Continuous Positive Airway Pressure plus Mandibular Advancement Therapy (PAPMAT): study protocol for an adaptive randomised crossover trial comparing the benefits and costs of combining two established treatments for obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) involves repeated breathing pauses during sleep due to upper airway obstruction. It causes excessive daytime sleepiness and has other health impacts. Continuous positive airway pressure (CPAP) therapy is effective first line treatment for moderate to severe OSA. Unfortunately, many patients have difficulty tolerating CPAP and pressure intolerance is probably an important contributing factor. Mandibular advancement devices (MAD) are an alternative to CPAP. They are worn in the mouth during sleep to reduce airway obstruction. There is some evidence that, when used in combination with CPAP, MADs improve airway anatomy enough to reduce the CPAP pressure required to treat OSA and that this combination therapy could improve CPAP adherence. METHODS: Consecutive patients starting on CPAP for moderate to severe OSA will be recruited at a regional NHS sleep service. Patients with high CPAP pressure requirements after initial titration, who satisfy all entry criteria and consent to participate, will undertake a 2-arm randomised crossover trial. The arms will be (i) standalone CPAP and (ii) CPAP + MAD therapy. Each arm will last 12 weeks, including 2 weeks acclimatisation. CPAP machines will be auto-titrating and with facility for data download, so the impact of MAD on CPAP pressure requirements and CPAP adherence can be easily measured. The primary outcome will be CPAP adherence. Secondary outcomes will include measures of OSA severity, patient-reported outcome measures including subjective daytime sleepiness, quality of life, and treatment preference at the trial exit and health service use. Cost-effectiveness analyses will be undertaken. DISCUSSION: If the intervention is shown to be effective and cost-effective in improving adherence in this standard CPAP-eligible OSA patient population it would be relatively straightforward to introduce into existing OSA treatment pathways, within the wider NHS and more widely. Both MAD and CPAP are already used by sleep services so their combination would require only minor adjustments to existing clinical pathways. It would be straightforward to disseminate the results of the study through regional, national, and international respiratory meetings. The health economics analysis would provide cost-effectiveness data to inform service planning and clinical guidelines through policy briefing papers, including those by NICE and SIGN. TRIAL REGISTRATION: PAPMAT was registered with ISRCTN prior to recruitment beginning (ISRCTN Registry 2021): https://www.isrctn.com/ISRCTN33966032 . Registered on 17th November 2021.

Effect of high-flow nasal therapy on patient-centred outcomes in patients at high risk of postoperative pulmonary complications after cardiac surgery: a statistical analysis plan for NOTACS, a multicentre adaptive randomised controlled trial.

BACKGROUND: The NOTACS trial will assess the efficacy, safety and cost-effectiveness of high-flow nasal therapy (HFNT) compared to standard oxygen therapy (SOT) on the outcomes of patients after cardiac surgery. METHODS/DESIGN: NOTACS is an adaptive, international, multicentre, parallel-group, randomised controlled trial, with a pre-planned interim sample size re-estimation (SSR). A minimum of 850 patients will be randomised 1:1 to receive either HFNT or SOT. The primary outcome is days alive and at home in the first 90 days after the planned surgery (DAH90), with a number of secondary analyses and cost-effectiveness analyses also planned. The interim SSR will take place after a minimum of 300 patients have been followed up for 90 days and will allow for the sample size to increase up to a maximum of 1152 patients. RESULTS: This manuscript provides detailed descriptions of the design of the NOTACS trial, and the analyses to be undertaken at the interim and final analyses. The main purpose of the interim analysis is to assess safety and to perform a sample size re-estimation. The main purpose of the final analysis is to examine the safety, efficacy and cost-effectiveness of HFNT compared to SOT on the outcomes of patients after cardiac surgery. DISCUSSION: This manuscript outlines the key features of the NOTACS statistical analysis plan and was submitted to the journal before the interim analysis in order to preserve scientific integrity under an adaptive design framework. The NOTACS SAP closely follows published guidelines for the content of SAPs in clinical trials. TRIAL REGISTRATION: ISRCTN14092678 . Registered on 13 May 2020.

Effect of high-flow nasal therapy on patient-centred outcomes in patients at high risk of postoperative pulmonary complications after cardiac surgery: a study protocol for a multicentre adaptive randomised controlled trial.

