Hospital trainees' worries, perceived sufficiency of information and reported psychological health during the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic has been unsurpassed in clinical severity or infectivity since the 1918 Spanish influenza pandemic and continues to impact the world. During the A/H1N1 pandemic, healthcare workers presented concerns regarding their own and their families' health, as well as high levels of psychological distress. We aim to assess hospital trainees' concerns, perceived sufficiency of information, behaviour and reported psychological health during the COVID-19 pandemic. DESIGN: Single 39-point questionnaire. SETTING: A large NHS foundation trust in London. PARTICIPANTS: 204 hospital trainee doctors. RESULTS: 204 trainees participated, of whom 91.7% (n=187) looked after COVID-19 patients. 91.6% (n=164) were worried about COVID-19; the most frequent concern was that of family and friends dying from COVID-19 (74.6%, n=126). 22.2% (n=36) reported being infected with COVID-19. 6.8% (n=11) of trainees considered avoiding going to work. Perceived sufficiency of information about COVID-19 was moderately high. 25.9% (n=42) reported social distancing at work compared with 94.4% (n=152) outside work. 98.2% (n=159) reported using PPE and 24.7% (n=40) were confident the provided PPE protected them. 41.9% (n=67) reported their psychological health had been adversely affected. 95.6% (n=153) supported provision of psychological support services and 62.5% (n=100) stated they would consider using them. CONCLUSIONS: A significant proportion of hospital trainees expressed worries about COVID-19, above all with regards to the wellbeing of their loved ones over their own. Confidence in sufficiency of provided information was high and in utilised infection control measures low. A larger proportion of trainees reported psychological as compared with physical health concerns, with a smaller proportion confirming having been infected with COVID-19 although most perceived their risk of infection as high. Seeking solutions to support hospital trainees in their duties and their wellbeing with their input would help to empower them and improve their health and morale while working during pandemics.

Pharmacological treatment for Type 2 diabetes integrating findings from cardiovascular outcome trials: an expert consensus in the UK.

In people with Type 2 diabetes, cardiovascular disease is a leading cause of morbidity and mortality. Thus, as well as controlling glucose, reducing the risk of cardiovascular events is a key goal. The results of cardiovascular outcome trials have led to updates for many national and international guidelines. England, Wales and Northern Ireland remain exceptions, with the most recent update to the National Institute for Health and Care Excellence (NICE) guidelines published in 2015. We reviewed current national and international guidelines and recommendations on the management of people with Type 2 diabetes. This article shares our consensus on clinical recommendations for the use of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) in people with Type 2 diabetes and established or at very high risk of cardiovascular disease in the UK. We also consider cost-effectiveness for these therapies. We recommend considering each person's cardiovascular risk and using diabetes therapies with proven cardiovascular benefits when appropriate to improve long-term outcomes and cost-effectiveness.

Admission ECG predicts long-term outcome in acute coronary syndromes without ST elevation.

BACKGROUND: Acute coronary syndromes (ACS) without ST elevation are a frequent cause of hospital admission, myocardial infarction and death. AIM: To explore the role of the ECG in stratifying ACS patients. DESIGN: Prospective, centrally-coordinated multicentre registry involving 56 centres throughout the UK. METHODS: Consecutive patients admitted with ACS without ST elevation on the presenting ECG (n = 1046) were followed for 6 months. A subgroup (n = 653) were flagged with the UK Office for National Statistics and followed-up for death over 4 years. RESULTS: Mean follow-up for the group as a whole was 2.4 years. In the first 6 months, the death rate was 7.3%. Survival at 1 year was 90.8% (95%CI 88.2%-92.8%); at 45 months it was 77.8% (95%CI 74.1%-81.1%). We compared data in those with ST depression or bundle branch block on the admission ECG (n = 304, 29%) with those with T wave inversion, Q waves and minor ST segment changes (n = 576, 55%) and those with a normal ECG (n = 166, 16%). Their respective incidences of death were 15%, 5% and 2% (p < 0.01) at 6 months, and 38%, 22% and 7% (p < 0.01) at 4 years. DISCUSSION: Rates of adverse events are high in patients admitted to UK hospitals with ACS without ST elevation. The ECG remains a very important and simple discriminator of both short- and long-term risk, enabling more aggressive, proven therapies to be targeted towards those at highest risk.

