Randomised trial of stable chest pain investigation: 3-year clinical and quality of life results from CE-MARC 2.

AIMS: Guidelines for suspected cardiac chest pain have used historical risk stratification tools, advocating invasive coronary angiography (ICA) first-line in those at highest risk. We aimed to determine whether different strategies to manage suspected stable angina affected medium-term cardiovascular event rates and patient-reported quality of life (QoL) measures. METHODS: CE-MARC 2, a three-arm parallel group trial, randomised patients with suspected stable cardiac chest pain and a Duke Clinical pretest likelihood of coronary artery disease between 10% and 90%. Patients were randomised to either first-line cardiovascular magnetic resonance (CMR), single-photon emission computed tomography (SPECT) or the UK National Institute for Health and Care Excellence (NICE) CG95 (2010) guidelines-directed care. For the three arms, 1-year and 3-year first major adverse cardiovascular event (MACE) rates and QoL assessed by the Seattle Angina Questionnaire, Short Form 12 (V.12) Questionnaire and EuroQol-5 Dimension Questionnaire were recorded. RESULTS: 1202 patients were randomised to CMR (n=481), SPECT (n=481) and NICE (n=240). Forty-two patients (18 CMR, 18 SPECT, 6 NICE) experienced one or more MACEs. The percentage rates (95% CIs) of MACE in the CMR, SPECT and NICE groups at 3 years were 3.7% (2.4%, 5.8%), 3.7% (2.4%, 5.8%) and 2.1% (0.9%, 4.8%), respectively. QoL scores did not significantly differ across domains. CONCLUSION: Despite a fourfold increase in referrals for ICA, the NICE CG95 (2010) guidelines risk-stratified care strategy did not significantly reduce 3-year MACE or improve QoL, as compared with functional imaging with CMR or SPECT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT01664858).

Multicenter Randomized Trial of Intermittently Scanned Continuous Glucose Monitoring Versus Self-Monitoring of Blood Glucose in Individuals With Type 2 Diabetes and Recent-Onset Acute Myocardial Infarction: Results of the LIBERATES Trial.

OBJECTIVE: To analyze the impact of modern glucose-monitoring strategies on glycemic and patient-related outcomes in individuals with type 2 diabetes (T2D) and recent myocardial infarction (MI) and assess cost effectiveness. RESEARCH DESIGN AND METHODS: LIBERATES was a multicenter two-arm randomized trial comparing self-monitoring of blood glucose (SMBG) with intermittently scanned continuous glucose monitoring (isCGM), also known as flash CGM, in individuals with T2D and recent MI, treated with insulin and/or a sulphonylurea before hospital admission. The primary outcome measure was time in range (TIR) (glucose 3.9-10 mmol/L/day) on days 76-90 post-randomization. Secondary and exploratory outcomes included time in hypoglycemia, hemoglobin A1c (HbA1c), clinical outcome, quality of life (QOL), and cost effectiveness. RESULTS: Of 141 participants randomly assigned (median age 63 years; interquartile range 53, 70), 73% of whom were men, isCGM was associated with increased TIR by 17 min/day (95% credible interval -105 to +153 min/day), with 59% probability of benefit. Users of isCGM showed lower hypoglycemic exposure (<3.9 mmol/L) at days 76-90 (-80 min/day; 95% CI -118, -43), also evident at days 16-30 (-28 min/day; 95% CI -92, 2). Compared with baseline, HbA1c showed similar reductions of 7 mmol/mol at 3 months in both study arms. Combined glycemic emergencies and mortality occurred in four isCGM and seven SMBG study participants. QOL measures marginally favored isCGM, and the intervention proved to be cost effective. CONCLUSIONS: Compared with SMBG, isCGM in T2D individuals with MI marginally increases TIR and significantly reduces hypoglycemic exposure while equally improving HbA1c, explaining its cost effectiveness. Studies are required to understand whether these glycemic differences translate into longer-term clinical benefit.

Visualising harms in publications of randomised controlled trials: consensus and recommendations.