BACKGROUND: High-flow nasal therapy is a non-invasive form of respiratory support that delivers low-level, flow dependent positive airway pressure. The device can be better tolerated by patients than alternatives such as continuous positive airway pressure. The primary objective is to determine if prophylactic high-flow nasal therapy after tracheal extubation can result in an increase in the number of days alive and at home within the first 90 days after surgery, when compared with standard oxygen therapy. The co-primary objective is to estimate the incremental cost-effectiveness and cost-utility of high-flow nasal therapy vs standard oxygen therapy at 90 days, from the view-point of the public sector, the health service and patients. METHODS: This is an adaptive, multicentre, international parallel-group, randomised controlled trial with embedded cost-effectiveness analysis comparing the use of high-flow nasal therapy with control in patients at high risk of respiratory complications following cardiac surgery. Participants will be randomised before tracheal extubation and allocated either high-flow nasal therapy or standard oxygen therapy for a minimum of 16 h immediately post extubation. Participants will be followed up until 90 days after surgery. The total sample size needed to detect a 2-day increase in DAH90 with 90% power with an intention to treat analysis is 850 patients. The adaptive design includes an interim sample size re-estimation which will provide protection against deviations from the original sample size assumptions made from the single-centre pilot study and will allow for a maximum sample size increase to 1152 patients. DISCUSSION: Evidence to support routine use of high-flow nasal therapy will inform the development of effective enhanced recovery care bundles. Reducing complications should reduce length of stay and re-admission to hospital and provide an important focus for cost reduction. However; high-quality studies evaluating the clinical and cost effectiveness of high-flow nasal therapy after cardiothoracic surgery are lacking. TRIAL REGISTRATION: The study has been registered with ISRCTN ( ISRCTN14092678 , 13/05/2020) Clinicaltrials.gov Registration Pending.

Five-year results of Amaze: a randomized controlled trial of adjunct surgery for atrial fibrillation.

OBJECTIVES: The Amaze trial showed that adding atrial fibrillation (AF) surgery to cardiac operations increased return to sinus rhythm (SR) without impact on quality of life or survival at 2 years. We report outcomes to 5 years. METHODS: In a multicentre, phase III, pragmatic, double-blind, randomized controlled superiority trial, cardiac surgery patients with >3 months of AF were randomized 1:1 to adjunct AF surgery or control. Primary outcomes of 1-year SR restoration and 2-year quality-adjusted survival were already reported. This study reports on rhythm, survival, quality-adjusted survival, stroke, medication and safety to 5 years. RESULTS: Between 2009 and 2014, 352 patients were randomized. By 5 years 79 died, 58 withdrew, 34 were lost to follow-up and the remaining 182 provided data. AF surgery significantly increased the odds of remaining in SR at 5 years {odds ratio = 2.98 [95% confidence interval (CI) 1.23, 7.17], P = 0.015}. There was a non-significant decrease in stroke incidence [odds ratio = 0.605 (95% CI 0.284, 1.287), P = 0.19], but no improved survival [5-year survival: AF surgery 77.3% (95% CI 71.1%, 83.5%), controls 77.8% (95% CI 71.7%, 84.0%), P = 0.85]. Quality-adjusted survival difference was negligible (-0.03; 95% CI -0.33, 0.27, P = 0.85). The composite of survival free of stroke and AF was better in the AF surgery group [odds ratio = 2.34 (95% CI 1.03, 5.31)]. There were no other differences. CONCLUSIONS: Adjunct AF surgery confers a higher rate of SR to 5 years and a better composite outcome of survival free of stroke and AF but has no impact on overall or quality-adjusted survival or other clinical outcomes. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN82731440.

Endovascular stent grafting and open surgical replacement for chronic thoracic aortic aneurysms: a systematic review and prospective cohort study.