A cost-utility analysis of clopidogrel in patients with non-ST-segment-elevation acute coronary syndromes in the UK.

OBJECTIVE: To assess the long-term cost effectiveness of 1 year's treatment with clopidogrel on top of standard therapy (including aspirin; ASA) compared with standard therapy alone, in patients diagnosed with non-ST-segment-elevation acute coronary syndromes (ACS) in the UK. DESIGN: Cost utility analysis using a Markov model, incorporating clinical data from CURE (a multicentre randomised controlled trial, involving 12,562 patients) and data from UK observational studies. SETTING: Health economic evaluation carried out from the perspective of the UK NHS. PATIENTS: A representative cohort of 1000 UK patients aged 66 years, diagnosed with non-ST-segment-elevation ACS. INTERVENTIONS: Either a combination of 75 mg/day clopidogrel (300 mg loading dose, within 24 h prior to hospital admission) and standard therapy (including ASA, 75-325 mg/day) for 1 year followed by standard therapy alone for their remaining lifetime, or standard therapy alone (including ASA, 75-325 mg/day) for life. MAIN OUTCOME MEASURES: Incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: In the base case, the incremental cost effectiveness of the clopidogrel combination vs standard therapy alone is estimated as pounds 6991 per life-year gained and pounds 7365 per QALY gained. The probability that clopidogrel remains cost effective within the generally accepted pounds 30,000 per QALY threshold is more than 80%. The confidence interval around the relative risk for vascular death was identified as the main parameter affecting the estimated cost effectiveness. CONCLUSIONS: One year's treatment with clopidogrel is a cost effective intervention compared with standard therapy that should be considered as a routine treatment for patients with non-ST-segment-elevation ACS.

Long term prognosis of heart failure after acute coronary syndromes without ST elevation.

BACKGROUND: Information about long term outcomes of patients with acute coronary syndromes (ACS) who have clinically diagnosed heart failure is scarce. METHODS: In a UK registry, this study evaluated patients with non-ST elevation ACS, recording treatment, and clinical outcomes for six months. In a subgroup, a four year mortality follow up was performed to estimate the impact of the clinical diagnosis of heart failure on survival. RESULTS: Of 1046 patients, 139 (13%) had a history of clinically diagnosed heart failure. At discharge, ACE inhibitors were prescribed for 58% and 28%, of those with and without a history of heart failure respectively (p<0.001). Rates of angiography, percutaneous intervention, and coronary artery bypass graft were 17.3% and 29.2% (p = 0.003), 5.0% and 8.4% (p = 0.17), and 5.0% and 7.5% (p = 0.3) for these groups respectively. Death or new myocardial infarction at six months occurred in 22% and 10% (p<0.001) and at four years death occurred in 60% and 20% of these groups respectively (p<0.001). In a multivariate analysis prior heart failure carried an odds ratio of 2.0 (p = 0.001) for death or myocardial infarction at six months and 2.4 (p<0.001) for death over four years. New heart failure was associated with an increased risk of death at six months (20% compared with 5%, p<0.001). CONCLUSION: A clinical history of heart failure carries a substantial risk of death in patients admitted with ACS without ST elevation. Nearly 60% of those with prior heart failure are dead after four years. After adjustment for confounding factors, prior heart failure more than doubles the risk compared with those with no history.

Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

OBJECTIVES: To identify and prioritise key areas of clinical uncertainty regarding the medical management of non-ST elevation acute coronary syndrome (ACS) in current UK practice. DATA SOURCES: Electronic databases. Consultations with clinical advisors. Postal survey of cardiologists. REVIEW METHODS: Potential areas of important uncertainty were identified and 'decision problems' prioritised. A systematic literature review was carried out using standard methods. The constructed decision model consisted of a short-term phase that applied the results of the systematic review and a long-term phase that included relevant information from a UK observational study to extrapolate estimated costs and effects. Sensitivity analyses were undertaken to examine the dependence of the results on baseline parameters, using alternative data sources. Expected value of information analysis was undertaken to estimate the expected value of perfect information associated with the decision problem. This provided an upper bound on the monetary value associated with additional research in the area. RESULTS: Seven current areas of clinical uncertainty (decision problems) in the drug treatment of unstable angina patients were identified. The agents concerned were clopidogrel, low molecular weight heparin, hirudin and intravenous glycoprotein antagonists (GPAs). Twelve published clinical guidelines for unstable angina or non-ST elevation ACS were identified, but few contained recommendations about the specified decision problems. The postal survey of clinicians showed that the greatest disagreement existed for the use of small molecule GPAs, and the greatest uncertainty existed for decisions relating to the use of abciximab (a large molecule GPA). Overall, decision problems concerning the GPA class of drugs were considered to be the highest priority for further study. Selected papers describing the clinical efficacy of treatment were divided into three groups, each representing an alternative strategy. The strategy involving the use of GPAs as part of the initial medical management of all non-ST elevation ACS was the optimal choice, with an incremental cost-effectiveness ratio (ICER) of 5738 pounds per quality-adjusted life-year (QALY) compared with no use of GPAs. Stochastic analysis showed that if the health service is willing to pay 10,000 pounds per additional QALY, the probability of this strategy being cost-effective was around 82%, increasing to 95% at a threshold of 50,000 pounds per QALY. A sensitivity analysis including an additional strategy of using GPAs as part of initial medical management only in patients at particular high risk (as defined by age, ST depression or diabetes) showed that this additional strategy was yet more cost-effective, with an ICER of 3996 pounds per QALY compared with no treatment with GPA. Value of information analysis suggested that there was considerable merit in additional research to reduce the level of uncertainty in the optimal decision. At a threshold of 10,000 pounds per QALY, the maximum potential value of such research in the base case was calculated as 12.7 million pounds per annum for the UK as a whole. Taking account of the greater uncertainty in the sensitivity analyses including clopidogrel, this figure was increased to approximately 50 million pounds. CONCLUSIONS: This study suggests the use of GPAs in all non-ST elevation ACS patients as part of their initial medical management. Sensitivity analysis showed that virtually all of the benefit could be realised by treating only high-risk patients. Further clarification of the optimum role of GPAs in the UK NHS depends on the availability of further high-quality observational and trial data. Value of information analysis derived from the model suggests that a relatively large investment in such research may be worthwhile. Further research should focus on the identification of the characteristics of patients who benefit most from GPAs as part of medical management, the comparison of GPAs with clopidogrel as an adjunct to standard care, follow-up cohort studies of the costs and outcomes of high-risk non-ST elevation ACS over several years, and exploring how clinicians' decisions combine a normative evidence-based decision model with their own personal behavioural perspective.

The SV stent study: a prospective, multicentre, angiographic evaluation of the BiodivYsio phosphorylcholine coated small vessel stent in small coronary vessels.

OBJECTIVE: To evaluate the use of the phosphorylcholine (PC) coated BiodivYsio small vessel (SV) stent in native coronary vessels of small calibre. DESIGN AND SETTING: Prospective, multi-centre, multi-national registry with 6-month clinical and core-lab angiographic follow-up. Adverse events were adjudicated by a Clinical Events Committee (CEC) and included peri-procedural analysis of cardiac enzymes. PATIENTS: Patients with signs or symptoms of ischaemia with an identified target lesion in an epicardial vessel with reference diameter 2.0-2.75 mm were enrolled. Intervention in other epicardial territories in the same patient was permitted. RESULTS: Recruitment of 150 consecutive lesions (in 143 patients) was completed in 19 centres in Europe and Israel. The stent was deployed successfully in all but one lesion. At 6 months, 1 patient (1%) had experienced sudden cardiac death, 4 further patients (3%) had a non-Q wave MI, and a further 24 patients (17%) had repeat revascularisation of a study target vessel. The mean reference vessel diameter prior to stenting was 2.2 mm (S.D. 0.4). Mean minimal luminal diameters at pre-procedure, post procedure and follow-up were 0.6 mm (S.D. 0.3), 2.0 mm (S.D. 0.4) and 1.2 mm (S.D. 0.6), respectively. The late lumen loss index was 0.55 (S.D. 0.53) with a binary restenosis rate of 32%. CONCLUSIONS: In stenting of selected lesions in small vessels, the BiodivYsio SV stent demonstrated high rates of implant success. The rates of major adverse cardiac events (MACE), angiographic restenosis and repeat revascularisation are similar to those reported in other small vessel bare metal stent studies.