OBJECTIVE: To improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes. DESIGN: Consensus study. SETTING: 15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and The BMJ. PARTICIPANTS: Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians. MAIN OUTCOME: measures A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached. RESULTS: 28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation. CONCLUSIONS: Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of information and enable more informative interpretations. The limitations of each visualisation are discussed and examples of where their use would be inappropriate are given. Although the decision tree aids the choice of visualisation, the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. Trialists should continue to examine crude numbers alongside visualisations to fully understand harm profiles.

A roadmap to using randomization in clinical trials.

BACKGROUND: Randomization is the foundation of any clinical trial involving treatment comparison. It helps mitigate selection bias, promotes similarity of treatment groups with respect to important known and unknown confounders, and contributes to the validity of statistical tests. Various restricted randomization procedures with different probabilistic structures and different statistical properties are available. The goal of this paper is to present a systematic roadmap for the choice and application of a restricted randomization procedure in a clinical trial. METHODS: We survey available restricted randomization procedures for sequential allocation of subjects in a randomized, comparative, parallel group clinical trial with equal (1:1) allocation. We explore statistical properties of these procedures, including balance/randomness tradeoff, type I error rate and power. We perform head-to-head comparisons of different procedures through simulation under various experimental scenarios, including cases when common model assumptions are violated. We also provide some real-life clinical trial examples to illustrate the thinking process for selecting a randomization procedure for implementation in practice. RESULTS: Restricted randomization procedures targeting 1:1 allocation vary in the degree of balance/randomness they induce, and more importantly, they vary in terms of validity and efficiency of statistical inference when common model assumptions are violated (e.g. when outcomes are affected by a linear time trend; measurement error distribution is misspecified; or selection bias is introduced in the experiment). Some procedures are more robust than others. Covariate-adjusted analysis may be essential to ensure validity of the results. Special considerations are required when selecting a randomization procedure for a clinical trial with very small sample size. CONCLUSIONS: The choice of randomization design, data analytic technique (parametric or nonparametric), and analysis strategy (randomization-based or population model-based) are all very important considerations. Randomization-based tests are robust and valid alternatives to likelihood-based tests and should be considered more frequently by clinical investigators.

Rationale and design of the LIBERATES trial: Protocol for a randomised controlled trial of flash glucose monitoring for optimisation of glycaemia in individuals with type 2 diabetes and recent myocardial infarction.

Hyperglycaemia in individuals with type 2 diabetes (T2D) and myocardial infarction (MI) is associated with guarded clinical prognosis. Studies improving glucose levels in T2D following MI relied on HbA1c as the main glycaemic marker, failing to address potential adverse effects of hypoglycaemia and glucose variability. We describe the design of the LIBERATES trial that investigates the role of flash glucose monitoring in optimising glycaemic markers in high vascular risk individuals with T2D. This multicentre trial is designed to recruit up to 150 insulin and/or sulphonylurea-treated T2D patients, within 5 days of a proven MI. Individuals will be randomised 1:1 into intervention and control groups using flash glucose monitoring sensors and traditional self-monitoring of blood glucose, respectively. The control group will also wear a blinded continuous glucose monitoring sensor. The primary outcome is the difference in time spent in euglycaemia (defined as glucose levels between 3.9-10.0 mmol/l), comparing study groups 3 months following recruitment, assessed daily for 14 days and as an average. Secondary and exploratory end points include time spent in hypoglycaemia and hyperglycaemia, HbA1c, quality of life measures, major adverse cardiac events and cost-effectiveness of the intervention. This study will establish the role of flash glucose monitoring in glycaemic management of individuals with T2D sustaining a cardiac event.(Trial Registration: ISRCTN14974233, registered 12th June 2017).

Evaluation of the impact of the GRACE risk score on the management and outcome of patients hospitalised with non-ST elevation acute coronary syndrome in the UK: protocol of the UKGRIS cluster-randomised registry-based trial.

