Preoperative N-terminal pro-B-type natriuretic peptide and myocardial injury after stopping or continuing renin-angiotensin system inhibitors in noncardiac surgery: a prespecified analysis of a phase 2 randomised controlled multicentre trial.

BACKGROUND: Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml-1) experience more complications after noncardiac surgery. Individuals prescribed renin-angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations. METHODS: In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L-1 or a ≥5 ng L-1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L-1) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml -1) and stopping or continuing RAS inhibitors. RESULTS: Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml -1 (median 339 [160-833] pg ml-1), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml-1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml -1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05-5.99); P<0.0001}. For subjects with preoperative NT-proBNP <100 pg ml-1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06-4.65]; P=0.03). For preoperative NT-proBNP >100 pg ml-1, myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44-2.22]). CONCLUSIONS: Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml -1) increased the likelihood of myocardial injury before noncardiac surgery.

Discontinuation vs. continuation of renin-angiotensin system inhibition before non-cardiac surgery: the SPACE trial.

BACKGROUND AND AIMS: Haemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin-angiotensin system (RAS) inhibitors (angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers). Whether stopping RAS inhibitors to minimise hypotension, or continuing RAS inhibitors to avoid hypertension, reduces peri-operative myocardial injury remains unclear. METHODS: From 31 July 2017 to 1 October 2021, patients aged ≥60 years undergoing elective non-cardiac surgery were randomly assigned to either discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. Renin-angiotensin system inhibitors were withheld for different durations (2-3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury [plasma high-sensitivity troponin-T (hs-TnT) ≥ 15 ng/L within 48 h after surgery, or ≥5 ng/L increase when pre-operative hs-TnT ≥15 ng/L]. Pre-specified adverse haemodynamic events occurring within 48 h of surgery included acute hypertension (>180 mmHg) and hypotension requiring vasoactive therapy. RESULTS: Two hundred and sixty-two participants were randomized to continue (n = 132) or stop (n = 130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomized to discontinue, compared with 50 (41.3%) patients who continued, RAS inhibitors [odds ratio (for continuing): 0.77; 95% confidence interval (CI) 0.45-1.31]. Hypertensive adverse events were more frequent when RAS inhibitors were stopped [16 (12.4%)], compared with 7 (5.3%) who continued RAS inhibitors [odds ratio (for continuing): 0.4; 95% CI 0.16-1.00]. Hypotension rates were similar when RAS inhibitors were stopped [12 (9.3%)] or continued [11 (8.4%)]. CONCLUSIONS: Discontinuing RAS inhibitors before non-cardiac surgery did not reduce myocardial injury, and could increase the risk of clinically significant acute hypertension. These findings require confirmation in future studies.

Starting a conversation about estimands with public partners involved in clinical trials: a co-developed tool.

BACKGROUND: Clinical trials aim to draw conclusions about the effects of treatments, but a trial can address many different potential questions. For example, does the treatment work well for patients who take it as prescribed? Or does it work regardless of whether patients take it exactly as prescribed? Since different questions can lead to different conclusions on treatment benefit, it is important to clearly understand what treatment effect a trial aims to investigate-this is called the 'estimand'. Using estimands helps to ensure trials are designed and analysed to answer the questions of interest to different stakeholders, including patients and public. However, there is uncertainty about whether patients and public would like to be involved in defining estimands and how to do so. Public partners are patients and/or members of the public who are part of, or advise, the research team. We aimed to (i) co-develop a tool with public partners that helps explain what an estimand is and (ii) explore public partner's perspectives on the importance of discussing estimands during trial design. METHODS: An online consultation meeting was held with 5 public partners of mixed age, gender and ethnicities, from various regions of the UK. Public partner opinions were collected and a practical tool describing estimands, drafted before the meeting by the research team, was developed. Afterwards, the tool was refined, and additional feedback sought via email. RESULTS: Public partners want to be involved in estimand discussions. They found an introductory tool, to be presented and described to them by a researcher, helpful for starting a discussion about estimands in a trial design context. They recommended storytelling, analogies and visual aids within the tool. Four topics related to public partners' involvement in defining estimands were identified: (i) the importance of addressing questions that are relevant to patients and public in trials, (ii) involving public partners early on, (iii) a need for education and communication for all stakeholders and (iv) public partners and researchers working together. CONCLUSIONS: We co-developed a tool for researchers and public partners to use to facilitate the involvement of public partners in estimand discussions.

Predictors of engagement with peer support: analysis of data from a randomised controlled trial of one-to-one peer support for discharge from inpatient psychiatric care.

