Comparative prognostic importance of measures of left atrial structure and function in non-ischaemic dilated cardiomyopathy.

AIMS: To compare the association between measures of left atrial (LA) structure and function, derived from cardiovascular magnetic resonance (CMR), with cardiovascular (CV) death or non-fatal heart failure (HF) events in patients with non-ischaemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: CMR studies of 580 prospectively recruited patients with DCM in sinus rhythm (median age 54 [interquartile range 44-64] years, 61% men, median LVEF 42% [30-51%]) were analysed for measures of LA structure (left atrial maximum volume index [LAVImax], left atrial minimum volume index [LAVImin]) and function (left atrial emptying fraction [LAEF], left atrial reservoir strain [LARS], left atrial conduit strain [LACS] and left atrial booster strain [LABS]). Over median follow-up of 7.4 years, 103 patients (18%) met the primary endpoint. Apart from LACS, each measure of LA structure and function was associated with the primary endpoint after adjusting for other important prognostic variables. The addition of each LA metric to a baseline model containing the same important prognostic covariates improved model discrimination, with LAVImin providing the greatest improvement (C-statistic improvement: 0.702 to 0.738; χ2 test comparing likelihood ratio p < 0.0001; categorical net reclassification index: 0.210 (95% CI 0.023-0.392)). Patients in the highest tercile of LAVImin had similar event rates to those with persistent atrial fibrillation. Measures of LA strain did not enhance model discrimination above LA volumetric measures. CONCLUSION: Measure of left atrial structure and function offer important prognostic information in patients with DCM and enhance prediction of adverse outcomes. LA strain was not incremental to volumetric analysis for risk prediction.

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.

A retrospective analysis of 20,178 adult neurological infection admissions to United Kingdom critical care units from 2001 to 2020.

BACKGROUND: Neurological infection is an important cause of critical illness, yet little is known on the epidemiology of neurological infections requiring critical care. METHODS: We analysed data on all adults with proven or probable neurological infection admitted to UK (NHS) critical care units between 2001 and 2020 reported to the Intensive Care National Audit and Research Centre. Diagnoses, physiological variables, organ support and clinical outcomes were analysed over the whole period, and for consecutive 5-year intervals within it. Predictors of in-hospital mortality were identified using a backward stepwise regression model. RESULTS: We identified 20,178 critical care admissions for neurological infection. Encephalitis was the most frequent presentation to critical care, comprising 6725 (33.3%) of 20,178 cases. Meningitis- bacterial, viral or unspecified cases - accounted for 10,056 (49.8%) of cases. In-hospital mortality was high, at 3945/19,765 (20.0%) overall. Over the four consecutive 5-year periods, there were trends towards higher Glasgow Coma Scale scores on admission, longer critical care admissions (from median 4 [IQR 2-8] to 5 days [IQR 2-10]), and reduced in-hospital mortality (from 24.9 to 18.1%). We identified 12 independent predictors of in-hospital death which when used together showed good discrimination between patients who die and those who survive (AUC = 0.79). CONCLUSIONS: Admissions with neurological infection to UK critical care services are increasing and the mortality, although improving, remains high. To further improve outcomes from severe neurological infection, novel approaches to the evaluation of risk stratification, monitoring and management strategies are required.

KEY POINTS: • Meningitis comprised 50% and encephalitis comprised 33% of neurological infections requiring critical care admission. • During the 20-year study period, there was a progressive trend of increasing neurological infection admissions to critical care, and a reduction in the overall mortality rate.

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.

Recurrent Events in Cardiovascular Trials: JACC State-of-the-Art Review.

Many randomized trials in cardiovascular disease have repeat nonfatal events (such as hospitalizations) occurring during patient follow-up; yet, it remains common practice to have time-to-first event as the primary outcome. We explore the value of analyses that include repeat events. Do they help us understand the effect of treatment and total disease burden? Do they enhance statistical power? Should they become a trial's primary analysis? It may also be difficult to choose which of the various statistical methods for analyzing repeat events to use, and we provide a nontechnical guide to what each method is doing. We compare several methods for repeat events: Lin Wei Yang Ying, negative binomial, joint frailty, win ratio, and area under the curve. We illustrate their performance in 5 large cardiovascular trials and compare them with time-to-first-event analyses. We review their use in recently published heart failure trials and make recommendations for their use in future trials.

