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Better Treatments for Refractory Breathlessness

Chronic breathlessness is a distressing and highly prevalent symptom of advanced chronic respiratory diseases. It is associated with social isolation, high healthcare costs and poor prognosis. Currently, there are few effective drug treatments thus, chronic breathlessness represents a huge unmet need.

At the core of the Better Treatments for Refractory Breathlessness project (BETTER-B) was an international, multicentre, randomised controlled trial testing the effectiveness of mirtazapine, an established antidepressant, in patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD).

The BETTER-B programme of work also included an online survey of physicians to understand current clinical management of breathlessness, the production of European wide guidance on the management of breathlessness in palliative and end of life care, and qualitative interviews with trial participants (patients and caregivers) to further understand their experiences.

Aims

To deliver a step-change in the evidence-based management of breathlessness in palliative and end of life care.

Methods

The BETTER-B investigators conducted a randomized, double-blind, clinical trial in order to test the efficacy and cost-effectiveness of mirtazapine compared to a dummy drug in patients located in the UK, several European countries, Australia and New Zealand. The project also included an online survey, the production of a Europe-wide guide on the management of breathlessness in palliative and end-of-life care, and interviews with trial participants to understand their experiences.

Summary of Findings

From the BETTER-B online survey, we found wide variations in how breathlessness is managed. People received different levels of care based on where they were treated and the disease that they had. Some people may be seen by respiratory physicians, while others may be treated by palliative care physicians. Of those that responded, a sizeable number of respiratory and palliative care physicians often or always recommended antidepressants for patients with advanced respiratory diseases, even where there was no evidence of depression. This finding demonstrated the need for proper assessment of medicines.

Trial results

We enrolled 225 patients and 75 caregivers across the UK, Europe, Australia and New Zealand into the trial. The project engaged with patient-led groups and clinicians across the countries.

Key finding: the antidepressant mirtazapine does not alleviate severe breathlessness. Our findings raise questions about using medicines in a manner different from its licence.

There was no difference in severe breathlessness between those people taking mirtazapine and those taking placebo during the main period of the trial, of 56 days.

Similar results were found for other measures. This included a person’s quality of life, broader symptoms, anxiety and depression, and frequency of breathlessness episodes. There were no differences found up to six months after the start of the trial.

Read more about the trial results.

Impact

BETTER-B provides a wide-reaching impact by translating the trial and research results to produce recommendations, educational materials and clinical improvements for clinicians and policymakers in palliative, supportive, respiratory, primary and end-of-life care.

Some resources developed by our King's team that you may find helpful in breathlessness management are listed below:

Breathlessness Support Service Toolkit

Free e-resources for professionals 

For further information on managing breathlessness in advanced illness, please read the feature article 'Managing breathlessness in advanced illness'.

Project Team

Sabrina Bajwah

Clinical Senior Lecturer and Honorary Consultant in Palliative Care

Irene Higginson

Director of Better Health and Care Futures

Matthew Maddocks

Professor of Health Services Research & Rehabilitation

Senior Lecturer in Health Economics

Charles Normand

Professor of Economics of Palliative Care & Rehabilitation

Publications

Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B): an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 mixed-method trial
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(24)00187-5/fulltext

Practice review: Pharmacological management of severe chronic breathlessness in adults with advanced life-limiting diseases https://journals.sagepub.com/doi/abs/10.1177/02692163241270945

Integrating home-based exercise training with a hospital at home service for patients hospitalised with acute exacerbations of COPD: Developing the model using accelerated experience-based co-design. https://www.dovepress.com/integrating-home-based-exercise-training-with-a-hospital-at-home-servi-peer-reviewed-fulltext-article-COPD

Integrating Comprehensive Geriatric Assessment for people with COPD and frailty starting pulmonary rehabilitation: the Breathe Plus feasibility trial protocol. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005693/

COPD discharge bundle and pulmonary rehabilitation referral and uptake following hospitalisation for acute exacerbation of COPD. https://thorax.bmj.com/content/early/2021/03/02/thoraxjnl-2020-215464.long