Diabetic patients with acute coronary syndromes in the UK: high risk and under treated. Results from the prospective registry of acute ischaemic syndromes in the UK (PRAIS-UK).

OBJECTIVES: Short-term randomised trials suggest that patients with diabetes mellitus (DM), admitted with acute coronary syndromes (ACS) are at increased risk of subsequent adverse events. We tested whether this hypothesis was true for an unselected population of ACS patients with and without DM admitted with non-ST elevation MI or unstable angina, in a non-trial setting over a longer term of follow-up. METHODS: Prospective, centrally, coordinated multicenter registry involving 56 centers throughout the UK (half having angiographic facilities). Consecutive patients admitted with ACS without ST elevation on the presenting ECG were followed up to 6 months. A sub-group of patients were flagged with the UK Office for National Statistics and followed-up for death over 4 years. RESULTS: Data were collected on 1046 ACS patients of whom 170 (16%) had a prior diagnosis of DM. DM patients had higher baseline co-morbidities and unadjusted mortality rates at 6 months (11.8% vs. 6.4%, p=0.01). After correcting for clinical variables such as age, gender, smoking status and chest pain/ischaemic ECG changes on admission, prior history of any of myocardial infarction, heart failure, hypertension, hypercholesterolemia (on treatment), stroke or coronary revascularisation (PTCA or CABG), mortality rates for DM patients were no longer significantly raised (hazard ratio 1.35, 95% CI: 0.79-2.30; p=0.27 at 6 months and 1.15, 95% CI 0.72-1.83 at 4 years). 30% of diabetics were dead after 4 years of follow-up. Patients with DM were more likely to have been revascularised at 6 months and were more likely to receive ACE inhibitors. Based on the rate of recruitment and the population covered in the study, about 21,000 patients with DM will be admitted with non-ST elevation ACS each year in the UK. CONCLUSIONS: DM is common amongst patients admitted with ACS without ST elevation and is associated with significant morbidity and mortality: approximately 1 in 8 will not survive up to 6 months and 1 in 3 to 4 years. DM patients should be managed aggressively to reduce their risk of future complications.

Percutaneous transluminal coronary angioplasty with stents versus coronary artery bypass grafting for people with stable angina or acute coronary syndromes.

