Left Atrial Appendage Pseudothrombus Is Associated With Stroke History in Patients With Atrial Fibrillation Undergoing Cardiac Computed Tomography.

BACKGROUND: In nonvalvular atrial fibrillation (NVAF), the left atrial appendage (LAA) is the source of thrombus in up to 90% of patients. LAA pseudothrombus (LAAPT), defined as a filling defect on the initial but not the 60-second delayed acquisition on cardiovascular computed tomography scan (CCT), is a recognized phenomenon in NVAF, with unknown clinical relevance. We aimed to determine the relationship between LAAPT and history of stroke in patients with NVAF. METHODS AND RESULTS: The study included 213 consecutive patients with NVAF undergoing CCT who were assessed for LAAPT. LA and LAA dimensions and LAA morphology correlated with clinical demographics including cardiovascular risk factors, history of stroke, thromboembolic stroke, and transient ischemic attack. Mean age (±SD) was 65.1±10.5 years (range 31-89) and 150 of 213 (70.4%) were men. LAAPT was present in 59 of 213 (27.7%) patients. Greater mean LAA ostium area (5.7 versus 4.5, P<0.001), greater mean LAA ostium area:curved length (0.11 versus 0.08, P<0.001), increased LAA volume (14.0 versus 10.2, P<0.001), and lower mean LAA tortuosity index (1.17 versus 1.38, P<0.001) were all associated with the presence of LAAPT. On multivariable analysis, LAAPT on CCT (odds ratio [OR], 3.20 [95% CI, 1.40-7.20]; P<0.006) and higher CHA2DS2-VASc score (OR, 1.65 [95% CI, 1.16-2.35]; P=0.01) were associated with all strokes, with LAAPT remaining a statistically significant risk factor even after adjustment for CHA2DS2-VASc score. CONCLUSIONS: LAAPT on CCT is common in patients with NVAF. It has a strong positive association with stroke prevalence, even after adjustment for CHA2DS2-VASc score. LAAPT on CCT may potentially allow further stratification for stroke risk, additive to the CHA2DS2-VASc score.

Does Time to Asystole in Donors After Circulatory Death Impact Recipient Outcome in Liver Transplantation?

BACKGROUND: The agonal phase can vary following treatment withdrawal in donor after circulatory death (DCD). There is little evidence to support when procurement teams should stand down in relation to donor time to death (TTD). We assessed what impact TTD had on outcomes following DCD liver transplantation. METHODS: Data were extracted from the UK Transplant Registry on DCD liver transplant recipients from 2006 to 2021. TTD was the time from withdrawal of life-sustaining treatment to asystole, and functional warm ischemia time was the time from donor systolic blood pressure and/or oxygen saturation falling below 50 mm Hg and 70%, respectively, to aortic perfusion. The primary endpoint was 1-y graft survival. Potential predictors were fitted into Cox proportional hazards models. Adjusted restricted cubic spline models were generated to further delineate the relationship between TTD and outcome. RESULTS: One thousand five hundred fifty-eight recipients of a DCD liver graft were included. Median TTD in the entire cohort was 13 min (interquartile range, 9-17 min). Restricted cubic splines revealed that the risk of graft loss was significantly greater when TTD ≤14 min. After 14 min, there was no impact on graft loss. Prolonged hepatectomy time was significantly associated with graft loss (hazard ratio, 1.87; 95% confidence interval, 1.23-2.83; P = 0.003); however, functional warm ischemia time had no impact (hazard ratio, 1.00; 95% confidence interval, 0.44-2.27; P > 0.9). CONCLUSIONS: A very short TTD was associated with increased risk of graft loss, possibly because of such donors being more unstable and/or experiencing brain stem death as well as circulatory death. Expanding the stand down times may increase the utilization of donor livers without significantly impairing graft outcome.

Risk Burden of Cancer in Patients Treated With Abbreviated Dual Antiplatelet Therapy After PCI: Analysis of Multicenter Controlled High-Bleeding Risk Trials.

