Topic: Heart Failure

Abstract

Early Surgery or Conservative Care for Asymptomatic Aortic Stenosis.

Kang DH, Park SJ, Lee SA, Lee S, ... Lee JW, Park SW
Background
The timing and indications for surgical intervention in asymptomatic patients with severe aortic stenosis remain controversial.
Methods
In a multicenter trial, we randomly assigned 145 asymptomatic patients with very severe aortic stenosis (defined as an aortic-valve area of ≤0.75 cm with either an aortic jet velocity of ≥4.5 m per second or a mean transaortic gradient of ≥50 mm Hg) to early surgery or to conservative care according to the recommendations of current guidelines. The primary end point was a composite of death during or within 30 days after surgery (often called operative mortality) or death from cardiovascular causes during the entire follow-up period. The major secondary end point was death from any cause during follow-up.
Results
In the early-surgery group, 69 of 73 patients (95%) underwent surgery within 2 months after randomization, and there was no operative mortality. In an intention-to-treat analysis, a primary end-point event occurred in 1 patient in the early-surgery group (1%) and in 11 of 72 patients in the conservative-care group (15%) (hazard ratio, 0.09; 95% confidence interval [CI], 0.01 to 0.67; P = 0.003). Death from any cause occurred in 5 patients in the early-surgery group (7%) and in 15 patients in the conservative-care group (21%) (hazard ratio, 0.33; 95% CI, 0.12 to 0.90). In the conservative-care group, the cumulative incidence of sudden death was 4% at 4 years and 14% at 8 years.
Conclusions
Among asymptomatic patients with very severe aortic stenosis, the incidence of the composite of operative mortality or death from cardiovascular causes during the follow-up period was significantly lower among those who underwent early aortic-valve replacement surgery than among those who received conservative care. (Funded by the Korean Institute of Medicine; RECOVERY ClinicalTrials.gov number, NCT01161732.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 08 Jan 2020; 382
Kang DH, Park SJ, Lee SA, Lee S, ... Lee JW, Park SW
N Engl J Med: 08 Jan 2020; 382 | PMID: 31733181
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.

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

J Am Coll Cardiol: 10 Feb 2020; 75:525-538
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:525-538 | PMID: 32029136
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Utilization and Outcomes of Measuring Fractional Flow Reserve in Patients With Stable Ischemic Heart Disease.

Parikh RV, Liu G, Plomondon ME, Sehested TSG, ... Waldo SW, Fearon WF
Background
The use and clinical outcomes of fractional flow reserve (FFR) measurement in patients with stable ischemic heart disease (SIHD) are uncertain, as prior studies have been based on selected populations.
Objectives
This study sought to evaluate contemporary, real-world patterns of FFR use and its effect on outcomes among unselected patients with SIHD and angiographically intermediate stenoses.
Methods
The authors used data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) Program to analyze patients who underwent coronary angiography between January 1, 2009, and September 30, 2017, and had SIHD with angiographically intermediate disease (40% to 69% diameter stenosis on visual inspection). The authors documented trends in FFR utilization and evaluated predictors using generalized mixed models. They applied Cox proportional hazards models to determine the association between an FFR-guided revascularization strategy and all-cause mortality at 1 year.
Results
A total of 17,989 patients at 66 sites were included. The rate of FFR use gradually increased from 14.8% to 18.5% among all patients with intermediate lesions, and from 44% to 75% among patients who underwent percutaneous coronary intervention. One-year mortality was 2.8% in the FFR group and 5.9% in the angiography-only group (p < 0.0001). After adjustment for patient, site-level, and procedural factors, FFR-guided revascularization was associated with a 43% lower risk of mortality at 1 year compared with angiography-only revascularization (hazard ratio: 0.57; 95% confidence interval: 0.45 to 0.71; p < 0.0001).
Conclusions
In patients with SIHD and angiographically intermediate stenoses, use of FFR has slowly risen, and was associated with significantly lower 1-year mortality.

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

J Am Coll Cardiol: 03 Feb 2020; 75:409-419
Parikh RV, Liu G, Plomondon ME, Sehested TSG, ... Waldo SW, Fearon WF
J Am Coll Cardiol: 03 Feb 2020; 75:409-419 | PMID: 32000953
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Incident Heart Failure and Long-Term Risk for Venous Thromboembolism.

Fanola CL, Norby FL, Shah AM, Chang PP, ... Cushman M, Folsom AR
Background
Heart failure (HF) hospitalization places patients at increased short-term risk for venous thromboembolism (VTE). Long-term risk for VTE associated with incident HF, HF subtypes, or structural heart disease is unknown.
Objectives
In the ARIC (Atherosclerosis Risk In Communities) cohort, VTE risk associated with incident HF, HF subtypes, and abnormal echocardiographic measures in the absence of clinical HF was assessed.
Methods
During follow-up, ARIC identified incident HF and subcategorized HF with preserved ejection fraction or reduced ejection fraction. At the fifth clinical examination, echocardiography was performed. Physicians adjudicated incident VTE using hospital records. Adjusted Cox proportional hazards models were used to evaluate the association between HF or echocardiographic exposures and VTE.
Results
Over a mean of 22 years in 13,728 subjects, of whom 2,696 (20%) developed incident HF, 729 subsequent VTE events were identified. HF was associated with increased long-term risk for VTE (adjusted hazard ratio: 3.13; 95% confidence interval: 2.58 to 3.80). In 7,588 subjects followed for a mean of 10 years, the risk for VTE was similar for HF with preserved ejection fraction (adjusted hazard ratio: 4.71; 95% CI: 2.94 to 7.52) and HF with reduced ejection fraction (adjusted hazard ratio: 5.53; 95% confidence interval: 3.42 to 8.94). In 5,438 subjects without HF followed for a mean of 3.5 years, left ventricular relative wall thickness and mean left ventricular wall thickness were independent predictors of VTE.
Conclusions
In this prospective population-based study, incident hospitalized HF (including both heart failure with preserved ejection fraction and reduced ejection fraction), as well as echocardiographic indicators of left ventricular remodeling, were associated with greatly increased risk for VTE, which persisted through long-term follow-up. Evidence-based strategies to prevent long-term VTE in patients with HF, beyond time of hospitalization, are needed.

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

J Am Coll Cardiol: 20 Jan 2020; 75:148-158
Fanola CL, Norby FL, Shah AM, Chang PP, ... Cushman M, Folsom AR
J Am Coll Cardiol: 20 Jan 2020; 75:148-158 | PMID: 31948643
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Pittsburgh B Compound Positron Emission Tomography in Patients With AL Cardiac Amyloidosis.

Lee SP, Suh HY, Park S, Oh S, ... Paeng JC, Sohn DW
Background
It remains unknown whether the noninvasive evaluation of the degree of amyloid deposition in the myocardium can predict the prognosis of patients with light chain (AL) cardiac amyloidosis.
Objectives
The purpose of this study was to demonstrate that C-Pittsburgh B compound positron emission tomography (C-PiB PET) is useful for prognostication of AL cardiac amyloidosis by noninvasively imaging the myocardial AL amyloid deposition.
Methods
This study consecutively enrolled 41 chemotherapy-naïve AL cardiac amyloidosis patients. The amyloid deposit was quantitatively assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial C-PiB uptake on PET. The primary endpoint was a composite of all-cause death, heart transplantation, and acute decompensated heart failure.
Results
The degree of myocardial C-PiB PET uptake was significantly higher in the cardiac amyloidosis patients compared with normal subjects and correlated well with the degree of amyloid deposit on histology (R = 0.343, p < 0.001). During follow-up (median: 423 days, interquartile range: 93 to 1,222 days), 24 patients experienced the primary endpoint. When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p = 0.014). The degree of myocardial PiB PET uptake was a significant predictor of clinical outcome on multivariate Cox regression analysis (adjusted hazard ratio: 1.185; 95% confidence interval: 1.054 to 1.332; p = 0.005).
Conclusions
These proof-of-concept results show that noninvasive evaluation of myocardial amyloid load by C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in AL cardiac amyloidosis patients.

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

J Am Coll Cardiol: 03 Feb 2020; 75:380-390
Lee SP, Suh HY, Park S, Oh S, ... Paeng JC, Sohn DW
J Am Coll Cardiol: 03 Feb 2020; 75:380-390 | PMID: 32000949
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review.

Zelniker TA, Braunwald E

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class approved for treatment of diabetes, have been shown to possess a favorable metabolic profile and to significantly reduce atherosclerotic events, hospitalization for heart failure, cardiovascular and total mortality, and progression of chronic kidney disease. Although initially considered to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. It is therefore critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with this drug class. This first part of this 2-part review provides an overview of the current understanding of the mechanisms of the cardio-metabolic-renal benefits of SGLT2i. The second part summarizes the recent clinical trials of SGLT2i.

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

J Am Coll Cardiol: 03 Feb 2020; 75:422-434
Zelniker TA, Braunwald E
J Am Coll Cardiol: 03 Feb 2020; 75:422-434 | PMID: 32000955
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A Contemporary Picture of Enterococcal Endocarditis.

Pericàs JM, Llopis J, Muñoz P, Gálvez-Acebal J, ... Miró JM,
Background
Enterococcal endocarditis (EE) is a growing entity in Western countries. However, quality data from large studies is lacking.
Objectives
The purpose of this study was to describe the characteristics and analyze the prognostic factors of EE in the GAMES cohort.
Methods
This was a post hoc analysis of a prospectively collected cohort of patients from 35 Spanish centers from 2008 to 2016. Characteristics and outcomes of 516 cases of EE were compared with those of 3,308 cases of nonenterococcal endocarditis (NEE). Logistic regression and Cox proportional hazards regression analysis were performed to investigate risk factors for in-hospital and 1-year mortality, as well as relapses.
Results
Patients with EE were significantly older; more frequently presented chronic lung disease, chronic heart failure, prior endocarditis, and degenerative valve disease; and had higher median age-adjusted Charlson score. EE more frequently involved the aortic valve and prosthesis (64.3% vs. 46.7%; p < 0.001; and 35.9% vs. 28.9%; p = 0.002, respectively) but less frequently pacemakers/defibrillators (1.5% vs. 10.5%; p < 0.001), and showed higher rates of acute heart failure (45% vs. 38.3%; p = 0.005). Cardiac surgery was less frequently performed in EE (40.7% vs. 45.9%; p = 0.024). No differences in in-hospital and 1-year mortality were found, whereas relapses were significantly higher in EE (3.5% vs. 1.7%; p = 0.035). Increasing Charlson score, LogEuroSCORE, acute heart failure, septic shock, and paravalvular complications were risk factors for mortality, whereas prior endocarditis was protective and persistent bacteremia constituted the sole risk factor for relapse.
Conclusions
Besides other baseline and clinical differences, EE more frequently affects prosthetic valves and less frequently pacemakers/defibrillators. EE presents higher rates of relapse than NEE.

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

J Am Coll Cardiol: 10 Feb 2020; 75:482-494
Pericàs JM, Llopis J, Muñoz P, Gálvez-Acebal J, ... Miró JM,
J Am Coll Cardiol: 10 Feb 2020; 75:482-494 | PMID: 32029130
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes.

Carew AS, Levy AP, Ginsberg HN, Coca S, ... Gardner M, Cahill LE
Background
Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia.
Objectives
This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype.
Methods
Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers).
Results
Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908).
Conclusions
Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.

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

J Am Coll Cardiol: 10 Feb 2020; 75:512-521
Carew AS, Levy AP, Ginsberg HN, Coca S, ... Gardner M, Cahill LE
J Am Coll Cardiol: 10 Feb 2020; 75:512-521 | PMID: 32029134
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiometabolic-Based Chronic Disease, Addressing Knowledge and Clinical Practice Gaps: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

In the second part of this JACC State-of-the-Art Review, an early and sustainable preventive care plan is described for cardiometabolic-based chronic disease. This plan can improve cardiometabolic health by targeting early mechanistic events to decrease the risk for certain cardiovascular diseases (e.g., coronary heart disease, heart failure, and atrial fibrillation). Included are various prevention modalities, intensive lifestyle interventions, pharmacotherapy and cardiovascular outcome trial evidence, and bariatric/metabolic procedures. A tactical approach of implementing published clinical practice guidelines/algorithms for early behavioral, adiposity, and dysglycemia targeting is emphasized, as well as relevant educational and research implications.

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

J Am Coll Cardiol: 10 Feb 2020; 75:539-555
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:539-555 | PMID: 32029137
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction.

Marsit O, Clavel MA, Côté-Laroche C, Hadjadj S, ... Levine RA, Beaudoin J
Background
Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves.
Objectives
This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves.
Methods
Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves.
Results
Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm vs. 15.1 ± 1.6 cm, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group.
Conclusions
In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.

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

J Am Coll Cardiol: 03 Feb 2020; 75:395-405
Marsit O, Clavel MA, Côté-Laroche C, Hadjadj S, ... Levine RA, Beaudoin J
J Am Coll Cardiol: 03 Feb 2020; 75:395-405 | PMID: 32000951
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Adverse Events, Radiation Exposure, and Reinterventions Following Transcatheter Pulmonary Valve Replacement.

Goldstein BH, Bergersen L, Armstrong AK, Boe BA, ... Goodman A, Petit CJ
Background
Transcatheter pulmonary valve replacement (TPVR) is associated with a risk of procedural serious adverse events (SAE) and exposure to ionizing radiation.
Objectives
The purpose of this study was to define the risk of, and associations with, SAE and high-dose radiation exposure using large-scale registry data.
Methods
The analysis of the multicenter C3PO-QI registry was limited to patients who underwent TPVR from January 1, 2014, to December 31, 2016. SAE were defined as the occurrence of ≥1 moderate, major, or catastrophic events. Radiation dose was reported as dose area product adjusted for weight. Associations with outcome measures were explored in univariate and multivariable analyses.
Results
A total of 530 patients (59% male) underwent TPVR at a median age of 18.3 years (interquartile range [IQR]: 12.9 to 27.3 years) and weight of 58 kg (IQR: 43 to 77 kg) at 14 centers. Implant substrate included homograft (41%), bioprosthesis (30%), native right ventricular outflow tract (RVOT) (27%) and other (2%). TPVR indications were pulmonary insufficiency (28%), stenosis (23%), and mixed (49%). AE and SAE occurred in 26% and 13% of cases, respectively, including 1 mortality. SAE were more frequent in homograft conduit than other RVOT substrates, although SAE type and severity differed between implant substrates. Median radiation dose was 198 μGy·m/kg (IQR: 94 to 350 μGy·m/kg). Higher radiation dose was associated with older age, greater RVOT obstruction, and concomitant interventions (p < 0.001). During a median follow-up duration of 1 year, 13.3% underwent catheterization, surgery, or both, unrelated to infection. Younger age, smaller size, and hemodynamic and anatomic factors indicative of greater RVOT obstruction were associated with TPV reintervention.
Conclusions
The incidence of SAE during TPVR in the C3PO-QI registry is high, but mortality is uncommon. Radiation dose is greater than for other congenital interventions and is associated with patient and procedural factors. Reintervention is common during early follow-up.

