Association is not causation: treatment effects cannot be estimated from observational data in heart failure

Aims: Treatment ‘effects’ are often inferred from non-randomized and observational studies. These studies have inherent biases and limitations, which may make therapeutic inferences based on their results unreliable. We compared the conflicting findings of these studies to those of prospective randomized controlled trials (RCTs) in relation to pharmacological treatments for heart failure (HF). Methods and results: We searched Medline and Embase to identify studies of the association between non-randomized drug therapy and all-cause mortality in patients with HF until 31 December 2017. The treatments of interest were: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists (MRAs), statins, and digoxin. We compared the findings of these observational studies with those of relevant RCTs. We identified 92 publications, reporting 94 non-randomized studies, describing 158 estimates of the ‘effect’ of the six treatments of interest on all-cause mortality, i.e. some studies examined more than one treatment and/or HF phenotype. These six treatments had been tested in 25 RCTs. For example, two pivotal RCTs showed that MRAs reduced mortality in patients with HF with reduced ejection fraction. However, only one of 12 non-randomized studies found that MRAs were of benefit, with 10 finding a neutral effect, and one a harmful effect. Conclusion: This comprehensive comparison of studies of non-randomized data with the findings of RCTs in HF shows that it is not possible to make reliable therapeutic inferences from observational associations. While trials undoubtedly leave gaps in evidence and enrol selected participants, they clearly remain the best guide to the treatment of patients

Redefining heart failure phenotypes based on ejection fraction

No abstract available

Talking to patients with heart failure about end of life

No abstract available

Personalized medicine and hospitalization for heart failure: if we understand it, we may be successful in treating it

Randomized trials in patients with hospitalized heart failure (HHF) continue to frustrate the cardiology community. Promising haemodynamic, structural and biomarker findings from phase 2 studies consistently fail to deliver substantive benefits in larger outcome trials. What underlies these recurrent failures? Why are persistently high readmission and post‐discharge mortality rates not being reduced? Challenging any pre‐conceived ideas about the existence of a ‘typical’ acutely decompensated heart failure patient is fundamental, as is the adoption of a carefully personalized approach. These individuals come from a remarkably heterogeneous group. Surely precise phenotyping should translate to a more successful therapeutic approach

Palliative care needs in patients hospitalized with heart failure (PCHF) study: rationale and design

Abstract Aims The primary aim of this study is to provide data to inform the design of a randomized controlled clinical trial (RCT) of a palliative care (PC) intervention in heart failure (HF). We will identify an appropriate study population with a high prevalence of PC needs defined using quantifiable measures. We will also identify which components a specific and targeted PC intervention in HF should include and attempt to define the most relevant trial outcomes. Methods An unselected, prospective, near-consecutive, cohort of patients admitted to hospital with acute decompensated HF will be enrolled over a 2-year period. All potential participants will be screened using B-type natriuretic peptide and echocardiography, and all those enrolled will be extensively characterized in terms of their HF status, comorbidity, and PC needs. Quantitative assessment of PC needs will include evaluation of general and disease-specific quality of life, mood, symptom burden, caregiver burden, and end of life care. Inpatient assessments will be performed and after discharge outpatient assessments will be carried out every 4 months for up to 2.5 years. Participants will be followed up for a minimum of 1 year for hospital admissions, and place and cause of death. Methods for identifying patients with HF with PC needs will be evaluated, and estimates of healthcare utilisation performed. Conclusion By assessing the prevalence of these needs, describing how these needs change over time, and evaluating how best PC needs can be identified, we will provide the foundation for designing an RCT of a PC intervention in HF

Development of Twitching in Sleeping Infant Mice Depends on Sensory Experience

SummaryMyoclonic twitches are jerky movements that occur exclusively and abundantly during active (or REM) sleep in mammals, especially in early development [1–4]. In rat pups, limb twitches exhibit a complex spatiotemporal structure that changes across early development [5]. However, it is not known whether this developmental change is influenced by sensory experience, which is a prerequisite to the notion that sensory feedback from twitches not only activates sensorimotor circuits but modifies them [4]. Here, we investigated the contributions of proprioception to twitching in newborn ErbB2 conditional knockout mice that lack muscle spindles and grow up to exhibit dysfunctional proprioception [6–8]. High-speed videography of forelimb twitches unexpectedly revealed a category of reflex-like twitching—comprising an agonist twitch followed immediately by an antagonist twitch—that developed postnatally in wild-types/heterozygotes, but not in knockouts. Contrary to evidence from adults that spinal reflexes are inhibited during twitching [9–11], this finding suggests that twitches trigger the monosynaptic stretch reflex and, by doing so, contribute to its activity-dependent development [12–14]. Next, we assessed developmental changes in the frequency and organization (i.e., entropy) of more-complex, multi-joint patterns of twitching; again, wild-types/heterozygotes exhibited developmental changes in twitch patterning that were not seen in knockouts. Thus, targeted deletion of a peripheral sensor alters the normal development of local and global features of twitching, demonstrating that twitching is shaped by sensory experience. These results also highlight the potential use of twitching as a uniquely informative diagnostic tool for assessing the functional status of spinal and supraspinal circuits

Referral for specialist follow-up and its association with post-discharge mortality among patients with systolic heart failure (from the National Heart Failure Audit for England and Wales)