BACKGROUND: Oncological patients with coronary artery disease face an elevated risk of hemorrhagic and ischemic events following percutaneous coronary intervention. Despite medical guidelines recommending minimal dual antiplatelet therapy (DAPT) duration for patients with cancer, dedicated data on abbreviated DAPT in this population is lacking. This study aims to evaluate the occurrence of ischemic and hemorrhagic events in patients with cancer compared with other high-bleeding risk individuals. METHODS: Patient-level data from 4 high-bleeding risk coronary drug-eluting stent studies (ONYX One, LEADERS FREE, LEADERS FREE II, and SENIOR trials) treated with short DAPT were analyzed. The comparison focused on patients with high-bleeding risk with and without cancer, assessing 1-year rates of net adverse clinical events (all-cause death, myocardial infarction, stroke, revascularization, and Bleeding Academic Research Consortium [BARC] types 3 to 5 bleeding) and major adverse clinical events (all-cause death, myocardial infarction, stroke). RESULTS: A total of 5232 patients were included, of whom 574 individuals had cancer, and 4658 were at high-bleeding risk without previous cancer. Despite being younger with fewer risk factors, patients with cancer had higher net adverse clinical event (HR, 1.25; P=0.01) and major adverse clinical event (HR, 1.26; P=0.02), primarily driven by all-cause mortality and major bleeding (BARC 3-5), but not myocardial infarction, stroke, stent thrombosis, or repeat revascularization. Cancer was an independent predictor of net adverse clinical event (P=0.005), major adverse clinical event (P=0.01), and major bleeding (P=0.03). CONCLUSIONS: The present work is the first report on abbreviated DAPT dedicated to patients with cancer. Cancer is a major marker of adverse outcomes and these events had high lethality. Despite short DAPT, patients with cancer experienced higher rates of major bleeding compared with patients without cancer with high-bleeding risk, which occurred mainly after DAPT discontinuation. These findings reinforce the need for a more detailed and individualized stratification of those patients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03344653, NCT01623180, NCT02843633, NCT0284.

The impact of time to death in donors after circulatory death on recipient outcome in simultaneous pancreas-kidney transplantation.

The time to arrest donors after circulatory death is unpredictable and can vary. This leads to variable periods of warm ischemic damage prior to pancreas transplantation. There is little evidence supporting procurement team stand-down times based on donor time to death (TTD). We examined what impact TTD had on pancreas graft outcomes following donors after circulatory death (DCD) simultaneous pancreas-kidney transplantation. Data were extracted from the UK transplant registry from 2014 to 2022. Predictors of graft loss were evaluated using a Cox proportional hazards model. Adjusted restricted cubic spline models were generated to further delineate the relationship between TTD and outcome. Three-hundred-and-seventy-five DCD simultaneous kidney-pancreas transplant recipients were included. Increasing TTD was not associated with graft survival (adjusted hazard ratio HR 0.98, 95% confidence interval 0.68-1.41, P = .901). Increasing asystolic time worsened graft survival (adjusted hazard ratio 2.51, 95% confidence interval 1.16-5.43, P = .020). Restricted cubic spline modeling revealed a nonlinear relationship between asystolic time and graft survival and no relationship between TTD and graft survival. We found no evidence that TTD impacts pancreas graft survival after DCD simultaneous pancreas-kidney transplantation; however, increasing asystolic time was a significant predictor of graft loss. Procurement teams should attempt to minimize asystolic time to optimize pancreas graft survival rather than focus on the duration of TTD.

Quantifying the benefit-risk trade-off for individual patients in a clinical trial: principles and antithrombotic case study.

