Introduction

The ACC.org Prevention, Stable Ischemic Heart Disease, and Arrhythmias and Clinical EP editorial teams have developed additional education from the European Society of Cardiology (ESC) Congress 2021 meeting. This education focuses on high-impact recommendations that can be potential areas of confusion or controversy or simply new evidence that represents a significant change from former standard of care. This review covers the STEP (STrategy of blood pressure intervention in the Elderly hypertensive Patients), EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial), MASTER DAPT (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated vs. Standard DAPT Regimen), LOOP (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals), TOMAHAWK (Angiography After Out-of-Hospital Cardiac Arrest Without ST-Segment Elevation), and IAMI (Influenza Vaccination After Myocardial Infarction) trials.

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Focus on Prevention
By Kim K. Birtcher, PharmD, AACC
University of Houston College of Pharmacy
Houston, TX

LOOP
By Michael D. Miedema, MD
Minneapolis Heart Institute
Minneapolis, MN

The LOOP Study¹ was a prospective randomized trial evaluating the impact of more aggressive screening for atrial fibrillation (AF), via implantation of an implantable loop recorder, and subsequent anticoagulation for stroke prophylaxis compared to usual care in older adults (aged 70-90 years) with one additional risk factor for stroke. In 6,004 participants followed for over 5 years, the study found that aggressive screening resulted in an approximate 2.5-fold increase (32% vs. 12%, p-value <0.0001) in diagnosed AF as well as a significant increase in the initiation of anticoagulation (30% vs. 13% p-vale <0.0001). There was a trend but no significant decrease in the subsequent rate of stroke or systemic arterial embolism in those aggressively screened for AF (4.5% vs. 5.6%, p-value 0.11) and well as a trend but no significant increase in the rate of major bleeding events (4.3% vs. 3.5%, p-value 0.11). The authors conclude that aggressive screening for AF may find brief, asymptomatic AF with limited benefit from anticoagulation. Alternatively, is it also likely that a study with a larger sample may demonstrate a small but significant decrease in stroke but also a small but significant increase in bleeding events. More aggressive screening for AF clearly results in an increase in the diagnosis of AF, but the net clinical benefit of more aggressive screening and subsequent anticoagulation for AF remains unclear.

TOMAHAWK
By Xiaoming Jia, MD
Baylor College of Medicine
Houston, TX

The TOMAHAWK trial² was a multicentered randomized study comparing early coronary angiography with initial intensive care management with delayed/selective coronary angiography among patients presenting with resuscitated out-of-hospital cardiac arrest without ST-segment elevation. The median age of the study population was 70 years, 30.4% were women and 37.6% had known coronary artery disease. About 62% of patients in the delayed/selective angiography group received coronary angiography. Significant coronary artery disease was found in 60.7% of patients undergoing immediate angiography of which 37.2% received percutaneous coronary intervention (PCI) versus 72.1% (who had angiography) in the delayed/selective group of which 43.2% received PCI. The primary outcome of all-cause mortality at 30 days was 54.0% in the early angiography group and 46.0% in the delayed/selective angiography group (HR 1.28, 95% CI 1.00-1.34, p=0.06), while the secondary outcome of death or severe neurologic deficit occurred in 64.3% or the early angiography group and 55.6% of the delayed/selective angiography group (RR 1.16, 95% CI 1.00-1.34). While coronary artery disease was present in a sizable proportion of patients presenting with out-of-hospital cardiac arrest without ST-elevation on electrocardiogram, the data from the TOMAHAWK trial did not show benefit of early coronary angiography over delayed/selective angiography with respect to 30-day survival.

IAMI
By Kim K. Birtcher, PharmD, AACC
University of Houston College of Pharmacy
Houston, TX

