An Update on Guidelines to Prevent and Manage Atrial Fibrillation After Cardiac Surgery and a Survey of Practice in the UK.

OBJECTIVES: Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery and affects around 30% of patients. Variable guidelines from multiple organizations exist for the prevention of POAF after cardiac surgery. A survey of UK practice was conducted to define "usual care" for a platform trial of interventions to prevent POAF after cardiac surgery. To provide context for the survey, all current guidelines for the prevention and management of atrial fibrillation (AF) after cardiac surgery were reviewed. DESIGN: Online survey and literature review. SETTING: All 35 UK National Health Service Cardiac Surgery Centres participated in the survey. Guidelines from specialist societies and other guideline-making organizations from the UK, Europe, and North America were reviewed. PARTICIPANTS: Established a link network of researchers. MEASUREMENTS AND MAIN RESULTS: Five relevant guidelines were identified from the literature review. All guidelines recommend ß-blockade for prevention of AF after cardiac surgery. Treatment of AF is recommended using either rate or rhythm control. Cardioversion is recommended only for the hemodynamically unstable patient. Patients who remain in AF for over 48 hours should be considered for anticoagulation. Patients should be followed up within 60 days to review the need for antiarrhythmic and anticoagulant therapy. Of 35 centers, 31 (89%) responded. A total of 11 of 31 (35.5%) centers followed local guidance for prevention of POAF, 4 (13%) centers followed Society of Cardiovascular Anesthesiologists/European Association of Cardiothoracic Anaesthesia guidelines, 4 (13%) followed UK National Institute of Health and Care Excellence guidance and 4 followed "other" guidance. Of 31 centers, 8 (26%) followed no guidelines to prevent POAF; 28 of 31 (90%) centers did not risk-stratify their patients for POAF. Most centers (23/31, 74%) did not have a care package in place to prevent POAF, but 14 of 31 (45%) try in some way to prevent AF in patients presenting with sinus rhythm. The most common interventions to prevent POAF are ß-blocker use postoperatively (23/31, 74%), magnesium (20/31, 64.5%), and maintaining a serum K+ ≥4.5 mmol/L (26/31, 84%). CONCLUSIONS: Guidance to prevent AF after cardiac surgery centers around the use of ß-blockade. Although patients in the UK do not appear to be risk-assessed for POAF, the main interventions used to prevent it are similar: ß-blockade and maintenance of serum K+ and Mg2+ levels.

Does previous asbestos exposure increase the risk of a post coronary artery bypass graft (CABG) pleural effusion - a routine data study?

BACKGROUND: Development of pleural effusion (PE) following CABG is common. Post-CABG PE are divided into early- (within 30 days of surgery) and delayed-onset (30 days-1 year) which are likely due to distinct pathological processes. Some experts suggest asbestos exposure may confer an independent risk for late-onset post-CABG PE, however no large studies have explored this potential association. RESEARCH QUESTION: To explore possible association between asbestos exposure and post-CABG PE using routine data. METHODS: All patients who underwent CABG 01/04/2013-31/03/2018 were identified from the Hospital Episode Statistics (HES) Database. This England-wide population was evaluated for evidence of asbestos exposure, pleural plaques or asbestosis and a diagnosis of PE or PE-related procedure from 30 days to 1 year post-CABG. Patients with evidence of PE three months prior to CABG were excluded, as were patients with a new mesothelioma diagnosis. RESULTS: 68,150 patients were identified, of whom 1,003 (1%) were asbestos exposed and 2,377 (3%) developed late-onset PE. After adjusting for demographic data, Index of Multiple Deprivation and Charlson Co-morbidity Index, asbestos exposed patients had increased odds of PE diagnosis or related procedure such as thoracentesis or drainage (OR 1.35, 95% CI 1.03-1.76, p = 0.04). In those with evidence of PE requiring procedure alone, the adjusted OR was 1.66 (95% CI 1.14-2.40, p = 0.01). Additional subgroup analysis of the 518 patients coded for pleural plaques and asbestosis alone revealed an adjusted OR of post-CABG PE requiring a procedure of 2.16 (95% CI 1.38-3.37, p = 0.002). INTERPRETATION: This large-scale study demonstrates prior asbestos exposure is associated with modestly increased risk of post-CABG PE development. The risk association appears higher in patients with assigned clinical codes indicative of radiological evidence of asbestos exposure (pleural plaques or asbestosis). This association may fit with a possible inflammatory co-pathogenesis, with asbestos exposure 'priming' the pleura resulting in greater propensity for PE evolution following the physiological insult of CABG surgery. Further work, including prospective studies and clinicopathological correlation are suggested to explore this further.

