Warm versus cold blood cardioplegia in paediatric congenital heart surgery: a randomized trial.

OBJECTIVES: Intermittent cold blood cardioplegia is commonly used in children, whereas intermittent warm blood cardioplegia is widely used in adults. We aimed to compare clinical and biochemical outcomes with these 2 methods. METHODS: A single-centre, randomized controlled trial was conducted to compare the effectiveness of warm (≥34°C) versus cold (4-6°C) antegrade cardioplegia in children. The primary outcome was cardiac troponin T over the 1st 48 postoperative hours. Intensive care teams were blinded to group allocation. Outcomes were compared by intention-to-treat using linear mixed-effects, logistic or Cox regression. RESULTS: 97 participants with median age of 1.2 years were randomized (49 to warm, 48 to cold cardioplegia); 59 participants (61%) had a risk-adjusted congenital heart surgery score of 3 or above. There were no deaths and 92 participants were followed to 3-months. Troponin release was similar in both groups [geometric mean ratio 1.07; 95% confidence interval (CI) 0.79-1.44; P = 0.66], as were other cardiac function measures (echocardiography, arterial and venous blood gases, vasoactive-inotrope score, arrhythmias). Intensive care stay was on average 14.6 h longer in the warm group (hazard ratio 0.52; 95% CI 0.34-0.79; P = 0.003), with a trend towards longer overall hospital stays (hazard ratio 0.66; 95% CI 0.43-1.02; P = 0.060) compared with the cold group. This could be related to more unplanned reoperations on bypass in the warm group compared to cold group (3 vs 1). CONCLUSIONS: Warm blood cardioplegia is a safe and reproducible technique but does not provide superior myocardial protection in paediatric heart surgery.

Impact of video-assisted thoracoscopic lobectomy versus open lobectomy for lung cancer on recovery assessed using self-reported physical function: VIOLET RCT.

BACKGROUND: Lung cancer is the leading cause of cancer death. Surgery remains the main method of managing early-stage disease. Minimal-access video-assisted thoracoscopic surgery results in less tissue trauma than open surgery; however, it is not known if it improves patient outcomes. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of video-assisted thoracoscopic surgery lobectomy with open surgery for the treatment of lung cancer. DESIGN, SETTING AND PARTICIPANTS: A multicentre, superiority, parallel-group, randomised controlled trial with blinding of participants (until hospital discharge) and outcome assessors conducted in nine NHS hospitals. Adults referred for lung resection for known or suspected lung cancer, with disease suitable for both surgeries, were eligible. Participants were followed up for 1 year. INTERVENTIONS: Participants were randomised 1 : 1 to video-assisted thoracoscopic surgery lobectomy or open surgery. Video-assisted thoracoscopic surgery used one to four keyhole incisions without rib spreading. Open surgery used a single incision with rib spreading, with or without rib resection. MAIN OUTCOME MEASURES: The primary outcome was self-reported physical function (using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) at 5 weeks. Secondary outcomes included upstaging to pathologic node stage 2 disease, time from surgery to hospital discharge, pain in the first 2 days, prolonged pain requiring analgesia at > 5 weeks, adverse health events, uptake of adjuvant treatment, overall and disease-free survival, quality of life (Quality of Life Questionnaire Core 30, Quality of Life Questionnaire Lung Cancer 13 and EQ-5D) at 2 and 5 weeks and 3, 6 and 12 months, and cost-effectiveness. RESULTS: A total of 503 patients were randomised between July 2015 and February 2019 (video-assisted thoracoscopic surgery, n = 247; open surgery, n = 256). One participant withdrew before surgery. The mean age of patients was 69 years; 249 (49.5%) patients were men and 242 (48.1%) did not have a confirmed diagnosis. Lobectomy was performed in 453 of 502 (90.2%) participants and complete resection was achieved in 429 of 439 (97.7%) participants. Quality of Life Questionnaire Core 30 physical function was better in the video-assisted thoracoscopic surgery group than in the open-surgery group at 5 weeks (video-assisted thoracoscopic surgery, n = 247; open surgery, n = 255; mean difference 4.65, 95% confidence interval 1.69 to 7.61; p = 0.0089). Upstaging from clinical node stage 0 to pathologic node stage 1 and from clinical node stage 0 or 1 to pathologic node stage 2 was similar (p ≥ 0.50). Pain scores were similar on day 1, but lower in the video-assisted thoracoscopic surgery group on day 2 (mean difference -0.54, 95% confidence interval -0.99 to -0.09; p = 0.018). Analgesic consumption was 10% lower (95% CI -20% to 1%) and the median hospital stay was less (4 vs. 5 days, hazard ratio 1.34, 95% confidence interval 1.09, 1.65; p = 0.006) in the video-assisted thoracoscopic surgery group than in the open-surgery group. Prolonged pain was also less (relative risk 0.82, 95% confidence interval 0.72 to 0.94; p = 0.003). Time to uptake of adjuvant treatment, overall survival and progression-free survival were similar (p ≥ 0.28). Fewer participants in the video-assisted thoracoscopic surgery group than in the open-surgery group experienced complications before and after discharge from hospital (relative risk 0.74, 95% confidence interval 0.66 to 0.84; p < 0.001 and relative risk 0.81, 95% confidence interval 0.66 to 1.00; p = 0.053, respectively). Quality of life to 1 year was better across several domains in the video-assisted thoracoscopic surgery group than in the open-surgery group. The probability that video-assisted thoracoscopic surgery is cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year is 1. LIMITATIONS: Ethnic minorities were under-represented compared with the UK population (< 5%), but the cohort reflected the lung cancer population. CONCLUSIONS: Video-assisted thoracoscopic surgery lobectomy was associated with less pain, fewer complications and better quality of life without any compromise to oncologic outcome. Use of video-assisted thoracoscopic surgery is highly likely to be cost-effective for the NHS. FUTURE WORK: Evaluation of the efficacy of video-assisted thoracoscopic surgery with robotic assistance, which is being offered in many hospitals. TRIAL REGISTRATION: This trial is registered as ISRCTN13472721. 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. 26, No. 48. See the NIHR Journals Library website for further project information.

