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AVATAR (Aortic Valve Replacement versus Watchful Waiting in Asymptomatic Severe Aortic Stenosis)
Insights by Victoria Delgado
Current guidelines recommend aortic valve replacement in asymptomatic patients with severe aortic stenosis if left ventricular systolic function is impaired or with demonstrable symptoms or sustained fall of blood pressure during exercise testing.
The AVATAR trial compared the safety and efficacy of early surgical aortic valve replacement in 157 asymptomatic patients with severe aortic stenosis, preserved left ventricular ejection fraction and negative exercise test (no inducible symptoms, normal response of blood pressure and no inducible myocardial ischemia). Patients were randomized to surgical aortic valve replacement versus watchful waiting strategy and were followed-up for the occurrence of the composite primary endpoint of all-cause mortality and major adverse cardiovascular events including myocardial infarction, unplanned heart failure hospitalization needing intravenous diuretic or inotrope treatment and stroke.
At 4 years of follow-up, patients randomized to early surgical aortic valve intervention presented significantly less cumulative event rates of the primary endpoint as compared to patients in the watchful waiting arm with a hazard ratio of 0.46.
These results provide additional evidence of the potential benefits of early surgical aortic valve replacement in asymptomatic patients with severe aortic stenosis and preserve ejection and may impact on the development of future guidelines recommendations.
A Remotely Delivered Hypertension and Lipid Program in 10,000 Patients Across a Diverse Health Care Network
Insights by Sanjay Sharma
Hypertension (HT) and hyperlipidaemia (HLD) are major risk factors for cardiovascular disease, affecting over 1 billion individuals globally. Between 30 and 50% of affected patients do not achieve therapeutic values recommended by current guidelines.
This study examined the role of a remote digital algorithm-based management programme to treat patients with HT and HLD. Over 10,000 affected individuals were enrolled, of which almost 7,000 had HLD and over 3,000 had HT. Non-licensed navigators collated information and worked with pharmacists who titrated therapy. Both groups engaged and communicated with patients via digital platforms. The median age of the population was 63 years old. 12% were aged over 75 years-old, 55% were female, 29% one non white and 8% were non-English speaking. During the 3-year study, 40% of the patients could not be retained. By the end of the study between 40-44% of patients were on maintenance therapy and 15-23% were receiving active titration. 90% achieved the therapeutic target for HT and 94% achieved therapeutic targets for LDL. These benefits were consistent across race, ethnicity, and primary language.
The results of this study suggest that standardised remote algorithmic care can effectively optimise guideline directed treatment at a large scale, reduce cardiovascular risk and improve healthcare outcomes without the need for inpatient visits and physician time. Populations who are traditionally considered to be underserved and undertreated can also be managed effectively using remote methods.
aMAZE (LAA Ligation Adjunctive to PVI for Persistent or Longstanding Persistent Atrial Fibrillation)
Insights by Elena Arbelo
Pulmonary vein isolation (PVI) has a well-established role in catheter ablation of atrial fibrillation (AF), in particularly paroxysmal AF. Ablation of persistent forms is more challenging and historically, results have been considered to be suboptimal. For this reason, adjunct strategies targeting sites outside the PV antra have been intensely explored.
The aMAZE trial is based on prior data from the BELIEF randomised trial and the LAALA-AF registry, that suggest that left atrial appendage (LAA) isolation improves arrhythmia free survival in longstanding persistent AF. The study randomised in a 2:1 manner 610 patients with persistent AF to PVI only or PVI + LAA ligation using a LARIAT device. Rhythm monitoring during follow-up included a 24-hour holter and symptomatic event monitoring. Most patients (aprox. 80%) had early persistent AF (i.e. of less than 6 months duration).
Successful closure of the LAA was safe and achieved in 85-99% of patients. However, it showed no significant benefit at 12 months in terms of freedom from documented AF, atrial flutter, or atrial tachycardia (63.9% in the PVI+LAA ligation group versus 59.9% in the PVI only group). Importantly, even if overall major complications were not increased, there were 3 cases of serious injuries requiring surgical interventions.
Finally, exploratory subgroup analyses, with all their limitations, suggested that the subgroups of early persistent and larger volume atria (>133 cm3) may benefit from LAA ligation. Further investigation is required to verify these exploratory observations.
CRAVE (The Coffee and Real-Time Atrial and Ventricular Ectopy Trial)
Insights by Elena Arbelo
The relationship of coffee consumption and cardiovascular health is complex. It has traditionally been considered to increase the risk of arrhythmias, although studies have failed to demonstrate it, and some population analyses have suggested reductions in mortality, which is not clearly understood. Unfortunately, previous research has been observational and based on self-reporting. For this reason, this well conducted study is one of a kind and provides relevant insights in relation to coffee consumption and cardiovascular health.