Sex-Based Differences in Early Outcomes Following Mitral Valve Surgery for Degenerative Disease.

OBJECTIVES: To determine whether sex-based differences exist following surgery for degenerative mitral valve disease. METHODS: Using a national database, we analysed data on mitral valve surgery for degenerative disease (n = 22,658) between January 2000 and March 2019 in the UK. We split the cohort into men (n = 14,681) and women (n = 7977) and compared background characteristics, intraoperative variables and early postoperative outcomes. Our primary outcome was hospital mortality; secondary outcomes included re-exploration for bleeding, prolonged admission (>10 days) and mitral replacement. We used binary logistic regression models for all outcomes, with multiplicative interaction terms to determine the nature of any differences. RESULTS: Women presented older (70 ± 11 years vs. 67 ± 11 years, p < 0.001) with worse symptom profiles (New York Heart Association Class III-IV 57% vs. 44%, p < 0.001). They had higher rates of preoperative atrial fibrillation (39% vs. 35%, p < 0.001) and tricuspid disease requiring surgery (21% vs. 15%, p < 0.001). They had lower repair rates (66% vs. 76%, p < 0.001), higher mortality (3% vs. 2%, p < 0.001) and were more likely to have a prolonged admission (48% vs. 40%, p < 0.001). Female sex was an independent predictor of mortality (odds ratio (OR): 1.52, 95% CI: 1.21-1.90, p < 0.001). Age and Canadian Cardiovascular Society (CCS) score showed significant interactions with sex. The relationship between advancing age and mortality was found to be more pronounced in women. CONCLUSIONS: (1) Female sex is an independent predictor of hospital mortality, prolonged hospital admission and mitral valve replacement. (2) The relationship between female sex and mortality is exacerbated by worsening CCS score and advancing age. (3) Women have significantly lower repair rates.

The IDEAL Reporting Guidelines: A Delphi Consensus Statement Stage Specific Recommendations for Reporting the Evaluation of Surgical Innovation.

OBJECTIVE: The aim of this study was to define reporting standards for IDEAL format studies. BACKGROUND: The IDEAL Framework and Recommendations establish an integrated pathway for evaluation of new surgical techniques and complex therapeutic technologies. However guidance on implementation has been incomplete, and incorrect use is commonly seen. We describe the consensus development of reporting guidelines for the IDEAL stages, and plans for their dissemination and evaluation. METHODS: Using the EQUATOR Network recommendations, participants with knowledge of IDEAL were surveyed to determine which IDEAL stages needed reporting guidelines. Draft checklists for stages 1, 2a, 2b, and 4 were subsequently developed by 3 researchers (N.B., A.H., P.M.), and revised through a 2-round Delphi consensus process. A final consensus teleconference resolved outstanding disagreements and clarified wording for checklist items. RESULTS: Sixty-one participants completed the initial survey, a clear majority indicating that new reporting guidelines were needed for IDEAL Stage 1 (69.5%), Stage 2a (78%), Stage 2b (74.6%), and Stage 4 (66%). A proposed set of checklists was modified by survey participants in 2 online Delphi rounds (n = 54 and n = 47, respectively), resulting in a penultimate checklist for each stage. Fourteen expert working group members finalized the checklist items and successfully resolved any outstanding areas without agreement on a consensus call. CONCLUSIONS: Participants familiar with IDEAL called for reporting guidelines for studies in all IDEAL stages except stage 3. The checklists developed have the potential to improve standards of reporting and thereby advance the quality of research on surgery and complex interventions and technologies, but require further evaluation in use.

Feasibility of identifying important changes in care management resulting from cardiovascular magnetic resonance (CMR) using hospital episode data in patients who activate the primary percutaneous coronary intervention (PPCI) pathway.

