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Abstract

Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.

Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Background
Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.
Methods
This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m), doxorubicin (50 mg/m), and vincristine (1·4 mg/m, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.
Findings
Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.
Interpretation
In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.
Funding
Deutsche Krebshilfe.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 20 Dec 2020; 394:2271-2281
Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Lancet: 20 Dec 2020; 394:2271-2281 | PMID: 31868632
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Abstract

Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement.

Makkar RR, Thourani VH, Mack MJ, Kodali SK, ... Leon MB,
Background
There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve replacement in patients with severe aortic stenosis and intermediate surgical risk.
Methods
We enrolled 2032 intermediate-risk patients with severe, symptomatic aortic stenosis at 57 centers. Patients were stratified according to intended transfemoral or transthoracic access (76.3% and 23.7%, respectively) and were randomly assigned to undergo either TAVR or surgical replacement. Clinical, echocardiographic, and health-status outcomes were followed for 5 years. The primary end point was death from any cause or disabling stroke.
Results
At 5 years, there was no significant difference in the incidence of death from any cause or disabling stroke between the TAVR group and the surgery group (47.9% and 43.4%, respectively; hazard ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; P = 0.21). Results were similar for the transfemoral-access cohort (44.5% and 42.0%, respectively; hazard ratio, 1.02; 95% CI, 0.87 to 1.20), but the incidence of death or disabling stroke was higher after TAVR than after surgery in the transthoracic-access cohort (59.3% vs. 48.3%; hazard ratio, 1.32; 95% CI, 1.02 to 1.71). At 5 years, more patients in the TAVR group than in the surgery group had at least mild paravalvular aortic regurgitation (33.3% vs. 6.3%). Repeat hospitalizations were more frequent after TAVR than after surgery (33.3% vs. 25.2%), as were aortic-valve reinterventions (3.2% vs. 0.8%). Improvement in health status at 5 years was similar for TAVR and surgery.
Conclusions
Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 Mar 2020; 382
Makkar RR, Thourani VH, Mack MJ, Kodali SK, ... Leon MB,
N Engl J Med: 26 Mar 2020; 382 | PMID: 31995682
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Abstract

Emerging Techniques for Risk Stratification in Nonischemic Dilated Cardiomyopathy: JACC Review Topic of the Week.

Marrow BA, Cook SA, Prasad SK, McCann GP

Dilated cardiomyopathy (DCM) is a common condition, which carries significant mortality from sudden cardiac death and pump failure. Left ventricular ejection fraction has conventionally been used as a risk marker for sudden cardiac death, but has performed poorly in trials. There have been significant advances in the areas of cardiac magnetic resonance imaging and genetics, which are able to provide useful rick prediction in DCM. Biomarkers and cardiopulmonary exercise testing are well validated in the prediction of risk in heart failure; however, they have been tested less specifically in the DCM setting. This review will discuss these methods with a view toward multiparametric risk assessment in DCM with the hope of creating parametric risk models to predict sudden cardiac death and pump failure in the DCM population.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 16 Mar 2020; 75:1196-1207
Marrow BA, Cook SA, Prasad SK, McCann GP
J Am Coll Cardiol: 16 Mar 2020; 75:1196-1207 | PMID: 32164893
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Abstract

Diuretic Therapy for Patients With Heart Failure: JACC State-of-the-Art Review.

Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM

Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling pressures, resulting in a constellation of signs and symptoms of heart failure referred to as congestion. Loop diuretics are one of the cornerstones of treatments for heart failure, but in contrast to other therapies, robust clinical trial evidence to guide the use of diuretics is sparse. A nuanced understanding of renal physiology and diuretic pharmacokinetics is essential for skillful use of diuretics in the management of heart failure in both the inpatient and outpatient settings. Diuretic resistance, defined as an inadequate quantity of natriuresis despite an adequate diuretic regimen, is a major clinical challenge that generally portends a poor prognosis. In this review, the authors discuss the fundamental mechanisms and physiological principles that underlie the use of diuretic therapy and the available data on the optimal use of diuretics.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Mar 2020; 75:1178-1195
Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM
J Am Coll Cardiol: 16 Mar 2020; 75:1178-1195 | PMID: 32164892
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Abstract

Cardiovascular Mortality After Type 1 and Type 2 Myocardial Infarction in Young Adults.

Singh A, Gupta A, DeFilippis EM, Qamar A, ... Bhatt DL, Blankstein R
Background
Type 2 myocardial infarction (MI) and myocardial injury are associated with increased short-term mortality. However, data regarding long-term mortality are lacking.
Objectives
This study compared long-term mortality among young adults with type 1 MI, type 2 MI, or myocardial injury.
Methods
Adults age 50 years or younger who presented with troponin >99th percentile or the International Classification of Diseases code for MI over a 17-year period were identified. All cases were adjudicated as type 1 MI, type 2 MI, or myocardial injury based on the Fourth Universal Definition of MI. Cox proportional hazards models were constructed for survival free from all-cause and cardiovascular death.
Results
The cohort consisted of 3,829 patients (median age 44 years; 30% women); 55% had type 1 MI, 32% had type 2 MI, and 13% had myocardial injury. Over a median follow-up of 10.2 years, mortality was highest for myocardial injury (45.6%), followed by type 2 MI (34.2%) and type 1 MI (12%) (p < 0.001). In an adjusted model, type 2 MI was associated with higher all-cause (hazard ratio: 1.8; 95% confidence interval: 1.2 to 2.7; p = 0.004) and cardiovascular mortality (hazard ratio: 2.7; 95% confidence interval: 1.4 to 5.1; p = 0.003) compared with type 1 MI. Those with type 2 MI or myocardial injury were younger and had fewer cardiovascular risk factors but had more noncardiovascular comorbidities. They were significantly less likely to be prescribed cardiovascular medications at discharge.
Conclusions
Young patients who experience a type 2 MI have higher long-term all-cause and cardiovascular mortality than those who experience type 1 MI, with nearly one-half of patients with myocardial injury and more than one-third of patients with type 2 MI dying within 10 years. These findings emphasize the need to provide more aggressive secondary prevention for patients who experience type 2 MI and myocardial injury.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Mar 2020; 75:1003-1013
Singh A, Gupta A, DeFilippis EM, Qamar A, ... Bhatt DL, Blankstein R
J Am Coll Cardiol: 09 Mar 2020; 75:1003-1013 | PMID: 32138959
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Abstract

Sleep Irregularity and Risk of Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis.

Huang T, Mariani S, Redline S
Background
The cardiovascular system exhibits strong circadian rhythms to maintain normal functioning. Irregular sleep schedules, characterized by high day-to-day variability in sleep duration or timing, represent possibly milder but much more common and chronic disruption of circadian rhythms in the general population than shift work.
Objectives
This study aimed to prospectively examine the association between sleep regularity and risk of cardiovascular disease (CVD).
Methods
In MESA (Multi-Ethnic Study of Atherosclerosis), 1,992 participants free of CVD completed 7-day wrist actigraphy for sleep assessment from 2010 to 2013 and were prospectively followed through 2016. The study assessed sleep regularity using the SD of actigraphy-measured sleep duration and sleep-onset timing across 7 days. Incident CVD included nonfatal and fatal cardiovascular events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incident CVD according to SD of sleep duration and timing, adjusted for traditional CVD risk factors (including CVD biomarkers) and other sleep-related factors (including average sleep duration).
Results
During a median follow-up of 4.9 years, 111 participants developed CVD events. The multivariable-adjusted HRs (95% confidence intervals) for CVD across categories of sleep duration SD were 1.00 (reference) for ≤60 min, 1.09 (0.62 to 1.92) for 61 to 90 min, 1.59 (0.91 to 2.76) for 91 to 120 min, and 2.14 (1.24 to 3.68) for >120 min (p trend = 0.002). Similarly, compared with participants with a sleep timing SD ≤30 min, the HRs (95% confidence intervals) for CVD were 1.16 (0.64 to 2.13) for 31 to 60 min, 1.52 (0.81 to 2.88) for 61 to 90 min, and 2.11 (1.13 to 3.91) for >90 min (p trend = 0.002). Exclusion of current shift workers yielded similar results.
Conclusions
Irregular sleep duration and timing may be novel risk factors for CVD, independent of traditional CVD risk factors and sleep quantity and/or quality.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Mar 2020; 75:991-999
Huang T, Mariani S, Redline S
J Am Coll Cardiol: 09 Mar 2020; 75:991-999 | PMID: 32138974
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Abstract

Effects of Liraglutide on Cardiovascular Outcomes in Patients With Diabetes With or Without Heart Failure.

Marso SP, Baeres FMM, Bain SC, Goldman B, ... Buse JB,
Background
More data regarding effects of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes (T2D) and heart failure (HF) are required.
Objectives
The purpose of this study was to investigate the effects of liraglutide on cardiovascular events and mortality in LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) participants, by HF history.
Methods
In the multinational, double-blind, randomized LEADER trial, 9,340 patients with T2D and high cardiovascular risk were assigned 1:1 to liraglutide (1.8 mg daily or maximum tolerated dose up to 1.8 mg daily) or placebo plus standard care, and followed for 3.5 to 5 years. New York Heart Association (NYHA) functional class IV HF was an exclusion criterion. The primary composite major adverse cardiovascular events outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Post hoc Cox regression analyses of outcomes by baseline HF history were conducted.
Results
At baseline, 18% of patients had a history of NYHA functional class I to III HF (liraglutide: n = 835 of 4,668; placebo: n = 832 of 4,672). Effects of liraglutide versus placebo on major adverse cardiovascular events were consistent in patients with (hazard ratio [HR]: 0.81 [95% confidence interval (CI): 0.65 to 1.02]) and without (HR: 0.88 [95% CI: 0.78 to 1.00]) a history of HF (p interaction = 0.53). In both subgroups, fewer deaths were observed with liraglutide (HR: 0.89 [95% CI: 0.70 to 1.14] with HF; HR: 0.83 [95% CI: 0.70 to 0.97] without HF; p interaction = 0.63) versus placebo. No increased risk of HF hospitalization was observed with liraglutide, regardless of HF history (HR: 0.98 [95% CI: 0.75 to 1.28] with HF; HR: 0.78 [95% CI: 0.61 to 1.00] without HF; p interaction = 0.22). Effects of liraglutide on the composite of HF hospitalization or cardiovascular death were consistent in patients with (HR: 0.92 [95% CI: 0.74 to 1.15]) and without (HR: 0.77 [95% CI: 0.65 to 0.91]) a history of HF (p interaction = 0.19).
Conclusions
Based on these findings, liraglutide should be considered suitable for patients with T2D with or without a history of NYHA functional class I to III HF. (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER]; NCT01179048).

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 16 Mar 2020; 75:1128-1141
Marso SP, Baeres FMM, Bain SC, Goldman B, ... Buse JB,
J Am Coll Cardiol: 16 Mar 2020; 75:1128-1141 | PMID: 32164886
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Abstract

Oral Anticoagulation and Cardiovascular Outcomes in Patients With Atrial Fibrillation and End-Stage Renal Disease.

Pokorney SD, Black-Maier E, Hellkamp AS, Friedman DJ, ... Peterson ED, Piccini JP
Background
Atrial fibrillation (AF) is common in patients with end-stage renal disease (ESRD). The impact of oral anticoagulation (OAC) in ESRD patients is uncertain.
Objectives
The purpose of this study was to describe patterns of OAC use in ESRD patients with AF and their associations with cardiovascular outcomes.
Methods
Using Medicare fee-for-service 5% claims data from 2007 to 2013, we analyzed treatment and outcomes in a cohort of patients with ESRD and AF. Prescription drug benefit information was used to determine the timing of OAC therapy. Cox proportional hazards modeling was used to compare outcomes including death, all-cause stroke, ischemic stroke, hemorrhagic stroke, and bleeding hospitalizations in ESRD patients treated with or without OAC.
Results
The cohort included 8,410 patients with AF and ESRD. A total of 3,043 (36.2%) patients were treated with OAC at some time during the study period. Propensity scores used to match 1,519 patients with AF and ESRD on OAC with 3,018 ESRD patients without OAC. Treatment with OAC was not associated with hospitalization for stroke (hazard ratio [HR]: 1.00; 95% confidence interval [CI]: 0.23 to 1.35; p = 0.97) or death (HR: 1.02; 95% CI: 0.94 to 1.10; p = 0.62). OAC was associated with an increased risk of hospitalization for bleeding (HR: 1.26; 95% CI: 1.09 to 1.46; p = 0.0017) and intracranial hemorrhage (HR: 1.30; 95% CI: 1.07 to 1.59; p = 0.0094).
Conclusions
OAC utilization was low in patients with AF and ESRD. We found no association between OAC use and reduced risk of stroke or death. OAC use was associated with increased risks of hospitalization for bleeding or intracranial hemorrhage. Alternative stroke prevention strategies are needed in patients with ESRD and AF.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Mar 2020; 75:1299-1308
Pokorney SD, Black-Maier E, Hellkamp AS, Friedman DJ, ... Peterson ED, Piccini JP
J Am Coll Cardiol: 23 Mar 2020; 75:1299-1308 | PMID: 32192656
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Abstract

Menopause-Related Estrogen Decrease and the Pathogenesis of HFpEF: JACC Review Topic of the Week.

Sabbatini AR, Kararigas G

Heart failure (HF) is a complex condition affecting >40 million people worldwide. It is defined by failure of the heart to pump (HF with reduced ejection fraction) or by the failure of the heart to relax, resulting in reduced filling but with preserved ejection fraction (HFpEF). HFpEF affects approximately 50% of patients with HF, most of whom are women. Given that the annual mortality ranges from 10% to 30% and as there are no treatments specifically directed for HFpEF, there is a need for better understanding of the underlying mechanisms of this condition. We put forward the hypothesis that the decline of estrogen at menopause might contribute to the pathogenesis of HFpEF and we highlight potential underlying mechanisms of estrogen action, which may attenuate the development of HFpEF. We also discuss areas in which additional research is needed to develop new approaches for prevention and treatment of HFpEF.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Mar 2020; 75:1074-1082
Sabbatini AR, Kararigas G
J Am Coll Cardiol: 09 Mar 2020; 75:1074-1082 | PMID: 32138968
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Abstract

Ventricular Arrhythmias in Myocarditis: Characterization and Relationships With Myocardial Inflammation.

Peretto G, Sala S, Rizzo S, Palmisano A, ... Basso C, Della Bella P
Background
Ventricular arrhythmias (VAs) have never been systematically investigated in patients with myocarditis at different stages.
Objectives
The purpose of this study was to compare baseline and follow-up characteristics of VAs in patients with active myocarditis (AM) versus previous myocarditis (PM).
Methods
A total of 185 consecutive patients (69% males, age 44 ± 15 years, left ventricular ejection fraction 49 ± 14%) with myocarditis and VA at index hospitalization, including ventricular fibrillation, ventricular tachycardia (VT), nonsustained ventricular tachycardia (NSVT), and Lown\'s grade ≥2 premature ventricular complexes, were enrolled. AM and PM groups were defined based on endomyocardial biopsy and cardiac magnetic resonance findings. A subset of patients (n = 46, 25%) also underwent electroanatomic mapping and VA transcatheter ablation.
Results
At presentation, AM patients (n = 123, 66%) more commonly had ventricular fibrillation (8 cases vs. 0 cases; p = 0.053), and both irregular (61% vs. 11%; p < 0.001) and polymorphic VA (NSVT and VT: 19% vs. 2%; p = 0.002; premature ventricular complexes: 63% vs. 16%; p < 0.001). Only in PM patients with NSVT or VT, the dominant morphology (right-bundle branch block with superior axis) was 100% predictive of abnormal LV inferoposterior substrate at both cardiac magnetic resonance and electroanatomic mapping. At 27 ± 7 months prospective follow-up, 55 patients (30%) experienced malignant VA (AM vs. PM, p = 0.385). Although a prevalence of polymorphic and irregular VA was confirmed in AM patients with persistent inflammation in follow-up (58%), a predominance of monomorphic and regular VA was found in AM patients after myocarditis healing (42%), as well as in PM patients (all p < 0.001).
Conclusions
In myocarditis patients, polymorphic and irregular VA are more common during the active inflammatory phase, whereas monomorphic and regular VA are associated with healed myocarditis.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Mar 2020; 75:1046-1057
Peretto G, Sala S, Rizzo S, Palmisano A, ... Basso C, Della Bella P
J Am Coll Cardiol: 09 Mar 2020; 75:1046-1057 | PMID: 32138965
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Abstract

Stem Cell-Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy.

Kamdar F, Das S, Gong W, Klaassen Kamdar A, ... Zhang J, Garry DJ
Background
Although cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure.
Objectives
The purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies.
Methods
To explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and β-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models.
Results
At baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive β-blocker therapy.
Conclusions
The results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Mar 2020; 75:1159-1174
Kamdar F, Das S, Gong W, Klaassen Kamdar A, ... Zhang J, Garry DJ
J Am Coll Cardiol: 16 Mar 2020; 75:1159-1174 | PMID: 32164890
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Abstract

Multiple Plasma Biomarkers for Risk Stratification in Patients With Heart Failure and Preserved Ejection Fraction.

Chirinos JA, Orlenko A, Zhao L, Basso MD, ... Moore JH, Cappola TP
Background
Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).
Objectives
The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF.
Methods
In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156).
Results
Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score.
Conclusions
Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Mar 2020; 75:1281-1295
Chirinos JA, Orlenko A, Zhao L, Basso MD, ... Moore JH, Cappola TP
J Am Coll Cardiol: 23 Mar 2020; 75:1281-1295 | PMID: 32192654
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Abstract

Survival After Coronary Revascularization With Paclitaxel-Coated Balloons.

Scheller B, Vukadinovic D, Jeger R, Rissanen TT, ... Lansky A, Mahfoud F
Background
Drug-coated balloons (DCBs) are accepted treatment strategies for coronary in-stent restenosis and are under clinical investigation for lesions without prior stent implantation. A recently published meta-analysis suggested an increased risk of death associated with the use of paclitaxel-coated devices in the superficial femoral artery. The reasons are incompletely understood as potential underlying pathomechanisms remain elusive, and no relationship to the administered dose has been documented.
Objectives
The purpose of this analysis was to investigate the available data on survival after coronary intervention with paclitaxel-coated balloons from randomized controlled trials (RCTs).
Methods
PubMed, Web of science, and the Cochrane library database were searched, and a meta-analysis from RCT was performed comparing DCB with non-DCB devices (such as conventional balloon angioplasty, bare-metal stents, or drug-eluting stents) for the treatment of coronary in-stent restenosis or de novo lesions. The primary outcome was all-cause death. The number of patients lost to follow-up was observed at different time points. Risk estimates are reported as risk ratios (RRs) with 95% confidence intervals (CIs).
Results
A total of 4,590 patients enrolled in 26 RCTs published between 2006 and 2019 were analyzed. At follow-up of 6 to 12 months, no significant difference in all-cause mortality was found, however, with numerically lower rates after DCB treatment (RR: 0.74; 95% CI: 0.51 to 1.08; p = 0.116). Risk of death at 2 years (n = 1,477, 8 RCTs) was similar between the 2 groups (RR: 0.84; 95% CI: 0.51 to 1.37; p = 0.478). After 3 years of follow-up (n = 1,775, 9 RCTs), all-cause mortality was significantly lower in the DCB group when compared with control treatment (RR: 0.73; 95% CI: 0.53 to 1.00; p = 0.047) with a number needed to treat of 36 to prevent 1 death. A similar reduction was seen in cardiac mortality (RR: 0.53; 95% CI: 0.33 to 0.85; p = 0.009).
Conclusions
In this meta-analysis, the use of paclitaxel DCBs for treatment of coronary artery disease was not associated with increased mortality, as has been suggested for peripheral arteries. On the contrary, use of coronary paclitaxel-coated balloons was associated with a trend toward lower mortality when compared with control treatments.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Mar 2020; 75:1017-1028
Scheller B, Vukadinovic D, Jeger R, Rissanen TT, ... Lansky A, Mahfoud F
J Am Coll Cardiol: 09 Mar 2020; 75:1017-1028 | PMID: 32138961
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Abstract

Tricuspid Intervention Following Pulmonary Valve Replacement in Adults With Congenital Heart Disease.