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

J Am Coll Cardiol: 03 Feb 2020; 75:363-376
Goldstein BH, Bergersen L, Armstrong AK, Boe BA, ... Goodman A, Petit CJ
J Am Coll Cardiol: 03 Feb 2020; 75:363-376 | PMID: 32000947
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clinical Benefit of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review.

Zelniker TA, Braunwald E

Changes in the regulatory guidelines by the U.S. Food and Drug Administration and the European Medical Agency requiring large-scale trials that study the cardiovascular safety of new glucose-lowering drugs have improved our understanding of type 2 diabetes mellitus. Unexpectedly, these trials demonstrated that sodium-glucose cotransporter 2 inhibitors reduce adverse cardiovascular outcomes. This second part of this 2-part review summarizes the findings of recent clinical trials and their clinical implications and describes ongoing trials and future areas of research.

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

J Am Coll Cardiol: 03 Feb 2020; 75:435-447
Zelniker TA, Braunwald E
J Am Coll Cardiol: 03 Feb 2020; 75:435-447 | PMID: 32000956
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Long-Term Outcomes and Associations With Major Adverse Limb Events After Peripheral Artery Revascularization.

Hess CN, Wang TY, Weleski Fu J, Gundrum J, ... Rogers RK, Hiatt WR
Background
Long-term cardiovascular and limb outcomes after revascularization for peripheral artery disease and, in particular, prognosis after post-procedure major adverse limb events (MALE) are not well-studied.
Objectives
This study sought to describe outcomes after peripheral revascularization and assess relationships between post-procedure MALE hospitalization and subsequent events.
Methods
Patients undergoing peripheral artery revascularization between January 1, 2009, and September 30, 2015, in the Premier Healthcare Database were examined for the co-primary outcomes of interest, composite myocardial infarction (MI) or stroke and composite major amputation or peripheral revascularization. Multivariable adjusted Cox proportional hazards models with post-procedure MALE hospitalization included as a time-dependent covariate were developed to estimate hazard ratios for outcomes.
Results
Among 393,017 revascularized patients followed for a median of 2.7 years (interquartile range: 1.3 to 4.4 years), the cumulative incidence of MI or stroke was 9.8% and that of major amputation or peripheral revascularization was 41.9%. A total of 50,750 patients (12.9%) had at least 1 post-procedure MALE hospitalization. In time-dependent covariate adjusted models, post-procedure MALE hospitalization was associated with greater risk of subsequent MI or stroke (hazard ratio: 1.34; 95% confidence interval: 1.28 to 1.40) and major amputation or peripheral revascularization (hazard ratio: 8.13; 95% confidence interval: 7.96 to 8.29). After peripheral revascularization with or without post-procedure MALE hospitalization, risk of limb events increased rapidly post-procedure and more slowly after the first year, whereas cardiac risk increased steadily during follow-up.
Conclusions
Revascularized peripheral artery disease patients face earlier limb and later cardiovascular ischemic risk that is heightened among patients with post-procedure MALE hospitalization. Increased provider awareness of these long-term risks may guide efforts to improve post-procedural outcomes.

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

J Am Coll Cardiol: 10 Feb 2020; 75:498-508
Hess CN, Wang TY, Weleski Fu J, Gundrum J, ... Rogers RK, Hiatt WR
J Am Coll Cardiol: 10 Feb 2020; 75:498-508 | PMID: 32029132
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Atrial Failure as a Clinical Entity: JACC Review Topic of the Week.

Bisbal F, Baranchuk A, Braunwald E, Bayés de Luna A, Bayés-Genís A

Atrial dysfunction has been widely considered a marker or consequence of other cardiac conditions rather than the cause itself. Here, we propose the term atrial failure as a clinically relevant entity, defined as any atrial dysfunction causing impaired heart performance, symptoms, and worsening quality of life or life expectancy. Aspects of the etiology, mechanisms, and consequences of atrial failure are discussed. Recent advances in cardiac electrophysiology and imaging have improved our understanding of the highly complex atrial anatomy and function, underlying the paramount importance of the atria in optimal heart performance. It is time to reappraise the concept of the failing atrium as a primary cause or aggravating factor of the symptoms in many of our patients. The concept of atrial failure may foster basic and translational research to gain a better understanding of how to identify and manage atrial dysfunction.

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

J Am Coll Cardiol: 20 Jan 2020; 75:222-232
Bisbal F, Baranchuk A, Braunwald E, Bayés de Luna A, Bayés-Genís A
J Am Coll Cardiol: 20 Jan 2020; 75:222-232 | PMID: 31948652
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Short-Term Hemodynamic and Electrophysiological Effects of Cardiac Resynchronization by Left Ventricular Septal Pacing.

Salden FCWM, Luermans JGLM, Westra SW, Weijs B, ... Prinzen FW, Vernooy K
Background
Cardiac resynchronization therapy (CRT) is usually performed by biventricular (BiV) pacing. Previously, feasibility of transvenous implantation of a lead at the left ventricular (LV) endocardial side of the interventricular septum, referred to as LV septal (LVs) pacing, was demonstrated.
Objectives
The authors sought to compare the acute electrophysiological and hemodynamic effects of LVs with BiV and His bundle (HB) pacing in CRT patients.
Methods
Temporary LVs pacing (transaortic approach) alone or in combination with right ventricular (RV) (LVs+RV), BiV, and HB pacing was performed in 27 patients undergoing CRT implantation. Electrophysiological changes were assessed using electrocardiography (QRS duration), vectorcardiography (QRS area), and multielectrode body surface mapping (standard deviation of activation times [SDAT]). Hemodynamic changes were assessed as the first derivative of LV pressure (LVdP/dtmax).
Results
As compared with baseline, LVs pacing resulted in a larger reduction in QRS area (to 73 ± 22 μVs) and SDAT (to 26 ± 7 ms) than BiV (to 93 ± 26 μVs and 31 ± 7 ms; both p < 0.05) and LVs+RV pacing (to 108 ± 37 μVs; p < 0.05; and 29 ± 8 ms; p = 0.05). The increase in LVdP/dtmax was similar during LVs and BiV pacing (17 ± 10% vs. 17 ± 9%, respectively) and larger than during LVs+RV pacing (11 ± 9%; p < 0.05). There were no significant differences between basal, mid-, or apical LVs levels in LVdP/dtmax and SDAT. In a subgroup of 16 patients, changes in QRS area, SDAT, and LVdP/dtmax were comparable between LVs and HB pacing.
Conclusions
LVs pacing provides short-term hemodynamic improvement and electrical resynchronization that is at least as good as during BiV and possibly HB pacing. These results indicate that LVs pacing may serve as a valuable alternative for CRT.

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

J Am Coll Cardiol: 03 Feb 2020; 75:347-359
Salden FCWM, Luermans JGLM, Westra SW, Weijs B, ... Prinzen FW, Vernooy K
J Am Coll Cardiol: 03 Feb 2020; 75:347-359 | PMID: 32000945
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Peripartum Cardiomyopathy: JACC State-of-the-Art Review.

Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U

Peripartum cardiomyopathy is a form of systolic heart failure affecting young women toward the end of pregnancy or in the months following delivery. Incidence is higher in African-American women and in women with older maternal age, hypertensive disorders of pregnancy, and multiple gestation pregnancies. Symptoms of heart failure mimic those of normal pregnancy, often resulting in a delay in diagnosis and preventable complications. Echocardiography showing decreased myocardial function is essential for the diagnosis. Medical management is similar to heart failure with reduced ejection fraction of other etiologies, but adjustments during pregnancy are necessary to ensure fetal safety. Variable outcomes include complete recovery, persistent heart failure, arrhythmias, thromboembolic events, and death. Subsequent pregnancy confers substantial risk of relapse and even death if there is incomplete myocardial recovery. Additional research about the etiology, optimal therapy including the use of bromocriptine, long-term outcomes, and duration of treatment after recovery are needed.

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

J Am Coll Cardiol: 20 Jan 2020; 75:207-221
Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U
J Am Coll Cardiol: 20 Jan 2020; 75:207-221 | PMID: 31948651
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Obesity as a Causal Risk Factor for Aortic Valve Stenosis.

Kaltoft M, Langsted A, Nordestgaard BG
Background
Causal risk factors for aortic valve stenosis are poorly understood, limiting the possibility of preventing the most common heart valve disease.
Objectives
The hypothesis was tested that genetically based obesity measured by body mass index is causally associated with risk of aortic valve stenosis and replacement.
Methods
The authors included 108,211 individuals from the Copenhagen General Population Study. Participants had measurements of body mass index, waist-hip ratio, and waist circumference, and information on 5 genetic variants associated with obesity. A Mendelian randomization design was used to investigate genetic and observational associations of obesity with incident aortic valve stenosis (n = 1,215) and replacement (n = 467) for a median follow-up time of 8.7 years.
Results
Genetically increased body mass index was causally associated with increased risk of aortic valve stenosis. Compared with an unweighted allele score of 0 to 3, individuals with an allele score 7 to 10 had a mean increase in body mass index of 0.87 kg/m, and the age and sex-adjusted hazard ratio for aortic valve stenosis was 1.3 (95% confidence interval [CI]: 1.0 to 1.7) for allele score 4, 1.4 (95% CI: 1.1 to 1.8) for allele score 5 to 6, and 1.6 (95% CI: 1.3 to 2.1) for allele score 7 to 10 (p for trend: 9 × 10). A 1-kg/m increase in body mass index was associated with causal risk ratios for aortic valve stenosis and replacement, respectively, of 1.52 (95% CI: 1.23 to 1.87) and 1.49 (95% CI: 1.07 to 2.08) genetically, and with corresponding hazard ratios of 1.06 (95% CI: 1.05 to 1.08) and 1.06 (95% CI: 1.03 to 1.08) observationally.
Conclusions
Obesity from human genetics was causally associated with higher risk of aortic valve stenosis and replacement.

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

J Am Coll Cardiol: 20 Jan 2020; 75:163-176
Kaltoft M, Langsted A, Nordestgaard BG
J Am Coll Cardiol: 20 Jan 2020; 75:163-176 | PMID: 31948645
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome.

Bittner VA, Szarek M, Aylward PE, Bhatt DL, ... Schwartz GG,
Background
Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).
Objectives
A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).
Methods
One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.
Results
Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).
Conclusions
Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

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

J Am Coll Cardiol: 20 Jan 2020; 75:133-144
Bittner VA, Szarek M, Aylward PE, Bhatt DL, ... Schwartz GG,
J Am Coll Cardiol: 20 Jan 2020; 75:133-144 | PMID: 31948641
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

Linde JJ, Kelbæk H, Hansen TF, Sigvardsen PE, ... Køber LV, Kofoed KF
Background
In patients with non-ST-segment elevation acute coronary syndrome (NSTEACS), coronary pathology may range from structurally normal vessels to severe coronary artery disease.
Objectives
The purpose of this study was to test if coronary computed tomography angiography (CTA) may be used to exclude coronary artery stenosis ≥50% in patients with NSTEACS.
Methods
The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial (NCT02061891) evaluated the outcome of patients with confirmed NSTEACS randomized 1:1 to very early (within 12 h) or standard (48 to 72 h) invasive coronary angiography (ICA). As an observational component of the trial, a clinically blinded coronary CTA was conducted prior to ICA in both groups. The primary endpoint was the ability of coronary CTA to rule out coronary artery stenosis (≥50% stenosis) in the entire population, expressed as the negative predictive value (NPV), using ICA as the reference standard.
Results
Coronary CTA was conducted in 1,023 patients-very early, 2.5 h (interquartile range [IQR]: 1.8 to 4.2 h), n = 583; and standard, 59.9 h (IQR: 38.9 to 86.7 h); n = 440 after the diagnosis of NSTEACS was made. A coronary stenosis ≥50% was found by coronary CTA in 68.9% and by ICA in 67.4% of the patients. Per-patient NPV of coronary CTA was 90.9% (95% confidence interval [CI]: 86.8% to 94.1%) and the positive predictive value, sensitivity, and specificity were 87.9% (95% CI: 85.3% to 90.1%), 96.5% (95% CI: 94.9% to 97.8%) and 72.4% (95% CI: 67.2% to 77.1%), respectively. NPV was not influenced by patient characteristics or clinical risk profile and was similar in the very early and the standard strategy group.
Conclusions
Coronary CTA has a high diagnostic accuracy to rule out clinically significant coronary artery disease in patients with NSTEACS.

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

J Am Coll Cardiol: 10 Feb 2020; 75:453-463
Linde JJ, Kelbæk H, Hansen TF, Sigvardsen PE, ... Køber LV, Kofoed KF
J Am Coll Cardiol: 10 Feb 2020; 75:453-463 | PMID: 32029126
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Alcohol Abstinence in Drinkers with Atrial Fibrillation.

Voskoboinik A, Kalman JM, De Silva A, Nicholls T, ... Taylor AJ, Kistler PM
Background
Excessive alcohol consumption is associated with incident atrial fibrillation and adverse atrial remodeling; however, the effect of abstinence from alcohol on secondary prevention of atrial fibrillation is unclear.
Methods
We conducted a multicenter, prospective, open-label, randomized, controlled trial at six hospitals in Australia. Adults who consumed 10 or more standard drinks (with 1 standard drink containing approximately 12 g of pure alcohol) per week and who had paroxysmal or persistent atrial fibrillation in sinus rhythm at baseline were randomly assigned in a 1:1 ratio to either abstain from alcohol or continue their usual alcohol consumption. The two primary end points were freedom from recurrence of atrial fibrillation (after a 2-week \"blanking period\") and total atrial fibrillation burden (proportion of time in atrial fibrillation) during 6 months of follow-up.
Results
Of 140 patients who underwent randomization (85% men; mean [±SD] age, 62±9 years), 70 were assigned to the abstinence group and 70 to the control group. Patients in the abstinence group reduced their alcohol intake from 16.8±7.7 to 2.1±3.7 standard drinks per week (a reduction of 87.5%), and patients in the control group reduced their alcohol intake from 16.4±6.9 to 13.2±6.5 drinks per week (a reduction of 19.5%). After a 2-week blanking period, atrial fibrillation recurred in 37 of 70 patients (53%) in the abstinence group and in 51 of 70 patients (73%) in the control group. The abstinence group had a longer period before recurrence of atrial fibrillation than the control group (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; P = 0.005). The atrial fibrillation burden over 6 months of follow-up was significantly lower in the abstinence group than in the control group (median percentage of time in atrial fibrillation, 0.5% [interquartile range, 0.0 to 3.0] vs. 1.2% [interquartile range, 0.0 to 10.3]; P = 0.01).
Conclusions
Abstinence from alcohol reduced arrhythmia recurrences in regular drinkers with atrial fibrillation. (Funded by the Government of Victoria Operational Infrastructure Support Program and others; Australian New Zealand Clinical Trials Registry number, ACTRN12616000256471.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 01 Jan 2020; 382:20-28
Voskoboinik A, Kalman JM, De Silva A, Nicholls T, ... Taylor AJ, Kistler PM
N Engl J Med: 01 Jan 2020; 382:20-28 | PMID: 31893513
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis.

