Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. Methods: We designed a multicenter randomized, double-blind, placebo-controlled trial to investigate the cardiac effects of empagliflozin in patients in NYHA functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomized 1:1 to empagliflozin 10 milligrams once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The co-primary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area (LVESVi) and LV global longitudinal strain (LV GLS) measured using cardiovascular magnetic resonance (CMR). Secondary efficacy outcomes included other CMR measures (LVEDVi, LVEF), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS)), 6-minute walk distance (6MWD), B-lines on lung ultrasound and biomarkers (including NT-proBNP). Results: From April 2018 to August 2019, 105 patients were randomized: 77 (73.3%) male, mean age 68.7 [SD 11.1] years, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% [9.8%], and 81 (77.1%) NYHA II and 24 (22.9%) NYHA III. Patients received standard treatment for HFrEF. Compared with placebo, empagliflozin reduced LVESVi by 6.0 (-10.8 to -1.2) ml/m 2 (p=0.015). There was no difference in LV GLS. Empagliflozin reduced LVEDVi by 8.2 (-13.7 to -2.6) ml/m 2 (p=0.0042) and reduced NT-proBNP by 28 (2 to 47) %, p=0.038. There were no between-group differences in other CMR measures, KCCQ-TSS, 6MWD or B-lines. Conclusions: The SGLT2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which SGLT2 inhibitors reduce HF hospitalization and mortality in HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT03485092.

Background: Microalbuminuria is an early sign of kidney disease in diabetes and indicates cardiovascular risk. We tested if a prespecified urinary proteomic risk classifier (CKD273) was associated with development of microalbuminuria and if progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. Methods: Prospective multicentre study in people with type 2 diabetes, normal urinary albumin excretion and preserved renal function in 15 European specialist centres. High-risk individuals determined by CKD273 were randomised 1:1 (interactive web response system) in a double-blind randomised controlled trial comparing spironolactone 25 mg o.d. to placebo. Primary endpoint was development of confirmed microalbuminuria in all individuals with available data. Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone and association between CKD273 and impaired renal function defined as a glomerular filtration rate < 60 ml/min per 1•73 m 2. This study is registered with ClinicalTrials.gov: NCT02040441 and is completed. Findings: From March 25, 2014 to September 30, 2018 we followed 1775 participants, 12% (n=216) had high-risk urinary proteomic pattern of which 209 were included in the trial and assigned spironolactone (n=102) or placebo (n=107). Median follow-up time was 2•51 years (IQR 2•0-3•0). Progression to microalbuminuria was seen in 28•2% of high-risk and 8•9% of low-risk people (P< 0•001) (hazard ratio (HR), 2•48; 95% confidence interval [CI], 1•80 to 3•42 P<0•001, independent of baseline clinical characteristics). A 30% decline in eGFR from baseline was seen in 42 (19•4 %) high-risk participants compared to 62 (3•9 %) low-risk participants, HR 5•15; 95 % CI (3•41 to 7•76; p<0.0001). Development of microalbuminuria was seen in 35 (33%) randomised to placebo and 26 (25%) randomised to spironolactone treatment (HR 0•81, 95% CI, 0•49 to 1•34, P=0•41). Harms: hyperkalaemia was seen in 13 versus 4, and gynaecomastia in 3 versus 0 subjects on spironolactone and placebo, respectively. Interpretation: In people with type 2 diabetes and normoalbuminuria, the urinary proteomic classifier CKD273 was associated with a 2•5 times increased risk for progression to microalbuminuria over a median of 2•5 years, independent of clinical characteristics. Spironolactone did not prevent progression to microalbuminuria in high-risk subjects.

Our results demonstrate that acute exposure to tobacco smoking as well as electronic cigarettes influences vascular and respiratory function. Where tobacco smoking significantly increased microparticle formation, indicative of possible endothelial injury, electronic cigarettes use induced vasoreactivity and decreased peak expiratory flow. These findings suggest that both electronic cigarettes and tobacco smoking negatively impact vascular function.

