Loop diuretic utilisation with or without heart failure: impact on prognosis.

BACKGROUND & AIMS: Many patients are prescribed loop diuretics without a diagnostic record of heart failure. Little is known about their characteristics and prognosis. METHODS: Glasgow regional health records (2009-2016) were obtained for adults with cardiovascular disease or taking loop diuretics. Outcomes were investigated using Cox models with hazard ratios adjusted for age, sex, socioeconomic deprivation, and co-morbid disease (adjHR). RESULTS: Of 198,898 patients (median age 65 years; 55% women), 161,935 (81%) neither took loop diuretics nor had a diagnostic record of heart failure (reference group), 23,963 (12%) were taking loop diuretics but had no heart failure recorded, 7,844 (4%) had heart failure recorded and took loop diuretics and 5,156 (3%) had heart failure recorded but were not receiving loop diuretics.Five-year mortality was only slightly higher for heart failure in absence of loop diuretics (22%; adjHR: 1.2 [95% CI 1.1-1.3]), substantially higher for those taking loop diuretics with no heart failure recorded (40%; adjHR: 1.8 [95% CI 1.7-1.8]) and highest for heart failure treated with loop diuretics (52%; adjHR: 2.2 [95% CI 2.0-2.2]). CONCLUSIONS: For patients with cardiovascular disease, many are prescribed loop diuretics without a diagnosis of heart failure being recorded. Mortality is more strongly associated with loop diuretic use than with a heart failure record. The diagnosis of heart failure may be often missed, or loop diuretic use is associated with other conditions with a prognosis similar to heart failure, or inappropriate loop diuretic use increases mortality; all might be true.

Dapagliflozin and Blood Pressure in Patients with Chronic Kidney Disease and Albuminuria.

BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with chronic kidney disease (CKD) is unknown. We conducted a prespecified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure (SBP) in patients with CKD, with and without type 2 diabetes. METHODS: A total of 4304 adults with baseline estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g were randomized to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in SBP was a prespecified outcome. RESULTS: Baseline mean (SD) SBP was 137.1 mmHg (17.4). By Week 2, dapagliflozin compared to placebo reduced SBP by 3.6 mmHg (95% CI 2.8-4.4 mmHg), an effect maintained over the duration of the trial (2.9 mmHg, 2.3-3.6 mmHg). Time-averaged reductions in SBP were 3.2 mmHg (2.5-4.0 mmHg) in patients with diabetes and 2.3 mmHg (1.2-3.4 mmHg) in patients without diabetes. The time-averaged effect of dapagliflozin on diastolic blood pressure (DBP) was 1.0 mmHg (0.6-1.4 mmHg); 0.8 mmHg (0.4-1.3 mmHg) in patients with diabetes and 1.4 mmHg (0.7-2.1 mmHg) in patients without diabetes. Benefits of dapagliflozin on the primary composite and secondary endpoints were evident across the spectrum of baseline SBP and DBP. CONCLUSION: In patients with CKD and albuminuria, randomization to dapagliflozin was associated with modest reductions in systolic and diastolic BP.

Efficacy of implantable haemodynamic monitoring in heart failure across ranges of ejection fraction: a systematic review and meta-analysis.

AIMS: We conducted a meta-analysis of randomised controlled trials (RCTs) of implantable haemodynamic monitoring (IHM)-guided care. METHODS: PubMed and Ovid MEDLINE were searched for RCTs of IHM in patients with heart failure (HF). Outcomes were examined in total (first and recurrent) event analyses. RESULTS: Five trials comparing IHM-guided care with standard care alone were identified and included 2710 patients across ejection fraction (EF) ranges. Data were available for 628 patients (23.2%) with heart failure with preserved ejection fraction (HFpEF) (EF ≥50%) and 2023 patients (74.6%) with heart failure with a reduced ejection fraction (HFrEF) (EF <50%). Chronicle, CardioMEMS and HeartPOD IHMs were used. In all patients, regardless of EF, IHM-guided care reduced total HF hospitalisations (HR 0.74, 95% CI 0.66 to 0.82) and total worsening HF events (HR 0.74, 95% CI 0.66 to 0.84). In patients with HFrEF, IHM-guided care reduced total worsening HF events (HR 0.75, 95% CI 0.66 to 0.86). The effect of IHM-guided care on total worsening HF events in patients with HFpEF was uncertain (fixed-effect model: HR 0.72, 95% CI 0.59 to 0.88; random-effects model: HR 0.60, 95% CI 0.32 to 1.14). IHM-guided care did not reduce mortality (HR 0.92, 95% CI 0.71 to 1.20). IHM-guided care reduced all-cause mortality and total worsening HF events (HR 0.80, 95% CI 0.72 to 0.88). CONCLUSIONS: In patients with HF across all EFs, IHM-guided care reduced total HF hospitalisations and worsening HF events. This benefit was consistent in patients with HFrEF but not consistent in HFpEF. Further trials with pre-specified analyses of patients with an EF of ≥50% are required. PROSPERO REGISTRATION NUMBER: CRD42021253905.

