General practice pharmacist-led antipsychotic physical health monitoring: a prospective intervention scoping study.

BACKGROUND: People with severe mental health illness die prematurely, often due to preventable cardiometabolic disease, which can be exacerbated by antipsychotic medicines that are effective for treating mental illness. Literature demonstrates that physical health monitoring, as recommended in guidelines, for people receiving antipsychotics is substandard. Therefore, we aimed to scope the potential of a general practice clinical pharmacist (GPCP)-led multidisciplinary intervention optimising adherence to cardiometabolic monitoring guidelines and delivering polypharmacy reviews. METHOD: Prospective intervention scoping study in three urban general practices; one usual care, two intervention. Patients 18-65 years old prescribed oral antipsychotics were identified from records, and invited for cardiometabolic monitoring and GPCP medication review, from January to December 2022. Interventions and onward referrals were recorded and collated. Anonymised pre- and post-review data were analysed, and actions were graded for clinical importance. RESULTS: In total 1.5% (210/14,159) of patients aged 18-65 years met inclusion criteria; usual care practice (n = 58); and intervention practices (n = 152). From baseline, the usual care practice achieved an absolute 7% increase in the cardiometabolic monitoring care bundle (glucose/glycosylated haemoglobin, lipids, blood pressure plus body mass index) versus 19-58% in the intervention practices. Two-thirds (92/152) of patients participated in medication reviews, requiring pharmacological and/or non-pharmacological clinical actions. The majority of actions were graded as moderate importance. Seven percentage of patients were identified as new pre-diabetic/diabetic and 6% were at high risk of cardiovascular disease requiring statin initiation. CONCLUSION: A pharmacist-led multidisciplinary general practice-based approach may be effective at optimising cardiometabolic monitoring; identifying and treating diabetic and cardiovascular risk factors.

People with severe mental illness die 15­20 years earlier than the general population, many due to preventable and/or treatable heart disease. While antipsychotic medicines are effective for treating mental illness they are associated with potential adverse effects; weight gain, increased blood pressure, blood sugar, and cholesterol. Therefore, guidelines advise regular physical health checks for people with severe mental illness, and those receiving antipsychotics, to reduce avoidable harms and optimise preventative treatments. However, routine monitoring is substandard. This study aimed to explore the potential of a general practice pharmacist-led intervention to optimise physical health monitoring and medication reviews, from January to December 2022. Three practices participated; one providing usual care, and two the pharmacist intervention. The usual care practice achieved a 7% increase in all monitoring parameters (weight, blood pressure, blood sugars plus cholesterol), whereas the pharmacist-led practices achieved a 19­58% increase in monitoring. Two in three patients (92/152) participated in a medication review with the pharmacists that addressed a range of mental and physical health issues. Of the 152 patients in the intervention practices 6% were identified as being at high risk of heart disease requiring preventative medicines, and 7% were identified as having new diabetes and/or pre-diabetes.

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research.

A study on prescriptions contributing to the risk of high anticholinergic burden in adults with intellectual disabilities: retrospective record linkage study.

