DPP-4 inhibitor dose selection according to manufacturer specifications:A Contemporary Experience From UK General Practice

Recently, 2 dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin and saxagliptin, adjusted dosing specification from creatinine clearance to glomerular filtration rate, more typically reported in routine laboratory tests. This cross-sectional study examines all DPP-4 inhibitor initiations that require dose adjustment and the dose selection using data from UK general practice. Results indicate that 34% of patients taking a nonlinagliptin DPP-4 inhibitor were given a higher dose and 11% a lower dose than specified in the Summary of Product Characteristics. This reinforces the deviation from Summary of Product Characteristics prescription of DPP-4 inhibitors identified in earlier studies despite improvement in compatibility with routine reporting. (C) 2019 The Authors. Published by Elsevier Inc

Are patients in heart failure trials representative of primary care populations? A systematic review.

BACKGROUND: Guidelines recommend drug treatment for patients with heart failure with a reduced ejection fraction (HFrEF), however the evidence for benefit in patients with mild disease, such as most in primary care, is uncertain. Importantly, drugs commonly used in heart failure account for one in seven of emergency admissions for adverse drug reactions. AIM: To determine to what extent patients included in studies of heart failure treatment with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and aldosterone antagonists were representative of a typical primary care population with HFrEF in England. DESIGN & SETTING: Systematic review of randomised controlled trials (RCTs) of drug treatment in patients with HFrEF. METHOD: MEDLINE, MEDLINE In-Process, EMBASE, and CENTRAL were searched from inception to March 2015. The characteristics of the patient's New York Heart Association (NYHA) classification were compared with a primary care reference population with HFrEF. RESULTS: Of the 30 studies included, two had incomplete data. None had a close match (defined as ≤10% deviation from reference study) for NYHA class I disease; 5/28 were a close match for NYHA class II; 5/28 for NYHA class III; and 18/28 for NYHA class IV. In general, pre-existing cardiovascular conditions, risk factors, and comorbidities were representative of the reference population. CONCLUSION: Patients recruited to studies typically had more severe heart failure than the reference primary care population. When evidence from sicker patients is generalised to less sick people, there is increased uncertainty about benefit and also a risk of harm from overtreatment. More evidence is needed on the effectiveness of treatment of heart failure in asymptomatic patients with NYHA class I

Knowledge of Driving Vehicle Licensing Agency guidelines among NHS doctors:A multicentre observational study

Objectives: Over half of the UK population holds a driver's licence. The DVLA have produced guidelines to ensure drivers with medical conditions drive safely. Doctors should ensure that patients are given appropriate information and advice if they have a medical condition affecting their driving. We sought to evaluate doctors' knowledge of DVLA guidelines. Design: A 25-point questionnaire was designed from DVLA guidelines (‘The DVLA Questionnaire’). Five questions were included for each of neurology, cardiology, drug and alcohol abuse, visual, and respiratory disorders. Setting: Ealing Hospital, Northwick Park Hospital, Watford General Hospital, Norfolk and Norwich University Hospital and Leeds Teaching Hospitals Trust. Participants: 140 UK doctors. Main outcome measures: Questionnaire scores assessing knowledge of DVLA guidelines in five specialty areas. Results: The median overall questionnaire score was 28%, interquartile range 20–36% and range 0–100% [Watford 28%, Leeds 30%, Norfolk and Norwich 36%, Ealing 30%, Northwick Park 28%]. There were no significant differences between the scores for each centre (p = 0.1332), Mean scores for specialty areas were: neurology 33.1%, standard deviation 22.1; cardiology 35.6%, standard deviation 26.9; drug and alcohol abuse 30.6%, standard deviation 23.8; visual disorders 33.9%, standard deviation 23.5 and respiratory disorders 20.3%, standard deviation 24.8; overall score 30.7%. There was no significant difference between the scores of the specialty areas (p = 0.4060). Conclusions: Knowledge of DVLA guidelines in our cohort was low. There is a need for increased awareness among hospital doctors through focused education on driving restrictions for common medical conditions. Improving physician knowledge in this area may help optimise patient safety

Effect of Bruton's tyrosine kinase inhibitors on platelet aggregation in patients with acute myocardial infarction