Deshaies C, Trottier H, Khairy P, Al-Aklabi M, ... Poirier NC,
Background
Tricuspid regurgitation (TR) is common among adults with corrected tetralogy of Fallot (TOF) or pulmonary stenosis (PS) referred for pulmonary valve replacement (PVR). Yet, combined valve surgery remains controversial.
Objectives
This study sought to evaluate the impact of concomitant tricuspid valve intervention (TVI) on post-operative TR, length of hospital stay, and on a composite endpoint consisting of 7 early adverse events (death, reintervention, cardiac electronic device implantation, infection, thromboembolic event, hemodialysis, and readmission).
Methods
The national Canadian cohort enrolled 542 patients with TOF or PS and mild to severe TR who underwent isolated PVR (66.8%) or PVR+TVI (33.2%). Outcomes were abstracted from charts and compared between groups using multivariable logistic and negative binomial regression.
Results
Median age at reintervention was 35.3 years. Regardless of surgery type, TR decreased by at least 1 echocardiographic grade in 35.4%, 66.9%, and 92.8% of patients with pre-operative mild, moderate, and severe insufficiency. In multivariable analyses, PVR+TVI was associated with an additional 2.3-fold reduction in TR grade (odds ratio [OR]: 0.44; 95% confidence interval [CI]: 0.25 to 0.77) without an increase in early adverse events (OR: 0.85; 95% CI: 0.46 to 1.57) or hospitalization time (incidence rate ratio: 1.17; 95% CI: 0.93 to 1.46). Pre-operative TR severity and presence of transvalvular leads independently predicted post-operative TR. In contrast, early adverse events were strongly associated with atrial tachyarrhythmia, extracardiac arteriopathy, and a high body mass index.
Conclusions
In patients with TOF or PS and significant TR, concomitant TVI is safe and results in better early tricuspid valve competence than isolated PVR.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Mar 2020; 75:1033-1043
Deshaies C, Trottier H, Khairy P, Al-Aklabi M, ... Poirier NC,
J Am Coll Cardiol: 09 Mar 2020; 75:1033-1043 | PMID: 32138963
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Abstract

Inflammation in Heart Failure: JACC State-of-the-Art Review.

Murphy SP, Kakkar R, McCarthy CP, Januzzi JL

It has long been observed that heart failure (HF) is associated with measures of systemic inflammation. In recent years, there have been significant advancements in our understanding of how inflammation contributes to the pathogenesis and progression of HF. However, although numerous studies have validated the association between measures of inflammation and HF severity and prognosis, clinical trials of anti-inflammatory therapies have proven mostly unsuccessful. On this backdrop emerges the yet unmet goal of targeting precise phenotypes within the syndrome of HF; if such precise definitions can be realized, and with better understanding of the roles played by specific inflammatory mediators, the expectation is that targeted anti-inflammatory therapies may improve prognosis in patients whose HF is driven by inflammatory pathobiology. Here, the authors describe mechanistic links between inflammation and HF, discuss traditional and novel inflammatory biomarkers, and summarize the latest evidence from clinical trials of anti-inflammatory therapies.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Mar 2020; 75:1324-1340
Murphy SP, Kakkar R, McCarthy CP, Januzzi JL
J Am Coll Cardiol: 23 Mar 2020; 75:1324-1340 | PMID: 32192660
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Abstract

Lipid Accumulation in Hearts Transplanted From Nondiabetic Donors to Diabetic Recipients.

Marfella R, Amarelli C, Cacciatore F, Balestrieri ML, ... Paolisso G, Napoli C
Background
Early pathogenesis of diabetic cardiomyopathy (DMCM) may involve lipotoxicity of cardiomyocytes in the context of hyperglycemia. There are many preclinical studies of DMCM pathogenesis, but the human evidence is still poorly understood.
Objectives
By using a nondiabetic mellitus (non-DM) heart transplanted (HTX) in diabetes mellitus (DM) recipients, this study conducted a serial study of human heart transplant recipients evaluating cardiac effects of diabetic milieu (hyperglycemia and insulin resistance) on lipotoxic-mediated injury. We evaluated cardiomyocyte morpho-pathology by seriated biopsies of healthy implanted hearts in DM recipients during 12-month follow-up from HTX. Because metformin reduces ectopic lipid accumulation, we evaluated the effects of the drug in a nonrandomized subgroup.
Methods
The DMCM-AHEAD (Diabetes and Lipid Accumulation and Heart Transplant) prospective ongoing study (NCT03546062) evaluated 158 first HTX recipients (82 non-DM, 76 DM of whom 35 [46%] were receiving metformin). HTX recipients were undergoing clinical standard evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsies). Biopsies evaluated immune response, Oil Red-O staining, ceramide, and triacylglycerol levels. Lipotoxic factors and insulin resistance were evaluated by reverse transcriptase-polymerase chain reaction.
Results
There was a significant early and progressive cardiomyocyte lipid accumulation in DM but not in non-DM recipients (p = 0.019). In the subgroup receiving metformin, independently from immunosuppressive therapy that was similar among groups, lipid accumulation was reduced in comparison with DM recipients not receiving the drug (hazard ratio: 6.597; 95% confidence interval: 2.516 to 17.296; p < 0.001). Accordingly, lipotoxic factors were increased in DM versus non-DM recipients, and, relevantly, metformin use was associated with fewer lipotoxic factors.
Conclusions
Early pathogenesis of human DMCM started with cardiomyocyte lipid accumulation following HTX in DM recipients. Metformin use was associated with reduced lipid accumulation independently of immunosuppressive therapy. This may constitute a novel target for therapy of DMCM.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Mar 2020; 75:1249-1262
Marfella R, Amarelli C, Cacciatore F, Balestrieri ML, ... Paolisso G, Napoli C
J Am Coll Cardiol: 23 Mar 2020; 75:1249-1262 | PMID: 32192650
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Abstract

Drug-Coated Balloon for De Novo Coronary Artery Disease: JACC State-of-the-Art Review.

Yerasi C, Case BC, Forrestal BJ, Torguson R, ... Garcia-Garcia HM, Waksman R

Percutaneous coronary intervention with a drug-eluting stent is the most common mode of revascularization for coronary artery disease. However, restenosis rates remain high. Non-stent-based local drug delivery by a drug-coated balloon (DCB) has been investigated, as it leaves no metallic mesh. A DCB consists of a semicompliant balloon coated with antiproliferative agents encapsulated in a polymer matrix, which is released into the wall after inflation and contact with the intima. DCB have demonstrated effectiveness in treating in-stent restenosis. Clinical studies using DCB in de novo coronary artery disease have shown mixed results, with a major benefit in small-vessel disease. Differences in study results are not only due to variations in DCB technology but also to disparity in procedural approach, \"leave nothing behind\" or \"combination therapy,\" and vessel size. This review focuses on the available evidence from randomized trials and proposes a design for future clinical trials.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 09 Mar 2020; 75:1061-1073
Yerasi C, Case BC, Forrestal BJ, Torguson R, ... Garcia-Garcia HM, Waksman R
J Am Coll Cardiol: 09 Mar 2020; 75:1061-1073 | PMID: 32138967
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Abstract

Nonculprit Lesion Myocardial Infarction Following Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome.

Scirica BM, Bergmark BA, Morrow DA, Antman EM, ... Braunwald E, Wiviott SD
Background
Recent emphasis on reduced duration and/or intensity of antiplatelet therapy following percutaneous coronary intervention (PCI) irrespective of indication for PCI may fail to account for the substantial risk of subsequent nontarget lesion events in acute coronary syndrome (ACS) patients.
Objectives
The authors sought to examine the effect of more potent antiplatelet therapy on the basis of the timing and etiology of recurrent myocardial infarction (MI) or cardiovascular death following PCI for ACS.
Methods
In the TRITON-TIMI 38 study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38), which randomized patients to prasugrel or clopidogrel, 12,844 patients with ACS received at least 1 stent. MI and cardiovascular death were categorized as: 1) procedural (related to revascularization); 2) definite or probable stent thrombosis (ST); or 3) spontaneous (non-ST or non-procedure-related). Median follow-up was 14.5 months.
Results
Among the first events occurring within 30 days, 584 (69.0%) were procedural, 126 (14.9%) ST-related, and 136 (16.1%) spontaneous. After 30 days, 22 (4.7%) were procedural, 63 (13.5%) were ST-related, and 383 (81.8%) spontaneous. Prasugrel significantly reduced the incidence of MI or cardiovascular death for ST-related (1.0% vs. 2.1%; p < 0.001) and spontaneous events (3.9% vs. 4.8%; p = 0.012), with a directionally consistent numerical reduction for procedural events (4.4% vs. 5.1%; p = 0.078). Prasugrel increased spontaneous, but not procedural, major bleeding.
Conclusions
Long-term potent antithrombotic therapy reduces de novo (spontaneous) atherothrombotic events in addition to preventing complications associated with stenting of the culprit lesion following ACS. In patients undergoing PCI for ACS, spontaneous events predominate after 30 days, with the later-phase cardiovascular benefit of potent dual antiplatelet therapy driven largely by reducing de novo atherothrombotic ischemic events. (Comparison of Prasugrel [CS-747] and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention; NCT00097591).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Mar 2020; 75:1095-1106
Scirica BM, Bergmark BA, Morrow DA, Antman EM, ... Braunwald E, Wiviott SD
J Am Coll Cardiol: 16 Mar 2020; 75:1095-1106 | PMID: 32164882
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Abstract

Clinical and Pharmacological Effects of Apixaban Dose Adjustment in the ARISTOTLE Trial.

Zeitouni M, Giczewska A, Lopes RD, Wojdyla DM, ... Alexander JH,
Background
In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, patients with atrial fibrillation and ≥2 dose-adjustment criteria (age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dl [133 μmol/l]) were randomized to receive apixaban 2.5 mg twice daily or warfarin.
Objectives
The purpose of this study was to describe the effects of apixaban dose adjustment on clinical and pharmacological outcomes.
Methods
Patients receiving the correct dose of study drug were included (n = 18,073). The effect of apixaban 2.5 mg twice daily versus warfarin on population pharmacokinetics, D-dimer, prothrombin fragment 1 + 2 (PF1+2), and clinical outcomes was compared with the standard dose (5 mg twice daily).
Results
Patients receiving apixaban 2.5 mg twice daily exhibited lower apixaban exposure (median area under the concentration time curve at a steady state 2,720 ng/ml vs. 3,599 ng/ml; p < 0.0001) than those receiving the standard dose. In patients with ≥2 dose-adjustment criteria, reductions in D-dimers (p interaction = 0.20) and PF1+2 (p interaction = 0.55) were consistent with those observed in the standard-dose population. Patients with ≥2 dose-adjustment criteria (n = 751) were at higher risk for stroke/systemic embolism, major bleeding, and all-cause death than the standard-dose population (0 or 1 dose-adjustment criterion, n = 17,322). The effect of apixaban 2.5 mg twice daily versus warfarin in the ≥2 dose-adjustment criteria population was consistent with the standard dose in the reductions in stroke or systemic embolism (p interaction = 0.26), major bleeding (p interaction = 0.25), and death (p interaction = 0.72).
Conclusions
Apixaban drug concentrations were lower in patients receiving 2.5 mg twice daily compared with 5 mg twice daily. However, the effects of apixaban dose adjustment to 2.5 mg versus warfarin were consistent for coagulation biomarkers and clinical outcomes, providing reassuring data on efficacy and safety. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Mar 2020; 75:1145-1155
Zeitouni M, Giczewska A, Lopes RD, Wojdyla DM, ... Alexander JH,
J Am Coll Cardiol: 16 Mar 2020; 75:1145-1155 | PMID: 32164888
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Abstract

Early Diagnosis of Myocardial Infarction With Point-of-Care High-Sensitivity Cardiac Troponin I.

Boeddinghaus J, Nestelberger T, Koechlin L, Wussler D, ... Mueller C,
Background
Until now, high-sensitivity cardiac troponin (hs-cTn) assays were mainly developed for large central laboratory platforms.
Objectives
This study aimed to assess the clinical performance of a point-of-care (POC)-hs-cTnI assay in patients with suspected myocardial infarction (MI).
Methods
This study enrolled patients presenting to the emergency department with symptoms suggestive of MI. Two cardiologists centrally adjudicated the final diagnosis using all clinical data including cardiac imaging. The primary objective was to directly compare diagnostic accuracy of POC-hs-cTnI-TriageTrue versus best-validated central laboratory assays. Secondary objectives included the derivation and validation of a POC-hs-cTnI-TriageTrue-specific 0/1-h algorithm.
Results
MI was the adjudicated final diagnosis in 178 of 1,261 patients (14%). The area under the curve (AUC) for POC-hs-cTnI-TriageTrue at presentation was 0.95 (95% confidence interval [CI]: 0.93 to 0.96) and was at least comparable to hs-cTnT-Elecsys (AUC: 0.94; 95% CI: 0.93 to 0.96; p = 0.213) and hs-cTnI-Architect (AUC: 0.92; 95% CI: 0.90 to 0.93; p < 0.001). A single cutoff concentration <3 ng/l at presentation identified 45% of patients at low risk with a negative predictive value (NPV) of 100% (95% CI: 99.4% to 100%). A single cutoff concentration >60 ng/l identified patients at high risk with a positive predictive value (PPV) of 76.8% (95% CI: 68.9% to 83.6%). The 0/1-h algorithm ruled out 55% of patients (NPV: 100%; 95% CI: 98.8% to 100%), and ruled in 18% of patients (PPV: 76.8%; 95% CI: 67.2% to 84.7%). Ruled-out patients had cumulative event rates of 0% at 30 days and 1.6% at 2 years. This study confirmed these findings in a secondary analysis including hs-cTnI-Architect for central adjudication.
Conclusions
The POC-hs-cTnI-TriageTrue assay provides high diagnostic accuracy in patients with suspected MI with a clinical performance that is at least comparable to that of best-validated central laboratory assays. (Advantageous Predictors of Acute Coronary Syndromes Evaluation Study [APACE]; NCT00470587).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Mar 2020; 75:1111-1124
Boeddinghaus J, Nestelberger T, Koechlin L, Wussler D, ... Mueller C,
J Am Coll Cardiol: 16 Mar 2020; 75:1111-1124 | PMID: 32164884
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Abstract

Sustainability of and Adherence to Preschool Health Promotion Among Children 9 to 13 Years Old.

Fernández-Jiménez R, Briceño G, Céspedes J, Vargas S, ... Carvajal I, Fuster V
Background
Long-term evaluations of child health promotion programs are required to assess their sustainability and the need for reintervention.
Objectives
This study sought to explore the long-term impact of a preschool health promotion intervention delivered in an urban low-income area of Colombia (phase 1) and to assess the effect of a new community-based intervention (phase 2).
Methods
In phase 1, a cross-sectional analysis of knowledge, attitudes, and habits (KAH) toward a healthy lifestyle and ideal cardiovascular health (ICH) scores of 1,216 children 9 to 13 years old was performed. Of the total, 596 had previously received a preschool health promotion intervention at 3 to 5 years old, whereas the remaining 620 were not previously intervened (intervention-naive group). In phase 2, all children were cluster randomized 1:1 to receive either a 4-month educational intervention (the SI! Program) to instill healthy behaviors in community centers (24 clusters, 616 children) or to control (24 clusters, 600 children). Previously intervened and intervention-naive children were not mixed in the same cluster. The primary outcomes were the change from baseline in KAH and ICH scores. Intervention effects were tested for with linear mixed-effects models.
Results
In phase 1, ∼85% of children had nonideal cardiovascular health, and those who previously received a preschool intervention showed a negligible residual effect compared with intervention-naive children. In phase 2, the between-group (control vs. intervention) differences in the change of the overall KAH and ICH scores were 0.92 points (95% confidence interval [CI]: -0.28 to 2.13; p = 0.133) and -0.20 points (95% CI: -0.43 to 0.03; p = 0.089), respectively. No booster effect was detected. However, a dose-response effect was observed, with maximal benefit in children attending >75% of the scheduled intervention; the difference in the change of KAH between the high- and low-adherence groups was 3.72 points (95% CI: 1.71 to 5.73; p < 0.001).
Conclusions
Although overall significant differences between the intervention and control groups were not observed, high adherence rates to health promotion interventions may improve effectiveness and outcomes in children. Reintervention strategies may be required at multiple stages to induce sustained health promotion effects (Salud Integral Colombia [SI! Colombia II]; NCT03119792).

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 06 Apr 2020; 75:1565-1578
Fernández-Jiménez R, Briceño G, Céspedes J, Vargas S, ... Carvajal I, Fuster V
J Am Coll Cardiol: 06 Apr 2020; 75:1565-1578 | PMID: 32241373
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Abstract

Preventing Complications in Pregnant Women With Cardiac Disease.

Pfaller B, Sathananthan G, Grewal J, Mason J, ... Siu SC, Silversides CK
Background
Pregnancy can lead to complications in women with heart disease, and these complications can be life threatening. Understanding serious complications and how they can be prevented is important.
Objectives
The primary objectives were to determine the incidence of serious cardiac events (SCEs) in pregnant women with heart disease, whether they were preventable, and their impact on fetal and neonatal outcomes. Serious obstetric events were also examined.
Methods
A prospectively assembled cohort of 1,315 pregnancies in women with heart disease was studied. SCEs included cardiac death or arrest, ventricular arrhythmias, congestive heart failure or arrhythmias requiring admission to an intensive care unit, myocardial infarction, stroke, aortic dissection, valve thrombosis, endocarditis, and urgent cardiac intervention. The Harvard Medical Study criteria were used to adjudicate preventability.
Results
Overall, 3.6% of pregnancies (47 of 1,315) were complicated by SCEs. The most frequent SCEs were cardiac death or arrest, heart failure, arrhythmias, and urgent interventions. Most SCEs (66%) occurred in the antepartum period. Almost one-half of SCEs (49%) were preventable; the majority of preventable SCEs (74%) were secondary to provider management factors. Adverse fetal and neonatal events were more common in pregnancies with SCEs compared with those without cardiac events (62% vs. 29%; p < 0.001). Serious obstetric events were less common (1.7%) and were primarily due to pre-eclampsia with severe features.
Conclusions
Pregnant women with heart disease are at risk for serious cardiac complications, and approximately one-half of all SCEs are preventable. Strategies to prevent serious cardiac complications in this high-risk cohort of women need to be developed.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Mar 2020; 75:1443-1452
Pfaller B, Sathananthan G, Grewal J, Mason J, ... Siu SC, Silversides CK
J Am Coll Cardiol: 30 Mar 2020; 75:1443-1452 | PMID: 32216913
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Abstract

Mobile Health Technology to Improve Care for Patients With Atrial Fibrillation.