Natriuretic peptide plasma concentrations and risk of cardiovascular versus non-cardiovascular events in heart failure with reduced ejection fraction: Insights from the PARADIGM-HF and ATMOSPHERE trials.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known. OBJECTIVE: To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations. METHODS: In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels (<400, 400-999, 1000-1999, 2000-2999, and >3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors. RESULTS: A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months. CONCLUSIONS: The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

Risk stratification scores for patients with acute heart failure in the Emergency Department: A systematic review.

AIMS: This study aimed to systematically identify and summarise all risk scores evaluated in the emergency department setting to stratify acute heart failure patients. METHODS AND RESULTS: A systematic review of PubMed and Web of Science was conducted including all multicentre studies reporting the use of risk predictive models in emergency department acute heart failure patients. Exclusion criteria were: (a) non-original articles; (b) prognostic models without predictive purposes; and (c) risk models without consecutive patient inclusion or exclusively tested in patients admitted to a hospital ward. We identified 28 studies reporting findings on 19 scores: 13 were originally derived in the emergency department (eight exclusively using acute heart failure patients), and six in emergency department and hospitalised patients. The outcome most frequently predicted was 30-day mortality. The performance of the scores tended to be higher for outcomes occurring closer to the index acute heart failure event. The eight scores developed using acute heart failure patients only in the emergency department contained between 4-13 predictors (age, oxygen saturation and creatinine/urea included in six scores). Five scores (Emergency Heart Failure Mortality Risk Grade, Emergency Heart Failure Mortality Risk Grade 30 Day mortality ST depression, Epidemiology of Acute Heart Failure in Emergency department 3 Day, Acute Heart Failure Risk Score, and Multiple Estimation of risk based on Emergency department Spanish Score In patients with Acute Heart Failure) have been externally validated in the same country, and two (Emergency Heart Failure Mortality Risk Grade and Multiple Estimation of risk based on Emergency department Spanish Score In patients with Acute Heart Failure) further internationally validated. The c-statistic for Emergency Heart Failure Mortality Risk Grade to predict seven-day mortality was between 0.74-0.81 and for Multiple Estimation of risk based on Emergency department Spanish Score In patients with Acute Heart Failure to predict 30-day mortality was 0.80-0.84. CONCLUSIONS: There are several scales for risk stratification of emergency department acute heart failure patients. Two of them are accurate, have been adequately validated and may be useful in clinical decision-making in the emergency department i.e. about whether to admit or discharge.

BMI and future risk for COVID-19 infection and death across sex, age and ethnicity: Preliminary findings from UK biobank.

AIMS: We examined the link between BMI and risk of a positive test for SARS-CoV-2 and risk of COVID-19-related death among UK Biobank participants. METHODS: Among 4855 participants tested for SARS-CoV-2 in hospital, 839 were positive and of these 189 died from COVID-19. Poisson models with penalised thin plate splines were run relating exposures of interest to test positivity and case-fatality, adjusting for confounding factors. RESULTS: BMI was associated strongly with positive test, and risk of death related to COVID-19. The gradient of risk in relation to BMI was steeper in those under 70, compared with those aged 70 years or older for COVID-19 related death (Pinteraction = 0.03). BMI was more strongly related to test positivity (Pinteraction = 0.010) and death (Pinteraction = 0.002) in non-whites (predominantly South Asians and Afro-Caribbeans), compared with whites. CONCLUSIONS: These data add support for adiposity being more strongly linked to COVID-19-related deaths in younger people and non-white ethnicities. If future studies confirm causality, lifestyle interventions to improve adiposity status may be important to reduce the risk of COVID-19 in all, but perhaps particularly, non-white communities.

Quantification of pleural effusions on thoracic ultrasound in acute heart failure.