BACKGROUND: A range of evidence for the effectiveness of one-to-one peer support in mental health services is emerging. Levels of engagement with peer support vary with limited studies showing few individual participant characteristics predicting engagement. Implementation factors that might predict engagement have not been considered. METHODS: Data were analysed from the intervention arm of the ENRICH trial of one-to-one peer support for discharge from acute psychiatric inpatient care. Two outcomes were considered: (1) a measure of 'engaged with peer worker'; (2) number of face-to-face contacts with peer worker post-discharge. Two sets of independent variables were analysed against each outcome: (1) pre-randomisation participant characteristics; (2) implementation factors measured pre-discharge. Analyses used logistic and zero-inflated negative binomial regression models according to outcome structure. RESULTS: Data were analysed for 265 participants randomised to peer support who had a known peer worker. Non-heterosexual participants had increased odds of engaging with peer support compared to heterosexual participants, OR = 4.38 (95% CI: 1.13, 16.9, p = .032). Longer duration of first contact with peer worker (OR = 1.03, 95% CI: 1.00, 1.04, p < .001) and more relationship building activities in the first contact (OR = 1.4, 95% CI: 1.13, 1.85, p = .004) were associated with greater odds of engaging with peer support. Analysis of number of contacts post-discharge showed consistent findings. CONCLUSIONS: Implementation of peer support should include a focus on relationship building in the first session of peer support. The potential for peer support to break down barriers to accessing mental health services experienced by people from marginalised communities warrants further investigation.

Peer support for discharge from inpatient mental health care versus care as usual in England (ENRICH): a parallel, two-group, individually randomised controlled trial.

BACKGROUND: High numbers of patients discharged from psychiatric hospital care are readmitted within a year. Peer support for discharge has been suggested as an approach to reducing readmission post-discharge. Implementation has been called for in policy, however, evidence of effectiveness from large rigorous trials is missing. We aimed to establish whether peer support for discharge reduces readmissions in the year post-discharge. METHODS: We report a parallel, two-group, individually randomised, controlled superiority trial, with trial personnel masked to allocation. Patients were adult psychiatric inpatients (age ≥18 years) with at least one previous admission in the preceding 2 years, excluding those who had a diagnosis of any organic mental disorder, or a primary diagnosis of learning disability, an eating disorder, or drug or alcohol dependency, recruited from seven state-funded mental health services in England. Patients were randomly assigned (1:1) to the intervention (peer support plus care as usual) or control (care as usual) groups by an in-house, online randomisation service, stratified by site and diagnostic group (psychotic disorders, personality disorders, and other eligible non-psychotic disorders) with randomly permuted blocks of randomly varying length to conceal the allocation sequence and achieve the allocation ratio. The peer support group received manual-based, one-to-one peer support, focused on building individual strengths and engaging with activities in the community, beginning during the index admission and continuing for 4 months after discharge, plus care as usual. Care as usual consisted of follow-up by community mental health services within 7 days of discharge. The primary outcome was psychiatric readmission 12 months after discharge (number of patients readmitted at least once), analysed on an intention-to-treat basis. All patients were included in a safety analysis, excluding those who withdrew consent for use of their data. The trial is registered with the ISRCTN registry, ISRCTN10043328. The trial was complete at the time of reporting. FINDINGS: Between Dec 1, 2016, and Feb 8, 2019, 590 patients were recruited and randomly assigned, with 294 allocated to peer support (287 included in the analysis after withdrawals and loss to follow-up), and 296 to care as usual (291 in the analysis). Mean age was 39·7 years (SD 13·7; range 18-75). 306 patients were women, 267 were men, three were transgender, and two preferred not to say. 353 patients were White, 94 were Black, African, Caribbean, or Black British, 68 were Asian or Asian British, 48 were of mixed or multiple ethnic groups, and 13 were of other ethnic groups. In the peer support group, 136 (47%) of 287 patients were readmitted at least once within 12 months of discharge. 146 (50%) of 291 were readmitted in the care as usual group. The adjusted risk ratio of readmission was 0·97 (95% CI 0·82-1·14; p=0·68), and the adjusted odds ratio for readmission was 0·93 (95% CI 0·66-1·30; p=0·68). The unadjusted risk difference was 0·03 (95% CI -0·11 to 0·05; p=0·51) in favour of the peer support group. Serious adverse events were infrequent (67 events) and similar between groups (34 in the peer support group, 33 in the care as usual group). Threat to life (self-harm) was the most common serious adverse event (35 [52%] of 67 serious adverse events). 391 other adverse events were reported, with self-harm (not life threatening) the most common (189 [48%] of 391). INTERPRETATION: One-to-one peer support for discharge from inpatient psychiatric care, plus care as usual, was not superior to care as usual alone in the 12 months after discharge. This definitive, high-quality trial addresses uncertainty in the evidence base and suggests that peer support should not be implemented to reduce readmission post-discharge for patients at risk of readmission. Further research needs to be done to improve engagement with peer support in high-need groups, and to explore differential effects of peer support for people from different ethnic communities. FUNDING: UK National Institute for Health Research.