Guo Y, Lane DA, Wang L, Zhang H, ... Lip GYH,
Background
Current management of patients with atrial fibrillation (AF) is limited by low detection of AF, non-adherence to guidelines, and lack of consideration of patients\' preferences, thus highlighting the need for a more holistic and integrated approach to AF management.
Objective
The objective of this study was to determine whether a mobile health (mHealth) technology-supported AF integrated management strategy would reduce AF-related adverse events, compared with usual care.
Methods
This is a cluster randomized trial of patients with AF older than 18 years of age who were enrolled in 40 cities in China. Recruitment began on June 1, 2018 and follow-up ended on August 16, 2019. Patients with AF were randomized to receive usual care, or integrated care based on a mobile AF Application (mAFA) incorporating the ABC (Atrial Fibrillation Better Care) Pathway: A, Avoid stroke; B, Better symptom management; and C, Cardiovascular and other comorbidity risk reduction. The primary composite outcome was a composite of stroke/thromboembolism, all-cause death, and rehospitalization. Rehospitalization alone was a secondary outcome. Cardiovascular events were assessed using Cox proportional hazard modeling after adjusting for baseline risk.
Results
There were 1,646 patients allocated to mAFA intervention (mean age, 67.0 years; 38.0% female) with mean follow-up of 262 days, whereas 1,678 patients were allocated to usual care (mean age, 70.0 years; 38.0% female) with mean follow-up of 291 days. Rates of the composite outcome of \'ischemic stroke/systemic thromboembolism, death, and rehospitalization\' were lower with the mAFA intervention compared with usual care (1.9% vs. 6.0%; hazard ratio [HR]: 0.39; 95% confidence interval [CI]: 0.22 to 0.67; p < 0.001). Rates of rehospitalization were lower with the mAFA intervention (1.2% vs. 4.5%; HR: 0.32; 95% CI: 0.17 to 0.60; p < 0.001). Subgroup analyses by sex, age, AF type, risk score, and comorbidities demonstrated consistently lower HRs for the composite outcome for patients receiving the mAFA intervention compared with usual care (all p < 0.05).
Conclusions
An integrated care approach to holistic AF care, supported by mHealth technology, reduces the risks of rehospitalization and clinical adverse events. (Mobile Health [mHealth] technology integrating atrial fibrillation screening and ABC management approach trial; ChiCTR-OOC-17014138).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Apr 2020; 75:1523-1534
Guo Y, Lane DA, Wang L, Zhang H, ... Lip GYH,
J Am Coll Cardiol: 06 Apr 2020; 75:1523-1534 | PMID: 32241367
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Abstract

Yoga-Based Cardiac Rehabilitation After Acute Myocardial Infarction: A Randomized Trial.

Prabhakaran D, Chandrasekaran AM, Singh K, Mohan B, ... Kinra S,
Background
Given the shortage of cardiac rehabilitation (CR) programs in India and poor uptake worldwide, there is an urgent need to find alternative models of CR that are inexpensive and may offer choice to subgroups with poor uptake (e.g., women and elderly).
Objectives
This study sought to evaluate the effects of yoga-based CR (Yoga-CaRe) on major cardiovascular events and self-rated health in a multicenter randomized controlled trial.
Methods
The trial was conducted in 24 medical centers across India. This study recruited 3,959 patients with acute myocardial infarction with a median and minimum follow-up of 22 and 6 months. Patients were individually randomized to receive either a Yoga-CaRe program (n = 1,970) or enhanced standard care involving educational advice (n = 1,989). The co-primary outcomes were: 1) first occurrence of major adverse cardiovascular events (MACE) (composite of all-cause mortality, myocardial infarction, stroke, or emergency cardiovascular hospitalization); and 2) self-rated health on the European Quality of Life-5 Dimensions-5 Level visual analogue scale at 12 weeks.
Results
MACE occurred in 131 (6.7%) patients in the Yoga-CaRe group and 146 (7.4%) patients in the enhanced standard care group (hazard ratio with Yoga-CaRe: 0.90; 95% confidence interval [CI]: 0.71 to 1.15; p = 0.41). Self-rated health was 77 in Yoga-CaRe and 75.7 in the enhanced standard care group (baseline-adjusted mean difference in favor of Yoga-CaRe: 1.5; 95% CI: 0.5 to 2.5; p = 0.002). The Yoga-CaRe group had greater return to pre-infarct activities, but there was no difference in tobacco cessation or medication adherence between the treatment groups (secondary outcomes).
Conclusions
Yoga-CaRe improved self-rated health and return to pre-infarct activities after acute myocardial infarction, but the trial lacked statistical power to show a difference in MACE. Yoga-CaRe may be an option when conventional CR is unavailable or unacceptable to individuals. (A study on effectiveness of YOGA based cardiac rehabilitation programme in India and United Kingdom; CTRI/2012/02/002408).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Apr 2020; 75:1551-1561
Prabhakaran D, Chandrasekaran AM, Singh K, Mohan B, ... Kinra S,
J Am Coll Cardiol: 06 Apr 2020; 75:1551-1561 | PMID: 32241371
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Abstract

Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality.

Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF
Background
More information is needed about the long-term effects of low-dose aspirin (≤160 mg) on incident hepatocellular carcinoma, liver-related mortality, and gastrointestinal bleeding in persons with chronic hepatitis B or hepatitis C virus infection.
Methods
Using nationwide Swedish registries, we identified all adults who received a diagnosis of chronic hepatitis B or hepatitis C from 2005 through 2015 and who did not have a history of aspirin use (50,275 patients). Patients who were starting to take low-dose aspirin (14,205 patients) were identified by their first filled prescriptions for 90 or more consecutive doses of aspirin. We constructed a propensity score and applied inverse probability of treatment weighting to balance baseline characteristics between groups. Using Cox proportional-hazards regression modeling, we estimated the risk of hepatocellular carcinoma and liver-related mortality, accounting for competing events.
Results
With a median of 7.9 years of follow-up, the estimated cumulative incidence of hepatocellular carcinoma was 4.0% among aspirin users and 8.3% among nonusers of aspirin (difference, -4.3 percentage points; 95% confidence interval [CI], -5.0 to -3.6; adjusted hazard ratio, 0.69; 95% CI, 0.62 to 0.76). This inverse association appeared to be duration-dependent; as compared with short-term use (3 months to <1 year), the adjusted hazard ratios were 0.90 (95% CI, 0.76 to 1.06) for 1 to less than 3 years of use, 0.66 (95% CI, 0.56 to 0.78) for 3 to less than 5 years of use, and 0.57 (95% CI, 0.42 to 0.70) for 5 or more years of use. Ten-year liver-related mortality was 11.0% among aspirin users and 17.9% among nonusers (difference, -6.9 percentage points [95% CI, -8.1 to -5.7]; adjusted hazard ratio, 0.73 [95% CI, 0.67 to 0.81]). However, the 10-year risk of gastrointestinal bleeding did not differ significantly between users and nonusers of aspirin (7.8% and 6.9%, respectively; difference, 0.9 percentage points; 95% CI, -0.6 to 2.4).
Conclusions
In a nationwide study of patients with chronic viral hepatitis in Sweden, use of low-dose aspirin was associated with a significantly lower risk of hepatocellular carcinoma and lower liver-related mortality than no use of aspirin, without a significantly higher risk of gastrointestinal bleeding. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 11 Mar 2020; 382:1018-1028
Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF
N Engl J Med: 11 Mar 2020; 382:1018-1028 | PMID: 32160663
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Abstract

Withdrawal of Neurohumoral Blockade After Cardiac Resynchronization Therapy.

Nijst P, Martens P, Dauw J, Tang WHW, ... Dupont M, Mullens W
Background
The necessity of neurohumoral blockers in patients with heart failure who demonstrate normalized ejection fractions after cardiac resynchronization therapy remains unclear.
Objectives
The aim of this study was to investigate the feasibility and safety of neurohumoral blocker withdrawal in patients with normalized ejection fractions after cardiac resynchronization therapy.
Methods
In this prospective, open-label, randomized controlled pilot trial with a 2 × 2 factorial design, subjects were randomized to withdrawal of renin-angiotensin-aldosterone system inhibitors and/or beta-blockers versus continuation of treatment. The primary endpoint was a recurrence of negative remodeling, defined as an increase in left ventricular end-systolic volume index of >15% at 24 months. The secondary endpoint was a composite safety endpoint of all-cause mortality, heart failure-related hospitalizations, and incidence of sustained ventricular arrhythmias at 24 months.
Results
Eighty subjects were consecutively enrolled and randomized among 4 groups (continuation of neurohumoral blocker therapy, n = 20; withdrawal of renin-angiotensin-aldosterone system inhibitors, n = 20; withdrawal of beta-blockers, n = 20; and withdrawal of renin-angiotensin-aldosterone system inhibitors and beta-blockers, n = 20). Of the 80 subjects, 6 (7.5%) met the primary and 4 (5%) the secondary endpoint. However, re-initiation of neurohumoral blockers occurred in 17 subjects because of hypertension or supraventricular arrhythmias.
Conclusions
The incidence of the primary and secondary endpoints over a follow-up period of 2 years was low in both the control group and in the groups in which neurohumoral blockers were discontinued. However, neurohumoral blocker withdrawal was hampered by cardiac comorbidities. (Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients [STOP-CRT]; NCT02200822).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Mar 2020; 75:1426-1438
Nijst P, Martens P, Dauw J, Tang WHW, ... Dupont M, Mullens W
J Am Coll Cardiol: 30 Mar 2020; 75:1426-1438 | PMID: 32216911
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Impact:
Abstract

Clinical characteristics, diagnosis, and risk stratification of pulmonary hypertension in severe tricuspid regurgitation and implications for transcatheter tricuspid valve repair.

Lurz P, Orban M, Besler C, Braun D, ... Hausleiter J, Rommel KP
Aims
Patients with pulmonary hypertension (PHT) are often excluded from surgical therapies for tricuspid regurgitation (TR). Transcatheter tricuspid valve repair (TTVR) with the MitraClip™ technique is a novel treatment option for these patients. We aimed to assess the role of PHT in severe TR and its implications for TTVR.
Methods and results
A total of 243 patients underwent TTVR at two centres. One hundred twenty-one patients were grouped as iPHT+ [invasive systolic pulmonary artery pressures (PAPs) ≥50 mmHg]. Patients were similarly stratified according to echocardiographic PAPs (ePHT). The occurrence of the combined clinical endpoint (death, heart failure hospitalization, and reintervention) was investigated during a follow-up of 330 (interquartile range 175-402) days. iPHT+ patients were at higher preoperative risk (P < 0.01), had more severe symptoms (P = 0.01), higher N-terminal pro-B-type natriuretic peptide levels (P < 0.01), more impaired right ventricular (RV) function (P < 0.01), and afterload corrected RV function (P < 0.01). Procedural TTVR success was similar in iPHT+ and iPHT- patients (84 vs. 84%, P = 0.99). The echocardiographic diagnostic accuracy to detect iPHT was only 55%. During follow-up, 35% of patients reached the combined clinical endpoint. The discordant diagnosis of iPHT+/ePHT- carried the highest risk for the combined clinical endpoint [HR 3.76 (CI 2.25-6.37), P < 0.01], while iPHT+/ePHT+ patients had a similar survival-free time from the combined endpoint compared to iPHT- patients (P = 0.48). In patients with isolated tricuspid procedure (n = 131) a discordant iPHT+/ePHT- diagnosis and an impaired afterload corrected RV function (P < 0.01 for both) were independent predictors for the occurrence of the combined endpoint.
Conclusion
The discordant echocardiographic and invasive diagnosis of PHT in severe TR predicts outcomes after TTVR.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 15 Mar 2020; epub ahead of print
Lurz P, Orban M, Besler C, Braun D, ... Hausleiter J, Rommel KP
Eur Heart J: 15 Mar 2020; epub ahead of print | PMID: 32176280
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Abstract

Intravenous Statin Administration During Myocardial Infarction Compared With Oral Post-Infarct Administration.

Mendieta G, Ben-Aicha S, Gutiérrez M, Casani L, ... Badimon L, Vilahur G
Background
Beyond lipid-lowering, statins exert cardioprotective effects. High-dose statin treatment seems to reduce cardiovascular complications in high-risk patients. The ideal timing and administration regime remain unknown.
Objectives
This study compared the cardioprotective effects of intravenous statin administration during myocardial infarction (MI) with oral administration immediately post-MI.
Methods
Hypercholesterolemic pigs underwent MI induction (90 min of ischemia) and were kept for 42 days. Animals were distributed in 3 arms (A): A1 received an intravenous bolus of atorvastatin during MI; A2 received an intravenous bolus of vehicle during MI; and A3 received oral atorvastatin within 2 h post-MI. A1 and A3 remained on daily oral atorvastatin for the following 42 days. Cardiac magnetic resonance analysis (days 3 and 42 post-MI) and molecular/histological studies were performed.
Results
At day 3, A1 showed a 10% reduction in infarct size compared with A3 and A2 and a 50% increase in myocardial salvage. At day 42, both A1 and A3 showed a significant decrease in scar size versus A2; however, A1 showed a further 24% reduction versus A3. Functional analyses revealed improved systolic performance in A1 compared with A2 and less wall motion abnormalities in the jeopardized myocardium versus both groups at day 42. A1 showed enhanced collagen content and AMP-activated protein kinase activation in the scar, increased vessel density in the penumbra, higher tumor necrosis factor α plasma levels and lower peripheral blood mononuclear cell activation versus both groups.
Conclusions
Intravenous administration of atorvastatin during MI limits cardiac damage, improves cardiac function, and mitigates remodeling to a larger extent than when administered orally shortly after reperfusion. This therapeutic approach deserves to be investigated in ST-segment elevation MI patients.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Mar 2020; 75:1386-1402
Mendieta G, Ben-Aicha S, Gutiérrez M, Casani L, ... Badimon L, Vilahur G
J Am Coll Cardiol: 30 Mar 2020; 75:1386-1402 | PMID: 32216907
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Abstract

2-Year Outcomes After Stenting of Lipid-Rich and Nonrich Coronary Plaques.

Yamamoto MH, Maehara A, Stone GW, Kini AS, ... Muller JE, Weisz G
Background
Autopsy studies suggest that implanting stents in lipid-rich plaque (LRP) may be associated with adverse outcomes.
Objectives
The purpose of this study was to evaluate the association between LRP detected by near-infrared spectroscopy (NIRS) and clinical outcomes in patients with coronary artery disease treated with contemporary drug-eluting stents.
Methods
In this prospective, multicenter registry, NIRS was performed in patients undergoing coronary angiography and possible percutaneous coronary intervention (PCI). Lipid core burden index (LCBI) was calculated as the fraction of pixels with the probability of LRP >0.6 within a region of interest. MaxLCBI was defined as the maximum LCBI within any 4-mm-long segment. Major adverse cardiac events (MACE) included cardiac death, myocardial infarction, definite or probable stent thrombosis, or unplanned revascularization or rehospitalization for progressive angina or unstable angina. Events were subcategorized as culprit (treated) lesion-related, nonculprit (untreated) lesion-related, or indeterminate.
Results
Among 1,999 patients who were enrolled in the COLOR (Chemometric Observations of Lipid Core Plaques of Interest in Native Coronary Arteries Registry), PCI was performed in 1,621 patients and MACE occurred in 18.0% of patients, of which 8.3% were culprit lesion-related, 10.7% were nonculprit lesion-related, and 3.1% were indeterminate during 2-year follow-up. Complications from NIRS imaging occurred in 9 patients (0.45%), which resulted in 1 peri-procedural myocardial infarction and 1 emergent coronary bypass. Pre-PCI NIRS imaging was obtained in 1,189 patients, and the 2-year rate of culprit lesion-related MACE was not significantly associated with maxLCBI (hazard ratio of maxLCBI per 100: 1.06; 95% confidence interval: 0.96 to 1.17; p = 0.28) after adjusting clinical and procedural factors.
Conclusions
Following PCI with contemporary drug-eluting stents, stent implantation in NIRS-defined LRPs was not associated with increased periprocedural or late adverse outcomes compared with those without significant lipid.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Mar 2020; 75:1371-1382
Yamamoto MH, Maehara A, Stone GW, Kini AS, ... Muller JE, Weisz G
J Am Coll Cardiol: 30 Mar 2020; 75:1371-1382 | PMID: 32216905
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Abstract

Wearable Devices for Ambulatory Cardiac Monitoring: JACC State-of-the-Art Review.

Sana F, Isselbacher EM, Singh JP, Heist EK, Pathik B, Armoundas AA

Ambulatory monitoring devices are enabling a new paradigm of health care by collecting and analyzing long-term data for reliable diagnostics. These devices are becoming increasingly popular for continuous monitoring of cardiac diseases. Recent advancements have enabled solutions that are both affordable and reliable, allowing monitoring of vulnerable populations from the comfort of their homes. They provide early detection of important physiological events, leading to timely alerts for seeking medical attention. In this review, the authors aim to summarize the recent developments in the area of ambulatory and remote monitoring solutions for cardiac diagnostics. The authors cover solutions based on wearable devices, smartphones, and other ambulatory sensors. The authors also present an overview of the limitations of current technologies, their effectiveness, and their adoption in the general population, and discuss some of the recently proposed methods to overcome these challenges. Lastly, we discuss the possibilities opened by this new paradigm, for the future of health care and personalized medicine.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Apr 2020; 75:1582-1592
Sana F, Isselbacher EM, Singh JP, Heist EK, Pathik B, Armoundas AA
J Am Coll Cardiol: 06 Apr 2020; 75:1582-1592 | PMID: 32241375
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Abstract

Transcatheter Correction of Superior Sinus Venosus Atrial Septal Defects as an Alternative to Surgical Treatment.

Hansen JH, Duong P, Jivanji SGM, Jones M, ... Qureshi SA, Rosenthal E
Background
The superior sinus venosus atrial septal defect (SVASD) is characterized by deficiency of the common wall between the superior vena cava (SVC) and the right upper pulmonary vein (RUPV), which is no longer committed to the left atrium.
Objectives
This study sought to evaluate the potential for redirecting the SVC and RUPV flow to the right and left atria, respectively, by implantation of a covered stent in the SVC.
Methods
Review of 48 consecutive adult SVASD patients undergoing assessment for correction. Pre-procedural evaluation included cross-sectional imaging and ex vivo simulation using printed or virtual 3-dimensional models.
Results
Transcatheter correction was performed in 25 patients, with a further 6 awaiting stent implantation. Only 8 patients were deemed technically unsuitable. The procedure involved balloon test inflation in the anticipated stent landing zone with simultaneous transesophageal echocardiography and pulmonary venography to confirm defect closure and unobstructed pulmonary venous drainage, followed by deployment of a 10-zig covered Cheatham platinum stent. Stents of lengths between 5 and 8 cm were implanted. A second, uncovered stent was used for anchoring in 9 patients. The RUPV was protected with a high-pressure balloon during stent implantation to prevent pulmonary venous obstruction in 4 patients. The median follow-up period was 1.4 (interquartile range: 0.8 to 1.7) years, with no mortality. Stent embolization occurred in 1 patient; another required drainage of hemopericardium. Cardiac computed tomography after 3 months confirmed unobstructed pulmonary venous return. At latest follow-up, a residual shunt was present in 1 patient.
Conclusions
Transcatheter correction of SVASD may be considered as an alternative to surgery in a substantial proportion of patients.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Mar 2020; 75:1266-1278
Hansen JH, Duong P, Jivanji SGM, Jones M, ... Qureshi SA, Rosenthal E
J Am Coll Cardiol: 23 Mar 2020; 75:1266-1278 | PMID: 32192652
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Abstract

Atrial Fibrillation: JACC Council Perspectives.