BACKGROUND: Coronary artery bypass graft surgery (CABG) replaces obstructed vessels with ones from other parts of the body. Alternatively, obstructions are remodelled using catheter-based techniques such as percutaneous coronary angioplasty with the use of stents. Though less invasive, stenting techniques are limited by the re-narrowing of treated vessels (restenosis). We examined evidence on cardiac-related outcomes occurring after CABG or stenting, with implications for resource use, resource allocation and informing patient choice. OBJECTIVES: To examine evidence from randomised controlled trials (RCTs) on benefit of stents or CABG in reducing cardiac events in people with stable angina or acute coronary syndrome (ACS). SEARCH STRATEGY: CENTRAL (Issue 2 2004), EMBASE (1990 to 2004), MEDLINE (1990 to 2004) and handsearching to July 2004. SELECTION CRITERIA: Only RCTs comparing stents used with PTCA with CABG were included. Participants were adults with stable angina or ACS and unstable angina and had either single or multiple vessel disease. Published and unpublished sources were considered. DATA COLLECTION AND ANALYSIS: Outcomes included composite event rate (major adverse cardiac event, event free survival), death, acute myocardial infarction (AMI), repeat revascularisation and binary restenosis as well as information on design and baseline characteristics. Quality assessment was completed independently. Meta-analyses are presented as odds ratios, 95% confidence intervals (CI) using a fixed-effect model. Heterogeneity between trials was assessed. MAIN RESULTS: Nine studies (3519 patients) were included. Four RCTs included patients with multiple vessel disease, five focused on single vessel disease. Four studies reported beyond 1 year. No statistical differences were observed between CABG and stenting for meta-analysis of mortality or AMI, but there was heterogeneity. Composite cardiac event and revascularisation rates were lower for CABG than for stents. Odds ratios resulting from meta-analysis of event rate data at 1 year were, odds ratio 0.43 (95% CI 0.35 to 0.54) and at 3 years, odds ratio 0.37 (95% CI 0.29 to 0.48). Odds ratios for revascularisation at 1 year were, odds ratio 0.18 (95% CI 0.13 to 0.25) and at 3 years, odds ratio 0.09 (95% CI 0.02 to 0.34). Binary restenosis at 6 months (single vessel trials) favoured CABG, odds ratio 0.29 (95% CI 0.17 to 0.51). AUTHORS' CONCLUSIONS: CABG is associated with reduced rates of major adverse cardiac events, mostly driven by reduced repeat revascularisation. However, the RCT data are limited by follow-up, unrepresentative samples and rapid development of both surgical techniques and stenting. Research on real-world patient population or patient level data meta-analyses may identify risk factors and groupings who may benefit most from one strategy over the other.

Coronary artery stents: a rapid systematic review and economic evaluation.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of the use of coronary artery stents in patients with coronary heart disease (CHD). DATA SOURCES: Electronic databases. REVIEW METHODS: The review was conducted following accepted guidelines for conducting systematic reviews. Randomised controlled trials that include comparisons of percutaneous transluminal coronary angioplasty (PTCA) versus PTCA with stent, stent versus coronary artery bypass graft (CABG), and drug-eluting stents (DES) versus non-DES in patients with CAD in native or graft vessels and those with stable angina or acute coronary syndrome (ACS) and unstable angina were also included. Data on the following outcome measures were included in the review: combined event rate or event-free survival, death, acute myocardial infarction, target vessel revascularisation, repeat treatment (PTCA, stent or CABG) and binary restenosis. An economic model was developed based on extrapolation of trends in mortality and revascularisation from clinical trials data to a 5-year time horizon. RESULTS: The inclusion criteria were fulfilled by 50 studies comparing the use of stents with PTCA, six comparing stents with CABG and 12 comparing DES eluting stents with non-DES. No studies were identified that compared DES with PTCA or DES with CABG. Existing quality of life data suggest that revascularisation procedures reduce the patient's quality of life for a short period only. Stents were found to be more effective than PTCA in preventing adverse events and revascularisations. In multiple-vessel disease there was no evidence of a difference in mortality (at 1 year) between patients treated surgically and those receiving a stent. Patients treated surgically required fewer revascularisations. There is no evidence of a difference in mortality between patients receiving DES and those treated with bare metal stents at 1 year. A reduction in event rate at 9 and 12 months was found in patients treated with DES. This event rate is primarily made up of increased revascularisation rates in patients treated with bare metal stents. Two-year outcome data from one study indicate that this benefit of DES continues over the longer term. The economic model proved sufficient to indicate long-term trends in cost-effectiveness. CABG was found initially to be more expensive than bare metal stenting in multivessel disease and may have higher immediate risks, but over time the cost differential is reduced and long-term outcomes favour CABG over stenting. A similar situation was found for DES versus CABG in multiple-vessel disease. However, DES may not generally be considered a cost-effective alternative to bare metal stenting in single-vessel disease by policy makers as substantially higher costs are involved with a very small outcome benefit. CONCLUSIONS: DES might be considered cost-effective if the additional cost (compared with ordinary stents) was substantially reduced, the outcome benefits from the use of DES were much improved, and/or its use were targeted on the subgroups of patients with the highest risks of requiring reintervention. Long-term clinical studies are needed that focus on significant outcomes such as mortality. Further research should consider: the differences among plain stents; head-to-head comparisons within DES, CABG compared with DES; and the evaluation of newer non-DES against DES. Evaluation of the effects of revascularisation procedures and especially repeat revascularisation procedures on the patient's quality of life would also be useful, as would the development and testing of risk assessment tools to identify patients likely to need further revascularisations.