BACKGROUND: The management of chronic thoracic aortic aneurysms includes conservative management, watchful waiting, endovascular stent grafting and open surgical replacement. The Effective Treatments for Thoracic Aortic Aneurysms (ETTAA) study investigates timing and intervention choice. OBJECTIVE: To describe pre- and post-intervention management of and outcomes for chronic thoracic aortic aneurysms. DESIGN: A systematic review of intervention effects; a Delphi study of 360 case scenarios based on aneurysm size, location, age, operative risk and connective tissue disorders; and a prospective cohort study of growth, clinical outcomes, costs and quality of life. SETTING: Thirty NHS vascular/cardiothoracic units. PARTICIPANTS: Patients aged > 17 years who had existing or new aneurysms of ≥ 4 cm in diameter in the arch, descending or thoracoabdominal aorta. INTERVENTIONS: Endovascular stent grafting and open surgical replacement. MAIN OUTCOMES: Pre-intervention aneurysm growth, pre-/post-intervention survival, clinical events, readmissions and quality of life; and descriptive statistics for costs and quality-adjusted life-years over 12 months and value of information using a propensity score-matched subsample. RESULTS: The review identified five comparative cohort studies (endovascular stent grafting patients, n = 3955; open surgical replacement patients, n = 21,197). Pooled short-term all-cause mortality favoured endovascular stent grafting (odds ratio 0.71, 95% confidence interval 0.51 to 0.98; no heterogeneity). Data on survival beyond 30 days were mixed. Fewer short-term complications were reported with endovascular stent grafting. The Delphi study included 20 experts (13 centres). For patients with aneurysms of ≤ 6.0 cm in diameter, watchful waiting was preferred. For patients with aneurysms of > 6.0 cm, open surgical replacement was preferred in the arch, except for elderly or high-risk patients, and in the descending aorta if patients had connective tissue disorders. Otherwise endovascular stent grafting was preferred. Between 2014 and 2018, 886 patients were recruited (watchful waiting, n = 489; conservative management, n = 112; endovascular stent grafting, n = 150; open surgical replacement, n = 135). Pre-intervention death rate was 8.6% per patient-year; 49.6% of deaths were aneurysm related. Death rates were higher for women (hazard ratio 1.79, 95% confidence interval 1.25 to 2.57; p = 0.001) and older patients (age 61-70 years: hazard ratio 2.50, 95% confidence interval 0.76 to 5.43; age 71-80 years: hazard ratio 3.49, 95% confidence interval 1.26 to 9.66; age > 80 years: hazard ratio 7.01, 95% confidence interval 2.50 to 19.62; all compared with age < 60 years, p < 0.001) and per 1-cm increase in diameter (hazard ratio 1.90, 95% confidence interval 1.65 to 2.18; p = 0.001). The results were similar for aneurysm-related deaths. Decline per year in quality of life was greater for older patients (additional change -0.013 per decade increase in age, 95% confidence interval -0.019 to -0.007; p < 0.001) and smokers (additional change for ex-smokers compared with non-smokers 0.003, 95% confidence interval -0.026 to 0.032; additional change for current smokers compared with non-smokers -0.034, 95% confidence interval -0.057 to -0.01; p = 0.004). At the time of intervention, endovascular stent grafting patients were older (age difference 7.1 years; 95% confidence interval 4.7 to 9.5 years; p < 0.001) and more likely to be smokers (75.8% vs. 66.4%; p = 0.080), have valve disease (89.9% vs. 71.6%; p < 0.0001), have chronic obstructive pulmonary disease (21.3% vs. 13.3%; p = 0.087), be at New York Heart Association stage III/IV (22.3% vs. 16.0%; p = 0.217), have lower levels of haemoglobin (difference -6.8 g/l, 95% confidence interval -11.2 to -2.4 g/l; p = 0.003) and take statins (69.3% vs. 42.2%; p < 0.0001). Ten (6.7%) endovascular stent grafting and 15 (11.1%) open surgical replacement patients died within 30 days of the procedure (p = 0.2107). One-year overall survival was 82.5% (95% confidence interval 75.2% to 87.8%) after endovascular stent grafting and 79.3% (95% confidence interval 71.1% to 85.4%) after open surgical replacement. Variables affecting survival were aneurysm site, age, New York Heart Association stage and time waiting for procedure. For endovascular stent grafting, utility decreased slightly, by -0.017 (95% confidence interval -0.062 to 0.027), in the first 6 weeks. For open surgical replacement, there was a substantial decrease of -0.160 (95% confidence interval -0.199 to -0.121; p < 0.001) up to 6 weeks after the procedure. Over 12 months endovascular stent grafting was less costly, with higher quality-adjusted life-years. Formal economic analysis was unfeasible. LIMITATIONS: The study was limited by small numbers of patients receiving interventions and because only 53% of patients were suitable for both interventions. CONCLUSIONS: Small (4-6 cm) aneurysms require close observation. Larger (> 6 cm) aneurysms require intervention without delay. Endovascular stent grafting and open surgical replacement were successful for carefully selected patients, but cost comparisons were unfeasible. The choice of intervention is well established, but the timing of intervention remains challenging. FUTURE WORK: Further research should include an analysis of the risk factors for growth/rupture and long-term outcomes. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04044627 and NCT02010892. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 6. See the NIHR Journals Library website for further project information.

