Key Takeaways:

• The OPTION TRIAL assessed the safety and efficacy of WATCHMAN FLX in a post-ablation contemporary clinical AF patient population at risk of stroke.
• The trial showed that left atrial appendage closure after AF ablation was associated with a lower risk of non–procedure-related major or clinically relevant nonmajor bleeding compared with oral anticoagulation.

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Key Points:

• Over 6 million people in the US live with heart failure (HF), but national rates of GDMT treatment remain low
• Because pharmacists can prescribe medication and often manage chronic medical conditions, the PHARM-HF A&F study aimed to determine if education alone versus a treatment audit-and-feedback (A&F) system increased the frequency of HF medication adjustments
• The A&F arm demonstrated an increase in monthly encounters and medication adjustments compared to education alone, as well as an increase in MRA adjustments
• Though there were no significant differences in other GDMT adjustment between both arms, both arms demonstrated an increase in GDMT initiation and uptitration with longer-term follow-up needed to assess additional outcomes

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Key Points

• SUMMIT, a randomized control trial of tirzepatide versus placebo in patients with HFpEF and obesity, found that tirzepatide significantly reduced the risk of worsening heart failure events and improved physical functioning.
• This sub-analysis found that tirzepatide also led to a significant decrease in systolic blood pressure, estimated plasma blood volume, CRP, and troponin-T in this population, as well as an increase in eGFR, providing insights into the mechanisms by which tirzepatide exerts is positive clinical effects

Tirzepatide is currently approved by the US Food and Drug Administration to treat obesity. The SUMMIT trial demonstrated a positive effect of tirzepatide versus placebo on a composite of worsening heart failure events and cardiovascular mortality among patients with HFpEF and obesity, but its impact on biometric outcomes in this population is uncertain.

On November 17^th  2024, the results of “Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial” were presented at AHA Scientific Sessions 2024 with simultaneous publication in the Nature. The purpose of this mechanist secondary analysis was to determine the impact of tirzepatide on biometric measures of cardiometabolic health. .

The SUMMIT trial randomized 731 adults aged 40 or older with HFpEF (congestive heart failure with an EF ≥ 50%) and obesity (BMI ≥ 30 kgm²) to weekly injections of tirzepatide or placebo in a 1:1 fashion, and found that at a a median of 2 years of follow up, tirzepatide was associated with a significantly lower risk of cardiovascular death or a worsening heart failure events — driven primarily by a decrease in worsening heart failure  — as well as a significant improvement in KCCQ scores compared to placebo.  This secondary analysis found that tirzepatide, when compared to placebo, was also associated with  a reduction in systolic blood pressure (estimated treatment difference [ETD] – 5 mmHg [95% CI -7 to -3]; p<0.001), estimated blood volume (ETD -0.58 L [-0.63 to -0.52]; p < 0.001), C-reactive protein (CRP) (ETD -37.2% [-45.7 to -27.3]; p < 0.001), and troponin T (-10.4% [-16.7 to -3.6]; p = 0.003).  In addition, tirzepatide was also associated with a significant increase in eGFR (+1.85 ml/min/1.73 m2 [0.19–3.51]; p = 0.029) and borderline significant reductions in N-terminal prohormone B-type natriuretic peptide levels  and urine albumin–creatinine ratio.  In a post-hoc exploratory analysis, a decrease in estimated blood volume was significantly correlated with a decrease in systolic blood pressure, microalbuminuria, and improved functional status as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-min walk distance. Similarly, a decrease in CRP was associated with a decrease in troponin-T levels. Overall, the hemodynamic effects were observed early in treatment, whereas the anti-inflammatory effects occurred later in the treatment course.

Dr. Barry A. Borlaug, MD, of the Mayo Clinic in Rochester, Minnesota concluded: “Tirzepatide reduced circulatory pressure-volume overload and mitigated end organ damage in the kidney and heart in patients with HFpEF and obesity, providing new insight into the mechanisms of benefit from tirzepatide in patients with obesity-related HFpEF.”

1. Borlaug, B.A., Zile, M.R., Kramer, C.M. et al.Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03374-z

Key Points

• Three prior randomized trials including over two million adults in Denmark demonstrated that a variety of electronic message reminders, or “nudges”, to receive the influenza vaccination led to higher vaccination rates.
• This pre-specified pooled analysis evaluated the effect of this intervention among those with a history of recent acute myocardial infarction (AMI) compared to those with no AMI history, and found that nudges which highlighted the cardiovascular benefits of vaccination led to larger improvement in vaccine uptake in the AMI group, particular among those who had not been vaccinated in the prior season.
• Targeted electronic nudges may be a low-cost, highly scalable intervention to improve influenza vaccine rates among those with a history of AMI.