Gender differences in the urinary excretion rates of cortisol and androgen metabolites.

Animal studies show significant differences in steroid metabolism between male and female subjects. Similar studies in human subjects are still needed. The aim of this study was to evaluate differences in 24-h urinary excretion of cortisol and androgen metabolites between healthy male and female volunteers to estimate if such differences were significant. Urinary metabolite measurements were performed by gas chromatography. The median urinary excretion of total cortisol metabolites was 6965 microg/day for men and 4595 microg/day for women (P = 0.0005). Urinary excretion of 11beta-hydroxyandrosterone, tetrahydrocortisone, tetrahydrocortisol (5beta), allotetrahydrocortisol (5alpha), alpha-cortolone, beta-cortolone + beta-cortol and alpha-cortol were also significantly different in men compared with women. Total androgen metabolites in men (2660 microg/day) were also higher than in women (1850 microg/day) (P<0.0003). Similarly, urinary excretion of androsterone (5alpha), aetiocholanolone (5beta) and dehydroepiandrosterone were also significantly greater (all P=0.01). This confirms significant differences in the steroid metabolite excretion profiles between men and women. Laboratories should consider adopting gender-related reference ranges for cortisol and androgen metabolite excretion in 24-h urine samples.

Managing high-risk patients with acute coronary syndromes: the Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS-UK).

A study was carried out to find out whether more intense treatment (both medical and revascularisation) is targeted towards higher-risk patients with acute coronary syndromes. A prospective UK registry of patients admitted with non-ST elevation acute coronary syndromes was established to examine practice patterns and clinical outcomes with respect to the risk profile of the patients. Clinically important high-risk subgroups included the elderly, diabetics, those with heart failure and those with ST depression or bundle branch block on the presenting ECG. Elderly patients were less likely to receive evidence-based treatments, including beta blockers, statins and revascularisation. Diabetics received more revascularisation procedures but the overall revascularisation rate was low. Heart failure patients received less evidence-based treatment, with the exception of angiotensin-converting enzyme (ACE) inhibitors. Heparin was used less frequently in those with a normal ECG, although rates of revascularisation were not different when compared with those with ECG abnormalities. The conclusions of the study were that groups of patients with particularly high event rates are readily identified by their clinical characteristics, but use of evidence-based treatments and invasive investigations do not appear to be targeted towards those at greatest risk. Risk stratification and the appropriate application of treatments for patients with acute coronary syndromes need to be reviewed in the clinical setting.

How easy is it to contact the duty medical doctor responsible for acute admissions?

OBJECTIVE: To ascertain ease or difficulty of contacting duty junior doctors responsible for acute medical admissions by telephone. DESIGN: Telephone survey of hospitals in six health regions in England and Wales. SETTING: 70 Randomly selected hospitals, 15 of which were excluded because of non-acceptance of acute medical admissions. PARTICIPANTS: 71 Duty doctors (duty house physicians, senior house officers, or registrars responsible for acute medical admissions) in 48 hospitals; seven duty doctors in seven hospitals were excluded (four declined to participate and three required a written explanation of the survey). 67 Doctors gave full information to all questions. MAIN OUTCOME MEASURES: Time taken for hospital switchboards and duty doctors to reply to telephone call, diagnoses of patients recently admitted, and on call rotas and hours of sleep of duty doctors. RESULTS: Hospital switchboards responded within 30 seconds in 87 (74%) calls, and in 76 calls (64%) the duty doctor requested was contacted within a further two minutes. Chest pain, possibly due to myocardial infarction, was the most common reason for acute medical admissions. Nearly half (48%) of the duty doctors in larger hospitals reported having 4-5 hours sleep or less on their nights on call. Most (30) were on a one in three rota; two were on a one in two rota. CONCLUSIONS: Despite impressions to the contrary contacting the duty medical team by telephone seemed fairly easy. Although most junior doctors were on a rota of one in three or better, insufficient recognition may be given to their deprivation of sleep during nights on duty.