BACKGROUND: Lung cancer is a common cause of cancer death worldwide. If the disease is caught early, the part of the lung containing the tumour can be removed in an operation called a lobectomy. The operation can be carried out through a large cut so that the surgeon has a full view of the lung, which is called open surgery, or using several small cuts and a camera, which is called video-assisted thoracoscopic (keyhole) surgery. It is thought that, as keyhole surgery is less invasive, patients recover quicker. However, to the best of our knowledge, there are no high-quality research studies that are applicable to UK practice to support this. This study was conducted so that it could be determined, based on high-quality evidence, which operation provides the best treatment and recovery for patients. WHO PARTICIPATED?: Five hundred and three adults referred for lobectomy for known or suspected lung cancer from nine hospitals in the UK. WHAT WAS INVOLVED?: Participants were randomly allocated to either receive keyhole or open surgery. Participants were followed up for 12 months. We collected information on further treatment, hospital visits, safety information and disease progression over this period. Participants were also asked to complete questionnaires about their health and recovery. WHAT DID THE TRIAL FIND?: For patients with early-stage lung cancer who underwent a lobectomy, keyhole surgery led to less pain, less time in hospital and better quality of life than open surgery, without having a detrimental effect on cancer progression or survival. Keyhole surgery was found to be cost-effective and to provide excellent value for money for the NHS.

Video-Assisted Thoracoscopic or Open Lobectomy in Early-Stage Lung Cancer.