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.

Efficacy of pulmonary artery pressure monitoring in patients with chronic heart failure: a meta-analysis of three randomized controlled trials.

AIMS: Adjustment of treatment based on remote monitoring of pulmonary artery (PA) pressure may reduce the risk of hospital admission for heart failure (HF). We have conducted a meta-analysis of large randomized trials investigating this question. METHODS AND RESULTS: A systematic literature search was performed for randomized clinical trials with PA pressure monitoring devices in patients with HF. The primary outcome of interest was the total number of HF hospitalizations. Other outcomes assessed were urgent visits leading to treatment with intravenous diuretics, all-cause mortality, and composites. Treatment effects are expressed as hazard ratios, and pooled effect estimates were obtained applying random effects meta-analyses. Three eligible randomized clinical trials were identified that included 1898 outpatients in New York Heart Association functional classes II-IV, either hospitalized for HF in the prior 12 months or with elevated plasma NT-proBNP concentrations. The mean follow-up was 14.7 months, 67.8% of the patients were men, and 65.8% had an ejection fraction ≤40%. Compared to patients in the control group, the hazard ratio (95% confidence interval) for total HF hospitalizations in those randomized to PA pressure monitoring was 0.70 (0.58-0.86) (P = .0005). The corresponding hazard ratio for the composite of total HF hospitalizations, urgent visits and all-cause mortality was 0.75 (0.61-0.91; P = .0037) and for all-cause mortality 0.92 (0.73-1.16). Subgroup analyses, including ejection fraction phenotype, revealed no evidence of heterogeneity in the treatment effect. CONCLUSION: The use of remote PA pressure monitoring to guide treatment of patients with HF reduces episodes of worsening HF and subsequent hospitalizations.

The win ratio method in heart failure trials: lessons learnt from EMPULSE.

AIMS: The EMPULSE trial evaluated the clinical benefit of empagliflozin versus placebo using the stratified win ratio approach in 530 patients with acute heart failure (HF) after initial stabilization. We aim to elucidate how this method works and what it means, thereby giving guidance for use of the win ratio in future trials. METHODS AND RESULTS: The primary trial outcome is a hierarchical composite of death, number of HF events, time to first HF event, or a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score change at 90 days. In an overall (unstratified) analysis we show how comparison of all 265 x 265 patients pairs contribute to 'wins' for empagliflozin and placebo at all four levels of the hierarchy, leading to an unstratified win ratio of 1.38 (95% confidence interval [CI] 1.11-1.71; p = 0.0036). How such a win ratio should (and should not) be interpreted is then described. The more complex primary analysis using a stratified win ratio is then presented in detail leading to a very similar overall result. Win ratios for de novo acute HF and decompensated chronic HF patients were 1.29 and 1.39, respectively, their weighted combination yielding an overall stratified win ratio of 1.36 (95% CI 1.09-1.68) (p = 0.0054). Alternative ways of including HF events and KCCQ scores in the clinical hierarchy are presented, leading to recommendations for their use in future trials. Specifically, inclusion of both number of HF events and time-to-first HF event appears an unnecessary complication. Also, the use of a 5-point margin for KCCQ score paired comparisons is not statistically necessary. CONCLUSIONS: The EMPULSE trial findings illustrate how deaths, clinical events and patient-reported outcomes can be integrated into a win ratio analysis strategy that yields clinically meaningful findings of patient benefit. This has implications for future trial designs that recognize the clinical priorities of patient evaluation and the need for efficient progress towards approval of new treatments.

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.

Multimorbidity, functional impairment, and mortality in older patients stable after prior acute myocardial infarction: Insights from the TIGRIS registry.

