Early computed tomography coronary angiography in adults presenting with suspected acute coronary syndrome: the RAPID-CTCA RCT.

BACKGROUND: Acute coronary syndrome is a common medical emergency. The optimal strategy to investigate patients who are at intermediate risk of acute coronary syndrome has not been fully determined. OBJECTIVE: To investigate the role of early computed tomography coronary angiography in the investigation and treatment of adults presenting with suspected acute coronary syndrome. DESIGN: A prospective, multicentre, open, parallel-group randomised controlled trial with blinded end-point adjudication. SETTING: Thirty-seven hospitals in the UK. PARTICIPANTS: Adults (aged ≥ 18 years) presenting to the emergency department, acute medicine services or cardiology department with suspected or provisionally diagnosed acute coronary syndrome and at least one of the following: (1) a prior history of coronary artery disease, (2) a cardiac troponin level > 99th centile and (3) an abnormal 12-lead electrocardiogram. INTERVENTIONS: Early computed tomography coronary angiography in addition to standard care was compared with standard care alone. Participants were followed up for 1 year. MAIN OUTCOME MEASURE: One-year all-cause death or subsequent type 1 (spontaneous) or type 4b (stent thrombosis) myocardial infarction, measured as the time to such event adjudicated by two cardiologists blinded to the computerised tomography coronary angiography ( CTCA ) arm. Cost-effectiveness was estimated as the lifetime incremental cost per quality-adjusted life-year gained. RESULTS: Between 23 March 2015 and 27 June 2019, 1748 participants [mean age 62 years (standard deviation 13 years), 64% male, mean Global Registry Of Acute Coronary Events score 115 (standard deviation 35)] were randomised to receive early computed tomography coronary angiography (n = 877) or standard care alone (n = 871). The primary end point occurred in 51 (5.8%) participants randomised to receive computed tomography coronary angiography and 53 (6.1%) participants randomised to receive standard care (adjusted hazard ratio 0.91, 95% confidence interval 0.62 to 1.35; p = 0.65). Computed tomography coronary angiography was associated with a reduced use of invasive coronary angiography (adjusted hazard ratio 0.81, 95% confidence interval 0.72 to 0.92; p = 0.001) but no change in coronary revascularisation (adjusted hazard ratio 1.03, 95% confidence interval 0.87 to 1.21; p = 0.76), acute coronary syndrome therapies (adjusted odds ratio 1.06, 95% confidence interval 0.85 to 1.32; p = 0.63) or preventative therapies on discharge (adjusted odds ratio 1.07, 95% confidence interval 0.87 to 1.32; p = 0.52). Early computed tomography coronary angiography was associated with longer hospitalisations (median increase 0.21 days, 95% confidence interval 0.05 to 0.40 days) and higher mean total health-care costs over 1 year (£561 more per patient) than standard care. LIMITATIONS: The principal limitation of the trial was the slower than anticipated recruitment, leading to a revised sample size, and the requirement to compromise and accept a larger relative effect size estimate for the trial intervention. FUTURE WORK: The potential role of computed tomography coronary angiography in selected patients with a low probability of obstructive coronary artery disease (intermediate or mildly elevated level of troponin) or who have limited access to invasive cardiac catheterisation facilities needs further prospective evaluation. CONCLUSIONS: In patients with suspected or provisionally diagnosed acute coronary syndrome, computed tomography coronary angiography did not alter overall coronary therapeutic interventions or 1-year clinical outcomes, but it did increase the length of hospital stay and health-care costs. These findings do not support the routine use of early computed tomography coronary angiography in intermediate-risk patients with acute chest pain. TRIAL REGISTRATION: This trial is registered as ISRCTN19102565 and Clinical Trials NCT02284191. 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. 37. See the NIHR Journals Library website for further project information.