BACKGROUND: There is limited randomized evidence on the comparative outcomes of early-stage lung cancer resection by video-assisted thoracoscopic surgery (VATS) versus open resection. METHODS: We conducted a parallel-group multicenter randomized trial that recruited participants with known or suspected early-stage lung cancer and randomly assigned them to open or VATS resection of their lesions. The primary outcome was physical function at 5 weeks as a measure of recovery using the European Organisation for Research and Treatment of Cancer core health-related quality of life questionnaire (QLQ-C30) (scores range from 0 to 100, with higher scores indicating better function; the clinical minimally important difference for improvement is 5 points). We followed the patients for an additional 47 weeks for other outcomes. RESULTS: A total of 503 participants were randomly assigned (247 to VATS and 256 to open lobectomy). At 5 weeks, median physical function was 73 in the VATS group and 67 in the open surgery group, with a mean difference of 4.65 points (95% confidence interval, 1.69 to 7.61). Of the participants allocated to VATS, 30.7% had serious adverse events after discharge compared with 37.8% of those allocated to open surgery (risk ratio, 0.81 [95% confidence interval, 0.66 to 1.00]). At 52 weeks, there were no differences in cancer progression-free survival (hazard ratio, 0.74 [0.43 to 1.27]) or overall survival (hazard ratio, 0.67 [0.32 to 1.40]). CONCLUSIONS: VATS lobectomy for lung cancer is associated with a better recovery of physical function in the 5 weeks after random assignment compared with open surgery. Long-term oncologic outcomes will require continued follow-up to assess. (Funded by the National Institute for Health Research Health Technology Assessment programme [reference number 13/04/03]; ISRCTN number, ISRCTN13472721.)

Self-regulation in Barth syndrome: a qualitative perspective of adolescents, adults and parents in the U.K.

BACKGROUND: Barth syndrome (BS) is a life-threatening genetic disease caused by abnormal lipids in the mitochondria of cells and mostly affects young males. Those living with BS have severe exercise intolerance, lethargy and fatigue due to muscle disease which affect their daily life. Previous research suggests a need for qualitative exploration of self-regulation in BS and the inter-personal processes at play in family life. Therefore this study aimed to explore self-regulation and coping strategies and inter-personal responses in individuals and families affected by Barth syndrome. A multi-perspective qualitative study based on face to face, semi-structured, in-depth interviews with 11 participants (9-27 years, mean 15 years) with BS and/or their parents participating in a randomised double-blind clinical drug trial (CARDIOMAN). Interviews were transcribed verbatim and managed in NVivo prior to conducting a thematic analysis (AS and GH). RESULTS: Four key themes were identified: diagnosis and treatment, social support, identity and social integration, symptoms and self-regulation. The present findings suggest that self-regulation and coping in boys with BS was interpersonal and contingent on parental awareness such that parents were aware that their child had a limited energy reserve and that had to be managed due to the implications of fatigue for daily living. CONCLUSION: The findings support previous quantitative work demonstrating that children and parents tend to share a coherent view of BS. However, there is a need for greater awareness from others within the wider context of social and employment networks to minimise adverse implications for future life choices.

Treatment of Barth Syndrome by Cardiolipin Manipulation (CARDIOMAN) With Bezafibrate: Protocol for a Randomized Placebo-Controlled Pilot Trial Conducted in the Nationally Commissioned Barth Syndrome Service.

BACKGROUND: Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. OBJECTIVE: The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. METHODS: The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. RESULTS: A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. CONCLUSIONS: This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/22533.

Is there a renoprotective value to leukodepletion during heart valve surgery? A randomized controlled trial (ROLO).