The primary objective of the Influenza Vaccination After Myocardial Infarction (IAMI) trial³ was to assess the impact of giving influenza vaccination, within 72 hours of a coronary procedure (angiography or percutaneous coronary intervention [PCI]) or hospitalization, to patients with a recent acute myocardial infarction (AMI) or high-risk coronary artery disease (CAD). The trial was a randomized, double-blind, placebo controlled, multicenter trial conducted in eight countries. The trial was halted early due to the COVID-19 pandemic. It enrolled 2,532 patients, which was 58% of the target enrollment. The median age of the patients was 60 years, and 18.2% were women. The majority of the patients had an AMI (54.5% STEMI, 45.2% NSTEMI), and 74.3% of the patients were treated with PCI. The composite primary outcome, which included all-cause death, MI, or stent thrombosis at 1-year, occurred less often in the patients who received the influenza vaccine compared to those who received the placebo (5.3% vs. 7.2%, hazard ratio 0.72, 95% CI 0.52-0.99, p=0.04). The rates of death from cardiovascular disease (2.7% vs. 4.5%, p=0.014) and all-cause death (2.9% vs. 4.9%, p=0.01) at 1-year were also lower in the vaccine group. There was no difference in the rate of MI between the groups (2.0% vs. 2.4%, p=0.57). The investigators concluded that early administration of an influenza vaccination, within 72 hours of a coronary procedure (angiography or PCI) or hospitalization, to patients with a recent AMI or high-risk CAD resulted in a lower risk of the composite outcome of all-cause death, MI, or stent thrombosis and lower risk of cardiovascular death and all-cause death at 1-year. The findings of the IAMI trial are consistent with other data showing the benefits of influenza vaccination in improving cardiovascular outcomes in patients with CAD.⁴ Based on the IAMI findings, clinicians should promote giving an influenza vaccination to patients early during a hospitalization for AMI or high-risk CAD.

STEP
By Romana Awan, MBBS, MD
National Institute of Cardiovascular Diseases
Karachi, Pakistan
Anum Saeed, MD
University of Pittsburgh Medical Center
Pittsburgh, PA

The optimal target for systolic BP (SBP) to reduce cardiovascular disease (CVD) events in older adults with hypertension remains undefined. In this multicenter, randomized, controlled trial, Zhang et al. assessed the effects of strict SBP target of 110 to <130 mmHg (intensive treatment) versus a target of 130 to <150 mmHg (standard treatment) in a cohort of older Chinese adults (60-80y).⁵ Due to CVD benefit in the composite primary outcome in the intensive-treatment group (Hazard Ratio = 0.74 [0.60 – 0.92]; p-value 0.007), the trial was stopped early.

The results of the STEP trial are noteworthy; however, careful interpretation should be stressed. This trial was conducted in a purely Chinese cohort  ̶  typically at a lower CVD risk than American counterparts  ̶  utilizing a smartphone-based app. The participants' SBP was recorded via observed and unobserved (at home) SBP measurements, and the study excluded all participants with a history of stroke. Like the SPRINT, the incidence of hypotension was higher (relative risk = 1.31 [1.02–1.68]; p=0.03) in the intensive treatment group, however, a quality-of-life measure was not accounted for.

In summary, the STEP trial indicates that intensive SBP to targets of 110 to <130 mmHg reduced CVD events in a Chinese cohort with a modest increase in hypotension. With similar results as SPRINT, this trial adds to the exciting data for overall antihypertensive strategies for CVD prevention. However, more research regarding CVD and quality of life benefit as well as a long-term adverse outcomes profile in a "safe range" (than a single point threshold of SBP) for older adults may be needed before unrestricted clinical implementation of aggressive SBP lowering.

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Focus on Stable Ischemic Heart Disease
By Julio A. Panza, MD, FACC
Westchester Medical Center
Valhalla, NY

MASTER DAPT
This trial, together with other recent similar studies, further supports the use of shorter duration of dual antiplatelet therapy in patients after percutaneous coronary interventions (PCI). It must be noted that the patients included in this study were carefully selected. All patients had high bleeding risk, underwent implantation of a biodegradable polymer stent, had no ischemic or bleeding events within the first 30 days after PCI, and had no previous treatment of in-stent restenosis or stent thrombosis. In addition, patients were randomized after the demonstration of 1 month of clinical stability and not before the procedure, an important consideration when trying to apply these findings to clinical practice. Importantly, approximately half of the patients were treated for stable disease and the other half for an acute coronary syndrome; no differences were observed in the results between these two groups. Clopidogrel was the most frequently used antiplatelet agent in both treatment arms, which may be different from the use of aspirin, still the predominant monotherapy antiplatelet agent. Finally, one must consider the results of previous trials showing that more aggressive antithrombotic treatment in patients at high cardiovascular risk leads to the prevention of ischemic adverse outcomes, somewhat in contradistinction to the findings of this study. Overall, the use and duration of dual antiplatelet therapy in coronary artery disease patients remains a moving target. Careful selection of patients with regard to the balance between their relative ischemic and bleeding risks is critical for decision-making.