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Key Points:

• In patients after surgical bioprosthetic valves, it remains unclear if edoxaban is safe and effective in preventing valve complicates early after surgery.
• In this randomized clinical trial, 389 patients who had surgical bioprosthetic valves implanted were randomized to receiving either standard dose endoxaban or warfar.
• Edoxaban was found to be as safe and effective treatment option to warfarin after surgical bioprosthetic valve implantation.

There is a high incidence of thromboembolic events after bioprosthetic surgical valves. Society guidelines recommend warfarin for 3-6 months following valve implantation. However, the off-label use of direct oral anticoagulants (DOACs) following bioprosthetic surgical valve implantation is rising although its efficacy and safety is unknown.

The Efficacy and Safety of Edoxaban in Anticoagulant Therapy Early After Surgical Bioprosthetic Valve Replacement (ENBALV) trial was an investigator-initiated, open-label, multicenter, randomized clinical trial performed at 24 institutions in Japan. The study enrolled 410 patients at 24 institutions in Japan who had bioprosthetic valve replacement at the aortic and/or mitral position between May 2022 and January 2024; 389 patients were included in the final analysis.  Participants were randomized to receive either edoxaban (60 mg or 30 mg taken orally, once daily) or warfarin (administered orally, with dosing adjusted by monitoring the time taken for the patient’s blood to clot) for 12 weeks after surgery. The primary outcome was composite stroke or systemic embolism. The results of the trial were presented as a late breaking clinical trial at the American Heart Association on November 17, 2024.

Patients were ages 41-84 years old, with an average age of 73 years. The edoxaban group was 51% male and 49% female; the warfarin group was 63% male and 37% female. The study randomized participants after surgical bioprosthetic valve implantation in either the mitral or aortic position to either standard dose edoxaban (195 participants) or warfarin (194 participants).

A primary-outcome event occurred in 1 patient (0.5%) in the endoxaban arm and 3 patients (1.5%) in the warfarin arm (risk difference -1.03; 95% confidence interval [CI] -4.34 to 1.95) at 12 week follow-up. The incidence of major bleeding was higher in the endoxaban group compared to the warfarin group although not clinically significant (risk difference 3.07; 95% confidence interval [CI] –0.67 to 7.27). No fatal bleeding or intracranial hemorrhage was observed in the edoxaban group while one patient had fata intracranial bleeding in the warfarin group.

Limitations of the trial include open-label protocol, heterogenous initiation of anticoagulation at the discretion of the surgeon, short time in the therapeutic range for the warfarin arm (19.0% ± 21.6%), and no TAVR patients included.

In the late breaking presentation at the American Heart Association Scientific Sessions, Dr. Chisato Izumi concluded that “the ENBALV trial provides the first large-scale evidence demonstrating that edoxaban is a potential alternative anticoagulant therapy in patients early after bioprosthetic valve surgery.”

Key Points:

• Transthoracic echocardiography is foundational to diagnosis and evaluation of myriad conditions, but image interpretation and results reporting depends on manual reporting
• As opposed to previous applications of artificial intelligence (AI) to TTE that have focused on individual views and medical conditions, PanEcho is a view-agnostic, multi-task AI model trained on 1.23 million echo videos that can perform 39 different TTE reporting tasks
• PanEcho demonstrated a median area under the receiver operating characteristic curve (AUC) of 0.91 across 18 different classification tasks as well as minimal mean absolute error (MAE) when estimating continuous parameters, ability to identify useful views for a specific task, and translation of accurate interpretation to novel pediatric populations
• Pan-Echo represents a view-agnostic, multi-task, externally validated, open-source AI model that can accurately interpret images and produce reports across a variety of views and patient populations

Transthoracic echocardiography (TTE) is key to diagnosis and evaluation of myriad conditions. However, interpretation of imaging and reporting of findings relies on manual reporting. Among varied disciplines, artificial intelligence (AI) is said to automate processes, theoretically increasing accuracy and efficiency exponentially. Current applications of AI to TTE have traditionally focused on individual echo views and medical conditions. Here, the investigators developed PanEcho, a view-agnostic, multi-task AI model that automates TTE interpretation across different views and acquisitions for all key echocardiographic metrics and notable findings.