BACKGROUND: Although pleural effusions are common among patients with acute heart failure, the relevance of pleural effusion size assessed on thoracic ultrasound has not been investigated systematically. METHODS: In this prospective observational study, we included patients hospitalised for acute heart failure and performed a thoracic ultrasound early after admission (thoracic ultrasound 1) and at discharge (thoracic ultrasound 2) independently of routine clinical management. A semiquantitative score was applied offline blinded to clinical findings to categorise and monitor pleural effusion size. RESULTS: Among 188 patients (median age 72 years, 62% men, 78% white, median left ventricular ejection fraction 38%), pleural effusions on thoracic ultrasound 1 were present in 66% of patients and decreased in size during the hospitalisation in 75% based on the pleural effusion score (P<0.0001). Higher values of the pleural effusion score were associated with higher pleural effusion volumes on computed tomography (P<0.001), higher NT-pro brain natriuretic peptide values (P=0.001) and a greater number of B-lines on lung ultrasound (P=0.004). Nevertheless, 47% of patients were discharged with persistent pleural effusions, 19% with large effusions. However, higher values of the pleural effusion score on thoracic ultrasound 2 did not identify patients at increased risk of 90-day heart failure rehospitalisations or death (adjusted hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.92-1.19; P=0.46) whereas seven or more B-lines on lung ultrasound at discharge were independently associated with adverse events (adjusted HR 2.43, 95% CI 1.11-5.37; P=0.027). CONCLUSION: Among patients with acute heart failure, pleural effusions are associated with other clinical, imaging and laboratory markers of congestion and improve with heart failure therapy. The prognostic relevance of persistent pleural effusions at discharge should be investigated in larger studies.

Effects of apixaban compared with warfarin as gain in event-free time - a novel assessment of the results of the ARISTOTLE trial.

BACKGROUND: A novel approach to determine the effect of a treatment is to calculate the delay of event, which estimates the gain of event-free time. The aim of this study was to estimate gains in event-free time for stroke or systemic embolism, death, bleeding events, and the composite of these events, in patients with atrial fibrillation randomized to either warfarin or apixaban in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial (ARISTOTLE). DESIGN: The ARISTOTLE study was a randomized double-blind trial comparing apixaban with warfarin. METHODS: Laplace regression was used to estimate the delay in time to the outcomes between the apixaban and the warfarin group in 6, 12, 18 and 22 months of follow-up. RESULTS: The gain in event-free time for apixaban versus warfarin was 181 (95% confidence interval 76 to 287) days for stroke or systemic embolism and 55 (-4 to 114) days for death after 22 months of follow-up. The corresponding gains in event-free times for major and intracranial bleeding were 206 (130 to 281) and 392 (249 to 535) days, respectively. The overall gain for the composite of all these events was a gain of 116 (60 to 171) days. CONCLUSIONS: In patients with atrial fibrillation, 22 months of treatment with apixaban, as compared with warfarin, provided gains of approximately 6 months in event-free time for stroke or systemic embolism, 7 months for major bleeding and 13 months for intracranial bleeding.

Winter Peaks in Heart Failure: An Inevitable or Preventable Consequence of Seasonal Vulnerability?

Climate change is a major contributor to annual winter peaks in cardiovascular events across the globe. However, given the paradoxical observation that cardiovascular seasonality is observed in relatively mild as well as cold climates, global warming may not be as positive for the syndrome of heart failure (HF) as some predict. In this article, we present our Model of Seasonal Flexibility to explain the spectrum of individual responses to climatic conditions. We have identified distinctive phenotypes of resilience and vulnerability to explain why winter peaks in HF occur. Moreover, we identify how better identification of climatic vulnerability and the use of multifaceted interventions focusing on modifiable bio-behavioural factors may improve HF outcomes.

Editor's Choice- Impact of insulin-treated diabetes on cardiovascular outcomes following high-risk myocardial infarction.