Aims: Despite widespread use of dual antiplatelet therapy in acute myocardial infarction, there remains a residual risk of morbidity and mortality. Bruton's Tyrosine Kinase inhibitors have been found to inhibit platelet aggregation through the Glycoprotein VI collagen-mediated pathway. The Bruton's Tyrosine Kinase inhibitor, Ibrutinib is used in the management of haematological malignancies and another Bruton's Tyrosine Kinase inhibitor, ONO-4059 (also known as tirabrutinib), is in clinical development. This is an observational study to evaluate the effects of Ibrutinib and ONO-4059 on platelet aggregation after acute myocardial infarction. Methods and results: Twenty patients with a confirmed diagnosis of acute myocardial infarction were enrolled and blood samples obtained within 48 h of hospital admission. All patients were on dual antiplatelet therapy; aspirin plus a P2Y12 inhibitor (clopidogrel or ticagrelor). Blood samples were treated ex vivo with increasing concentrations of Ibrutinib (0, 0.5, 1, 2 μM) and ONO-4059 (0, 0.2, 0.5, 1 μM). Platelet aggregation was measured in response to collagen using a Multiplate analyser to estimate the area under the curve, with lower values indicating lower platelet aggregation. The median age was 63 years and 80% were male. The median area under the curve values for Ibrutinib concentrations 0 (control), 0.5, 1 and 2 mmol/l were 18.5, 8 (P = 0.0004), 4.5 (P < 0.0001) and 2 (P < 0.0001) units and for ONO-4059 concentrations 0 (control), 0.2, 0.5 and1μM, median area under the curve values were 13, 12 (P = 0.7), 6.5 (P = 0.0001) and 5.5 (P = 0.0004 compared to control). Conclusion: The Bruton's Tyrosine Kinase inhibitors, Ibrutinib and ONO-4059, show further inhibition of platelet aggregation in blood samples from patients with acute myocardial infarction, receiving dual antiplatelet therapy in a dose dependent manner. These results provide a rationale for Bruton's Tyrosine Kinase inhibitors to be tested as a potential new antiplatelet strategy for acute myocardial infarction

Epidemiology of ssymptomatic pre-heart failure:a systematic review

Purpose of Review: To quantify the prevalence of asymptomatic pre-heart failure (pre-HF), progression to more severe stages, and associated mortality. Recent Findings: A systematic review was conducted between 01 January 2010 and 12 March 2020 (PROSPERO: CRD42020176141). Data of interest included prevalence, disease progression, and mortality rates. In total, 1030 sources were identified, of which, 12 reported on pre-HF (using the ACC/AHA definition for stage B HF) and were eligible. Prevalence estimates of pre-HF ranged from 11 to 42.7% (10 sources) with higher estimates found in the elderly, in patients with hypertension, and in men. Three studies reported on disease progression with follow-up ranging from 13 months to 7 years. The incidence of symptomatic HF (HF/advanced HF) ranged from 0.63 to 9.8%, and all-cause mortality from 1.6 to 5.4%. Summary: Further research is required to investigate whether early detection and intervention can slow or stop the progression from asymptomatic to symptomatic HF

Determinants of Length of Stay Following Total Anterior Circulatory Stroke

Identification of factors that determine length of stay (LOS) in total anterior circulatory stroke (TACS) has potential for targeted intervention to reduce the associated health care burden. This study aimed to determine which factors predict LOS following either ischaemic or haemorrhagic TACS. The study sample population was drawn from the Norfolk and Norwich Stroke and Transient Ischemic Attack (TIA) Register (1996 – 2012), a prospective registry. 2965 patients admitted with TACS verified by a stroke specialist team were included. Primary analysis identified predictors of length of stay (LOS) in either haemorrhagic or ischaemic TACS. Secondary analyses identified predictors of LOS in patients who were discharged alive or who died during admission separately. Moderate (p=0.014) to severe disability (p=0.015) and history of congestive heart failure (p=0.027) in the primary analysis and pre-stroke residence in a care facility among patients who survived to discharge (p=0.013) were associated with a shorter length of stay. Factors associated with increased length of stay included presence of neurological lateralisation in the primary analysis (p=0.004) and amongst patients who died (p=0.003 and p=0.014 for ischaemic and haemorrhagic stroke, respectively). Patients with advanced age (≥85 years) with haemorrhagic stroke had longer LOS regardless of mortality outcome. Patients with low pre-morbid disability (modified Rankin score ≤2 who died following haemorrhagic TACS also had longer LOS. Our study found predictors of LOS following TACS include neurological lateralisation, pre-stroke disability status, congestive heart failure, pre-morbid residence and age. The identification of such factors would assist in resource allocation and discharge planning

Diastolic Ventricular Interaction in Heart Failure With Preserved Ejection Fraction