BACKGROUND: A treatment's overall favorable benefit-risk profile does not imply that every individual patient will benefit from the treatment. OBJECTIVES: To describe a statistical methodology for quantifying the benefit-risk trade-off in individual patients. METHODS: The method requires a large randomized controlled trial containing a primary efficacy outcome and a primary safety outcome, for instance, the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 placebo-controlled trial of vorapaxar in 17 779 patients following myocardial infarction. Multivariate regression models predict each individual patient's risk of ischemic events (benefit) and major bleeding events (harm) based on their profile. Hence, each patient's predicted benefit from vorapaxar (reduction in ischemic events) and predicted risk (increase in bleeding events) were estimated. The relative importance of ischemic and bleeding events based on links to all-cause mortality was quantified, although the limitations of such weightings are noted. RESULTS: Overall results demonstrated both clear benefit and harm from vorapaxar. Substantial interindividual variation in both benefit and risk facilitated distinguishing patients with a favorable benefit-risk trade-off from those who did not. Such findings were applied to recommend vorapaxar in as many as 98.3% of patients in which a favorable mortality-weighted benefit-risk trade-off was present, in 77.2% of patients with ischemic benefit 20% greater than bleeding risk, or in as few as 45.5% of patients if an annual decrease in ischemic risk of ≥0.5% was also required. CONCLUSION: While overall randomized controlled trials of treatment benefit vs risk are valuable, models determining each individual patient's estimated absolute benefit and risk provide more useful insight regarding patient-specific benefit-risk trade-offs to better enable personalized therapeutic decision-making.

Assessing the association between genetic and phenotypic features of dilated cardiomyopathy and outcome in patients with coronary artery disease.

AIMS: To examine the relevance of genetic and cardiovascular magnetic resonance (CMR) features of dilated cardiomyopathy (DCM) in individuals with coronary artery disease (CAD). METHODS AND RESULTS: This study includes two cohorts. First, individuals with CAD recruited into the UK Biobank (UKB) were evaluated. Second, patients with CAD referred to a tertiary centre for evaluation with late gadolinium enhancement (LGE)-CMR were recruited (London cohort); patients underwent genetic sequencing as part of the research protocol and long-term follow-up. From 31 154 individuals with CAD recruited to UKB, rare pathogenic variants in DCM genes were associated with increased risk of death or major adverse cardiac events (hazard ratio 1.57, 95% confidence interval [CI] 1.22-2.01, p < 0.001). Of 1619 individuals with CAD included from the UKB CMR substudy, participants with a rare variant in a DCM-associated gene had lower left ventricular ejection fraction (LVEF) compared to genotype negative individuals (mean 47 ± 10% vs. 57 ± 8%, p < 0.001). Of 453 patients in the London cohort, 63 (14%) had non-infarct pattern LGE (NI-LGE) on CMR. Patients with NI-LGE had lower LVEF (mean 38 ± 18% vs. 48 ± 16%, p < 0.001) compared to patients without NI-LGE, with no significant difference in the burden of rare protein altering variants in DCM-associated genes between groups (9.5% vs. 6.7%, odds ratio 1.5, 95% CI 0.4-4.3, p = 0.4). NI-LGE was not independently associated with adverse clinical outcomes. CONCLUSION: Rare pathogenic variants in DCM-associated genes impact left ventricular remodelling and outcomes in stable CAD. NI-LGE is associated with adverse remodelling but is not an independent predictor of outcome and had no rare genetic basis in our study.

Sex Differences in the Clinical Presentation and Natural History of Dilated Cardiomyopathy.

BACKGROUND: Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved. OBJECTIVES: This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors. METHODS: The authors conducted a prospective observational cohort study of DCM patients assessing baseline characteristics, cardiac magnetic resonance imaging, biomarkers, and genotype. The composite outcome was cardiovascular mortality or major heart failure (HF) events. RESULTS: Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline, female patients had higher left ventricular ejection fraction, smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%), and lower high-sensitivity cardiac troponin I than males (all P < 0.05) with no difference in time from diagnosis, age at enrollment, N-terminal pro-B-type natriuretic peptide levels, pathogenic DCM genetic variants, myocardial fibrosis extent, or medications used for HF. Despite a more favorable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted HR: 3.14; 95% CI: 1.55-6.35; P = 0.001). Between 2 and 5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, left ventricular ejection fraction, left atrial volume, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin I, left bundle branch block, and NYHA functional class were not sex-specific prognostic factors. CONCLUSIONS: The authors identified a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences.

Comparing the long-term outcomes in chronic coronary syndrome patients with prior ST-segment and non-ST-segment elevation myocardial infarction: findings from the TIGRIS registry.