Awadalla M, Mahmood SS, Groarke JD, Hassan MZO, ... Fradley MG, Neilan TG
Background
There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis.
Objectives
This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis.
Methods
This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death.
Results
Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8).
Conclusions
GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.

Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:467-478
Awadalla M, Mahmood SS, Groarke JD, Hassan MZO, ... Fradley MG, Neilan TG
J Am Coll Cardiol: 10 Feb 2020; 75:467-478 | PMID: 32029128
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Reporting of Cardiovascular Events in Clinical Trials Supporting FDA Approval of Contemporary Cancer Therapies.

Bonsu JM, Guha A, Charles L, Yildiz VO, ... Paskett ED, Addison D
Background
Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.
Objectives
The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.
Methods
From the [email protected], clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.
Results
Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).
Conclusions
Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 17 Feb 2020; 75:620-628
Bonsu JM, Guha A, Charles L, Yildiz VO, ... Paskett ED, Addison D
J Am Coll Cardiol: 17 Feb 2020; 75:620-628 | PMID: 32057377
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Stent-Related Adverse Events >1 Year After Percutaneous Coronary Intervention.

Madhavan MV, Kirtane AJ, Redfors B, Généreux P, ... Pocock SJ, Stone GW
Background
The majority of stent-related major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) are believed to occur within the first year. Very-late (>1-year) stent-related MACE have not been well described.
Objectives
The purpose of this study was to assess the frequency and predictors of very-late stent-related events or MACE by stent type.
Methods
Individual patient data from 19 prospective, randomized metallic stent trials maintained at a leading academic research organization were pooled. Very-late MACE (a composite of cardiac death, myocardial infarction [MI], or ischemia-driven target lesion revascularization [ID-TLR]), and target lesion failure (cardiac death, target-vessel MI, or ID-TLR) were assessed within year 1 and between 1 and 5 years after PCI with bare-metal stents (BMS), first-generation drug-eluting stents (DES1) and second-generation drug-eluting stents (DES2). A network meta-analysis was performed to evaluate direct and indirect comparisons.
Results
Among 25,032 total patients, 3,718, 7,934, and 13,380 were treated with BMS, DES1, and DES2, respectively. MACE rates within 1 year after PCI were progressively lower after treatment with BMS versus DES1 versus DES2 (17.9% vs. 8.2% vs. 5.1%, respectively, p < 0.0001). Between years 1 and 5, very-late MACE occurred in 9.4% of patients (including 2.9% cardiac death, 3.1% MI, and 5.1% ID-TLR). Very-late MACE occurred in 9.7%, 11.0%, and 8.3% of patients treated with BMS, DES1, and DES2, respectively (p < 0.0001), linearly increasing between 1 and 5 years. Similar findings were observed for target lesion failure in 19,578 patients from 12 trials. Findings were confirmed in the network meta-analysis.
Conclusions
In this large-scale, individual patient data pooled study, very-late stent-related events occurred between 1 and 5 years after PCI at a rate of ∼2%/year with all stent types, with no plateau evident. New approaches are required to improve long-term outcomes after PCI.

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

J Am Coll Cardiol: 17 Feb 2020; 75:590-604
Madhavan MV, Kirtane AJ, Redfors B, Généreux P, ... Pocock SJ, Stone GW
J Am Coll Cardiol: 17 Feb 2020; 75:590-604 | PMID: 32057373
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Sex-Specific Risks of Major Cardiovascular and Limb Events in Patients With Symptomatic Peripheral Artery Disease.

Haine A, Kavanagh S, Berger JS, Hess CN, ... Baumgartner I,
Background
Patients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD.
Objectives
The aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial.
Methods
Cox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection.
Results
EUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex.
Conclusions
Although women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

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

J Am Coll Cardiol: 17 Feb 2020; 75:608-617
Haine A, Kavanagh S, Berger JS, Hess CN, ... Baumgartner I,
J Am Coll Cardiol: 17 Feb 2020; 75:608-617 | PMID: 32057375
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Oral Anticoagulation for Patients With Atrial Fibrillation on Long-Term Hemodialysis.

Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
Background
Patients on long-term dialysis are at increased risk of bleeding. Although oral anticoagulants (OACs) are recommended for atrial fibrillation (AF) to reduce the risk of stroke, randomized trials have excluded these populations. As such, the net clinical benefit of OACs among patients on dialysis is unknown.
Objectives
This study aimed to investigate the efficacy and safety of OACs in patients with AF on long-term dialysis.
Methods
MEDLINE and EMBASE were searched through June 10, 2019, for studies that investigated the efficacy and safety of different OAC strategies in patients with AF on long-term dialysis. The efficacy outcomes were ischemic stroke and/or systemic thromboembolism, all-cause mortality, and the safety outcome was major bleeding.
Results
This study identified 16 eligible observational studies (N = 71,877) regarding patients on long-term dialysis who had AF. Only 2 of 16 studies investigated direct OACs. Outcomes for dabigatran and rivaroxaban were limited to major bleeding events. Compared with no anticoagulants, apixaban and warfarin were not associated with a significant decrease in stroke and/or systemic thromboembolism (apixaban 5 mg, hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.30 to 1.17; apixaban 2.5 mg, HR: 1.00; 95% CI: 0.52 to 1.93; warfarin, HR: 0.91; 95% CI: 0.72 to 1.16). Apixaban 5 mg was associated with a significantly lower risk of mortality (vs. warfarin, HR: 0.65; 95% CI: 0.45 to 0.93; vs. apixaban 2.5 mg, HR: 0.62; 95% CI: 0.42 to 0.90; vs. no anticoagulant, HR: 0.61; 95% CI: 0.41 to 0.90). Warfarin was associated with a significantly higher risk of major bleeding than apixaban 5 min/2.5 mg and no anticoagulant (vs. apixaban 5 mg, HR: 1.41; 95% CI: 1.07 to 1.88; vs. apixaban 2.5 mg, HR: 1.40; 95% CI: 1.07 to 1.82; vs. no anticoagulant, HR: 1.31; 95% CI: 1.15 to 1.50). Dabigatran and rivaroxaban were also associated with significantly higher risk of major bleeding than apixaban and no anticoagulant.
Conclusions
This meta-analysis showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. Warfarin, dabigatran, and rivaroxaban were associated with significantly higher bleeding risk compared with apixaban and no anticoagulant. The benefit-to-risk ratio of OACs in patients with AF on long-term dialysis warrants validation in randomized clinical trials.

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

J Am Coll Cardiol: 27 Jan 2020; 75:273-285
Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
J Am Coll Cardiol: 27 Jan 2020; 75:273-285 | PMID: 31976865
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Marijuana Use in Patients With Cardiovascular Disease: JACC Review Topic of the Week.

DeFilippis EM, Bajaj NS, Singh A, Malloy R, ... Bhatt DL, Vaduganathan M

Marijuana use is increasing as more states are legalizing cannabis for both medicinal and recreational purposes. National survey data estimate that >2 million Americans with established cardiovascular diseases currently use or have used marijuana in its variety of forms, including inhalation and vaping. Cannabinoid receptors are distributed in multiple tissue beds and cells, including platelets, adipose tissue, and myocytes. Observational data suggest associations between marijuana and a broad range of adverse cardiovascular risks. Marijuana is becoming increasingly potent, and smoking marijuana carries many of the same cardiovascular health hazards as smoking tobacco. Synthetic cannabinoids have been linked to more sustained and deleterious pharmacodynamic effects. Marijuana is classified as a Schedule I substance, thus limiting its rigorous study for cardiovascular health effects. This review summarizes cardiovascular considerations related to marijuana use, pharmacological interactions, and future steps to provide clearer guidance regarding its cardiovascular safety. Screening for marijuana use is encouraged, especially in young patients presenting with cardiovascular disease.

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

J Am Coll Cardiol: 27 Jan 2020; 75:320-332
DeFilippis EM, Bajaj NS, Singh A, Malloy R, ... Bhatt DL, Vaduganathan M
J Am Coll Cardiol: 27 Jan 2020; 75:320-332 | PMID: 31976871
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Extracellular Myocardial Volume in Patients With Aortic Stenosis.

Everett RJ, Treibel TA, Fukui M, Lee H, ... Moon JC, Dweck MR
Background
Myocardial fibrosis is a key mechanism of left ventricular decompensation in aortic stenosis and can be quantified using cardiovascular magnetic resonance (CMR) measures such as extracellular volume fraction (ECV%). Outcomes following aortic valve intervention may be linked to the presence and extent of myocardial fibrosis.
Objectives
This study sought to determine associations between ECV% and markers of left ventricular decompensation and post-intervention clinical outcomes.
Methods
Patients with severe aortic stenosis underwent CMR, including ECV% quantification using modified Look-Locker inversion recovery-based T1 mapping and late gadolinium enhancement before aortic valve intervention. A central core laboratory quantified CMR parameters.
Results
Four-hundred forty patients (age 70 ± 10 years, 59% male) from 10 international centers underwent CMR a median of 15 days (IQR: 4 to 58 days) before aortic valve intervention. ECV% did not vary by scanner manufacturer, magnetic field strength, or T1 mapping sequence (all p > 0.20). ECV% correlated with markers of left ventricular decompensation including left ventricular mass, left atrial volume, New York Heart Association functional class III/IV, late gadolinium enhancement, and lower left ventricular ejection fraction (p < 0.05 for all), the latter 2 associations being independent of all other clinical variables (p = 0.035 and p < 0.001). After a median of 3.8 years (IQR: 2.8 to 4.6 years) of follow-up, 52 patients had died, 14 from adjudicated cardiovascular causes. A progressive increase in all-cause mortality was seen across tertiles of ECV% (17.3, 31.6, and 52.7 deaths per 1,000 patient-years; log-rank test; p = 0.009). Not only was ECV% associated with cardiovascular mortality (p = 0.003), but it was also independently associated with all-cause mortality following adjustment for age, sex, ejection fraction, and late gadolinium enhancement (hazard ratio per percent increase in ECV%: 1.10; 95% confidence interval [1.02 to 1.19]; p = 0.013).
Conclusions
In patients with severe aortic stenosis scheduled for aortic valve intervention, an increased ECV% is a measure of left ventricular decompensation and a powerful independent predictor of mortality.

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

J Am Coll Cardiol: 27 Jan 2020; 75:304-316
Everett RJ, Treibel TA, Fukui M, Lee H, ... Moon JC, Dweck MR
J Am Coll Cardiol: 27 Jan 2020; 75:304-316 | PMID: 31976869
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Pre-Hospital Administration of Epinephrine in Pediatric Patients With Out-of-Hospital Cardiac Arrest.

Matsuyama T, Komukai S, Izawa J, Gibo K, ... Ohta B, Kitamura T
Background
There is little evidence about pre-hospital advanced life support including epinephrine administration for pediatric out-of-hospital cardiac arrests (OHCAs).
Objectives
This study aimed to assess the effect of pre-hospital epinephrine administration by emergency-medical-service (EMS) personnel for pediatric OHCA.
Methods
This nationwide population-based observational study in Japan enrolled pediatric patients age 8 to 17 years with OHCA between January 2007 and December 2016. Patients were sequentially matched with or without epinephrine during cardiac arrest using a risk-set matching based on time-dependent propensity score (probability of receiving epinephrine) calculated at each minute after initiation of cardiopulmonary resuscitation by EMS personnel. The primary endpoint was 1-month survival. Secondary endpoints were 1-month survival with favorable neurological outcome, defined as the cerebral performance category scale of 1 or 2, and pre-hospital return of spontaneous circulation (ROSC).
Results
During the study period, a total of 1,214,658 OHCA patients were registered, and 3,961 pediatric OHCAs were eligible for analyses. Of these, 306 (7.7%) patients received epinephrine and 3,655 (92.3%) did not receive epinephrine. After time-dependent propensity score-sequential matching, 608 patients were included in the matched cohort. In the matched cohort, there were no significant differences between the epinephrine and no epinephrine groups in 1-month survival (epinephrine: 10.2% [31 of 304] vs. no epinephrine: 7.9% [24 of 304]; risk ratio [RR]: 1.13 [95% confidence interval (CI): 0.67 to 1.93]) and favorable neurological outcome (epinephrine: 3.6% [11 of 304] vs. no epinephrine: 2.6% [8 of 304]; RR: 1.56 [95% CI: 0.61 to 3.96]), whereas the epinephrine group had a higher likelihood of achieving pre-hospital ROSC (epinephrine: 11.2% [34 of 304] vs. no epinephrine: 3.3% [10 of 304]; RR: 3.17 [95% CI: 1.54 to 6.54]).
Conclusions
In this study, pre-hospital epinephrine administration was associated with ROSC, whereas there were no significant differences in 1-month survival and favorable neurological outcome between those with and without epinephrine.

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

J Am Coll Cardiol: 20 Jan 2020; 75:194-204
Matsuyama T, Komukai S, Izawa J, Gibo K, ... Ohta B, Kitamura T
J Am Coll Cardiol: 20 Jan 2020; 75:194-204 | PMID: 31948649
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Acute Stroke During Pregnancy and Puerperium.

Elgendy IY, Gad MM, Mahmoud AN, Keeley EC, Pepine CJ
Background
Acute stroke during pregnancy or within 6 weeks of childbirth is devastating for the mother and her family, yet data regarding incidence and contemporary trends are very limited.
Objectives
This study sought to investigate the incidence and outcomes of acute stroke and transient ischemic attack during pregnancy or within 6 weeks of childbirth in a large database.
Methods
The National Inpatient Sample was queried to identify women age ≥18 years in the United States with pregnancy-related hospitalizations from January 1, 2007, to September 30, 2015. Temporal trends in acute stroke (ischemic and hemorrhagic)/transient ischemic attack incidence and in-hospital mortality were extracted.
Results
Among 37,360,772 pregnancy-related hospitalizations, 16,694 (0.045%) women had an acute stroke. The rates of acute stroke did not change (42.8 per 100,000 hospitalizations in 2007 vs. 42.2 per 100,000 hospitalizations in 2015; p = 0.10). Among those with acute stroke, there were increases in prevalence of obesity, smoking, hyperlipidemia, migraine, and gestational hypertension. Importantly, in-hospital mortality rates were almost 385-fold higher among those who had a stroke (42.1 per 1,000 pregnancy-related hospitalizations vs. 0.11 per 1,000 pregnancy-related hospitalizations; p < 0.0001). The rates of in-hospital mortality among pregnant women with acute stroke decreased (5.5% in 2007 vs. 2.7% in 2015; p < 0.001).
Conclusions
In this contemporary analysis of pregnancy-related hospitalizations, acute stroke occurred in 1 of every 2,222 hospitalizations, and these rates did not decrease over approximately 9 years. The prevalence of most stroke risk factors has increased. Acute stroke during pregnancy and puerperium was associated with high maternal mortality, although it appears to be trending downward. Future studies to better identify mechanisms and approaches to prevention and management of acute stroke during pregnancy and puerperium are warranted.