INTRODUCTION: For non-ST-segment elevation acute coronary syndrome (NSTEACS) there is a gap between the use of class I guideline recommended therapies and clinical practice. The Global Registry of Acute Coronary Events (GRACE) risk score is recommended in international guidelines for the risk stratification of NSTEACS, but its impact on adherence to guideline-indicated treatments and reducing adverse clinical outcomes is unknown. The objective of the UK GRACE Risk Score Intervention Study (UKGRIS) trial is to assess the effectiveness of the GRACE risk score tool and associated treatment recommendations on the use of guideline-indicated care and clinical outcomes. METHODS AND ANALYSIS: The UKGRIS, a parallel-group cluster randomised registry-based controlled trial, will allocate hospitals in a 1:1 ratio to manage NSTEACS by standard care or according to the GRACE risk score and associated international guidelines. UKGRIS will recruit a minimum of 3000 patients from at least 30 English National Health Service hospitals and collect healthcare data from national electronic health records. The co-primary endpoints are the use of guideline-indicated therapies, and the composite of cardiovascular death, non-fatal myocardial infarction, new onset heart failure hospitalisation or cardiovascular readmission at 12 months. Secondary endpoints include duration of inpatient hospital stay over 12 months, EQ-5D-5L responses and utilities, unscheduled revascularisation and the components of the composite endpoint over 12 months follow-up. ETHICS AND DISSEMINATION: The study has ethical approval (North East - Tyne & Wear South Research Ethics Committee reference: 14/NE/1180). Findings will be announced at relevant conferences and published in peer-reviewed journals in line with the funder's open access policy. TRIAL REGISTRATION NUMBER: ISRCTN29731761; Pre-results.

Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following failure of initial TNFi in rheumatoid arthritis: the SWITCH RCT.

BACKGROUND: Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population. OBJECTIVES: To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy. DESIGN: Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status. SETTING: UK outpatient rheumatology departments. PARTICIPANTS: Patients aged ≥ 18 years who were diagnosed with RA and were receiving MTX, but had not responded to two or more conventional synthetic disease-modifying antirheumatic drug therapies and had shown an inadequate treatment response to a first TNFi. INTERVENTIONS: Alternative TNFi, abatacept or rituximab (and continued background MTX). MAIN OUTCOME MEASURES: The primary outcome was absolute reduction in the Disease Activity Score of 28 joints (DAS28) at 24 weeks post randomisation. Secondary outcome measures over 48 weeks were additional measures of disease activity, quality of life, cost-effectiveness, radiographic measures, safety and toxicity. LIMITATIONS: Owing to third-party contractual issues, commissioning challenges delaying centre set-up and thus slower than expected recruitment, the funders terminated the trial early. RESULTS: Between July 2012 and December 2014, 149 patients in 35 centres were registered, of whom 122 were randomised to treatment (alternative TNFi, n = 41; abatacept, n = 41; rituximab, n = 40). The numbers, as specified, were analysed in each group [in line with the intention-to-treat (ITT) principle]. Comparing alternative TNFi with rituximab, the difference in mean reduction in DAS28 at 24 weeks post randomisation was 0.3 [95% confidence interval (CI) -0.45 to 1.05] in the ITT patient population and -0.58 (95% CI -1.72 to 0.55) in the per protocol (PP) population. Corresponding results for the abatacept and rituximab comparison were 0.04 (95% CI -0.72 to 0.79) in the ITT population and -0.15 (95% CI -1.27 to 0.98) in the PP population. General improvement in the Health Assessment Questionnaire Disability Index, Rheumatoid Arthritis Quality of Life and the patients' general health was apparent over time, with no notable differences between treatment groups. There was a marked initial improvement in the patients' global assessment of pain and arthritis at 12 weeks across all three treatment groups. Switching to alternative TNFi may be cost-effective compared with rituximab [incremental cost-effectiveness ratio (ICER) £5332.02 per quality-adjusted life-year gained]; however, switching to abatacept compared with switching to alternative TNFi is unlikely to be cost-effective (ICER £253,967.96), but there was substantial uncertainty in the decisions. The value of information analysis indicated that further research would be highly valuable to the NHS. Ten serious adverse events in nine patients were reported; none were suspected unexpected serious adverse reactions. Two patients died and 10 experienced toxicity. FUTURE WORK: The results will add to the randomised evidence base and could be included in future meta-analyses. CONCLUSIONS: How to manage first-line TNFi treatment failures remains unresolved. Had the trial recruited to target, more credible evidence on whether or not either of the interventions were non-inferior to rituximab may have been provided, although this remains speculative. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89222125 and ClinicalTrials.gov NCT01295151. 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. 22, No. 34. See the NIHR Journals Library website for further project information.