The Coffee And Real-time Atrial And Ventricular Ectopy (CRAVE) Trial randomised 100 adults to coffee consumption or abstinence over 2 weeks and monitored them using continuous monitoring of the ECG, physical activity (step count), sleep, glucose and geolocation. Individuals were tested for their DNA variants of caffeine metabolism. Compliance was high in both groups. The study participants did not have any prior history of arrhythmias or cardiovascular disease, their mean age was 38 years and mean BMI was 24 kg/m2.
The main findings of the study were that coffee did not result in any increase in atrial arrhythmias (in fact, in the per protocol analysis, coffee consumers experienced fewer SVTs). On the contrary, premature ventricular beats were more frequent, particularly in fast caffeine metabolizers. Additionally, participants in the intervention group substantially performed more physical activity and showed less sleep hours, which was heightened in slow caffeine metabolizers. There were no significant differences in glucose levels.
This trial assessed the acute effects of coffee in healthy volunteers, and it is difficult to translate it to the individual patients and their long-time risks. How these findings translate in improved or worse health needs to be further explored.
REVeAL-HF (Risk EValuation And Its Impact on ClinicAL Decision Making and Outcomes in Heart Failure)
Insights by Johann Bauersachs
Decompensated heart failure (HF) is associated with high mortality and morbidity. No study to date has examined in a randomized fashion the impact of providing prognostic information on provider behavior and downstream clinical outcomes.
REVeAL-HF tested the clinical impact of providing prognostic information to the treating physicians in the inpatient settings on HF outcomes. The study hypothesis was that electronic alerting about prognostic information on HF patients along with links to guidelines will lead to reductions in all-cause mortality at 1 year and 30-day hospital readmission via improved use of guideline directed medical therapy and more adequate decongestion. The study recruited >3,000 patients hospitalized for HF with NTproBNP levels of >500 pg/mL and iv diuretic treatment within 24h of admission. 18% of patients were admitted to the ICU, and 28% had HFrEF with an LVEF <40%. Intervention was an alert of their prognosis based on the best available prognostic models generated with information from their electronic health record, which "pop-up" when providers accessed a patient record.
The main result was that there is no difference in the primary outcome of 30-day hospital readmission and all-cause mortality at 1 year. Also, the use of guideline directed medical therapy at discharge in the HFrEF patients was not different. These results indicate that information about prognosis in HF does not impact clinical decision making and patient outcomes in high risk HF inpatients.
Fitbit Heart Study (Detection of Atrial Fibrillation in a Large Population using Wearable Devices)
Insights by Sanjay Sharma
Atrial fibrillation (AF) is a highly prevalent arrhythmia with a 5-fold increase in stroke. Anticoagulation reduces the risk of an embolic stroke by 60%, however between 25-30% of AF remains undiagnosed.
This study investigated the role of Fitbit monitors and smart watches for detecting AF using a novel pulse photoplethysmography algorithm. Over 455,000 adults with a median age of 47 years old were enrolled (12% ≥65 years-old, 71% female and 23% non-white). Patients with a prior history of AF, pacemaker, or ICD were excluded. Individuals with 11 consecutive 5 minute episodes of an irregular heart rhythm detection (IHRD) during rest were invited to schedule visits with a telehealth provider. Eligible individuals were fitted with a 7-day ECG monitor to check for AF. The primary endpoint of the study was to assess the positive predictive value of a first irregular HR detection and the identification of AF on the prolonged ECG monitor. An IHRD was identified in 1% (over 4,000), however, only 1,057 could be investigated. AF was present in 340 (32.2%) of these individuals. An IHRD occurred during ECG monitoring in 225 individuals of 98% had concurrent AF. The median AF burden was 7% and the median longest duration was 7 hours.
This study shows that wearable devices with a novel software algorithm can reliably facilitate identification of individuals with undiagnosed AF. This algorithm was limited to resting conditions and the study did not investigate whether AF diagnosis correlated with change in management or outcomes.
DREAM-HF (Randomized Trial of Targeted Transendocardial Delivery of Mesenchymal Precursor Cells in High-Risk Chronic Heart Failure Patients With Reduced Ejection Fraction)
Insights by Victoria Delgado
Stem cell therapy in patients with heart failure and reduced ejection fraction (HFrEF) is an experimental therapy with unclear benefits.