BACKGROUND: We determined whether it is feasible to identify important changes in care management resulting from cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway from hospital episode data, in order to construct a composite primary outcome (hypothesised to reduce the risk of major adverse cardiac-related events, MACE) to compare patients exposed to CMR or not. METHODS: We used Hospital Episode Statistics (HES) and Patient Episode Database for Wales (PEDW) to identify clinical events that reflected important changes in management in the year following the index admission in five subgroups of patients who activated the PPCI pathway recruited as part of a feasibility cohort study (n = 1655 with HES/PEDW data). For all subgroups, we identified frequency of events and time to the first event for each change in management. RESULTS: We identified all clinical events (new diagnoses, additional diagnostic tests and procedures) except for medication prescriptions. Diagnostic tests were underestimated because most are carried out in outpatient clinics and outpatient datasets had missing procedure codes for 74% of patients (some tests done in hospital may also not be recorded). We successfully tabulated frequencies of events and distributions of times to first event for most changes in management by CMR status and in CMR / non CMR centres. CONCLUSIONS: It is feasible to identify changes in care management between patients who have / do not have CMR within relevant patient subgroups. Further work to derive a weighting algorithm is required before attempting to combine the events in a composite endpoint.

Correction to: Feasibility of identifying important changes in care management resulting from cardiovascular magnetic resonance (CMR) using hospital episode data in patients who activate the primary percutaneous coronary intervention (PPCI) pathway.

In the original publication of this article [1], the author noted two corrections after publication.

Health-related quality of life impact of minor and major bleeding events during dual antiplatelet therapy: a systematic literature review and patient preference elicitation study.

BACKGROUND: Dual antiplatelet therapy (DAPT) is the recommended preventative treatment for secondary ischaemic events, but increases the risk of bleeding, potentially affecting patients' health-related quality-of-life (HRQoL). Varied utility decrements have been used in cost-effectiveness models assessing alternative DAPT regimens, but it is unclear which of these decrements are most appropriate. Therefore, we reviewed existing sources of utility decrements for bleeds in patients receiving DAPT and undertook primary research to estimate utility decrements through a patient elicitation exercise using vignettes and the EuroQol EQ-5D. METHODS: MEDLINE, PubMed and references of included studies were searched. Primary research and decision analytic modelling studies reporting utility decrements for bleeds related to DAPT were considered. For the primary research study, 21 participants completed an elicitation exercise involving vignettes describing minor and major bleeds and the EQ-5D-3 L and EQ-5D-5 L. Utility decrements were derived using linear regression and compared to existing estimates. RESULTS: Four hundred forty-two citations were screened, of which 12 studies were included for review. Reported utility decrements ranged from - 0.002 to - 0.03 for minor bleeds and - 0.007 to - 0.05 for major bleeds. Data sources used to estimate the decrements, however, lacked relevance to our population group and few studies adequately reported details of their measurement and valuation approaches. No study completely adhered to reimbursement agency requirements in the UK according to the National Institute for Health and Care Excellence reference case. Our primary research elicited utility decrements overlapped existing estimates, ranging from - 0.000848 to - 0.00828 for minor bleeds and - 0.0187 to - 0.0621 for major bleeds. However, the magnitude of difference depended on the instrument, estimation method and valuation approach applied. CONCLUSIONS: Several sources of utility decrements for bleeds are available for use in cost-effectiveness analyses, but are of limited quality and relevance. Our elicitation exercise has derived utility decrements from a relevant patient population, based on standardised definitions of minor and major bleeding events, using a validated HRQoL instrument and have been valued using general population tariffs. We suggest that our utility decrements be used in future cost-effectiveness analyses of DAPT.

Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients.

Aim: We sought to determine whether the optimal dual antiplatelet therapy (DAPT) duration after drug-eluting stent (DES) placement varies according to clinical presentation. Methods and Results: We performed an individual patient data pairwise and network meta-analysis comparing short-term (≤6-months) versus long-term (1-year) DAPT as well as 3-month vs. 6-month vs 1-year DAPT. The primary study outcome was the 1-year composite risk of myocardial infarction (MI) or definite/probable stent thrombosis (ST). Six trials were included in which DAPT after DES consisted of aspirin and clopidogrel. Among 11 473 randomized patients 6714 (58.5%) had stable CAD and 4758 (41.5%) presented with acute coronary syndrome (ACS), the majority of whom (67.0%) had unstable angina. In ACS patients, ≤6-month DAPT was associated with non-significantly higher 1-year rates of MI or ST compared with 1-year DAPT (Hazard Ratio (HR) 1.48, 95% Confidence interval (CI) 0.98-2.22; P = 0.059), whereas in stable patients rates of MI and ST were similar between the two DAPT strategies (HR 0.93, 95%CI 0.65-1.35; P = 0.71; Pinteraction = 0.09). By network meta-analysis, 3-month DAPT, but not 6-month DAPT, was associated with higher rates of MI or ST in ACS, whereas no significant differences were apparent in stable patients. Short DAPT was associated with lower rates of major bleeding compared with 1-year DAPT, irrespective of clinical presentation. All-cause mortality was not significantly different with short vs. long DAPT in both patients with stable CAD and ACS. Conclusions: Optimal DAPT duration after DES differs according to clinical presentation. In the present meta-analysis, despite the fact that most enrolled ACS patients were relatively low risk, 3-month DAPT was associated with increased ischaemic risk, whereas 3-month DAPT appeared safe in stable CAD. Prolonged DAPT increases bleeding regardless of clinical presentation. Further study is required to identify the optimal duration of DAPT after DES in individual patients based on their relative ischaemic and bleeding risks.