BACKGROUND: Diabetes is associated with poor cardiovascular outcomes, and insulin-treated patients usually have a worse prognosis than non-insulin-treated subjects. The relationship between insulin treatment and outcomes in high-risk myocardial infarction patients has not been described in a large dataset. METHODS: To investigate the association between insulin-treated diabetes and long-term cardiovascular outcomes in patients with high-risk myocardial infarction, we used adjusted Cox models to compare cardiovascular mortality and hospitalisation among 28,771 patients grouped by diabetes status and insulin treatment from four randomised clinical trials (VALIANT, EPHESUS, OPTIMAAL, CAPRICORN) of acute myocardial infarction complicated by heart failure and/or left ventricular systolic dysfunction. RESULTS: After an approximately 2-year follow-up, patients with no diabetes (21,386 subjects, 74.3%), non-insulin-treated diabetes (4977 patients, 17.3%) and insulin-treated diabetes (2409 subjects, 8.4%) had an incremental yearly mortality risk (15.8%, 21.3% and 28.1%, respectively). Insulin-treated diabetes patients presented with a higher cardiovascular burden and comorbidities. After adjustment for 18 baseline covariates, patients with non-insulin-treated and insulin-treated diabetes were at higher risk of cardiovascular death (hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.13-1.38 and HR 1.49, 95% CI 1.31-1.69, respectively; P for comparison of non-insulin-treated vs. insulin-treated diabetes =0.016) and cardiovascular hospitalisation (HR 1.33, 95% CI 1.25-1.41 and HR 1.16, 95% CI 1.11-1.22, respectively) compared to patients without diabetes. These results remained consistent after further adjustment for medications and left ventricular ejection fraction. CONCLUSIONS: Insulin-treated diabetes patients had higher event rates than diabetes patients taking oral treatments and patients without diabetes. However, insulin-treated diabetes patients had more comorbidities and atherosclerotic disease, precluding any causality suggestion between insulin treatment and outcomes. This high-risk population may require specific and/or more intense cardiovascular protective therapies.

Initiation of domiciliary care and nursing home admission following first hospitalization of heart failure patients: a nationwide cohort study.

BACKGROUND: Heart failure (HF) has a major impact on a patient's quality of life and functional status. This impact may be sufficiently profound to prevent independent living although how often this is the case is unknown. We examined the need for domiciliary assistance and admission to a nursing home following first HF hospitalization. METHODS: In nationwide Danish registries, we identified a cohort of patients discharged alive after a first-time HF hospitalization in the period 2008-2014 who were matched 1:5 with comparison subjects based on age and sex and followed for 5 years. RESULTS: We included 37,547 patients (69% men) discharged after a first-time HF-hospitalization and 187,735 comparison subjects. The 5-year incidence of initiation of domiciliary care was 24.1% [23.7%-24.6%] among HF patients and 9.2% [9.1%-9.4%] among the comparison cohort and yielded a corresponding adjusted HR of 2.02 [1.96-2.09]. Covariates associated with initiation of domiciliary support included older age (HR 1.08 [1.07-1.08] per 1 year increase in age), living alone (HR 2.09 [2.04-2.15]) and comorbidities. The 5-year incidence of nursing home admission was 3.9% [3.7%-4.0%] among HF patients and 1.7% [1.7%-1.8%] among the comparison cohort and this resulted in an adjusted HR of 1.91 [1.77-2.06]. Covariates associated with nursing home admission included older age (HR 1.10 [1.10-1.11]), living alone (HR 2.15 [2.02-2.28]) and history of stroke (HR 2.71 [2.53-2.90]). CONCLUSION: Hospitalization for HF is associated with increased need for domiciliary support and nursing home admissions. Older age, living alone, and comorbidities were associated with higher risk of both outcomes.

Effect of single and dual renin-angiotensin blockade on stroke in patients with and without diabetes in VALIANT.

INTRODUCTION: Concern has been raised about a possible increase in risk of stroke in patients with diabetes treated with the combination of the renin-inhibitor aliskiren and an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. We compared the rate of stroke in patients with and without diabetes treated with single or dual renin-angiotensin system blockade after acute myocardial infarction. PATIENTS AND METHODS: We performed a post hoc analysis of the Valsartan in Acute Myocardial Infarction trial in which 14,703 patients with heart failure, left ventricular systolic dysfunction or both, were randomised to captopril (C), valsartan (V) or both (C + V) after 0.5-10 days after acute myocardial infarction and followed for a median of 2.1 years. We used Cox proportional-hazard regression to estimate the hazard ratios [HR (95% CI)] of stroke in each treatment group. RESULTS: Among patients with diabetes, 60/1303 (4.6%) receiving captopril, 60/1337 (4.5%) valsartan and 41/1340 (3.1%) valsartan plus captopril suffered a stroke: V + C versus V or C HR 0.68 (0.47-0.96), p = 0.03. The corresponding numbers in patients without diabetes were 106/3606 (2.9%), 97/3572 (2.7%) and 99/3545 (2.8%): V + C versus V or C HR 0.99 (0.78-1.26), p = 0.92 (interaction p = 0.08). CONCLUSION: The risk of stroke after myocardial infarction in patients with diabetes was lower in patients treated with both an angiotensin converting enzyme inhibitor and angiotensin receptor blocker than in patients receiving either monotherapy.