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

J Am Coll Cardiol: 20 Jan 2020; 75:180-190
Elgendy IY, Gad MM, Mahmoud AN, Keeley EC, Pepine CJ
J Am Coll Cardiol: 20 Jan 2020; 75:180-190 | PMID: 31948647
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Coronary Artery Target Selection and Survival After Bilateral Internal Thoracic Artery Grafting.

Bakaeen FG, Ravichandren K, Blackstone EH, Houghtaling PL, ... Gillinov AM, Svensson LG
Background
The importance of a coronary artery, based on the myocardial mass it perfuses, is well documented, but little is known about the importance of a vessel that has been bypassed and its effect on survival in the context of bilateral internal thoracic artery (BITA) grafting.
Objectives
This study determined the effect of a dominant left anterior descending (LAD) artery and important non-LAD targets on outcomes after BITA grafting.
Methods
From January 1972 to January 2011, of 6,127 patients who underwent BITA grafting, 2,551 received 1 ITA grafted to the LAD and had an evaluable coronary angiogram. A dominant LAD was defined as one that was wrapped around the left ventricular apex. Non-LAD targets were graded based on their terminal reach toward the apex: important: >75% (n = 1,698); and less important: ≤75% (n = 853). Mean follow-up was 14 ± 8.7 years. Multivariable analysis was performed to identify risk factors for time-related mortality.
Results
A dominant LAD was present more frequently in patients with less important additional targets (51% vs. 35%; p < 0.0001). A total of 179 patients (7.0%) received a second ITA to multiple targets, 77 (43%) of which were to multiple important target vessels. Unadjusted late survival was similar regardless of degree of importance of the second ITA target-77% at 15 years (p = 0.70) for the important and less important targets, respectively. In the multivariable model, grafting the second ITA to multiple important targets was associated with better long-term survival (p = 0.005). In patients with a nondominant LAD, a second ITA grafted to a less important artery was associated with higher risk of operative mortality (2.4% vs. 0.51%; p = 0.007). A saphenous vein graft to an important or less important target did not influence long-term survival.
Conclusions
In BITA grafting, bypassing multiple important targets to maximize myocardium supplied by ITAs improved long-term survival. In patients with a nondominant LAD, selecting an important target for the second ITA lowered operative mortality.

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

J Am Coll Cardiol: 27 Jan 2020; 75:258-268
Bakaeen FG, Ravichandren K, Blackstone EH, Houghtaling PL, ... Gillinov AM, Svensson LG
J Am Coll Cardiol: 27 Jan 2020; 75:258-268 | PMID: 31976863
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Carotid Artery Stenting in Asymptomatic Carotid Artery Stenosis: JACC Review Topic of the Week.

Beckman JA, Ansel GM, Lyden SP, Das TS

The advance of therapies to reduce the stroke impact of asymptomatic carotid artery stenosis has proved difficult over the last decade. Disagreement concerning the underlying randomized control trials has limited entry into the care arena of endovascular therapies. Recently, advances in percutaneous therapies for carotid artery disease have been reported and provide a substantial database supporting the further incorporation of endovascular-based therapies in patients who need revascularization and meet selection criteria. With a second randomized control trial now published, it is time for a re-evaluation of endovascular therapy as a component of carotid artery care. This review describes the advances in the field in the last 5 years, clarifying the current position of these therapies in the care of the patient with asymptomatic carotid artery disease.

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

J Am Coll Cardiol: 17 Feb 2020; 75:648-656
Beckman JA, Ansel GM, Lyden SP, Das TS
J Am Coll Cardiol: 17 Feb 2020; 75:648-656 | PMID: 32057380
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Salt Reduction to Prevent Hypertension and Cardiovascular Disease: JACC State-of-the-Art Review.

He FJ, Tan M, Ma Y, MacGregor GA

There is strong evidence for a causal relationship between salt intake and blood pressure. Randomized trials demonstrate that salt reduction lowers blood pressure in both individuals who are hypertensive and those who are normotensive, additively to antihypertensive treatments. Methodologically robust studies with accurate salt intake assessment have shown that a lower salt intake is associated with a reduced risk of cardiovascular disease, all-cause mortality, and other conditions, such as kidney disease, stomach cancer, and osteoporosis. Multiple complex and interconnected physiological mechanisms are implicated, including fluid homeostasis, hormonal and inflammatory mechanisms, as well as more novel pathways such as the immune response and the gut microbiome. High salt intake is a top dietary risk factor. Salt reduction programs are cost-effective and should be implemented or accelerated in all countries. This review provides an update on the evidence relating salt to health, with a particular focus on blood pressure and cardiovascular disease, as well as the potential mechanisms.

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

J Am Coll Cardiol: 17 Feb 2020; 75:632-647
He FJ, Tan M, Ma Y, MacGregor GA
J Am Coll Cardiol: 17 Feb 2020; 75:632-647 | PMID: 32057379
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ticagrelor With or Without Aspirin After PCI: The TWILIGHT Platelet Substudy.

Baber U, Zafar MU, Dangas G, Escolar G, ... Mehran R, Badimon JJ
Background
An evolving strategy in the setting of percutaneous coronary intervention (PCI) involves withdrawal of acetylsalicylic acid (ASA), or aspirin, while maintaining P2Y inhibition. However, the pharmacodynamic effects of this approach on blood thrombogenicity and platelet reactivity remain unknown.
Objectives
This study sought to compare the antithrombotic potency of ticagrelor alone versus ticagrelor plus ASA among high-risk patients undergoing PCI with drug-eluting stents.
Methods
This was a mechanistic substudy within the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, which randomized patients undergoing PCI to ticagrelor plus placebo versus ticagrelor plus ASA following 3 months of dual antiplatelet therapy. Substudy participants were enrolled after randomization, at which time ex vivo assays to quantify thrombus size under dynamic flow conditions and platelet reactivity were performed. Pharmacodynamic assessments were repeated 1 to 6 months thereafter. The primary endpoint was thrombus size at the post-randomization visit with platelet reactivity following stimuli to arachidonic acid, collagen, adenosine diphosphate, and thrombin as secondary endpoints. Results were analyzed using analysis of covariance.
Results
A total of 51 patients were enrolled, among whom 42 underwent perfusion assays at baseline and follow-up with a median time between studies of 1.5 months. The adjusted mean difference in post-randomization thrombus area was similar between groups: -218.2 μm (95% confidence interval [CI]: -575.9 to 139.9 μm; p = 0.22). Markers sensitive to cyclo-oxygenase-1 blockade, including platelet reactivity in response to arachidonic acid (mean difference: 10.9 U; 95% CI: 1.9 to 19.9 U) and collagen (mean difference: 9.8 U; 95% CI: 0.8 to 18.8 U) stimuli were higher among patients receiving placebo, whereas levels of platelet reactivity were similar with adenosine diphosphate and thrombin.
Conclusions
Among high-risk patients receiving drug-eluting stents, the antithrombotic potency of ticagrelor monotherapy is similar to that of ticagrelor plus ASA with respect to ex vivo blood thrombogenicity, whereas markers sensitive to cyclo-oxygenase-1 blockade are increased in the absence of ASA. (Platelet Substudy of the TWILIGHT Trial; NCT04001374).

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

J Am Coll Cardiol: 17 Feb 2020; 75:578-586
Baber U, Zafar MU, Dangas G, Escolar G, ... Mehran R, Badimon JJ
J Am Coll Cardiol: 17 Feb 2020; 75:578-586 | PMID: 32057371
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Long-Term Evolocumab in Patients With Familial Hypercholesterolemia.

Santos RD, Stein EA, Hovingh GK, Blom DJ, ... Hamer AW, Raal FJ
Background
Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals.
Objectives
The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH).
Methods
In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids.
Results
In total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was -21.2% (-59.8 mg/dl) in patients with HoFH and -54.9% (-104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from -19.6% at week 12 to -29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis.
Conclusions
Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.

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

J Am Coll Cardiol: 17 Feb 2020; 75:565-574
Santos RD, Stein EA, Hovingh GK, Blom DJ, ... Hamer AW, Raal FJ
J Am Coll Cardiol: 17 Feb 2020; 75:565-574 | PMID: 32057369
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography.

Furtado RHM, Nicolau JC, Guo J, Im K, ... Newby LK, Giugliano RP
Background
Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial.
Objectives
This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls.
Methods
Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days.
Results
In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; p = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; p = 0.46).
Conclusions
When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome; NCT00089895).

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

J Am Coll Cardiol: 27 Jan 2020; 75:289-300
Furtado RHM, Nicolau JC, Guo J, Im K, ... Newby LK, Giugliano RP
J Am Coll Cardiol: 27 Jan 2020; 75:289-300 | PMID: 31976867
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Embolic Stroke of Undetermined Source: JACC Review Topic of the Week.

Ntaios G

The term embolic stroke of undetermined source (ESUS) was introduced in 2014 to describe patients with a nonlacunar ischemic stroke and no convincing etiology. The terms ESUS and cryptogenic stroke are not synonyms, as the latter also includes patients with multiple stroke etiologies or incomplete diagnostic work-up. ESUS involves approximately 17% of all ischemic stroke patients, and these patients are typically younger with mild strokes and an annual rate of stroke recurrence of 4% to 5%. It was hypothesized that oral anticoagulation may decrease the risk of stroke recurrence in ESUS, which was tested in 2 large randomized controlled trials: the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) and the RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source). The present review discusses the trials of anticoagulation in patients with ESUS, suggests potential explanations for their neutral results, and highlights the rationale that supports ongoing and future research in this population aiming to reduce the associated risk for stroke recurrence.

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

J Am Coll Cardiol: 27 Jan 2020; 75:333-340
Ntaios G
J Am Coll Cardiol: 27 Jan 2020; 75:333-340 | PMID: 31976872
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Chronic infarct size after spontaneous coronary artery dissection: implications for pathophysiology and clinical management.

Al-Hussaini A, Abdelaty AMSEK, Gulsin GS, Arnold JR, ... McCann GP, Adlam D
Aims
To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury.
Methods and results
One hundred and fifty-eight angiographically confirmed SCAD-survivors (98% female) were phenotyped by CMR and compared in a case-control study with 59 (97% female) healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, P < 0.01) and increases in left ventricular dimensions (end-diastolic volume: 85 ± 14 mL/m2 vs. 80 ± 11 mL/m2, P < 0.05; end-systolic volume: 37 ± 11 mL/m2 vs. 32 ± 7 mL/m2, P <0.01) compared to healthy controls. Infarcts were small with few large infarcts (median 4.06%; range 0-30.9%) and 39% having no detectable late gadolinium enhancement (LGE). Female SCAD patients presenting with STEMI had similar sized infarcts to female Type-1 STEMI patients age <75 years. Multivariate modelling demonstrated STEMI at presentation, initial TIMI 0/1 flow, multivessel SCAD, and a Beighton score >4 were associated with larger infarcts [>10% left ventricular (LV) mass].
Conclusion
The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts.

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

Eur Heart J: 02 Jan 2020; epub ahead of print
Al-Hussaini A, Abdelaty AMSEK, Gulsin GS, Arnold JR, ... McCann GP, Adlam D
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31898721
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Low and elevated B-type natriuretic peptide levels are associated with increased mortality in patients with preserved ejection fraction undergoing transcatheter aortic valve replacement: an analysis of the PARTNER II trial and registry.

Chen S, Redfors B, O\'Neill BP, Clavel MA, ... Leon MB, Lindman BR
Aims
B-type natriuretic peptide (BNP) is a cardiac neurohormone that is secreted in response to ventricular volume expansion and pressure overload. There are conflicting data regarding the association between BNP levels and outcomes after transcatheter aortic valve replacement (TAVR). We therefore sought to assess the association between baseline BNP and adverse outcomes in patients with symptomatic, severe aortic stenosis (AS), and left ventricular ejection fraction (LVEF) ≥50%, undergoing TAVR in the PARTNER 2 Trial and Registry.
Methods and results
A total of 1782 patients were included in the analysis, and BNP was evaluated both as a continuous log-transformed value and by a priori categories: low (<50 pg/mL), normal (≥50 and <100 pg/mL), moderately elevated (≥100 and <400 pg/mL), or markedly elevated (≥400 pg/mL). Clinical outcomes from discharge to 2 years were compared between patients according to their baseline BNP level, using Kaplan-Meier event rates and multivariable Cox proportional hazards regression models. After adjustment, spline curves revealed a non-linear association between log-transformed BNP and all-cause and cardiovascular mortality in which both the lowest and highest values were associated with increased mortality. Two-year all-cause mortality rates for those with low (n = 86), normal (n = 202), moderately elevated (n = 885), and markedly elevated (n = 609) baseline BNP were 20.0%, 9.8%, 17.7%, and 26.1%, respectively. In adjusted models, compared to a normal baseline BNP, low [adjusted hazard ratio (HR) 2.6, 95% confidence interval (CI) 1.3-5.0, P-value 0.005], moderately elevated (adjusted HR 1.6, 95% CI 1.0-2.6, P-value 0.06), and markedly elevated (adjusted HR 2.1, 95% CI 1.3-3.5, P-value 0.003) BNP were associated with increased all-cause mortality, driven by cardiovascular mortality.
Conclusions
In a large cohort of patients with severe symptomatic AS and preserved LVEF undergoing TAVR, all-cause and cardiovascular mortality rates at 2 years were higher in patients with low and markedly elevated BNP levels.
Clinical trial registration
https://clinicaltrials.gov/ unique identifier #NCT01314313, #NCT02184442, #NCT03222128, and #NCT03222141.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 27 Dec 2019; epub ahead of print
Chen S, Redfors B, O'Neill BP, Clavel MA, ... Leon MB, Lindman BR
Eur Heart J: 27 Dec 2019; epub ahead of print | PMID: 31883339
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction.

Ford TJ, Corcoran D, Padmanabhan S, Aman A, ... Davenport AP, Berry C
Aims
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD).
Methods and results
Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status.
Conclusion
We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina.
Trial registration
ClinicalTrials.gov: NCT03193294.

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: 22 Jan 2020; epub ahead of print
Ford TJ, Corcoran D, Padmanabhan S, Aman A, ... Davenport AP, Berry C
Eur Heart J: 22 Jan 2020; epub ahead of print | PMID: 31972008
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A.

