Anthony Michael Heagerty

Objectives The burden of cardiovascular disease (CVD) is increasing. Cardiac rehabilitation (CR) is a complex intervention offered to patients with CVD, following a heart event, diagnosis or intervention, and it aims to reduce mortality and morbidity. The objective of this within-trial economic evaluation was to compare the cost-effectiveness of metacognitive therapy (MCT) plus usual care (UC) to UC, from a health and social care perspective in the UK. Methods A multicentre, single-blind, randomised controlled trial (ISRCTN74643496) was conducted in the UK involving 332 patients with CR with elevated symptoms of anxiety and/or depression and compared group-based MCT with UC. The primary outcome of the cost-effectiveness analysis was quality-adjusted life-years (QALYs). The time horizon of the primary analysis was a 12-month follow-up. Missing data were imputed using multiple imputation. Uncertainty was explored by probabilistic bootstrapping. Sensitivity analyses tested the impact of the study design and assumptions on the incremental cost-effectiveness ratio. Results In the primary cost-effectiveness analysis, MCT intervention was dominant, with a cost-saving (net cost −£219; 95% CI −£1446, £1007) and QALY gains (net QALY 0.015; 95% CI −0.015, 0.045). However, there is a high level of uncertainty in the estimates. At a threshold of £30 000 per QALY, MCT intervention of around 76% was likely to be cost-effective. Conclusions Results suggest that intervention may be cost-saving and health-increasing; however, findings are uncertain and subject to limitations. Further research should aim to reduce the uncertainty in the findings (eg, with larger sample sizes) and explore potential longer-term economic benefits associated with MCT in this setting.

Background: Cardiac rehabilitation improves health and quality of life and reduces risk of further cardiac events. Twenty-eight per cent of cardiac rehabilitation patients experience clinically significant anxiety and 19% suffer depression. Such patients are at greater risk of death, further cardiac events and poorer quality of life and use more health care, leading to higher NHS costs. The available psychological treatments for cardiac patients have small effects on anxiety and depression and quality of life; therefore, more effective treatments are needed. Research shows that a thinking style dominated by rumination and worry maintains anxiety and depression. A psychological intervention (metacognitive therapy) effectively reduces this style of thinking and alleviates depression and anxiety in mental health settings. The PATHWAY study evaluated two versions of metacognitive therapy applied in cardiac rehabilitation services. Objectives: The primary aim was to improve psychological outcomes for cardiac rehabilitation patients. We evaluated two formats of metacognitive therapy: (1) a group-based face-to-face intervention delivered by cardiac rehabilitation staff (group-based metacognitive therapy) and (2) a paper-based, self-directed intervention (home-based metacognitive therapy). Each was compared with usual cardiac rehabilitation alone in separate randomised controlled trials. Design: A randomised feasibility trial (work stream 1) and a full-scale randomised controlled trial (work stream 2) evaluated group-metacognitive therapy, while separate feasibility and full-scale trials (work stream 3 and work stream 3+, respectively) evaluated home-based metacognitive therapy. A cost-effectiveness analysis of group-metacognitive therapy was conducted, along with stated preference surveys and qualitative studies examining patient psychological needs and therapists’ perspectives on metacognitive therapy. Setting: Seven NHS cardiac rehabilitation services across the north-west of England. Participants: Adults aged ≥ 18 years who met cardiac rehabilitation eligibility criteria, scored ≥ 8 on depression or anxiety subscales of the Hospital Anxiety and Depression Scale, and were able to read, understand and complete questionnaires in English. Interventions: Work stream 1 and work stream 2 – a 6-week group-metacognitive therapy intervention delivered by cardiac rehabilitation staff plus usual cardiac rehabilitation compared with usual cardiac rehabilitation alone. Group-metacognitive therapy was delivered once per week for 6 weeks, with each session lasting 90 minutes. Work stream 3 and work stream 3+ – home-based metacognitive therapy plus usual cardiac rehabilitation compared with usual cardiac rehabilitation alone. Home-metacognitive therapy was a paper-based manual that included six modules and two supportive telephone calls delivered by cardiac rehabilitation staff. Main outcome measures: The Hospital Anxiety and Depression Scale total score at 4-month follow-up was the primary outcome in all trials. A range of secondary outcomes were also evaluated. Results: Our qualitative study with 46 patients across three cardiac rehabilitation services suggested that cardiac rehabilitation patients’ psychological needs were not met by current approaches and that metacognitive therapy might offer an improved fit with their psychological symptoms. The internal pilot feasibility study (work stream 1; n = 54) demonstrated that a full-scale randomised controlled trial was feasible and acceptable and confirmed our sample size estimation. A subsequent full-scale, single-blind randomised controlled trial (work stream 2; n = 332) showed that adding group-based metacognitive therapy to cardiac rehabilitation was associated with statistically significant improvements on the Hospital Anxiety and Depression Scale (primary outcome) in anxiety and depression compared with cardiac rehabilitation alone at 4-month (adjusted mean difference −3.24, 95% confidence interval −4.67 to −1.81, p < 0.001; standardised mean difference 0.52) and 12-month follow-up (adjusted mean difference −2.19, 95% confidence interval −3.72 to −0.66, p = 0.005; standardised mean difference 0.33). The cost-effectiveness analysis suggested that group-metacognitive therapy was dominant, that it could be cost saving (net cost −£219, 95% confidence interval −£1446 to £1007) and health increasing (net quality-adjusted life-year 0.015, 95% confidence interval −0.015 to 0.045). However, confidence intervals were wide and overlapped zero, indicating high variability in the data and uncertainty in the estimates. A pilot feasibility trial (work stream 3; n = 108) supported a full-scale trial of home-metacognitive therapy and was extended (work stream 3+; n = 240). In the full trial, the adjusted mean difference on the Hospital and Anxiety and Depression Scale favoured the metacognitive therapy + cardiac rehabilitation arm (adjusted mean difference −2.64, 95% confidence interval −4.49 to −0.78, p = 0.005; standardised mean difference 0.38), with statistically significant greater improvements in anxiety and depression in home-metacognitive therapy plus cardiac rehabilitation than in cardiac rehabilitation alone at 4-month follow-up. A stated preference survey on clinic-delivered psychological therapy (not specific to metacognitive therapy) indicated a preference for including psychological therapy as part of cardiac rehabilitation. Participants favoured individual therapy, delivered by cardiac rehabilitation staff, with information provided prior to therapy and at a lower cost to the NHS. A pilot stated preference study focused on preferences for home- or clinic-based psychological therapy. Preferences were stronger for home-based therapy than for centre-based, but this was not statistically significant and participants highly valued receiving therapy and having reduced waiting times. Limitations: Limitations include no control for additional contact as part of metacognitive therapy to estimate non-specific effects. Work stream 3+ did not include 12-month follow-up and therefore the long-term effects of home-based metacognitive therapy are unknown. The health economics analysis was limited by sample size and large amount of missing data in the final follow up. Findings from the qualitative study cannot necessarily be generalised. Conclusions: Both group-based and home-based metacognitive therapy were associated with significantly greater reductions in anxiety and depression symptoms at 4 months, compared with cardiac rehabilitation alone. The results in group-based metacognitive therapy appeared to be stable over 12 months. Introducing metacognitive therapy into cardiac rehabilitation has the potential to improve mental health outcomes. Future work: Future studies should evaluate the long-term effects of home-metacognitive therapy and the effect of metacognitive therapy against other treatments offered in cardiac rehabilitation. Given the uncertainty in the economic evaluation, further work is needed to determine the cost-effectiveness of metacognitive therapy. Trial registration: Work stream 1/work stream 2: NCT02420431 and ISRCTN74643496; work stream 3: NCT03129282; work stream 3+: NCT03999359. The trial is registered with clinicaltrials.gov NCT03999359. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-1211-20011) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 7. See the NIHR Funding and Awards website for further award information.