WHY DID WE DO THE RESEARCH?: Chest pain is a common medical emergency. It is important to decide if the cause is a heart attack. The two tests that are often used are a heart recording (electrocardiogram) and a blood test (troponin levels). If both are normal, the cause of chest pain is unlikely to be a heart attack and the patient is often discharged home. If either test is positive or if the patient has had previous heart problems, then the patient may require further investigation. We wanted to test whether or not adding a heart scan called a computerised tomography coronary angiogram improved patients' care. HOW DID WE DO THE RESEARCH?: We carried out a randomised trial in which half of the patients attending hospital with chest pain had a computerised tomography coronary angiography scan as part of their assessment and half of the patients did not. In total, 1749 patients were recruited and followed up for 1 year. BRINGING IT ALL TOGETHER: The use of an additional early computerised tomography coronary angiography scan for chest pain patients of medium risk produced only small improvements in patient care.

The RAPID-CTCA trial (Rapid Assessment of Potential Ischaemic Heart Disease with CTCA) - a multicentre parallel-group randomised trial to compare early computerised tomography coronary angiography versus standard care in patients presenting with suspected or confirmed acute coronary syndrome: study protocol for a randomised controlled trial.

BACKGROUND: Emergency department attendances with chest pain requiring assessment for acute coronary syndrome (ACS) are a major global health issue. Standard assessment includes history, examination, electrocardiogram (ECG) and serial troponin testing. Computerised tomography coronary angiography (CTCA) enables additional anatomical assessment of patients for coronary artery disease (CAD) but has only been studied in very low-risk patients. This trial aims to investigate the effect of early CTCA upon interventions, event rates and health care costs in patients with suspected/confirmed ACS who are at intermediate risk. METHODS/DESIGN: Participants will be recruited in about 35 tertiary and district general hospitals in the UK. Patients ≥18 years old with symptoms with suspected/confirmed ACS with at least one of the following will be included: (1) ECG abnormalities, e.g. ST-segment depression >0.5 mm; (2) history of ischaemic heart disease; (3) troponin elevation above the 99th centile of the normal reference range or increase in high-sensitivity troponin meeting European Society of Cardiology criteria for 'rule-in' of myocardial infarction (MI). The early use of ≥64-slice CTCA as part of routine assessment will be compared to standard care. The primary endpoint will be 1-year all-cause death or recurrent type 1 or type 4b MI at 1 year, measured as the time to such event. A number of secondary clinical, process and safety endpoints will be collected and analysed. Cost effectiveness will be estimated in terms of the lifetime incremental cost per quality-adjusted life year gained. We plan to recruit 2424 (2500 with ~3% drop-out) evaluable patients (1212 per arm) to have 90% power to detect a 20% versus 15% difference in 1-year death or recurrent type 1 MI or type 4b MI, two-sided p < 0.05. Analysis will be on an intention-to-treat basis. The relationship between intervention and the primary outcome will be analysed using Cox proportional hazard regression adjusted for study site (used to stratify the randomisation), age, baseline Global Registry of Acute Coronary Events score, previous CAD and baseline troponin level. The results will be expressed as a hazard ratio with the corresponding 95% confidence intervals and p value. DISCUSSION: The Rapid Assessment of Potential Ischaemic Heart Disease with CTCA (RAPID-CTCA) trial will recruit 2500 participants across about 35 hospital sites. It will be the first study to investigate the role of CTCA in the early assessment of patients with suspected or confirmed ACS who are at intermediate risk and including patients who have raised troponin measurements during initial assessment. TRIAL REGISTRATION: ISRCTN19102565 . Registered on 3 October 2014. ClinicalTrials.gov: NCT02284191.

Gabapentin for the Management of Chronic Pelvic Pain in Women (GaPP1): A Pilot Randomised Controlled Trial.

