Dickson says I am right about the STRONG-HF trial, which used cardiologists for the majority of follow-up visits. And while cardiologist-led care may currently be the case in many clinics across the country, he writes, times are changing. Hospitalists, primary care practitioners (PCPs), and advanced practice practitioners are becoming more comfortable with these life-saving medication classes. The future of heart failure care isn't just the burden of cardiologists, but internal medicine where there are more reinforcements. Dr Dickson says that in his clinic they run a '4 Weeks 4 Meds' program for patients with heart failure with reduced ejection fraction (HFrEF), mainly through nurse practitioners that he guides and manages. He says it's 'quite aggressive but I can assure you my CEO loves seeing his readmissions drop.' My comment to this is that I fully support programs like '4 weeks 4 meds' programs. It's a great idea, but of course, it takes administrative support, incentives. And, I would add that this is a great use of advanced practice clinicians. I say congratulations and I hope more programs like this become a reality. Clearly, HF care would improve if it did. The obvious advantage of such a program is not only getting more patients on max GDMT but also avoiding harm from overzealous GDMT titration. Cardiac Resynchronization Therapy vs Conduction System Pacing – CONSYST-CRT As many of you know, because I have said it so many times, the most exciting thing in EP right now is not ablation but pacing, specifically, conduction system pacing (CSP). I saw a Tweet this week, saying that ablation has become more anatomic and rote, and pacing is becoming more physiologic. It used to be the opposite. In an ablation, we would map and study electrophysiology, and in pacing we would simply flop a catheter in the right ventricle (RV) and we would just screw it in wherever it fell into the RV. Now in ablation we put in a pulsed field ablation (PFA) catheter and boom. E-grams are gone. PFA ablation is ruining EP. Now, during a pacemaker we meticulously record and pace in areas of the conduction system. 6+ years ago, we were doing it with the His bundle, and now it's the left bundle. To do CSP is to bathe yourself in beautiful physiology. But beautiful images of CSP on an ECG are not evidence. What we need is evidence that it is superior to biventricular (BiV) pacing for the treatment of patients with heart failure and left bundle branch block (LBBB). The thing is, in BiV pacing, we have strong evidence, from multiple trials, that biV pacing reduces hard outcomes, like mortality, compared to standard RV implantable cardioverter defibrillators (ICDs) or medical therapy. We think, emphasis on think, that because CSP narrows the QRS, and some smaller studies have shown improved hemodynamics with CSP, it is similar to, or superior to, BiV pacing. We need trials. Well, I am a local principal investigator here at my hospital for the US government-funded Left vs Left trial, which will have death and hospitalization for heart failure (HHF) as a primary endpoint. Planned enrollment is 2100 patients and follow-up is for 5 years. That's a long time to wait. This month, JACC EP has published another attempt to compare CSP to BiV pacing in CRT-eligible patients. Spanish investigators have now published the CONSYST-CRT trial. This was a randomized controlled trial (RCT) of just 134 patients of CSP vs BiV pacing. The design was non-inferiority of CSP. The primary endpoint was a composite of many things: death, transplant, HHF, or a left ventricular ejection fraction (LVEF) improvement of less than 5% at only 12 months. I hope you are seeing the problems: I will go over the issues in the comments. First finding: 18 of 67 patients crossed over from CSP to BiV pacing. Second finding: 23.9% in the CSP group had a primary outcome event vs 29.8% of the BiV pacing. The absolute risk difference was –5.9%. The confidence interval went from –21.2%, which is far better with CSP, to 9.2% worse for CSP. The accepted non-inferiority margin was 10% worse, and so 9% is less than 10% and this allowed a claim of non-inferiority with a P value of .02. Secondary endpoints also favored CSP. QRS narrowing was better in the CSP arm. Echo response was better, as was a NYHA functional class improvement. The combined endpoint of death, transplant, and HHF also showed non-inferiority, though I could not find confidence intervals on the difference. The authors concluded: CSP was non-inferior to biV pacing in achieving clinical and echocardiographic response, suggesting that CSP could be an alternative to biV pacing. I laud trials and clinicians who attempt them. CSP vs biV pacing is an important question. But if you are going to experiment on people, you need to have a chance of telling a difference. There is no way this trial had a chance with only 134 patients—1 in three who crossed over—to detect signal from noise. There were 16 vs 20 primary outcome events, respectively. There were 1 vs 3 deaths, 0 vs 1 transplant, and 8 vs 10 HHF. The most common outcome was failing to improve an ejection fraction (EF), which is far from a hard clinical outcome. That is a tiny number of events. Not only was the