OBJECTIVES: Compared with ST-segment elevation myocardial infarction (STEMI) patients, non-STEMI (NSTEMI) patients have more comorbidities and extensive coronary artery disease. Contemporary comparative data on the long-term prognosis of stable post-myocardial infarction subtypes are needed. DESIGN: Long-Term rIsk, clinical manaGement and healthcare Resource utilisation of stable coronary artery dISease (TIGRIS) was a multinational, observational and longitudinal cohort study. SETTING: Patients were enrolled from 350 centres, with >95% coming from cardiology practices across 24 countries, from 19 June 2013 to 31 March 2017. PARTICIPANTS: This study enrolled 8277 stable patients 1-3 years after myocardial infarction with ≥1 additional risk factor. OUTCOME MEASURES: Over a 2 year follow-up, cardiovascular events and deaths and self-reported health using the EuroQol 5-dimension questionnaire score were recorded. Relative risk of clinical events and health resource utilisation in STEMI and NSTEMI patients were compared using multivariable Poisson regression models, adjusting for prognostically relevant patient factors. RESULTS: Of 7752 patients with known myocardial infarction type, 46% had NSTEMI; NSTEMI patients were older with more comorbidities than STEMI patients. NSTEMI patients had significantly poorer self-reported health and lower prevalence of dual antiplatelet therapy at hospital discharge and at enrolment 1-3 years later. NSTEMI patients had a higher incidence of combined myocardial infarction, stroke and cardiovascular death (5.6% vs 3.9%, p<0.001) and higher all-cause mortality (4.2% vs 2.6%, p<0.001) compared with STEMI patients. Risks were attenuated after adjusting for other patient characteristics. Health resource utilisation was higher in NSTEMI patients, although STEMI patients had more cardiologist visits. CONCLUSIONS: Post-NSTEMI chronic coronary syndrome patients had a less favourable risk factor profile, poorer self-reported health and more adverse cardiovascular events during long-term follow-up than individuals post STEMI. Efforts are needed to recognise the risks of stable patients after NSTEMI and optimise secondary prevention and care. TRIAL REGISTRATION NUMBER: NCT01866904.

Determinants of Progression and Regression of Subclinical Atherosclerosis Over 6 Years.

BACKGROUND: Atherosclerosis is a systemic disease that frequently begins early in life. However, knowledge about the temporal disease dynamics (ie, progression or regression) of human subclinical atherosclerosis and their determinants is scarce. OBJECTIVES: This study sought to investigate early subclinical atherosclerosis disease dynamics within a cohort of middle-aged, asymptomatic individuals by using multiterritorial 3-dimensional vascular ultrasound (3DVUS) imaging. METHODS: A total of 3,471 participants from the PESA (Progression of Early Subclinical Atherosclerosis) cohort study (baseline age 40-55 years; 36% female) underwent 3 serial 3DVUS imaging assessments of peripheral arteries at 3-year intervals. Subclinical atherosclerosis was quantified as global plaque volume (mm3) (bilateral carotid and femoral plaque burden). Multivariable logistic regression models for progression and regression were developed using stepwise forward variable selection. RESULTS: Baseline to 6-year subclinical atherosclerosis progression occurred in 32.7% of the cohort (17.5% presenting with incident disease and 15.2% progressing from prevalent disease at enrollment). Regression was observed in 8.0% of those patients with baseline disease. The effects of higher low-density lipoprotein cholesterol (LDL-C) and elevated systolic blood pressure (SBP) on 6-year subclinical atherosclerosis progression risk were more pronounced among participants in the youngest age stratum (Pinteraction = 0.04 and 0.02, respectively). CONCLUSIONS: Over 6 years, subclinical atherosclerosis progressed in one-third of middle-age asymptomatic subjects. Atherosclerosis regression is possible in early stages of the disease. The impact of LDL-C and SBP on subclinical atherosclerosis progression was more pronounced in younger participants, a finding suggesting that the prevention of atherosclerosis and its progression could be enhanced by tighter risk factor control at younger ages, with a likely long-term impact on reducing the risk of clinical events. (Progression of Early Subclinical Atherosclerosis [PESA; also PESA-CNIC-Santander]; NCT01410318).