The aorta is the main artery that carries oxygen-rich blood from the heart to the body. An aneurysm is a swelling or bulging in a blood vessel, which usually occurs where the wall has become weak and has lost its elastic properties, which means that it does not return to its normal shape after the blood has passed through. A thoracic aortic aneurysm, or TAA for short, is an aneurysm in the section of the aorta in the chest (www.bhf.org.uk/informationsupport/conditions/thoracic-aortic-aneurysms). The Effective Treatments for Thoracic Aortic Aneurysms (ETTAA) study aimed to investigate aneurysm growth rates, patient outcomes, quality of life and costs, including those from surgery. Surgical treatments include open heart surgery, in which the section of the aorta that contains the aneurysm is removed and replaced by a new aorta made from a synthetic material, and stent grafting, in which tubes are inserted into arteries to allow blood to flow freely, using less invasive 'keyhole' surgery. The existing research evidence was reviewed, but data comparing the effectiveness of these two approaches were sparse or of limited quality, and outdated. Between 2014 and 2018, clinical experts were surveyed and 886 NHS patients with chronic thoracic aortic aneurysms (≥ 4 cm in diameter) were observed to monitor aneurysm growth and patient outcomes. If patients were unfit or unwilling to have surgery, they had conservative management with medication and lifestyle changes. For small aneurysms, experts recommended watchful waiting, with regular monitoring, until the aneurysm grew to about 6 cm in diameter. Open surgery was preferred for larger arch aneurysms and for descending aneurysms in patients with genetic disorders. Otherwise, stent grafting was preferred. The observational study recruited 321 women and 565 men with an average age of 71 years from 30 English hospitals. A total of 489 patients underwent watchful waiting and 112 received conservative management. Without surgery, death rates were higher for women and older patients, while the risk of dying doubled for each centimetre of aneurysm diameter at baseline. Of the remaining patients, 150 underwent stent grafting and 135 had open surgery. One-year overall survival was 83% after stent grafting and 79% after open surgery but the difference could be due to chance. The factors affecting survival after stent grafting or open surgery were aneurysm location, age, breathlessness and time waiting for a procedure. Small aneurysms are low risk, so blood pressure management and smoking cessation are recommended. For larger aneurysms, it is important that surgery is not delayed, as a longer waiting time to surgery means that outcomes are poorer. Only about half of patients who had surgery were considered suitable for both stent grafting and open surgery, which limited the ability to determine the best use of NHS resources. No comparative cost-effectiveness analysis was feasible. The main cost in a stent grafting procedure was the stent graft, and the main cost in an open surgery procedure was days in an intensive care unit.

Rituximab in patients with acute ST-elevation myocardial infarction: an experimental medicine safety study.

AIMS: In pre-clinical models of acute myocardial infarction (MI), mature B cells mobilize inflammatory monocytes into the heart, leading to increased infarct size and deterioration of cardiac function, whilst anti-CD20 antibody-mediated depletion of B cells limits myocardial injury and improves cardiac function. Rituximab is a monoclonal anti-CD20 antibody targeted against human B cells. However, its use in cardiovascular disease is untested and is currently contraindicated. Therefore, we assessed the safety, feasibility, and pharmacodynamic effect of rituximab given to patients with acute ST-elevation MI (STEMI). METHODS AND RESULTS: Rituximab in patients with acute ST-elevation myocardial infarction (RITA-MI) was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48 h of symptom onset. Four escalating doses (200, 500, 700, and 1000 mg) were used. The primary endpoint was safety, whilst secondary endpoints were changes in circulating immune cell subsets including B cells, and cardiac and inflammatory biomarkers. A total of 24 patients were dosed. Rituximab appeared well tolerated. Seven serious adverse events were reported, none of which were assessed as being related to the rituximab infusion. Rituximab caused a mean 96.3% (95% confidence interval 93.8-98.8%) depletion of circulating B cells within 30 min of starting the infusion. Maximal B-cell depletion was seen at Day 6, which was significantly lower than baseline for all doses (P < 0.001). B-cell repopulation at 6 months was dose-dependent, with modulation of returning B-cell subsets. Immunoglobulin (IgG, IgM, and IgA) levels were not affected during the 6 months of follow-up. CONCLUSIONS: A single infusion of rituximab appears safe when given in the acute STEMI setting and substantially alters circulating B-cell subsets. We provide important new insight into the feasibility and pharmacodynamics of rituximab in acute STEMI, which will inform further clinical translation of this potential therapy. CLINICAL TRIAL REGISTRATION: NCT03072199 at https://www.clinicaltrials.gov/.