BACKGROUND: People with intellectual disabilities may face a disproportionate risk of experiencing high anticholinergic burden, and its negative sequalae, from a range of medications, and at younger ages than the general population, but there has been little previous study. Our aim was to determine the source of anticholinergic burden from prescribed medication. METHODS: Retrospective matched observational study using record linkage. Adults with (n = 4,305), and without (n = 12,915), intellectual disabilities matched by age-, sex- and neighbourhood deprivation. The main outcome measure was the prescription of long-term (approximately 12 months use) anticholinergic medications overall (classified according to the Anticholinergic Risk Scale [ARS]), by drug class, individual drugs, and polypharmacy. RESULTS: Adults with n = 1,654 (38.4%), and without n = 3,047 (23.6%), intellectual disabilities were prescribed medications long-term with anticholinergic effects. Of those on such drugs, adults with intellectual disabilities were most likely to be on central nervous system (62.6%), gastrointestinal (46.7%), and cardiovascular (28.4%) medications. They were prescribed more central nervous system, gynaecological/urinary tract, musculoskeletal, and respiratory medications, and less cardiovascular, infection, and endocrine medications than their matched comparators. Regardless of age, sex, or neighbourhood deprivation, adults with intellectual disabilities had greater odds of being prescribed antipsychotics (OR = 5.37 [4.40-6.57], p < 0.001), antiepileptics (OR = 2.57 [2.22-2.99], p < 0.001), and anxiolytics/hypnotics (OR = 1.28 [1.06-1.56], p = 0.012). Compared to the general population, adults with intellectual disabilities were more likely to be exposed to overall anticholinergic polypharmacy (OR = 1.48 [1.33-1.66], p < 0.001), and to psychotropic polypharmacy (OR = 2.79 [2.41-3.23], p < 0.001). CONCLUSIONS: Adults with intellectual disabilities are exposed to a greater risk of having very high anticholinergic burden through polypharmacy from several classes of medications, which may be prescribed by several different prescribers. There is a need for evidence-based recommendations specifically about people with intellectual disabilities with multiple physical and mental ill-health conditions to optimise medication use, reduce inappropriate prescribing and adverse anticholinergic effects.

Antipsychotic and antidepressant prescribing for 704 297 children and young people with and without intellectual disabilities: record linkage study.

BACKGROUND: Psychotropics are overprescribed for adults with intellectual disabilities; there are few studies in children and young people. AIMS: To investigate antipsychotic and antidepressant prescribing in children and young people with and without intellectual disabilities, and prescribing trends. METHOD: Scotland's annual Pupil Census, which identifies pupils with and without intellectual disabilities, was record-linked to the Prescribing Information System. Antidepressant and antipsychotic data were extracted. Logistic regression was used to analyse prescribing between 2010 and 2013. RESULTS: Of the 704 297 pupils, 16 142 (2.29%) had a record of intellectual disabilities. Antipsychotic and antidepressant use increased over time, and was higher in older pupils; antipsychotic use was higher in boys, and antidepressant use was higher in girls. Overall, antipsychotics were prescribed to 281 (1.74%) pupils with intellectual disabilities and 802 (0.12%) without (adjusted odds ratio 16.85, 95% CI 15.29-18.56). The higher use among those with intellectual disabilities fell each year (adjusted odds ratio 20.19 in 2010 v. 14.24 in 2013). Overall, 191 (1.18%) pupils with intellectual disabilities and 4561 (0.66%) without were prescribed antidepressants (adjusted odds ratio 2.28, 95% CI 2.03-2.56). The difference decreased each year (adjusted odds ratio 3.10 in 2010 v. 2.02 in 2013). CONCLUSIONS: Significantly more pupils with intellectual disabilities are prescribed antipsychotics and antidepressants than are other pupils. Prescribing overall increased over time, but less so for pupils with intellectual disabilities; either they are not receiving the same treatment advances as other pupils, or possible overprescribing in the past is changing. More longitudinal data are required.

Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: The REMOVAL trial.

AIM: To determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status. METHODS: Regression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial. RESULTS: In 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.012 mm, 95% CI -0.021 to -0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI -0.008 to 0.014; p = .5767); and similarly in non-current smokers (-0.008 mm, 95% CI -0.015 to -0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI -0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.020 mm, 95% CI -0.034 to -0.006; p = .0067) but not in ever-smokers (-0.006 mm, 95% CI -0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term. CONCLUSIONS: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.

Long-term outcomes of chronic coronary syndrome worldwide: insights from the international CLARIFY registry.