'Hearts and minds': association, causation and implication of cognitive impairment in heart failure.

The clinical syndrome of heart failure is one of the leading causes of hospitalisation and mortality in older adults. An association between cognitive impairment and heart failure is well described but our understanding of the relationship between the two conditions remains limited. In this review we provide a synthesis of available evidence, focussing on epidemiology, the potential pathogenesis, and treatment implications of cognitive decline in heart failure. Most evidence available relates to heart failure with reduced ejection fraction and the syndromes of chronic cognitive decline or dementia. These conditions are only part of a complex heart failure-cognition paradigm. Associations between cognition and heart failure with preserved ejection fraction and between acute delirium and heart failure also seem evident and where data are available we will discuss these syndromes. Many questions remain unanswered regarding heart failure and cognition. Much of the observational evidence on the association is confounded by study design, comorbidity and insensitive cognitive assessment tools. If a causal link exists, there are several potential pathophysiological explanations. Plausible underlying mechanisms relating to cerebral hypoperfusion or occult cerebrovascular disease have been described and it seems likely that these may coexist and exert synergistic effects. Despite the prevalence of the two conditions, when cognitive impairment coexists with heart failure there is no specific guidance on treatment. Institution of evidence-based heart failure therapies that reduce mortality and hospitalisations seems intuitive and there is no signal that these interventions have an adverse effect on cognition. However, cognitive impairment will present a further barrier to the often complex medication self-management that is required in contemporary heart failure treatment.

¿Cuál debería ser el fármaco que se añadiera a un IECA y un bloqueador beta en la insuficiencia cardiaca por disfunción sistólica: un antagonista de la aldosterona o un ARA-II? Evidencias clínicas con ambos / Which drug should be added to an ace inhibitor and a beta blocker in systolic heart failure -an aldosterone antagonist or an Angiotensin II receptor blocker? Review of the clinical evidence

La combinación de un inhibidor de la enzima de conversión de la angiotensina (IECA) y un bloqueador beta es el tratamiento clave de primera línea para pacientes con insuficiencia cardiaca crónica (ICC) y disfunción sistólica del ventrículo izquierdo (DSVI), así como para pacientes con insuficiencia cardiaca, DSVI o ambos tras un infarto agudo de miocardio (IAM). La adición de un antagonista de los receptores de la angiotensina (ARA-II) a un IECA proporciona mayor beneficio en la ICC en clase funcional II-IV de la New York Heart Association (NYHA). En el caso del IAM, no se ha observado ningún beneficio por añadir un ARA-II. La adición de un antagonista de la aldosterona (AA) reduce la mortalidad en la ICC de clase funcional III y IV de la NYHA y también en pacientes con DSVI y síntomas de insuficiencia cardiaca o diabetes mellitus tras un IAM. Por tanto, la controversia surge solamente al considerar la elección de un tercer agente para pacientes con ICC sistólica que estén en clase funcional III de la NYHA, donde está justificada la adición de un ARA-II o de un AA. Desafortunadamente, ningún ensayo ha comparado un ARA-II con un AA en esta situación y no hay ninguno previsto actualmente, aunque si hay un ensayo con un AA en pacientes con ICC sistólica en clase funcional II de la NYHA. Tenemos la posibilidad de elegir, pero hay que añadir uno u otro agente. A menudo la elección del fármaco vendrá dada por la tolerabilidad del paciente (AU)

The combination of an ACE inhibitor and a beta blocker is the key first line treatment for patients with chronic heart failure (CHF) and left ventricular systolic dysfunction (LVSD), as well as patients with heart failure, LVSD or both after acute myocardial infarction (AMI). Adding an angiotensin receptor blocker (ARB) to an ACE inhibitor gives further benefit In NYHA class II-IV CHF. In the case of AMI, there is no benefit from adding an ARB. Adding an aldosterone antagonist (AA) reduces mortality in NYHA class III and IV CHF and in patients with LVSD and symptoms of heart failure or diabetes after AMI. Controversy therefore only arises when considering the choice of a third agent for patients with systolic CHF who are in NYHA class III where adding either an ARB or an AA is justified. Unfortunately, no trial has compared an ARB and AA in this situation and none is currently planned, though a trial with an AA in patients with NYHA class II systolic CHF is. We have a choice, but one or other agent should be added. Often the choice of drug will be dictated by patient tolerability (AU)