Background: Patients with left ventricular systolic dysfunction (LVSD) following myocardial infarction (MI) are at high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system (RAS) inhibition may result in greater attenuation of adverse LV remodeling due to increased levels of substrates for neprilysin with vasodilatory, anti-hypertrophic, anti-fibrotic and sympatholytic effects. Methods: We performed a prospective, multi-center, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103mg twice daily with valsartan 160mg twice daily in patients ≥3 months following MI with a LV ejection fraction (LVEF) ≤40% who were taking a RAS inhibitor (equivalent dose of ramipril ≥2.5mg twice daily), and a beta-blocker unless contraindicated or intolerant. Patients in New York Heart Association functional classification ≥II or with signs and symptoms of HF were excluded. The primary outcome was change from baseline to 52-weeks in LV end-systolic volume index (LVESVI) measured using cardiac magnetic resonance imaging (MRI). Secondary outcomes included other MRI measurements of LV remodeling, change in N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-TnI), and a patient global assessment of change questionnaire. Results: From July 2018 to June 2019, 93 patients were randomized: mean age 60.7±10.4 years, median time from MI 3.6 years (IQR 1.2-7.2), mean LVEF 36.8%±7.1, median NT-proBNP 230pg/mL (124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LVESVI; adjusted between-group difference -1.9mL/m 2 (95%CI -4.9, 1.0); p=0.19. There were no significant between-group differences in NT-proBNP, hs-TnI, LV end-diastolic volume index, left atrial volume index, LVEF, LV mass index, or patient global assessment of change. Conclusions: In patients with asymptomatic LVSD following MI, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique identifier: NCT03552575

BackgroundMallet finger injuries are usually successfully treated non-operatively with a splint. Most patients are reviewed at least twice in a clinic after the initial presentation in A&E. A new protocol promoting “self-care” was introduced at our institution. Patients were provided with structured verbal and written information, and given access to a telephone helpline.MethodsA prospective electronic patient record was used to identify all patients who presented to the emergency department with a mallet finger with a minimum six month follow-up. A satisfaction and patient reported outcome measure was administered via a postal questionnaire. The response rate was 36/47 (77%).ResultsThe median QuickDASH score was 2.3 (IQR 0 to 4.6). All patients were satisfied with the treatment plan provided. Nine used the helpline and all were satisfied with information given. Although 13 patients reported some extensor lag, or bump, they had no functional limitation. Seven patients were reviewed by the general practitioner or other clinicians during their treatment period for issues such a skin care, splint size changes or sickness certification. Five were subsequently reviewed at the end of their treatment period in a clinic at their request, or their general practitioner, but did not require further surgical intervention.ConclusionsSelf-care for mallet finger injuries, with adequate patient information and telephone back-up, leads to acceptable functional results and satisfaction.Level of evidence: III

Background and Aims To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. Methods A multi-centre, open-label, randomized, active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 hours). The primary endpoint was diuretic effect, assessed by change in weight (kg). Secondary endpoints included change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. Results 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 hours was 976 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 hours was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; p=0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) versus 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; p=0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. Conclusion In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. ClinicalTrials.gov Identifier NCT04860011