Amaze: a randomized controlled trial of adjunct surgery for atrial fibrillation.

OBJECTIVES: Atrial fibrillation (AF) reduces survival and quality of life (QoL). It can be treated at the time of major cardiac surgery using ablation procedures ranging from simple pulmonary vein isolation to a full maze procedure. The aim of this study is to evaluate the impact of adjunct AF surgery as currently performed on sinus rhythm (SR) restoration, survival, QoL and cost-effectiveness. METHODS: In a multicentre, Phase III, pragmatic, double-blinded, parallel-armed randomized controlled trial, 352 cardiac surgery patients with >3 months of documented AF were randomized to surgery with or without adjunct maze or similar AF ablation between 2009 and 2014. Primary outcomes were SR restoration at 1 year and quality-adjusted life years at 2 years. Secondary outcomes included SR at 2 years, overall and stroke-free survival, medication, QoL, cost-effectiveness and safety. RESULTS: More ablation patients were in SR at 1 year [odds ratio (OR) 2.06, 95% confidence interval (CI) 1.20-3.54; P = 0.009]. At 2 years, the OR increased to 3.24 (95% CI 1.76-5.96). Quality-adjusted life years were similar at 2 years (ablation - control -0.025, P = 0.6319). Significantly fewer ablation patients were anticoagulated from 6 months postoperatively. Stroke rates were 5.7% (ablation) and 9.1% (control) (P = 0.3083). There was no significant difference in stroke-free survival [hazard ratio (HR) = 0.99, 95% CI 0.64-1.53; P = 0.949] nor in serious adverse events, operative or overall survival, cardioversion, pacemaker implantation, New York Heart Association, EQ-5D-3L and SF-36. The mean additional ablation cost per patient was £3533 (95% CI £1321-£5746). Cost-effectiveness was not demonstrated at 2 years. CONCLUSIONS: Adjunct AF surgery is safe and increases SR restoration and costs but not survival or QoL up to 2 years. A continued follow-up will provide information on these outcomes in the longer term. Study registration: ISRCTN82731440 (project number 07/01/34).

Effect of rituximab on a salivary gland ultrasound score in primary Sjögren's syndrome: results of the TRACTISS randomised double-blind multicentre substudy.

OBJECTIVES: To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren's syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. METHODS: Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0-11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. RESULTS: 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were -1.2 (95% CI -2.1 to -0.3; P=0.0099) and -1.2 (95% CI -2.0 to -0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. CONCLUSIONS: We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. TRIAL REGISTRATION NUMBER: 65360827, 2010-021430-64; Results.

Randomized Controlled Trial of Rituximab and Cost-Effectiveness Analysis in Treating Fatigue and Oral Dryness in Primary Sjögren's Syndrome.

