A Randomised Controlled Trial of Renin-Angiotensin System Inhibition for Reduction of Cardiovascular Events after Takotsubo Cardiomyopathy (EVEREST)

1) Research question. Does renin-angiotensin system inhibition (RAS inhibition) reduce recurrent cardiovascular events and improve quality of life in patients after acute takotsubo cardiomyopathy?

2) Background. Takotsubo cardiomyopathy is an acute potentially fatal cardiac emergency that presents with sudden severe left ventricular dysfunction. It predominantly affects women (90%), particularly in their middle age, and is commonly triggered by an emotional or physical stress.

Its symptoms are indistinguishable from acute myocardial infarction, but patients with takotsubo cardiomyopathy have unobstructed coronary arteries in the presence of typical localised dysfunction of the left ventricle without any myocardial infarction or scarring. The left ventricular dysfunction follows a natural course of spontaneous resolution within several weeks from the acute event.

Despite this, patients who recover from an acute takotsubo episode have substantially reduced long-term survival and we have recently shown that this is due to subsequent major cardiovascular events.

3) Aims and objectives. To establish the clinical and cost effectiveness of RAS inhibitor therapy after acute takotsubo cardiomyopathy.

i) Primary objective: Establish if RAS inhibition is clinically effective in preventing recurrent major cardiovascular events

ii) Secondary objectives: Establish if RAS inhibition improves patient reported outcomes - participants’ ongoing symptoms, quality of life, treatment acceptability; and the individual components of the primary composite endpoint iii) Health economic analysis: Evaluate cost-effectiveness of RAS inhibitor therapy

4) Methods. • Design: two-arm multicentre open label randomised (1:1) clinical trial • Health technology: RAS inhibition (intervention) versus no RAS inhibition (control) • Inclusions: acute takotsubo cardiomyopathy episode within the previous 3 months • Exclusions: pregnancy or breast feeding, life expectancy <2-years, clinical indication that mandates RAS inhibition

• Outcome measures:

Primary outcome: composite of all-cause death or hospitalisation for heart failure, myocardial infarction, stroke, or recurrence of acute takotsubo cardiomyopathy

Secondary outcomes: patient reported outcomes, specifically participants’ ongoing symptoms, quality of life, treatment acceptability, and the individual components of the primary outcome Health economic analysis: cost per quality adjusted life-year gained from a UK NHS perspective • Sample size: 930 participants to detect a hazard ratio of 0.70 with 5% significance and 90% power

5) Timelines for delivery. 1-6 months: set-up; 7-21 months: recruitment (internal pilot 7-18); 7-54 months ongoing recruitment; 55-78 months: follow up; 78-84 months: analysis and write-up

Anticipated impact and dissemination. Clinical results will be presented in international peer-reviewed journals and conferences. Lay summaries will be disseminated to participants, and to patient organisations, heart charities, websites, and social media. We will inform policy makers shaping NHS practice, such as NICE, NHS and international societal guideline committees.