Bivalirudin for the treatment of ST-segment elevation myocardial infarction: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer (The Medicines Company) of bivalirudin to submit evidence for its clinical and cost effectiveness within its licensed indication for the treatment of adults with ST-segment elevation myocardial infarction (STEMI) intended for primary percutaneous coronary intervention (PPCI), as part of NICE's single technology appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG), which produced a review of the evidence within the manufacturer's submission to NICE. This article describes the manufacturer's submission, the ERG review and NICE's subsequent decisions. The main evidence was derived from one randomized controlled trial (RCT) of STEMI patients intended for PPCI, comparing bivalirudin with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors (GPIs). Bivalirudin was associated with a significant reduction in cardiac mortality at 30 days (p = 0.03) and at 1-year follow-up (p = 0.005), and a significant reduction in major bleeding at 30 days (p < 0.001) and 1 year (p < 0.0001), compared with heparin plus GPI. Stent thrombosis up to 24 hours following PPCI was significantly (p < 0.001) more common with bivalirudin. However, there was no significant treatment effect for stent thrombosis from 1 to 30 days (p = 0.28), or at 1-year follow-up (p = 0.53). There were no significant treatment group differences at 30 days and at 1 year in stroke (p = 0.68 and p = 0.99, respectively), in myocardial infarction [MI] (p = 0.90 and p = 0.22, respectively), or in the need for the revascularization of the target vessel for ischaemia (p = 0.18 and p = 0.12, respectively). There were two decision-analytic models: the base-case scenario used 1-year follow-up data from the RCT; and a sensitivity analysis used 3-year follow-up data. Resource use was primarily drawn from this RCT. Health-related quality-of-life (HR-QOL) estimates were drawn from a UK cohort study. Both models evaluated the incremental costs and outcomes of bivalirudin compared with heparin plus GPI for patients with STEMI intended for PPCI. The analysis adopted a UK NHS perspective over a lifetime horizon. Unit costs were based on year 2009-2010 prices. The model adopted a decision-tree structure to reflect initial events for the initial period (stroke, repeat MI, minor/major bleeding events, repeat revascularization and death) and a two-state Markov component to simulate longer-term survival. The economic analysis suggested that bivalirudin is expected to dominate the heparin plus GPI strategy. This finding was consistent across the probabilistic sensitivity analysis and the vast majority of deterministic sensitivity analyses undertaken. Three exceptions to this finding were observed for the following sensitivity analyses: (1) the exclusive use of eptifibatide as the GPI (incremental cost-effectiveness ratio [ICER] = £1,764); (2) the combination of 100 % eptifibatide use, 100 % radial arterial access and no differential length between strategies for initial hospital stay (ICER = £4,106); and (3) a longer length of ward stay (increase of 0.33 days) for the initial hospitalization (ICER = £415). The Appraisal Committee (AC) gave a positive recommendation for bivalirudin for the treatment of adults with STEMI undergoing PPCI.

A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure.