OBJECTIVE: To investigate whether rituximab, an anti-B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögren's syndrome (SS). METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that included health economic analysis. Anti-Ro-positive patients with primary SS, symptomatic fatigue, and oral dryness were recruited from 25 UK rheumatology clinics from August 2011 to January 2014. Patients were centrally randomized to receive either intravenous (IV) placebo (250 ml saline) or IV rituximab (1,000 mg in 250 ml saline) in 2 courses at weeks 0, 2, 24, and 26, with pre- and postinfusion medication including corticosteroids. The primary end point was the proportion of patients achieving a 30% reduction in either fatigue or oral dryness at 48 weeks, as measured by visual analog scale. Other outcome measures included salivary and lacrimal flow rates, quality of life, scores on the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient Reported Index and EULAR Sjögren's Syndrome Disease Activity Index, symptoms of ocular and overall dryness, pain, globally assessed disease activity, and cost-effectiveness. RESULTS: All 133 patients who were randomized to receive placebo (n = 66) or rituximab (n = 67) were included in the primary analysis. Among patients with complete data, 21 of 56 placebo-treated patients and 24 of 61 rituximab-treated patients achieved the primary end point. After multiple imputation of missing outcomes, response rates in the placebo and rituximab groups were 36.8% and 39.8%, respectively (adjusted odds ratio 1.13 [95% confidence interval 0.50, 2.55]). There were no significant improvements in any outcome measure except for unstimulated salivary flow. The mean ± SD costs per patient for rituximab and placebo were £10,752 ± 264.75 and £2,672 ± 241.71, respectively. There were slightly more adverse events (AEs) reported in total for rituximab, but there was no difference in serious AEs (10 in each group). CONCLUSION: The results of this study indicate that rituximab is neither clinically effective nor cost-effective in this patient population.

Effect of Care Guided by Cardiovascular Magnetic Resonance, Myocardial Perfusion Scintigraphy, or NICE Guidelines on Subsequent Unnecessary Angiography Rates: The CE-MARC 2 Randomized Clinical Trial.

IMPORTANCE: Among patients with suspected coronary heart disease (CHD), rates of invasive angiography are considered too high. OBJECTIVE: To test the hypothesis that among patients with suspected CHD, cardiovascular magnetic resonance (CMR)-guided care is superior to National Institute for Health and Care Excellence (NICE) guidelines-directed care and myocardial perfusion scintigraphy (MPS)-guided care in reducing unnecessary angiography. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, 3-parallel group, randomized clinical trial using a pragmatic comparative effectiveness design. From 6 UK hospitals, 1202 symptomatic patients with suspected CHD and a CHD pretest likelihood of 10% to 90% were recruited. First randomization was November 23, 2012; last 12-month follow-up was March 12, 2016. INTERVENTIONS: Patients were randomly assigned (240:481:481) to management according to UK NICE guidelines or to guided care based on the results of CMR or MPS testing. MAIN OUTCOMES AND MEASURES: The primary end point was protocol-defined unnecessary coronary angiography (normal fractional flow reserve >0.8 or quantitative coronary angiography [QCA] showing no percentage diameter stenosis ≥70% in 1 view or ≥50% in 2 orthogonal views in all coronary vessels ≥2.5 mm diameter) within 12 months. Secondary end points included positive angiography, major adverse cardiovascular events (MACEs), and procedural complications. RESULTS: Among 1202 symptomatic patients (mean age, 56.3 years [SD, 9.0]; women, 564 [46.9%] ; mean CHD pretest likelihood, 49.5% [SD, 23.8%]), number of patients with invasive coronary angiography after 12 months was 102 in the NICE guidelines group (42.5% [95% CI, 36.2%-49.0%])], 85 in the CMR group (17.7% [95% CI, 14.4%-21.4%]); and 78 in the MPS group (16.2% [95% CI, 13.0%-19.8%]). Study-defined unnecessary angiography occurred in 69 (28.8%) in the NICE guidelines group, 36 (7.5%) in the CMR group, and 34 (7.1%) in the MPS group; adjusted odds ratio of unnecessary angiography: CMR group vs NICE guidelines group, 0.21 (95% CI, 0.12-0.34, P < .001); CMR group vs the MPS group, 1.27 (95% CI, 0.79-2.03, P = .32). Positive angiography proportions were 12.1% (95% CI, 8.2%-16.9%; 29/240 patients) for the NICE guidelines group, 9.8% (95% CI, 7.3%-12.8%; 47/481 patients) for the CMR group, and 8.7% (95% CI, 6.4%-11.6%; 42/481 patients) for the MPS group. A MACE was reported at a minimum of 12 months in 1.7% of patients in the NICE guidelines group, 2.5% in the CMR group, and 2.5% in the MPS group (adjusted hazard ratios: CMR group vs NICE guidelines group, 1.37 [95% CI, 0.52-3.57]; CMR group vs MPS group, 0.95 [95% CI, 0.46-1.95]). CONCLUSIONS AND RELEVANCE: In patients with suspected angina, investigation by CMR resulted in a lower probability of unnecessary angiography within 12 months than NICE guideline-directed care, with no statistically significant difference between CMR and MPS strategies. There were no statistically significant differences in MACE rates. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01664858.

