Lucy Culliford

Increased Mortality, Postoperative Morbidity, and Cost After Red Blood Cell Transfusion in Patients Having Cardiac Surgery

Background— Red blood cell transfusion can both benefit and harm. To inform decisions about transfusion, we aimed to quantify associations of transfusion with clinical outcomes and cost in patients having cardiac surgery. Methods and Results— Clinical, hematology, and blood transfusion databases were linked with the UK population register. Additional hematocrit information was obtained from intensive care unit charts. Composite infection (respiratory or wound infection or septicemia) and ischemic outcomes (myocardial infarction, stroke, renal impairment, or failure) were prespecified as coprimary end points. Secondary outcomes were resource use, cost, and survival. Associations were estimated by regression modeling with adjustment for potential confounding. All adult patients having cardiac surgery between April 1, 1996, and December 31, 2003, with key exposure and outcome data were included (98%). Adjusted odds ratios for composite infection (737 of 8516) and ischemic outcomes (832 of 8518) for transfused versus nontransfused patients were 3.38 (95% confidence interval [CI], 2.60 to 4.40) and 3.35 (95% CI, 2.68 to 4.35), respectively. Transfusion was associated with increased relative cost of admission (any transfusion, 1.42 times [95% CI, 1.37 to 1.46], varying from 1.11 for 1 U to 3.35 for >9 U). At any time after their operations, transfused patients were less likely to have been discharged from hospital (hazard ratio [HR], 0.63; 95% CI, 0.60 to 0.67) and were more likely to have died (0 to 30 days: HR, 6.69; 95% CI, 3.66 to 15.1; 31 days to 1 year: HR, 2.59; 95% CI, 1.68 to 4.17; >1 year: HR, 1.32; 95% CI, 1.08 to 1.64). Conclusions— Red blood cell transfusion in patients having cardiac surgery is strongly associated with both infection and ischemic postoperative morbidity, hospital stay, increased early and late mortality, and hospital costs.

Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial

BACKGROUND Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. METHODS In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. FINDINGS Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80-3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27-1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22-1·03; p=0·05), but did not differ by drug group (0·96, 0·46-2·02; p=0·91). INTERPRETATION Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought. FUNDING UK National Institute for Health Research Health Technology Assessment programme.

Effects of on- and off-pump coronary artery surgery on graft patency, survival, and health-related quality of life: long-term follow-up of 2 randomized controlled trials.

OBJECTIVE Off-pump coronary artery bypass grafting reduces postoperative morbidity and uses fewer resources than conventional surgical intervention with cardiopulmonary bypass. However, only 15% to 20% of coronary artery bypass grafting operations use off-pump coronary artery bypass. One reason for not using off-pump coronary artery bypass might be the surgeons concern about the long-term patency of grafts performed with this technique. Therefore our objective was to compare long-term outcomes in patients randomized to off-pump coronary artery bypass or coronary artery bypass grafting with cardiopulmonary bypass. METHODS Participants in 2 randomized trials comparing off-pump coronary artery bypass and coronary artery bypass grafting with cardiopulmonary bypass were followed up for 6 to 8 years after surgical intervention to assess graft patency, major adverse cardiac-related events, and health-related quality of life. Patency was assessed by using multidetector computed tomographic coronary angiographic analysis with a 16-slice scanner. Two blinded observers classified proximal, body, and distal segments of each graft as occluded or not. Major adverse cardiac-related events and health-related quality of life were obtained from questionnaires given to participants and family practitioners. RESULTS Patency was studied in 199 and health-related quality of life was studied in 299 of 349 survivors. There was no evidence of attrition bias. The likelihood of graft occlusion was no different between off-pump coronary artery bypass (10.6%) and coronary artery bypass grafting with cardiopulmonary bypass (11.0%) groups (odds ratio, 1.00; 95% confidence interval, 0.55-1.81; P > .99). Graft occlusion was more likely at the distal than the proximal anastomosis (odds ratio, 1.11; 95% confidence interval, 1.02-1.20). There were also no differences between the off-pump coronary artery bypass and coronary artery bypass grafting with cardiopulmonary bypass groups in the hazard of death (hazard ratio, 1.24; 95% confidence interval, 0.72-2.15) or major adverse cardiac-related events or death (hazard ratio, 0.84; 95% confidence interval, 0.58-1.24), or mean health-related quality of life across a range of domains and instruments. CONCLUSIONS Long-term health outcomes with off-pump coronary artery bypass are similar to those with coronary artery bypass grafting with cardiopulmonary bypass when both operations are performed by experienced surgeons.