For patients admitted with worsening heart failure, early follow-up after discharge is recommended. Whether outcomes can be improved when follow-up is done by cardiologists is uncertain. We aimed to determine the association between cardiology follow-up and risk of death for patients with heart failure discharged from hospital. Using data from the National Heart Failure Audit (England & Wales), we investigated the effect of referral to cardiology follow-up on 30-day and one-year mortality in 68 772 patients with heart failure and a reduced left ventricular ejection fraction (HFREF) discharged from 185 hospitals between 2007 to 2013. The primary analyses used instrumental variable analysis complemented by hierarchical logistic and propensity matched models. At the hospital level, rates of referral to cardiologists varied from 6% to 96%. The median odds ratio (OR) for referral to cardiologist was 2.3 (95% confidence interval [CI] 2.1, 2.5), suggesting that, on average, the odds of a patient being referred for cardiologist follow-up after discharge differed approximately 2.3 times from one randomly selected hospital to another one. Based on the proportion of patients (per region) referred for cardiology follow-up, referral for cardiology follow-up was associated with lower 30-day (OR 0.70; CI 0.55, 0.89) and one-year mortality (OR 0.81; CI 0.68, 0.95) compared with no plans for cardiology follow-up (i.e., standard follow-up done by family doctors). Results from hierarchical logistic models and propensity matched models were consistent (30-day mortality OR 0.66; CI 0.61, 0.72 and 0.66; CI 0.58, 0.76 for hierarchical and propensity matched models, respectively). For patients with HFREF admitted to hospital with worsening symptoms, referral to cardiology services for follow-up after discharge is strongly associated with reduced mortality, both early and late

Return to the workforce following first hospitalization for heart failure: a Danish nationwide cohort study

Background: Return to work is important financially, as a marker of functional status and for self-esteem in patients developing chronic illness. We examined return to work after first heart failure (HF) hospitalization. Methods: By individual-level linkage of nationwide Danish registries, we identified 21455 patients of working age (18-60 years) with a first HF hospitalization in the period of 1997-2012. Of these 11880 (55%) were in the workforce prior to HF hospitalization and comprised the study population. We applied logistic regression to estimate odds ratios (OR) for associations between age, sex, length of hospital stay, level of education, income, comorbidity and return to work. Results: One year after first HF hospitalization, 8040 (67.7%) returned to the workforce, 2981 (25.1%) did not, 805 (6.7%) died and 54 (0.5%) emigrated. Predictors of return to work included younger age (18-30 vs. 51-60 years, OR 3.12; 95% CI 2.42-4.03), male sex (OR 1.22 [1.18-1.34]) and level of education (long-higher vs. basic school OR 2.06 [1.63-2.60]). Conversely, hospital stay >7 days (OR 0.56 [0.51-0.62]) and comorbidity including history of stroke (OR 0.55 [0.45-0.69]), chronic kidney disease (OR 0.46 [0.36-0.59]), chronic obstructive pulmonary disease (OR 0.62 [0.52-0.75]), diabetes (OR 0.76 [0.68-0.85]) and cancer (OR 0.49 [0.40-0.61]) were all significantly associated with lower chance of return to work. Conclusions: Patients in the workforce prior to HF hospitalization had low mortality but high risk of detachment from the workforce one year later. Young age, male sex, and higher level of education were predictors of return to work

Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction. A report from the Irbesartan in Heart Failure with Preserved Ejection Fraction Trial (I-Preserve)

Background—In patients with HF and preserved ejection fraction (HFpEF), little is known about the characteristics of and outcomes in those with and without diabetes. Methods—We examined clinical and echocardiographic characteristics and outcomes in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), according to history of diabetes. Cox regression models were used to estimate hazard ratios (HR) for cardiovascular outcomes adjusted for known predictors, including age, sex, natriuretic peptides, and comorbidity. Echocardiographic data were available in 745 patients and were additionally adjusted for in supplementary analyses. Results—Overall, 1134 of 4128 patients (27%) had diabetes. Compared to those without diabetes, they were more likely to have a history of myocardial infarction (28% vs. 22%), higher BMI (31kg/m2 vs. 29kg/m2), worse Minnesota living with HF score (48 vs. 40), higher median NT-proBNP concentration (403 vs 320 pg/ml; all p<0.01), more signs of congestion but no significant difference in LVEF. Patients with diabetes had a greater left ventricular (LV) mass and left atrial area than patients without diabetes. Doppler E wave velocity (86 vs 76 cm/sec, p<0.0001) and the ratio of E/e' (11.7 vs 10.4, p=0.010) were higher in patients with diabetes. Over a median follow-up of 4.1 years, cardiovascular death or HF hospitalization occurred in 34% of patients with diabetes vs. 22% of those without diabetes; adjusted HR 1.75 (95% CI 1.49-2.05) and 28% vs. 19% of patients with and without diabetes died; adjusted HR 1.59 (1.33-1.91). Conclusions—In HFpEF, patients with diabetes have more signs of congestion, worse quality of life, higher NT-proBNP levels, and a poorer prognosis. They also display greater structural and functional echocardiographic abnormalities. Further investigation is needed to determine the mediators of the adverse impact of diabetes on outcomes in HFPEF, and whether they are modifiable