Measurement of myocardium at risk with cardiovascular MR: comparison of techniques for edema imaging.

PURPOSE: To determine variability and agreement for detecting myocardial edema with T2-weighted short-tau inversion recovery (STIR), acquisition for cardiac unified T2 edema (ACUT2E), T2 mapping, and early gadolinium enhancement (EGE) after successfully reperfused ST-segment-elevation myocardial infarction (STEMI) and diagnostic accuracy of each sequence to predict infarct-related artery (IRA). MATERIALS AND METHODS: Local ethics committee approved the study, with patient informed written consent. On day 2 after successful primary angioplasty for STEMI, 53 patients were prospectively enrolled; 40 patients (mean age, 60 years) completed study. Two sets of cardiac magnetic resonance (MR) images were obtained on same day 6 hours apart. Basal, midcavity, and apical sections were obtained with each sequence. Interobserver, intraobserver, and interimage variability (1 minus intraclass correlation coefficient) and agreement (Bland-Altman method) were assessed. RESULTS: Size of myocardial edema significantly differed. Mean size of myocardium at risk was similar between T2-weighted STIR (18.2 g) and T2 mapping (17.3 g) (P = .54). Mean size differed between T2-weighted STIR (18.2 g) and ACUT2E (14.0 g) (P = .01) and between T2-weighted STIR (18.2 g) and EGE (14.2 g) (P = .003). T2 mapping and EGE had best agreement (interobserver bias: T2-weighted STIR, -0.9 [mean difference] ± 9.6 [standard deviation]; ACUT2E, -2.5 ± 6.9; T2 mapping, -3.8 ± 4.7; EGE, -5.3 ± 5.9; interimage bias: T2-weighted STIR, 1.5 ± 5.8; ACUT2E, -0.8 ± 4.9; T2 mapping, 3.1 ± 4.0; EGE, 1.1 ± 4.9; intraobserver bias: T2-weighted STIR, 1.4 ± 5.8; ACUT2E, 0.6 ± 4.7; T2 mapping, 2.2 ± 3.1; EGE, 1.7 ± 2.9). Variability was lowest for T2 mapping (intraobserver, 0.05; interobserver, 0.09; interimage, 0.1) followed by EGE (intraobserver, 0.03; interobserver, 0.14; interimage, 0.14), with improved detection of territory of IRA versus ACUT2E (intraobserver, 0.11; interobserver, 0.22; interimage, 0.12) and T2-weighted STIR (intraobserver, 0.1; interobserver, 0.32; interimage, 0.1). CONCLUSION: Cardiac MR methods to detect and quantify infarct myocardial edema are not interchangeable; T2 mapping is the most reproducible method, followed by EGE, ACUT2E, and T2-weighted STIR. Clinical trial registration no. NCT01468662

Inequalities in access to and outcomes of cardiac surgery in England: retrospective analysis of Hospital Episode Statistics (2010-2019).

BACKGROUND: We aimed to characterise the variation in access to and outcomes of cardiac surgery for people in England. METHODS: We included people >18 years of age with hospital admission for ischaemic heart disease (IHD) and heart valve disease (HVD) between 2010 and 2019. Within these populations, we identified people who had coronary artery bypass graft (CABG) and/or valve surgery, respectively. We fitted logistic regression models to examine the effects of age, sex, ethnicity and socioeconomic deprivation on having access to surgery and in-hospital mortality, 1-year mortality and hospital readmission. RESULTS: We included 292 140 people, of whom 28% were women, 11% were from an ethnic minority and 17% were from the most deprived areas. Across all types of surgery, one in five people are readmitted to hospital within 1 year, rising to almost one in four for valve surgery. Women, black people and people living in the most deprived areas were less likely to have access to surgery (CABG: 59%, 32% and 35% less likely; valve: 31%, 33% and 39% less likely, respectively) and more likely to die within 1 year of surgery (CABG: 24%, 85% and 18% more likely, respectively; valve: 19% (women) and 10% (people from most deprived areas) more likely). CONCLUSIONS: Female sex, black ethnicity and economic deprivation are independently associated with limited access to cardiac surgery and higher post-surgery mortality. Actions are required to address these inequalities.

Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage.

BACKGROUND: Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. METHODS: The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. RESULTS: Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. CONCLUSIONS: We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

Does melatonin administration reduce the incidence of postoperative delirium in adults? Systematic review and meta-analysis.

Postoperative delirium (POD) is common. It is associated with increased morbidity and mortality. Many cases may be preventable and melatonin offers promise as a preventative agent. OBJECTIVE: This systematic review provides an up-to-date synthesis of the evidence on the effect of melatonin in preventing POD. DESIGN: A systematic search of randomised controlled trials of melatonin in POD was run across multiple databases (EMBASE, MEDLINE, CINAHL, PsycINFO) and a clinical trials registry (ClinicalTrials.org) (1 January 1990 to 5 April 2022). Studies examining the effects of melatonin on POD incidence in adults are included. Risk of bias was assessed using the Cochrane risk of bias 2 tool. OUTCOME MEASURES: The primary outcome is POD incidence. Secondary outcomes are POD duration and length of hospital stay. Data synthesis was undertaken using a random-effects meta-analysis and presented using forest plots. A summary of methodology and outcome measures in included studies is also presented. RESULTS: Eleven studies, with 1244 patients from a range of surgical specialties were included. Seven studies used melatonin, in variable doses, and four used ramelteon. Eight different diagnostic tools were used to diagnose POD. Time points for assessment also varied. Six studies were assessed as low risk of bias and five as some concern. The combined OR of developing POD in the melatonin groups versus control was 0.41 (95% CI 0.21 to 0.80, p=0.01). CONCLUSION: This review found that melatonin may reduce the incidence of POD in adults undergoing surgery. However, included studies displayed inconsistency in their methodology and outcome reporting. Further work to determine the optimum regime for melatonin administration, along with consensus of how best to evaluate results, would be beneficial. PROSPERO REGISTRATION NUMBER: CRD42021285019.

Pharmacological and non-pharmacological interventions to prevent delirium after cardiac surgery: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Delirium is a syndrome characterised by a disturbance in attention, awareness and cognition as a result of another physical condition. It occurs in up to 50% of patients after cardiac surgery and is associated with increased mortality, prolonged intensive care and hospital stay and long-term cognitive dysfunction. Identifying effective preventive interventions is important. We will therefore conduct a systematic review to identify all randomised controlled studies that have tested a pharmacological or non-pharmacological intervention to prevent delirium. METHODS AND ANALYSIS: We will search electronic databases (CDSR (Reviews), CENTRAL (Trials), MEDLINE Ovid, Embase Ovid, PsycINFO Ovid) as well as trial registers (clinicaltrials.gov and ISCRTN) for randomised controlled trials of both pharmacological and non-pharmacological interventions designed to prevent delirium after cardiac surgery in adults. Screening of search results and data extraction from included articles will be performed by two independent reviewers using Rayyan. The primary outcome will be the incidence of delirium. Secondary outcomes include: duration of postoperative delirium, all-cause mortality, length of postoperative hospital and intensive care stay, postoperative neurological complications other than delirium, health-related quality of life and intervention-specific adverse events. Studies will be assessed for risk of bias using the Cochrane RoB2 tool. A narrative synthesis of all included studies will be presented and meta-analysis (if appropriate network meta-analysis) will be undertaken where there are sufficient studies (three or more) for pooling results. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. ETHICS AND DISSEMINATION: No ethical approval is required. This review will be disseminated via peer-reviewed manuscript and conferences. PROSPERO REGISTRATION NUMBER: CRD42022369068.

Mitral repair versus replacement: 20-year outcome trends in the UK (2000-2019).