The investigators developed PanEcho using 1.23 million echocardiographic videos from 33,927 TTE studies performed at a health system in New England from 2016 to 2022. The model can perform 39 different TTE reporting tasks, including myocardial and valvular structure and function from any parasternal, apical, and subcostal views, including B-mode and color Doppler. PanEcho has an image encoder to learn spatial features, a Transformer (a neural network converting input to output) for temporal modeling, and task-specific output heads. In this study, PanEcho was evaluated on a distinct patient cohort from July to December 2022 as well as two external California-based cohorts from 2008 to 2020 to assess its diagnostic performance and ability to serve as a foundation model for fine-tuning in new domains.

PanEcho demonstrated a median area under the receiver operating characteristic curve (AUC) of 0.91 across 18 different classification tasks. Selected results include detection of severe aortic stenosis (AS) with 0.99 AUC, moderate-severe left ventricular (LV) systolic dysfunction with 0.98 AUC, moderate-severe LV dilation with 0.95 AUC, among others. Furthermore, the model estimates continuous metrics with a medial normalized mean absolute error (MAE) of 0.13 across 21 tasks (e.g. defining LV ejection fraction (EF) with 4.4% MAE). PanEcho’s multi-view evaluation demonstrates its ability to determine which views are more informative for each task. In addition, PanEcho’s learned representations transfer efficiently to LVEF estimation in pediatric population, outperforming current approaches (3.9% MAE vs 4.5% for the next-best).

Ultimately, the investigators conclude that PanEcho is a view-agnostic, multi-task, externally validated, open-source AI model that can accurately interpret images and produce reports across a variety of views and patient populations. Currently, PanEcho is limited by retrospective validation in previously acquired datasets. However, next steps include prospective validation in real-world patient care settings as well as evaluation of its utility among settings utilizing portable and point-of-care ultrasound (POCUS).

Key Points:

The global burden of hypertension (HTN) with high globally at 1.3 billion people and locally in India with 300 million affected
Despite making up 25% of the global population, there has never been a randomized controlled trial to investigate the optimal initial guideline-recommended combination therapy to treat HTN in those of Indian ancestry
Nearly 2000 patients were randomized to one of the three recommended initial HTN combination therapies to determine the mean change in 24-hour ambulatory systolic blood pressure (SBP) as well as other secondary outcomes
All three groups demonstrated a 14mmHg reduction in ambulatory SBP, suggesting that any of the three recommended combination therapies is reasonable for initial HTN treatment in patients of Indian ancestry

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Key Points:

• Though physical inactivity leads to poor cardiovascular outcomes, especially for those with cardiovascular disease, few studies have been performed to validate the utility of effective lifestyle interventions in this patient population
• The MyoMobile Study was a single-center randomized controlled trial to assess the effect of a personalized mobile health intervention compared to usual care on physical activity level in patients with heart failure with preserved ejection fraction (HFpEF)
• The trial compared three patient groups – usual care, patients receiving a pedometer to measure daily step count (tracking arm), and patients receiving an individualized, app-based physical activity coaching based on pedometer-based assessment of daily step count (coaching arm) – to assess change in daily step count as well as other secondary outcomes
• The coaching arm demonstrated a significant increase in daily step count compared to not only usual care, but also the tracking arm, which may demonstrate the benefits of personalized coaching for lifestyle modification therapy

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Key Points

• Maximizing lipid lowering therapy (LLTs) to optimize residual cardiovascular disease (CVD) risk after acute coronary syndrome (ACS) is usually a stepwise approach that can take months or years for many patients.
• This randomized control trial tested whether a decision support system (DSS) that provided information about residual CVD risk after ACS as well as the potential benefits of various LLTs would lead to earlier optimization compared to standard of care (SoC) pathways.
• The DDS did not significantly improve intensity of LLT treatment of percentage of patients receiving LDL-C goals within the study timeframe – however the favorable trends observed implies that this system may have value in other settings where the current SOC performance is lower than in the trial.

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KEY POINTS:

• Exenatide is a glucaon-like-peptide-1 agonist (GLP-1) improves glycemic control, and other medications in this class, appear to reduce the risk of cardiovascular disease
• The GLORIOUS Trial evaluated intravenous exenatide vs placebo in patients undergoing coronary artery bypass (CABG) or aortic valve replacement (AVR) with cardiopulmonary bypass (CPB)
• After a median follow-up of 5.9 years, no significant difference was observed in composite endpoint death, stroke, renal failure requiring dialysis, and new or worsening heart failure between the exenatide and placebo groups

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Key Points:

• Familial chylomicronemia syndrome (FCS) is characterized by extremely high plasma triglycerides (TGs) due to failure of clearance of chylomicrons, of which the most severe sequela is acute pancreatitis (AP)
• The PALISADE trial investigated a novel siRNA therapeutic, plozasiran, hypothesized to treat FCS by targeting the main regulator implicated, APOC3, which precipitates persistent chylomicronemia by inhibiting lipolysis and decreasing hepatic clearance of triglyceride-rich lipoproteins (TRLs)
• The investigators previously randomized groups to low-dose or high-dose plozasiran vs placebo to investigate primary outcome of median percent change in TGs at 10 months, as well as notable secondary outcomes, including overall reduction in TGs and APOC3 as well as reduced risk of AP, finding that plozasiran met all clinical endpoints, including reduction in TGs, APOC3, and reduced risk of AP
• The authors now present the longer-term effects of therapy, noting rapid and significant (>80%) reductions in TGs and APOC3, independent of gene variants, as well as sustained reduction of TG levels below the threshold to prevent AP among >50% of included patients

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Key Takeaways:

• The VANISH2 trial compared catheter ablation with systematic antiarrhythmic drug therapy as a first-line treatment strategy in patients with an ICD ischemic cardiomyopathy, and ventricular tachycardia who had no history of nonresponse to antiarrhythmic drug therapy.
• Catheter ablation significantly reduced the composite primary outcome (death, VT storm, ICD shock, and VT emergency treatment) compared with antiarrhythmic drug therapy (HR, 0.75; 95% CI, 0.58–0.97; P=0.03).
• Sustained VT requiring treatment below the detection limit of an ICD was notably reduced in the catheter ablation group (HR, 0.26; 95% CI, 0.13–0.55; P<0.001).
• Mortality rates were similar between groups, with no statistically significant difference (HR, 0.84; 95% CI, 0.56–1.24; P=0.38).
• Catheter ablation demonstrated a comparable safety profile, with fewer drug-related adverse events compared to antiarrhythmic drugs.

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Key Takeaways:

• The CLEAR SYNERGY trial was a multicenter trial with a 2-by-2 factorial design which randomly assigned patients with myocardial infarction who had undergone percutaneous coronary intervention to receive either a) spironolactone or placebo and b) either colchicine or placebo.
• Among patients with myocardial infarction, spironolactone did not reduce the incidence of death from cardiovascular causes or new or worsening heart failure or the incidence of a composite of death from cardiovascular causes, myocardial infarction, stroke, or new or worsening heart failure.
• Safety outcomes, including hyperkalemia and gynecomastia, were more common in the spironolactone group compared to placebo.

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Key Takeaways:

• A single dose of nexiguran ziclumeran (nex-z), a CRISPR-Cas9-based therapy, achieved a 90% reduction in serum transthyretin (TTR) levels at 12 months (95% CI, −93 to −87).
• NT-proBNP levels showed stability with a geometric mean factor change of 1.02 (95% CI, 0.88 to 1.17), while high-sensitivity cardiac troponin T had a mean factor change of 0.95 (95% CI, 0.89 to 1.01).
• Of the 14 patients with serious adverse events, 7 had an event leading to hospitalization associated with cardiac failure (4 patients), arrhythmia (2 patients), or both (1 patient). The observed rate of cardiac events was 0.16 per patient per year (95% CI, 0.08 to 0.36).

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Key Points

• SUMMIT was a multi-national trial that compared cardiovascular outcomes among patients with heart failure with preserved ejection fraction (HFpEF) and obesity that were randomized to tirzepatide (a GLP-1 receptor agonist) or placebo.
• Patients in the tirzepatide arm had a significantly lower risk of a composite of worsening heart failure events and cardiovascular death, driven by a reduction in heart failure events. In addition, they experienced significantly larger gains in health status and physical functioning compared to placebo.

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Key Points

• BPROAD was a randomized control trial in China that assigned nearly 13,000 participants
  with type 2 diabetes (T2DM) and hypertension (HTN) to either a systolic blood pressure
  target of 120mmHg (intensive arm) or 140mmHg (standard arm).
• At 5 years of follow up, the intensive arm had significantly lower rates of major
  cardiovascular events (MACE: a composite of heart attack, stroke, heart failure, and
  cardiovascular death), however symptomatic hypotension and hyperkalemia occurred more frequently in the intensive arm.
• This trial supports targeting a systolic blood pressure of<120 mmHg to prevent MACE
  among patients with T2DM and HTN, with close monitoring for adverse effects.