AIMS: Over the last decades, the profile of chronic coronary syndrome has changed substantially. We aimed to determine characteristics and management of patients with chronic coronary syndrome in the contemporary era, as well as outcomes and their determinants. METHODS AND RESULTS: Data from 32 703 patients (45 countries) with chronic coronary syndrome enrolled in the prospective observational CLARIFY registry (November 2009 to June 2010) with a 5-year follow-up, were analysed. The primary outcome [cardiovascular death or non-fatal myocardial infarction (MI)] 5-year rate was 8.0% [95% confidence interval (CI) 7.7-8.3] overall [male 8.1% (7.8-8.5); female 7.6% (7.0-8.3)]. A cox proportional hazards model showed that the main independent predictors of the primary outcome were prior hospitalization for heart failure, current smoking, atrial fibrillation, living in Central/South America, prior MI, prior stroke, diabetes, current angina, and peripheral artery disease. There was an interaction between angina and prior MI (P = 0.0016); among patients with prior MI, angina was associated with a higher primary event rate [11.8% (95% CI 10.9-12.9) vs. 8.2% (95% CI 7.8-8.7) in patients with no angina, P < 0.001], whereas among patients without prior MI, event rates were similar for patients with [6.3% (95% CI 5.4-7.3)] or without angina [6.4% (95% CI 5.9-7.0)], P > 0.99. Prescription rates of evidence-based secondary prevention therapies were high. CONCLUSION: This description of the spectrum of chronic coronary syndrome patients shows that, despite high rates of prescription of evidence-based therapies, patients with both angina and prior MI are an easily identifiable high-risk group who may deserve intensive treatment. CLINICAL REGISTRY: ISRCTN43070564.

Changes over time in the management of long-term conditions in primary health care for adults with intellectual disabilities, and the healthcare inequality gap.

BACKGROUND: Quality of primary healthcare impacts on health outcomes. This study aimed to quantify trends in good practice and the healthcare inequalities gap. METHOD: Indicators of best-practice management of long-term conditions and health promotion were extracted from primary healthcare records on 721 adults with intellectual disabilities in 2007-2010, and 3638 in 2014. They were compared over time, and with the general population in 2014, using Fisher's Exact test and ordinal regression. RESULTS: Management improved for adults with intellectual disabilities over time (OR = 5.32; CI = 2.69-10.55), but not for the general population (OR = 0.74; CI = 0.34-1.64). However, it remained poorer, but to a lesser extent, compared with the general population (OR = 0.38; CI = 0.20-0.73 in 2014, and OR = 0.05; CI = 0.02-0.12 in 2007-2010). In 2014, health care was comparable to the general population on 49/78 (62.8%) indicators. CONCLUSIONS: The extent of the healthcare inequality gap reduced over this period, but remaining inequalities highlight that further action is still necessary.

ß-blockers, calcium antagonists, and mortality in stable coronary artery disease: an international cohort study.

AIMS: The effect of first-line antianginal agents, ß-blockers, and calcium antagonists on clinical outcomes in stable coronary artery disease (CAD) remains uncertain. METHODS AND RESULTS: We analysed the use of ß-blockers or calcium antagonists (baseline and annually) and outcomes in 22 006 stable CAD patients (enrolled 2009-2010) followed annually to 5 years, in the CLARIFY registry (45 countries). Primary outcome was all-cause death. Secondary outcomes were cardiovascular death and the composite of cardiovascular death/non-fatal myocardial infarction (MI). After multivariable adjustment, baseline ß-blocker use was not associated with lower all-cause death [1345 (7.8%) in users vs. 407 (8.4%) in non-users; hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.84-1.06; P = 0.30]; cardiovascular death [861 (5.0%) vs. 262 (5.4%); HR 0.91, 95% CI 0.79-1.05; P = 0.20]; or cardiovascular death/non-fatal MI [1272 (7.4%) vs. 340 (7.0%); HR 1.03, 95% CI 0.91-1.16; P = 0.66]. Sensitivity analyses according to ß-blocker use over time and to prescribed dose produced similar results. Among prior MI patients, for those enrolled in the year following MI, baseline ß-blocker use was associated with lower all-cause death [205 (7.0%) vs. 59 (10.3%); HR 0.68, 95% CI 0.50-0.91; P = 0.01]; cardiovascular death [132 (4.5%) vs. 49 (8.5%); HR 0.52, 95% CI 0.37-0.73; P = 0.0001]; and cardiovascular death/non-fatal MI [212 (7.2%) vs. 59 (10.3%); HR 0.69, 95% CI 0.52-0.93; P = 0.01]. Calcium antagonists were not associated with any difference in mortality. CONCLUSION: In this contemporary cohort of stable CAD, ß-blocker use was associated with lower 5-year mortality only in patients enrolled in the year following MI. Use of calcium antagonists was not associated with superior mortality, regardless of history of MI.

Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure.

BACKGROUND: Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction. METHODS: After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure. RESULTS: After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001). CONCLUSIONS: In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).

Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT).

BACKGROUND: Selective cyclooxygenase-2 inhibitors and conventional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) have been associated with adverse cardiovascular (CV) effects. We compared the CV safety of switching to celecoxib vs. continuing nsNSAID therapy in a European setting. METHOD: Patients aged 60 years and over with osteoarthritis or rheumatoid arthritis, free from established CV disease and taking chronic prescribed nsNSAIDs, were randomized to switch to celecoxib or to continue their previous nsNSAID. The primary endpoint was hospitalization for non-fatal myocardial infarction or other biomarker positive acute coronary syndrome, non-fatal stroke or CV death analysed using a Cox model with a pre-specified non-inferiority limit of 1.4 for the hazard ratio (HR). RESULTS: In total, 7297 participants were randomized. During a median 3-year follow-up, fewer subjects than expected developed an on-treatment (OT) primary CV event and the rate was similar for celecoxib, 0.95 per 100 patient-years, and nsNSAIDs, 0.86 per 100 patient-years (HR = 1.12, 95% confidence interval, 0.81-1.55; P = 0.50). Comparable intention-to-treat (ITT) rates were 1.14 per 100 patient-years with celecoxib and 1.10 per 100 patient-years with nsNSAIDs (HR = 1.04; 95% confidence interval, 0.81-1.33; P = 0.75). Pre-specified non-inferiority was achieved in the ITT analysis. The upper bound of the 95% confidence limit for the absolute increase in OT risk associated with celecoxib treatment was two primary events per 1000 patient-years exposure. There were only 15 adjudicated secondary upper gastrointestinal complication endpoints (0.078/100 patient-years on celecoxib vs. 0.053 on nsNSAIDs OT, 0.078 vs. 0.053 ITT). More gastrointestinal serious adverse reactions and haematological adverse reactions were reported on nsNSAIDs than celecoxib, but more patients withdrew from celecoxib than nsNSAIDs (50.9% patients vs. 30.2%; P < 0.0001). INTERPRETATION: In subjects 60 years and over, free from CV disease and taking prescribed chronic nsNSAIDs, CV events were infrequent and similar on celecoxib and nsNSAIDs. There was no advantage of a strategy of switching prescribed nsNSAIDs to prescribed celecoxib. This study excluded an increased risk of the primary endpoint of more than two events per 1000 patient-years associated with switching to prescribed celecoxib. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/show/NCT00447759; Unique identifier: NCT00447759.

Management and prevalence of long-term conditions in primary health care for adults with intellectual disabilities compared with the general population: A population-based cohort study.