OBJECTIVES: Using a large national database, we sought to describe outcome trends in mitral valve surgery between 2000 and 2019. METHODS: The study cohort was split into mitral valve repair (MVr) or replacement, including all patients regardless of concomitant procedures. Patients were grouped by four-year admission periods into groups (A to E). The primary outcome was in hospital mortality and secondary outcomes were return to theatre, postoperative stroke and postoperative length of stay. We investigated trends over time in patient demographics, comorbidities, intraoperative characteristics and postoperative outcomes. We used a multivariable binary logistic regression model to assess the relationship between mortality and time. Cohorts were further stratified by sex and aetiology. RESULTS: Of the 63 000 patients in the study cohort, 31 644 had an MVr and 31 356 had a replacement. Significant demographic shifts were observed. Aetiology has shifted towards degenerative disease; endocarditis rates in MVr dropped initially but are now rising (period A = 6%, period C = 4%, period E = 6%; P < 0.001). The burden of comorbidities has increased over time. In the latest time period, women had lower repair rates (49% vs 67%, P < 0.001) and higher mortality rates when undergoing repair (3% vs 2%, P = 0.001) than men. Unadjusted postoperative mortality dropped in MVr (5% vs 2%, P < 0.001) and replacement (9% vs 7%, P = 0.015). Secondary outcomes have improved. Time period was an independent predictor for reduced mortality in both repair (odds ratio: 0.41, 95% confidence interval: 0.28-0.61, P < 0.001) and replacement (odds ratio: 0.50, 95% confidence interval: 0.41-0.61, P < 0.001). CONCLUSIONS: In-hospital mortality has dropped significantly over time for mitral valve surgery in the UK. MVr has become the more common procedure. Sex-based discrepancies in repair rates and mortality require further investigation. Endocarditis rates in MVS are rising.

Bleeding risk in patients prescribed dual antiplatelet therapy and triple therapy after coronary interventions: the ADAPTT retrospective population-based cohort studies.

Background: Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives: The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design: The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting: The study was set in primary and secondary care in England from 2010 to 2017. Participants: Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources: Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions: Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures: Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval -£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval -£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions: This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations: The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work: Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration: This trial is registered as ISRCTN76607611. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

People who have a heart attack are treated with a stent to open up the blocked artery that caused the heart attack, with surgery to bypass the blocked artery or with medication only. Whatever the treatment, they are prescribed one or more antiplatelet drugs, either aspirin only or aspirin and an additional antiplatelet (clopidogrel, prasugrel or ticagrelor), for 12 months after the heart attack. Antiplatelets are given to prevent another heart attack, but increase the risk of bleeding. We used a large general practice database and a database describing patients' attendances and admissions to hospital to determine how many people bleed with different antiplatelet combinations. We found that, overall, up to 1 in 10 people taking antiplatelets (rising to 2 in 10 if also taking an anticoagulant such as warfarin or dabigatran) reported a bleed. Among patients treated with surgery or medication only, we compared aspirin only (which is a less potent therapy) with aspirin and clopidogrel (a more potent therapy). Among patients treated with stents, we compared aspirin and clopidogrel (less potent therapy) with aspirin and prasugrel or ticagrelor (more potent therapy). In all three populations, the more potent therapy increased the risk of bleeding by about one and a half times, but this was not offset by a reduced risk of having a subsequent heart attack. This may be explained by low adherence to the medication: between one-third and almost half of all patients did not adhere to their regimen, and non-adherence was generally higher among patients taking a more potent therapy. It may also be explained by bias inherent in the study, for example if the groups prescribed different antiplatelet regimens had different risks of having another heart attack. Nevertheless, the results show that doctors should be cautious about prescribing more potent antiplatelet therapy because it may increase serious bleeds without necessarily reducing the number of heart attacks.

Hospital resource utilization in a national cohort of functionally single ventricle patients undergoing surgical treatment.