What do patients really want? Patients' preferences for treatment for angina.

Objective  To measure preferences for angina treatments among patients admitted from accident and emergency with acute coronary syndrome.

The Effect of Patient-Specific Cerebral Oxygenation Monitoring on Postoperative Cognitive Function: A Multicenter Randomized Controlled Trial

Background Indices of global tissue oxygen delivery and utilization such as mixed venous oxygen saturation, serum lactate concentration, and arterial hematocrit are commonly used to determine the adequacy of tissue oxygenation during cardiopulmonary bypass (CPB). However, these global measures may not accurately reflect regional tissue oxygenation and ischemic organ injury remains a common and serious complication of CPB. Near-infrared spectroscopy (NIRS) is a noninvasive technology that measures regional tissue oxygenation. NIRS may be used alongside global measures to optimize regional perfusion and reduce organ injury. It may also be used as an indicator of the need for red blood cell transfusion in the presence of anemia and tissue hypoxia. However, the clinical benefits of using NIRS remain unclear and there is a lack of high-quality evidence demonstrating its efficacy and cost effectiveness. Objective The aim of the patient-specific cerebral oxygenation monitoring as part of an algorithm to reduce transfusion during heart valve surgery (PASPORT) trial is to determine whether the addition of NIRS to CPB management algorithms can prevent cognitive decline, postoperative organ injury, unnecessary transfusion, and reduce health care costs. Methods Adults aged 16 years or older undergoing valve or combined coronary artery bypass graft and valve surgery at one of three UK cardiac centers (Bristol, Hull, or Leicester) are randomly allocated in a 1:1 ratio to either a standard algorithm for optimizing tissue oxygenation during CPB that includes a fixed transfusion threshold, or a patient-specific algorithm that incorporates cerebral NIRS monitoring and a restrictive red blood cell transfusion threshold. Allocation concealment, Internet-based randomization stratified by operation type and recruiting center, and blinding of patients, ICU and ward care staff, and outcome assessors reduce the risk of bias. The primary outcomes are cognitive function 3 months after surgery and infectious complications during the first 3 months after surgery. Secondary outcomes include measures of inflammation, organ injury, and volumes of blood transfused. The cost effectiveness of the NIRS-based algorithm is described in terms of a cost-effectiveness acceptability curve. The trial tests the superiority of the patient-specific algorithm versus standard care. A sample size of 200 patients was chosen to detect a small to moderate target difference with 80% power and 5% significance (two tailed). Results Over 4 years, 208 patients have been successfully randomized and have been followed up for a 3-month period. Results are to be reported in 2015. Conclusions This study provides high-quality evidence, both valid and widely applicable, to determine whether the use of NIRS monitoring as part of a patient-specific management algorithm improves clinical outcomes and is cost effective. Trial Registration International Standard Randomized Controlled Trial Number (ISRCTN): 23557269; http://www.isrctn.com/ISRCTN23557269 (Archived by Webcite at http://www.webcitation.org/6buyrbj64)

Normothermic Versus Hypothermic Cardiopulmonary Bypass in Children Undergoing Open Heart Surgery (Thermic-2): Study Protocol for a Randomized Controlled Trial