The DREAM-HF trial provides new evidence on the mechanism of action and the benefits of allogenic mesenchymal percussor cells, a type of stem cell therapy, in patients with HFrEF. The mesenchymal precursor cells are known for their immunomodulatory and angiogenic mechanisms of action that target inflammatory processes that contribute to the myocardial cell loss and atherosclerotic cardiovascular disease. A total of 565 patients with ischemic and non-ischemic HFrEF were randomized to myocardial infection of mesenchymal precursor cells using a 3-dimensional electromagnetic navigation system or to a sham scripted procedure. The primary endpoint was reduction of recurrent of decompensated heart failure events. In addition, there were prespecified endpoints of cardiovascular morbimortality including non-fatal myocardial infarction and stroke and cardiac death.
During a follow-up of 30 months, the stem cell therapy did not reduce the occurrence of the primary endpoint. However, stem cell therapy reduced the incidence of non-fatal myocardial infarction and stroke by 65%, the incidence of cardiac death by 57% among patients with heart failure symptoms NYHA class II and the time to first event of cardiovascular morbimortality among those with systemic inflammation.
Therefore, while this type of stem cell therapy is not beneficial to reduce the events of decompensated heart failure, it improves the cardiovascular morbimortality of patients with HFrEF who are at an early stage of the disease (NYHA II) and with systemic inflammation.
CHIEF-HF (Canagliflozin Impact on Health Status, Quality of Life and Functional Status in Heart Failure Clinical Trial)
Insights by Johann Bauersachs
SGLT2 inhibitors such as Empagliflozin and Dapagliflozin improve hard outcomes and quality of life (QoL) in HFrEF, and Empagliflozin also in HFpEF. However, it is unknown whether also Canagliflozin is effective.
CHIEF-HF determined the effectiveness of Canagliflozin 100 mg once daily versus placebo in patients with symptomatic heart failure (HF) in improving the overall Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score after 12 weeks. The study is also interesting, as a new concept of performing clinical studies without a face-to-face visit was employed. CHIEF-HF included almost 500 stable HFrEF and HFpEF patients. Patients were invited by the sites either by email, portal, phone, or at a visit, and if interested and eligible, they downloaded the study app and the electronic consent was obtained by the PI. Study medications and materials were delivered to the patients.
The main result was that Canagliflozin 100mg daily improved HF symptoms regardless of EF or diabetes status. The beneficial effects were observed early, and were sustained to 12 weeks. These results indicate that the beneficial effects of SGLT2 inhibitors regarding symptoms and QoL in HF patients extend also to Canagliflozin, however, whether this holds true for hard clinical outcomes needs to be established. Also, the study shows that it is feasible to perform randomised placebo controlled studies without face-to-face visits, which is important for the conduct of trials not only during COVID-19 times.
EMPULSE (Efficacy and Safety of Empagliflozin in Hospitalized Heart Failure Patients)
Insights by Carlos Aguiar
Treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors improves outcomes in patients with chronic heart failure (HF) with reduced ejection fraction (EF), and is a class I recommendation with level of evidence A in the current ESC guidelines.
EMPULSE was designed to investigate whether the in-hospital initiation of SGLT2 inhibition in patients with acute HF can improve outcomes. EMPULSE enrolled 530 patients randomly assigned to receive empagliflozin 10 mg once daily or placebo after clinical stabilization and for up to 90 days. 33% had de novo acute HF, 45% diabetes, and 32% left ventricular EF >40%. The primary outcome was clinical benefit at 90 days, defined as a hierarchical composite of time to all-cause death, the number of HF events, time to the first HF event, and a >=5-point difference in change from baseline in KCCQ total symptom score, assessed using a stratified win ratio. Patients treated with empagliflozin were 36% more likely to experience a clinical benefit as compared with placebo. This effect was consistent across all components of the primary outcome: a) all-cause mortality (4.2% with empagliflozin vs. 8.3% with placebo); b) HFE (10.6% with empagliflozin vs. 14.7% with placebo); and c) KCCQ-TSS (mean change from baseline: +36.9 with empagliflozin vs. +31.6 with placebo). Empagliflozin was well tolerated, with fewer patients experiencing serious adverse events vs. placebo.
The results of the EMPULSE trial are clinically meaningful, they extend the benefits of SGLT2 inhibition to patients hospitalized with acute HF, and will very likely impact on future guidelines for the management of acute HF.
REVERSE-IT (Bentracimab in Ticagrelor-Treated Patients With Uncontrolled Major or Life-Threatening Bleeding or Requiring Urgent Surgery or Invasive Procedure)
Insights by Stephan Achenbach
The REDUCE-IT trial investigated bentracimab, a monoclonal antibody to reverse the effect of ticagrelor.