Pasi KJ, Rangarajan S, Mitchell N, Lester W, ... Pierce GF, Wong WY
Background
Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ.
Methods
We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years.
Results
Three years after infusion, two participants (one who had received 6×10 vector genomes [vg] per kilogram of body weight and one who had received 2×10 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed.
Conclusions
Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10 vg per kilogram or 6×10 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 01 Jan 2020; 382:29-40
Pasi KJ, Rangarajan S, Mitchell N, Lester W, ... Pierce GF, Wong WY
N Engl J Med: 01 Jan 2020; 382:29-40 | PMID: 31893514
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Circulating stem cells and cardiovascular outcomes: from basic science to the clinic.

Fadini GP, Mehta A, Dhindsa DS, Bonora BM, ... Nagareddy P, Quyyumi AA

The cardiovascular and haematopoietic systems have fundamental inter-relationships during development, as well as in health and disease of the adult organism. Although haematopoietic stem cells (HSCs) emerge from a specialized haemogenic endothelium in the embryo, persistence of haemangioblasts in adulthood is debated. Rather, the vast majority of circulating stem cells (CSCs) is composed of bone marrow-derived HSCs and the downstream haematopoietic stem/progenitors (HSPCs). A fraction of these cells, known as endothelial progenitor cells (EPCs), has endothelial specification and vascular tropism. In general, the levels of HSCs, HSPCs, and EPCs are considered indicative of the endogenous regenerative capacity of the organism as a whole and, particularly, of the cardiovascular system. In the last two decades, the research on CSCs has focused on their physiologic role in tissue/organ homoeostasis, their potential application in cell therapies, and their use as clinical biomarkers. In this review, we provide background information on the biology of CSCs and discuss in detail the clinical implications of changing CSC levels in patients with cardiovascular risk factors or established cardiovascular disease. Of particular interest is the mounting evidence available in the literature on the close relationships between reduced levels of CSCs and adverse cardiovascular outcomes in different cohorts of patients. We also discuss potential mechanisms that explain this association. Beyond CSCs\' ability to participate in cardiovascular repair, levels of CSCs need to be interpreted in the context of the broader connections between haematopoiesis and cardiovascular function, including the role of clonal haematopoiesis and inflammatory myelopoiesis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 30 Dec 2019; epub ahead of print
Fadini GP, Mehta A, Dhindsa DS, Bonora BM, ... Nagareddy P, Quyyumi AA
Eur Heart J: 30 Dec 2019; epub ahead of print | PMID: 31891403
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Temporal trends in the incidence, treatment patterns, and outcomes of coronary artery disease and peripheral artery disease in the UK, 2006-2015.

Sundaram V, Bloom C, Zakeri R, Halcox J, ... Rajagopalan S, Quint JK
Aims
Most reports estimating national incidence rates of coronary (CAD) and peripheral arterial disease (PAD) have focused on stable outpatients or acute or elective hospital admissions, but not on the overall burden of disease. In this study, we report the changing trends in the population-level incidence of CAD and PAD, respectively from 2006 to 2015, statin utilization for secondary prevention and survival outcomes using multiple nationally representative data sources from the UK (primary care encounters, hospital admissions, and procedure-level data).
Methods and results
A nationally representative study of linked primary and secondary care electronic health records of 4.6 million individuals from the UK. We calculated crude and standardized annual incidence rates separately for CAD and PAD. Statin use for secondary prevention, trends in annual major vascular event rates, and mortality between 2006 and 2015, were estimated for CAD and PAD, respectively. We identified 160 376 and 70 753 patients with incident CAD and PAD, respectively. The age- and sex-standardized incidence of CAD was similar in 2006 (443 per 100 000 person-years) and 2015 [436 per 100 000 person-years; adjusted incidence rate ratio (IRR) 0.98, 95% confidence interval (CI) 0.96-1.00]. In contrast, there was a 15% decline in the standardized incidence of PAD (236 per 100 000 person-years in 2006 to 202 per 100 000 person-years in 2015; adjusted IRR 0.85, 95% CI 0.82-0.88). The proportion of incident CAD and PAD patients prescribed long-term statins, was only 66% and 55%, respectively and was less common amongst women, patients aged >70 years, with heart failure, chronic lung disease, or depression. Cardiovascular mortality declined by 43% for incident CAD (adjusted IRR 0.57, 95% CI 0.50-0.64) between 2006 and 2015 but did not decline for incident PAD (adjusted IRR 0.84, 95% CI 0.70-1.00).
Conclusion and relevance
In the UK, the standardized incidence of CAD appears stable but mortality rates are falling, whereas the standardized incidence of PAD is falling but mortality rates are not.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 27 Dec 2019; epub ahead of print
Sundaram V, Bloom C, Zakeri R, Halcox J, ... Rajagopalan S, Quint JK
Eur Heart J: 27 Dec 2019; epub ahead of print | PMID: 31883328
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clinical impact of conduction disturbances in transcatheter aortic valve replacement recipients: a systematic review and meta-analysis.

Faroux L, Chen S, Muntané-Carol G, Regueiro A, ... Nazif T, Rodés-Cabau J
Aims
The clinical impact of new-onset persistent left bundle branch block (NOP-LBBB) and permanent pacemaker implantation (PPI) on transcatheter aortic valve replacement (TAVR) recipients remains controversial. We aimed to evaluate the impact of (i) periprocedural NOP-LBBB and PPI post-TAVR on 1-year all-cause death, cardiac death, and heart failure hospitalization and (ii) NOP-LBBB on the need for PPI at 1-year follow-up.
Methods and results
We performed a systematic search from PubMed and EMBASE databases for studies reporting raw data on 1-year clinical impact of NOP-LBBB or periprocedural PPI post-TAVR. Data from 30 studies, including 7792 patients (12 studies) and 42 927 patients (21 studies) for the evaluation of the impact of NOP-LBBB and PPI after TAVR were sourced, respectively. NOP-LBBB was associated with an increased risk of all-cause death [risk ratio (RR) 1.32, 95% confidence interval (CI) 1.17-1.49; P < 0.001], cardiac death (RR 1.46, 95% CI 1.20-1.78; P < 0.001), heart failure hospitalization (RR 1.35, 95% CI 1.05-1.72; P = 0.02), and PPI (RR 1.89, 95% CI 1.58-2.27; P < 0.001) at 1-year follow-up. Periprocedural PPI after TAVR was associated with a higher risk of all-cause death (RR 1.17, 95% CI 1.11-1.25; P < 0.001) and heart failure hospitalization (RR 1.18, 95% CI 1.03-1.36; P = 0.02). Permanent pacemaker implantation was not associated with an increased risk of cardiac death (RR 0.84, 95% CI 0.67-1.05; P = 0.13).
Conclusion
NOP-LBBB and PPI after TAVR are associated with an increased risk of all-cause death and heart failure hospitalization at 1-year follow-up. Periprocedural NOP-LBBB also increased the risk of cardiac death and PPI within the year following the procedure. Further studies are urgently warranted to enhance preventive measures and optimize the management of conduction disturbances post-TAVR.

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 Jan 2020; epub ahead of print
Faroux L, Chen S, Muntané-Carol G, Regueiro A, ... Nazif T, Rodés-Cabau J
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31899484
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Complete revascularization reduces cardiovascular death in patients with ST-segment elevation myocardial infarction and multivessel disease: systematic review and meta-analysis of randomized clinical trials.

Pavasini R, Biscaglia S, Barbato E, Tebaldi M, ... D\'Ascenzo F, Campo G
Aims
The aim of this work was to investigate the prognostic impact of revascularization of non-culprit lesions in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease by performing a meta-analysis of available randomized clinical trials (RCTs).
Methods and results
Data from six RCTs comparing complete vs. culprit-only revascularization in STEMI patients with multivessel disease were analysed with random effect generic inverse variance method meta-analysis. The endpoints were expressed as hazard ratio (HR) with 95% confidence interval (CI). The primary outcome was cardiovascular death. Main secondary outcomes of interest were all-cause death, myocardial infarction (MI), and repeated coronary revascularization. Overall, 6528 patients were included (3139 complete group, 3389 culprit-only group). After a follow-up ranging between 1 and 3 years (median 2 years), cardiovascular death was significantly reduced in the group receiving complete revascularization (HR 0.62, 95% CI 0.39-0.97, I2 = 29%). The number needed to treat to prevent one cardiovascular death was 70 (95% CI 36-150). The secondary endpoints MI and revascularization were also significantly reduced (HR 0.68, 95% CI 0.55-0.84, I2 = 0% and HR 0.29, 95% CI 0.22-0.38, I2 = 36%, respectively). Needed to treats were 45 (95% CI 37-55) for MI and 8 (95% CI 5-13) for revascularization. All-cause death (HR 0.81, 95% CI 0.56-1.16, I2 = 27%) was not affected by the revascularization strategy.
Conclusion
In a selected study population of STEMI patients with multivessel disease, a complete revascularization strategy is associated with a reduction in cardiovascular death. This reduction is concomitant with that of MI and the need of repeated revascularization.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 30 Dec 2019; epub ahead of print
Pavasini R, Biscaglia S, Barbato E, Tebaldi M, ... D'Ascenzo F, Campo G
Eur Heart J: 30 Dec 2019; epub ahead of print | PMID: 31891653
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort.

Elliott AD, Linz D, Mishima R, Kadhim K, ... La Gerche A, Sanders P
Aims
Physical activity reduces cardiovascular disease burden and mortality, although its relationship with cardiac arrhythmias is less certain. The aim of this study was to assess the association between self-reported physical activity and atrial fibrillation (AF), ventricular arrhythmias and bradyarrhythmias, across the UK Biobank cohort.
Methods and results
We included 402 406 individuals (52.5% female), aged 40-69 years, with over 2.8 million person-years of follow-up who underwent self-reported physical activity assessment computed in metabolic equivalent-minutes per week (MET-min/wk) at baseline, detailed physical assessment and medical history evaluation. Arrhythmia episodes were diagnosed through hospital admissions and death reports. Incident AF risk was lower amongst physically active participants, with a more pronounced reduction amongst female participants [hazard ratio (HR) for 1500 vs. 0 MET-min/wk: 0.85, 95% confidence interval (CI) 0.74-0.98] than males (HR for 1500 vs. 0 MET-min/wk: 0.90, 95% CI 0.82-1.0). Similarly, we observed a significantly lower risk of ventricular arrhythmias amongst physically active participants (HR for 1500 MET-min/wk 0.78, 95% CI 0.64-0.96) that remained relatively stable over a broad range of physical activity levels between 0 and 2500 MET-min/wk. A lower AF risk amongst female participants who engaged in moderate levels of vigorous physical activity was observed (up to 2500 MET-min/wk). Vigorous physical activity was also associated with reduced ventricular arrhythmia risk. Total or vigorous physical activity was not associated with bradyarrhythmias.
Conclusion
The risk of AF and ventricular arrhythmias is lower amongst physically active individuals. These findings provide observational support that physical activity is associated with reduced risk of atrial and ventricular arrhythmias.

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: 16 Jan 2020; epub ahead of print
Elliott AD, Linz D, Mishima R, Kadhim K, ... La Gerche A, Sanders P
Eur Heart J: 16 Jan 2020; epub ahead of print | PMID: 31951255
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Changes in Quality of Care after Hospital Mergers and Acquisitions.

Beaulieu ND, Dafny LS, Landon BE, Dalton JB, Kuye I, McWilliams JM
Background
The hospital industry has consolidated substantially during the past two decades and at an accelerated pace since 2010. Multiple studies have shown that hospital mergers have led to higher prices for commercially insured patients, but research about effects on quality of care is limited.
Methods
Using Medicare claims and Hospital Compare data from 2007 through 2016 on performance on four measures of quality of care (a composite of clinical-process measures, a composite of patient-experience measures, mortality, and the rate of readmission after discharge) and data on hospital mergers and acquisitions occurring from 2009 through 2013, we conducted difference-in-differences analyses comparing changes in the performance of acquired hospitals from the time before acquisition to the time after acquisition with concurrent changes for control hospitals that did not have a change in ownership.
Results
The study sample included 246 acquired hospitals and 1986 control hospitals. Being acquired was associated with a modest differential decline in performance on the patient-experience measure (adjusted differential change, -0.17 SD; 95% confidence interval [CI], -0.26 to -0.07; P = 0.002; the change was analogous to a fall from the 50th to the 41st percentile) and no significant differential change in 30-day readmission rates (-0.10 percentage points; 95% CI, -0.53 to 0.34; P = 0.72) or in 30-day mortality (-0.03 percentage points; 95% CI, -0.20 to 0.14; P = 0.72). Acquired hospitals had a significant differential improvement in performance on the clinical-process measure (0.22 SD; 95% CI, 0.05 to 0.38; P = 0.03), but this could not be attributed conclusively to a change in ownership because differential improvement occurred before acquisition.
Conclusions
Hospital acquisition by another hospital or hospital system was associated with modestly worse patient experiences and no significant changes in readmission or mortality rates. Effects on process measures of quality were inconclusive. (Funded by the Agency for Healthcare Research and Quality.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 01 Jan 2020; 382:51-59
Beaulieu ND, Dafny LS, Landon BE, Dalton JB, Kuye I, McWilliams JM
N Engl J Med: 01 Jan 2020; 382:51-59 | PMID: 31893515
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Health Care Hotspotting - A Randomized, Controlled Trial.

Finkelstein A, Zhou A, Taubman S, Doyle J
Background
There is widespread interest in programs aiming to reduce spending and improve health care quality among \"superutilizers,\" patients with very high use of health care services. The \"hotspotting\" program created by the Camden Coalition of Healthcare Providers (hereafter, the Coalition) has received national attention as a promising superutilizer intervention and has been expanded to cities around the country. In the months after hospital discharge, a team of nurses, social workers, and community health workers visits enrolled patients to coordinate outpatient care and link them with social services.
Methods
We randomly assigned 800 hospitalized patients with medically and socially complex conditions, all with at least one additional hospitalization in the preceding 6 months, to the Coalition\'s care-transition program or to usual care. The primary outcome was hospital readmission within 180 days after discharge.
Results
The 180-day readmission rate was 62.3% in the intervention group and 61.7% in the control group. The adjusted between-group difference was not significant (0.82 percentage points; 95% confidence interval, -5.97 to 7.61). In contrast, a comparison of the intervention-group admissions during the 6 months before and after enrollment misleadingly suggested a 38-percentage-point decline in admissions related to the intervention because the comparison did not account for the similar decline in the control group.
Conclusions
In this randomized, controlled trial involving patients with very high use of health care services, readmission rates were not lower among patients randomly assigned to the Coalition\'s program than among those who received usual care. (Funded by the National Institute on Aging and others; ClinicalTrials.gov number, NCT02090426; American Economic Association registry number, AEARCTR-0000329.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 08 Jan 2020; 382:152-162
Finkelstein A, Zhou A, Taubman S, Doyle J
N Engl J Med: 08 Jan 2020; 382:152-162 | PMID: 31914242
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Echocardiographic phenotype and prognosis in transthyretin cardiac amyloidosis.