Supervised pulmonary rehabilitation using minimal or specialist exercise equipment in COPD: a propensity-matched analysis. https://thorax.bmj.com/content/76/3/264.long

Pharmacological and nonpharmacological interventions to improve symptom control, functional exercise capacity and quality of life in interstitial lung disease: an evidence synthesis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836673/

Management of breathlessness in patients with cancer: ESMO Clinical Practice Guidelines†. Electronic address: clinicalguidelines@esmo.org. https://www.esmoopen.com/article/S2059-7029(20)32759-9/fulltext 

Trajectories of disability in activities of daily living in advanced cancer or respiratory disease: a systematic review. https://www.tandfonline.com/doi/abs/10.1080/09638288.2020.1820587

Palliative care and the management of common distressing symptoms in advanced cancer: Pain, breathlessness, nausea and vomiting and fatigue. https://ascopubs.org/doi/10.1200/JCO.19.00470?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed& 

Randomised, double-blind, multicentre, mixed-methods, dose-escalation feasibility trial of mirtazapine for better treatment of severe breathlessness in advanced lung disease (BETTER-B feasibility) https://thorax.bmj.com/content/75/2/176

To What Extent Do the NRS and CRQ Capture Change in Patients' Experience of Breathlessness in Advanced Disease? Findings From a Mixed-Methods Double-Blind Randomized Feasibility Trial. https://www.jpsmjournal.com/article/S0885-3924(19)30309-4/fulltext

Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential. https://www.tandfonline.com/doi/abs/10.1080/17476348.2019.1563486

Holistic services for people with advanced disease and chronic breathlessness: a systematic review and meta-analysis. https://thorax.bmj.com/content/74/3/270

Control and context are central for people with advanced illness experiencing breathlessness: A systematic review and thematic synthesis. https://www.sciencedirect.com/science/article/pii/S0885392418305050

Recommendations for services for people living with chronic breathlessness in advanced disease: results of a transparent expert consultation Chronic Respiratory Disease.
https://journals.sagepub.com/doi/full/10.1177/1479973118816448

Use of mirtazapine in patients with chronic breathlessness: A case series. https://journals.sagepub.com/doi/10.1177/0269216318787450

The publication feed is not currently available.

Trials

BETTER-B: An International, Multicentre, Randomised Controlled Pragmatic Trial of Mirtazapine to alleviate Breathlessness in Palliative and End of Life Care

The aim of the trial is to assess the effectiveness and cost-effectiveness of mirtazapine for the reduction of chronic or refractory breathlessness and quality of life in patients with COPD or ILD over a 56-day period and with an extended follow-up period of 180 days. Caregivers (as nominated by participating patients) are also encouraged to take part so that their own experience can also be assessed. Eligible patients meet the following criteria • diagnosed with COPD or ILD with mMRC breathlessness score 3 or 4 • ≥18 years old • on optimal treatment for their condition • management of condition unchanged for the previous 2 weeks • no exclusion criteria For further details please contact beter-b@kcl.ac.uk or visit our website https://betterbreathe.eu/

    Project Team

    Sabrina Bajwah

    Clinical Senior Lecturer and Honorary Consultant in Palliative Care

    Irene Higginson

    Director of Better Health and Care Futures

    Matthew Maddocks

    Professor of Health Services Research & Rehabilitation

    Senior Lecturer in Health Economics

    Charles Normand

    Professor of Economics of Palliative Care & Rehabilitation

    Publications

    Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B): an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 mixed-method trial
    https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(24)00187-5/fulltext

    Practice review: Pharmacological management of severe chronic breathlessness in adults with advanced life-limiting diseases https://journals.sagepub.com/doi/abs/10.1177/02692163241270945

    Integrating home-based exercise training with a hospital at home service for patients hospitalised with acute exacerbations of COPD: Developing the model using accelerated experience-based co-design. https://www.dovepress.com/integrating-home-based-exercise-training-with-a-hospital-at-home-servi-peer-reviewed-fulltext-article-COPD