Prognostic Value of Cardiovascular Magnetic Resonance and Single-Photon Emission Computed Tomography in Suspected Coronary Heart Disease: Long-Term Follow-up of a Prospective, Diagnostic Accuracy Cohort Study.

BACKGROUND: There are no prospective, prognostic data comparing cardiovascular magnetic resonance (CMR) and single-photon emission computed tomography (SPECT) in the same population of patients with suspected coronary heart disease (CHD). OBJECTIVE: To establish the ability of CMR and SPECT to predict major adverse cardiovascular events (MACEs). DESIGN: Annual follow-up of the CE-MARC (Clinical Evaluation of MAgnetic Resonance imaging in Coronary heart disease) study for a minimum of 5 years for MACEs (cardiovascular death, acute coronary syndrome, unscheduled revascularization or hospital admission for cardiovascular cause). (Current Controlled Trials registration: ISRCTN77246133). SETTING: Secondary and tertiary care cardiology services. PARTICIPANTS: 752 patients from the CE-MARC study who were being investigated for suspected CHD. MEASUREMENTS: Prediction of time to MACE was assessed by using univariable (log-rank test) and multivariable (Cox proportional hazards regression) analysis. RESULTS: 744 (99%) of the 752 recruited patients had complete follow-up. Of 628 who underwent CMR, SPECT, and the reference standard test of X-ray angiography, 104 (16.6%) had at least 1 MACE. Abnormal findings on CMR (hazard ratio, 2.77 [95% CI, 1.85 to 4.16]; P < 0.001) and SPECT (hazard ratio, 1.62 [CI, 1.11 to 2.38; P = 0.014) were both strong and independent predictors of MACE. Only CMR remained a significant predictor after adjustment for other cardiovascular risk factors, angiography result, or stratification for initial patient treatment. LIMITATION: Data are from a single-center observational study (albeit conducted in a high-volume institution for both CMR and SPECT). CONCLUSION: Five-year follow-up of the CE-MARC study indicates that compared with SPECT, CMR is a stronger predictor of risk for MACEs, independent of cardiovascular risk factors, angiography result, or initial patient treatment. This further supports the role of CMR as an alternative to SPECT for the diagnosis and management of patients with suspected CHD. PRIMARY FUNDING SOURCE: British Heart Foundation.

Factors associated with false-negative cardiovascular magnetic resonance perfusion studies: A Clinical evaluation of magnetic resonance imaging in coronary artery disease (CE-MARC) substudy.