Chacko L, Martone R, Bandera F, Lane T, ... Gillmore JD, Fontana M
Aims
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. We sought to characterize the structural and functional echocardiographic phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis.
Methods and results
We studied 1240 patients with ATTR-CM who underwent prospective protocolized evaluations comprising full echocardiographic assessment and survival between 2000 and 2019, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60AhATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e\' were all independently associated with mortality (P < 0.05 for all). Severe aortic stenosis (AS) was also independently associated with prognosis, conferring a significantly shorter survival (median survival 22 vs. 53 months, P = 0.001).
Conclusion
The three distinct genotypes present with varying degrees of severity. Echocardiography indicates a complex pathophysiology in which both systolic and diastolic function are independently associated with mortality. The presence of severe AS was independently associated with significantly reduced patient survival.

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: 16 Jan 2020; epub ahead of print
Chacko L, Martone R, Bandera F, Lane T, ... Gillmore JD, Fontana M
Eur Heart J: 16 Jan 2020; epub ahead of print | PMID: 31950987
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study.

Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Aims
To evaluate the fracture risk among patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin.
Methods and results
We conducted a real-world nationwide retrospective cohort study using Taiwan\'s National Health Insurance Research Database. All adult patients in Taiwan newly diagnosed with AF between 2012 and 2016 who received NOACs or warfarin were enrolled and followed up until 2017. Patients treated with NOACs were sub-grouped according to the NOAC used (dabigatran, rivaroxaban, and apixaban). Propensity score matching was performed for each head-to-head comparison. Cox regression analysis, with a shared frailty model, was used to calculate the adjusted hazard ratios (aHRs) for hip, vertebral, and humerus/forearm/wrist fractures. After matching, 19 414 patients were included (9707 in each NOAC and warfarin groups). The median follow-up time was 2.4 years. Compared with warfarin, NOACs were associated with a reduced fracture risk [aHR = 0.84, 95% confidence interval (CI) = 0.77-0.93; P < 0.001]. Sub-analyses revealed that each NOAC, namely dabigatran (aHR = 0.88, 95% CI = 0.78-0.99; P = 0.027), rivaroxaban (aHR = 0.81, 95% CI = 0.72-0.90; P < 0.001), and apixaban (aHR = 0.67, 95% CI = 0.52-0.87; P = 0.003), had a reduced fracture risk. Analyses including all eligible patients, without propensity score matching, generated similar results.
Conclusion
Compared with warfarin, NOAC was associated with a reduced fracture risk among AF patients. Therefore, if oral anticoagulants are indicated, NOACs rather than warfarin should be considered to lower the risk of fractures. However, further studies are needed to investigate the underlying mechanisms and elucidate causality.

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: 31 Jan 2020; epub ahead of print
Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Eur Heart J: 31 Jan 2020; epub ahead of print | PMID: 32006423
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Trends in U.S. Ambulatory Cardiovascular Care 2013 to 2017: JACC Review Topic of the Week.

Maddox TM, Song Y, Allen J, Chan PS, ... Virani SS, Masoudi FA

The National Cardiovascular Data Registry PINNACLE (Practice Innovation and Clinical Excellence) Registry is the largest outpatient cardiovascular practice registry in the world. It tracks real-world management and quality of 4 common cardiovascular conditions: heart failure, coronary artery disease, atrial fibrillation, and hypertension. In 2013, the PINNACLE Registry contained information on 2,898,505 patients, cared for by 4,859 providers in 431 practices. By 2017, the registry contained information on 6,040,996 patients, cared for by 8,853 providers in 724 practices. During this time period, care processes for PINNACLE patients generally improved. Among patients with heart failure, combined beta-blocker and renin-angiotensin antagonist medication rates increased from 60.7% to 72.8%. Among patients with coronary artery disease, statin medication rates increased from 66% to 80.1%. Among patients with atrial fibrillation, oral anticoagulation rates increased from 52.7% to 65.2%. In contrast, blood pressure control rates among patients with hypertension were largely stable. PINNACLE data also fueled a variety of quality measurement programs and 51 peer-reviewed publications.

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

J Am Coll Cardiol: 06 Jan 2020; 75:93-112
Maddox TM, Song Y, Allen J, Chan PS, ... Virani SS, Masoudi FA
J Am Coll Cardiol: 06 Jan 2020; 75:93-112 | PMID: 31918838
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Fractional flow reserve in clinical practice: from wire-based invasive measurement to image-based computation.

Tu S, Westra J, Adjedj J, Ding D, ... Reiber JHC, Wijns W

Fractional flow reserve (FFR) and instantaneous wave-free ratio are the present standard diagnostic methods for invasive assessment of the functional significance of epicardial coronary stenosis. Despite the overall trend towards more physiology-guided revascularization, there remains a gap between guideline recommendations and the clinical adoption of functional evaluation of stenosis severity. A number of image-based approaches have been proposed to compute FFR without the use of pressure wire and induced hyperaemia. In order to better understand these emerging technologies, we sought to highlight the principles, diagnostic performance, clinical applications, practical aspects, and current challenges of computational physiology in the catheterization laboratory. Computational FFR has the potential to expand and facilitate the use of physiology for diagnosis, procedural guidance, and evaluation of therapies, with anticipated impact on resource utilization and patient outcomes.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 29 Dec 2019; epub ahead of print
Tu S, Westra J, Adjedj J, Ding D, ... Reiber JHC, Wijns W
Eur Heart J: 29 Dec 2019; epub ahead of print | PMID: 31886479
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Sex associations and computed tomography coronary angiography-guided management in patients with stable chest pain.

Mangion K, Adamson PD, Williams MC, Hunter A, ... McAllister DA, Berry C
Aims
The relative benefits of computed tomography coronary angiography (CTCA)-guided management in women and men with suspected angina due to coronary heart disease (CHD) are uncertain.
Methods and results
In this post hoc analysis of an open-label parallel-group multicentre trial, we recruited 4146 patients referred for assessment of suspected angina from 12 cardiology clinics across the UK. We randomly assigned (1:1) participants to standard care alone or standard care plus CTCA. Fewer women had typical chest pain symptoms (n = 582, 32.0%) when compared with men (n = 880, 37.9%; P < 0.001). Amongst the CTCA-guided group, more women had normal coronary arteries [386 (49.6%) vs. 263 (26.2%)] and less obstructive CHD [105 (11.5%) vs. 347 (29.8%)]. A CTCA-guided strategy resulted in more women than men being reclassified as not having CHD {19.2% vs. 13.1%; absolute risk difference, 5.7 [95% confidence interval (CI): 2.7-8.7, P < 0.001]} or having angina due to CHD [15.0% vs. 9.0%; absolute risk difference, 5.6 (2.3-8.9, P = 0.001)]. After a median of 4.8 years follow-up, CTCA-guided management was associated with similar reductions in the risk of CHD death or non-fatal myocardial infarction in women [hazard ratio (HR) 0.50, 95% CI 0.24-1.04], and men (HR 0.63, 95% CI 0.42-0.95; Pinteraction = 0.572).
Conclusion
Following the addition of CTCA, women were more likely to be found to have normal coronary arteries than men. This led to more women being reclassified as not having CHD, resulting in more downstream tests and treatments being cancelled. There were similar prognostic benefits of CTCA for women and men.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 27 Dec 2019; epub ahead of print
Mangion K, Adamson PD, Williams MC, Hunter A, ... McAllister DA, Berry C
Eur Heart J: 27 Dec 2019; epub ahead of print | PMID: 31883330
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

Juul SE, Comstock BA, Wadhawan R, Mayock DE, ... Heagerty PJ,
Background
High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established.
Methods
In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.
Results
A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events.
Conclusions
High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Jan 2020; 382:233-243
Juul SE, Comstock BA, Wadhawan R, Mayock DE, ... Heagerty PJ,
N Engl J Med: 15 Jan 2020; 382:233-243 | PMID: 31940698
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes.

Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, ... Komrokji RS, List AF
Background
Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study.
Methods
In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48.
Results
Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time.
Conclusions
Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 08 Jan 2020; 382:140-151
Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, ... Komrokji RS, List AF
N Engl J Med: 08 Jan 2020; 382:140-151 | PMID: 31914241
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Soluble Urokinase Receptor and Acute Kidney Injury.

Hayek SS, Leaf DE, Samman Tahhan A, Raad M, ... Quyyumi AA, Reiser J
Background
Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target.
Methods
We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR.
Results
The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells.
Conclusions
High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:416-426
Hayek SS, Leaf DE, Samman Tahhan A, Raad M, ... Quyyumi AA, Reiser J
N Engl J Med: 29 Jan 2020; 382:416-426 | PMID: 31995687
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis.

Stojanović SD, Fiedler J, Bauersachs J, Thum T, Sedding DG

Inflammation is a hallmark and potent driver of pathological vascular remodelling in atherosclerosis. However, current anti-inflammatory therapeutic strategies have shown mixed results. As an alternative perspective on the conundrum of chronic inflammation emerging evidence points towards a small subset of senescent cells as a critical player and central node driving atherosclerosis. Senescent cells belonging to various cell types are a dominant and chronic source of a large array of pro-inflammatory cytokines and various additional plaque destabilizing factors, being involved with various aspects of atherosclerosis pathogenesis. Antagonizing these key agitators of local chronic inflammation and plaque instability may provide a causative and multi-purpose therapeutic strategy to treat atherosclerosis. Anti-senescence treatment options with translational potential are currently in development. However, several questions and challenges remain to be addressed before these novel treatment approaches may enter the clinical setting.

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

Eur Heart J: 02 Jan 2020; epub ahead of print
Stojanović SD, Fiedler J, Bauersachs J, Thum T, Sedding DG
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31898722
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.

Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, ... Witztum JL,
Background
Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels.
Methods
We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-L, referred to here as APO(a)-L (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses).
Results
The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-L resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-L dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions.
Conclusions
APO(a)-L reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 31 Dec 2019; epub ahead of print
Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, ... Witztum JL,
N Engl J Med: 31 Dec 2019; epub ahead of print | PMID: 31893580
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Aims
Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes.
Methods and results
One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson\'s trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01].
Conclusion
Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

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

Eur Heart J: 11 Feb 2020; epub ahead of print
Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Eur Heart J: 11 Feb 2020; epub ahead of print | PMID: 32049275
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction.

Carnevale R, Sciarretta S, Valenti V, di Nonno F, ... Tanzilli G, Violi F
Aims
Low-grade endotoxaemia is detectable in human circulation but its role in thrombosis is still unclear.
Methods and results
We measured serum lipopolysaccharide (LPS) concentration, soluble P-selectin (sP-selectin), a marker of platelet activation, and zonulin, a marker of gut permeability, in peripheral circulation, coronary thrombi, and intracoronary blood of patients with ST-elevation myocardial infarction (STEMI, n = 50) and stable angina (SA) (n = 50), respectively, and in controls (n = 50). Experimental study was carried out in mice to assess if Escherichia coli-LPS (E. coli-LPS) possess thrombotic property. Coronary thrombi from STEMI showed higher concentrations of LPS, sP-selectin vs. intracoronary blood of SA and peripheral blood of controls (P < 0.001). Zonulin was higher in STEMI compared to the other two groups [4.57 (3.34-5.22); 2.56 (0.41-4.36); 1.95 (1.22-2.65) ng/mL; P < 0.001] and correlated with LPS (Rs = 0.585; P < 0.001). Escherichia coli DNA was positive in 34% of STEMI vs. 12% of SA and 4% of controls (P < 0.001). In a subgroup of 12 STEMI, immunohistochemical analysis of coronary thrombi showed positivity for leucocyte Toll-like receptor 4 (TLR4), cathepsin G, and LPS from E. coli in 100%, 80%, and 25% of samples, respectively. E. coli-LPS injected in mice to reach LPS concentrations like those detected in coronary thrombi was associated with enhanced artery thrombosis and platelet activation, an effect blunted by TLR4 inhibitor co-administration. In vitro study demonstrated that LPS from E. coli enhanced platelet aggregation via TLR4-mediated leucocyte cathepsin G activation.
Conclusion
ST-elevation myocardial infarction patients disclose an enhanced gut permeability that results in LPS translocation in human circulation and eventually thrombus growth at site of artery lesion via leucocyte-platelet interaction.

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 Jan 2020; epub ahead of print
Carnevale R, Sciarretta S, Valenti V, di Nonno F, ... Tanzilli G, Violi F
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31898723
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A Novel Coronavirus from Patients with Pneumonia in China, 2019.

Zhu N, Zhang D, Wang W, Li X, ... Tan W,

In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed another clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 23 Jan 2020; epub ahead of print
Zhu N, Zhang D, Wang W, Li X, ... Tan W,
N Engl J Med: 23 Jan 2020; epub ahead of print | PMID: 31978945
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Long-term clinical outcome and performance of transcatheter aortic valve replacement with a self-expandable bioprosthesis.

Testa L, Latib A, Brambilla N, De Marco F, ... Petronio AS, Bedogni F
Aims 
In the last decade, transcatheter aortic valve (TAV) replacement determined a paradigm shift in the treatment of patients with severe symptomatic aortic stenosis. Data on long-term TAV performance are still limited. We sought to evaluate the clinical and haemodynamic outcomes of the CoreValve self-expandable valve up to 8-year follow-up (FU).
Methods and results 
Nine hundred and ninety inoperable or high-risk patients were treated with the CoreValve TAV in eight Italian Centres from June 2007 to December 2011. The median FU was 4.4 years (interquartile range 1.4-6.7 years). Longest FU reached 11 years. A total of 728 died within 8-year FU (78.3% mortality from Kaplan-Meier curve analysis). A significant functional improvement was observed in the majority of patients and maintained over time, with 79.3% of surviving patients still classified New York Heart Association class ≤ II at 8 years. Echocardiographic data showed that the mean transprosthetic aortic gradient remained substantially unchanged (9 ± 4 mmHg at discharge, 9 ± 5 mmHg at 8 years, P = 0.495). The rate of Grade 0/1 paravalvular leak was consistent during FU with no significant change from post-procedure to FU ≥5 years in paired analysis (P = 0.164). Structural valve deterioration (SVD) and late bioprosthetic valve failure (BVF) were defined according to a modification of the 2017 EAPCI/ESC/EACTS criteria. In cumulative incidence functions at 8 years, moderate and severe SVD were 3.0% [95% confidence interval (CI) 2.1-4.3%] and 1.6% (95% CI 0.6-3.9%), respectively, while late BVF was 2.5% (95% CI 1.2-5%).
Conclusion 
While TAVs are questioned about long-term performance and durability, the results of the present research provide reassuring 8-year evidence on the CoreValve first-generation self-expandable bioprosthesis.