    Integrating Comprehensive Geriatric Assessment for people with COPD and frailty starting pulmonary rehabilitation: the Breathe Plus feasibility trial protocol. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005693/

    COPD discharge bundle and pulmonary rehabilitation referral and uptake following hospitalisation for acute exacerbation of COPD. https://thorax.bmj.com/content/early/2021/03/02/thoraxjnl-2020-215464.long

    Supervised pulmonary rehabilitation using minimal or specialist exercise equipment in COPD: a propensity-matched analysis. https://thorax.bmj.com/content/76/3/264.long

    Pharmacological and nonpharmacological interventions to improve symptom control, functional exercise capacity and quality of life in interstitial lung disease: an evidence synthesis.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836673/

    Management of breathlessness in patients with cancer: ESMO Clinical Practice Guidelines†. Electronic address: clinicalguidelines@esmo.org. https://www.esmoopen.com/article/S2059-7029(20)32759-9/fulltext 

    Trajectories of disability in activities of daily living in advanced cancer or respiratory disease: a systematic review. https://www.tandfonline.com/doi/abs/10.1080/09638288.2020.1820587

    Palliative care and the management of common distressing symptoms in advanced cancer: Pain, breathlessness, nausea and vomiting and fatigue. https://ascopubs.org/doi/10.1200/JCO.19.00470?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed& 

    Randomised, double-blind, multicentre, mixed-methods, dose-escalation feasibility trial of mirtazapine for better treatment of severe breathlessness in advanced lung disease (BETTER-B feasibility) https://thorax.bmj.com/content/75/2/176

    To What Extent Do the NRS and CRQ Capture Change in Patients' Experience of Breathlessness in Advanced Disease? Findings From a Mixed-Methods Double-Blind Randomized Feasibility Trial. https://www.jpsmjournal.com/article/S0885-3924(19)30309-4/fulltext

    Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential. https://www.tandfonline.com/doi/abs/10.1080/17476348.2019.1563486

    Holistic services for people with advanced disease and chronic breathlessness: a systematic review and meta-analysis. https://thorax.bmj.com/content/74/3/270

    Control and context are central for people with advanced illness experiencing breathlessness: A systematic review and thematic synthesis. https://www.sciencedirect.com/science/article/pii/S0885392418305050

    Recommendations for services for people living with chronic breathlessness in advanced disease: results of a transparent expert consultation Chronic Respiratory Disease.
    https://journals.sagepub.com/doi/full/10.1177/1479973118816448

    Use of mirtazapine in patients with chronic breathlessness: A case series. https://journals.sagepub.com/doi/10.1177/0269216318787450

    The publication feed is not currently available.

    Trials

    BETTER-B: An International, Multicentre, Randomised Controlled Pragmatic Trial of Mirtazapine to alleviate Breathlessness in Palliative and End of Life Care

    The aim of the trial is to assess the effectiveness and cost-effectiveness of mirtazapine for the reduction of chronic or refractory breathlessness and quality of life in patients with COPD or ILD over a 56-day period and with an extended follow-up period of 180 days. Caregivers (as nominated by participating patients) are also encouraged to take part so that their own experience can also be assessed. Eligible patients meet the following criteria • diagnosed with COPD or ILD with mMRC breathlessness score 3 or 4 • ≥18 years old • on optimal treatment for their condition • management of condition unchanged for the previous 2 weeks • no exclusion criteria For further details please contact beter-b@kcl.ac.uk or visit our website https://betterbreathe.eu/

      Project status: Completed
      Better B

      Principal Investigator

      Investigators

      Project websites

      Funding

      Funding Body: European Commission

      Amount: €3.7million

      Period: January 2019 - December 2023

      Keywords

      PALLIATIVEBREATHLESSNESSRESPIRATORYMIRTAZAPINEANTIDEPRESSANTINTERNATIONALCLINICAL TRIAL