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22/158 Inhibition of the renin-angiotensin system in takotsubo cardiomyopathy commissioning brief

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Published: 01 December 2022

Version: 1.0 November 2022

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Introduction

The aim of the Health Technology Assessment (HTA) Programme is to ensure that high quality research information on the clinical effectiveness, cost-effectiveness and broader impact of healthcare treatments and tests are produced in the most efficient way for those who plan, provide or receive care from NHS and social care services. The commissioned workstream invites applications in response to calls for research on specific questions which have been identified and prioritised for their importance to the NHS, patients and social care.

Research question

What is the clinical and cost-effectiveness of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) to prevent major adverse cardiovascular events and death in patients with takotsubo cardiomyopathy?

  1. Patient group: Patients with confirmed diagnosis of takotsubo cardiomyopathy/syndrome. Applicants to define and justify criteria for inclusion/exclusion including how late after index event/diagnosis patients can be recruited and start in the trial. Applicants should provide robust information on how they anticipate recruiting patients to this study.
  2. Intervention: Angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) therapy in addition to usual care (applicants to define and justify drug(s) of choice and associated dosing regimen).
  3. Control: Placebo in addition to usual care (applicants to define and justify).
  4. Important outcomes: To include major adverse cardiac and cerebrovascular events (MACCE) such as cardiac death, recurrence of takotsubo cardiomyopathy, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.
    Other outcomes: Acceptability; quality of life; cost-effectiveness.
    Existing Core Outcomes should be included amongst the list of outcomes unless a good rationale is provided to do otherwise. Applicants are encouraged to report recruitment and findings disaggregated by sex (and other demographic factors where relevant). 
  5. Setting: Tertiary and secondary care hospitals.
  6. Study design: A randomised controlled trial with an internal pilot phase to test key trial processes such as recruitment and adherence. Clear stop/go criteria should be provided to inform progression from pilot to full trial.
  7. Minimum duration of follow-up: Applicants to define and justify.
    Longer-term follow up: If appropriate, researchers should consider obtaining consent to allow potential future follow-up through efficient means (such as routine data) as part of a separately funded study.

Uncertainty remains about how these drugs may improve left ventricular recovery in this patient group. Applicants who are successful in applying to this call are therefore encouraged to consider applying to the MRC-NIHR Efficacy and Mechanism Evaluation (EME) Programme to investigate the mechanism of action. See the EME Researcher-led funding opportunity.

Rationale

Takotsubo cardiomyopathy or Takotsubo syndrome (TTS) is a type of non-ischaemic cardiomyopathy in which there is a sudden temporary weakening of the muscular portion of the heart. The term Takotsubo is taken from the Japanese word meaning ‘octopus trap’ due to the characteristic apical ballooning appearance of the left ventricle.

Patients with TTS classically present with acute-onset chest pain, dyspnoea, and changes on the ECG (this presentation mimics, and is often initially managed as, an acute coronary syndrome (ACS)) occurring in association with an acute physical or emotional stressful event such as an unexpected bereavement, conflict, or another major life event. It is from this association with stress related events that TTS has also been referred to as ‘broken heart syndrome’.

Previously believed to be a benign self-limiting condition, TTS is now known to be associated with substantial short- and long-term morbidity and mortality. Long-lasting clinical consequences with subclinical cardiac dysfunction and recurrence have been demonstrated with similar potential mortality outcomes between TTS and ACS patients.

There is significant uncertainty about longer-term TTS management but the primary therapeutic candidates from the available low-quality evidence are drugs targeted against the renin-angiotensin system, the angiotensin converting enzyme inhibitors (ACEi) and the angiotensin II receptor blockers (ARBs).

ACEi and ARBs are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart, and are often used in the longer-term post myocardial infarction to prevent future events and deterioration.

The HTA programme therefore seeks applications for a high-quality randomised trial of ACEi/ARBs for long- term treatment following TTS to determine their role in preventing death and major cardiovascular events including TTS recurrence.

Additional commissioning brief background information

A background document is available that provides further information to support applicants for this call. It is intended to summarise what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. If you would like a copy please email htaresearchers@nihr.ac.uk.

Making an application

If you wish to submit a Stage 1 application for this call, the online application form can be found on the funding opportunities page. To select this call, use the filters on the right of the screen or search using the call name and/or number.

Your application must be submitted on-line no later than 1pm on the 29 March 2023. Applications will be considered by the HTA Funding Committee at its meeting in May 2023.

Guidance notes and supporting information for HTA Programme applications are available.

Important: Shortlisted Stage 1 applicants will be given eight weeks to submit a Stage 2 application. The Stage 2 application will be considered at the Funding Committee in September 2023.

Applications received electronically after 1300 hours on the due date will not be considered.

For commissioned topics, the Programme strongly discourages the practice of the same co-applicant joining more than one competing team. There may be unusual circumstances where the same person could be included on more than on application eg a lead from a named charity or a unique national expert in a condition.

For such exceptions (i) each application needs to state the case as to why the same person is included (ii) the shared co-applicant should not divulge application details between teams and (iii) both teams should acknowledge in their application that they are aware that one of their co-applicants is part of a competing application and that study details have not been shared. 

Should you have any queries please contact us: htacommissioning@nihr.ac.uk.