BACKGROUND: Data on the association of multimorbidity and functional impairment with cardiovascular (CV) and non-CV outcomes among older myocardial infarction (MI) patients are limited. HYPOTHESIS: Multimorbidity and functional impairment among older MI patients are associated with CV and non-CV mortality. METHODS: Patients aged ≥65 years, 1-3 years post-MI, and enrolled between June 2013 and Novemeber 2014 from 349 sites in 25 countries in the global TIGRIS registry were categorized by age, number of comorbidities, and presence and degree of functional impairment. Functional impairment was calculated using five-dimension EuroQol based on three domains-mobility, self-care, and usual activities. The association between age, number of comorbid conditions, and degree of functional impairment with 2-year incidence of CV and non-CV death was evaluated using Poisson regression analysis. RESULTS: Older age was associated with higher number of comorbidities and functional impairment; after adjustment, increasing age was significantly associated with non-CV mortality (p = .03) but not CV mortality (p = .38). Greater functional impairment was associated with a higher rate and relatively equal magnitude risk of CV (rate ratios [RR] 1.52, 95% confidence intervals [CI]: 1.29-1.79, per one-step increase) and non-CV mortality (RR 1.42, 95% CI: 1.17-1.73). Multimorbidity was more strongly associated with CV mortality (RR 1.52, 95% CI: 1.38-1.67, per additional comorbidity) versus non-CV mortality (RR 1.29, 95% CI: 1.14-1.47, per additional comorbidity). CONCLUSIONS: Multimorbidity and functional impairment are prevalent among older post-MI patients and are associated with increased CV and non-CV mortality. These findings highlight the importance of considering comorbid conditions and functional impairment as predictors of risk for adverse outcomes and aspects of medical decision making. Clinical Trial Registration: NCT01866904.

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.

Long-term outcomes in patients who received veno-venous extracorporeal membrane oxygenation and renal replacement therapy: a retrospective cohort study.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication in patients with severe respiratory failure receiving extracorporeal membrane oxygenation (ECMO). However, little is known of long-term kidney function in ECMO survivors. We aimed to assess the long-term mortality and kidney outcomes in adult patients treated with veno-venous ECMO (VV-ECMO). METHODS: This was a single-centre retrospective study of adult patients (≥ 18 years old) who were treated with VV-ECMO at a commissioned ECMO centre in the UK between 1st September 2010, and 30th November 2016. AKI was defined and staged using the serum creatinine and urine output criteria of the Kidney Diseases: Improving Global Outcomes (KDIGO) classification. The primary outcome was 1-year mortality. Secondary outcomes were long-term mortality (up to March 2020), 1-year incidence of end-stage kidney disease (ESKD) or chronic kidney disease (CKD) among AKI patients who received renal replacement therapy (AKI-RRT), AKI patients who did not receive RRT (AKI-no RRT) and patients without AKI (non-AKI). RESULTS: A total of 300 patients [57% male; median age 44.5; interquartile range (IQR) 34-54] were included in the final analysis. Past medical histories included diabetes (12%), hypertension (17%), and CKD (2.3%). The main cause of severe respiratory failure was pulmonary infection (72%). AKI occurred in 230 patients (76.7%) and 59.3% received renal replacement therapy (RRT). One-year mortality was 32% in AKI-RRT patients vs. 21.4% in non-AKI patients (p = 0.014). The median follow-up time was 4.35 years. Patients who received RRT had a higher risk of 1-year mortality than those who did not receive RRT (adjusted HR 1.80, 95% CI 1.06, 3.06; p = 0.029). ESKD occurred in 3 patients, all of whom were in the AKI-RRT group. At 1-year, 41.2% of survivors had serum creatinine results available. Among these, CKD was prevalent in 33.3% of AKI-RRT patients vs. 4.3% in non-AKI patients (p = 0.004). CONCLUSIONS: VV-EMCO patients with AKI-RRT had high long-term mortality. Monitoring of kidney function after hospital discharge was poor. In patients with follow-up creatinine results available, the CKD prevalence was high at 1 year, especially in AKI-RRT patients. More awareness about this serious long-term complication and appropriate follow-up interventions are required.

The 2nd European Carotid Surgery Trial (ECST-2): rationale and protocol for a randomised clinical trial comparing immediate revascularisation versus optimised medical therapy alone in patients with symptomatic and asymptomatic carotid stenosis at low to intermediate risk of stroke.