Perioperative blood transfusion in major abdominal cancer surgery: a multi-centre service evaluation and national survey.

Background: Anaemia is associated with complications and death after surgery. Perioperative red-cell transfusion triggers are not well defined in patients having oncological surgery, or with cardiovascular disease. Methods: We carried out a prospective multicentre cohort study and a clinician survey of UK transfusion practice in adult patients undergoing surgery for abdominal malignancy. The primary outcome was red cell transfusion. Secondary outcomes were transfusion trigger haemoglobin, incidence of complications, length of hospital stay, and acute hospital mortality. Results: In this prospective cohort study, data were collected on 412 patients undergoing surgery for intrabdominal malignancy in 14 NHS hospitals. Twenty-two (5.2%) patients received preoperative, 42 (10.2%) intraoperative, and 52 (12.2%) postoperative red blood cell transfusion. The mean postoperative transfusion trigger was 75.3 g L-1, and the mean number of units of red blood cells transfused was 1.5 (standard deviation, 1.1). Seventeen (4.0%) patients had a documented postoperative troponin elevation. Five (1.2%) patients died within 30 days of surgery. In the survey, 117 clinicians submitted complete responses, of whom 62 (53%) indicated that a transfusion threshold of 70 g L-1 was appropriate: however, this decreased to six (5.1%) if there was evidence of recent cardiac ischaemia. There were 100 (86%) respondents who indicated equipoise for a trial of restrictive vs liberal transfusion, decreasing to 56% if there was coexisting cardiovascular disease. Conclusions: Many patients having oncological surgery receive red cell transfusion, the majority being given postoperatively. Restrictive transfusion practice is generally followed; however, variability exists especially in cardiovascular disease. Equipoise exists for a study of transfusion thresholds in this group.

Identification of myocardial injury using perioperative troponin surveillance in major noncardiac surgery and net benefit over the Revised Cardiac Risk Index.

BACKGROUND: Patients with perioperative myocardial injury are at risk of death and major adverse cardiovascular and cerebrovascular events (MACCE). The primary aim of this study was to determine optimal thresholds of preoperative and perioperative changes in high-sensitivity cardiac troponin T (hs-cTnT) to predict MACCE and mortality. METHODS: Prospective, observational, cohort study in patients ≥50 yr of age undergoing elective major noncardiac surgery at seven hospitals in Sweden. The exposures were hs-cTnT measured before and days 0-3 after surgery. Two previously published thresholds for myocardial injury and two thresholds identified using receiver operating characteristic analyses were evaluated using multivariable logistic regression models and externally validated. The weighted comparison net benefit method was applied to determine the additional value of hs-cTnT thresholds when compared with the Revised Cardiac Risk Index (RCRI). The primary outcome was a composite of 30-day all-cause mortality and MACCE. RESULTS: We included 1291 patients between April 2017 and December 2020. The primary outcome occurred in 124 patients (9.6%). Perioperative increase in hs-cTnT ≥14 ng L-1 above preoperative values provided statistically optimal model performance and was associated with the highest risk for the primary outcome (adjusted odds ratio 2.9, 95% confidence interval 1.8-4.7). Validation in an independent, external cohort confirmed these findings. A net benefit over RCRI was demonstrated across a range of clinical thresholds. CONCLUSIONS: Perioperative increases in hsTnT ≥14 ng L-1 above baseline values identifies acute perioperative myocardial injury and provides a net prognostic benefit when added to RCRI for the identification of patients at high risk of death and MACCE. CLINICAL TRIAL REGISTRATION: NCT03436238.

Contemporary use of antimicrobial prophylaxis for surgical patients: An observational cohort study.

