Early Discharge to Clinic-Based Therapy of Patients Presenting With Decompensated Heart Failure (EDICT-HF): Study Protocol for a Multi-Centre Randomised Controlled Trial.

BACKGROUND: Acute decompensated heart failure involves a high rate of mortality and complications. Management typically involves a multi-day hospital admission. However, patients often lose part of their function with each successive admission, and are at a high risk for hospital-associated complications such as nosocomial infection. This study aims to determine the safety and efficacy of the management of patients presenting with acute decompensated heart failure to clinic-based therapy vs usual inpatient care using a reproducible management pathway. METHOD: An investigator-initiated, prospective, non-inferiority, 1:1 randomised-controlled trial, stratified by left ventricular ejection fraction including 460 patients with a minimum follow-up of 7 days. This is a multi-centre study to be performed in centres across Victoria, Australia. Participants will be patients with either heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), admitted for acute decompensation of heart failure. INTERVENTION: Early discharge to an outpatient-based Heart Failure Rapid Access Clinical Review (RACER) in addition to frequent medical/nursing at-home review for patients admitted with decompensated heart failure. RESULTS: The primary endpoint will be a non-inferiority assessment of re-hospitalisation at 30 days. Secondary outcomes include superiority assessment of hospitalisation at 30 days, a composite clinical endpoint of major adverse cardiac and cerebrovascular event (MACCE), hospital re-admission or mortality at 3 months, achievement of guideline-directed medical therapy, patient assessment of symptoms (visual-analogue scale quantified as area under curve and Kansas City Cardiomyopathy Questionnaire-12 [KCCQ-12]), attendance at 3-month outpatient follow-up, number of bed stays/clinics attended, proportion of patients free from congestion, change in serum creatinine level, treatment for electrolyte disturbances, time to transition from intravenous to oral diuretics, and health economics analysis (cost-benefit analysis, cost-utility analysis, incremental cost-effectiveness ratio). CONCLUSIONS: The Early Discharge to Clinic-Based Therapy of Patients Presenting with Decompensated Heart Failure (EDICT-HF) trial will help determine whether earlier discharge to out-of-hospital care is non-inferior to the usual practice of inpatient care, in patients with heart failure admitted to hospital for acute decompensation, as an alternative model of care.

Healthcare services use by patients with heart failure in Australia: Findings from the SHAPE study.

BACKGROUND AND OBJECTIVES: General practitioners (GPs) play a central role in healthcare, serving as the first point of contact, making appropriate referrals and coordinating care for chronic conditions such as heart failure (HF). We sought to determine healthcare use by people with HF in primary care. METHOD: In this Study of Heart failure in the Australian Primary carE setting (SHAPE), we analysed records of 1.93 million adult patients who attended a total of 43 practices between 1 July 2013 and 30 June 2018. We identified and examined the data of 20,219 patients with HF to describe the frequency of visits and use of Medicare Benefits Schedule items. RESULTS: Patients with HF saw GPs 14.4 times per annum on average; 59.5% had a General Practice Management Plan (GPMP), 2.9% of GPMPs were reviewed annually or more frequently, and 46.8% of patients had been referred to a cardiologist. A total of 3761 had coexisting anxiety or depression, and of these 37.1% had a mental health plan. DISCUSSION: Patients with HF visit their GP frequently, with many not reaching guideline therapy nor referred to cardiologists. Low use of care planning and reviews presents an opportunity for GPs to improve care.

Clinical characteristics of people with heart failure in Australian general practice: results from a retrospective cohort study.

AIMS: Heart failure (HF) causes significant morbidity and mortality, but the rates and characteristics of people with HF in Australia are not well studied. SHAPE set out to describe the characteristics of HF patients seen in the real-world setting. METHODS: We analysed anonymized patient data extracted from the clinical software of 43 participating GP clinics for the 5 year period from 1 July 2013 to 30 June 2018. Patients were stratified into 'definite' and 'probable' HF based on a hierarchy of selection criteria and analysed for their clinical characteristics. Symptoms and signs of HF and ejection fraction data were searched for within the free text of the medical notes. RESULTS: Of the 1.12 million adults seen regularly, 20 219 were classified as having definite or probable HF. The mean age of the population was 69.8 years, 50.6% were female, and mean body mass index was 31.2 kg/m2 . Fewer than 1 in 6 had the HF diagnosis optimally recorded. Only 3.2% (650 patients) had their left ventricular ejection fraction (EF) quantified: 40.9% had an EF ≥50% and 59.1% had an EF <50%. The most common comorbidities in people with HF were hypertension (41.1%), chronic obstructive pulmonary disease/asthma (25.1%) and depression/anxiety (18.4%). Hypotension (2.3%), bradycardia (6.3%), severe renal impairment (6.4%) and hyperkalaemia (2.0%) were uncommon. Just over one-third (37.8%) had iron deficiency. Loop diuretic use was common (56.7%) but only 33.7% were on a guideline recommended beta-blockers. Use of ivabradine (1.4%) and sacubitril/valsartan (1.2%) was very low, while 39.9% had been prescribed an angiotensin-converting enzyme inhibitor, 31.6% an angiotensin receptor blocker and 16.0% spironolactone. Many patients were prescribed medications that may worsen HF or are relatively contraindicated, such as macrolide antibiotics (29.9%), corticosteroids (25.8%), nonsteroidal anti-inflammatory drugs (23.9%), and tricyclic antidepressants (9.4%). CONCLUSIONS: Heart failure is poorly documented in general practice records and may be contributing to untoward downstream effects, such as low documentation of echocardiography, poor use of guideline recommended therapies and frequent use of medications that may worsen HF.