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

Eur Heart J: 05 Jan 2020; epub ahead of print
Testa L, Latib A, Brambilla N, De Marco F, ... Petronio AS, Bedogni F
Eur Heart J: 05 Jan 2020; epub ahead of print | PMID: 31904800
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Meningococcal B Vaccine and Meningococcal Carriage in Adolescents in Australia.

Marshall HS, McMillan M, Koehler AP, Lawrence A, ... Vadivelu K, Richmond P
Background
The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain.
Methods
We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing(group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for(encoding porin protein A) andgenogroups. Secondary outcomes included carriage prevalence and acquisition of alland individual disease-causing genogroups. Risk factors for carriage were assessed at baseline.
Results
A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causingbetween the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P = 0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causingincluded later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified.
Conclusions
Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 22 Jan 2020; 382:318-327
Marshall HS, McMillan M, Koehler AP, Lawrence A, ... Vadivelu K, Richmond P
N Engl J Med: 22 Jan 2020; 382:318-327 | PMID: 31971677
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture.

Luo W, Wang Y, Zhang L, Ren P, ... LeMaire SA, Shen YH
Background
Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation.
Methods
The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in -deficient () mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro.
Results
In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model,mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challengedmice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development.
Conclusions
Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.



Circulation: 06 Jan 2020; 141:42-66
Luo W, Wang Y, Zhang L, Ren P, ... LeMaire SA, Shen YH
Circulation: 06 Jan 2020; 141:42-66 | PMID: 31887080
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency.

Drutman SB, Mansouri D, Mahdaviani SA, Neehus AL, ... Nathan C, Casanova JL
Background
Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 () are susceptible to the related murine CMV infection.
Methods
We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally.
Results
We found a homozygous frameshift mutation inencoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, allvariants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001.
Conclusions
These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:437-445
Drutman SB, Mansouri D, Mahdaviani SA, Neehus AL, ... Nathan C, Casanova JL
N Engl J Med: 29 Jan 2020; 382:437-445 | PMID: 31995689
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group.

Seligman WH, Das-Gupta Z, Jobi-Odeneye AO, Arbelo E, ... Yutao G, Camm AJ
Aims
As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings.
Methods and results
Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set.
Conclusion
Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

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

Eur Heart J: 28 Jan 2020; epub ahead of print
Seligman WH, Das-Gupta Z, Jobi-Odeneye AO, Arbelo E, ... Yutao G, Camm AJ
Eur Heart J: 28 Jan 2020; epub ahead of print | PMID: 31995195
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Variation in Bystander Cardiopulmonary Resuscitation Delivery and Subsequent Survival From Out-of-Hospital Cardiac Arrest Based on Neighborhood-Level Ethnic Characteristics.

Blewer AL, Schmicker RH, Morrison LJ, Aufderheide TP, ... Abella BS,
Background
Bystander cardiopulmonary resuscitation (B-CPR) delivery and survival after out-of-hospital cardiac arrest vary at the neighborhood level, with lower survival seen in predominantly black neighborhoods. Although the Hispanic population is the fastest-growing minority population in the United States, few studies have assessed whether the proportion of Hispanic residents in a neighborhood is associated with B-CPR delivery and survival from out-of-hospital cardiac arrest. We assessed whether B-CPR rates and survival vary by neighborhood-level ethnicity. We hypothesized that neighborhoods with a higher proportion of Hispanic residents have lower B-CPR rates and lower survival.
Methods
We conducted a retrospective cohort study using data from the Resuscitation Outcomes Consortium Epistry at US sites. Neighborhoods were classified by census tract based on percentage of Hispanic residents: <25%, 25% to 50%, 51% to 75%, or >75%. We independently modeled the likelihood of receipt of B-CPR and survival by neighborhood-level ethnicity controlling for site and patient-level confounding characteristics.
Results
From 2011 to 2015, the Resuscitation Outcomes Consortium collected 27 481 US arrest events; after excluding pediatric arrests, emergency medical services-witnessed arrests, or arrests occurring in a healthcare or institutional facility, 18 927 were included. B-CPR was administered in 37% of events. In neighborhoods with <25% Hispanic residents, B-CPR was administered in 39% of events, whereas it was administered in 27% of events in neighborhoods with >75% Hispanic residents. Compared with <25% Hispanic neighborhoods in a multivariable analysis, out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods had lower B-CPR rates (51% to 75% Hispanic: odds ratio, 0.79 [CI, 0.65-0.95], =0.014; >75% Hispanic: odds ratio, 0.72 [CI, 0.55-0.96], =0.025) and lower survival rates (globalvalue 0.029; >75% Hispanic: odds ratio, 0.56 [CI, 0.34-0.93], =0.023).
Conclusions
Individuals with out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods were less likely to receive B-CPR and had lower likelihood of survival. These findings suggest a need to understand the underlying disparities in cardiopulmonary resuscitationdelivery and an unmet cardiopulmonary resuscitationtraining need in Hispanic communities.



Circulation: 06 Jan 2020; 141:34-41
Blewer AL, Schmicker RH, Morrison LJ, Aufderheide TP, ... Abella BS,
Circulation: 06 Jan 2020; 141:34-41 | PMID: 31887076
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Vaccination of Infants with Meningococcal Group B Vaccine (4CMenB) in England.

Ladhani SN, Andrews N, Parikh SR, Campbell H, ... Borrow R, Ramsay ME
Background
In September 2015, the United Kingdom introduced the multicomponent meningococcal group B vaccine (4CMenB, Bexsero) into its publicly funded national immunization program at a reduced two-dose priming schedule for infants, with a 12-month booster.
Methods
Using data from enhanced national surveillance of invasive meningococcal disease in England, we evaluated the effect of vaccination on the incidence of meningococcal group B disease during the first 3 years of the program. The effect of vaccination was assessed by comparing the observed incidence of disease with the expected incidence based on the incidence during the 4-year prevaccination period in equivalent cohorts and with the use of disease trends in cohorts of children younger than 5 years of age who were not eligible to receive the vaccine. Vaccine effectiveness was estimated with the use of the indirect screening method.
Results
4CMenB uptake in England remained consistently high; data from the first 3 months of 2018 showed that 92.5% of children had completed the primary immunizations by their first birthday and 87.9% had received all three doses by 2 years. From September 2015 through August 2018, the incidence of meningococcal group B disease in England (average annual birth cohort, approximately 650,000 infants) was significantly lower in vaccine-eligible cohorts than the expected incidence (63 observed cases as compared with 253 expected cases; incidence rate ratio, 0.25; 95% confidence interval [CI], 0.19 to 0.36), with a 75% reduction in age groups that were fully eligible for vaccination. The adjusted vaccine effectiveness against meningococcal group B disease was 52.7% (95% CI, -33.5 to 83.2) with a two-dose priming schedule for infants and 59.1% (95% CI, -31.1 to 87.2) with a two-dose priming schedule plus a booster at 1 year). Over the 3-year period, there were 169 cases of meningococcal group B disease in the vaccine-eligible cohorts, and an estimated 277 cases (95% CI, 236 to 323) were prevented.
Conclusions
The 4CMenB program was associated with continued positive effect against meningococcal group B disease in children in England, and protection after three doses of the vaccine was sustained for at least 2 years. (Funded by Public Health England.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 22 Jan 2020; 382:309-317
Ladhani SN, Andrews N, Parikh SR, Campbell H, ... Borrow R, Ramsay ME
N Engl J Med: 22 Jan 2020; 382:309-317 | PMID: 31971676
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.

Schlaff WD, Ackerman RT, Al-Hendy A, Archer DF, ... Watts NB, Muneyyirci-Delale O
Background
Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding.
Methods
We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal \"add-back\" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation.
Results
A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy.
Conclusions
Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 22 Jan 2020; 382:328-340
Schlaff WD, Ackerman RT, Al-Hendy A, Archer DF, ... Watts NB, Muneyyirci-Delale O
N Engl J Med: 22 Jan 2020; 382:328-340 | PMID: 31971678
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Conservative versus Interventional Treatment for Spontaneous Pneumothorax.

Brown SGA, Ball EL, Perrin K, Asha SE, ... Beasley R,
Background
Whether conservative management is an acceptable alternative to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax is unknown.
Methods
In this open-label, multicenter, noninferiority trial, we recruited patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax. Patients were randomly assigned to immediate interventional management of the pneumothorax (intervention group) or a conservative observational approach (conservative-management group) and were followed for 12 months. The primary outcome was lung reexpansion within 8 weeks.
Results
A total of 316 patients underwent randomization (154 patients to the intervention group and 162 to the conservative-management group). In the conservative-management group, 25 patients (15.4%) underwent interventions to manage the pneumothorax, for reasons prespecified in the protocol, and 137 (84.6%) did not undergo interventions. In a complete-case analysis in which data were not available for 23 patients in the intervention group and 37 in the conservative-management group, reexpansion within 8 weeks occurred in 129 of 131 patients (98.5%) with interventional management and in 118 of 125 (94.4%) with conservative management (risk difference, -4.1 percentage points; 95% confidence interval [CI], -8.6 to 0.5; P = 0.02 for noninferiority); the lower boundary of the 95% confidence interval was within the prespecified noninferiority margin of -9 percentage points. In a sensitivity analysis in which all missing data after 56 days were imputed as treatment failure (with reexpansion in 129 of 138 patients [93.5%] in the intervention group and in 118 of 143 [82.5%] in the conservative-management group), the risk difference of -11.0 percentage points (95% CI, -18.4 to -3.5) was outside the prespecified noninferiority margin. Conservative management resulted in a lower risk of serious adverse events or pneumothorax recurrence than interventional management.
Conclusions
Although the primary outcome was not statistically robust to conservative assumptions about missing data, the trial provides modest evidence that conservative management of primary spontaneous pneumothorax was noninferior to interventional management, with a lower risk of serious adverse events. (Funded by the Emergency Medicine Foundation and others; PSP Australian New Zealand Clinical Trials Registry number, ACTRN12611000184976.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:405-415
Brown SGA, Ball EL, Perrin K, Asha SE, ... Beasley R,
N Engl J Med: 29 Jan 2020; 382:405-415 | PMID: 31995686
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency.

Alsohime F, Martin-Fernandez M, Temsah MH, Alabdulhafid M, ... Bogunovic D, Alangari AA

Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on . The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Jan 2020; 382:256-265
Alsohime F, Martin-Fernandez M, Temsah MH, Alabdulhafid M, ... Bogunovic D, Alangari AA
N Engl J Med: 15 Jan 2020; 382:256-265 | PMID: 31940699
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

S-Nitrosylation of Muscle LIM Protein Facilitates Myocardial Hypertrophy Through Toll-Like Receptor 3-Mediated Receptor-Interacting Protein Kinase 3 and NLRP3 Inflammasome Activation.

Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y

S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of S-nitrosylation of muscle LIM protein (MLP) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload.Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. S-nitrosylation sites were further identified through liquid chromatography-tandem mass spectrometry (LCMS/MS). Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase (GSNOR) was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry (MS) and confirmed by co-immunoprecipitation. Recruitment of toll-like receptor 3 (TLR3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA (siRNA)-transfected neonatal rat cardiomyocytes (NRCMs) and in TLR3 knockout mouse model.SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction (TAC). The level of SNO-MLP also increased in angiotensin II (Ang II) or phenylephrine (PE)-treated NRCMs. S-nitrosylated site of MLP at cysteine (Cys) 79 was identified by LCMS/MS and further confirmed in NRCMs. Mutation of Cys79 significantly reduced hypertrophic growth in Ang II or PE-treated NRCMs and TAC mice. Reducing MLP Snitrosylation level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, MLP S-nitrosylation stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupting this interaction by downregulating TLR3 attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and receptor-interacting protein kinase 3 (RIP3). This interaction in turn induced NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting the development of myocardial hypertrophy.Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a novel therapeutic target for myocardial hypertrophy and heart failure.



Circulation: 05 Jan 2020; epub ahead of print
Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y
Circulation: 05 Jan 2020; epub ahead of print | PMID: 31902237
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease.

Liberale L, Montecucco F, Tardif JC, Libby P, Camici GG

The ongoing worldwide increase in life expectancy portends a rising prevalence of age-related cardiovascular (CV) diseases in the coming decades that demands a deeper understanding of their molecular mechanisms. Inflammation has recently emerged as an important contributor for CV disease development. Indeed, a state of chronic sterile low-grade inflammation characterizes older organisms (also known as inflamm-ageing) and participates pivotally in the development of frailty, disability, and most chronic degenerative diseases including age-related CV and cerebrovascular afflictions. Due to chronic activation of inflammasomes and to reduced endogenous anti-inflammatory mechanisms, inflamm-ageing contributes to the activation of leucocytes, endothelial, and vascular smooth muscle cells, thus accelerating vascular ageing and atherosclerosis. Furthermore, inflamm-ageing promotes the development of catastrophic athero-thrombotic complications by enhancing platelet reactivity and predisposing to plaque rupture and erosion. Thus, inflamm-ageing and its contributors or molecular mediators might furnish targets for novel therapeutic strategies that could promote healthy ageing and conserve resources for health care systems worldwide. Here, we discuss recent findings in the pathophysiology of inflamm-ageing, the impact of these processes on the development of age-related CV diseases, results from clinical trials targeting its components and the potential implementation of these advances into daily clinical practice.

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: 31 Jan 2020; epub ahead of print
Liberale L, Montecucco F, Tardif JC, Libby P, Camici GG
Eur Heart J: 31 Jan 2020; epub ahead of print | PMID: 32006431
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry.

López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, ... Cadenas Chamorro R, López Fernández T
Aim
Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking.
Methods and results
We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40-49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22-40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5-19.2) (P < 0.001).
Conclusions
The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.

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: 03 Feb 2020; epub ahead of print
López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, ... Cadenas Chamorro R, López Fernández T
Eur Heart J: 03 Feb 2020; epub ahead of print | PMID: 32016393
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Teprotumumab for the Treatment of Active Thyroid Eye Disease.

Douglas RS, Kahaly GJ, Patel A, Sile S, ... Holt RJ, Smith TJ
Background
Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease.
Methods
In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves\' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful).
Results
A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation.
Conclusions
Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 22 Jan 2020; 382:341-352
Douglas RS, Kahaly GJ, Patel A, Sile S, ... Holt RJ, Smith TJ
N Engl J Med: 22 Jan 2020; 382:341-352 | PMID: 31971679
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study.