BACKGROUND: In the UK, general practitioners/family physicians receive pay for performance on management of long-term conditions, according to best-practice indicators. METHOD: Management of long-term conditions was compared between 721 adults with intellectual disabilities and the general population (n = 764,672). Prevalence of long-term conditions was determined, and associated factors were investigated via logistic regression analyses. RESULTS: Adults with intellectual disabilities received significantly poorer management of all long-term conditions on 38/57 (66.7%) indicators. Achievement was high (75.1%-100%) for only 19.6% of adults with intellectual disabilities, compared with 76.8% of the general population. Adults with intellectual disabilities had higher rates of epilepsy, psychosis, hypothyroidism, asthma, diabetes and heart failure. There were no clear associations with neighbourhood deprivation. CONCLUSIONS: Adults with intellectual disabilities receive poorer care, despite conditions being more prevalent. The imperative now is to find practical, implementable means of supporting the challenges that general practices face in delivering equitable care.

Cardiovascular event rates and mortality according to achieved systolic and diastolic blood pressure in patients with stable coronary artery disease: an international cohort study.

BACKGROUND: The optimum blood pressure target in hypertension remains debated, especially in coronary artery disease, given concerns for reduced myocardial perfusion if diastolic blood pressure is too low. We aimed to study the association between achieved blood pressure and cardiovascular outcomes in patients with coronary artery disease and hypertension. METHODS: We analysed data from 22 672 patients with stable coronary artery disease enrolled (from Nov 26, 2009, to June 30, 2010) in the CLARIFY registry (including patients from 45 countries) and treated for hypertension. Systolic and diastolic blood pressures before each event were averaged and categorised into 10 mm Hg increments. The primary outcome was the composite of cardiovascular death, myocardial infarction, or stroke. Hazard ratios (HRs) were estimated with multivariable adjusted Cox proportional hazards models, using the 120-129 mm Hg systolic blood pressure and 70-79 mm Hg diastolic blood pressure subgroups as reference. FINDINGS: After a median follow-up of 5·0 years, increased systolic blood pressure of 140 mm Hg or more and diastolic blood pressure of 80 mm Hg or more were each associated with increased risk of cardiovascular events. Systolic blood pressure of less than 120 mm Hg was also associated with increased risk for the primary outcome (adjusted HR 1·56, 95% CI 1·36-1·81). Likewise, diastolic blood pressure of less than 70 mm Hg was associated with an increase in the primary outcome (adjusted HR 1·41 [1·24-1·61] for diastolic blood pressure of 60-69 mm Hg and 2·01 [1·50-2·70] for diastolic blood pressure of less than 60 mm Hg). INTERPRETATION: In patients with hypertension and coronary artery disease from routine clinical practice, systolic blood pressure of less than 120 mm Hg and diastolic blood pressure of less than 70 mm Hg were each associated with adverse cardiovascular outcomes, including mortality, supporting the existence of a J-curve phenomenon. This finding suggests that caution should be taken in the use of blood pressure-lowering treatment in patients with coronary artery disease. FUNDING: Servier.

Is speed of healing a good predictor of eventual healing of pyoderma gangrenosum?

BACKGROUND: Pyoderma gangrenosum is a rare inflammatory skin condition. Two prospective studies have evaluated treatments for pyoderma gangrenosum using a primary outcome of healing speed at 6 weeks. OBJECTIVE: Using data from both studies we assessed the predictive value of 3 early predictors for healing at 6 months: speed of healing, Investigator Global Assessment (IGA), and resolution of inflammation, recorded at 2 and 6 weeks. METHODS: Logistic regression models were applied and the effectiveness of the 3 measures was assessed through estimating the positive and negative predictive values and the area under the receiver operating characteristic curve. RESULTS: The positive and negative predictive value at 6 weeks were, respectively, 63.5% (95% confidence interval [CI] 52.4%-73.7%) and 74.6% (95% CI 62.5%-84.5%) for speed of healing; 80% (95% CI 68.7%-88.6%) and 74.2% (95% CI 64.1%-82.7%) for IGA; and 72.1% (95% CI 59.9%-82.3%) and 68.1% (95% CI 57.7%-77.3%) for resolution of inflammation. IGA had the best combined positive predictive value, negative predictive value, and area under the receiver operating characteristic curve at 2 and 6 weeks. LIMITATIONS: We were limited by data available from existing datasets. CONCLUSION: Speed of healing, IGA, and resolution of inflammation were all shown to be good predictors of eventual healing of pyoderma gangrenosum.

Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: A prospective cohort study.

BACKGROUND: Pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. OBJECTIVE: We sought to estimate the effectiveness of topical therapies in the treatment of patients with PG. METHODS: This was a prospective cohort study of UK secondary care patients with a clinical diagnosis of PG that was suitable for topical treatment (recruited between July 2009 and June 2012). Participants received topical therapy after normal clinical practice (primarily topical corticosteroids [classes I-III] and tacrolimus 0.03% or 0.1%). The primary outcome was speed of healing at 6 weeks. Secondary outcomes included the following: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality of life; treatment failure; and recurrence. RESULTS: Sixty-six patients (22-85 years of age) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28 of 66 (43.8%) ulcers healed by 6 months. The median time to healing was 145 days (95% confidence interval, 96 days to ∞). Initial ulcer size was a significant predictor of time to healing (hazard ratio, 0.94 [95% confidence interval, 0.88-1.00); P = .043). Four patients (15%) had a recurrence. LIMITATIONS: Our study did not include a randomized comparator. CONCLUSION: Topical therapy is potentially an effective first-line treatment for PG that avoids the possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone.

A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure.

AIMS: Although active-controlled trials with renin­angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. METHODS AND RESULTS: We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34­50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21­44%; P < 0.0001) and heart failure hospitalization (49%, 39­58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15­39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27­48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16­45%; P < 0.0001) for cardiovascular death, 46% (33­56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11­39%; P < 0.0001) for all-cause mortality. CONCLUSION: These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.

Management of coronary artery disease patients in Latvia compared with practice in Central-Eastern Europe and globally: analysis of the CLARIFY registry.

BACKGROUND AND OBJECTIVE: Management of outpatients with stable coronary artery disease (CAD) is important in secondary prevention. The objective was to describe differences in the characteristics of CAD patients in Latvia compared with other countries. MATERIALS AND METHODS: CLARIFY is an ongoing international, prospective, observational, longitudinal registry of outpatients with CAD. Data regarding treated outpatients with established CAD from the CLARIFY registry in Latvia (n=120) were compared with those from the rest of Central-Eastern Europe (CEE) (n=2888) and worldwide (n=33,163). RESULTS: Patients in Latvia had a larger waist circumference (101 [95-109] vs. 99 [91-106] in CEE, 96.5 [88-105]cm worldwide; P=0.023 and P<0.001, respectively) and higher blood pressure (systolic: 138.28±17.13 vs. 133.77±16.47 in CEE and 130.97±16.65mm Hg worldwide, P=0.003 and P<0.001; diastolic: 82.98±8.58 vs. 80.01±9.61 in CEE and 77.22±9.97mm Hg worldwide, P<0.001 and P<0.001, respectively). Body mass index in Latvia did not differ significantly from that in CEE (P=0.422), but was higher than worldwide (28.8 [26.2-32.0] vs. worldwide 27.3 [24.8-30.3]kg/m(2), P<0.001). The history of percutaneous coronary intervention was more frequent in Latvia (74.17% vs. 59.34% in CEE and 58.61% worldwide, P=0.001 and P<0.001, respectively). Latvian patients more frequently used aspirin (97.50% in Latvia vs. 89.75% in CEE and 87.64% worldwide, P=0.005 and P=0.001, respectively). CONCLUSIONS: Latvian CAD patients are well managed in terms of aspirin use and frequency of percutaneous coronary intervention. Control of obesity and high BP is poorer and needs further improvement.

Emergency medical admissions, deaths at weekends and the public holiday effect. Cohort study.