Epidemiology of heart failure: Study of Heart failure in the Australian Primary carE setting (SHAPE).

AIMS: At present, there is no robust information on the prevalence and incidence of heart failure (HF) in the general Australian community. The present study of primary care data sought to estimate the prevalence and incidence of HF in the community and to describe the demographic and clinical profile of Australians with HF. METHODS AND RESULTS: We undertook a retrospective cohort study based on analysis of anonymized medical records of adult patients cared for at 43 Australian general practices between 1 July 2013 and 30 June 2018. Data were extracted from coded and uncoded fields in electronic medical records. The prevalence and annual incidence of HF were calculated, along with 95% confidence intervals, using the 'active' population of people who were regular attenders at the practices. Age-standardized estimates were also derived using the 2017 Australian population as reference. The mean age of the population with HF was 69.8 years, 50.6% were female, and mean body mass index was 31.2 kg/m2 . The age-standardized prevalence was 2.199% [95% confidence interval (CI): 2.168-2.23%], and the age-standardized annual incidence was 0.348% (95% CI: 0.342-0.354%). These estimates accord with almost 420 000 people living with HF in Australia in 2017, and >66 000 new cases of HF occurring that year. Only 18.9% of patients with definite HF had this formally captured as a 'diagnosis' in their medical record. HF was more frequent among those of lower socio-economic status. CONCLUSIONS: HF is common in Australia. The majority of HF patients do not have this diagnosis optimally noted in their primary care medical records.

The epidemiology of heart failure in the general Australian community - study of heart failure in the Australian primary carE setting (SHAPE): methods.

BACKGROUND: There is a paucity of information on the epidemiology of heart failure (HF) in Australia. The Study of Heart failure in the Australian Primary carE setting (SHAPE) study aims to estimate the prevalence and annual incidence of HF in the general Australian community and to describe the demographic and key clinical profile of Australians with HF. METHODS: We undertook a retrospective cohort study based on analysis of non-identifiable medical records of adult patients cared for at 43 general practices between 1 July 2013 and 30 June 2018. Data were extracted from coded (diagnosis, pathology and prescription fields) and uncoded fields (clinical notes) in the medical records. The latter searches of free text looked for common synonyms relevant to HF. The population was stratified into three groups based on a hierarchy of selection criteria: (1) definite HF, (2) probable HF and (3) possible HF. The prevalence and annual incidence of HF were calculated, along with 95% confidence intervals. RESULTS: The practices provided care to 2.3 million individual patients over the five-year study period, of whom 1.93 million were adults and 1.12 million were regular patients. Of these patients 15,468 were classified as having 'definite HF', 4751 as having 'probable HF' and 33,556 as having 'possible HF'. A further 39,247 were identified as having an aetiological condition associated with HF. A formal HF diagnosis, HF terms recorded as text in the notes and HF-specific medication were the most common methods to identify 'definite' HF patients. Typical signs and symptoms in combination with a diuretic prescription was the most common method to identify 'probable HF' patients. The majority of 'possible' HF patients were identified by the presence of 2 or more of the typical signs or symptoms. Dyspnoea was the commonest recorded symptom and an elevated jugular venous pressure the commonest recorded sign. CONCLUSIONS: This novel approach to undertaking retrospective research of primary care data successfully analysed a combination of coded and uncoded data from the electronic medical records of patients routinely managed in the GP setting. SHAPE is the first real-world study of the epidemiology of HF in the general Australian community setting.

Spontaneous omental bleeding in the setting of dual anti-platelet therapy with ticagrelor.

