Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab

Targeted Adverse Events were prospectively assessed according to the CTCAE v5.0. The number of patients experiencing any adverse event (Grade 2-5) was tabulated by risk group and by treatment arm during carvedilol intervention (baseline - 12 months). In the CTCAE, grade refers to the severity of the event. Grade 2 events are moderate, or have non-urgent/non-invasive intervention indicated, or limit age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 events are severe/medically significant but not immediately life-threatening, or have hospitalization or prolongation of hospitalization indicated, or limit self-care ADLs. Grade 4 events have life-threatening consequences or have urgent intervention indicated. Grade 5 indicates a death related to the adverse event.

Time frame: Up to 12 months

Population: Safety was analyzed, evaluating the three groups according to the treatment the participants actually received (as treated).~After randomization, three participants refused carvedilol but agreed to remain on study for follow-up, and one participant assigned to usual care started carvedilol for clinical indications at the baseline visit. As a result, there were 11 participants treated with carvedilol and 8 treated as per usual care.

LVEF by echocardiogram. Left ventricular ejection fraction (LVEF) is defined as the left ventricular stroke volume (left ventricular end diastolic volume minus the left ventricular end systolic volume) divided by the left ventricular end diastolic volume. This fraction is multiplied by 100 to yield the LVEF, and is defined as a % (the unit of measure) (J Am Soc Echocardiogr 2015;28:1-39.). 2D left ventricular volumes are estimated according to the biplane method of disks (modified Simpson's rule), as recommended by societal guidelines. Higher values are generally considered more favorable.

Time frame: up to 24 months

Population: Exploratory cardiac efficacy by cardiac function (LVEF) was analyzed, evaluating the three groups according to the treatment the participants actually received (as treated).~After randomization, three participants refused carvedilol but agreed to remain on study for follow-up, and one participant assigned to usual care started carvedilol for clinical indications at the baseline visit. As a result, there were 11 participants treated with carvedilol and 8 treated as per usual care.

Rate of compliance with prescribed dose of carvedilol assessed based on pill count. Patients in the elevated-risk carvedilol group were asked to bring their study medications to all study visits and remaining pills were counted by the study coordinator to determine how many pills had been taken. Treatment adherence was calculated as the ratio of number of pills taken to expected number of pills taken, and is reported as a percentage. An adherence rate closer to 100 is better. Treatment adherence is reported only for those patients who were assigned to the elevated risk/carvedilol group, and therefore expected to take study medication.

Time frame: 12 months

Population: Adherence to the carvedilol intervention was calculated only among the elevated-risk carvedilol group.

Global longitudinal strain (GLS, %) averaged from 3 apical views (left ventricular apical 4-chamber, 2-chamber, and 3-chamber) was obtained using speckle-tracking technology using Tomtec Imaging Systems. GLS is a more sensitive measure of cardiac function, with values greater than -16% (e.g., -15%) for GLS associated with worse outcomes. Circumferential strain (GCS, %) from the short axis view (mid left ventricle) was obtained using speckle-tracking technology using Tomtec Imaging Systems. Circumferential strain is a more sensitive measure of cardiac function, with values or greater than -20% (e.g., -19%) associated with worse outcomes. GLS and GCS are core-lab quantified, blinded to patient and treatment characteristics.

Time frame: up to 24 months

Population: Exploratory cardiac efficacy by longitudinal strain was analyzed, evaluating the three groups according to the treatment the participants actually received (as treated).~After randomization, three participants refused carvedilol but agreed to remain on study for follow-up, and one participant assigned to usual care started carvedilol for clinical indications at the baseline visit. As a result, there were 11 participants treated with carvedilol and 8 treated as per usual care.

E/e' is a measure of diastolic function derived from the ratio of the pulse wave Doppler interrogations of the mitral inflow at the mitral valve leaflet tips and at the lateral and septal mitral annulus via tissue Doppler imaging. This measure provided insight into myocardial relaxation, preload, and left ventricular filling pressures, with values \> 14 indicative of elevated filling pressure. This is core-lab quantified, blinded to patient and treatment characteristics.

Time frame: up to 24 months

Population: Exploratory cardiac efficacy by diastolic function was analyzed, evaluating the three groups according to the treatment the participants actually received (as treated).~After randomization, three participants refused carvedilol but agreed to remain on study for follow-up, and one participant assigned to usual care started carvedilol for clinical indications at the baseline visit. As a result, there were 11 participants treated with carvedilol and 8 treated as per usual care.

Frequency of individuals with cardiac dysfunction, as defined by reduction in LVEF of \>/= 10% to \< 50%.

Time frame: up to 24 months

Population: Exploratory cardiac efficacy was analyzed, evaluating the three groups according to the treatment the participants actually received (as treated).~After randomization, three participants refused carvedilol but agreed to remain on study for follow-up, and one participant assigned to usual care started carvedilol for clinical indications at the baseline visit. As a result, there were 11 participants treated with carvedilol and 8 treated as per usual care.

Change in the cardiac biomarker of injury hsTnT over time, defined as a continuous variable. hsTnT is a biomarker that is indicative of cardiac injury, with higher values associated with more severe injury. This is core-lab quantified, blinded to patient and treatment characteristics.

Time frame: up to 24 months

Population: Exploratory cardiac efficacy was analyzed, evaluating the three groups according to the treatment the participants actually received (as treated).~After randomization, three participants refused carvedilol but agreed to remain on study for follow-up, and one participant assigned to usual care started carvedilol for clinical indications at the baseline visit. As a result, there were 11 participants treated with carvedilol and 8 treated as per usual care.

LV mass by echocardiogram. Measurements of left ventricular mass (g) provided insight into cardiac structure, size, and remodeling. LV mass was calculated by the area-length method, as recommended by societal guidelines. This is core-lab quantified, blinded to patient and treatment characteristics.

Time frame: up to 24 Months

Population: Exploratory cardiac efficacy was analyzed, evaluating the three groups according to the treatment the participants actually received (as treated).~After randomization, three participants refused carvedilol but agreed to remain on study for follow-up, and one participant assigned to usual care started carvedilol for clinical indications at the baseline visit. As a result, there were 11 participants treated with carvedilol and 8 treated as per usual care.

Change in the cardiac biomarker, NT-proBNP over time, defined as a continuous variable. NTproBNP is a biomarker that is indicative of neurohormonal stress, with higher levels associated with more neurohormonal stress. This is core-lab quantified, blinded to patient and treatment characteristics.

Time frame: up to 24 months

Population: Exploratory cardiac efficacy was analyzed, evaluating the three groups according to the treatment the participants actually received (as treated).~After randomization, three participants refused carvedilol but agreed to remain on study for follow-up, and one participant assigned to usual care started carvedilol for clinical indications at the baseline visit. As a result, there were 11 participants treated with carvedilol and 8 treated as per usual care.

Ventricular-arterial (VA) coupling, the ratio between effective arterial elastance (Ea), indicative of load, and end-systolic elastance (Ees), indicative of LV contractility, was also quantified. Ea/Ees is a measure of cardiac efficiency, with normal values of 0.8-1.0, and lower numbers typically indicative of greater efficiency and higher values reflective of worse function. This is core-lab quantified, blinded to patient and treatment characteristics.

Time frame: up to 24 months

Population: Exploratory cardiac efficacy by ventricular arterial coupling was analyzed, evaluating the three groups according to the treatment the participants actually received (as treated).~After randomization, three participants refused carvedilol but agreed to remain on study for follow-up, and one participant assigned to usual care started carvedilol for clinical indications at the baseline visit. As a result, there were 11 participants treated with carvedilol and 8 treated as per usual care.