Chung MK, Refaat M, Shen WK, Kutyifa V, ... Lakkireddy DR,

Atrial fibrillation (AF) is an increasingly prevalent arrhythmia; its pathophysiology and progression are well studied. Stroke and bleeding risk models have been created and validated. Decision tools for stroke prophylaxis are evolving, with better options at hand. Utilization of various diagnostic tools offer insight into AF burden and thromboembolic risk. Rate control, rhythm control, and stroke prophylaxis are the cornerstones of AF therapy. Although antiarrhythmic drugs are useful, AF ablation has become a primary therapeutic strategy. Pulmonary vein isolation is the cornerstone of AF ablation, and methods to improve ablation safety and efficacy continue to progress. Ablation of nonpulmonary vein sites is increasingly being recognized as an important strategy for treating nonparoxysmal AF. Several new ablation techniques and technologies and stroke prophylaxis are being explored. This is a contemporary review on the prevalence, pathophysiology, risk prediction, prophylaxis, treatment options, new insights for optimizing treatment outcomes, and emerging concepts of AF.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 13 Apr 2020; 75:1689-1713
Chung MK, Refaat M, Shen WK, Kutyifa V, ... Lakkireddy DR,
J Am Coll Cardiol: 13 Apr 2020; 75:1689-1713 | PMID: 32273035
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Abstract

Low-Dose Alteplase During Primary Percutaneous Coronary Intervention According to Ischemic Time.

McCartney PJ, Maznyczka AM, Eteiba H, McEntegart M, ... Berry C,
Background
Microvascular obstruction affects one-half of patients with ST-segment elevation myocardial infarction and confers an adverse prognosis.
Objectives
This study aimed to determine whether the efficacy and safety of a therapeutic strategy involving low-dose intracoronary alteplase infused early after coronary reperfusion associates with ischemic time.
Methods
This study was conducted in a prospective, multicenter, parallel group, 1:1:1 randomized, dose-ranging trial in patients undergoing primary percutaneous coronary intervention. Ischemic time, defined as the time from symptom onset to coronary reperfusion, was a pre-specified subgroup of interest. Between March 17, 2016, and December 21, 2017, 440 patients, presenting with ST-segment elevation myocardial infarction within 6 h of symptom onset (<2 h, n = 107; ≥2 h but <4 h, n = 235; ≥4 h to 6 h, n = 98), were enrolled at 11 U.K. hospitals. Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145). The primary outcome was the amount of microvascular obstruction (MVO) (percentage of left ventricular mass) quantified by cardiac magnetic resonance imaging at 2 to 7 days (available for 396 of 440).
Results
Overall, there was no association between alteplase dose and the extent of MVO (p for trend = 0.128). However, in patients with an ischemic time ≥4 to 6 h, alteplase increased the mean extent of MVO compared with placebo: 1.14% (placebo) versus 3.11% (10 mg) versus 5.20% (20 mg); p = 0.009 for the trend. The interaction between ischemic time and alteplase dose was statistically significant (p = 0.018).
Conclusion
In patients presenting with ST-segment elevation myocardial infarction and an ischemic time ≥4 to 6 h, adjunctive treatment with low-dose intracoronary alteplase during primary percutaneous coronary intervention was associated with increased MVO. Intracoronary alteplase may be harmful for this subgroup. (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI [T-TIME]; NCT02257294).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Mar 2020; 75:1406-1421
McCartney PJ, Maznyczka AM, Eteiba H, McEntegart M, ... Berry C,
J Am Coll Cardiol: 30 Mar 2020; 75:1406-1421 | PMID: 32216909
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Abstract

Evaluation for Heart Transplantation and LVAD Implantation: JACC Council Perspectives.

Guglin M, Zucker MJ, Borlaug BA, Breen E, ... Bozkurt B,

Timely referrals for transplantation and left ventricular assist device implantation play a key role in favorable outcomes in patients with advanced heart failure. Nonetheless, evaluation usually occurs at advanced heart failure centers and is obscured from referring physicians. The purposes of this review are to explain the decision-making process for candidacy for advanced therapies and to describe the potential impact of the new organ allocation algorithm on center decision making. The document first addresses the signs of advanced heart failure, specifically focusing on the importance of the syndrome of low cardiac output as a key feature of advanced heart failure, and then summarizes the evaluation as a 3-step process addressing the following questions: 1) Is transplantation or durable assist device placement indicated? 2) Are there contraindications to either intervention? 3) How can one choose between transplantation and left ventricular assist device implantation if advanced therapies are indicated and not contraindicated?

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 30 Mar 2020; 75:1471-1487
Guglin M, Zucker MJ, Borlaug BA, Breen E, ... Bozkurt B,
J Am Coll Cardiol: 30 Mar 2020; 75:1471-1487 | PMID: 32216916
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Abstract

Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide in Elderly Patients With Valvular Heart Disease.

Zhang B, Xu H, Zhang H, Liu Q, ... Wu Y,
Background
N-terminal pro-B-type natriuretic peptide (NT-proBNP) may reflect early prognosis in patients with valvular heart disease (VHD).
Objectives
The aim of this study was to examine the association between NT-proBNP and mortality in elderly patients with VHD.
Methods
A total of 5,983 elderly patients (age ≥60 years) with moderate or severe VHD underwent echocardiography and NT-proBNP measurement. VHD examined included aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid regurgitation, and multivalvular heart disease. NT-proBNP ratio was defined as measured NT-proBNP relative to the maximal normal values specific to age and sex. Disease-specific thresholds were defined on the basis of penalized splines and maximally selected rank statistics.
Results
The cohort had a mean age of 71.1 ± 7.6 years. At 1-year follow-up, 561 deaths (9.4%) had occurred. In penalized splines, relative hazards showed a monotonic increase with greater NT-proBNP ratio for death with different VHDs (p < 0.001 for all) except mitral stenosis. Higher NT-proBNP ratio, categorized by disease-specific thresholds, was independently associated with mortality (overall adjusted hazard ratio: 1.99; 95% confidence interval: 1.76 to 2.24; p < 0.001). Different subtypes of VHD all incurred excess mortality with elevated NT-proBNP ratio, with the strongest association detected for aortic stenosis (adjusted hazard ratio: 10.5; 95% confidence interval: 3.9 to 28.27; p < 0.001). The addition of NT-proBNP ratio to the prediction algorithm including traditional risk factors improved outcome prediction (overall net reclassification index = 0.28; 95% CI: 0.24 to 0.34; p < 0.001; likelihood ratio test p < 0.001). Results remained consistent in patients under medical care, with normal left ventricular ejection fractions, and with primary VHD.
Conclusions
NT-proBNP provides incremental prognostic information for mortality in various VHDs. It could aid in risk stratification as a pragmatic and versatile biomarker in elderly patients.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 13 Apr 2020; 75:1659-1672
Zhang B, Xu H, Zhang H, Liu Q, ... Wu Y,
J Am Coll Cardiol: 13 Apr 2020; 75:1659-1672 | PMID: 32273031
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Abstract

Short-Term Progression of Multiterritorial Subclinical Atherosclerosis.

López-Melgar B, Fernández-Friera L, Oliva B, García-Ruiz JM, ... Sanz J, Fuster V
Background
Atherosclerosis progression predicts cardiovascular events; however, progression of multiterritorial subclinical atherosclerosis is incompletely understood.
Objectives
This study sought to study short-term progression of atherosclerosis using different noninvasive imaging techniques and their relationship with cardiovascular risk.
Methods
The study included 3,514 PESA (Progression of Early Subclinical Atherosclerosis) study participants (45.7 ± 4.2 years of age; 63% men). Participants underwent 2-dimensional vascular ultrasound (2DVUS) of abdominal aorta, carotid, iliac, and femoral territories to determine a plaque number score; 3DVUS to quantify carotid and femoral plaque volume; and coronary artery calcium score (CACS) at baseline and 2.8 years later. The authors calculated the rate of new disease incidence and changes in disease extent. Logistic regression models were used to evaluate associations of progression rates with baseline cardiovascular risk factors and estimated 10-year risk.
Results
Imaging detected short-term (3-year) atherosclerosis progression in 41.5% of participants (26.4% by 2DVUS, 21.3% by 3DVUS, and 11.5% by CACS), particularly in peripheral territories examined by vascular ultrasound. New atherosclerosis onset accounted for approximately one-third of total progression, also more frequently by 2DVUS and 3DVUS (29.1% and 16.6%, respectively), than by CACS (2.9%). Participants with baseline disease by all 3 modalities (n = 432) also showed significant atherosclerosis progression (median: 1 plaque [interquartile range (IQR): -1 to 3 plaques] by 2DVUS; 7.6 mm [IQR: -32.2 to 57.6 mm] by 3DVUS; and 21.6 Agatston units [IQR: 4.8 to 62.6 Agatston units] by CACS). Age, sex, dyslipidemia, hypertension, smoking, and family history of premature cardiovascular disease contributed to progression, with dyslipidemia the strongest modifiable risk factor. Although disease progression correlated with cardiovascular risk, progression was detected in 36.5% of participants categorized as low risk.
Conclusions
With this multimodal and multiterritorial approach, the authors detected short-term progression of early subclinical atherosclerosis in a substantial proportion (41.5%) of apparently healthy middle-aged men and women, more frequently by peripheral 2D/3DVUS than by CACS. Disease progression, as defined in this study, correlated with almost all cardiovascular risk factors and estimated risk. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 13 Apr 2020; 75:1617-1627
López-Melgar B, Fernández-Friera L, Oliva B, García-Ruiz JM, ... Sanz J, Fuster V
J Am Coll Cardiol: 13 Apr 2020; 75:1617-1627 | PMID: 32273027
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Abstract

Long-Term Outcomes in Women and Men Following Percutaneous Coronary Intervention.

Kosmidou I, Leon MB, Zhang Y, Serruys PW, ... Mehran R, Stone GW
Background
Studies examining sex-related outcomes following percutaneous coronary intervention (PCI) have reported conflicting results.
Objectives
The purpose of this study was to examine the sex-related risk of 5-year cardiovascular outcomes after PCI.
Methods
The authors pooled patient-level data from 21 randomized PCI trials and assessed the association between sex and major adverse cardiac events (MACE) (cardiac death, myocardial infarction [MI], or ischemia-driven target lesion revascularization [ID-TLR]) as well as its individual components at 5 years.
Results
Among 32,877 patients, 9,141 (27.8%) were women. Women were older and had higher body mass index, more frequent hypertension and diabetes, and less frequent history of surgical or percutaneous revascularization compared with men. By angiographic core laboratory analysis, lesions in women had smaller reference vessel diameter and shorter lesion length. At 5 years, women had a higher unadjusted rate of MACE (18.9% vs. 17.7%; p = 0.003), all-cause death (10.4% vs. 8.7%; p = 0.0008), cardiac death (4.9% vs. 4.0%; p = 0.003) and ID-TLR (10.9% vs. 10.2%; p = 0.02) compared with men. By multivariable analysis, female sex was an independent predictor of MACE (hazard ratio [HR:]: 1.14; 95% confidence interval [CI:]: 1.01 to 1.30; p = 0.04) and ID-TLR (HR: 1.23; 95% CI: 1.05 to 1.44; p = 0.009) but not all-cause death (HR: 0.91; 95% CI: 0.75 to 1.09; p = 0.30) or cardiac death (HR: 0.97; 95% CI: 0.73 to 1.29; p = 0.85).
Conclusions
In the present large-scale, individual patient data pooled analysis of contemporary PCI trials, women had a higher risk of MACE and ID-TLR compared with men at 5 years following PCI.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 13 Apr 2020; 75:1631-1640
Kosmidou I, Leon MB, Zhang Y, Serruys PW, ... Mehran R, Stone GW
J Am Coll Cardiol: 13 Apr 2020; 75:1631-1640 | PMID: 32273029
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Abstract

Effect of Smoking on Outcomes of Primary PCI in Patients With STEMI.

Redfors B, Furer A, Selker HP, Thiele H, ... Ben-Yehuda O, Stone GW
Background
Smoking is a well-established risk factor for ST-segment elevation myocardial infarction (STEMI); however, once STEMI occurs, smoking has been associated with favorable short-term outcomes, an observation termed the \"smoker\'s paradox.\" It has been postulated that smoking might exert protective effects that could reduce infarct size, a strong independent predictor of worse outcomes after STEMI.
Objectives
The purpose of this study was to determine the relationship among smoking, infarct size, microvascular obstruction (MVO), and adverse outcomes after STEMI.
Methods
Individual patient-data were pooled from 10 randomized trials of patients with STEMI undergoing primary percutaneous coronary intervention. Infarct size was assessed at median 4 days by either cardiac magnetic resonance imaging or technetium-99m sestamibi single-photon emission computed tomography. Multivariable analysis was used to assess the relationship between smoking, infarct size, and the 1-year rates of death or heart failure (HF) hospitalization and reinfarction.
Results
Among 2,564 patients with STEMI, 1,093 (42.6%) were recent smokers. Smokers were 10 years younger and had fewer comorbidities. Infarct size was similar in smokers and nonsmokers (adjusted difference: 0.0%; 95% confidence interval [CI]: -3.3% to 3.3%; p = 0.99). Nor was the extent of MVO different between smokers and nonsmokers. Smokers had lower crude 1-year rates of all-cause death (1.0% vs. 2.9%; p < 0.001) and death or HF hospitalization (3.3% vs. 5.1%; p = 0.009) with similar rates of reinfarction. After adjustment for age and other risk factors, smokers had a similar 1-year risk of death (adjusted hazard ratio [adjHR]: 0.92; 95% CI: 0.46 to 1.84) and higher risks of death or HF hospitalization (adjHR: 1.49; 95% CI: 1.09 to 2.02) as well as reinfarction (adjHR: 1.97; 95% CI: 1.17 to 3.33).
Conclusions
In the present large-scale individual patient-data pooled analysis, recent smoking was unrelated to infarct size or MVO, but was associated with a worse prognosis after primary PCI in STEMI. The smoker\'s paradox may be explained by the younger age and fewer cardiovascular risk factors in smokers compared with nonsmokers.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Apr 2020; 75:1743-1754
Redfors B, Furer A, Selker HP, Thiele H, ... Ben-Yehuda O, Stone GW
J Am Coll Cardiol: 20 Apr 2020; 75:1743-1754 | PMID: 32299585
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Impact:
Abstract

Effect of bariatric surgery on long-term cardiovascular outcomes: a nationwide nested cohort study.

Moussa O, Ardissino M, Heaton T, Tang A, ... Collins P, Purkayastha S
Aims
This study aims to evaluate the long-term effect of bariatric surgery on cardiovascular outcomes of patients with obesity.
Methods and results
A nested cohort study was carried out within the Clinical Practice Research Datalink. The study cohort included the 3701 patients on the database who had undergone bariatric surgery and 3701 age, gender, and body mass index-matched controls. The primary endpoint was the composite of fatal or non-fatal myocardial infarction and fatal or non-fatal ischaemic stroke. Secondary endpoints included fatal or non-fatal myocardial infarction alone, fatal or non-fatal ischaemic stroke alone, incident heart failure, and mortality. The median follow-up achieved was 11.2 years. Patients who had undergone bariatric surgery had a significantly lower occurrence of major adverse cardiovascular events [hazard ratio (HR) 0.410, 95% confidence interval (CI) 0.274-0.615; P < 0.001]. This was mainly driven by a reduction in myocardial infarction (HR 0.412, 95% CI 0.280-0.606; P < 0.001) and not in acute ischaemic stroke (HR 0.536, 95% CI 0.164-1.748; P = 0.301). A reduction was also observed in new diagnoses of heart failure (HR 0.403, 95% CI 0.181-0.897; P = 0.026) and mortality (HR 0.254, 95% CI 0.183-0.353; P < 0.001).
Conclusion
The results of this large, nationwide cohort study support the association of bariatric surgery with lower long-term risk of major cardiovascular events and incident heart failure in patients with obesity.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 18 Mar 2020; epub ahead of print
Moussa O, Ardissino M, Heaton T, Tang A, ... Collins P, Purkayastha S
Eur Heart J: 18 Mar 2020; epub ahead of print | PMID: 32188981
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Abstract

Antithrombotic Therapy for Patients With Left Ventricular Mural Thrombus.

Lattuca B, Bouziri N, Kerneis M, Portal JJ, ... Silvain J,
Background
Contemporary data are lacking regarding the prognosis and management of left ventricular thrombus (LVT).
Objectives
The purpose of this study was to quantify the effect of anticoagulation therapy on LVT evolution using sequential imaging and to determine the impact of LVT regression on the incidence of thromboembolism, bleeding, and mortality.
Methods
From January 2011 to January 2018, a comprehensive computerized search of LVT was conducted using 90,065 consecutive echocardiogram reports. Only patients with a confirmed LVT were included after imaging review by 2 independent experts. Major adverse cardiovascular events (MACE), which included death, stroke, myocardial infarction, or acute peripheral artery emboli, were determined as well as major bleeding events (BARC ≥3) and all-cause mortality rates.
Results
There were 159 patients with a confirmed LVT. Patients were treated with vitamin K antagonists (48.4%), parenteral heparins (27.7%), and direct oral anticoagulants (22.6%). Antiplatelet therapy was used in 67.9% of the population. A reduction of the LVT area from baseline was observed in 121 patients (76.1%), and total LVT regression occurred in 99 patients (62.3%) within a median time of 103 days (interquartile range: 32 to 392 days). The independent correlates of LVT regression were a nonischemic cardiomyopathy (hazard ratio [HR]: 2.74; 95% confidence interval [CI]: 1.43 to 5.26; p = 0.002) and a smaller baseline thrombus area (HR: 0.66; 95% CI: 0.45 to 0.96; p = 0.031). The frequency of MACE was 37.1%; mortality 18.9%; stroke 13.3%; and major bleeding 13.2% during a median follow-up of 632 days (interquartile range: 187 to 1,126 days). MACE occurred in 35.4% and 40.0% of patients with total LVT regression and those with persistent LVT (p = 0.203). A reduced risk of mortality was observed among patients with total LVT regression (HR: 0.48; 95% CI: 0.23 to 0.98; p = 0.039), whereas an increased major bleeding risk was observed among patients with persistent LVT (9.1% vs. 12%; HR 0.34; 95% CI: 0.14 to 0.82; p = 0.011). A left ventricular ejection fraction ≥35% (HR: 0.46; 95% CI: 0.23 to 0.93; p = 0.029) and anticoagulation therapy >3 months (HR: 0.42; 95% CI: 0.20 to 0.88; p = 0.021) were independently associated with less MACE.
Conclusions
The presence of LVT was associated with a very high risk of MACE and mortality. Total LVT regression, obtained with different anticoagulant regimens, was associated with reduced mortality.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 13 Apr 2020; 75:1676-1685
Lattuca B, Bouziri N, Kerneis M, Portal JJ, ... Silvain J,
J Am Coll Cardiol: 13 Apr 2020; 75:1676-1685 | PMID: 32273033
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Impact:
Abstract

Relevance of Fitness to Mortality Risk in Men Receiving Contemporary Medical Care.