A 68 year-old man, initially managed with primary percutaneous coronary intervention (PCI) to the right coronary artery (RCA) for an inferior ST elevation myocardial infarction (STEMI) with residual disease requiring coronary artery bypass graft surgery (CABG), re-presented with chest pain. There were no acute ischaemic changes on ECG and his pain settled with nitrates. A day later, he developed left sided abdominal pain and hypovolaemic shock after straining in the toilet. A subsequent computed tomography (CT) scan of his abdomen revealed an omental bleed. He proceeded to emergency laparotomy, recovered well, and was discharged on aspirin and clopidogrel. Apart from dual antiplatelet therapy with aspirin and ticagrelor, and presumed raised intra-abdominal pressure, there were no other identified risk factors for increased bleeding.

Elevated brain serotonin turnover in patients with depression: effect of genotype and therapy.

CONTEXT: The biological basis for the development of major depressive disorder (MDD) remains incompletely understood. OBJECTIVE: To quantify brain serotonin (5-hydroxytryptamine [5-HT]) turnover in patients with MDD. DESIGN: Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated. SETTING: Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. PARTICIPANTS: Studies were performed in 21 patients fulfilling the DSM-IV and International Statistical Classification of Diseases, 10th Revision diagnostic criteria for MDD and in 40 healthy volunteers. INTERVENTIONS: Treatment for patients consisted of SSRI administration for approximately 12 weeks. MAIN OUTCOME MEASURES: Brain serotonin turnover before and after SSRI therapy. RESULTS: Brain serotonin turnover was significantly elevated in unmedicated patients with MDD compared with healthy subjects (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 4.4 [4.3] vs 1.6 [2.4] nmol/L, respectively; P = .003). Analysis of the influence of the 5-HTT genotype in MDD indicated that carriage of the s allele compared with the l allele was associated with greater than a 2-fold increase in brain serotonin turnover (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.5 [4.7] vs 2.7 [2.9] nmol/L, respectively; P = .04). Following SSRI therapy, brain serotonin turnover was substantially reduced (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.0 [4.0] nmol/L prior to treatment vs 2.0 [3.3] nmol/L following therapy; P = .008). CONCLUSIONS: Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD.

Sympathetic activity in major depressive disorder: identifying those at increased cardiac risk?

BACKGROUND: Evidence exists linking major depressive disorder (MDD) with clinical cardiovascular events. The importance of the sympathetic nervous system in the generation of cardiac risk in other contexts is established. OBJECTIVE: To examine the importance of the sympathetic nervous system in the generation of cardiac risk in patients with major depressive disorder (MDD). METHODS: Studies were performed in 39 patients meeting the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for MDD and in 76 healthy subjects. Treatment for patients consisted of selective serotonin reuptake inhibition (SSRI) for 12 weeks. Whole body and cardiac sympathetic activity were examined using noradrenaline isotope dilution methodology and sympathetic nerve recording techniques. Measurement of the extraction of infused tritiated noradrenaline by the heart, and estimation of cardiac dihydroxyphenylglycol production provided direct quantification of neuronal noradrenaline reuptake. RESULTS: Sympathetic activity, particularly in the heart and for the whole body, in patients with MDD followed a bimodal distribution. Elevated values were observed in patients with co-morbid panic disorder (P = 0.006). Consistent with a defect in noradrenaline reuptake, the cardiac extraction of tritiated noradrenaline (0.80 +/- 0.01 versus 0.56 +/- 0.04%, P < 0.001) and cardiac dihydroxyphenylglycol overflow (109 +/- 8 versus 73 +/- 11, P = 0.01) were reduced in patients with MDD. SSRI therapy abolished the excessive sympathetic activation, with whole body noradrenaline spillover falling from 518 +/- 83 to 290 +/- 41 ng/min (P = 0.008). CONCLUSIONS: We have identified a subset of patients with MDD in whom sympathetic nervous activity is extraordinarily high, including in the sympathetic outflow to the heart. Treatment with an SSRI may reduce sympathetic activity in a manner likely to reduce cardiac risk.

Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor.

Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.

Specific serotonin reuptake inhibition in major depressive disorder adversely affects novel markers of cardiac risk.