Aneurysm growth, survival, and quality of life in untreated thoracic aortic aneurysms: the effective treatments for thoracic aortic aneurysms study.

AIMS: To observe, describe, and evaluate management and timing of intervention for patients with untreated thoracic aortic aneurysms. METHODS AND RESULTS: Prospective study of UK National Health Service (NHS) patients aged ≥18 years, with new/existing arch or descending thoracic aortic aneurysms of ≥4 cm diameter, followed up until death, intervention, withdrawal, or July 2019. Outcomes were aneurysm growth, survival, quality of life (using the EQ-5D-5L utility index), and hospital admissions. Between 2014 and 2018, 886 patients were recruited from 30 NHS vascular/cardiothoracic units. Maximum aneurysm diameter was in the descending aorta in 725 (82%) patients, growing at 0.2 cm (0.17-0.24) per year. Aneurysms of ≥4 cm in the arch increased by 0.07 cm (0.02-0.12) per year. Baseline diameter was related to age and comorbidities, and no clinical correlates of growth were found. During follow-up, 129 patients died, 64 from aneurysm-related events. Adjusting for age, sex, and New York Heart Association dyspnoea index, risk of death increased with aneurysm size at baseline [hazard ratio (HR): 1.88 (95% confidence interval: 1.64-2.16) per cm, P < 0.001] and with growth [HR: 2.02 (1.70-2.41) per cm, P < 0.001]. Hospital admissions increased with aneurysm size [relative risk: 1.21 (1.05-1.38) per cm, P = 0.008]. Quality of life decreased annually for each 10-year increase in age [-0.013 (-0.019 to -0.007), P < 0.001] and for current smoking [-0.043 (-0.064 to -0.023), P = 0.004]. Aneurysm size was not associated with change in quality of life. CONCLUSION: International guidelines should consider increasing monitoring intervals to 12 months for small aneurysms and increasing intervention thresholds. Individualized decisions about surveillance/intervention should consider age, sex, size, growth, patient characteristics, and surgical risk.

Dynamic individual vital sign trajectory early warning score (DyniEWS) versus snapshot national early warning score (NEWS) for predicting postoperative deterioration.

AIMS: International early warning scores (EWS) including the additive National Early Warning Score (NEWS) and logistic EWS currently utilise physiological snapshots to predict clinical deterioration. We hypothesised that a dynamic score including vital sign trajectory would improve discriminatory power. METHODS: Multicentre retrospective analysis of electronic health record data from postoperative patients admitted to cardiac surgical wards in four UK hospitals. Least absolute shrinkage and selection operator-type regression (LASSO) was used to develop a dynamic model (DyniEWS) to predict a composite adverse event of cardiac arrest, unplanned intensive care re-admission or in-hospital death within 24 h. RESULTS: A total of 13,319 postoperative adult cardiac patients contributed 442,461 observations of which 4234 (0.96%) adverse events in 24 h were recorded. The new dynamic model (AUC = 0.80 [95% CI 0.78-0.83], AUPRC = 0.12 [0.10-0.14]) outperforms both an updated snapshot logistic model (AUC = 0.76 [0.73-0.79], AUPRC = 0.08 [0.60-0.10]) and the additive National Early Warning Score (AUC = 0.73 [0.70-0.76], AUPRC = 0.05 [0.02-0.08]). Controlling for the false alarm rates to be at current levels using NEWS cut-offs of 5 and 7, DyniEWS delivers a 7% improvement in balanced accuracy and increased sensitivities from 41% to 54% at NEWS 5 and 18% to -30% at NEWS 7. CONCLUSIONS: Using an advanced statistical approach, we created a model that can detect dynamic changes in risk of unplanned readmission to intensive care, cardiac arrest or in-hospital mortality and can be used in real time to risk-prioritise clinical workload.