Background Exercise‐induced pulmonary hypertension is common in heart failure with preserved ejection fraction (HFpEF). We hypothesized that this could result in pericardial constraint and diastolic ventricular interaction in some patients during exercise. Methods and Results Contrast stress echocardiography was performed in 30 HFpEF patients, 17 hypertensive controls, and 17 normotensive controls (healthy). Cardiac volumes, and normalized radius of curvature (NRC) of the interventricular septum at end‐diastole and end‐systole, were measured at rest and peak‐exercise, and compared between the groups. The septum was circular at rest in all 3 groups at end‐diastole. At peak‐exercise, end‐systolic NRC increased to 1.47±0.05 (P<0.001) in HFpEF patients, confirming development of pulmonary hypertension. End‐diastolic NRC also increased to 1.54±0.07 (P<0.001) in HFpEF patients, indicating septal flattening, and this correlated significantly with end‐systolic NRC (ρ=0.51, P=0.007). In hypertensive controls and healthy controls, peak‐exercise end‐systolic NRC increased, but this was significantly less than observed in HFpEF patients (HFpEF, P=0.02 versus hypertensive controls; P<0.001 versus healthy). There were also small, non‐significant increases in end‐diastolic NRC in both groups (hypertensive controls, +0.17±0.05, P=0.38; healthy, +0.06±0.03, P=0.93). In HFpEF patients, peak‐exercise end‐diastolic NRC also negatively correlated (r=−0.40, P<0.05) with the change in left ventricular end‐diastolic volume with exercise (ie, the Frank‐Starling mechanism), and a trend was noted towards a negative correlation with change in stroke volume (r=−0.36, P=0.08). Conclusions Exercise pulmonary hypertension causes substantial diastolic ventricular interaction on exercise in some patients with HFpEF, and this restriction to left ventricular filling by the right ventricle exacerbates the pre‐existing impaired Frank‐Starling response in these patients

Prescribing in type 2 diabetes patients with and without cardiovascular disease history: A descriptive analysis in the UK CPRD

PURPOSE: Some classes of glucose-lowering medications, including sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1-receptor agonists (GLP1-RAs) have cardio-protective benefit, but it is unclear whether this influences prescribing in the United Kingdom (UK). This study aims to describe class-level prescribing in adults with type 2 diabetes mellitus (T2DM) by cardiovascular disease (CVD) history using the Clinical Practice Research Datalink (CPRD). METHODS: Four cross-sections of people with T2DM aged 18-90 and registered with their general practice for >1 year on 1st January 2017 (n = 166,012), 1st January 2018 (n = 155,290), 1st January 2019 (n = 152,602) and 31st December 2019 (n = 143,373) were identified. Age-standardised proportions for class use through time were calculated separately in those with and without CVD history and by total number of medications prescribed (one, two, three, four+). An analysis by UK country was also performed. FINDINGS: Around 31% of patients had CVD history at each cross-section. Metformin was the most common treatment (>70% of those with and without CVD had prescriptions across all treatment lines). Overall use of SGLT2is and GLP1-RAs was low, with slightly less use in patients with CVD (SGLT2i: 9.8% and 13.8% in those with and without CVD respectively; GLP1-RA: 4.3% and 4.9%, December 2019). Use of SGLT2is as part of dual therapy was low but rose throughout the study. In January 2017, estimated use was 8.0% (95% CI 6.9-9.1%) and 8.9% (8.6-9.3%) in those with and without CVD. By December 2019 this reached 18.3% (17.0-19.5%) and 21.2% (20.6-21.7%) for those with and without CVD respectively. SGLT2i use as triple therapy increased: 22.7% (21.0-24.4%) and 25.9% (25.2-26.6%) in January 2017 to 41.3% (39.5-43.0%) and 45.5% (44.7-46.3%) in December 2019. GLP1-RA use also increased, but observed usage remained lower than SGLT2 inhibitors. Insulin use remained stable throughout, with higher use observed in those with CVD (16% vs 9.7% Dec 2019). Time trends in England, Wales, Scotland and Northern Ireland were similar, although class prevalence varied. IMPLICATIONS: Although use of SGLT2is and GLP1-RAs has increased, overall usage remains low with slightly lower use in those with CVD history, suggesting there is opportunity to optimise use of these medicines in T2DM patients to manage CVD risk. Insulin use was substantially more prevalent in those with CVD despite no evidence of CVD benefit. Further investigation of factors influencing this finding may highlight strategies to improve patient access to the most appropriate treatments, including those with evidence of cardiovascular benefit