composite endpoint problematic, but follow-up for a year is totally inadequate. Left vs Left is asking the same question and enrolling 2000 patients — almost 20 times more patients. It would have been fine to compare hemodynamics, but we have oodles of these studies showing similar effects on EF with CSP. I mean no malice to the Spanish team, and to be sure, I was part of the His-SYNC trial, another woefully underpowered trial, but this type of effort tells us little to nothing about the long-term effects of the two strategies. Underpowered trials, I think, should be avoided. Since the beauty of the ECG is what got me interested in cardiology, I am always on the lookout for studies on the ECG. A UCSF group reports a research letter in Circulation EP on the association between a fragmented QRS and myocardial fibrosis burden and autopsy-defined arrhythmic causes among presumed sudden cardiac death (SCD). QRS complexes should be sharp and narrow. There should be no notches or fragments. This is a report from the ongoing project called the POST SCD or 'Postmortem Systematic Investigation of Sudden Cardiac Death' study. The idea is to use autopsy and clinical data to adjudicate arrhythmic (potentially treatable with an ICD) vs nonarrhythmic death (overdose, pulmonary embolism, stroke, etc). So far, the team has had 943 presumed SCD, of which 402 had ECGs before death. And 98 (or about 1 in 4) of these had histogical data. Fragmented QRS was defined as greater than 1 notch for QRS <120 milliseconds (ms) and >2 notches if the QRS ≥120 ms and fragmented QRS's had to be in 2 leads. The findings of this research letter were: Presumed SCD with a fractionated QRS on more than 1 lead were more likely to have arrhythmic causes compared with presumed SCDs without fractionated QRS 76% versus 55%; odds ratio, 2.6 [95% CI, 1.11–6.5]; P = .036, No other ECG marker was associated with higher odds of arrhythmic death. Coronary artery disease (CAD) was the most common cause of fractionated QRS. Presumed SCDs with fractionated QRS in greater than 1 lead had higher mean total and replacement fibrosis as well as more interstitial fibrosis burden than presumed SCDs without fractionated QRS ( P < .05 for all). I cover this imperfect study because the value of the ECG is under-recognized. I say imperfect because only half the presumed SCD had ECGs before death; and only a fraction of these had histological samples. What's more, the difference in associations were statistically significant but the positive and negative predictive value of fractionated QRS is surely low. But I want to consider this a public service announcement to my colleagues in cardiology. When you are sorting out whether a patient (say with syncope or near syncope) has a worrisome structural heart condition, study the QRS. When someone is telling me the story of syncope, my first question after the story is what does the QRS look like? Fragmented QRS is an electrical manifestation of disordered ventricular conduction, which is often due to scar, and disordered conduction, aka, anisotropy, sets the stage for reentry. Recall one of the fundamentals of cardiology: reentry requires three things: two pathways, delayed conduction, and unidirectional block. Scar sets the stage because there all three possible. In the same way that atrial structural disease increases the odds that a PAC fibrillates the atria, ventricular structural disease makes it more likely that a PVC fibrillates the ventricle. No, I am not saying that every notched fragmented QRS is malignant, but it's a clue, it's one piece of data. Don't overreact, but don't ignore the QRS. EHJ has a substudy from the French ABYSS trial of beta-blocker (BB) interruption vs continuation after myocardial infarction (MI). The substudy purported to show 'spikes' in HR and blood pressure (BP) after BB discontinuation. And this explains why the ABYSS study failed to show that stopping beta-blocker therapy could be safely done in stable post-MI patients. None of this is correct. None. And I want to correct the record about ABYSS, again. In my mind, ABYSS is entirely consistent with the REDUCE-AMI trial of not using BB in the post-MI patient. REDUCE-AMI found that not giving long-term BB resulted in similar major adverse cardiovascular events (MACE) outcomes compared with standard BB in post-MI patients with a normal EF. The main ABYSS trial, published in NEJM in August 2024, compared interruption of BB or continuation of BB in patients who had a previous MI and EF > 40% and MI at least 6 months before randomization. The median time from MI to randomization was just about 3 years. ABYSS enrolled about 3700 patients. It had a non-inferiority (NI) design with a 4-point composite endpoint of MI, stroke, death, or hospitalization for cardiac reason. The NI margin was a difference of 3% points for the upper bound of the 95% CI. The results were that interruption was not only not non-inferior to continuation but actually inferior to continuation. The numbers: 23.8% primary outcome events in the interruption group vs 21.1% primary outcome events in the continuation group Absolute risk increase of 2.8% with 95% CI that went from 0.1 to 5.5. Since 5.5% was greater than the NI margin