Objective: The study objective was to provide a detailed overview of health resource use from birth to 18 years old for patients with functionally single ventricles and identify associated risk factors. Methods: All patients with functionally single ventricles treated between 2000 and 2017 in England and Wales were linked to hospital and outpatient records using data from the Linking AUdit and National datasets in Congenital HEart Services project. Hospital stay was described in yearly age intervals, and associated risk factors were explored using quantile regression. Results: A total of 3037 patients with functionally single ventricles were included, 1409 (46.3%) undergoing a Fontan procedure. During the first year of life, the median days spent in hospital was 60 (interquartile range, 37-102), mostly inpatient days, mirroring a mortality of 22.8%. This decreases to between 2 and 9 in-hospital days/year afterward. Between 2 and 18 years, most hospital days were outpatient, with a median of 1 to 5 days/year. Lower age at the first procedure, hypoplastic left heart syndrome/mitral atresia, unbalanced atrioventricular septal defect, preterm birth, congenital/acquired comorbidities, additional cardiac risk factors, and severity of illness markers were associated with fewer days at home and more intensive care unit days in the first year of life. Only markers of early severe illness were associated with fewer days at home in the first 6 months after the Fontan procedure. Conclusions: Hospital resource use in functionally single ventricle cases is not uniform, decreasing 10-fold during adolescence compared with the first year of life. There are subsets of patients with worse outcomes during their first year of life or with persistently high hospital use throughout their childhood, which could be the target of future research.

Efficacy and safety of carbon dioxide insufflation for brain protection for patients undergoing planned left-sided open heart valve surgery: protocol for a multicentre, placebo-controlled, blinded, randomised controlled trial (the CO2 Study).

INTRODUCTION: Brain injury is common following open heart valve surgery. Carbon dioxide insufflation (CDI) has been proposed to reduce the incidence of brain injury by reducing the number of air microemboli entering the bloodstream in surgery. The CO2 Study will evaluate the efficacy and safety of CDI in patients undergoing planned left-sided open heart valve surgery. METHODS AND ANALYSIS: The CO2 Study is a multicentre, blinded, placebo-controlled, randomised controlled trial. Seven-hundred and four patients aged 50 years and over undergoing planned left-sided heart valve surgery will be recruited to the study, from at least eight UK National Health Service hospitals, and randomised in a 1:1 ratio to receive CDI or medical air insufflation (placebo) in addition to standard de-airing. Insufflation will be delivered at a flow rate of 5 L/min from before the initiation of cardiopulmonary bypass until 10 min after cardiopulmonary bypass weaning. Participants will be followed up until 3 months post-surgery. The primary outcome is acute ischaemic brain injury within 10 days post-surgery based on new brain lesions identified with diffusion-weighted MRI or clinical evidence of permanent brain injury according to the current definition of stroke. ETHICS AND DISSEMINATION: The study was approved by the East Midlands-Nottingham 2 Research Ethics Committee in June 2020 and the Medicines and Healthcare products Regulatory Agency in May 2020. All participants will provide written informed consent prior to undertaking any study assessments. Consent will be obtained by the principal investigator or a delegated member of the research team who has been trained in the study and undergone Good Clinical Practice training. Results will be disseminated through peer-reviewed publications and presentations at national and international meetings. Study participants will be informed of results through study notifications and patient organisations. TRIAL REGISTRATION NUMBER: ISRCTN30671536.

Formal consensus study on surgery to replace the aortic valve in adults aged 18-60 years.

OBJECTIVE: There is uncertainty about surgical procedures for adult patients aged 18-60 years undergoing aortic valve replacement (AVR). Options include conventional AVR (mechanical, mAVR; tissue, tAVR), the pulmonary autograft (Ross) and aortic valve neocuspidisation (Ozaki). Transcatheter treatment may be an option for selected patients. We used formal consensus methodology to make recommendations about the suitability of each procedure. METHODS: A working group, supported by a patient advisory group, developed a list of clinical scenarios across seven domains (anatomy, presentation, cardiac/non-cardiac comorbidities, concurrent treatments, lifestyle, preferences). A consensus group of 12 clinicians rated the appropriateness of each surgical procedure for each scenario on a 9-point Likert scale on two separate occasions (before and after a 1-day meeting). RESULTS: There was a consensus that each procedure was appropriate (A) or inappropriate (I) for all clinical scenarios as follows: mAVR: total 76% (57% A, 19% I); tAVR: total 68% (68% A, 0% I); Ross: total 66% (39% A, 27% I); Ozaki: total 31% (3% A, 28% I). The remainder of percentages to 100% reflects the degree of uncertainty. There was a consensus that transcatheter aortic valve implantation is appropriate for 5 of 68 (7%) of all clinical scenarios (including frailty, prohibitive surgical risk and very limited life span). CONCLUSIONS: Evidence-based expert opinion emerging from a formal consensus process indicates that besides conventional AVR options, there is a high degree of certainty about the suitability of the Ross procedure in patients aged 18-60 years. Future clinical guidelines should include the option of the Ross procedure in aortic prosthetic valve selection.