OBJECTIVES: To assess whether mortality of patients admitted on weekends and public holidays was higher in a district general hospital whose consultants are present more than 6 h per day on the acute medical unit with no other fixed clinical commitments. DESIGN: Cohort study. SETTING: Secondary care. PARTICIPANTS: All emergency medical admissions to Dumfries and Galloway Royal Infirmary between 1 January 2008 and 31 December 2010. METHODS: We examined 7 and 30 day mortality for all weekend and for all public holiday admissions, using all weekday and non-public holiday admissions, respectively, as comparators. We adjusted mortality for age, gender, comorbidity, deprivation, diagnosis and year of admission. RESULTS: 771 (3.8%) of 20 072 emergency admissions died within 7 days of admission and 1780 (8.9%) within 30 days. Adjusted weekend mortality in the all weekend versus all other days analysis was not significantly higher at 7 days (OR 1.10, 95% CI 0.92 to 1.31; p=0.312) or at 30 days (OR 1.07, 95% CI 0.94 to 1.21; p=0.322). By contrast, adjusted public holiday mortality in the all public holidays versus all other days analysis was 48% higher at 7 days (OR 1.48, 95% CI 1.12 to 1.95; p=0.006) and 27% higher at 30 days (OR 1.27, 95% CI 1.02 to 1.57; p=0.031). Interactions between the weekend variable and the public holiday variable were not statistically significant for mortality at either 7 or 30 days. CONCLUSIONS: Patients admitted as emergencies to medicine on public holidays had significantly higher mortality at 7 and 30 days compared with patients admitted on other days of the week.

Insufficient control of heart rate in stable coronary artery disease patients in Latvia.

BACKGROUND AND OBJECTIVE: Heart rate (HR) ≥70 beats per minute (bpm) increases cardiovascular risk in coronary artery disease (CAD) patients. The objective of the analysis is to characterize HR as well as other clinical parameters in outpatients with stable CAD in Latvia. MATERIALS AND METHODS: CLARIFY is an ongoing international registry of outpatients with established CAD. Latvian data regarding 120 patients enrolled in CLARIFY and collected at baseline visit during 2009-2010 were analyzed. RESULTS: The mean HR was 67.7±9.5 and 66.9±10.7bpm when measured by pulse palpation and electrocardiography, respectively. HR ≤60bpm and ≥70bpm was observed in 25% and 35.8% of patients, respectively. When analyzing patients with angina symptoms, 22.8% had HR ≤60bpm while HR ≥70bpm was observed in 33.3% of the cases. HR ≥70bpm was observed in 36.2% of patients with symptoms of chronic heart failure. Beta-blockers were used in 81.7% of the patients. Metoprolol (long acting succinate), bisoprolol, nebivolol and carvedilol in average daily doses 63.8, 5.3, 4.5, and 10.4mg/d were used in 47, 37, 11 and 3 cases, respectively. Among patients with HR ≥70bpm 79.1% were using beta-blockers. Medications did not differ significantly between the three groups according to HR level (≤60, 61-69 and ≥70bpm). CONCLUSIONS: Despite the wide use of beta-blockers, HR is insufficiently controlled in the analyzed sample of stable CAD patients in Latvia. Target HR ≤60bpm is achieved only in 25% of the patients while more than one third have increased HR ≥70bpm.

A practical review of barriers and challenges to a definitive randomised trial of grafts versus fistula.

A definitive randomised controlled trial of arteriovenous fistula (AVF) versus arteriovenous grafts (AVG) has been advocated for more than a decade, but as yet, none has been completed. The aim of this article is to summarise the theoretical barriers, review the difficulties in trial design and practicalities that have thus far prevented this from occurring.

Clinical outcomes and adverse events of bariatric surgery in adults with severe obesity in Scotland: the SCOTS observational cohort study.