Farrell SW, DeFina LF, Radford NB, Leonard D, ... Haskell WL, Lee IM
Background
An inverse association between cardiorespiratory fitness and mortality was robustly demonstrated 3 decades ago.
Objectives
The purpose of this study was to determine whether significant advances in disease prevention, detection, and treatment since that time have modified this association.
Methods
A total of 47,862 men completed baseline examinations, including a maximal treadmill test. Cohort 1 (n = 24,475) was examined during 1971 to 1991 and followed for mortality through 1992. Cohort 2 (n = 23,387) was examined during 1992 to 2013 with follow-up through 2014. Men were categorized as low fit, moderate fit, or high fit using Cooper Clinic normative data. Hazard ratios (HRs) for all-cause, cardiovascular disease, and cancer mortality were determined across fitness categories in the 2 cohorts.
Results
A significant inverse trend between fitness categories and all-cause (HR: 1.0, 0.60, and 0.53 in cohort 1 and HR: 1.0, 0.76, and 0.52 in cohort 2) and cardiovascular disease mortality (HR: 1.0, 0.55, and 0.43 in cohort 1 and HR: 1.0, 0.84, and 0.52 in cohort 2) was observed (p trend <0.001 for all). The trend across fitness categories and cancer mortality was significant for cohort 1 (HR: 1.0, 0.62, and 0.48; p < 0.001), but not for cohort 2 (HR: 1.0, 1.08, and 0.74; p = 0.19). HRs for all-cause mortality were 0.86 (95% confidence interval: 0.82 to 0.90) and 0.87 (95% confidence interval: 0.83 to 0.91) per 1-MET increment in fitness for cohorts 1 and 2, respectively (p < 0.001 for both). Similar values were seen for cardiovascular disease and cancer mortality.
Conclusions
Despite significant advances in disease prevention, detection, and treatment since fitness was first shown to be associated with mortality, the inverse association between fitness and mortality remains consistent in a contemporary cohort of men.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Apr 2020; 75:1538-1547
Farrell SW, DeFina LF, Radford NB, Leonard D, ... Haskell WL, Lee IM
J Am Coll Cardiol: 06 Apr 2020; 75:1538-1547 | PMID: 32241369
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Abstract

Select Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic of the Week.

Wiggins BS, Dixon DL, Neyens RR, Page RL, Gluckman TJ

Millions of individuals in the United States require long-term treatment with an oral anticoagulant. For decades, vitamin K antagonists were the only oral option available; however, they have a number of well-known limitations. Introduction of the direct oral anticoagulants (DOACs) has long been considered a major therapeutic advance, largely because they lack the need for therapeutic monitoring. Despite this, DOACs, like vitamin K antagonists, can still cause major and clinically relevant nonmajor bleeding, even when used appropriately. Drug-drug interactions (DDIs) involving the DOACs represent an important contributor to increased bleeding risk. Awareness of these DDIs and how best to address them is of critical importance in optimizing management while mitigating bleeding risk. This review provides an overview of DOAC metabolism, the most common drugs likely to contribute to DOAC DDIs, their underlying mechanisms, and how best to address them.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Mar 2020; 75:1341-1350
Wiggins BS, Dixon DL, Neyens RR, Page RL, Gluckman TJ
J Am Coll Cardiol: 23 Mar 2020; 75:1341-1350 | PMID: 32192661
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Abstract

AntimiR-21 Prevents Myocardial Dysfunction in a Pig Model of Ischemia/Reperfusion Injury.

Hinkel R, Ramanujam D, Kaczmarek V, Howe A, ... Kupatt C, Engelhardt S
Background
miR-21 is a central regulator of cardiac fibrosis, and its inhibition in small-animal models has been shown to be an effective antifibrotic strategy in various organs, including the heart. Effective delivery of therapeutic antisense micro-ribonucleic acid (antimiR) molecules to the myocardium in larger organisms is challenging, though, and remains to be established for models of chronic heart failure.
Objectives
The aims of this study were to test the applicability and therapeutic efficacy of local, catheter-based delivery of antimiR-21 in a pig model of heart failure and determine its effect on the cardiac transcriptomic signature and cellular composition.
Methods
Pigs underwent transient percutaneous occlusion of the left coronary artery and were followed up for 33 days. AntimiR-21 (10 mg) was applied by intracoronary infusion at days 5 and 19 after the injury. Cardiac function was assessed in vivo, followed by histological analyses and deep ribonucleic acid sequencing (RNA-seq) of the myocardium and genetic deconvolution analysis.
Results
AntimiR-21 effectively suppressed the remodeling-associated increase of miR-21. At 33 days after ischemia/reperfusion injury, LNA-21-treated hearts exhibited reduced cardiac fibrosis and hypertrophy and improved cardiac function. Deep RNA-seq revealed a significant derepression of the miR-21 targetome in antimiR-21-treated myocardium and a suppression of the inflammatory response and mitogen-activated protein kinase signaling. A genetic deconvolution approach built on deep RNA-seq and single-cell RNA-seq data identified reductions in macrophage and fibroblast numbers as the key cell types affected by antimiR-21 treatment.
Conclusions
This study provides the first evidence for the feasibility and therapeutic efficacy of miR-21 inhibition in a large animal model of heart failure.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Apr 2020; 75:1788-1800
Hinkel R, Ramanujam D, Kaczmarek V, Howe A, ... Kupatt C, Engelhardt S
J Am Coll Cardiol: 20 Apr 2020; 75:1788-1800 | PMID: 32299591
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Abstract

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

Cao B, Wang Y, Wen D, Liu W, ... Zhang D, Wang C
Background
No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.
Methods
We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao) to the fraction of inspired oxygen (Fio) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.
Results
A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.
Conclusions
In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 17 Mar 2020; epub ahead of print
Cao B, Wang Y, Wen D, Liu W, ... Zhang D, Wang C
N Engl J Med: 17 Mar 2020; epub ahead of print | PMID: 32187464
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Abstract

The role of genetics in cardiovascular disease: arrhythmogenic cardiomyopathy.

James CA, Syrris P, van Tintelen JP, Calkins H

Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiomyopathy characterized by frequent ventricular arrhythmias and progressive ventricular dysfunction. Risk of sudden cardiac death is elevated in ACM patients and can be the presenting symptom particularly in younger individuals and athletes. This review describes current understanding of the genetic architecture of ACM and molecular mechanisms of ACM pathogenesis. We consider an emerging threshold model for ACM inheritance in which multiple factors including pathogenic variants in known ACM genes, genetic modifiers, and environmental exposures, particularly exercise, are required to reach a threshold for disease expression. We also review best practices for integrating genetics-including recent discoveries-in caring for ACM families and emphasize the utility of genotype for both management of affected individuals and predictive testing in family members.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.[email protected]

Eur Heart J: 18 Mar 2020; epub ahead of print
James CA, Syrris P, van Tintelen JP, Calkins H
Eur Heart J: 18 Mar 2020; epub ahead of print | PMID: 32191298
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Impact:
Abstract

Randomized Trials in Cardiac Surgery: JACC Review Topic of the Week.

Gaudino M, Kappetein AP, Di Franco A, Bagiella E, ... Zenati MA, Fremes SE

Compared with randomized controlled trials (RCTs) in medical specialties, RCTs in cardiac surgery face specific issues. Individual and collective equipoise, rapid evolution of the surgical techniques, as well as difficulties in obtaining funding, and limited education in clinical epidemiology in the surgical community are among the most important challenges in the design phase of the trial. Use of complex interventions and learning curve effect, differences in individual operators\' expertise, difficulties in blinding, and slow recruitment make the successful completion of cardiac surgery RCTs particularly challenging. In fact, over the course of the last 20 years, the number of cardiac surgery RCTs has declined significantly. In this review, a team of surgeons, trialists, and epidemiologists discusses the most important challenges faced by RCTs in cardiac surgery and provides a list of suggestions for the successful design and completion of cardiac surgery RCTs.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Apr 2020; 75:1593-1604
Gaudino M, Kappetein AP, Di Franco A, Bagiella E, ... Zenati MA, Fremes SE
J Am Coll Cardiol: 06 Apr 2020; 75:1593-1604 | PMID: 32241376
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Abstract

Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome.

Barrot L, Asfar P, Mauny F, Winiszewski H, ... ,
Background
In patients with acute respiratory distress syndrome (ARDS), the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network recommends a target partial pressure of arterial oxygen (Pao) between 55 and 80 mm Hg. Prospective validation of this range in patients with ARDS is lacking. We hypothesized that targeting the lower limit of this range would improve outcomes in patients with ARDS.
Methods
In this multicenter, randomized trial, we assigned patients with ARDS to receive either conservative oxygen therapy (target Pao, 55 to 70 mm Hg; oxygen saturation as measured by pulse oximetry [Spo], 88 to 92%) or liberal oxygen therapy (target Pao, 90 to 105 mm Hg; Spo, ≥96%) for 7 days. The same mechanical-ventilation strategies were used in both groups. The primary outcome was death from any cause at 28 days.
Results
After the enrollment of 205 patients, the trial was prematurely stopped by the data and safety monitoring board because of safety concerns and a low likelihood of a significant difference between the two groups in the primary outcome. Four patients who did not meet the eligibility criteria were excluded. At day 28, a total of 34 of 99 patients (34.3%) in the conservative-oxygen group and 27 of 102 patients (26.5%) in the liberal-oxygen group had died (difference, 7.8 percentage points; 95% confidence interval [CI], -4.8 to 20.6). At day 90, 44.4% of the patients in the conservative-oxygen group and 30.4% of the patients in the liberal-oxygen group had died (difference, 14.0 percentage points; 95% CI, 0.7 to 27.2). Five mesenteric ischemic events occurred in the conservative-oxygen group.
Conclusions
Among patients with ARDS, early exposure to a conservative-oxygenation strategy with a Pao between 55 and 70 mm Hg did not increase survival at 28 days. (Funded by the French Ministry of Health; LOCO ClinicalTrials.gov number, NCT02713451.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 11 Mar 2020; 382:999
Barrot L, Asfar P, Mauny F, Winiszewski H, ... ,
N Engl J Med: 11 Mar 2020; 382:999 | PMID: 32160661
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Abstract

Prevalence and outcome of dual aortic stenosis and cardiac amyloid pathology in patients referred for transcatheter aortic valve implantation.

Scully PR, Patel KP, Treibel TA, Thornton GD, ... Hawkins PN, Moon JC
Aims
Cardiac amyloidosis is common in elderly patients with aortic stenosis (AS) referred for transcatheter aortic valve implantation (TAVI). We hypothesized that patients with dual aortic stenosis and cardiac amyloid pathology (AS-amyloid) would have different baseline characteristics, periprocedural and mortality outcomes.
Methods and results
Patients aged ≥75 with severe AS referred for TAVI at two sites underwent blinded bone scintigraphy prior to intervention (Perugini Grade 0 negative, 1-3 increasingly positive). Baseline assessment included echocardiography, electrocardiogram (ECG), blood tests, 6-min walk test, and health questionnaire, with periprocedural complications and mortality follow-up. Two hundred patients were recruited (aged 85 ± 5 years, 50% male). AS-amyloid was found in 26 (13%): 8 Grade 1, 18 Grade 2. AS-amyloid patients were older (88 ± 5 vs. 85 ± 5 years, P = 0.001), with reduced quality of life (EQ-5D-5L 50 vs. 65, P = 0.04). Left ventricular wall thickness was higher (14 mm vs. 13 mm, P = 0.02), ECG voltages lower (Sokolow-Lyon 1.9 ± 0.7 vs. 2.5 ± 0.9 mV, P = 0.03) with lower voltage/mass ratio (0.017 vs. 0.025 mV/g/m2, P = 0.03). High-sensitivity troponin T and N-terminal pro-brain natriuretic peptide were higher (41 vs. 21 ng/L, P < 0.001; 3702 vs. 1254 ng/L, P = 0.001). Gender, comorbidities, 6-min walk distance, AS severity, prevalence of disproportionate hypertrophy, and post-TAVI complication rates (38% vs. 35%, P = 0.82) were the same. At a median follow-up of 19 (10-27) months, there was no mortality difference (P = 0.71). Transcatheter aortic valve implantation significantly improved outcome in the overall population (P < 0.001) and in those with AS-amyloid (P = 0.03).
Conclusions
AS-amyloid is common and differs from lone AS. Transcatheter aortic valve implantation significantly improved outcome in AS-amyloid, while periprocedural complications and mortality were similar to lone AS, suggesting that TAVI should not be denied to patients with AS-amyloid.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 07 Apr 2020; epub ahead of print
Scully PR, Patel KP, Treibel TA, Thornton GD, ... Hawkins PN, Moon JC
Eur Heart J: 07 Apr 2020; epub ahead of print | PMID: 32267922
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Abstract

Surgery versus Conservative Care for Persistent Sciatica Lasting 4 to 12 Months.

Bailey CS, Rasoulinejad P, Taylor D, Sequeira K, ... Glennie A, Urquhart JC
Background
The treatment of chronic sciatica caused by herniation of a lumbar disk has not been well studied in comparison with acute disk herniation. Data are needed on whether diskectomy or a conservative approach is better for sciatica that has persisted for several months.
Methods
In a single-center trial, we randomly assigned patients with sciatica that had lasted for 4 to 12 months and lumbar disk herniation at the L4-L5 or L5-S1 level in a 1:1 ratio to undergo microdiskectomy or to receive 6 months of standardized nonoperative care followed by surgery if needed. Surgery was performed by spine surgeons who used conventional microdiskectomy techniques. The primary outcome was the intensity of leg pain on a visual analogue scale (ranging from 0 to 10, with higher scores indicating more severe pain) at 6 months after enrollment. Secondary outcomes were the score on the Oswestry Disability Index, back and leg pain, and quality-of-life scores at 6 weeks, 3 months, 6 months, and 1 year.
Results
From 2010 through 2016, a total of 790 patients were screened; of those patients, 128 were enrolled, with 64 in each group. Among the patients assigned to undergo surgery, the median time from randomization to surgery was 3.1 weeks; of the 64 patients in the nonsurgical group, 22 (34%) crossed over to undergo surgery at a median of 11 months after enrollment. At baseline, the mean score for leg-pain intensity was 7.7 in the surgical group and 8.0 in the nonsurgical group. The primary outcome of the leg-pain intensity score at 6 months was 2.8 in the surgical group and 5.2 in the nonsurgical group (adjusted mean difference, 2.4; 95% confidence interval, 1.4 to 3.4; P<0.001). Secondary outcomes including the score on the Owestry Disability Index and pain at 12 months were in the same direction as the primary outcome. Nine patients had adverse events associated with surgery, and one patient underwent repeat surgery for recurrent disk herniation.
Conclusions
In this single-center trial involving patients with sciatica lasting more than 4 months and caused by lumbar disk herniation, microdiskectomy was superior to nonsurgical care with respect to pain intensity at 6 months of follow-up. (Funded by Physicians\' Services Incorporated Foundation; ClinicalTrials.gov number, NCT01335646.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 18 Mar 2020; 382:1093-1102
Bailey CS, Rasoulinejad P, Taylor D, Sequeira K, ... Glennie A, Urquhart JC
N Engl J Med: 18 Mar 2020; 382:1093-1102 | PMID: 32187469
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Abstract

Consequences of Undervaccination - Measles Outbreak, New York City, 2018-2019.

Zucker JR, Rosen JB, Iwamoto M, Arciuolo RJ, ... Daskalakis DC, Barbot O
Background
Measles was declared eliminated in the United States in 2000, but the risk of outbreaks owing to international importations remains. An outbreak of measles in New York City began when one unvaccinated child returned home from Israel with measles; onset of rash occurred on September 30, 2018, 9 days after the child returned home.
Methods
We investigated suspected cases of measles by conducting interviews, reviewing medical and immunization records, identifying exposed persons, and performing diagnostic testing. Measles-mumps-rubella (MMR) vaccine (given as either MMR or measles-mumps-rubella-varicella vaccine and collectively referred to as MMR vaccine) uptake was monitored with the use of the Citywide Immunization Registry. The total direct cost to the New York City Department of Health and Mental Hygiene was calculated.
Results
A total of 649 cases of measles were confirmed, with onsets of rash occurring between September 30, 2018, and July 15, 2019. A majority of the patients (93.4%) were part of the Orthodox Jewish community, and 473 of the patients (72.9%) resided in the Williamsburg area of Brooklyn, New York. The median age was 3 years; 81.2% of the patients were 18 years of age or younger, and 85.8% of the patients with a known vaccination history were unvaccinated. Serious complications included pneumonia (in 37 patients [5.7%]) and hospitalization (in 49 patients [7.6%]); among the patients who were hospitalized, 20 (40.8%) were admitted to an intensive care unit. As a result of efforts to promote vaccination, the percentage of children in Williamsburg who received at least one dose of MMR vaccine increased from 79.5% to 91.1% among children 12 to 59 months of age. As of September 9, 2019, a total of 559 staff members at the Department of Health and Mental Hygiene (7% of the agency) had been involved in the measles response. The cost of the Department of Health and Mental Hygiene response was $8.4 million.
Conclusions
Importation of measles and vaccination delays among young children led to an outbreak of measles in New York City. The outbreak response was resource intensive and caused serious illness, particularly among unvaccinated children.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 11 Mar 2020; 382:1009-1017
Zucker JR, Rosen JB, Iwamoto M, Arciuolo RJ, ... Daskalakis DC, Barbot O
N Engl J Med: 11 Mar 2020; 382:1009-1017 | PMID: 32160662
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Impact:
Abstract

Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol.

Ray KK, Wright RS, Kallend D, Koenig W, ... Kastelein JJP,
Background
Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing.
Methods
We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540.
Results
A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent.
Conclusions
Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 17 Mar 2020; epub ahead of print
Ray KK, Wright RS, Kallend D, Koenig W, ... Kastelein JJP,
N Engl J Med: 17 Mar 2020; epub ahead of print | PMID: 32187462
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Impact:
Abstract

Left atrial appendage occlusion with the Amplatzer™ Amulet™ device: full results of the prospective global observational study.