Chronic pelvic pain (CPP) affects 2.1-24% of women. Frequently, no underlying pathology is identified, and the pain is difficult to manage. Gabapentin is prescribed for CPP despite no robust evidence of efficacy. We performed a pilot trial in two UK centres to inform the planning of a future multicentre RCT to evaluate gabapentin in CPP management. Our primary objective was to determine levels of participant recruitment and retention. Secondary objectives included estimating potential effectiveness, acceptability to participants of trial methodology, and cost-effectiveness of gabapentin. Women with CPP and no obvious pelvic pathology were assigned to an increasing regimen of gabapentin (300-2700 mg daily) or placebo. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to six months. The analyses by treatment group were by intention-to-treat. Interviews were conducted to evaluate women's experiences of the trial. A probabilistic decision analytical model was used to estimate cost-effectiveness. Between September 2012-2013, 47 women (34% of those eligible) were randomised (22 to gabapentin, 25 to placebo), and 25 (53%) completed six-month follow-up. Participants on gabapentin had less pain (BPI difference 1.72 points, 95% CI:0.07-3.36), and an improvement in mood (HADS difference 4.35 points, 95% CI:1.97-6.73) at six months than those allocated placebo. The majority of participants described their trial experience favorably. At the UK threshold for willingness-to-pay, the probabilities of gabapentin or no treatment being cost-effective are similar. A pilot trial assessing gabapentin for CPP was feasible, but uncertainty remains, highlighting the need for a large definitive trial.

Exploring the role and function of trial steering committees: results of an expert panel meeting.

BACKGROUND: The independent oversight of clinical trials, which is recommended by the Medical Research Council (MRC) Guidelines for Good Clinical Practice, is typically provided by an independent advisory Data Monitoring Committee (DMC) and an independent executive committee, to whom the DMC makes recommendations. The detailed roles and function of this executive committee, known as the Trial Steering Committee (TSC), have not previously been studied or reviewed since those originally proposed by the MRC in 1998. METHODS: An expert panel (n = 7) was convened comprising statisticians, clinicians and trial methodologists with prior TSC experience. Twelve questions about the role and responsibilities of the TSC were discussed by the panel at two full-day meetings. Each meeting was transcribed in full and the discussions were summarised. RESULTS: The expert panel reached agreement on the role of the TSC, to which it was accountable, the membership, the definition of independence, and the experience and training needed. The management of ethical issues, difficult/complex situations and issues the TSC should not ask the DMC to make recommendations on were more difficult to discuss without specific examples, but support existed for further work to help share issues and to provide appropriate training for TSC members. Additional topics discussed, which had not been identified by previous work relating to the DMCs but were pertinent to the role of the TSC, included the following: review of data sharing requests, indemnity, lifespan of the TSC, general TSC administration, and the roles of both the Funder and the Sponsor. CONCLUSIONS: This paper presents recommendations that will contribute to the revision and update of the MRC TSC terms of reference. Uncertainty remains in some areas due to the absence of real-life examples; future guidance on these issues would benefit from a repository of case studies. Notably, the role of a patient and public involvement (PPI) contributor was not discussed, and further work is warranted to explore the role of a PPI contributor in independent trial oversight.

Bronchiolitis of Infancy Discharge Study (BIDS): a multicentre, parallel-group, double-blind, randomised controlled, equivalence trial with economic evaluation.

