The STOP-MED CTRCD Trial

Study Overview
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Brief Summary
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Cancer therapy-related cardiac dysfunction (CTRCD) is when the heart's ability to pump oxygenated blood to the body is compromised. It is a side effect of cancer therapy which can occur as commonly as in 1 in 5 patients. When this occurs, heart failure medications are started to protect the heart from progressing to heart failure. With early detection and treatment, heart function recovers to normal in >80% of patients. Unfortunately, heart failure medications are associated with an undesirable long-term pill burden, financial costs, and side-effects (e.g., dizziness and fatigue). As a result, cancer survivors frequently ask if they can safely stop their heart failure medications once their heart function has returned to normal. Currently there is no scientific evidence in this area of Cardio-Oncology. To address this knowledge gap, we have designed a randomized control trial to assess the safety of stopping heart failure medication in patients with CTRCD and recovered heart function. We will enrol patients who have completed their cancer therapy and are on heart medications for their CTRCD, which has now normalized. We will randomize patients with no other reasons to continue heart failure medications (e.g., kidney disease) to continuing or stopping their heart medications safely. All patients will undergo a cardiac MRI at baseline 1 and 5 years with safety assessments at 6-8 weeks, 6 and 9 months and 3 and 5 years. We will determine if stopping medications is non-inferior to continuing medications by counting the numbers of patients who develop heart dysfunction by 1 year in each group.

Official Title
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A Multi-Centre Non-Inferiority Randomized Controlled Trial of STOPping Cardiac MEDications in Patients With Normalized Cancer Therapy Related Cardiac Dysfunction: The STOP-MED CTRCD Trial

Conditions
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Heart Failure, Cardiotoxicity, Cardiac Toxicity, Antineoplastics Toxicity, Cancer

Intervention / Treatment
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* Other: Stopping Heart Failure Medication(s)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (age ≥18 years) with cancer therapy completed more than 6 months prior (other than hormonal therapy) and no plan for further cancer treatments with potential risk for CTRCD. Prior cancer therapy with anthracyclines and/ or HER2-targeted therapy. Prior asymptomatic, moderate CTRCD, defined using the ESC criteria (LVEF 40-49.9%)1, diagnosed within 1 year of completing potentially cardiotoxic cancer therapy. Current use of ≥1 HF medication started for CTRCD for at least 6 months with LVEF ≥55%, and normal LV volumes by recently performed (≤6 months) echocardiogram, normal NT-proBNP, and no symptoms attributable to HF. Confirmation of LVEF ≥55% and normal volumes at baseline CMR (i.e., some patients recruited based on echocardiography, may be excluded if baseline CMR LVEF/volumes are not normal). This is included given that the primary outcome includes the use of CMR LVEF. Exclusion Criteria: Indication for continuation of HF medications i.e., ongoing HF symptoms, chronic kidney disease (CKD), vascular disease, atrial or ventricular arrythmias, other (note: participants with hypertension will be switched to other guideline-based antihypertensive therapy). Contraindications for CMR (e.g., MRI non-compatible implanted pacemakers). Patients with severe CTRCD defined as having a nadir LVEF <40%1 due to the known poor prognosis in these patients2. Continued use of loop diuretic therapy for heart failure purposes i.e., furosemide. Life expectancy <1 year or metastatic disease. Prior history of major cardiovascular event (defined as myocardial infarction, cerebral vascular event, admission for HF) or therapeutic cardiovascular procedure (e.g., PCI, CABG). Issues that prevent communication, understanding or presentation for study-related visits and inability to provide informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stop Group<br>This group will stop their heart failure medication(s) under the supervision of the study team. We expect most participants in the STOP group to only be on beta-blockers and/or ACEi or ARBs. The ACEi or ARB will be stopped first. The ACEi or ARB will be reduced by 50% every 7 days and stopped 7 days after 25% of maximal recommended dose for HF is reached. At this point (or at baseline if only on BB), the BB dose will be reduced by 50% every 7 days then stopped once 25% of the maximal dose is reached. | Other: Stopping Heart Failure Medication(s)<br>* This group will stop their heart failure medication(s) under the supervision of the study team.<br>|
| No Intervention: Standard of Care Group<br>This group with continue with their heart failure medication(s) for at least 1 year. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cancer Therapy Related Cardiac Dysfunction Relapse | To compare the proportion of those that develop by 1 year of follow-up one or both of the following (i) left ventricular ejection fraction <50% by cardiac magnetic resonance (ii) new heart failure signs and/or symptoms accompanied by elevated natriuretic peptides. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in cardiac magnetic resonance parameters | Differences between the two groups in the following measures. Changes in CMR LVEF as a continuous parameter. Proportion of participants with increased CMR indexed LV volumes by ≥10% to higher-than-normal limits. Proportion of participants with decline in CMR LVEF to <50% with a >10% absolute fall compared to pre-HF medication withdrawal. CMR peak systolic global longitudinal strain (GLS) worsening by >15%. | 1 year | 
| Left ventricular diastolic function | Proportion of participants with new diastolic dysfunction or worsening diastolic function ≥1 grade by echocardiography between the two study groups. | 1 year | 
| Non-adherence of heart failure medication(s) | Proportion of participants with non-adherence of heart failure medication(s) by 1 year between the two study groups. Non-adherence is defined in the STOP group as the proportion of participants in whom successful cessation of all medications used to treat CTRCD was not possible or re-addition of the same medications used in that participant for HF was necessary for non-HF indications (e.g., palpitations). In the SOC group non-adherence is defined as the proportion of participants who stopped all HF medications used to treat CTRCD. | 1 year | 
| NT-pro BNP | Doubling of NT-pro BNP compared to pre-HF therapy cessation between the two study groups. | 1 year | 
| Changes in quality of life score | Difference in patient questionnaires scores between the two groups using the following patient questionnaires: Kansas City Cardiomyopathy Questionnaire SF-36 EQ-5D-5L | 1 year | 
| Cost effectiveness analysis | We will compare the cost per quality adjusted life years between the two study groups. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer therapy related cardiac dysfunction