PURPOSE: To examine factors associated with false-negative cardiovascular magnetic resonance (MR) perfusion studies within the large prospective Clinical Evaluation of MR imaging in Coronary artery disease (CE-MARC) study population. Myocardial perfusion MR has excellent diagnostic accuracy to detect coronary heart disease (CHD). However, causes of false-negative MR perfusion studies are not well understood. MATERIALS AND METHODS: CE-MARC prospectively recruited patients with suspected CHD and mandated MR, myocardial perfusion scintigraphy, and invasive angiography. This subanalysis identified all patients with significant coronary stenosis by quantitative coronary angiography (QCA) and MR perfusion (1.5T, T1 -weighted gradient echo), using the original blinded image read. We explored patient and imaging characteristics related to false-negative or true-positive MR perfusion results, with reference to QCA. Multivariate regression analysis assessed the likelihood of false-negative MR perfusion according to four characteristics: poor image quality, triple-vessel disease, inadequate hemodynamic response to adenosine, and Duke jeopardy score (angiographic myocardium-at-risk score). RESULTS: In all, 265 (39%) patients had significant angiographic disease (mean age 62, 79% male). Thirty-five (5%) had false-negative and 230 (34%) true-positive MR perfusion. Poor MR perfusion image quality, triple-vessel disease, and inadequate hemodynamic response were similar between false-negative and true-positive groups (odds ratio, OR [95% confidence interval, CI]: 4.1 (0.82-21.0), P = 0.09; 1.2 (0.20-7.1), P = 0.85, and 1.6 (0.65-3.8), P = 0.31, respectively). Mean Duke jeopardy score was significantly lower in the false-negative group (2.6 ± 1.7 vs. 5.4 ± 3.0, OR 0.34 (0.21-0.53), P < 0.0001). CONCLUSION: False-negative cardiovascular MR perfusion studies are uncommon, and more common in patients with lower angiographic myocardium-at-risk. In CE-MARC, poor image quality, triple-vessel disease, and inadequate hemodynamic response were not significantly associated with false-negative MR perfusion.

Individual component analysis of the multi-parametric cardiovascular magnetic resonance protocol in the CE-MARC trial.

BACKGROUND: The CE-MARC study assessed the diagnostic performance investigated the use of cardiovascular magnetic resonance (CMR) in patients with suspected coronary artery disease (CAD). The study used a multi-parametric CMR protocol assessing 4 components: i) left ventricular function; ii) myocardial perfusion; iii) viability (late gadolinium enhancement (LGE)) and iv) coronary magnetic resonance angiography (MRA). In this pre-specified CE-MARC sub-study we assessed the diagnostic accuracy of the individual CMR components and their combinations. METHODS: All patients from the CE-MARC population (n = 752) were included using data from the original blinded-read. The four individual core components of the CMR protocol was determined separately and then in paired and triplet combinations. Results were then compared to the full multi-parametric protocol. RESULTS: CMR and X-ray angiography results were available in 676 patients. The maximum sensitivity for the detection of significant CAD by CMR was achieved when all four components were used (86.5%). Specificity of perfusion (91.8%), function (93.7%) and LGE (95.8%) on its own was significantly better than specificity of the multi-parametric protocol (83.4%) (all P < 0.0001) but with the penalty of decreased sensitivity (86.5% vs. 76.9%, 47.4% and 40.8% respectively). The full multi-parametric protocol was the optimum to rule-out significant CAD (Likelihood Ratio negative (LR-) 0.16) and the LGE component alone was the best to rue-in CAD (LR+ 9.81). Overall diagnostic accuracy was similar with the full multi-parametric protocol (85.9%) compared to paired and triplet combinations. The use of coronary MRA within the full multi-parametric protocol had no additional diagnostic benefit compared to the perfusion/function/LGE combination (overall accuracy 84.6% vs. 84.2% (P = 0.5316); LR- 0.16 vs. 0.21; LR+ 5.21 vs. 5.77). CONCLUSIONS: From this pre-specified sub-analysis of the CE-MARC study, the full multi-parametric protocol had the highest sensitivity and was the optimal approach to rule-out significant CAD. The LGE component alone was the optimal rule-in strategy. Finally the inclusion of coronary MRA provided no additional benefit when compared to the combination of perfusion/function/LGE. TRIAL REGISTRATION: Current Controlled Trials ISRCTN77246133.

Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): a prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease.

BACKGROUND: A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance. TRIAL DESIGN: CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance-guided care, single-photon emission computed tomography-guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines-based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed. CONCLUSIONS: The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation.

The 'Switch' study protocol: a randomised-controlled trial of switching to an alternative tumour-necrosis factor (TNF)-inhibitor drug or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-inhibitor drug.