BACKGROUND: Two aldosterone inhibitors are currently licensed for heart failure (HF) in the UK: spironolactone and eplerenone. Recent clinical guidelines recommend eplerenone after an acute myocardial infarction (MI) for patients with symptoms and/or signs of HF and left ventricular dysfunction. OBJECTIVES: The primary objective was to evaluate relative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone in patients with postMI HF and explore the possibility of conducting an indirect comparison of spironolactone and eplerenone. A second objective was to undertake value-of-information (VOI) analyses to determine the need for further research to identify research questions critical to decision-making and to help inform the design of future studies. DATA SOURCES: Relevant databases including MEDLINE, EMBASE and CENTRAL were searched between September and December 2008. Randomised controlled trials (RCTs) of spironolactone, eplerenone, canrenone or potassium canrenoate were included if conducted in a postMI HF population. Trials of general HF patients with a subgroup of postMI HF patients were considered if they had at least 100 ischaemic participants per arm and the authors provided subgroup data when contacted. Adverse events summary data were sought from recognised reference sources and RCTs or observational studies in any population that recruited more than 100 participants. REVIEW METHODS: The comparative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone was derived using Bayesian meta-regression drawing on a wider 'network' of aldosterone trials to those considered in the main clinical effectiveness review. An alternative scenario was also considered assuming a 'class effect' for the aldosterone antagonists in terms of major clinical events, but allowing for potential differences in side effect profiles. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) where appropriate. Uncertainty in cost-effectiveness results was also presented and used to inform future research priorities using VOI analyses based on expected value of perfect information (EVPI). A probabilistic decision analytic model was developed to estimate cost-effectiveness of spironolactone, eplerenone and standard care for management of postMI HF, provide estimates relevant to the NHS and explore alternative approaches to an indirect comparison between spironolactone and eplerenone. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the NHS persepctive. In the base-case analysis, 2-year treatment duration was assumed, consistent with the follow-up in the main RCTs. Other scenarios were explored to examine the robustness of alternative assumptions including impact of different treatment durations. RESULTS: Searches yielded five RCTs: two spironolactone trials of poor methodological quality and three trials of which only one (of eplerenone) specifically examined postMI HF (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, EPHESUS). One trial of spironolactone (Randomised Aldactone Evaluation Study, RALES) and one of canrenone (Antiremodelling Effect of Aldosterone receptors blockade with canrenone In mild Chronic Heart Failure, AREA IN-CHF) comprised general HF, but data were available for an ischaemic subgroup. Structural similarity of spironolactone and eplerenone suggests that they may be interchangeable, but formal indirect comparison between the three trials was severely limited by trial differences. Relative safety data were limited from RCTs and observational sources. Hyperkalaemia rates varied, but were generally higher than for placebo; data were insufficient to assess discontinuation because of hyperkalaemia.Gynaecomastia rates were higher with spironolactone. Adverse event data were sparse. Systematic review of economic evidence identified three main published studies but none used a UK perspective or attempted to compare cost-effectiveness in postMI HF. The new decision model indicated that eplerenone was the most cost-effective strategy for postMI HF (ICER of eplerenone compared with standard care was 4457 pounds per QALY, increasing to 7893 pounds per QALY if treatment continued over the patient's lifetime); in neither scenario did spironolactone appear cost-effective. The ICER of eplerenone was consistently under the 20,000-30,000 pounds per QALY threshold used to establish value for money in the NHS. Uncertainty resulted in EVPI estimates between 820M pounds (base-case) and 1265M pounds (lifetime treatment duration scenario). When class effect for mortality and hospitalisations was assumed spironolactone emerged as the most cost-effective treatment and EVPI estimates were negligible. If class effect is considered more plausible than the results of the evidence synthesis model then there would be limited value in additional research. LIMITATIONS: Exchangeability between trials was poor and there was a lack of robust data in RCTs. CONCLUSIONS: Only two good-quality trials of aldosterone inhibitors in the postMI HF population were found, but lack of exchangeability with respect to study populations, meant that a comparison between these drugs could not be done. It consistently emerged that, compared with usual care, use of an aldosterone antagonist appears to be a highly cost-effective strategy for the management of postMI HF patients in the NHS. An adequately powered, well-conducted RCT that directly compares spironolactone and eplerenone is required to provide more robust evidence on the optimal management of postMI HF patients.

Adipokines--targeting a root cause of cardiometabolic risk.

Obesity often co-presents with other cardiometabolic risk factors such as dyslipidaemia, insulin resistance and hypertension. Less well appreciated is that dysregulation of adipokine production by excess adipose tissue also promotes a state of low-level systemic chronic inflammation and a prothrombotic state, implicated in the development of both atherosclerosis and subsequently cardiovascular events. Lifestyle modification and pharmacological therapy can reduce cardiometabolic risk, a benefit that may be partly due to their effects on adipokine levels.