REDUCE-IT was not randomized. In 150 patients on ticagrelor of which the majority underwent urgent surgery and a few others had spontaneous bleeding, it investigated the efficacy and safety of the intravenous application of bentracimab to reverse the platelet inhibition effect of ticagrelor.
The trial found that measured platelet inhibition was reduced quickly with bentracimab (within 5 minutes). Bleeding control could be achieved in all 141 patients undergoing urgent surgery (mostly bypass surgery) and 9 patients with spontaneous bleeding – but, as pointed out before, there is no comparison to any control group, so it is not known how patients would have done without bentracimab. Regarding side effects, the major concern would obviously be thrombotic events. Overall, there were 8 patients with thrombotic events such as graft occlusion, TIA, or peripheral ischemia, all after bypass surgery. 4 were late, 4 on the same day, and the mechanisms are unclear – no stent thrombosis was reported.
The investigators conclude that the trial shows how bentracimab has a well controlled reversal effect of ticagrelor – the discussant Gilles Montalescor pointed out that this is true, but clinically, there would have been alternatives, such as waiting 3-5 days with the surgery. The trial does show that bentracimab acts rapidly and is effective, data are not so conclusive regarding safety, and we will need to wait to develop clinical strategies of when and when not to use it.
AXIOMATIC-TKR (Milvexian for Prevention of Venous Thromboembolism)
Insights by Carlos Aguiar
Direct oral anticoagulants represent a major advance over vitamin K antagonists, but annual rates of major and clinically relevant nonmajor bleeding remain a reason for fear of treatment and inappropriate underdosing in eligible patients. It has been suggested that targeting Factor XI may be more effective and associated with less bleeding than current anticoagulants. Milvexian is an oral selective inhibitor of factor XIa. It is metabolized in the liver and has <20% renal clearance.
The AXIOMATIC-TKR trial is a phase 2 study designed to compare the efficacy and safety of milvexian and enoxaparin in patients undergoing unilateral elective knee arthroplasty. AXIOMATIC enrolled 1,242 patients randomized to receive one of 7 regimens of milvexian given twice or once daily or to receive 40 mg of subcutaneous enoxaparin once-daily. Treatment was given for 10-14 days. The primary efficacy outcome was venous thromboembolism (VTE), which included asymptomatic deep venous thrombosis documented on mandatory venography of the operated leg. The principal safety outcome was any bleeding, defined as any major, clinically relevant nonmajor or minimal bleeding. The rates of VTE with milvexian given in daily doses >100 mg were significantly lower than with enoxaparin. The rates of any bleeding were similar for both treatments, but the composite of major or clinically relevant nonmajor bleeding was lower with milvexian.
These results suggest milvexian is a promising new oral anticoagulant. This agent is currently undergoing phase 2 evaluation for secondary stroke prevention. Other potential indications include the prevention of thrombotic events in patients with end-stage renal disease, mechanical heart valves, left ventricular assist devices, or requiring concomitant antiplatelet therapy.
Wrap-up Basic and Translational Science
Insights by Carol Ann Remme
This year’s Scientific Sessions of the American Heart Association featured some excellent basic and translational science.
A number of sessions highlighted the increasing application of single cell RNA sequencing and transcriptomics. This approach has greatly facilitated the identification of distinct subtypes of immune cells and smooth muscle cells within atherosclerotic plaques. Similar studies have also established the heterogeneity of smooth muscle cell phenotypes in aortic aneurysms as well as the diverse cellular landscape of human right ventricular failure. Such single-cell profiles in cardiovascular disease are highly informative: they allow for the identification of distinct disease pathways as well as biomarkers of disease severity and outcome, and may ultimately reveal novel therapeutic targets.
As discussed during various sessions, cardioprotective strategies for heart failure are now increasingly targeting cardiac metabolism and mitochondrial dysfunction, as well as the immune system and inflammasome. Approaches for cardiac repair were also featured, including those employing extracellular vesicles, exosomes, and nanoparticles. Basic science is furthermore increasingly informing novel therapeutic approaches for rare, inherited cardiomyopathies and arrhythmia disorders, including gene therapy, microproteins and peptide therapeutics.
Finally, this year’s meeting highlighted the recent advances made in the field of stem cell platforms and cardiac organoids. Tissue bioengineering approaches are becoming increasingly important for disease modelling, including cardiovascular effects of COVID-19. Furthermore, new and improved 3D bioprinting technologies and scaffolds now allow for the generation of vascular networks, contractile ventricular models, and increasingly complex cardiovascular structures. Progress in this field is truly impressive, paving the way for improved disease modelling, development of novel therapies and ultimately alternative transplant solutions.