CASPA (CArdiac Sarcoidosis in PApworth) improving the diagnosis of cardiac involvement in patients with pulmonary sarcoidosis: protocol for a prospective observational cohort study.

INTRODUCTION: Sarcoidosis is a multisystem disease, predominantly affecting the lungs but can involve the heart, resulting in cardiac sarcoidosis (CS). Patients require MRI/Positron Emission Tomography (PET) scans for diagnosis. Echocardiography, ECG and Holter monitoring may be indicative but not diagnostic alone. Patients can present late with conduction defects, heart failure or sudden death. The CASPA (CArdiac Sarcoidosis in PApworth) study protocol aims to (1) use MRI to identify CS prevalence; (2) use speckle-tracking echocardiography, signal averaged ECG and Holter monitoring to look for diagnostic pathways; and (3) identify serum proteins which may be associated with CS. METHODS AND ANALYSIS: Participants with pulmonary sarcoidosis (and no known cardiac disease) from Royal Papworth Hospital will have the following: cardiac MRI with late gadolinium, two-dimensional transthoracic echocardiography with speckle tracking, signal averaged ECG and 24-hour Holter monitor. They will provide a serum sample for brain natriuretic peptide levels and proteomics by liquid chromatography coupled to high-resolution mass spectrometry. All data will be collected on OpenClinica platform and analysed approximately 6 months after final patient recruitment. ETHICS AND DISSEMINATION: The Camden & Kings Cross Research Ethics Committee approved the protocol (REC number: 17/LO/0667). Integrated Research Approval System (IRAS) 222 720. Dissemination of findings will be via conference presentations and submitted to peer-reviewed journals.

Outcomes of the NHS England National Extracorporeal Membrane Oxygenation Service for adults with respiratory failure: a multicentre observational cohort study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is increasingly used to support adults with severe respiratory failure refractory to conventional measures. In 2011, NHS England commissioned a national service to provide ECMO to adults with refractory acute respiratory failure. Our aims were to characterise the patients admitted to the service, report their outcomes, and highlight characteristics potentially associated with survival. METHODS: An observational cohort study was conducted of all patients treated by the NHS England commissioned ECMO service between December 1, 2011 and December 31, 2017. Analysis was conducted according to a prespecified protocol (NCT: 03979222). Data are presented as median [inter-quartile range, IQR]. RESULTS: A total of 1205 patients were supported with ECMO during the study period; the majority (n=1150; 95%) had veno-venous ECMO alone. The survival rate at ECMO ICU discharge was 74% (n=887). Survivors had a lower median age (43 yr [32-52]), compared with non-survivors (49 y [39-60]). Increased severity of hypoxaemia at time of decision-to-cannulate was associated with a lower probability of survival: survivors had a median Sao2 of 90% (84-93%; median Pao2/Fio2, 9.4 kPa [7.7-12.6]), compared with non-survivors (Sao2 88% [80-92%]; Pao2/Fio2 ratio: 8.5 kPa [7.1-11.5]). Patients requiring ECMO because of asthma were more likely to survive (95% survival rate (95% CI, 91-99%), compared with a survival of 71% (95% CI, 69-74%) in patients with respiratory failure attributable to other diagnoses. CONCLUSION: A national ECMO service can achieve good short-term outcomes for patients with undifferentiated respiratory failure refractory to conventional management. CLINICAL TRIAL REGISTRATION: NCT03979222.

A critical review of graphics for subgroup analyses in clinical trials.

Subgroup analyses are a routine part of clinical trials to investigate whether treatment effects are homogeneous across the study population. Graphical approaches play a key role in subgroup analyses to visualise effect sizes of subgroups, to aid the identification of groups that respond differentially, and to communicate the results to a wider audience. Many existing approaches do not capture the core information and are prone to lead to a misinterpretation of the subgroup effects. In this work, we critically appraise existing visualisation techniques, propose useful extensions to increase their utility and attempt to develop an effective visualisation approach. We focus on forest plots, UpSet plots, Galbraith plots, subpopulation treatment effect pattern plot, and contour plots, and comment on other approaches whose utility is more limited. We illustrate the methods using data from a prostate cancer study.