of 3%, NI was not met. And when you looked at the CI, the entire 95% CI was above 0 for the interruption group so it was actually inferior. But, But. The entire composite was driven by hospitalization for cardiac reasons — 349 vs 307. There were no differences in death, no difference in MI, and no difference in stroke. The major MACE outcomes were nearly identical. The only reason ABYSS found to be against interruption was a surrogate outcome requiring adjudication of hospitalization. The less biased outcomes of death, stroke, and MI were identical. Now to the EHJ substudy, which looked at changes in BP and HR from baseline to post-randomization in the two groups. They also assessed the changes in HR and BP impact on the primary endpoint for the prespecified subgroups of patients with or without history of hypertension. With little to no surprise the BB interruption group sustained an increase in heart rate (about 10 bpm) and systolic blood pressure (SBP) (3.7 mmHg). These deltas remained stable after discontinuation over months. With regard to the hypertension (HTN) and no-HTN groups which were almost 50-50 split, there were largely similar effects. That was an increase in heart rate and SBP. Also not surprising was that the primary outcome occurred more often in patients with HTN than those without HTN, showing that HTN patients are higher risk. I am not sure we needed that analysis because HTN is a known risk factor. The observed harm (higher rate of the primary outcome) was numerically higher in the HTN group; the difference was not statistically significant. In other words, there was no evidence of a heterogenous treatment effect for HTN or no HTN. But remember, 'harm' as described by the primary outcome in ABYSS is flawed because it was driven only CV hospitalizations. In Table 2, the authors show the results of the components of the primary outcome in the BB interruption and continuation arm based on the subgroup of HTN — and in MI, stroke, and death, the P values for interactions were close to 1, as in absolutely no difference. The authors concluded: Interruption of beta-blocker treatment after an uncomplicated MI led to a sustained increase in BP and HR, with potentially deleterious effects on outcomes, especially in patients with history of hypertension. My friends, the ABYSS trial was a perfectly nice trial. It addressed an important question. The problem was the choice of endpoint. When you look at MI, stroke, and death, BB interruption was totally fine. This substudy showing why ABYSS found harm is flawed because the main trial chose a flawed endpoint. Further, finding that HR and BP go up slightly when a BB is stopped is like finding out you get wet when walking in the rain. BB reduce HR and BP. When you stop them, HR and BP go up a bit. Since the main trial found no increase in MACE, we can say that that small rise in HR and BP don't have deleterious effects. The most we can take from this study is that there does not seem to be a heterogenous treatment effect for the presence of HTN. I think we can stop BB in patients with a history of MI if they have normal EF and no other reason to take BB. The one caveat to my argument that death, MI, and stroke were not different was that it was a little underpowered. For the composite of death, MI, and stroke, the hazard ratio was 0.96 in the interruption vs continuation arm, but the confidence interval went from 0.74 to 1.24. So, interruption could be 26% better or 24% worse than continuation. And perhaps that is why the authors decided to add CV hospitalizations. Yet when you combine the data from REDUCE-AMI and recent observational data from Denmark, the ABYSS finding of no increase in MACE after BB interruption supports the idea that interruption of BB after MI is reasonable and safe. And, of course, less medicine is better. Is Lifelong LDL-C Lowering Within Reach? The heart-1 Gene-Editing Trial Heart-1 Gene Therapy Trial Pauses Enrollment JACC has published a phase 2 dose-ranging study with another oral PCSK9 inhibitor, called AZD0780. In other words, it doesn't have a name yet. The drug has a novel mechanism, which I won't delve into at this point, but it did achieve a dose-dependent drop in LDL cholesterol (LDL-C). The max dose of 30 mg achieved a 50% placebo-adjusted reduction of LDL-C and all patients were on statins but had LDL-C > 70 mg/dL. No adverse effects were noted but the study was quite short at only 12 weeks. The accompanying editorial was quite good. I learned a lot from it. First, there are multiple oral PCSK9 inhibitors in development. I think this is a good thing because pills are better than shots. I say that because shots increase the work of being a patient. There is just more inertia and insurance restrictions and effort required to take a shot, however infrequently. The editorialists also discussed the pricing dilemma and the role of pharmacy benefit managers (PBM) whose rebate-based pricing models often dictate drug availability. To be honest, I don't quite understand PBMs well enough to explain them, but I can say that I don't get the feeling they contribute much to the health of US citizens. There is also a potential — and I emphasize the potential part — for permanent