TOMAHAWK
The results of this trial show that routine immediate coronary angiography does not improve outcomes of patients with out-of-hospital cardiac arrest, and confirm those of the recent COACT study, which only included patients with shockable rhythms. TOMAHAWK included patients with shockable and those with non-shockable rhythms, thus applying its results to a broader population of patients. These investigative efforts are very important given the preconceived notion, still prevalent in many centers and among many physicians  ̶  and previously endorsed in the medical literature  ̶ , that all patients with out-of-hospital cardiac arrest should go immediately to the cath lab. A detailed look at the data from TOMAHAWK explains why this strategy does not work. First, only about 40% of patients had coronary artery disease that was interpreted as the culprit for the cardiac arrest. Accordingly, only 40% of patients underwent percutaneous coronary intervention (PCI) in both groups of immediate and/or delayed coronary angiography. Finally, and most importantly, most patients died of anoxic brain injury, which means that even in those patients with clear evidence of a culprit vessel treated with a PCI, the ultimate benefit of coronary angiography is limited due to the lack of neurologic recovery. Of note, in TOMAHAWK, even when patients were stratified by shockable versus non-shockable rhythm, there was no advantage of the immediate angiography strategy. Based on these findings, it is clear that in patients without ST-segment elevation (and perhaps even in those with ST-segment elevation), the use of immediate angiography should be reserved for selected patients, such as those in whom an ischemic etiology of the cardiac arrest is strongly suspected (e.g., angina prior to the arrest), immediate bystander cardiopulmonary resuscitation (CPR), shockable rhythms, and those who present without significant neurological deficits after the return of spontaneous circulation. Ongoing studies addressing these questions may help to provide further direction about the best strategy to follow in patients who survive a cardiac arrest.

IAMI
This is a trial with confirmatory findings of previous observations that further support the recommendation for influenza vaccination. The mechanism of benefit is not entirely clear, but likely resides in a potential anti-inflammatory effect of the vaccine. Alternatively, one could postulate that contracting the influenza infection may lead to acute cardiovascular events that are prevented by the vaccine. However, only 6% of patients reported an acute respiratory illness during the 12-month follow-up and the incidence was similar between the two treatment groups. The findings of this and other similar studies (including a recently published meta-analysis) with nearly identical results definitely support the concept that patients hospitalized with acute myocardial infarction (MI) should receive the vaccine prior to discharge, at least during the influenza season.

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Focus on Arrhythmias and Clinical EP
By Luigi DiBiase, MD, PhD, FACC
Montefiore Medical Center
New York, NY

EAST-AFNET 4
The EAST-AFNET 4 trial aimed to answer the growing popular question asked in the recent practice of atrial fibrillation (AF): are early rhythm-control strategies better than conventional care in patients with cardiovascular diseases? A total of 2,789 patients with early AF (diagnosed ≤12 months before enrollment) were randomized to early rhythm-control versus usual care in a 1:1 fashion. The primary-outcome of composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome occurred 3.9/100 person-years in the early rhythm-control group versus 5.0/100 person-years in the usual care group with statistical significance.⁶ A pre-specified analysis of the study also compared the effect of early rhythm-control therapy in asymptomatic to symptomatic patients and revealed no difference in outcomes regardless of symptoms.⁷ These results were different from earlier trials such as the CABANA and AFFIRM trials. The differences can be explained by the early onset of AF ≤12 months enrolled in the EAST-AFNET 4 trial compared to longer durations in other trials. Moreover, a reasonable number of patients received ablations as the rhythm-control strategy, representing the current clinical practice better, as ablations are becoming more prevalent. Together with other recent trials such as EARLY-AF⁸ and STOP-AF⁹ that showed a more effective role of cryoablation as a first-line rhythm control strategy compared to antiarrhythmic drugs, the results from this trial can potentially influence guidelines and change clinical management of AF in the future.