Schnorbus B, Daiber A, Jurk K, Warnke S, ... Münzel T, Gori T
Aims
In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome.
Methods and results
The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor group (both P < 0.01), but not in the prasugrel group. During follow-up, prasugrel was superior to clopidogrel [mean difference 2.13, 95% confidence interval (CI) 0.68-3.58; P = 0.0047] and ticagrelor (mean difference 1.57, 95% CI 0.31-2.83; P = 0.0155), but this difference was limited to patients who received the study therapy 2 h before stenting. Ticagrelor was not significantly superior to clopidogrel (mean difference 0.55, 95% CI -0.73 to 1.82; P = 0.39). No significant differences were seen among groups for low-flow-mediated dilation. Plasma interleukin (IL)-6 (P = 0.02 and P = 0.01, respectively) and platelet aggregation reactivity in response to adenosine diphosphate (P = 0.002 and P = 0.035) were lower in the prasugrel compared to clopidogrel and ticagrelor group.
Conclusion
As compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an acute coronary syndrome is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels, all of which may have prognostic implications. This effect was lost in patients who received the study medication immediately after stenting.
Eudract-no
2011-005305-73.

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 Jan 2020; epub ahead of print
Schnorbus B, Daiber A, Jurk K, Warnke S, ... Münzel T, Gori T
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31899473
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Understanding the use of observational and randomized data in cardiovascular medicine.

Bowman L, Baras A, Bombien R, Califf RM, ... Wallentin L, Casadei B

The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally, improved digital access to health information has facilitated the conduct of efficient randomized controlled trials (RCTs) upon which clinical management decisions can be based, for instance, by permitting the identification of eligible patients for recruitment and/or linkage for follow-up via their EHRs. Given these advances in cardiovascular data science and the complexities they behold, it is important that health professionals have clarity on the appropriate use and interpretation of observational, so-called \'real-world\', and randomized data in cardiovascular medicine. The Cardiovascular Roundtable of the European Society of Cardiology (ESC) held a workshop to explore the future of RCTs and the current and emerging opportunities for gathering and exploiting complex observational datasets in cardiovascular research. The aim of this article is to provide a perspective on the appropriate use of randomized and observational data and to outline the ESC plans for supporting the collection and availability of clinical data to monitor and improve the quality of care of patients with cardiovascular disease in Europe and provide an infrastructure for undertaking pragmatic RCTs. Moreover, the ESC continues to campaign for greater engagement amongst regulators, industry, patients, and health professionals in the development and application of a more efficient regulatory framework that is able to take maximal advantage of new opportunities for improving the design and efficiency of observational studies and RCT in patients with cardiovascular 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: 03 Feb 2020; epub ahead of print
Bowman L, Baras A, Bombien R, Califf RM, ... Wallentin L, Casadei B
Eur Heart J: 03 Feb 2020; epub ahead of print | PMID: 32016367
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Family History of Gastric Cancer and Treatment.

Choi IJ, Kim CG, Lee JY, Kim YI, ... Park B, Joo J
Background
infection and a family history of gastric cancer are the main risk factors for gastric cancer. Whether treatment to eradicatecan reduce the risk of gastric cancer in persons with a family history of gastric cancer in first-degree relatives is unknown.
Methods
In this single-center, double-blind, placebo-controlled trial, we screened 3100 first-degree relatives of patients with gastric cancer. We randomly assigned 1838 participants withinfection to receive either eradication therapy (lansoprazole [30 mg], amoxicillin [1000 mg], and clarithromycin [500 mg], each taken twice daily for 7 days) or placebo. The primary outcome was development of gastric cancer. A prespecified secondary outcome was development of gastric cancer according toeradication status, assessed during the follow-up period.
Results
A total of 1676 participants were included in the modified intention-to-treat population for the analysis of the primary outcome (832 in the treatment group and 844 in the placebo group). During a median follow-up of 9.2 years, gastric cancer developed in 10 participants (1.2%) in the treatment group and in 23 (2.7%) in the placebo group (hazard ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.94; P = 0.03 by log-rank test). Among the 10 participants in the treatment group in whom gastric cancer developed, 5 (50.0%) had persistentinfection. Gastric cancer developed in 0.8% of participants (5 of 608) in whominfection was eradicated and in 2.9% of participants (28 of 979) who had persistent infection (hazard ratio, 0.27; 95% CI, 0.10 to 0.70). Adverse events were mild and were more common in the treatment group than in the placebo group (53.0% vs. 19.1%; P<0.001).
Conclusions
Among persons withinfection who had a family history of gastric cancer in first-degree relatives,eradication treatment reduced the risk of gastric cancer. (Funded by the National Cancer Center, South Korea; ClinicalTrials.gov number, NCT01678027.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:427-436
Choi IJ, Kim CG, Lee JY, Kim YI, ... Park B, Joo J
N Engl J Med: 29 Jan 2020; 382:427-436 | PMID: 31995688
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca Handling After Pressure Overload.

Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J

Orai1 is a critical ion channel subunit, best recognized as a mediator of storeoperated Ca entry (SOCE) in non-excitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop JPIII, a small-molecule Orai1 channel inhibitor suitable fordelivery.Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. 5 weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and pro-hypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca signaling alterations (increased SOCE, decreased [Ca]i transients amplitude and decay rate, lower SR Ca load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from CdnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult.The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.



Circulation: 06 Jan 2020; epub ahead of print
Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J
Circulation: 06 Jan 2020; epub ahead of print | PMID: 31906693
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cytokine mRNA Degradation in Cardiomyocytes Restrains Sterile Inflammation in Pressure Overloaded Hearts.

Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K

Proinflammatory cytokines play an important role in the pathogenesis of heart failure. However, the mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of the mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in non-immune cells such as cardiomyocytes remains to be elucidated.To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Furthermore, interleukin-6 (IL-6) signaling was inhibited by the administration with its receptor antibody. Finally, overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer.Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared to the control littermates. Four weeks after TAC, themRNA level was upregulated, but not other cytokine mRNAs including tumor necrosis factor-α in Regnase-1-deficient hearts. Although themRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-IL-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction ofmRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9- mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice.The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.



Circulation: 13 Jan 2020; epub ahead of print
Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K
Circulation: 13 Jan 2020; epub ahead of print | PMID: 31931613
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Machine learning-based mortality prediction of patients undergoing cardiac resynchronization therapy: the SEMMELWEIS-CRT score.

Tokodi M, Schwertner WR, Kovács A, Tősér Z, ... Merkely B, Kosztin A
Aims
Our aim was to develop a machine learning (ML)-based risk stratification system to predict 1-, 2-, 3-, 4-, and 5-year all-cause mortality from pre-implant parameters of patients undergoing cardiac resynchronization therapy (CRT).
Methods and results
Multiple ML models were trained on a retrospective database of 1510 patients undergoing CRT implantation to predict 1- to 5-year all-cause mortality. Thirty-three pre-implant clinical features were selected to train the models. The best performing model [SEMMELWEIS-CRT score (perSonalizEd assessMent of estiMatEd risk of mortaLity With machinE learnIng in patientS undergoing CRT implantation)], along with pre-existing scores (Seattle Heart Failure Model, VALID-CRT, EAARN, ScREEN, and CRT-score), was tested on an independent cohort of 158 patients. There were 805 (53%) deaths in the training cohort and 80 (51%) deaths in the test cohort during the 5-year follow-up period. Among the trained classifiers, random forest demonstrated the best performance. For the prediction of 1-, 2-, 3-, 4-, and 5-year mortality, the areas under the receiver operating characteristic curves of the SEMMELWEIS-CRT score were 0.768 (95% CI: 0.674-0.861; P < 0.001), 0.793 (95% CI: 0.718-0.867; P < 0.001), 0.785 (95% CI: 0.711-0.859; P < 0.001), 0.776 (95% CI: 0.703-0.849; P < 0.001), and 0.803 (95% CI: 0.733-0.872; P < 0.001), respectively. The discriminative ability of our model was superior to other evaluated scores.
Conclusion
The SEMMELWEIS-CRT score (available at semmelweiscrtscore.com) exhibited good discriminative capabilities for the prediction of all-cause death in CRT patients and outperformed the already existing risk scores. By capturing the non-linear association of predictors, the utilization of ML approaches may facilitate optimal candidate selection and prognostication of patients undergoing CRT implantation.

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

Eur Heart J: 09 Jan 2020; epub ahead of print
Tokodi M, Schwertner WR, Kovács A, Tősér Z, ... Merkely B, Kosztin A
Eur Heart J: 09 Jan 2020; epub ahead of print | PMID: 31923316
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis Following Myocardial Infarction.

Sreejit G, Abdel-Latif A, Athmanathan B, Annabathula R, ... Murphy AJ, Nagareddy PR

Myocardial infarction (MI) triggers myelopoiesis resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.Using a mouse model of the permanent ligation of the left anterior descending (LAD) artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of acute inflammatory response and the underlying signaling pathways. Utilizing a combination of genetic and pharmacological strategies, we identified the sequalae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indices of neutrophilia with major adverse cardiovascular events (MACE) was studied in a cohort of acute MI patients.Induction of MI resulted in a rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll Like Receptor (TLR) 4 and prime the Nod Like Receptor (NLR) family Pyrin Domain-Containing 3 (Nlrp3) inflammasome in naïve neutrophils and promote interleukin 1 (IL-1β) secretion. The released IL-1β interact with its receptor (Interleukin 1 Receptor Type 1, IL1R1) on hematopoietic stem and progenitor cells in the bone marrow (BM), and stimulate granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and its downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome (ACS), higher neutrophil count on admission and post-revascularization correlates positively with major adverse cardiovascular disease (CVD) outcomes.Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response following myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or its downstream mediators (e.g. Nlrp3, IL-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in ACS patients.



Circulation: 15 Jan 2020; epub ahead of print
Sreejit G, Abdel-Latif A, Athmanathan B, Annabathula R, ... Murphy AJ, Nagareddy PR
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941367
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

First Case of 2019 Novel Coronavirus in the United States.

Holshue ML, DeBolt C, Lindquist S, Lofy KH, ... Pillai SK,

An outbreak of novel coronavirus (2019-nCoV) that began in Wuhan, China, has spread rapidly, with cases now confirmed in multiple countries. We report the first case of 2019-nCoV infection confirmed in the United States and describe the identification, diagnosis, clinical course, and management of the case, including the patient\'s initial mild symptoms at presentation with progression to pneumonia on day 9 of illness. This case highlights the importance of close coordination between clinicians and public health authorities at the local, state, and federal levels, as well as the need for rapid dissemination of clinical information related to the care of patients with this emerging infection.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 30 Jan 2020; epub ahead of print
Holshue ML, DeBolt C, Lindquist S, Lofy KH, ... Pillai SK,
N Engl J Med: 30 Jan 2020; epub ahead of print | PMID: 32004427
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia.

van Kempen AAMW, Eskes PF, Nuytemans DHGM, van der Lee JH, ... Boluyt N,
Background
Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment.
Methods
In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group.
Results
Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death.
Conclusions
In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 05 Feb 2020; 382:534-544
van Kempen AAMW, Eskes PF, Nuytemans DHGM, van der Lee JH, ... Boluyt N,
N Engl J Med: 05 Feb 2020; 382:534-544 | PMID: 32023373
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Six-Year Follow-up of a Trial of Antenatal Vitamin D for Asthma Reduction.

Litonjua AA, Carey VJ, Laranjo N, Stubbs BJ, ... Hollis BW, Weiss ST
Background
We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze.
Methods
In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children\'s sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups.
Results
There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance.
Conclusions
Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 05 Feb 2020; 382:525-533
Litonjua AA, Carey VJ, Laranjo N, Stubbs BJ, ... Hollis BW, Weiss ST
N Engl J Med: 05 Feb 2020; 382:525-533 | PMID: 32023372
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.

Liu E, Marin D, Banerjee P, Macapinlac HA, ... Shpall EJ, Rezvani K
Background
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.
Methods
In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin\'s lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×10, 1×10, or 1×10 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy.
Results
The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter\'s transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.
Conclusions
Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 05 Feb 2020; 382:545-553
Liu E, Marin D, Banerjee P, Macapinlac HA, ... Shpall EJ, Rezvani K
N Engl J Med: 05 Feb 2020; 382:545-553 | PMID: 32023374
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

COMPARE: prospective, randomized, non-inferiority trial of high- vs. low-dose paclitaxel drug-coated balloons for femoropopliteal interventions.

Steiner S, Schmidt A, Zeller T, Tepe G, ... Weiss N, Scheinert D
Aims
Drug-coated balloons (DCBs) for femoropopliteal interventions have not been tested against each other. We aimed to directly compare efficacy and safety of a high-dose (In.Pact™) vs. low-dose (Ranger™) DCB with nominal paclitaxel densities of 3.5 vs. 2.0 μg/mm2.
Methods and results
Within a prospective, multicentre, non-inferiority, clinical trial 414 patients with symptomatic femoropopliteal lesions (Rutherford classification 2-4) were randomly assigned in a 1:1 ratio to endovascular treatment with either high- or low-dose DCB after stratification for lesion length. Primary efficacy and safety endpoints comprised primary patency and freedom from major adverse events (i.e. device and procedure-related deaths through 1 month, major amputations, and clinically driven target lesion revascularization through 12 months). We set a non-inferiority margin of -10% at 12 months. Total occlusions were observed frequently (>40%) and provisional stenting was performed in every fourth intervention. Non-inferiority was determined for both primary efficacy and safety endpoints at 12 months. Primary patency was 81.5% in the high-dose and 83.0% in low-dose DCB group {difference: 1.5% [lower bound of the 90% two-sided confidence interval (CI) -5.2%]; Pnon-inferiority < 0.01}. Freedom from major adverse events was determined in 92.6% in high-dose and in 91.0% in low-dose DCB group [difference -1.6% (lower bound of the 90% two-sided CI -6.5%); Pnon-inferiority < 0.01]. Overall death rate was low (2.0%) and no major amputation occurred.
Conclusion
Two DCBs with different coating characteristics exhibited comparable results with excellent effectiveness and safety through 12 months for femoropopliteal interventions including a wide range of lesion lengths.
Clinical trial registration
The trial is registered with ClinicalTrials.gov (NCT02701543).

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

Eur Heart J: 27 Jan 2020; epub ahead of print
Steiner S, Schmidt A, Zeller T, Tepe G, ... Weiss N, Scheinert D
Eur Heart J: 27 Jan 2020; epub ahead of print | PMID: 31989155
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

Rasmussen PV, Dalgaard F, Gislason GH, Brandes A, ... Pallisgaard JL, Hansen ML
Aims
Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer.
Methods and results
A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively.
Conclusion
In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

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 Feb 2020; epub ahead of print
Rasmussen PV, Dalgaard F, Gislason GH, Brandes A, ... Pallisgaard JL, Hansen ML
Eur Heart J: 06 Feb 2020; epub ahead of print | PMID: 32030399
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia.

Li Q, Guan X, Wu P, Wang X, ... Leung GM, Feng Z
Background
The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP.
Methods
We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number.
Results
Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9).
Conclusions
On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 Jan 2020; epub ahead of print
Li Q, Guan X, Wu P, Wang X, ... Leung GM, Feng Z
N Engl J Med: 28 Jan 2020; epub ahead of print | PMID: 31995857
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Older ...

This program is still in alpha version.