A multicenter study of anticoagulation in operable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary emboli necessitating lifelong anticoagulation. Despite this, few data exist on the safety and efficacy of vitamin K antagonists (VKAs) in CTEPH and none for direct oral anticoagulants (DOACs). OBJECTIVES: To evaluate outcomes and complication rates in CTEPH following pulmonary endarterectomy (PEA) for individuals receiving VKAs or DOACs. METHODS: Consecutive CTEPH patients undergoing PEA between 2007 and 2018 were included in a retrospective analysis. Postoperative outcomes, recurrent venous thromboembolism (VTE), and bleeding events were obtained from patient medical records. RESULTS: Seven hundred ninety-four individuals were treated with VKAs and 206 with DOACs following PEA. Mean observation period was 612 (standard deviation: 702) days. Significant improvements in hemodynamics and functional status were observed in both groups following PEA (P < .001). Major bleeding events were equivalent (P = 1) in those treated with VKAs (0.67%/person-year) and DOACs (0.68%/person-year). The VTE recurrence was proportionately higher (P = .008) with DOACs (4.62%/person-year) than VKAs (0.76%/person-year), although survival did not differ. CONCLUSIONS: Post-PEA functional and hemodynamic outcomes appear unaffected by anticoagulant choice. Bleeding events were similar, but recurrent VTE rates significantly higher in those receiving DOACs. Our study provides a strong rationale for prospective registry data and/or studies to evaluate the safety of DOACs in CTEPH.

Obstructive Sleep Apnea in Patients With Primary-open Angle Glaucoma: No Role for a Screening Program.

PRéCIS:: In this study, we found a high prevalence of obstructive sleep apnea (OSA) among patients with primary open-angle glaucoma (POAG) but this was not different (nor was OSA more severe) to matched people without glaucoma. RATIONALE: It has been proposed that OSA might be a contributing factor in the development of POAG and by extension that there could be a role for screening people with POAG for OSA. OBJECTIVES: To assess whether the prevalence of OSA among patients with POAG is different from that in people without glaucoma and to examine for associations between apnea-hypopnea index (AHI) and markers of functional and structural changes in POAG. METHODS: Unselected POAG patients and control subjects were consecutively recruited in a single center. A comprehensive ocular assessment and nocturnal multichannel cardiorespiratory monitoring were performed. RESULTS: Data from 395 participants, 235 POAG patients, and 160 controls were analyzed. The prevalence of OSA was 58% [95% confidence interval (CI), 52-65] in POAG patients and 54% (95% CI, 47-62) in controls, with 22% (95% CI, 16-27) of POAG patients and 16% (95% CI, 11-22) of controls diagnosed with moderate or severe OSA. A total of 160 POAG participants were matched to the controls using propensity score matching. There was no significant difference in OSA prevalence between the matched groups (P=0.91 for AHI≥5 and P=0.66 for AHI≥15). The AHI was not associated with the severity of visual field defect or retinal nerve fiber layer thinning after adjustment for confounders. CONCLUSIONS: This study confirms a high prevalence of OSA among patients with POAG which is, however, not higher than in people without glaucoma matched for known OSA risk factors. Our results do not support screening for OSA in patients with POAG.

Design and estimation in clinical trials with subpopulation selection.

Population heterogeneity is frequently observed among patients' treatment responses in clinical trials because of various factors such as clinical background, environmental, and genetic factors. Different subpopulations defined by those baseline factors can lead to differences in the benefit or safety profile of a therapeutic intervention. Ignoring heterogeneity between subpopulations can substantially impact on medical practice. One approach to address heterogeneity necessitates designs and analysis of clinical trials with subpopulation selection. Several types of designs have been proposed for different circumstances. In this work, we discuss a class of designs that allow selection of a predefined subgroup. Using the selection based on the maximum test statistics as the worst-case scenario, we then investigate the precision and accuracy of the maximum likelihood estimator at the end of the study via simulations. We find that the required sample size is chiefly determined by the subgroup prevalence and show in simulations that the maximum likelihood estimator for these designs can be substantially biased.