LOOP
The LOOP trial investigated whether using ambulatory electrocardiogram (ECG) monitoring to screen for atrial fibrillation (AF) and direct anticoagulation (AC) initiation can prevent stroke in patients at risk. This is a very important question in AF management because committing patients to lifelong AC is often associated with bleeding risk, especially in the elderly population. The LOOP trial randomized 6,004 patients from Denmark in 1:3 ratio to either receive continuous ECG monitoring using implantable loop recorder (ILR) or standard care. As expected, AF was detected three times more frequently in the ILR group and AC was initiation in 29.5% of patients in the ILR group versus 13.1% in standard care.¹⁰ However, this did not translate to decreased stroke or systemic embolism or mortality in the ILR group during a median follow-up period of 64.5 months. One point of contention in this study might be the AF detection burden in the ILR group to initiate AC: defined as at least 6 minutes of AF on ILR. This detection limit might have included more patients with smaller AF burden who were less prone to develop embolic strokes. Nevertheless, this trial brings more attention to AC management of patients with asymptomatic and subclinical AF and whether AF screening in this population is warranted.

References

1. Svendsen JH, Diederichsen SZ, Homberg S, et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomized controlled trial. Lancet 2021;Aug 27:[Epub ahead of print].
2. Desch S, Freund A, Akin I, et al. Angiography after out-of-hospital cardiac arrest without ST-segment elevation. N Engl J Med 2021;Aug 29:[Epub ahead of print].
3. Frøbert O, Götberg M, Erlinge D, et al. Influenza vaccination after myocardial infarction: a randomized, double-blind, placebo-controlled, multicenter trial. Circulation 2021;Aug 30:[Epub ahead of print].
4. Udell JA, Zawi R, Bhatt DL, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA 2013;310:1711-20.
5. Zhang W, Zhang S, Deng Y, et al. Trial of intensive blood-pressure control in older patients with hypertension. N Engl J Med 2021;385:1286-79.
6. Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med 2020;383:1305-16.
7. Willems S, Borof K, Brandes A, et al. Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial. Eur Heart J 2021;Aug 27:[Epub ahead of print].
8. Andrade JG, Wells GA, Deyell MW, et al. Cryoablation or drug therapy for initial treatment of atrial fibrillation. N Engl J Med 2021;384:305-15.
9. Wazni OM, Dandamudi G, Sood N, et al. Cryoballoon ablation as initial therapy for atrial fibrillation. N Engl J Med 2021;384:316-24.
10. Svennberg E, Friberg L, Frykman V, Al-Khalili F, Engdahl J, Rosenqvist M. Clinical outcomes in systematic screening for atrial fibrillation (STROKESTOP): a multicentre, parallel group, unmasked, randomised controlled trial. Lancet 2021;Aug 27:[Epub ahead of print].

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, COVID-19 Hub, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Acute Heart Failure, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Nuclear Imaging, Hypertension, Chronic Angina

Keywords: ESC Congress, ESC21, Acute Coronary Syndrome, Anticoagulants, Coronary Artery Disease, Coronary Restenosis, Drug-Eluting Stents, Hemorrhage, Myocardial Infarction, Myocardial Ischemia, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors, Primary Prevention, Risk, Sirolimus, Stents, Stroke, Thrombosis, Acute Coronary Syndrome, Coronary Angiography, Coronary Disease, COVID-19, Influenza Vaccines, Influenza, Human, Myocardial Infarction, Percutaneous Coronary Intervention, Risk Factors, Secondary Prevention, ST Elevation Myocardial Infarction, Stents, Thrombosis, Vaccination, Acute Coronary Syndrome, Angina, Unstable, Antihypertensive Agents, Atrial Fibrillation, Blood Pressure, Blood Pressure Determination, Dizziness, Geriatrics, Glomerular Filtration Rate, Heart Failure, Hypertension, Kidney Diseases, Myocardial Revascularization, Primary Prevention, Renal Insufficiency, Chronic, Stroke, Acute Coronary Syndrome, Arrhythmias, Cardiac, Coronary Angiography, Coronary Vessels, Critical Care, Electrocardiography, Heart Arrest, Heart Failure, Neurology, Out-of-Hospital Cardiac Arrest, Secondary Prevention, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Diabetes Mellitus, Diagnostic Tests, Routine, Electrocardiography, Ambulatory, Embolism, Geriatrics, Heart Failure, Hemorrhage, Hypertension, Primary Prevention, Stroke, Vascular Diseases, Acute Coronary Syndrome, Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Anticoagulants, Atrial Fibrillation, Catheter Ablation, Coronary Artery Disease, Diabetes Mellitus, Electric Countershock, Geriatrics, Heart Failure, Hypertension, Hypertrophy, Left Ventricular, Ischemic Attack, Transient, Renal Insufficiency, Stroke, Stroke Volume, Secondary Prevention, Ventricular Function, Left

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