BACKGROUND: Acute Kidney Injury (AKI) adversely affects outcomes after cardiac surgery. A major mediator of AKI is the activation of leukocytes through exposure to the cardiopulmonary bypass circuit. We evaluate the use of leukodepletion filters throughout bypass to protect against post-operative AKI by removing activated leukocytes during cardiac surgery. METHODS: This is a single-centre, double-blind, randomized controlled trial comparing the use of leukodepletion versus a standard arterial filter throughout bypass. Elective adult patients undergoing heart valve surgery with or without concomitant procedures were investigated. The primary clinical outcome measured was the development of AKI according to the KDIGO criteria. Secondary measures included biomarkers of renal tubular damage (urinary Retinol Binding Protein and Kidney Injury Molecule-1), glomerular kidney injury (urinary Micro Albumin and serum Cystatin C) and urinary Neutrophil Gelatinase Associated Lipocalin, as well as the length of hospital stay and quality of life measures through EQ-5D-5L questionnaires. RESULTS: The ROLO trial randomized 64 participants with a rate of recruitment higher than anticipated (57% achieved, 40% anticipated). The incidence of AKI was greater in the leukodepletion filter group (44% versus 23%, risk difference 21, 95% CI - 2 to 44%). This clinical finding was supported by biomarker levels especially by a tendency toward glomerular insult at 48 h, demonstrated by a raised serum Cystatin C (mean difference 0.11, 95% CI 0.00 to 0.23, p = 0.068) in the leukodepleted group. There was however no clear association between the incidence or severity of AKI and length of hospital stay. On average, health related quality of life returned to pre-operative levels in both groups within 3 months of surgery. CONCLUSIONS: Leukocyte depletion during cardiopulmonary bypass does not significantly reduce the incidence of AKI after valvular heart surgery. Other methods to ameliorate renal dysfunction after cardiac surgery need to be investigated. TRIAL REGISTRATION: The trial was registered by the International Standard Randomized Controlled Trial Number Registry ISRCTN42121335 . Registered on the 18 February 2014. The trial was run by the Bristol Clinical Trials and Evaluation Unit. This trial was financially supported by the National Institute of Health Research (Research for Patient Benefit), award ID: PB-PG-0711-25,090.

A randomized controlled trial comparing controlled reoxygenation and standard cardiopulmonary bypass in paediatric cardiac surgery.

OBJECTIVES: Controlled reoxygenation on starting cardiopulmonary bypass (CPB) rather than hyperoxic CPB may confer clinical advantages during surgery for congenital cyanotic heart disease. METHODS: A single-centre, randomized controlled trial was carried out to compare the effectiveness of controlled reoxygenation (normoxia) versus hyperoxic CPB in children with congenital cyanotic heart disease undergoing open-heart surgery (Oxic-2). The co-primary clinical outcomes were duration of inotropic support, intubation time and postoperative intensive care unit (ICU) and hospital stay. Analysis of the primary outcomes included data from a previous trial (Oxic-1) conducted to the same protocol. RESULTS: Ninety participants were recruited to Oxic-2 and 79 were recruited to the previous Oxic-1 trial. There were no significant differences between the groups for any of the co-primary outcomes: inotrope duration geometric mean ratio (normoxia/hyperoxic) 0.97, 95% confidence interval (CI) (0.69-1.37), P-value = 0.87; intubation time hazard ratio (HR) 1.03, 95% CI (0.74-1.42), P-value = 0.87; postoperative ICU stay HR 1.14 95% CI (0.77-1.67), P-value = 0.52, hospital stay HR 0.90, 95% CI (0.65-1.25), P-value = 0.53. Lower oxygen levels were successfully achieved during the operative period in the normoxic group. Serum creatinine levels were lower in the normoxic group at day 2, but not on days 1, 3-5. Childhood developmental outcomes were similar. In the year following surgery, 85 serious adverse events were reported (51 normoxic group and 34 hyperoxic group). CONCLUSIONS: Controlled reoxygenation (normoxic) CPB is safe but with no evidence of a clinical advantage over hyperoxic CPB. CLINICAL TRIAL REGISTRATION NUMBER: Current Controlled Trials-ISRCTN81773762.

Study protocol for VIdeo assisted thoracoscopic lobectomy versus conventional Open LobEcTomy for lung cancer, a UK multicentre randomised controlled trial with an internal pilot (the VIOLET study).