Background During open heart surgery, patients are connected to a heart-lung bypass machine that pumps blood around the body (“perfusion”) while the heart is stopped. Typically the blood is cooled during this procedure (“hypothermia”) and warmed to normal body temperature once the operation has been completed. The main rationale for “whole body cooling” is to protect organs such as the brain, kidneys, lungs, and heart from injury during bypass by reducing the body’s metabolic rate and decreasing oxygen consumption. However, hypothermic perfusion also has disadvantages that can contribute toward an extended postoperative hospital stay. Research in adults and small randomized controlled trials in children suggest some benefits to keeping the blood at normal body temperature throughout surgery (“normothermia”). However, the two techniques have not been extensively compared in children. Objective The Thermic-2 study will test the hypothesis that the whole body inflammatory response to the nonphysiological bypass and its detrimental effects on different organ functions may be attenuated by maintaining the body at 35°C-37°C (normothermic) rather than 28°C (hypothermic) during pediatric complex open heart surgery. Methods This is a single-center, randomized controlled trial comparing the effectiveness and acceptability of normothermic versus hypothermic bypass in 141 children with congenital heart disease undergoing open heart surgery. Children having scheduled surgery to repair a heart defect not requiring deep hypothermic circulatory arrest represent the target study population. The co-primary clinical outcomes are duration of inotropic support, intubation time, and postoperative hospital stay. Secondary outcomes are in-hospital mortality and morbidity, blood loss and transfusion requirements, pre- and post-operative echocardiographic findings, routine blood gas and blood test results, renal function, cerebral function, regional oxygen saturation of blood in the cerebral cortex, assessment of genomic expression changes in cardiac tissue biopsies, and neuropsychological development. Results A total of 141 patients have been successfully randomized over 2 years and 10 months and are now being followed-up for 1 year. Results will be published in 2015. Conclusions We believe this to be the first large pragmatic study comparing clinical outcomes during normothermic versus hypothermic bypass in complex open heart surgery in children. It is expected that this work will provide important information to improve strategies of cardiopulmonary bypass perfusion and therefore decrease the inevitable organ damage that occurs during nonphysiological body perfusion. Trial Registration ISRCTN Registry: ISRCTN93129502, http://www.isrctn.com/ISRCTN93129502 (Archived by WebCitation at http://www.webcitation.org/6Yf5VSyyG).

Investigating the effect of remote ischaemic preconditioning on biomarkers of stress and injury-related signalling in patients having isolated coronary artery bypass grafting or aortic valve replacement using cardiopulmonary bypass: study protocol for a randomized controlled trial

BackgroundIschaemia-reperfusion injury occurs during heart surgery that uses cardiopulmonary bypass (CPB) and cardioplegic arrest. It is hypothesised that remote ischaemic preconditioning (RIPC) protects the heart against such injury. Despite the numerous studies investigating the protective effects of RIPC, there is still uncertainty about the interpretation of the findings as well as conflicting results between studies. The objective of this trial is to investigate the cardioprotective effect of RIPC in patients having coronary artery bypass grafting (CABG) or aortic valve replacement surgery. This will be achieved by estimating the effect of the intervention in the two groups of pathologies and by investigating the signalling mechanisms that may underpin the cardioprotective effect.Methods/DesignA two-centre randomised controlled trial will be used to investigate the effects of RIPC in two pathologies: patients having isolated CABG and those having aortic valve replacement surgery (AVR) with CPB. Participants will be randomised to RIPC or control (sham RIPC), stratified by surgical stratum. The intervention will be delivered by a research nurse. Data will be collected by a research nurse blinded to the intervention. The patient and the theatre staff are also blinded to the allocation. Markers of myocardial injury and inflammation will be measured in myocardial biopsies and in blood samples at different times.DiscussionThis trial is designed to investigate whether RIPC will reduce myocardial injury and inflammation following heart surgery and whether there is a difference in effect between participants having CABG or AVR. This trial is a unique opportunity to study the mechanisms associated with RIPC using human myocardial tissue and blood, and to relate these to the extent of myocardial injury/protection.Trial registrationCurrent Controlled Trials ISRCTN33084113 (25 March 2013).