BACKGROUND: Carotid endarterectomy is currently recommended for patients with recently symptomatic carotid stenosis ≥50%, based on randomised trials conducted 30 years ago. Several factors such as carotid plaque ulceration, age and associated comorbidities might influence the risk-benefit ratio of carotid revascularisation. A model developed in previous trials that calculates the future risk of stroke based on these features can be used to stratify patients into low, intermediate or high risk. Since the original trials, medical treatment has improved significantly. Our hypothesis is that patients with carotid stenosis ≥50% associated with a low to intermediate risk of stroke will not benefit from additional carotid revascularisation when treated with optimised medical therapy. We also hypothesise that prediction of future risk of stroke in individual patients with carotid stenosis can be improved using the results of magnetic resonance imaging (MRI) of the carotid plaque. METHODS: Patients are randomised between immediate revascularisation plus OMT versus OMT alone. Suitable patients are those with asymptomatic or symptomatic carotid stenosis ≥50% with an estimated 5-year risk of stroke of <20%, as calculated using the Carotid Artery Risk score. MRI of the brain at baseline and during follow-up will be used as a blinded measure to assess the incidence of silent infarction and haemorrhage, while carotid plaque MRI at baseline will be used to investigate the hypotheses that plaque characteristics determine future stroke risk and help identify a subgroup of patients that will benefit from revascularisation. An initial analysis will be conducted after recruitment of 320 patients with baseline MRI and a minimum of 2 years of follow-up, to provide data to inform the design and sample size for a continuation or re-launch of the study. The primary outcome measure of this initial analysis is the combined 2-year rate of any clinically manifest stroke, new cerebral infarct on MRI, myocardial infarction or periprocedural death. DISCUSSION: ECST-2 will provide new data on the efficacy of modern optimal medical therapy alone versus added carotid revascularisation in patients with carotid stenosis at low to intermediate risk of future stroke selected by individualised risk assessment. We anticipate that the results of baseline brain and carotid plaque MRI will provide data to improve the prediction of the risk of stroke and the effect of treatment in patients with carotid stenosis. TRIAL REGISTRATION: ISRCTN registry ISRCTN97744893 . Registered on 05 July 2012.

Survival Outcomes and Prognostic Factors in Glioblastoma.

Background: IDH-wildtype glioblastoma is the most common malignant primary brain tumour in adults. As there is limited information on prognostic factors outside of clinical trials; thus, we conducted a retrospective study to characterise the glioblastoma population at our centre. Methods: Demographic, tumour molecular profiles, treatment, and survival data were collated for patients diagnosed with glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazard model associations with survival. Results: 490 patients were included; 60% had debulking surgery and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% had non-standard chemo/radio-therapy, and 19% had no further treatment. Overall survival was 9.2 months. In the multivariate analysis, longer survival was associated with debulking surgery vs. biopsy alone (14.9 vs. 8 months) (HR 0.54 [95% CI 0.41−0.70]), subsequent treatment after diagnosis (HR 0.12 [0.08−0.16]) (standard chemoradiotherapy [16.9 months] vs. non-standard regimens [9.2 months] vs. none [2.0 months]), tumour MGMT promotor methylation (HR 0.71 [0.58−0.87]), and younger age (hazard ratio vs. age < 50: 1.70 [1.26−2.30] for ages 50−59; 3.53 [2.65−4.70] for ages 60−69; 4.82 [3.54−6.56] for ages 70+). Conclusions: The median survival for patients with glioblastoma is less than a year. Younger age, debulking surgery, treatment with chemoradiotherapy, and MGMT promotor methylation are independently associated with longer survival.

Socioeconomic Deprivation: An Important, Largely Unrecognized Risk Factor in Primary Prevention of Cardiovascular Disease.