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Background: The mechanism of the perivascular adipose tissue (PVAT) anticontractile effect is well characterized in rodent visceral vascular beds; however, little is known about the mechanism of PVAT anticontractile function in subcutaneous vessels. In addition, we have previously shown that PVAT anticontractile function is nitric oxide synthase (NOS) dependent but have not investigated the roles of NOS isoforms. Objective: Here, we examined PVAT anticontractile function in the mouse gracilis artery, a subcutaneous fat depot, in lean control and obese mice and investigated the mechanism in comparison to a visceral depot. Method: Using the wire myograph, we generated responses to noradrenaline and electrical field stimulation in the presence of pharmacological tools targeting components of the known PVAT anticontractile mechanism. In addition, we performed ex vivo “fat transplants” in the organ bath. Results: The mechanism of PVAT anticontractile function is similar between subcutaneous and visceral PVAT depots. Both endothelial and neuronal NOS isoforms mediated the PVAT anticontractile effect. Loss of PVAT anticontractile function in obesity is independent of impaired vasoreactivity, and function can be restored in visceral PVAT by NOS activation. Conclusions: Targeting NOS isoforms may be useful in restoring PVAT anticontractile function in obesity, ameliorating increased vascular tone, and disease.

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Background: Patients presenting with chest pain represent a large proportion of attendances to emergency departments. In these patients clinicians often consider the diagnosis of acute myocardial infarction (AMI), the timely recognition and treatment of which is clinically important. Clinical prediction models (CPMs) have been used to enhance early diagnosis of AMI. The Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid is currently in clinical use across Greater Manchester. CPMs have been shown to deteriorate over time through calibration drift. We aim to assess potential calibration drift with T-MACS and compare methods for updating the model. Methods: We will use routinely collected electronic data from patients who were treated using TMACS at two large NHS hospitals. This is estimated to include approximately 14,000 patient episodes spanning June 2016 to October 2020. The primary outcome of acute myocardial infarction will be sourced from NHS Digital’s admitted patient care dataset. We will assess the calibration drift of the existing model and the benefit of updating the CPM by model recalibration, model extension and dynamic updating. These models will be validated by bootstrapping and one step ahead prequential testing. We will evaluate predictive performance using calibrations plots and c-statistics. We will also examine the reclassification of predicted probability with the updated TMACS model. Discussion: CPMs are widely used in modern medicine, but are vulnerable to deteriorating calibration over time. Ongoing refinement using routinely collected electronic data will inevitably be more efficient than deriving and validating new models. In this analysis we will seek to exemplify methods for updating CPMs to protect the initial investment of time and effort. If successful, the updating methods could be used to continually refine the algorithm used within TMACS, maintaining or even improving predictive performance over time. Trial registration: ISRCTN number: ISRCTN41008456