inhibition of the PCSK9 complex via CRISPR/Cas9-mediated gene editing. Dr Sekar Kathiresan's company Verve Therapeutics is working on that, and it has progressed to early-stage human trials. The one-and-done approach to LDL-C management is obviously a high reward, high risk strategy and there will need to be rigorous safety data before this could become a reality. Two safety issues have arisen: one a patient developed very high hepatic enzymes, and in another trial, two patients had serious cardiac events — not felt to be due to the intervention. So we shall see. There would have to be a heck of lot more data on safety before I signed up to permanently change my genes — especially when you can accomplish the same thing with a tiny daily pill. I know that I sound old saying this, but if you stop and think, it's quite shocking that such an approach could be close to becoming a possibility. Editing genes so as to reduce LDL-C, for life. Wow. One of the toughest calls in EP is deciding on ICD treatment of patients with suspected cardiac sarcoid. It's hard for many reasons, not least because the diagnosis of cardiac sarcoid, and its risk stratification is difficult. European Heart Journal has published a nice study from a Dutch center and two American centers. They had about 1500 patients with biopsy proven sarcoid, mostly non-cardiac who had not had ventricular tachycardia (VT) and therefore were being considered only for a primary prevention ICD. They then compared outcomes based on multiple ways to risk stratify. I, for instance, did not know that there were multiple professional societal recommendations for an ICD. There is the 2014 Heart Rhythm Society (HRS) statement, the 2017 AHA/ACC guideline and the 2022 European Society of Cardiology (ESC) guideline. And they're all a little different. The purpose of this study is that Dutch and American authors propose is that cardiovascular magnetic resonance imaging (CMR) phenotyping is better. CMR phenotyping sounded tricky but it they made it seem easy. You are either CMR high or low risk. It's based on EF and 'pathology frequent LGE'. There were four CMR phenotypes: (1) no late gadolinium enhancement (LGE) and normal LVEF, (2) no LGE and abnormal LVEF, (3) pathology-frequent LGE, and (4) pathology-rare LGE. Pathology-frequent LGE included at least one of four features: sub-epicardial, multifocal, septal, and right ventricular free wall involvement. They then dichotomized CMR phenotypes into high-risk (pathology-frequent LGE) and low-risk (no LGE and normal LVEF, no LGE and abnormal LVEF, or pathology-rare LGE) phenotypes. The next step was to follow the 1500 or so patients over 5-10 years for VT events. Of note, most were young, average age 54 years. Let me stop there and say when you have a 50-something year old with heart block, before putting in a pacemaker, stop and think about sarcoid. Do a CMR first. The first finding was that when an ICD was indicated based on either the society or CMR phenotype the likelihood of a ventricular arrhythmia (VA) event at 10 years was high. Ranging from 20% to 35% for the high risk CMR group. When an ICD was not indicated by either the society recommendations or CMR phenotype, the rates of VA were low, but ranged from 5% in the HRS statement to 2.6% for CMR low risk. They key findings were seen in Figure 3: the CMR dichotomized method had the best are under the curve (AUC). At 5 years, it was 0.86 for VT events. That's pretty darn good, and statistically better than each of the professional society criteria for ICD. The problem of course is that the ICD need is imperfect. A subgroup of the 1500, about 8% or 119 patients received a loop recorder. About a third had high risk CMR and two thirds had CMR low risk. 4 of 38 patients (or 4% per year) had VT in the CMR high risk 1 of 81 patients in the CMR low-risk had a VA for a 0.4% per year risk. This illustrates the problem of prediction: most high-risk patients do not have a VT event and not every low-risk patient remains free of VT. As it is ischemic and non-ischemic HF patients. I do like the CMR approach, though. And this study is quite nice, as there were more than 1000 patients, all with biopsy-proven sarcoid, good follow-up, and centrally adjudicated blinded CMR. There were — as always — limitations. ICD therapy as a VT event is not always a surrogate for SCD. Just because a person has VT therapy (shock or anti-tachycardia pacing) does not mean it was aborted SCD. Second, patients without ICDs in this study may have had VT and it went undetected. To me, if we had some replication or confirmation of such a simple CMR high- or low-risk strategy, it would seem best. Realizing of course the imperfect nature of prediction of VA events. The things to keep in mind with ICD therapy is that a) it is not an insurance policy; insurance policies confer no risk to the policy holder, and ICDs surely do; b) you always want to deploy an ICD in a patient with a high-risk of the primary outcome (the VA) and a low-risk of competing risks, such as severe HF, or dementia or chronic kidney disease, or a host of disease seen in the elderly. The 54-year-old patient with heart block and LGE and reduced EF seems like an ideal patient for an ICD.