INTRODUCTION: Lung cancer is a leading cause of cancer deaths worldwide and surgery remains the main treatment for early stage disease. Prior to the introduction of video-assisted thoracoscopic surgery (VATS), lung resection for cancer was undertaken through an open thoracotomy. To date, the evidence base supporting the different surgical approaches is based on non-randomised studies, small randomised trials and is focused mainly on short-term in-hospital outcomes. METHODS AND ANALYSIS: The VIdeo assisted thoracoscopic lobectomy versus conventional Open LobEcTomy for lung cancer study is a UK multicentre parallel group randomised controlled trial (RCT) with blinding of outcome assessors and participants (to hospital discharge) comparing the effectiveness, cost-effectiveness and acceptability of VATS lobectomy versus open lobectomy for treatment of lung cancer. We will test the hypothesis that VATS lobectomy is superior to open lobectomy with respect to self-reported physical function 5 weeks after randomisation (approximately 1 month after surgery). Secondary outcomes include assessment of efficacy (hospital stay, pain, proportion and time to uptake of chemotherapy), measures of safety (adverse health events), oncological outcomes (proportion of patients upstaged to pathologic N2 (pN2) disease and disease-free survival), overall survival and health related quality of life to 1 year. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment. ETHICS AND DISSEMINATION: This trial has been approved by the UK (Dulwich) National Research Ethics Service Committee London. Findings will be written-up as methodology papers for conference presentation, and publication in peer-reviewed journals. Many aspects of the feasibility work will inform surgical RCTs in general and these will be reported at methodology meetings. We will also link with lung cancer clinical studies groups. The patient and public involvement group that works with the Respiratory Biomedical Research Unit at the Brompton Hospital will help identify how we can best publicise the findings. TRIAL REGISTRATION NUMBER: ISRCTN13472721.

B-type natriuretic peptide-guided therapy for heart failure (HF): a systematic review and meta-analysis of individual participant data (IPD) and aggregate data.

BACKGROUND: We estimated the effectiveness of serial B-type natriuretic peptide (BNP) blood testing to guide up-titration of medication compared with symptom-guided up-titration of medication in patients with heart failure (HF). METHODS: Systematic review and meta-analysis of randomised controlled trials (RCTs). We searched: MEDLINE (Ovid) 1950 to 9/06/2016; Embase (Ovid), 1980 to 2016 week 23; the Cochrane Library; ISI Web of Science (Citations Index and Conference Proceedings). The primary outcome was all-cause mortality; secondary outcomes were death related to HF, cardiovascular death, all-cause hospital admission, hospital admission for HF, adverse events, and quality of life. IPD were sought from all RCTs identified. Random-effects meta-analyses (two-stage) were used to estimate hazard ratios (HR) and confidence intervals (CIs) across RCTs, including HR estimates from published reports of studies that did not provide IPD. We estimated treatment-by-covariate interactions for age, gender, New York Heart Association (NYHA) class, HF type; diabetes status and baseline BNP subgroups. Dichotomous outcomes were analysed using random-effects odds ratio (OR) with 95% CI. RESULTS: We identified 14 eligible RCTs, five providing IPD. BNP-guided therapy reduced the hazard of hospital admission for HF by 19% (13 RCTs, HR 0.81, 95% CI 0.68 to 0.98) but not all-cause mortality (13 RCTs; HR 0.87, 95% CI 0.75 to 1.01) or cardiovascular mortality (5 RCTs; OR 0.88, 95% CI 0.67 to 1.16). For all-cause mortality, there was a significant interaction between treatment strategy and age (p = 0.034, 11 RCTs; HR 0.70, 95% CI 0.53-0.92, patients < 75 years old and HR 1.07, 95% CI 0.84-1.37, patients ≥ 75 years old); ejection fraction (p = 0.026, 11 RCTs; HR 0.84, 95% CI 0.71-0.99, patients with heart failure with reduced ejection fraction (HFrEF); and HR 1.33, 95% CI 0.83-2.11, patients with heart failure with preserved ejection fraction (HFpEF)). Adverse events were significantly more frequent with BNP-guided therapy vs. symptom-guided therapy (5 RCTs; OR 1.29, 95% CI 1.04 to 1.60). CONCLUSION: BNP-guided therapy did not reduce mortality but reduced HF hospitalisation. The overall quality of the evidence varied from low to very low. The relevance of these findings to unselected patients, particularly those managed by community generalists, are unclear. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013005335.

Effectiveness and cost-effectiveness of serum B-type natriuretic peptide testing and monitoring in patients with heart failure in primary and secondary care: an evidence synthesis, cohort study and cost-effectiveness model.