Hildick-Smith D, Landmesser U, Camm AJ, Diener HC, ... Nielsen-Kudsk JE, Tondo C
Aims
To evaluate the safety and efficacy of left atrial appendage occlusion (LAAO) with the Amplatzer™ Amulet™ occluder.
Methods and results
Patients with atrial fibrillation eligible for LAAO were recruited to a prospective global study. Implant procedures were undertaken with echocardiographic guidance. Transoesophageal echocardiography (TOE) was undertaken 1-3 months post-LAAO. Implant and follow-up TOEs were evaluated by a CoreLab. The primary endpoint was a composite of ischaemic stroke and cardiovascular death at 2 years. Serious adverse events were adjudicated by an independent clinical events committee. A total of 1088 patients were enrolled, aged 75.2 ± 8.5 years; 64.5% were male. CHA2DS2-VASc and HAS-BLED scores were 4.2 ± 1.6 and 3.3 ± 1.1, respectively. A total of 71.7% had prior major bleeding, and 82.8% had contraindications to oral anticoagulants. Implant success was 99.1%. Major adverse events (≤7 days post-procedure) occurred in 4.0%, including death (0.3%), stroke (0.4%), major vascular (1.3%), and device embolization (0.2%). A total of 80.2% of patients were discharged on antiplatelet therapy alone. Peridevice flow was <3 mm in 98.4% at follow-up TOE. Device-related thrombus (DRT) was seen in 1.6% of cases. Cardiovascular death or ischaemic stroke occurred in 8.7% of patients at 2 years. The ischaemic stroke rate was 2.2%/year-a 67% reduction compared to the CHA2DS2-VASc predicted rate. Major bleeding (Bleeding Academic Research Consortium type ≥ 3) occurred at rates of 10.1%/year (year 1) and 4.0%/year (year 2).
Conclusion
Following LAAO with the Amplatzer Amulet device, the ischaemic stroke rate was reduced by 67% compared to the predicted risk. Closure was complete in 98.4% of cases and DRT seen in only 1.6%.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 02 Apr 2020; epub ahead of print
Hildick-Smith D, Landmesser U, Camm AJ, Diener HC, ... Nielsen-Kudsk JE, Tondo C
Eur Heart J: 02 Apr 2020; epub ahead of print | PMID: 32243499
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Impact:
Abstract

Targeting cardiovascular inflammation: next steps in clinical translation.

Lawler PR, Bhatt DL, Godoy LC, Lüscher TF, ... Verma S, Ridker PM

Systemic vascular inflammation plays multiple maladaptive roles which contribute to the progression and destabilization of atherosclerotic cardiovascular disease (ASCVD). These roles include: (i) driving atheroprogression in the clinically stable phase of disease; (ii) inciting atheroma destabilization and precipitating acute coronary syndromes (ACS); and (iii) responding to cardiomyocyte necrosis in myocardial infarction (MI). Despite an evolving understanding of these biologic processes, successful clinical translation into effective therapies has proven challenging. Realizing the promise of targeting inflammation in the prevention and treatment of ASCVD will likely require more individualized approaches, as the degree of inflammation differs among cardiovascular patients. A large body of evidence has accumulated supporting the use of high-sensitivity C-reactive protein (hsCRP) as a clinical measure of inflammation. Appreciating the mechanistic diversity of ACS triggers and the kinetics of hsCRP in MI may resolve purported inconsistencies from prior observational studies. Future clinical trial designs incorporating hsCRP may hold promise to enable individualized approaches. The aim of this Clinical Review is to summarize the current understanding of how inflammation contributes to ASCVD progression, destabilization, and adverse clinical outcomes. We offer forward-looking perspective on what next steps may enable successful clinical translation into effective therapeutic approaches-enabling targeting the right patients with the right therapy at the right time-on the road to more individualized ASCVD care.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 15 Mar 2020; epub ahead of print
Lawler PR, Bhatt DL, Godoy LC, Lüscher TF, ... Verma S, Ridker PM
Eur Heart J: 15 Mar 2020; epub ahead of print | PMID: 32176778
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Impact:
Abstract

Effects of dapagliflozin in DAPA-HF according to background heart failure therapy.

Docherty KF, Jhund PS, Inzucchi SE, Køber L, ... Solomon SD, McMurray JJV
Aims
In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure (HF) and death in patients with HF and reduced ejection fraction. We examined whether this benefit was consistent in relation to background HF therapy.
Methods and results
In this post hoc analysis, we examined the effect of study treatment in the following yes/no subgroups: diuretic, digoxin, mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillating (ICD) device, and cardiac resynchronization therapy. We also examined the effect of study drug according to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose, beta-blocker (BB) dose, and MRA (≥50% and <50% of target dose). We analysed the primary composite endpoint of cardiovascular death or a worsening HF event. Most randomized patients (n = 4744) were treated with a diuretic (84%), renin-angiotensin system (RAS) blocker (94%), and BB (96%); 52% of those taking a BB and 38% taking a RAS blocker were treated with ≥50% of the recommended dose. Overall, the dapagliflozin vs. placebo hazard ratio (HR) was 0.74 [95% confidence interval (CI) 0.65-0.85] for the primary composite endpoint (P < 0.0001). The effect of dapagliflozin was consistent across all subgroups examined: the HR ranged from 0.57 to 0.86 for primary endpoint, with no significant randomized treatment-by-subgroup interaction. For example, the HR in patients taking a RAS blocker, BB, and MRA at baseline was 0.72 (95% CI 0.61-0.86) compared with 0.77 (95% CI 0.63-0.94) in those not on all three of these treatments (P-interaction 0.64).
Conclusion
The benefit of dapagliflozin was consistent regardless of background therapy for HF.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 27 Mar 2020; epub ahead of print
Docherty KF, Jhund PS, Inzucchi SE, Køber L, ... Solomon SD, McMurray JJV
Eur Heart J: 27 Mar 2020; epub ahead of print | PMID: 32221582
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Abstract

Initial Invasive or Conservative Strategy for Stable Coronary Disease.

Maron DJ, Hochman JS, Reynolds HR, Bangalore S, ... Rosenberg Y,
Background
Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.
Methods
We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.
Results
Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).
Conclusions
Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Mar 2020; epub ahead of print
Maron DJ, Hochman JS, Reynolds HR, Bangalore S, ... Rosenberg Y,
N Engl J Med: 29 Mar 2020; epub ahead of print | PMID: 32227755
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Abstract

Transcatheter Electrosurgery: JACC State-of-the-Art Review.

Khan JM, Rogers T, Greenbaum AB, Babaliaros VC, ... Ratnayaka K, Lederman RJ

Transcatheter electrosurgery refers to a family of procedures using radiofrequency energy to vaporize and traverse or lacerate tissue despite flowing blood. The authors review theory, simulations, and benchtop demonstrations of how guidewires, insulation, adjunctive catheters, and dielectric medium interact. For tissue traversal, all but the tip of traversing guidewires is insulated to concentrate current. For leaflet laceration, the \"Flying V\" configuration concentrates current at the inner lacerating surface of a kinked guidewire. Flooding the field with non-ionic dextrose eliminates alternative current paths. Clinical applications include traversing occlusions (pulmonary atresia, arterial and venous occlusion, and iatrogenic graft occlusion), traversing tissue planes (atrial and ventricular septal puncture, radiofrequency valve repair, transcaval access, Potts and Glenn shunts), and leaflet laceration (BASILICA, LAMPOON, ELASTA-Clip, and others). Tips are provided for optimizing these techniques. Transcatheter electrosurgery already enables a range of novel therapeutic procedures for structural heart disease, and represents a promising advance toward transcatheter surgery.

Published by Elsevier Inc.

J Am Coll Cardiol: 30 Mar 2020; 75:1455-1470
Khan JM, Rogers T, Greenbaum AB, Babaliaros VC, ... Ratnayaka K, Lederman RJ
J Am Coll Cardiol: 30 Mar 2020; 75:1455-1470 | PMID: 32216915
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Abstract

Contrast-Associated Acute Kidney Injury and Serious Adverse Outcomes Following Angiography.

Weisbord SD, Palevsky PM, Kaufman JS, Wu H, ... Gallagher M,
Background
Contrast-associated acute kidney injury (CA-AKI) associates with an increased relative risk for serious adverse outcomes. However, the magnitude of this risk and the incidence of clinically significant CA-AKI derived from analyses of large cohorts with prospective assessment of CA-AKI and subsequent outcomes are unknown.
Objectives
This study sought to characterize the relative risk for and incidence of serious adverse outcomes following the development of CA-AKI and to explore whether CA-AKI mediates the association of pre-angiography estimated glomerular filtration rate with adverse outcomes.
Methods
Among 4,418 participants in the PRESERVE (Prevention of Serious Adverse Outcomes Following Angiography) trial with comprehensive baseline and outcome data, we assessed whether CA-AKI was associated with the 90-day outcome comprising death, need for dialysis, or persistent impairment in kidney function. We calculated the incidence of clinically significant CA-AKI (i.e., proportion of patients who developed CA-AKI and the 90-day outcome) and examined whether CA-AKI was a mediator of the association of baseline kidney function with the 90-day outcome.
Results
CA-AKI was associated with an increased relative risk for 90-day death, need for dialysis, or persistent kidney impairment (odds ratio: 3.93; 95% confidence interval: 2.82 to 5.49; p < 0.0001). The incidence of clinically significant CA-AKI was 1.2% (53 of 4,418 patients). CA-AKI was not a mediator of the association of pre-angiography estimated glomerular filtration rate with the primary outcome.
Conclusions
Whereas CA-AKI is associated with an increased relative risk of serious, adverse 90-day outcomes, the incidence of clinically significant CA-AKI is very low. CA-AKI does not mediate the association of the pre-angiography estimated glomerular filtration rate with these outcomes.

Published by Elsevier Inc.

J Am Coll Cardiol: 23 Mar 2020; 75:1311-1320
Weisbord SD, Palevsky PM, Kaufman JS, Wu H, ... Gallagher M,
J Am Coll Cardiol: 23 Mar 2020; 75:1311-1320 | PMID: 32192658
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Abstract

Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure.

Zhou W, Brown JM, Bajaj NS, Chandra A, ... O\'Gara P, Di Carli MF
Aims
Hypertension is a well-established heart failure (HF) risk factor, especially in the context of adverse left ventricular (LV) remodelling. We aimed to use myocardial flow reserve (MFR) and global longitudinal strain (GLS), markers of subclinical microvascular and myocardial dysfunction, to refine hypertensive HF risk assessment.
Methods and results
Consecutive patients undergoing symptom-prompted stress cardiac positron emission tomography (PET)-computed tomography and transthoracic echocardiogram within 90 days without reduced left ventricular ejection fraction (<40%) or flow-limiting coronary artery disease (summed stress score ≥ 3) were included. Global MFR was quantified by PET, and echocardiograms were retrospectively analysed for cardiac structure and function. Patients were followed over a median 8.75 (Q1-3 4.56-10.04) years for HF hospitalization and a composite of death, HF hospitalization, MI, or stroke. Of 194 patients, 155 had adaptive LV remodelling while 39 had maladaptive remodelling, which was associated with lower MFR and impaired GLS. Across the remodelling spectrum, diastolic parameters, GLS, and N-terminal pro-B-type natriuretic peptide were independently associated with MFR. Maladaptive LV remodelling was associated with increased adjusted incidence of HF hospitalization and death. Importantly, the combination of abnormal MFR and GLS was associated with a higher rate of HF hospitalization compared to normal MFR and GLS [adjusted hazard ratio (HR) 3.21, 95% confidence interval (CI) 1.09-9.45, P = 0.034), including in the adaptive remodelling subset (adjusted HR 3.93, 95% CI 1.14-13.56, P = 0.030).
Conclusion
We have demonstrated important associations between coronary microvascular dysfunction and myocardial mechanics that refine disease characterization and HF risk assessment of patients with hypertension based on subclinical target organ injury.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 27 Mar 2020; epub ahead of print
Zhou W, Brown JM, Bajaj NS, Chandra A, ... O'Gara P, Di Carli MF
Eur Heart J: 27 Mar 2020; epub ahead of print | PMID: 32221588
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Abstract

Management of Acute Ischemic Stroke Due to Large-Vessel Occlusion: JACC Focus Seminar.

Ospel JM, Holodinsky JK, Goyal M

Acute ischemic stroke is a severe and life-threatening disease, particularly when caused by a large-vessel occlusion. The only available 2 treatment options are intravenous alteplase and endovascular therapy (mechanical clot removal), both of which are highly time-dependent. Thus, rapid patient transfer, diagnosis, and treatment are crucial, and time-consuming imaging methods and overly selective treatment selection criteria should be avoided. A combined endovascular therapy approach using stent-retrievers and aspiration is the most effective way to achieve fast first-pass complete reperfusion and should thus be used. To diagnose and treat patients as fast as possible, the organization of existing systems of care, and particularly pre-hospital transfer systems, have to be changed. Several different transport models are currently in use because the optimal patient transfer paradigm is highly dependent on local geography and hospital efficiency.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Apr 2020; 75:1832-1843
Ospel JM, Holodinsky JK, Goyal M
J Am Coll Cardiol: 20 Apr 2020; 75:1832-1843 | PMID: 32299595
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Abstract

Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction.

Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, ... O\'Connor CM,
Background
The effect of vericiguat, a novel oral soluble guanylate cyclase stimulator, in patients with heart failure and reduced ejection fraction who had recently been hospitalized or had received intravenous diuretic therapy is unclear.
Methods
In this phase 3, randomized, double-blind, placebo-controlled trial, we assigned 5050 patients with chronic heart failure (New York Heart Association class II, III, or IV) and an ejection fraction of less than 45% to receive vericiguat (target dose, 10 mg once daily) or placebo, in addition to guideline-based medical therapy. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure.
Results
Over a median of 10.8 months, a primary-outcome event occurred in 897 of 2526 patients (35.5%) in the vericiguat group and in 972 of 2524 patients (38.5%) in the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P = 0.02). A total of 691 patients (27.4%) in the vericiguat group and 747 patients (29.6%) in the placebo group were hospitalized for heart failure (hazard ratio, 0.90; 95% CI, 0.81 to 1.00). Death from cardiovascular causes occurred in 414 patients (16.4%) in the vericiguat group and in 441 patients (17.5%) in the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06). The composite of death from any cause or hospitalization for heart failure occurred in 957 patients (37.9%) in the vericiguat group and in 1032 patients (40.9%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P = 0.02). Symptomatic hypotension occurred in 9.1% of the patients in the vericiguat group and in 7.9% of the patients in the placebo group (P = 0.12), and syncope occurred in 4.0% of the patients in the vericiguat group and in 3.5% of the patients in the placebo group (P = 0.30).
Conclusions
Among patients with high-risk heart failure, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower among those who received vericiguat than among those who received placebo. (Funded by Merck Sharp & Dohme [a subsidiary of Merck] and Bayer; VICTORIA ClinicalTrials.gov number, NCT02861534.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 Mar 2020; epub ahead of print
Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, ... O'Connor CM,
N Engl J Med: 27 Mar 2020; epub ahead of print | PMID: 32222134
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Abstract

A putative placebo analysis of the effects of sacubitril/valsartan in heart failure across the full range of ejection fraction.

Vaduganathan M, Jhund PS, Claggett BL, Packer M, ... McMurray JJV, Solomon SD
Aims
The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin-angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF).
Methods and results
We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45-0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 48% (95% CI 35-58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 29% (95% CI 7-46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64-0.82), first HF hospitalization (RR 0.67, 95% CI 0.58-0.78), cardiovascular death (RR 0.76, 95% CI 0.64-0.89), and all-cause death (RR 0.83, 95% CI 0.71-0.96); all P < 0.02.
Conclusion
This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 27 Mar 2020; epub ahead of print
Vaduganathan M, Jhund PS, Claggett BL, Packer M, ... McMurray JJV, Solomon SD
Eur Heart J: 27 Mar 2020; epub ahead of print | PMID: 32221596
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Abstract

Selumetinib in Children with Inoperable Plexiform Neurofibromas.

Gross AM, Wolters PL, Dombi E, Baldwin A, ... Doyle LA, Widemann BC
Background
No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1.
Methods
We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable).
Results
A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia.
Conclusions
In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 17 Mar 2020; epub ahead of print
Gross AM, Wolters PL, Dombi E, Baldwin A, ... Doyle LA, Widemann BC
N Engl J Med: 17 Mar 2020; epub ahead of print | PMID: 32187457
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Abstract

Management of Coronary Disease in Patients with Advanced Kidney Disease.

Bangalore S, Maron DJ, O\'Brien SM, Fleg JL, ... Hochman JS,
Background
Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease.
Methods
We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest.
Results
At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03).
Conclusions
Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Mar 2020; epub ahead of print
Bangalore S, Maron DJ, O'Brien SM, Fleg JL, ... Hochman JS,
N Engl J Med: 29 Mar 2020; epub ahead of print | PMID: 32227756
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Abstract

A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia.

Koblan KS, Kent J, Hopkins SC, Krystal JH, ... Goldman R, Loebel A
Background
An oral compound, SEP-363856, that does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT) receptors, may represent a new class of psychotropic agent for the treatment of psychosis in schizophrenia.
Methods
We performed a randomized, controlled trial to evaluate the efficacy and safety of SEP-363856 in adults with an acute exacerbation of schizophrenia. The patients were randomly assigned in a 1:1 ratio to receive once-daily treatment with SEP-363856 (50 mg or 75 mg) or placebo for 4 weeks. The primary end point was the change from baseline in the total score on the Positive and Negative Symptom Scale (PANSS; range, 30 to 210; higher scores indicate more severe psychotic symptoms) at week 4. There were eight secondary end points, including the changes from baseline in the scores on the Clinical Global Impressions Severity (CGI-S) scale and the Brief Negative Symptom Scale (BNSS).
Results
A total of 120 patients were assigned to the SEP-363856 group and 125 to the placebo group. The mean total score on the PANSS at baseline was 101.4 in the SEP-363856 group and 99.7 in the placebo group, and the mean change at week 4 was -17.2 points and -9.7 points, respectively (least-squares mean difference, -7.5 points; 95% confidence interval, -11.9 to -3.0; P = 0.001). The reductions in the CGI-S and BNSS scores at week 4 were generally in the same direction as those for the primary outcome, but the results were not adjusted for multiple comparisons. Adverse events with SEP-363856 included somnolence and gastrointestinal symptoms; one sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin were similar in the trial groups.
Conclusions
In this 4-week trial involving patients with an acute exacerbation of schizophrenia, SEP-363856, a non-D2-receptor-binding antipsychotic drug, resulted in a greater reduction from baseline in the PANSS total score than placebo. Longer and larger trials are necessary to confirm the effects and side effects of SEP-363856, as well as its efficacy relative to existing drug treatments for patients with schizophrenia. (Funded by Sunovion Pharmaceuticals; ClinicalTrials.gov number, NCT02969382.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Apr 2020; 382:1497-1506
Koblan KS, Kent J, Hopkins SC, Krystal JH, ... Goldman R, Loebel A
N Engl J Med: 15 Apr 2020; 382:1497-1506 | PMID: 32294346
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Abstract

The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development.