BACKGROUND: There are no randomised trials of peripheral capillary oxygen saturation (SpO2) targets in acute respiratory infection. Two national guidelines recommended different targets for the management of acute viral bronchiolitis. OBJECTIVES: To compare the American Academy of Pediatrics guideline target of SpO2 ≥ 90% with the Scottish Intercollegiate Guidelines Network target of SpO2 ≥ 94%. DESIGN: A multicentre, parallel-group, double-blind, randomised controlled, equivalence trial with economic evaluation. SETTING: Eight paediatric hospital departments in the UK. PARTICIPANTS: Infants > 6 weeks and ≤ 12 months of age (corrected for prematurity) with physician-diagnosed bronchiolitis admitted to hospital from a paediatric emergency assessment area. Follow-up for 6 months by standardised telephone contacts. INTERVENTION: Infants were randomised to a target oxygen saturation of ≥ 94% (standard care) or ≥ 90% (modified care) displayed by a pulse saturation oximeter (Masimo Corporation Limited, CA, USA). ROUTINE CARE: All infants received routine care in addition to the study intervention. Infants were eligible for discharge when they exhibited a SpO2 of ≥ 94% in room air for 4 hours including a period of sleep and were also feeding adequately (≥ 75% usual volume). PRIMARY OUTCOME: A total of 615 infants were recruited, of whom 308 were allocated to the standard care group and 307 to the modified care group. The primary outcome was time to cough resolution. There was equivalence at the prespecified variance of ± 2 days [time to cough resolution: standard care group, 15 days; modified care group, 15 days; median difference 1 day (benefit modified), 95% confidence interval (CI) -1 to 2 days]. SECONDARY RESULTS: Return to adequate feeding occurred sooner in infants in the modified care group than in those in the standard care group (19.5 vs. 24.1 hours). This difference was non-equivalent [median difference 2.7 hours (95% CI -0.3 to 7.0 hours) versus prespecified ± 4 hours; post-hoc hazard ratio 1.22 (95% CI 1.04 to 1.44 (p-value = 0.015)]. Parent perspective of the time taken to return to normal was not equivalent, being 12 days in the standard care group compared with 11 days in the modified care group [median difference 1.0 day (95% CI 0.0 to 3.0 days) versus prespecified ± 2 days; post-hoc hazard ratio 1.19 (95% CI 1.00 to 1.41); p-value = 0.043]. At 28 days, SpO2 was equivalent [mean difference 0.11% (95% CI -0.35% to 0.57%), within the 1% prespecified]. The modified care group (55.6%) required oxygen less than the standard care group (73.1%), and for a shorter period (5.7 hours vs. 27.6 hours). Infants in the modified care group were fit for discharge (30.2 hours vs. 44.2 hours, hazard ratio 1.46, 95% CI 1.23 to 1.73; p-value < 0.001) and were discharged (40.9 hours vs. 50.9 hours; hazard ratio 1.28, 95% CI 1.06 to 1.50; p-value < 0.003) sooner than those in the standard care group. There were 35 serious adverse events in the standard care group, compared with 25 in the modified care group. Eight infants in the standard care group and 12 in the modified care group were admitted to a high-dependency unit. By 28 days, 23 infants had been readmitted to hospital in the standard care group and 12 infants in the modified care group. Parents of infants in the modified care group did not experience higher levels of anxiety and, by 14 days, had lost 28% fewer hours to usual activities. NHS costs were £290 lower in the modified care group than in the standard care group, with additional societal costs also being lower in the modified care group. CONCLUSIONS: Management of infants to a SpO2 target of ≥ 90% is as clinically effective as ≥ 94%, gives rise to no additional safety concerns, and appears to be cost-effective. Future work could focus on the safety and effectiveness of using intermittent oxygen saturation monitoring in secondary care, and to consider what are safe and effective oxygen saturation targets for children with bronchiolitis managed in primary care. TRIAL REGISTRATION: This trial is registered as ISRCTN28405428. FUNDING: This project was funded by the NIHR Health Technology Assessment programme. Masimo Corporation Limited, CA, USA, kindly provided oxygen saturation monitors with standard and altered algorithms.

Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial.

BACKGROUND: The American Academy of Pediatrics recommends a permissive hypoxaemic target for an oxygen saturation of 90% for children with bronchiolitis, which is consistent with the WHO recommendations for targets in children with lower respiratory tract infections. No evidence exists to support this threshold. We aimed to assess whether the 90% or higher target for management of oxygen supplementation was equivalent to a normoxic 94% or higher target for infants admitted to hospital with viral bronchiolitis. METHODS: We did a parallel-group, randomised, controlled, equivalence trial of infants aged 6 weeks to 12 months of age with physician-diagnosed bronchiolitis newly admitted into eight paediatric hospital units in the UK (the Bronchiolitis of Infancy Discharge Study [BIDS]). A central computer randomly allocated (1:1) infants, in varying length blocks of four and six and without stratification, to be clipped to standard oximeters (patients treated with oxygen if pulse oxygen saturation [SpO2] <94%) or modified oximeters (displayed a measured value of 90% as 94%, therefore oxygen not given until SpO2 <90%). All parents, clinical staff, and outcome assessors were masked to allocation. The primary outcome was time to resolution of cough (prespecified equivalence limits of plus or minus 2 days) in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN28405428. FINDINGS: Between Oct 3, and March 30, 2012, and Oct 1, and March 29, 2013, we randomly assigned 308 infants to standard oximeters and 307 infants to modified oximeters. Cough resolved by 15·0 days (median) in both groups (95% CI for difference -1 to 2) and so oxygen thresholds were equivalent. We recorded 35 serious adverse events in 32 infants in the standard care group and 25 serious adverse events in 24 infants in the modified care group. In the standard care group, eight infants transferred to a high-dependency unit, 23 were readmitted, and one had a prolonged hospital stay. In the modified care group, 12 infants were transferred to a high-dependency unit and 12 were readmitted to hospital. Recorded adverse events did not differ significantly. INTERPRETATION: Management of infants with bronchiolitis to an oxygen saturation target of 90% or higher is as safe and clinically effective as one of 94% or higher. Future research should assess the benefits and risks of different oxygen saturation targets in acute respiratory infection in older children, particularly in developing nations where resources are scarce. FUNDING: National Institute for Health Research, Health Technology Assessment programme.