BackgroundCoronary angiography is performed to assess for obstructive coronary artery disease (CAD), but “nonobstructive CAD” is a common finding. Microvascular or vasospastic angina may be relevant, but routine confirmatory testing is not evidence based and thus rarely performed.AimThe aim was to assess the effect of stratified medicine guided by coronary function testing on the diagnosis, treatment, and well-being of patients with angina and nonobstructive CAD.DesignThe BHF CorMicA trial is a prospective, multicenter, randomized, blinded, sham-controlled trial of stratified medicine (NCT03193294). All-comers referred for elective coronary angiography for investigation of suspected CAD will be screened. Following informed consent, eligible patients with angina and nonobstructive CAD will be randomized 1:1 immediately in the catheter laboratory to either coronary artery function–guided diagnosis and treatment (intervention group) or not (control group). Coronary function will be assessed using a pressure-temperature–sensitive guidewire and adenosine followed by pharmacological testing with intracoronary acetylcholine. Patients will be stratified into endotypes with linked therapy. The primary outcome is change in Seattle Angina Questionnaire score at 6 months. Secondary outcomes include safety, feasibility, diagnostic utility (impact on diagnosis and diagnostic certainty), and clinical utility (impact on treatment and investigations). Health status is a key secondary outcome assessed according to the following domains: quality of life, treatment satisfaction, illness perception, physical activity, and anxiety-depression score. Patients with obstructive disease who are not randomized will form a registry group who will be followed up as a comparator for secondary outcomes including health status. Health and economic outcomes will be evaluated in the longer term using electronic health record linkage.ValueCorMicA is a proof-of-concept clinical trial of a disruptive stratified intervention with potential benefits to patients and health care providers.

BackgroundReliable non-invasive diagnosis of meniscal tears is difficult. Magnetic resonance imaging (MRI) is often used but is expensive and incidental findings are problematic. There are a number of physical examination tests for the diagnosis of meniscal tears that are simple, cheap and non-invasive.ObjectivesTo determine the diagnostic accuracy of the Thessaly test and to determine if the Thessaly test (alone or in combination with other physical tests) can obviate the need for further investigation by MRI or arthroscopy for patients with a suspected meniscal tear.DesignSingle-centre prospective diagnostic accuracy study.SettingAlthough the study was performed in a secondary care setting, it was designed to replicate the results that would have been achieved in a primary care setting.ParticipantsTwo cohorts of patients were recruited: patients with knee pathology (n = 292) and a control cohort with no knee pathology (n = 75).Main outcome measuresSensitivity, specificity and diagnostic accuracy of the Thessaly test in determining the presence of meniscal tears.MethodsParticipants were assessed by both a primary care clinician and a musculoskeletal clinician. Both clinicians performed the Thessaly test, McMurray’s test, Apley’s test, joint line tenderness test and took a standardised clinical history from the patient.ResultsThe Thessaly test had a sensitivity of 0.66, a specificity of 0.39 and a diagnostic accuracy of 54% when utilised by primary care clinicians. This compared with a sensitivity of 0.62, a specificity of 0.55 and diagnostic accuracy of 59% when used by musculoskeletal clinicians. The diagnostics accuracy of the other tests when used by primary care clinicians was 54% for McMurray’s test, 53% for Apley’s test, 54% for the joint line tenderness test and 55% for clinical history. For primary care clinicians, age and past history of osteoarthritis were both significant predictors of MRI diagnosis of meniscal tears. For musculoskeletal clinicians age and a positive diagnosis of meniscal tears on clinical history taking were significant predictors of MRI diagnosis. No physical tests were significant predictors of MRI diagnosis in our multivariate models. The specificity of MRI diagnosis was tested in subgroup of patients who went on to have a knee arthroscopy and was found to be low [0.53 (95% confidence interval 0.28 to 0.77)], although the sensitivity was 1.0.ConclusionsThe Thessaly test was no better at diagnosing meniscal tears than other established physical tests. The sensitivity, specificity and diagnostic accuracy of all physical tests was too low to be of routine clinical value as an alternative to MRI. Caution needs to be exercised in the indiscriminate use of MRI scanning in the identification of meniscal tears in the diagnosis of the painful knee, due to the low specificity seen in the presence of concomitant knee pathology. Further research is required to determine the true diagnostic accuracy and cost-effectiveness of MRI for the detection of meniscal tears.Trial registrationCurrent Controlled Trial ISRCTN43527822.FundingThe National Institute for Health Research Health Technology Assessment programme.