Demetz E, Tymoszuk P, Hilbe R, Volani C, ... Tancevski I, Weiss G
Aims
Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice.
Methods and results
Our analysis of the Global Lipids Genetics Consortium (GLGC) dataset revealed that single nucleotide polymorphisms (SNPs) in the haemochromatosis gene HFE associate with reduced low-density lipoprotein cholesterol (LDL-C) in human plasma. The LDL-C lowering effect could be phenocopied in dyslipidaemic ApoE-/- mice lacking Hfe, which translated into reduced atherosclerosis burden. Mechanistically, we identified HFE as a negative regulator of LDL receptor expression in hepatocytes. Moreover, we uncovered liver-resident Kupffer cells (KCs) as central players in cholesterol homeostasis as they were found to acquire and transfer LDL-derived cholesterol to hepatocytes in an Abca1-dependent fashion, which is controlled by iron availability.
Conclusion
Our results disentangle novel regulatory interactions between iron metabolism, KC biology and cholesterol homeostasis which are promising targets for treating dyslipidaemia but also provide a mechanistic explanation for reduced cardiovascular morbidity in subjects with haemochromatosis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 29 Mar 2020; epub ahead of print
Demetz E, Tymoszuk P, Hilbe R, Volani C, ... Tancevski I, Weiss G
Eur Heart J: 29 Mar 2020; epub ahead of print | PMID: 32227235
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Abstract

Genetic predisposition to smoking in relation to 14 cardiovascular diseases.

Larsson SC, Mason AM, Bäck M, Klarin D, ... Michaëlsson K, Burgess S
Aims
The aim of this study was to use Mendelian randomization (MR) to determine the causality of the association between smoking and 14 different cardiovascular diseases (CVDs).
Methods and results
Our primary genetic instrument comprised 361 single-nucleotide polymorphisms (SNPs) associated with smoking initiation (ever smoked regularly) at genome-wide significance. Data on the associations between the SNPs and 14 CVDs were obtained from the UK Biobank study (N = 367 643 individuals), CARDIoGRAMplusC4D consortium (N = 184 305 individuals), Atrial Fibrillation Consortium (2017 dataset; N = 154 432 individuals), and Million Veteran Program (MVP; N = 190 266 individuals). The main analyses were conducted using the random-effects inverse-variance weighted method and complemented with multivariable MR analyses and the weighted median and MR-Egger approaches. Genetic predisposition to smoking initiation was most strongly and consistently associated with higher odds of coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension. Genetic predisposition to smoking initiation was additionally associated with higher odds of deep vein thrombosis and pulmonary embolism in the UK Biobank but not with venous thromboembolism in the MVP. There was limited evidence of causal associations of smoking initiation with atrial fibrillation, aortic valve stenosis, thoracic aortic aneurysm, and intracerebral and subarachnoid haemorrhage.
Conclusion
This MR study supports a causal association between smoking and a broad range of CVDs, in particular, coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 15 Apr 2020; epub ahead of print
Larsson SC, Mason AM, Bäck M, Klarin D, ... Michaëlsson K, Burgess S
Eur Heart J: 15 Apr 2020; epub ahead of print | PMID: 32300774
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Abstract

Physical Therapy versus Glucocorticoid Injection for Osteoarthritis of the Knee.

Deyle GD, Allen CS, Allison SC, Gill NW, ... Dusenberry DI, Rhon DI
Background
Both physical therapy and intraarticular injections of glucocorticoids have been shown to confer clinical benefit with respect to osteoarthritis of the knee. Whether the short-term and long-term effectiveness for relieving pain and improving physical function differ between these two therapies is uncertain.
Methods
We conducted a randomized trial to compare physical therapy with glucocorticoid injection in the primary care setting in the U.S. Military Health System. Patients with osteoarthritis in one or both knees were randomly assigned in a 1:1 ratio to receive a glucocorticoid injection or to undergo physical therapy. The primary outcome was the total score on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 1 year (scores range from 0 to 240, with higher scores indicating worse pain, function, and stiffness). The secondary outcomes were the time needed to complete the Alternate Step Test, the time needed to complete the Timed Up and Go test, and the score on the Global Rating of Change scale, all assessed at 1 year.
Results
We enrolled 156 patients with a mean age of 56 years; 78 patients were assigned to each group. Baseline characteristics, including severity of pain and level of disability, were similar in the two groups. The mean (±SD) baseline WOMAC scores were 108.8±47.1 in the glucocorticoid injection group and 107.1±42.4 in the physical therapy group. At 1 year, the mean scores were 55.8±53.8 and 37.0±30.7, respectively (mean between-group difference, 18.8 points; 95% confidence interval, 5.0 to 32.6), a finding favoring physical therapy. Changes in secondary outcomes were in the same direction as those of the primary outcome. One patient fainted while receiving a glucocorticoid injection.
Conclusions
Patients with osteoarthritis of the knee who underwent physical therapy had less pain and functional disability at 1 year than patients who received an intraarticular glucocorticoid injection. (ClinicalTrials.gov number, NCT01427153.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 08 Apr 2020; 382:1420-1429
Deyle GD, Allen CS, Allison SC, Gill NW, ... Dusenberry DI, Rhon DI
N Engl J Med: 08 Apr 2020; 382:1420-1429 | PMID: 32268027
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Impact:
Abstract

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.

Raal FJ, Kallend D, Ray KK, Turner T, ... Kastelein JJP,
Background
Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.
Methods
In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540.
Results
The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.
Conclusions
Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 17 Mar 2020; epub ahead of print
Raal FJ, Kallend D, Ray KK, Turner T, ... Kastelein JJP,
N Engl J Med: 17 Mar 2020; epub ahead of print | PMID: 32197277
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Abstract

Simple electrocardiographic measures improve sudden arrhythmic death prediction in coronary disease.

Chatterjee NA, Tikkanen JT, Panicker GK, Narula D, ... Albert CM,
Aims
To determine whether the combination of standard electrocardiographic (ECG) markers reflecting domains of arrhythmic risk improves sudden and/or arrhythmic death (SAD) risk stratification in patients with coronary heart disease (CHD).
Methods and results
The association between ECG markers and SAD was examined in a derivation cohort (PREDETERMINE; N = 5462) with adjustment for clinical risk factors, left ventricular ejection fraction (LVEF), and competing risk. Competing outcome models assessed the differential association of ECG markers with SAD and competing mortality. The predictive value of a derived ECG score was then validated (ARTEMIS; N = 1900). In the derivation cohort, the 5-year cumulative incidence of SAD was 1.5% [95% confidence interval (CI) 1.1-1.9] and 6.2% (95% CI 4.5-8.3) in those with a low- and high-risk ECG score, respectively (P for Δ < 0.001). A high-risk ECG score was more strongly associated with SAD than non-SAD mortality (adjusted hazard ratios = 2.87 vs. 1.38 respectively; P for Δ = 0.003) and the proportion of deaths due to SAD was greater in the high vs. low risk groups (24.9% vs. 16.5%, P for Δ = 0.03). Similar findings were observed in the validation cohort. The addition of ECG markers to a clinical risk factor model inclusive of LVEF improved indices of discrimination and reclassification in both derivation and validation cohorts, including correct reclassification of 28% of patients in the validation cohort [net reclassification improvement 28 (7-49%), P = 0.009].
Conclusion
For patients with CHD, an externally validated ECG score enriched for both absolute and proportional SAD risk and significantly improved risk stratification compared to standard clinical risk factors including LVEF.
Clinical trial registration
https://clinicaltrials.gov/ct2/show/NCT01114269. ClinicalTrials.gov ID NCT01114269.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 06 Apr 2020; epub ahead of print
Chatterjee NA, Tikkanen JT, Panicker GK, Narula D, ... Albert CM,
Eur Heart J: 06 Apr 2020; epub ahead of print | PMID: 32259257
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Abstract

Supracardiac atherosclerosis in embolic stroke of undetermined source: the underestimated source.

Ntaios G, Wintermark M, Michel P

The term \'embolic stroke of undetermined source\' (ESUS) is used to describe patients with a non-lacunar ischaemic stroke without any identified embolic source from the heart or the arteries supplying the ischaemic territory, or any other apparent cause. When the ESUS concept was introduced, covert atrial fibrillation was conceived to be the main underlying cause in the majority of ESUS patients. Another important embolic source in ESUS is the atherosclerotic plaque in the carotid, vertebrobasilar, and intracranial arteries, or the aortic arch-collectively described as supracardiac atherosclerosis. There is emerging evidence showing that the role of supracardiac atherosclerosis is larger than it was initially perceived. Advanced imaging methods are available to identify plaques which high embolic risk. The role of novel antithrombotic strategies in these patients needs to be assessed in randomized controlled trials. This review presents the evidence which points towards a major aetiological association between atherosclerotic plaques and ESUS, summarizes the imaging features which may aid to identify plaques more likely to be associated with ESUS, discusses strategies to reduce the associated stroke risk, and highlights the rationale for future research in this field.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 15 Apr 2020; epub ahead of print
Ntaios G, Wintermark M, Michel P
Eur Heart J: 15 Apr 2020; epub ahead of print | PMID: 32300781
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Abstract

Primary and Secondary Prevention of Ischemic Stroke and Cerebral Hemorrhage: JACC Focus Seminar.

Diener HC, Hankey GJ

Stroke is a leading cause of permanent disability. Therefore, primary prevention of first stroke and secondary prevention of recurrent stroke are a high priority. Primary prevention of ischemic stroke includes lifestyle modification and diet, treatment of risk factors including hypertension, diabetes mellitus and lipid disorders, antiplatelet therapy for high vascular risk patients, and anticoagulation in atrial fibrillation. Secondary prevention of ischemic stroke includes additional carotid surgery or stenting in selected symptomatic patients, closure of patent foramen ovale after cryptogenic stroke, treatment of insulin resistance, and best medical treatment of intracranial stenosis. The most important preventive strategies in the primary and secondary prevention of cerebral hemorrhage include the treatment of hypertension, reduction in alcohol intake, and occlusion of the left atrial appendage in patients with atrial fibrillation and permanent contraindications for oral anticoagulation.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Apr 2020; 75:1804-1818
Diener HC, Hankey GJ
J Am Coll Cardiol: 20 Apr 2020; 75:1804-1818 | PMID: 32299593
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Abstract

Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1.

Mazzanti A, Guz D, Trancuccio A, Pagan E, ... Bagnardi V, Priori SG
Background
Andersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported.
Objectives
This study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1.
Methods
Clinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis.
Results
We enrolled 118 patients with ATS1 from 57 families (age 23 ± 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p < 0.001). The rate of LAE without therapy (1.24 per 100 person-years [py]) was not reduced by beta-blockers alone (1.37 per 100 py; p = 1.00), or in combination with Class Ic antiarrhythmic drugs (1.46 per 100 py, p = 1.00).
Conclusions
Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 20 Apr 2020; 75:1772-1784
Mazzanti A, Guz D, Trancuccio A, Pagan E, ... Bagnardi V, Priori SG
J Am Coll Cardiol: 20 Apr 2020; 75:1772-1784 | PMID: 32299589
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Abstract

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

Grein J, Ohmagari N, Shin D, Diaz G, ... Childs R, Flanigan T
Background
Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2.
Methods
We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.
Results
Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.
Conclusions
In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 09 Apr 2020; epub ahead of print
Grein J, Ohmagari N, Shin D, Diaz G, ... Childs R, Flanigan T
N Engl J Med: 09 Apr 2020; epub ahead of print | PMID: 32275812
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Abstract

Progression of ultrasound plaque attenuation and low echogenicity associates with major adverse cardiovascular events.

Shishikura D, Kataoka Y, Di Giovanni G, Takata K, ... Nissen SE, Nicholls SJ
Aims 
Intravascular ultrasound (IVUS) imaging can visualize vulnerable plaque features including attenuation (AP) and echolucency (ELP). While IVUS-derived vulnerable plaque features associate with microvascular obstruction during percutaneous coronary intervention, the relationship between these plaque features and clinical outcomes has not been established. This analysis aimed to evaluate the association of AP/ELP with cardiovascular events.
Methods and results 
Serial IVUS imaging was reviewed in 1497 patients, followed for 18-24 months, with coronary artery disease from two clinical trials. Attenuated plaque and ELP were identified to measure each characteristics (AP arc, ELP area, and lengths), which permitted calculation of an AP index (API) and ELP volume. Attenuated plaque/ELP progression was defined as patients with any increase of API or ELP volume on serial imaging. The major cardiovascular events (MACEs) were defined as death, myocardial infarction, stroke, and coronary revascularization. AP or ELP was identified in 282 patients (18.8%) at baseline and 160 (10.7%) patients demonstrated an increase in AP or ELP at follow-up. The incidence of MACE was higher in patients with baseline AP/ELP than those without (8.2% vs. 3.9%, P = 0.002). Patients with AP/ELP progression were more likely to be acute coronary syndrome (41.9 vs. 33.2%, P = 0.03) and have greater baseline percent atheroma volume (40.0% vs. 35.8%, P < 0.001) than those without. On multivariable analysis, AP/ELP progression was more strongly associated with MACE [baseline AP/ELP: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.05-2.97, AP/ELP progression: HR 2.19, 95% CI 1.24-3.86].
Conclusion 
Attenuation/ELP progression was associated with a higher prevalence of cardiovascular events, supporting a potential role for the identification of high-risk vulnerable plaques in patients with coronary artery disease.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 02 Apr 2020; epub ahead of print
Shishikura D, Kataoka Y, Di Giovanni G, Takata K, ... Nissen SE, Nicholls SJ
Eur Heart J: 02 Apr 2020; epub ahead of print | PMID: 32243512
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Abstract

Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease.

Spertus JA, Jones PG, Maron DJ, O\'Brien SM, ... Mark DB,
Background
In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients.
Methods
We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency.
Results
At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina).
Conclusions
In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Mar 2020; epub ahead of print
Spertus JA, Jones PG, Maron DJ, O'Brien SM, ... Mark DB,
N Engl J Med: 29 Mar 2020; epub ahead of print | PMID: 32227753
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Abstract

Hyperacute Management of Ischemic Strokes: JACC Focus Seminar.

Patel P, Yavagal D, Khandelwal P

Acute ischemic stroke is the leading cause of disability and among the leading causes of mortality worldwide. Intravenous tissue plasminogen activator has been a cornerstone for treatment of acute ischemic stroke for more than 20 years; however, its use is limited due to a narrow therapeutic window, several contraindications, and low efficacy to recanalize the artery in large vessel occlusion. Recently, the addition of endovascular mechanical thrombectomy of large artery occlusion has revolutionized the stroke treatment for most disabling strokes. The paper reviews updates to the thrombolytic treatment as well as catheter-based treatment, and results from recent trials in the selection of patients in an extended time window using perfusion imaging.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Apr 2020; 75:1844-1856
Patel P, Yavagal D, Khandelwal P
J Am Coll Cardiol: 20 Apr 2020; 75:1844-1856 | PMID: 32299596
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Abstract

Management of Intracerebral Hemorrhage: JACC Focus Seminar.

Schrag M, Kirshner H

Intracerebral hemorrhage (ICH) accounts for a disproportionate amount of stroke-related morbidity and mortality. Although chronic hypertension and cerebral amyloid angiopathy are the underlying cerebral vasculopathies accounting for the majority of ICH, there are a broad range of potential causes, and effective management requires accurate identification and treatment of the underlying mechanism of hemorrhage. Magnetic resonance imaging and vascular imaging techniques play a critical role in identifying disease mechanisms. Modern treatment of ICH focuses on rapid stabilization, often requiring urgent treatment of mass effect, aggressive blood pressure reduction and correction of contributing coagulopathies to achieve hemostasis. We discuss management of patients with ICH who continue to require long-term anticoagulation, the interaction of ICH with neurodegenerative diseases, and our approach to prognostication after ICH. We close this review with a discussion of novel medical and surgical approaches to ICH treatment that are being tested in clinical trials.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Apr 2020; 75:1819-1831
Schrag M, Kirshner H
J Am Coll Cardiol: 20 Apr 2020; 75:1819-1831 | PMID: 32299594
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Abstract

Health Status after Invasive or Conservative Care in Coronary and Advanced Kidney Disease.

Spertus JA, Jones PG, Maron DJ, Mark DB, ... Bangalore S,
Background
In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of <30 ml per minute per 1.73 m or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status.
Methods
We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy.
Results
Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, -0.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, -2.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, -1.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, -2.2 to 3.4).
Conclusions
Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy. (Funded by the National Heart, Lung, and Blood Institute; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Mar 2020; epub ahead of print
Spertus JA, Jones PG, Maron DJ, Mark DB, ... Bangalore S,
N Engl J Med: 29 Mar 2020; epub ahead of print | PMID: 32227754
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Abstract

Transvalvular Flow Rate Determines Prognostic Value of Aortic Valve Area in Aortic Stenosis.

Namasivayam M, He W, Churchill TW, Capoulade R, ... Levine RA, Hung J
Background
Aortic valve area (AVA) ≤1.0 cm is a defining characteristic of severe aortic stenosis (AS). AVA can be underestimated at low transvalvular flow rate. Yet, the impact of flow rate on prognostic value of AVA ≤1.0 cm is unknown and is not incorporated into AS assessment.
Objectives
This study aimed to evaluate the effect of flow rate on prognostic value of AVA in AS.
Methods
In total, 1,131 patients with moderate or severe AS and complete clinical follow-up were included as part of a longitudinal database. The effect of flow rate (ratio of stroke volume to ejection time) on prognostic value of AVA ≤1.0 cm for time to death was evaluated, adjusting for confounders. Sensitivity analysis was performed to identify the optimal cutoff for prognostic threshold of AVA. The findings were validated in a separate external longitudinal cohort of 939 patients.
Results
Flow rate had a significant effect on prognostic value of AVA. AVA ≤1.0 cm was not prognostic for mortality (p = 0.15) if AVA was measured at flow rates below median (≤242 ml/s). In contrast, AVA ≤1.0 cm was highly prognostic for mortality (p = 0.003) if AVA was measured at flow rates above median (>242 ml/s). Findings were irrespective of multivariable adjustment for age, sex, and surgical/transcatheter aortic valve replacement (as time-dependent covariates); comorbidities; medications; and echocardiographic features. AVA ≤1.0 cm was also not an independent predictor of mortality below median flow rate in the validation cohort. The optimal flow rate cutoff for prognostic threshold was 210 ml/s.
Conclusions
Transvalvular flow rate determines prognostic value of AVA in AS. AVA measured at low flow rate is not a good prognostic marker and therefore not a good diagnostic marker for truly severe AS. Flow rate assessment should be incorporated into clinical diagnosis, classification, and prognosis of AS.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Apr 2020; 75:1758-1769
Namasivayam M, He W, Churchill TW, Capoulade R, ... Levine RA, Hung J
J Am Coll Cardiol: 20 Apr 2020; 75:1758-1769 | PMID: 32299587
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Abstract

Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial.