Phenotype, outcomes and natural history of early-stage non-ischaemic cardiomyopathy.

AIMS: To characterize the phenotype, clinical outcomes and rate of disease progression in patients with early-stage non-ischaemic cardiomyopathy (early-NICM). METHODS AND RESULTS: We conducted a prospective observational cohort study of patients with early-NICM assessed by late gadolinium enhancement cardiovascular magnetic resonance (CMR). Cases were classified into the following subgroups: isolated left ventricular dilatation (early-NICM H-/D+), non-dilated left ventricular cardiomyopathy (early-NICM H+/D-), or early dilated cardiomyopathy (early-NICM H+/D+). Clinical follow-up for major adverse cardiovascular events (MACE) included non-fatal life-threatening arrhythmia, unplanned cardiovascular hospitalization or cardiovascular death. A subset of patients (n = 119) underwent a second CMR to assess changes in cardiac structure and function. Of 254 patients with early-NICM (median age 46 years [interquartile range 36-58], 94 [37%] women, median left ventricular ejection fraction [LVEF] 55% [52-59]), myocardial fibrosis was present in 65 (26%). There was no difference in the prevalence of fibrosis between subgroups (p = 0.90), however fibrosis mass was lowest in early-NICM H-/D+, higher in early-NICM H+/D- and highest in early-NICM H+/D+ (p = 0.03). Over a median follow-up of 7.9 (5.5-10.0) years, 28 patients (11%) experienced MACE. Non-sustained ventricular tachycardia (hazard ratio [HR] 5.1, 95% confidence interval [CI] 2.36-11.00, p < 0.001), myocardial fibrosis (HR 3.77, 95% CI 1.73-8.20, p < 0.001) and diabetes mellitus (HR 5.12, 95% CI 1.73-15.18, p = 0.003) were associated with MACE in a multivariable model. Only 8% of patients progressed from early-NICM to dilated cardiomyopathy with LVEF <50% over a median of 16 (11-34) months. CONCLUSION: Early-NICM is not benign. Fibrosis develops early in the phenotypic course. In-depth characterization enhances risk stratification and might aid clinical management.

Long-term outcomes among stable post-acute myocardial infarction patients living in rural versus urban areas: insights from the prospective, observational TIGRIS registry.

BACKGROUND: Insights on the differences in clinical outcomes, quality of life (QoL) and health resource utilisation (HRU) with different levels of care available to post-acute myocardial infarction (AMI) populations in rural and urban settings are limited. METHODS: The long-Term rIsk, clinical manaGement, and healthcare Resource utilisation of stable coronary artery dISease (TIGRIS), a prospective, observational registry, enrolled 8452 patients aged ≥50 years 1-3 years post-AMI from June 2013 to November 2014 from 24 countries in Asia Pacific/Australia, Europe, North America and South America. Differences in QoL (measured using the EuroQol Research Foundation instrument) and HRU between patients in rural and urban settings were evaluated in this post hoc analysis. The incidence of clinical endpoints (cardiovascular (CV) death, AMI, unstable angina with urgent revascularisation and stroke; bleeding; and all-cause mortality) was analysed. Data were collected at baseline and every 6 months for 24 months. RESULTS: There were fewer hospitalisations and visits to general practitioners (GPs) and cardiologists in the rural versus urban populations (adjusted event rate ratio (ERR)=0.90 (95% CI, 0.82 to 1.00, p=0.04); ERR=0.84 (95% CI, 0.78 to 0.92, p<0.001); ERR=0.86 (95% CI, 0.81 to 0.92, p<0.001), respectively). No statistically significant differences were observed between rural and urban populations in all-cause death, AMI, unstable angina with urgent revascularisation, CV death, stroke, major bleeding events and health-related QoL. The adjusted incidence rate ratio was 0.92 (95% CI, 0.74 to 1.15) for the composite of CV death, AMI and stroke. CONCLUSIONS: Living in rural areas was associated with fewer GP/cardiologist visits and hospitalisations; no significant differences in clinical outcomes and QoL were observed. TRIAL REGISTRATION NUMBER: NCT01866904.

Biolimus-eluting vs. other limus-eluting stents in NSTE-ACS: A pooled analysis of GLASSY and TWILIGHT.