Background: Bariatric surgery is a common procedure worldwide for the treatment of severe obesity and associated comorbid conditions but there is a lack of evidence as to medium-term safety and effectiveness outcomes in a United Kingdom setting. Objective: To establish the clinical outcomes and adverse events of different bariatric surgical procedures, their impact on quality of life and the effect on comorbidities. Design: Prospective observational cohort study. Setting: National Health Service secondary care and private practice in Scotland, United Kingdom. Participants: Adults (age >16 years) undergoing their first bariatric surgery procedure. Main outcome measures: Change in weight, hospital length of stay, readmission and reoperation rate, mortality, diabetes outcomes (HbA1c, medications), quality of life, anxiety, depression. Data sources: Patient-reported outcome measures, hospital records, national electronic health records (Scottish Morbidity Record 01, Scottish Care Information Diabetes, National Records Scotland, Prescription Information System). Results: Between December 2013 and February 2017, 548 eligible patients were approached and 445 participants were enrolled in the study. Of those, 335 had bariatric surgery and 1 withdrew from the study. Mean age was 46.0 (9.2) years, 74.7% were female and the median body mass index was 46.4 (42.4; 52.0) kg/m2. Weight was available for 128 participants at 3 years: mean change was -19.0% (±14.1) from the operation and -24.2% (±12.8) from the start of the preoperative weight-management programme. One hundred and thirty-nine (41.4%) participants were readmitted to hospital in the same or subsequent 35 months post surgery, 18 (5.4% of the operated cohort) had a reoperation or procedure considered to be related to bariatric surgery gastrointestinal complications or revisions. Fewer than five participants (<2%) died during follow-up. HbA1c was available for 93/182 and diabetes medications for 139/182 participants who had type 2 diabetes prior to surgery; HbA1c mean change was -5.72 (±16.71) (p = 0.001) mmol/mol and 65.5% required no diabetes medications (p < 0.001) at 3 years post surgery. Physical quality of life, available for 101/335 participants, improved in the 3 years post surgery, mean change in Rand 12-item Short Form Survey physical component score 8.32 (±8.95) (p < 0.001); however, there was no change in the prevalence of anxiety or depression. Limitations: Due to low numbers of bariatric surgery procedures in Scotland, recruitment was stopped before achieving the intended 2000 participants and follow-up was reduced from 10 years to 3 years. Conclusions: Bariatric surgery is a safe and effective treatment for obesity. Patients in Scotland, UK, appear to be older and have higher body mass than international comparators, which may be due to the small number of procedures performed. Future work: Intervention studies are required to identify the optimal pre- and post surgery pathway to maximise safety and cost-effectiveness. Study registration: This study is registered as ISRCTN47072588. Funding details: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 10/42/02) and is published in full in Health Technology Assessment; Vol. 28, No. 7. See the NIHR Funding and Awards website for further award information.

Bariatric surgery is performed on the stomach and small bowel to help people living with obesity lose weight. Our research study has looked at who is getting bariatric surgery, if they are having problems afterwards, how much weight they lose and if their medical conditions improve. A total of 444 people who were attending bariatric surgery services in Scotland, UK, agreed to take part and 336 had surgery. One hundred and eighty-nine of them completed a questionnaire before their surgery and 85 of them after 3 years, to tell us about how they were feeling physically and mentally. We looked at their computer hospital records to see how long they spent in hospital, any medical problems and changes to diabetes medicines and tests. One in five people taking part did not have surgery after all; they changed their mind or the hospital teams did not think it would be safe or work well for the patient. Those who had surgery lost 19% of their body weight and those with type 2 diabetes needed less or no medication 3 years after the surgery. The effect of physical symptoms on day-to-day activities improved but mental health did not. Compared to other countries, the people taking part were older, heavier and sicker. They spent longer in hospital after surgery and were more likely to be readmitted to hospital. How many appointments they had or what type of health professional they saw before or after surgery did not change these results. We had hoped to have far more people in this study and be able to answer more questions, but not enough people were getting bariatric surgery in Scotland for us to ask them to take part. Further research is needed to find the best ways to care for people living with obesity who would benefit from bariatric surgery.