Ridker PM, MacFadyen JG, Glynn RJ, Bradwin G, Hasan AA, Rifai N
Aims
In epidemiologic cohorts initiated >30 years ago, inflammatory biomarkers, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were shown to independently predict future cardiovascular events with a magnitude of effect comparable to that of low-density lipoprotein cholesterol (LDLC). Whether aggressive contemporary therapy for atherosclerosis has altered these relationships is unknown yet has major implications for future drug development.
Methods and results
Interleukin-6, hsCRP, and LDLC were measured at baseline in up to 4168 North American patients enrolled in the contemporary Cardiovascular Inflammation Reduction Trial with prior myocardial infarction or multivessel coronary disease who additionally had diabetes or metabolic syndrome and were followed for a period of up to 5 years for incident major recurrent cardiovascular events and all-cause mortality. Three-quarters of the cohort were previously revascularized and the great majority was taking statins, angiotensin blocking agents, beta-blockers, and antithrombotic agents. Participants were randomly allocated to low-dose methotrexate 15 mg weekly or to placebo. Randomized use of methotrexate had no effect on event rates nor plasma levels of IL-6, hsCRP, or LDL over time. Yet, baseline levels of IL-6, hsCRP, and LDLC were all predictors of major recurrent cardiovascular events; adjusted hazard ratios [HR; 95% confidence interval (CI)] for the lowest to highest baseline quartiles of IL-6 were 1.0 (referent), 1.66 (1.18-2.35), 1.92 (1.36-2.70), and 2.11 (1.49-2.99; P < 0.0001), while adjusted HRs for increasing quartiles of hsCRP were 1.0 (referent), 1.28 (0.92-1.79), 1.73 (1.25-2.38), and 1.79 (1.28-2.50; P < 0.0001) and adjusted HRs for increasing quartiles of LDLC were 1.0 (referent), 1.12 (0.78-1.62), 1.25 (0.87-1.79), and 2.38 (1.72-3.30; P < 0.0001). Effect estimates were not statistically different in these analyses for comparisons between IL-6, hsCRP, or LDLC, although IL-6 was the strongest predictor of all-cause mortality. The highest absolute risks were observed among those with elevated levels of both cholesterol and inflammation [HR 6.4 (95% CI 2.9-14.1) for those in the top quartiles of baseline IL-6 and LDLC, HR 4.9 (95% CI 2.6-9.4) for those in the top quartiles of baseline hsCRP and LDLC, both P < 0.0001].
Conclusion
Despite aggressive contemporary secondary prevention efforts, the relationships between inflammation, cholesterol, and cardiovascular risk are largely unchanged from those described two decades ago. These data are consistent with the hypothesis that future treatments for atherosclerosis may require a combination of inflammation inhibition and additional cholesterol reduction.
Clinical trial
ClinicalTrials.gov NCT01594333.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 27 Mar 2020; epub ahead of print
Ridker PM, MacFadyen JG, Glynn RJ, Bradwin G, Hasan AA, Rifai N
Eur Heart J: 27 Mar 2020; epub ahead of print | PMID: 32221587
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Abstract

Triglycerides and remnant cholesterol associated with risk of aortic valve stenosis: Mendelian randomization in the Copenhagen General Population Study.

Kaltoft M, Langsted A, Nordestgaard BG
Aims
We tested the hypothesis that higher levels of plasma triglycerides and remnant cholesterol are observationally and genetically associated with increased risk of aortic valve stenosis.
Methods and results
We included 108 559 individuals from the Copenhagen General Population Study. Plasma triglycerides, remnant cholesterol (total cholesterol minus low-density lipoprotein and high-density lipoprotein cholesterol), and 16 genetic variants causing such increased or decreased levels were determined. Incident aortic valve stenosis occurred in 1593 individuals. Observationally compared to individuals with triglycerides <1 mmol/L (<89 mg/dL), the multifactorially adjusted hazard ratio for aortic valve stenosis was 1.02 [95% confidence interval (CI) 0.87-1.19] for individuals with triglycerides of 1.0-1.9 mmol/L (89-176 mg/dL), 1.22 (1.02-1.46) for 2.0-2.9 mmol/L (177-265 mg/dL), 1.40 (1.11-1.77) for 3.0-3.9 mmol/L (266-353 mg/dL), 1.29 (0.88-1.90) for 4.0-4.9 mmol/L (354-442 mg/dL), and 1.52 (1.02-2.27) for individuals with triglycerides ≥5 mmol/L (≥443 mg/dL). By age 85, the cumulative incidence of aortic valve stenosis was 5.1% for individuals with plasma triglycerides <2.0 mmol/L (77 mg/dL), 6.5% at 2.0-4.9 mmol/L (177-442 mg/dL), and 8.2% for individuals with plasma triglycerides ≥5.0 mmol/L (443 mg/dL). The corresponding values for remnant cholesterol categories were 4.8% for <0.5 mmol/L (19 mg/dL), 5.6% for 0.5-1.4 mmol/L (19-57 mg/dL), and 7.4% for ≥1.5 mmol/L (58 mg/dL). Genetically, compared to individuals with allele score 13-16, odds ratios for aortic valve stenosis were 1.30 (95% CI 1.20-1.42; Δtriglycerides +12%; Δremnant cholesterol +11%) for allele score 17-18, 1.41 (1.31-1.52; +25%; +22%) for allele score 19-20, and 1.51 (1.22-1.86; +51%; +44%) for individuals with allele score 21-23.
Conclusion
Higher triglycerides and remnant cholesterol were observationally and genetically associated with increased risk of aortic valve stenosis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 07 Apr 2020; epub ahead of print
Kaltoft M, Langsted A, Nordestgaard BG
Eur Heart J: 07 Apr 2020; epub ahead of print | PMID: 32267934
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Abstract

2019 vs. 2016 ESC/EAS statin guidelines for primary prevention of atherosclerotic cardiovascular disease.

Mortensen MB, Nordestgaard BG
Aims 
The 2019 vs. 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidaemia guidelines contains new recommendations for primary prevention with statins; however, the potential impact of these changes is unclear. We compared the 2019 and 2016 guidelines regarding statin eligibility and potential impact on prevention of atherosclerotic cardiovascular disease (ASCVD) in the general population.
Methods and results 
We examined 45 750 individuals aged 40-75 from the Copenhagen General Population Study, all free of ASCVD and statin use at baseline. During the 9.2-year follow-up, 3337 experienced ASCVD (myocardial infarction, stroke, and cardiovascular death). For Class I/A recommendations, 32.3% (95% confidence interval: 31.8-32.7) and 15.4% (15.1-15.7) of individuals were statin eligible according to the 2019 and 2016 guidelines. The increased statin eligibility by the 2019 guidelines was explained by lower low-density lipoprotein cholesterol (LDL-C) thresholds alone (explaining 33.2%), older age range alone (49.4%), older age range in combination with lower LDL-C thresholds (14.7%), and updated SCORE risk algorithm (2.8%). If fully implemented, the estimated percentage of ASCVD events that can be prevented by using high-intensity statins for 10 years were 25% and 11% with the 2019 and 2016 guidelines. Mainly because of older age range in the 2019 guidelines, the corresponding estimated numbers needed to treat (NNT) to prevent one ASCVD event were 19 and 20.
Conclusion 
Due to lower LDL-C threshold and older age range, the 2019 vs. 2016 ESC/EAS guidelines doubles the number of individuals eligible for primary prevention with statins. This considerably improves the potential for ASCVD prevention in the general population, with similar NNT to prevent one event.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 29 Mar 2020; epub ahead of print
Mortensen MB, Nordestgaard BG
Eur Heart J: 29 Mar 2020; epub ahead of print | PMID: 32227172
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Abstract

Epidemiology of Covid-19 in a Long-Term Care Facility in King County, Washington.

McMichael TM, Currie DW, Clark S, Pogosjans S, ... Clark TA, Duchin JS
Background
Long-term care facilities are high-risk settings for severe outcomes from outbreaks of Covid-19, owing to both the advanced age and frequent chronic underlying health conditions of the residents and the movement of health care personnel among facilities in a region.
Methods
After identification on February 28, 2020, of a confirmed case of Covid-19 in a skilled nursing facility in King County, Washington, Public Health-Seattle and King County, aided by the Centers for Disease Control and Prevention, launched a case investigation, contact tracing, quarantine of exposed persons, isolation of confirmed and suspected cases, and on-site enhancement of infection prevention and control.
Results
As of March 18, a total of 167 confirmed cases of Covid-19 affecting 101 residents, 50 health care personnel, and 16 visitors were found to be epidemiologically linked to the facility. Most cases among residents included respiratory illness consistent with Covid-19; however, in 7 residents no symptoms were documented. Hospitalization rates for facility residents, visitors, and staff were 54.5%, 50.0%, and 6.0%, respectively. The case fatality rate for residents was 33.7% (34 of 101). As of March 18, a total of 30 long-term care facilities with at least one confirmed case of Covid-19 had been identified in King County.
Conclusions
In the context of rapidly escalating Covid-19 outbreaks, proactive steps by long-term care facilities to identify and exclude potentially infected staff and visitors, actively monitor for potentially infected patients, and implement appropriate infection prevention and control measures are needed to prevent the introduction of Covid-19.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 Mar 2020; epub ahead of print
McMichael TM, Currie DW, Clark S, Pogosjans S, ... Clark TA, Duchin JS
N Engl J Med: 26 Mar 2020; epub ahead of print | PMID: 32220208
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Abstract

A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity.

Kelly AS, Auerbach P, Barrientos-Perez M, Gies I, ... Arslanian S,
Background
Obesity is a chronic disease with limited treatment options in pediatric patients. Liraglutide may be useful for weight management in adolescents with obesity.
Methods
In this randomized, double-blind trial, which consisted of a 56-week treatment period and a 26-week follow-up period, we enrolled adolescents (12 to <18 years of age) with obesity and a poor response to lifestyle therapy alone. Participants were randomly assigned (1:1) to receive either liraglutide (3.0 mg) or placebo subcutaneously once daily, in addition to lifestyle therapy. The primary end point was the change from baseline in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) standard-deviation score at week 56.
Results
A total of 125 participants were assigned to the liraglutide group and 126 to the placebo group. Liraglutide was superior to placebo with regard to the change from baseline in the BMI standard-deviation score at week 56 (estimated difference, -0.22; 95% confidence interval [CI], -0.37 to -0.08; P = 0.002). A reduction in BMI of at least 5% was observed in 51 of 113 participants in the liraglutide group and in 20 of 105 participants in the placebo group (estimated percentage, 43.3% vs. 18.7%), and a reduction in BMI of at least 10% was observed in 33 and 9, respectively (estimated percentage, 26.1% vs. 8.1%). A greater reduction was observed with liraglutide than with placebo for BMI (estimated difference, -4.64 percentage points) and for body weight (estimated difference, -4.50 kg [for absolute change] and -5.01 percentage points [for relative change]). After discontinuation, a greater increase in the BMI standard-deviation score was observed with liraglutide than with placebo (estimated difference, 0.15; 95% CI, 0.07 to 0.23). More participants in the liraglutide group than in the placebo group had gastrointestinal adverse events (81 of 125 [64.8%] vs. 46 of 126 [36.5%]) and adverse events that led to discontinuation of the trial treatment (13 [10.4%] vs. 0). Few participants in either group had serious adverse events (3 [2.4%] vs. 5 [4.0%]). One suicide, which occurred in the liraglutide group, was assessed by the investigator as unlikely to be related to the trial treatment.
Conclusions
In adolescents with obesity, the use of liraglutide (3.0 mg) plus lifestyle therapy led to a significantly greater reduction in the BMI standard-deviation score than placebo plus lifestyle therapy. (Funded by Novo Nordisk; NN8022-4180 ClinicalTrials.gov number, NCT02918279.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 30 Mar 2020; epub ahead of print
Kelly AS, Auerbach P, Barrientos-Perez M, Gies I, ... Arslanian S,
N Engl J Med: 30 Mar 2020; epub ahead of print | PMID: 32233338
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Abstract

Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a).

Stiekema LCA, Prange KHM, Hoogeveen RM, Verweij SL, ... de Winther MPJ, Bahjat M
Aims
Elevated lipoprotein(a) [Lp(a)] is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a).
Methods and results
Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) [apo(a)] antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (-17%, P < 0.001). In contrast, PCSK9ab treatment lowered Lp(a) by 16% and did not alter transcriptome nor functional properties of monocytes, despite an additional reduction of 65% in low-density lipoprotein cholesterol (LDL-C).
Conclusion
Potent Lp(a)-lowering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 07 Apr 2020; epub ahead of print
Stiekema LCA, Prange KHM, Hoogeveen RM, Verweij SL, ... de Winther MPJ, Bahjat M
Eur Heart J: 07 Apr 2020; epub ahead of print | PMID: 32268367
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Abstract

Diabetic Agents, From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists: JACC Focus Seminar.

Wilcox T, De Block C, Schwartzbard AZ, Newman JD

Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of pharmacologic agents used to treat patients with type 2 diabetes.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Apr 2020; 75:1956-1974
Wilcox T, De Block C, Schwartzbard AZ, Newman JD
J Am Coll Cardiol: 27 Apr 2020; 75:1956-1974 | PMID: 32327107
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Abstract

Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery.

Samama CM, Laporte S, Rosencher N, Girard P, ... Mismetti P,
Background
Nonmajor orthopedic surgery of the lower limbs that results in transient reduced mobility places patients at risk for venous thromboembolism. Rivaroxaban may be noninferior to enoxaparin with regard to the prevention of major venous thromboembolism in these patients.
Methods
In this international, parallel-group, randomized, double-blind, noninferiority trial, we randomly assigned adult patients undergoing lower-limb nonmajor orthopedic surgery who were considered to be at risk for venous thromboembolism on the basis of the investigator\'s judgment to receive either rivaroxaban or enoxaparin. The primary efficacy outcome of major venous thromboembolism was a composite of symptomatic distal or proximal deep-vein thrombosis, pulmonary embolism, or venous thromboembolism-related death during the treatment period or asymptomatic proximal deep-vein thrombosis at the end of treatment. A test for superiority was planned if rivaroxaban proved to be noninferior to enoxaparin. For all outcomes, multiple imputation was used to account for missing data. Prespecified safety outcomes included major bleeding (fatal, critical, or clinically overt bleeding or bleeding at the surgical site leading to intervention) and nonmajor clinically relevant bleeding.
Results
A total of 3604 patients underwent randomization; 1809 patients were assigned to receive rivaroxaban, and 1795 to receive enoxaparin. Major venous thromboembolism occurred in 4 of 1661 patients (0.2%) in the rivaroxaban group and in 18 of 1640 patients (1.1%) in the enoxaparin group (risk ratio with multiple imputation, 0.25; 95% confidence interval, 0.09 to 0.75; P<0.001 for noninferiority; P = 0.01 for superiority). The incidence of bleeding did not differ significantly between the rivaroxaban group and the enoxaparin group (1.1% and 1.0%, respectively, for major bleeding or nonmajor clinically relevant bleeding; 0.6% and 0.7%, respectively, for major bleeding).
Conclusions
Rivaroxaban was more effective than enoxaparin in the prevention of venous thromboembolic events during a period of immobilization after nonmajor orthopedic surgery of the lower limbs. (Funded by Centre Hospitalier Universitaire de Saint-Etienne and Bayer; PRONOMOS ClinicalTrials.gov number, NCT02401594.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 Mar 2020; epub ahead of print
Samama CM, Laporte S, Rosencher N, Girard P, ... Mismetti P,
N Engl J Med: 28 Mar 2020; epub ahead of print | PMID: 32223113
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Abstract

Covid-19 in Critically Ill Patients in the Seattle Region - Case Series.

Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, ... O\'Mahony S, Mikacenic C
Background
Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020.
Methods
We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up.
Results
We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63% were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58% had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU.
Conclusions
During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Mar 2020; epub ahead of print
Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, ... O'Mahony S, Mikacenic C
N Engl J Med: 29 Mar 2020; epub ahead of print | PMID: 32227758
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Abstract

Spread of SARS-CoV-2 in the Icelandic Population.

Gudbjartsson DF, Helgason A, Jonsson H, Magnusson OT, ... Thorsteinsdottir U, Stefansson K
Background
During the current worldwide pandemic, coronavirus disease 2019 (Covid-19) was first diagnosed in Iceland at the end of February. However, data are limited on how SARS-CoV-2, the virus that causes Covid-19, enters and spreads in a population.
Methods
We targeted testing to persons living in Iceland who were at high risk for infection (mainly those who were symptomatic, had recently traveled to high-risk countries, or had contact with infected persons). We also carried out population screening using two strategies: issuing an open invitation to 10,797 persons and sending random invitations to 2283 persons. We sequenced SARS-CoV-2 from 643 samples.
Results
As of April 4, a total of 1221 of 9199 persons (13.3%) who were recruited for targeted testing had positive results for infection with SARS-CoV-2. Of those tested in the general population, 87 (0.8%) in the open-invitation screening and 13 (0.6%) in the random-population screening tested positive for the virus. In total, 6% of the population was screened. Most persons in the targeted-testing group who received positive tests early in the study had recently traveled internationally, in contrast to those who tested positive later in the study. Children under 10 years of age were less likely to receive a positive result than were persons 10 years of age or older, with percentages of 6.7% and 13.7%, respectively, for targeted testing; in the population screening, no child under 10 years of age had a positive result, as compared with 0.8% of those 10 years of age or older. Fewer females than males received positive results both in targeted testing (11.0% vs. 16.7%) and in population screening (0.6% vs. 0.9%). The haplotypes of the sequenced SARS-CoV-2 viruses were diverse and changed over time. The percentage of infected participants that was determined through population screening remained stable for the 20-day duration of screening.
Conclusions
In a population-based study in Iceland, children under 10 years of age and females had a lower incidence of SARS-CoV-2 infection than adolescents or adults and males. The proportion of infected persons identified through population screening did not change substantially during the screening period, which was consistent with a beneficial effect of containment efforts. (Funded by deCODE Genetics-Amgen.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 13 Apr 2020; epub ahead of print
Gudbjartsson DF, Helgason A, Jonsson H, Magnusson OT, ... Thorsteinsdottir U, Stefansson K
N Engl J Med: 13 Apr 2020; epub ahead of print | PMID: 32289214
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Abstract

Rivaroxaban in Peripheral Artery Disease after Revascularization.

Bonaca MP, Bauersachs RM, Anand SS, Debus ES, ... Berkowitz SD, Hiatt WR
Background
Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and safety of rivaroxaban in this context are uncertain.
Methods
In a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification; major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) was a secondary safety outcome.
Results
A total of 6564 patients underwent randomization; 3286 were assigned to the rivaroxaban group, and 3278 were assigned to the placebo group. The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and in 584 in the placebo group; the Kaplan-Meier estimates of the incidence at 3 years were 17.3% and 19.9%, respectively (hazard ratio, 0.85, 95% confidence interval [CI], 0.76 to 0.96; P = 0.009). TIMI major bleeding occurred in 62 patients in the rivaroxaban group and in 44 patients in the placebo group (2.65% and 1.87%; hazard ratio, 1.43; 95% CI, 0.97 to 2.10; P = 0.07). ISTH major bleeding occurred in 140 patients in the rivaroxaban group, as compared with 100 patients in the placebo group (5.94% and 4.06%; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P = 0.007).
Conclusions
In patients with peripheral artery disease who had undergone lower-extremity revascularization, rivaroxaban at a dose of 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes than aspirin alone. The incidence of TIMI major bleeding did not differ significantly between the groups. The incidence of ISTH major bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone. (Funded by Bayer and Janssen Pharmaceuticals; VOYAGER PAD ClinicalTrials.gov number, NCT02504216.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 Mar 2020; epub ahead of print
Bonaca MP, Bauersachs RM, Anand SS, Debus ES, ... Berkowitz SD, Hiatt WR
N Engl J Med: 27 Mar 2020; epub ahead of print | PMID: 32222135
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