BACKGROUND: Biodegradable polymer biolimus-eluting stents (BP-BES) may be associated with better outcomes in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) compared to other current-generation limus-eluting stents (LES). AIMS: To compare BP-BES with other current-generation LES in ACS patients undergoing PCI. METHODS: We pooled individual data of Non-ST-segment elevation (NSTE)-ACS patients from two large randomized controlled trials (GLASSY and TWILIGHT). The BP-BES groups consisted mostly of GLASSY patients, while the control group (other current-generation LES) included exclusively TWILIGHT patients. The primary outcome was major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, or stent thrombosis; the key secondary outcome was target-vessel failure (TVF). To account for trial design differences, outcomes were assessed at 3 months (short-term) and between 3 and 12 months (long-term) after PCI and subsequently pooled to estimate the 12-month hazards. RESULTS: Of 7107 and 6053 NSTE-ACS patients included in the short- and long-term analysis, 32.7% and 36.5% received a BP-BES, respectively. Risk of MACE associated with BP-BES versus other LES was similar at short-term (1.1% vs 1.3%, adjusted HR 0.86, 95%CI 0.53-1.38), lower at long-term (1.7% vs 3.1%, adjusted HR 0.49, 95%CI 0.34-0.72), and lower in the entire 12-month period (pooled adjusted HR 0.61, 95%CI 0.45-0.82). The cumulative 12-month risk of TVF was reduced with BP-BES (adjusted HR 0.52, 95%CI 0.38-0.70). CONCLUSION: BP-BES was associated with lower 12-month risks of MACE and TVF compared to other current generation LES among NSTE-ACS patients treated with abbreviated or standard ticagrelor-based DAPT. These non-randomized findings are hypothesis-generating. CONDENSED ABSTRACT: Differences in clinical outcomes may exist between biodegradable polymer biolimus-eluting stents (BP-BES) and other current-generation limus-eluting stent (LES) in patients with acute coronary syndrome (ACS). We pooled individual data of about 7000 Non-ST-segment elevation ACS patients undergoing PCI and treated with ticagrelor with or without aspirin from two large randomized controlled trials (GLASSY and TWILIGHT). BP-BES patients derived very largely from GLASSY and other LES patients from TWILIGHT. In this population, BP-BES compared to other current generation LES, were associated with a lower 12-month risk of major adverse cardiovascular events and target-vessel failure.

Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19.

BACKGROUND: Prior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results. OBJECTIVES: We sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19. METHODS: Patients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group. RESULTS: Between August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent. CONCLUSIONS: Among noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079).

Comprehensive Phenotypic Characterization of Late Gadolinium Enhancement Predicts Sudden Cardiac Death in Coronary Artery Disease.

BACKGROUND: Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD). OBJECTIVES: The authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD). METHODS: Patients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD. RESULTS: Of 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell's C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell's C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models. CONCLUSIONS: Comprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in implantable cardioverter-defibrillator (ICD) insertion guidelines. These results signify the potential for a more personalized approach to determining ICD candidacy in CAD.

Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease.

Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

Multi-Centre UK Analysis of Simultaneous Pancreas and Kidney (SPK) Transplant in Recipients With Type 2 Diabetes Mellitus.

90% of the UK diabetic population are classified as T2DM. This study aims to compare outcomes after SPK transplant between recipients with T1DM or T2DM. Data on all UK SPK transplants from 2003-2019 were obtained from the NHSBT Registry (n = 2,236). Current SPK transplant selection criteria for T2DM requires insulin treatment and recipient BMI < 30 kg/m2. After exclusions (re-transplants/ambiguous type of diabetes) we had a cohort of n = 2,154. Graft (GS) and patient (PS) survival analyses were conducted using Kaplan-Meier plots and Cox-regression models. Complications were compared using chi-squared analyses. 95.6% of SPK transplants were performed in recipients with T1DM (n = 2,060). Univariate analysis showed comparable outcomes for pancreas GS at 1 year (p = 0.120), 3 years (p = 0.237), and 10 years (p = 0.196) and kidney GS at 1 year (p = 0.438), 3 years (p = 0.548), and 10 years (p = 0.947). PS was comparable at 1 year (p = 0.886) and 3 years (p = 0.237) and at 10 years (p = 0.161). Multi-variate analysis showed comparable outcomes in pancreas GS (p = 0.564, HR 1.221, 95% CI 0.619, 2.406) and PS(p = 0.556, HR 1.280, 95% CI 0.563, 2.911). Comparable rates of common complications were demonstrated. This is the largest series outside of the US evaluating outcomes after SPK transplants and shows similar outcomes between T1DM and T2DM recipients. It is hoped dissemination of this data will lead to increased referral rates and assessment of T2DM patients who could benefit from SPK transplantation.

Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy.

BACKGROUND: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. METHODS: This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. RESULTS: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (P=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv, found in 7% (all with left ventricular ejection fraction <50%) compared with 1% in controls (odds ratio, 3.6; P=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9-7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (Padjusted=0.08). CONCLUSIONS: We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP-tv in those with normal left ventricular ejection fraction and TTN-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.

Polypill Strategy in Secondary Cardiovascular Prevention.

BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

Covariate Adjustment in Cardiovascular Randomized Controlled Trials: Its Value, Current Practice, and Need for Improvement.

In randomized controlled trials, patient characteristics are expected to be well balanced between treatment groups; however, adjustment for characteristics that are prognostic can still be beneficial with a modest gain in statistical power. Nevertheless, previous reviews show that many trials use unadjusted analyses. In this article, we review current practice regarding covariate adjustment in cardiovascular trials among all 84 randomized controlled trials relating to cardiovascular disease published in the New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association during 2019. We identify trials in which use of covariate adjustment led to a change in the trial conclusions. By using these trials as case studies, along with data from the CHARM trial and simulation studies, we demonstrate some of the potential benefits and pitfalls of covariate adjustment. We discuss some of the complexities of using covariate adjustment, including how many covariates to choose, how covariates should be modeled, how to handle missing data for baseline covariates, and how adjusted analyses are viewed by regulators. We conclude that contemporary cardiovascular trials do not make best use of covariate adjustment and that more frequent use could lead to improvements in the efficiency of future trials.

Changes in clinical and imaging variables during withdrawal of heart failure therapy in recovered dilated cardiomyopathy.

AIMS: This study aimed to profile the changes in non-invasive clinical, biochemical, and imaging markers during withdrawal of therapy in patients with recovered dilated cardiomyopathy, providing insights into the pathophysiology of relapse. METHODS AND RESULTS: Clinical, biochemical, and imaging data from patients during phased withdrawal of therapy in the randomized or single-arm cross-over phases of TRED-HF were profiled. Clinical variables were measured at each study visit and imaging variables were measured at baseline, 16 weeks, and 6 months. Amongst the 49 patients [35% women, mean age 53.6 years (standard deviation 11.6)] who withdrew therapy, 20 relapsed. Increases in mean heart rate [7.6 beats per minute (95% confidence interval, CI, 4.5, 10.7)], systolic blood pressure [6.6 mmHg (95% CI 2.7, 10.5)], and diastolic blood pressure [5.8 mmHg (95% CI 3.1, 8.5)] were observed within 4-8 weeks of starting to withdraw therapy. A rise in mean left ventricular (LV) mass [5.1 g/m2 (95% CI 2.8, 7.3)] and LV end-diastolic volume [3.9 mL/m2 (95% CI 1.1, 6.7)] and a reduction in mean LV ejection fraction [-4.2 (95% CI -6.6, -1.8)] were seen by 16 weeks, the earliest imaging follow-up. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) fell immediately after withdrawing beta-blockers and only tended to increase 6 months after beginning therapy withdrawal [mean change in log NT-proBNP at 6 months: 0.2 (95% CI -0.1, 0.4)]. CONCLUSIONS: Changes in plasma NT-proBNP are a late feature of relapse, often months after a reduction in LV function. A rise in heart rate and blood pressure is observed soon after withdrawing therapy in recovered dilated cardiomyopathy, typically accompanied or closely followed by early changes in LV structure and function.