BACKGROUND: Heart failure (HF) affects around 500,000 people in the UK. HF medications are frequently underprescribed and B-type natriuretic peptide (BNP)-guided therapy may help to optimise treatment. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of BNP-guided therapy compared with symptom-guided therapy in HF patients. DESIGN: Systematic review, cohort study and cost-effectiveness model. SETTING: A literature review and usual care in the NHS. PARTICIPANTS: (a) HF patients in randomised controlled trials (RCTs) of BNP-guided therapy; and (b) patients having usual care for HF in the NHS. INTERVENTIONS: Systematic review: BNP-guided therapy or symptom-guided therapy in primary or secondary care. Cohort study: BNP monitored (≥ 6 months' follow-up and three or more BNP tests and two or more tests per year), BNP tested (≥ 1 tests but not BNP monitored) or never tested. Cost-effectiveness model: BNP-guided therapy in specialist clinics. MAIN OUTCOME MEASURES: Mortality, hospital admission (all cause and HF related) and adverse events; and quality-adjusted life-years (QALYs) for the cost-effectiveness model. DATA SOURCES: Systematic review: Individual participant or aggregate data from eligible RCTs. Cohort study: The Clinical Practice Research Datalink, Hospital Episode Statistics and National Heart Failure Audit (NHFA). REVIEW METHODS: A systematic literature search (five databases, trial registries, grey literature and reference lists of publications) for published and unpublished RCTs. RESULTS: Five RCTs contributed individual participant data (IPD) and eight RCTs contributed aggregate data (1536 participants were randomised to BNP-guided therapy and 1538 participants were randomised to symptom-guided therapy). For all-cause mortality, the hazard ratio (HR) for BNP-guided therapy was 0.87 [95% confidence interval (CI) 0.73 to 1.04]. Patients who were aged < 75 years or who had heart failure with a reduced ejection fraction (HFrEF) received the most benefit [interactions (p = 0.03): < 75 years vs. ≥ 75 years: HR 0.70 (95% CI 0.53 to 0.92) vs. 1.07 (95% CI 0.84 to 1.37); HFrEF vs. heart failure with a preserved ejection fraction (HFpEF): HR 0.83 (95% CI 0.68 to 1.01) vs. 1.33 (95% CI 0.83 to 2.11)]. In the cohort study, incident HF patients (1 April 2005-31 March 2013) were never tested (n = 13,632), BNP tested (n = 3392) or BNP monitored (n = 71). Median survival was 5 years; all-cause mortality was 141.5 out of 1000 person-years (95% CI 138.5 to 144.6 person-years). All-cause mortality and hospital admission rate were highest in the BNP-monitored group, and median survival among 130,433 NHFA patients (1 January 2007-1 March 2013) was 2.2 years. The admission rate was 1.1 patients per year (interquartile range 0.5-3.5 patients). In the cost-effectiveness model, in patients aged < 75 years with HFrEF or HFpEF, BNP-guided therapy improves median survival (7.98 vs. 6.46 years) with a small QALY gain (5.68 vs. 5.02) but higher lifetime costs (£64,777 vs. £58,139). BNP-guided therapy is cost-effective at a threshold of £20,000 per QALY. LIMITATIONS: The limitations of the trial were a lack of IPD for most RCTs and heterogeneous interventions; the inability to identify BNP monitoring confidently, to determine medication doses or to distinguish between HFrEF and HFpEF; the use of a simplified two-state Markov model; a focus on health service costs and a paucity of data on HFpEF patients aged < 75 years and HFrEF patients aged ≥ 75 years. CONCLUSIONS: The efficacy of BNP-guided therapy in specialist HF clinics is uncertain. If efficacious, it would be cost-effective for patients aged < 75 years with HFrEF. The evidence reviewed may not apply in the UK because care is delivered differently. FUTURE WORK: Identify an optimal BNP-monitoring strategy and how to optimise HF management in accordance with guidelines; update the IPD meta-analysis to include the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) RCT; collect routine long-term outcome data for completed and ongoing RCTs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37248047 and PROSPERO CRD42013005335. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 40. See the NIHR Journals Library website for further project information. The British Heart Foundation paid for Chris A Rogers' and Maria Pufulete's time contributing to the study. Syed Mohiuddin's time is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West at University Hospitals Bristol NHS Foundation Trust. Rachel Maishman contributed to the study when she was in receipt of a NIHR Methodology Research Fellowship.