There exists a growing body of evidence linking depression with cardiovascular events, although the mechanisms responsible remain unknown. We investigated the role of the autonomic nervous system and inflammation in the link between coronary heart disease and major depressive disorder (MDD), and examined the cardiac risk modification following pharmacological treatment of depression. We measured cardiac baroreflex function, heart rate variability, pulse pressure and high sensitivity C-reactive protein (hsCRP), all of which have an impact on cardiac risk, pre- and post-treatment in 25 patients with MDD, with no history of coronary heart disease, and in 15 healthy subjects. Treatment consisted of selective serotonin reuptake inhibitors for approximately 12 weeks. No significant differences were observed between untreated MDD patients and healthy subjects in blood pressure, heart rate, baroreflex sensitivity or heart rate variability. Pulse pressure and hsCRP, however, were significantly elevated in patients with MDD prior to treatment (p=0.023 and p=0.025, respectively). Moreover, while pharmacotherapy was effective in alleviating depression, surprisingly, each of cardiac baroreflex function, heart rate variability, pulse pressure and hsCRP was modified (p<0.05) in a manner likely to increase cardiac risk. In conclusion, this study demonstrated higher pulse pressure and hsCRP plasma levels in patients with MDD, which might contribute to increased cardiac risk. Following treatment vagal activity was reduced, as indicated by reductions in baroreflex sensitivity and heart rate variability, accompanied by increases in pulse pressure and plasma hsCRP levels. Mechanisms potentially responsible for generating cardiac risk in patients treated with selective serotonin reuptake inhibitors may need to be therapeutically targeted to reduce the incidence of coronary heart disease in this population.

The neuronal noradrenaline transporter, anxiety and cardiovascular disease.

Panic disorder can serve as a clinical model for testing whether mental stress can cause heart disease. Potential neural mechanisms of cardiac risk are the sympathetic activation during panic attacks, continuing release of adrenaline as a co-transmitter in the cardiac sympathetic nerves, and impairment of noradrenaline neuronal reuptake, augmenting sympathetic neural respnses. The phenotype of impaired neuronal reuptake of noradrenaline: an epigenetic mechanism? We suspect that this phenotype, in sensitizing people to heart symptom development, is a cause of panic disorder, and by magnifying the sympathetic neural signal in the heart, underlies increased cardiac risk. No loss of function mutations of the coding region of the norepinephrine transporter (NET) are evident, but we do detect hypermethylation of CpG islands in the NET gene promoter region. Chromatin immunoprecipitation methodology demonstrates binding of the inhibitory transcription factor, MeCP2, to promoter region DNA in panic disorder patients. Cardiovascular illnesses co-morbid with panic disorder. Panic disorder commonly coexists with essential hypertension and the postural tachycardia syndrome. In both of these cardiovascular disorders the impaired neuronal noradrenaline reuptake phenotype is also present and, as with panic disorder, is associated with NET gene promoter region DNA hypermethylation. An epigenetic 'co-morbidity' perhaps underlies the clinical concordance. Brain neurotransmitters. Using internal jugular venous sampling, in the absence of a panic attack we find normal norepinephrine turnover, but based on measurements of the overflow of the serotonin metabolite, 5HIAA, a marked increase (six to sevenfold) in brain serotonin turnover in patients with panic disorder. This appears to represent the underlying neurotransmitter substrate for the disorder. Whether this brain serotonergic activation is a prime mover, or consequential on other primary causes of panic disorder, including cardiac sensitization by faulty neuronal noradrenaline reuptake leading to cardiac symptoms and the enhanced vigilance which accompanies them, is unclear at present.

Acute electrophysiologic effects of intravenous amiodarone are independent of a sympatholytic action in humans.

Previous experiments in animals demonstrated a novel sympatholytic action of acute intravascular amiodarone (AM). It is not known if this action also occurs in humans. Twelve male volunteers performed handgrip for 10 min before and after 300 mg intravenous (IV) AM over 60 min. The effect of handgrip was determined from changes in blood pressure (BP), heart rate (HR), and cardiac noradrenaline (NA) spillover. Changes in cardiac spillover of dihydroxyphenylglycol (DHPG), the metabolite of NA, were measured during AM infusion. The electrophysiological effects of AM were determined from changes to the A-H intervals during right atrial stimulation (100 beats/min). Handgrip increased HR (63 +/- 2 to 84 +/- 5 beats/min and 65 +/- 3 to 84 +/- 4 beats/min), systolic BP (141 +/- 4 to 179 +/- 6 mm Hg and 140 +/- 4 to 179 +/- 7 mm Hg), and cardiac NA spillover (11.9 +/- 4 to 44.3 +/- 13 ng/min and 17.3 +/- 4 to 55.5 +/- 11 ng/min) before and after AM, respectively (P < 0.02 in all groups). There was good correlation between increases in cardiac NA spillover and HR (r2 = 0.86) and systolic BP (r2 = 0.87). AM increased the A-H interval (95.5 +/- 18 to 107.8 +/- 20 ms, P < 0.02). There was no difference in hemodynamic or NA response to handgrip before or after the AM infusion. There was also no change in DHPG cardiac spillover during AM infusion. Acute IV AM did not exert a sympatholytic action in humans, with no attenuation in hemodynamic or NA response to handgrip or increase in DHPG production, despite producing an electrophysiologic response.