Nearly 75% of patients with T2DM have high blood pressure. Hypertension is a major risk
factor for cardiovascular disease (CVD), including myocardial infarction, stroke, and heart
failure. While the SPRINT trial demonstrated that intensive blood pressure control improves
cardiovascular risk among those with HTN, patients with T2DM were excluded. 1 The ACCORD
BP trial found no benefit to an intensive blood pressure control strategy among those with
T2DM, however the power of this study was limited, and the interaction between intensive blood pressure control and intensive glycemic control strategies pursued in this study affected the overall results. 2 Therefore, benefit of intensive blood pressure control among those with T2DM remains uncertain.

On November 16, 2024 the results of Blood Pressure Control Target in Diabetes (BPROAD)
Study were presented at AHA Scientific Sessions 2024 with simultaneous publication in the New England Journal of Medicine. The purpose of this study was to determine whether targeting an intensive systolic blood pressure goal of <120 mmHg was more effective than the standard target of <140 mmHg in reducing the risk major cardiovascular adverse events (MACE) –including non-fatal stroke, myocardial infarction, heart failure, and cardiovascular death –among adults with T2DM.

BPROAD randomized 12,821 adults aged 50 or older with T2DM, HTN, and an increased risk of
CVD at 145 study sites across mainland China in 1:1 fashion to the intensive or standard
treatment arm. HTN for this study was defined as an systolic blood pressure of ≥ 140 mmHg on no medications or a systolic blood pressure of ≥130 mmHg on at least one medication. Increased CVD risk was defined as a history of clinical or subclinical cardiovascular disease prior to trial enrollment, at least two cardiovascular risk factors, or CKD. The average age was 64 years, 45% were women, and 23% self-reported a history of CVD. The groups were well balanced in terms of baseline characteristics, including blood pressure, BMI, smoking status, and hemoglobin A1c and lipid levels.

After 1 year of follow up, the mean systolic blood pressure in the intensive arm was 121.6
mmHg compared to 133.2 mmHg in the standard arm. At a median follow up for 4.2 years, rates of MACE were lower in the intensive arm (1.65 per 100 person-years) than in the standard arm (2.09 per 100 person-years), a significant reduction (HR 0.79 [95% CI 0.69-0.90]; p<0.001). The benefit of intensive control was consistent across the pre-specified subgroups. While the incidence of serious adverse events were similar, symptomatic hypotension and hyperkalemia was more frequent in the intensive arm.

Limitations of this study include lack of blinding for participants and study physicians, study
interruptions due to COVID-19 pandemic (the study enrolled from February 2019 through
December 2021), and limited generalizability to other populations.

Guang Ning, M.D., Ph.D., an elected member of the Chinese Academy of Engineering and a
professor at Ruijin Hospital at Shanghai Jiao Tong University School of Medicine in Shanghai,
China, concluded: “We found that for most people with Type 2 diabetes, lowering systolic blood pressure to less than 120 mm Hg reduced the risk of major cardiovascular events. These findings provide strong support for a more intensive systolic blood pressure target in people with Type 2 diabetes for the prevention of major cardiovascular events.”

References
1. The SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-
Pressure Control. N Engl J Med. 2015;373(22):2103-2116. doi:10.1056/NEJMoa1511939
2. Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. N Engl J Med.
2010;362(17):1575-1585. doi:10.1056/NEJMoa1001286

Key Points:

• In patients with atrial fibrillation, it remains unclear if anticoagulation therapy reduces the incidence of neurocognitive impairment
• In this randomized clinical trial, young patients who had atrial fibrillation with low stroke risk were randomized to receiving either rivaroxaban 15mg or placebo.
• Anticoagulation with rivaroxaban 15mg in young patients with atrial fibrillation with low stroke risk did not reduce composite end point of ischemic stroke, TIA, and neurocognitive decline at a median of 3.7 years.

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• The FAVOR III Europe study aimed to investigate whether a QFR-based diagnostic strategy yields a non-inferior 12-month clinical outcome compared with an FFR-based strategy.
• The findings do not support the use of QFR if FFR is available to guide revascularization decisions in patients with intermediate coronary stenosis.

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• The ECLIPSE trial evaluated orbital atherectomy (OA) vs conventional balloon dilatation (BA) in patients with de novo severely calcified lesions.
• The trial found no difference in target vessel failure (TVF) at one year between the two groups. The minimum stent area at the maximum calcium site was similar, but there was a numerical increase in favor of OA

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• Several randomized trials have shown reductions in MACE with colchicine in the treatment of coronary artery disease.
• The CLEAR SYNERGY (OASIS 9) trial showed that in patients with acute MI undergoing PCI, daily treatment with colchicine did not reduce MACE at 5 years compared with placebo.

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