BACKGROUND: Socioeconomic deprivation is associated with higher cardiovascular morbidity and mortality. Whether deprivation status should be incorporated in more cardiovascular risk estimation scores remains unclear. This study evaluates how socioeconomic deprivation status affects the performance of 3 primary prevention cardiovascular risk scores. METHODS: The Generation Scotland Scottish Family Health Study was used to evaluate the performance of 3 cardiovascular risk scores with (ASSIGN [Assessing cardiovascular risk using SIGN (Scottish Intercollegiate Guidelines Network) guidelines to ASSIGN preventive treatment]) and without (SCORE2 [Systematic Coronary Risk Evaluation 2 algorithm], Pooled Cohort Equations) socioeconomic deprivation as a covariate in the risk prediction model. Deprivation was defined by Scottish Index of Multiple Deprivation score. The predicted 10-year risk was evaluated against the observed event rate for the cardiovascular outcome of each risk score. The comparison was made across 3 groups defined by the deprivation index score consisting of group 1 defined as most deprived, group 3 defined as least deprived, and group 2, which consisted of individuals in the middle deprivation categories. RESULTS: The study population consisted of 15 506 individuals (60.0% female, median age of 51). Across the population, 1808 (12%) individuals were assigned to group 1 (most deprived), 8119 (52%) to group 2, and 4708 (30%) to group 3 (least deprived), and 871 (6%) individuals had a missing deprivation score. Risk scores based on models that did not include deprivation status significantly under predicted risk in the most deprived (6.43% observed versus 4.63% predicted for SCORE2 [P=0.001] and 6.69% observed versus 4.66% predicted for Pooled Cohort Equations [P<0.001]). Both risk scores also significantly overpredicted the risk in the least deprived group (3.97% observed versus 4.72% predicted for SCORE2 [P=0.007] and 4.22% observed versus 4.85% predicted for Pooled Cohort Equations [P=0.028]). In contrast, no significant difference was demonstrated in the observed versus predicted risk when using the ASSIGN risk score, which included socioeconomic deprivation status in the risk model. CONCLUSIONS: Socioeconomic status is a largely unrecognized risk factor in primary prevention of cardiovascular disease. Risk scores that exclude socioeconomic deprivation as a covariate under- and overestimate the risk in the most and least deprived individuals, respectively. This study highlights the importance of incorporating socioeconomic deprivation status in risk estimation systems to ultimately reduce inequalities in health care provision for cardiovascular disease.

Early changes in estimated glomerular filtration rate post-initiation of empagliflozin in EMPEROR-Reduced.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may induce an early post-initiation decrease of estimated glomerular filtration rate (eGFR), which does not impact the SGLT2i benefits. The occurrence, characteristics, determinants, and clinical significance of an initial eGFR change among patients with heart failure with reduced ejection fraction require further study. In this study we aimed to describe eGFR change from randomization to week 4 (as percent of change relative to randomization) and assess its impact in EMPEROR-Reduced. METHODS AND RESULTS: Landmark analyses (week 4) were performed. eGFR change was available in 3547 patients out of 3730 (95%). The tertiles of post-initiation % eGFR change for empagliflozin were: tertile 1 (T1) ≤-11.4%; T2 ≥-11.4% to ≤-1.0% and T3 ≥0.0%. The placebo group tertiles were: T1 ≤-6.5%; T2 ≥-6.4% to ≤+3.6%; and T3 ≥+3.6%. On average, empagliflozin induced a leftward distributional shift of initial eGFR changes of -2.5 ml/min/1.73 m2 versus placebo. In the empagliflozin group, after covariate adjustment, the risk of cardiovascular and renal outcomes did not differ between patients in whom early post-treatment initiation eGFR decreased (T1) and patients in whom it increased (T3). However, in the placebo group, patients in whom early post-treatment initiation eGFR decreased (T1) had a higher risk of sustained worsening kidney function and all-cause mortality compared to patients in whom eGFR increased (T3) (hazard ratio [HR] 2.38, 95% confidence interval [CI] 1.25-4.55 and HR 1.37, 95% CI 1.01-1.85, respectively). CONCLUSION: A mild eGFR decrease may be expected after the initiation of empagliflozin, and it is not associated with untoward heart failure, mortality, or kidney safety events. Clinicians should not be concerned with early eGFR changes post-initiation of empagliflozin.

Precision Phenotyping of Dilated Cardiomyopathy Using Multidimensional Data.

BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine.

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.