Observer variability in the assessment of CT coronary angiography and coronary artery calcium score: substudy of the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial.

INTRODUCTION: Observer variability can influence the assessment of CT coronary angiography (CTCA) and the subsequent diagnosis of angina pectoris due to coronary heart disease. METHODS: We assessed 210 CTCAs from the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial for intraobserver and interobserver variability. Calcium score, coronary angiography and image quality were evaluated. Coronary artery disease was defined as none (<10%), mild (10-49%), moderate (50-70%) and severe (>70%) luminal stenosis and classified as no (<10%), non-obstructive (10-70%) or obstructive (>70%) coronary artery disease. Post-CTCA diagnosis of angina pectoris due to coronary heart disease was classified as yes, probable, unlikely or no. RESULTS: Patients had a mean body mass index of 29 (28, 30) kg/m(2), heart rate of 58 (57, 60)/min and 62% were men. Intraobserver and interobserver agreements for the presence or absence of coronary artery disease were excellent (95% agreement, κ 0.884 (0.817 to 0.951) and good (91%, 0.791 (0.703 to 0.879)). Intraobserver and interobserver agreement for the presence or absence of angina pectoris due to coronary heart disease were excellent (93%, 0.842 (0.918 to 0.755) and good (86%, 0.701 (0.799 to 0.603)), respectively. Observer variability of calcium score was excellent for calcium scores below 1000. More segments were categorised as uninterpretable with 64-multidetector compared to 320-multidetector CTCA (10.1% vs 2.6%, p<0.001) but there was no difference in observer variability. CONCLUSIONS: Multicentre multidetector CTCA has excellent agreement in patients under investigation for suspected angina due to coronary heart disease. TRIAL REGISTRATION NUMBER: NCT01149590.

Methodological quality of meta-analyses: matched-pairs comparison over time and between industry-sponsored and academic-sponsored reports.

CONTEXT: Meta-analyses are regularly used to inform healthcare decisions. Concerns have been expressed about the quality of meta-analyses and, in particular, about those supported by the pharmaceutical industry. OBJECTIVE: The objective of this study is to compare the quality of pharmaceutical-industry-supported meta-analyses with academic meta-analyses and of meta-analyses published before and after companies started to disclose their data. DATA SOURCES: We identified industry-supported meta-analyses by searching the Scopus bibliographic database, using author affiliations. We matched each industry-supported meta-analysis with an academic meta-analysis using high-level MeSH terms in PubMed. STUDY SELECTION: We included meta-analyses of randomized trials assessing the efficacy or safety of any pharmaceutical intervention in humans, published in 2002-2004 or 2008-2009. Cochrane reviews were excluded. Two individuals independently selected papers, with discrepancies resolved by two further individuals. ASSESSMENT: We developed and piloted a quality-assessment tool, consisting of 43 questions in four domains, with a key summary question covering each domain. Two individuals independently assessed each meta-analysis. RESULTS: We examined 126 meta-analysis publications in 63 matched pairs. The average quality was low, with fewer than 50% adequate in three of the four domains. Industry-supported meta-analyses less often demonstrated adequate methods for locating studies and assessing their quality (odds ratio 0.44, 95% confidence interval 0.21 to 0.92), for analysing the included studies (0.52, 0.25 to 1.06), for undertaking meta-analyses (0.82, 0.40 to 1.68) and in reaching sound conclusions (0.62, 0.30 to 1.28). Quality generally improved over time, particularly for some aspects of industry reports. CONCLUSIONS: Academic meta-analysis papers are generally of higher quality than industry-supported ones. This is largely due to less detailed reporting in industry-supported meta-analyses and a tendency for them to take the included studies at face value, probably arising from the implicit assumption that these studies already have high methodological standards to meet licensing requirements. The improved quality over time does not appear to be due to the use of data disclosed by industry. The main limitations of this study are the small sample of papers and the subjective nature of some of the assessment processes.