BACKGROUND: Antimicrobial prophylaxis is commonly used to prevent surgical site infection (SSI), despite concerns of overuse leading to antimicrobial resistance. However, it is unclear how often antimicrobials are used and whether guidelines are followed. OBJECTIVES: To describe contemporary clinical practice for antimicrobial prophylaxis including guideline compliance, the rate of postoperative infection and associated side effects. DESIGN: A prospective, multicentre, observational cohort study. SETTING: Twelve United Kingdom National Health Service hospitals. PARTICIPANTS: One thousand one hundred and sixteen patients, aged at least 18 years undergoing specific colo-rectal, obstetric, gynaecological, urological or orthopaedic surgical procedures. EXPOSURE: Compliance with guidelines for antimicrobial prophylaxis. OUTCOMES: The primary outcome was SSI within 30 days after surgery. Secondary outcomes were number of doses of antimicrobials for prophylaxis and to treat infection, incidence of antimicrobial-related side effects and mortality within 30 days after surgery. Data are presented as number with percentage (%) or median with interquartile range [IQR].Results of logistic regression analyses are presented as odds ratio/rate ratio (OR/RR) with 95% confidence intervals (95% CIs). RESULTS: 1102 out of 1106 (99.6%) patients received antimicrobial prophylaxis, which was compliant with local guidelines in 929 out of 1102 (84.3%) cases. 2169 out of 51 28 (42.3%) doses of antimicrobials were administered as prophylaxis (median 1 [1 to 2] dose) and 2959 out of 5128 (57.7%) were administered to treat an infection (median 21 [11 to 28] doses). 56 patients (5.2%) developed SSI. Antimicrobial prophylaxis administered according to local guidelines was not associated with a lower incidence of SSI compared with administration outside guidelines [OR 0.90 (0.35 to 2.29); P  = 0.823]. 23 out of 1072 (2.2%) patients experienced a side effect of antimicrobial therapy. 7 out of 1082 (0.6%) patients died. The median hospital stay was 3 [1 to 5] days. CONCLUSION: Antimicrobial prophylaxis was administered for almost all the surgical procedures under investigation. However, this was not always compliant with guidelines. Further research is required to determine whether the amount of prophylactic antimicrobials could be safely and effectively reduced without increasing the incidence of SSI.

Postoperative infection and mortality following elective surgery in the International Surgical Outcomes Study (ISOS).

BACKGROUND: Postoperative infection is one of the most frequent and important complications after surgery. The epidemiology of infection following elective surgery remains poorly described. METHODS: This was a prospective analysis of the International Surgical Outcomes Study (ISOS) describing infection by 30 days after elective surgery. Associations between postoperative infection (primary outcome) and baseline demographic, surgical, and anaesthetic risk factors were assessed. Analyses were carried out using logistic and linear regression models. Secondary outcomes were 30-day mortality and duration of hospital stay. Treatments received by patients after different types of infection were evaluated. RESULTS: Some 44 814 patients were included in the analysis, with a total of 4032 infections occurring in 2927 patients (6.5 per cent). Overall, 206 patients died, of whom 99 of 2927 (3.4 per cent) had infection. Some 737 of 4032 infections (18.3 per cent) were severe; the most frequent types were superficial surgical-site infection (1320, 32.7 per cent), pneumonia (708, 17.6 per cent), and urinary tract infection (681, 16.9 per cent). Excluding missing data, antimicrobials were used in 2126 of 2749 infections (77.3 per cent), and 522 of 2164 patients (24.1 per cent) required admission to critical care. Factors associated with an increased incidence of infection in adjusted analyses were: age, male sex, ASA grade, co-morbid disease, preoperative anaemia, anaesthetic technique, surgical category, surgical severity, and cancer surgery. Infection significantly increased the risk of death (odds ratio 4.68, 95 per cent c.i. 3.39 to 6.47; P < 0.001), and duration of hospital stay by on average 6.45 (6.23 to 6.66) days (P < 0.001). CONCLUSION: Infection is a common complication after elective surgery. Recognition of modifiable risk factors will help inform appropriate prevention strategies.

Prospective observational study of postoperative infection and outcomes after noncardiac surgery: analysis of prospective data from the VISION cohort.

BACKGROUND: Infection is a frequent cause of postoperative morbidity and mortality. The incidence, risk factors, and outcomes for postoperative infections remain poorly characterised. METHODS: This is a secondary analysis of a prospective international cohort study of patients aged ≥45 yr who had noncardiac surgery (VISION), including data describing infection within 30 days after surgery. The primary outcome was postoperative infection. The secondary outcome was 30 day mortality. We used univariable and multivariable logistic regression to identify baseline risk factors for infection. Results are presented as n (%) or odds ratio (OR) with 95% confidence intervals. Some denominators vary according to rates of missing data. RESULTS: Among 39 996 surgical patients, 3905 (9.8%) experienced 5152 postoperative infections and 715 (1.8%) died. The most frequent infection was surgical site infection (1555/3905 [39.8%]). Infection was most strongly associated with general surgery (OR: 3.74 [3.11-4.49]; P<0.01) and open surgical technique (OR: 2.03 [1.82-2.27]; P<0.01); 30 day mortality was greater amongst patients who experienced infection (262/3905 [6.7%] vs 453/36 091 patients who did not [1.3%]; OR: 3.47 [2.84-4.22]; P<0.01). Mortality was highest amongst patients with CNS infections (OR: 14.72 [4.41-49.12]; P<0.01). CONCLUSIONS: Infection is a common and important complication of noncardiac surgery, which is associated with high mortality. Further research is needed to identify more effective measures to prevent infections after surgery.