BACKGROUND: Rheumatoid Arthritis (RA) is one of the most common autoimmune diseases, affecting approximately 1% of the UK adult population. Patients suffer considerable pain, stiffness and swelling and can sustain various degrees of joint destruction, deformity, and significant functional decline. In addition, the economic burden due to hospitalisation and loss of employment is considerable, with over 50% of patients being work-disabled within 10 years of diagnosis. Despite several biologic disease modifying anti-rheumatic drugs (bDMARD) now available, there is a lack of data to guide biologic sequencing. In the UK, second-line biologic treatment is restricted to a single option, rituximab. The aim of the SWITCH trial is to establish whether an alternative-mechanism-TNF-inhibitor (TNFi) or abatacept are as effective as rituximab in patients with RA who have failed an initial TNFi drug. METHODS/DESIGN: SWITCH is a pragmatic, phase IV, multi-centre, parallel-group design, open-label, randomised, controlled trial (RCT) comparing alternative-mechanism-TNFi and abatacept with rituximab in patients with RA who have failed an initial TNFi drug. Participants are randomised in a 1:1:1 ratio to receive alternative mechanism TNFi, (monoclonal antibodies: infliximab, adalimumab, certolizumab or golimumab or the receptor fusion protein, etanercept), abatacept or rituximab during the interventional phase (from randomisation up to week 48). Participants are subsequently followed up to a maximum of 96 weeks, which constitutes the observational phase. The primary objective is to establish whether an alternative-mechanism-TNFi or abatacept are non-inferior to rituximab in terms of disease response at 24 weeks post randomisation. The secondary objectives include the comparison of alternative-mechanism-TNFi and abatacept to rituximab in terms of disease response, quality of life, toxicity, safety and structural and bone density outcomes over a 12-month period (48 weeks) and to evaluate the cost-effectiveness of switching patients to alternative active therapies compared to current practice. DISCUSSION: SWITCH is a well-designed trial in this therapeutic area that aims to develop a rational treatment algorithm to potentially inform personalised treatment regimens (as opposed to switching all patients to only one available (and possibly unsuccessful) therapy), which may lead to long-term improved patient outcomes and gains in population health. TRIAL REGISTRATION: UKCRN Portfolio ID: 12343; ISRCTN89222125 ; NCT01295151.

Comparison of cardiovascular magnetic resonance and single-photon emission computed tomography in women with suspected coronary artery disease from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) Trial.

BACKGROUND: Coronary artery disease is the leading cause of death in women, and underdiagnosis contributes to the high mortality. This study compared the sex-specific diagnostic performance of cardiovascular magnetic resonance (CMR) and single-photon emission computed tomography (SPECT). METHODS AND RESULTS: A total of 235 women and 393 men with suspected angina underwent CMR, SPECT, and x-ray angiography as part of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) study. CMR comprised adenosine stress/rest perfusion, cine imaging, late gadolinium enhancement, and magnetic resonance coronary angiography. Gated adenosine stress/rest SPECT was performed with (99m)Tc-tetrofosmin. For CMR, the sensitivity in women and men was similar (88.7% versus 85.6%; P=0.57), as was the specificity (83.5% versus 82.8%; P=0.86). For SPECT, the sensitivity was significantly worse in women than in men (50.9% versus 70.8%; P=0.007), but the specificities were similar (84.1% versus 81.3%; P=0.48). The sensitivity in both the female and male groups was significantly higher with CMR than SPECT (P<0.0001 for both), but the specificity was similar (P=0.77 and P=1.00, respectively). For perfusion-only components, CMR outperformed SPECT in women (area under the curve, 0.90 versus 0.67; P<0.0001) and in men (area under the curve, 0.89 versus 0.74; P<0.0001). Diagnostic accuracy was similar in both sexes with perfusion CMR (P=1.00) but was significantly worse in women with SPECT (P<0.0001). CONCLUSIONS: In both sexes, CMR has greater sensitivity than SPECT. Unlike SPECT, there are no significant sex differences in the diagnostic performance of CMR. These findings, plus an absence of ionizing radiation exposure, mean that CMR should be more widely adopted in women with suspected coronary artery disease. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN77246133.