Mechanical heart valves in septuagenarians

Abstract  Aim: To report on the use of a third‐generation bileaflet mechanical valve in septuagenarians, selected to receive a mechanical valve, as compared to (a) a younger cohort undergoing same valve implant (study 1) and to (b) a matched group of septuagenarians undergoing biological implant (study 2). Methods: The study was carried out in a tertiary regional hospital in South‐West England. Study 1: Consecutive series of 567 patients undergoing Sorin Bileaflet (SB) mechanical valve implant (437 patients < 70 years; 130 patients ≥ 70 years). Study 2: 113 septuagenarians undergoing biological implant matched on age, valve type, concomitant coronary surgery, and operative priority to the SB septuagenarian group. Main outcome measures included in‐hospital mortality and morbidity and mid‐term valve‐related outcome. Results: Study 1: Septuagenarians were more likely to present with coronary disease, and to undergo coronary surgery (p < 0.01). In‐hospital mortality was 2.8% and 2.3% (p = 0.79) and neurological complications 1.4% versus 3.8% (p = 0.026) in the younger and older groups, respectively. Valve‐related mortality at two years was 1.8% (95%CI, 0.8% to 3.6%) and 4.8% (95% CI, 2.0% to 9.7%); cumulative three‐ year incidence of thromboembolic or major hemorrhagic event was 8.3% (95% CI, 5.7% to 12.0%) and 4.6% (95% CI, 1.7% to 12.4%) in the younger and older groups, respectively. Study 2: In‐hospital mortality was 1.8% and 7.1% in the SB and biological groups, respectively (ratio 0.25; 95% CI, 0.05 to 1.18, p = 0.058). The incidence of acute renal failure was greater in the biological group (risk ratio 0.30; 95% CI, 0.09 to 0.98, p = 0.035). There was no difference in mid‐term valve‐related mortality between groups (hazard ratio 0.53; 95% CI, 0.18 to 1.52, p = 0.24). Conclusion: The performance of SB valve in septuagenarians seems to be effective with no increased risk of in‐hospital mortality, bleeding, or thromboembolic events.

Pre-admission interventions to improve outcome after elective surgery—protocol for a systematic review

BackgroundPoor physical health and fitness increases the risk of death and complications after major elective surgery. Pre-admission interventions to improve patients’ health and fitness (referred to as prehabilitation) may reduce postoperative complications, decrease the length of hospital stay and facilitate the patient’s recovery. We will conduct a systematic review of RCTs to examine the effectiveness of different types of prehabilitation interventions in improving the surgical outcomes of patients undergoing elective surgery.MethodsThis review will be conducted and reported according to the Cochrane and PRISMA reporting guidelines. MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO, ISI Web of Science and clinical trial registers will be searched for any intervention administered before any elective surgery (including physical activity, nutritional, educational, psychological, clinical or multicomponent), which aims to improve postoperative outcomes. Reference lists of included studies will be searched, and grey literature including conference proceedings, theses, dissertations and preoperative assessment protocols will be examined. Study quality will be assessed using Cochrane’s risk of bias tool, and meta-analyses for trials that use similar interventions and report similar outcomes will be undertaken where possible.DiscussionThis systematic review will determine whether different types of interventions administered before elective surgery are effective in improving postoperative outcomes. It will also determine which components or combinations of components would form the most effective prehabilitation intervention.Systematic review registrationPROSPERO CRD42015019191

Development of a standardised set of metrics for monitoring site performance in multicentre randomised trials: a Delphi study

BackgroundSite performance is key to the success of large multicentre randomised trials. A standardised set of clear and accessible summaries of site performance could facilitate the timely identification and resolution of potential problems, minimising their impact.The aim of this study was to identify and agree a core set of key performance metrics for managing multicentre randomised trials.MethodsWe used a mixed methods approach to identify potential metrics and to achieve consensus about the final set, adapting methods that are recommended by the COMET Initiative for developing core outcome sets in health care.We used performance metrics identified from our systematic search and focus groups to create an online Delphi survey. We invited respondents to score each metric for inclusion in the final core set, over three survey rounds. Metrics scored as critical by ≥70% and unimportant by <15% of respondents were taken forward to a consensus meeting of representatives from key UK-based stakeholders. Participants in the consensus meeting discussed and voted on each metric, using anonymous electronic voting. Metrics with >50% of participants voting for inclusion were retained.ResultsRound 1 of the Delphi survey presented 28 performance metrics, and a further six were added in round 2. Of 294 UK-based stakeholders who registered for the Delphi survey, 211 completed all three rounds.At the consensus meeting, 17 metrics were discussed and voted on: 15 metrics were retained following survey round 3, plus two others that were preferred by consensus meeting participants. Consensus was reached on a final core set of eight performance metrics in three domains: (1) recruitment and retention, (2) data quality and (3) protocol compliance. A simple tool for visual reporting of the metrics is available from the Nottingham Clinical Trials Unit website.ConclusionsWe have established a core set of metrics for measuring the performance of sites in multicentre randomised trials. These metrics could improve trial conduct by enabling researchers to identify and address problems before trials are adversely affected. Future work could evaluate the effectiveness of using the metrics and reporting tool.