Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy

Study Overview
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Brief Summary
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Women treated for breast cancer are at increased risk for cardiovascular disease, including heart failure. In this study, by using magnetic resonance imaging (MRI), the investigators want to assess if heart failure medications such as beta blockers and angiotensin receptor blockers can prevent cardiac dysfunction during early breast cancer therapy.

Detailed Description
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Breast cancer is one of the most common malignancies in women. Recent progress in the detection and treatment of breast cancer has resulted in survival gains, but a consequence of therapeutic advances is an increasing number of long-term survivors who may be at risk for development of cardiovascular disease. Several studies suggest that women treated for breast cancer may be at increased risk for cardiovascular disease, the probable causes being multi-factorial. Importantly, therapies for breast cancer, including radiotherapy, anti-HER-2 regimens and certain chemotherapeutic regimens, may increase the risk of subsequent cardiovascular disease, including atherosclerotic disease, left ventricular dysfunction, and heart failure. In the current study we propose to undertake a randomized, placebo-controlled, 2x2 factorial, double-blind trial to assess whether left ventricular dysfunction and/or injury is preventable, completely or partly, by the concomitant administration of the angiotensin receptor blocker (ARB), candesartan, and the beta blocker, metoprolol, during postoperative chemotherapy and radiotherapy. The proposed study addresses an important clinical problem in a large patient group. Thus, the possibility of preventing cardiovascular side effects of contemporary therapy for breast cancer is important both clinically and scientifically.

Official Title
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Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: A Randomized, Placebo-controlled, 2x2 Factorial, Double Blind Trial of Candesartan and Metoprolol

Conditions
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Breast Cancer, Heart Failure

Intervention / Treatment
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* Drug: Metoprolol
* Drug: Placebo
* Drug: Candesartan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 18-70 years Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Serum creatinine < 140 μmol/L or estimated creatinine clearance > 60 ml/min (using the modification of diet and renal disease (MDRD) formula) Systolic blood pressure >= 110 mgHg and < 170 mmHg LVEF >= 50% Exclusion Criteria: Hypotension, defined as systolic blood pressure < 110 mmHg Bradycardia, defined as heart rate < 50 b.p.m. Prior anthracycline chemotherapy regimen Prior malignancy requiring chemotherapy or radiotherapy Symptomatic heart failure Systolic dysfunction (LVEF < 50%) Clinically significant coronary artery disease, valvular heart disease, significant arrhythmias, or conduction delays. Uncontrolled arterial hypertension defined as systolic blood pressure > 170 mm Hg Treatment with ACEI, ARB or beta-blocker within the last 4 weeks prior to study start Intolerance to ACEI, ARB or beta-blocker Uncontrolled concomitant serious illness Pregnancy or breastfeeding Active abuse of drugs or alcohol Suspected poor compliance Inability to tolerate the MRI scanning protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

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: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metoprolol<br>Tablet, target dose 100 mg once daily | Drug: Metoprolol<br>* Tablet, target dose 100 mg once daily<br>|
| Placebo Comparator: Placebo for Metoprolol<br>Tablet, target dose 100 mg once daily | Drug: Placebo<br>* Tablet, target dose 100 mg once daily<br>|
| Experimental: Candesartan<br>Tablet, target dose 32 mg once daily | Drug: Candesartan<br>* Tablet, target dose 32 mg once daily<br>|
| Placebo Comparator: Placebo for Candesartan<br>Tablet, target dose 32 mg once daily | Drug: Placebo<br>* Tablet, 32 mg once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left ventricular ejection fraction, as assessed by cardiac MRI |  | Baseline and end of study (up to 72 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in contrast enhancement by MRI |  | Baseline and approximately 4 weeks | 
| Change in left 2D global strain, as assessed by echocardiography |  | Baseline and end of study (up to 72 weeks) | 
| Incidence of clinical of heart failure or objective left ventricular dysfunction | Left ventricular dysfunction defined as ejection fraction < 55% by cardiac MRI | Up to 72 weeks | 
| Change in biochemical markers of cardiac injury, i.e. hs-cTnT |  | Baseline and end of study (up to 72 weeks) | 
| Change in left ventricular diastolic function, as assessed by echocardiography | Diastolic function assessed by e/e' | Baseline and end of study (up to 72 weeks) | 
| Change in biochemical markers of cardiac function, i.e. NT-proBNP |  | Baseline and end of study (up to 72 weeks) | 
| Change in contrast enhancement, as assessed by cardiac MRI |  | Baseline and end of study (up to 72 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anthracyclines, Trastuzumab