Clinical trial NCT01434134: Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy
Official title: Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: A Randomized, Placebo-controlled, 2x2 Factorial, Double Blind Trial of Candesartan and Metoprolol
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Heart Failure
Keywords: Anthracyclines
Trastuzumab
Lead sponsor: University Hospital, Akershus
Sponsor class: OTHER
Collaborators: name: University of Oslo
name: Norwegian Cancer Society
name: AstraZeneca
First posted: 2011-09-14
Enrollment: 130
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in left ventricular ejection fraction, as assessed by cardiac MRI
timeFrame: Baseline and end of study (up to 72 weeks)
Secondary outcomes:
measure: Change in contrast enhancement by MRI
timeFrame: Baseline and approximately 4 weeks
measure: Change in left 2D global strain, as assessed by echocardiography
timeFrame: Baseline and end of study (up to 72 weeks)
measure: Incidence of clinical of heart failure or objective left ventricular dysfunction
timeFrame: Up to 72 weeks
measure: Change in biochemical markers of cardiac injury, i.e. hs-cTnT
timeFrame: Baseline and end of study (up to 72 weeks)
measure: Change in left ventricular diastolic function, as assessed by echocardiography
timeFrame: Baseline and end of study (up to 72 weeks)
measure: Change in biochemical markers of cardiac function, i.e. NT-proBNP
timeFrame: Baseline and end of study (up to 72 weeks)
measure: Change in contrast enhancement, as assessed by cardiac MRI
timeFrame: Baseline and end of study (up to 72 weeks)
Other outcomes:
Locations:
city: Lørenskog
country: Norway
facility: Akershus University Hospital
Study officials:
affiliation: University Hospital, Akershus
name: Stein Vaaler
role: STUDY_DIRECTOR
References:
citation: Heck SL, Mecinaj A, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, Gravdehaug B, Rosjo H, Steine K, Geisler J, Gulati G, Omland T. Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2x2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol. Circulation. 2021 Jun 22;143(25):2431-2440. doi: 10.1161/CIRCULATIONAHA.121.054698. Epub 2021 May 16.
citation: Gulati G, Heck SL, Rosjo H, Ree AH, Hoffmann P, Hagve TA, Norseth J, Gravdehaug B, Steine K, Geisler J, Omland T. Neurohormonal Blockade and Circulating Cardiovascular Biomarkers During Anthracycline Therapy in Breast Cancer Patients: Results From the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) Study. J Am Heart Assoc. 2017 Nov 8;6(11):e006513. doi: 10.1161/JAHA.117.006513.
citation: Heck SL, Gulati G, Ree AH, Schulz-Menger J, Gravdehaug B, Rosjo H, Steine K, Bratland A, Hoffmann P, Geisler J, Omland T. Rationale and design of the prevention of cardiac dysfunction during an Adjuvant Breast Cancer Therapy (PRADA) Trial. Cardiology. 2012;123(4):240-7. doi: 10.1159/000343622. Epub 2012 Nov 30.