Role of multidetector computed tomography in the diagnosis and management of patients attending the rapid access chest pain clinic, The Scottish computed tomography of the heart (SCOT-HEART) trial: study protocol for randomized controlled trial.

BACKGROUND: Rapid access chest pain clinics have facilitated the early diagnosis and treatment of patients with coronary heart disease and angina. Despite this important service provision, coronary heart disease continues to be under-diagnosed and many patients are left untreated and at risk. Recent advances in imaging technology have now led to the widespread use of noninvasive computed tomography, which can be used to measure coronary artery calcium scores and perform coronary angiography in one examination. However, this technology has not been robustly evaluated in its application to the clinic. METHODS/DESIGN: The SCOT-HEART study is an open parallel group prospective multicentre randomized controlled trial of 4,138 patients attending the rapid access chest pain clinic for evaluation of suspected cardiac chest pain. Following clinical consultation, participants will be approached and randomized 1:1 to receive standard care or standard care plus ≥64-multidetector computed tomography coronary angiography and coronary calcium score. Randomization will be conducted using a web-based system to ensure allocation concealment and will incorporate minimization. The primary endpoint of the study will be the proportion of patients diagnosed with angina pectoris secondary to coronary heart disease at 6 weeks. Secondary endpoints will include the assessment of subsequent symptoms, diagnosis, investigation and treatment. In addition, long-term health outcomes, safety endpoints, such as radiation dose, and health economic endpoints will be assessed. Assuming a clinic rate of 27.0% for the diagnosis of angina pectoris due to coronary heart disease, we will need to recruit 2,069 patients per group to detect an absolute increase of 4.0% in the rate of diagnosis at 80% power and a two-sided P value of 0.05. The SCOT-HEART study is currently recruiting participants and expects to report in 2014. DISCUSSION: This is the first study to look at the implementation of computed tomography in the patient care pathway that is outcome focused. This study will have major implications for the management of patients with cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01149590.

Observer agreement in the angiographic assessment of arteriovenous malformations of the brain.

PURPOSE: We aimed to determine intraobserver and interobserver agreement in the characterization of brain arteriovenous malformation (AVM) angioarchitecture on intra-arterial digital subtraction angiograms. METHODS: Five experienced interventional neuroradiologists independently reviewed 40 anonymized angiograms obtained at the time of first-ever AVM diagnosis. The allocation of the films to observers was balanced for AVM size and complexity. Every observer was compared with himself and all the others by distributing the films in 2 batches 3 months apart. The observers used standard forms to collect both quantitative and categorized qualitative angiographic data. To measure agreement we used the kappa statistic (kappa) for nominal data, weighted kappa for ordinal and discrete interval data, and Bland & Altman analysis for continuous data. RESULTS: Intraobserver agreement was generally moderate to substantial, with 95% confidence intervals ranging from fair to almost perfect. However, for every characteristic, interobserver agreement was less than intraobserver agreement. Interobserver agreement was generally slight to moderate, with 95% confidence intervals ranging from less than chance to almost perfect. CONCLUSION: This study demonstrates the need for robust and generalizeable definitions of AVM angioarchitecture and methods of nidus size measurement-with proof of good intraobserver and interobserver agreement-for future efforts to understand the prognosis and best treatment of AVMs.