Trial Outcomes & Findings for Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab (NCT NCT04023110)

Last Updated: 2025-10-09

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

68 participants

Primary outcome timeframe

up to 24 months

Results posted on

2025-10-09

Participant Flow

The cardiotoxicity risk score was calculated using Cox proportional hazards regression with race, systolic blood pressure, left ventricular ejection fraction, systemic cancer therapy, smoking status, diabetes and hypertension as selected predictors (PMID 4012740). A threshold of 4.5% risk of cardiac dysfunction at 1 year was set to prioritize sensitivity. 49 patients were classified as low risk and 19 as elevated risk. 13 elevated risk patients were randomized to carvedilol and 6 to usual care.

Participant milestones

Participant milestones
Measure	Elevated Risk / Carvedilol Patients determined to be elevated risk and randomized to carvedilol (elevated risk/carvedilol arm) initiated carvedilol at a dose of 3.125 mg twice daily on the evening of the first cancer therapy cycle and continued for 12 months. Dose adjustments were based on tolerability and targeted parameters as determined by the study physician, and carvedilol was titrated to maximum tolerated dose by the participant or to a SBP of 110-120mmHg or heart rate (HR) of 50-55 beats per minute. Titration steps were predefined at doses of 6.25 mg, 12.5 mg, and up to 25 mg twice daily. Clinical, echocardiographic, and biomarker data were collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9 12 and 24 months.	Elevated Risk/Usual Care Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Overall Study STARTED	13	6	49
Overall Study 12 Month	10	6	47
Overall Study 24 Month	10	6	47
Overall Study COMPLETED	10	6	47
Overall Study NOT COMPLETED	3	0	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Elevated Risk / Carvedilol n=13 Participants Patients determined to be elevated risk and randomized to carvedilol (elevated risk/carvedilol arm) initiated carvedilol at a dose of 3.125 mg twice daily on the evening of the first cancer therapy cycle and continued for 12 months. Dose adjustments were based on tolerability and targeted parameters as determined by the study physician, and carvedilol was titrated to maximum tolerated dose by the participant or to a SBP of 110-120mmHg or heart rate (HR) of 50-55 beats per minute. Titration steps were predefined at doses of 6.25 mg, 12.5 mg, and up to 25 mg twice daily. Clinical, echocardiographic, and biomarker data were collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9 12 and 24 months.	Elevated Risk/Usual Care n=6 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Total n=68 Participants Total of all reporting groups
Age, Continuous	47 years n=93 Participants	51 years n=4 Participants	52 years n=27 Participants	52 years n=483 Participants
Sex: Female, Male Female	13 Participants n=93 Participants	6 Participants n=4 Participants	49 Participants n=27 Participants	68 Participants n=483 Participants
Sex: Female, Male Male	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	1 Participants n=483 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants n=93 Participants	5 Participants n=4 Participants	49 Participants n=27 Participants	67 Participants n=483 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Asian	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	2 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Black or African American	3 Participants n=93 Participants	4 Participants n=4 Participants	17 Participants n=27 Participants	24 Participants n=483 Participants
Race (NIH/OMB) White	7 Participants n=93 Participants	1 Participants n=4 Participants	29 Participants n=27 Participants	37 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants	5 Participants n=483 Participants
Systolic Blood Pressure (SBP)	127 mmHg n=93 Participants	121 mmHg n=4 Participants	125 mmHg n=27 Participants	125 mmHg n=483 Participants
Left Ventricular Ejection Fraction (LVEF)	61.1 percent n=93 Participants	59.6 percent n=4 Participants	61.9 percent n=27 Participants	61.2 percent n=483 Participants
Systemic Cancer Therapy (Anthracyclines and Her2 targeted agents) Doxorubicin	10 Participants n=93 Participants	4 Participants n=4 Participants	26 Participants n=27 Participants	40 Participants n=483 Participants
Systemic Cancer Therapy (Anthracyclines and Her2 targeted agents) Her2 Targeted	2 Participants n=93 Participants	1 Participants n=4 Participants	23 Participants n=27 Participants	26 Participants n=483 Participants
Systemic Cancer Therapy (Anthracyclines and Her2 targeted agents) Doxorubicin + Her2 Targeted	1 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	2 Participants n=483 Participants
Smoking Status	6 Participants n=93 Participants	2 Participants n=4 Participants	14 Participants n=27 Participants	22 Participants n=483 Participants
Diabetes	2 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants	5 Participants n=483 Participants
Hypertension (HTN)	2 Participants n=93 Participants	2 Participants n=4 Participants	10 Participants n=27 Participants	14 Participants n=483 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=11 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care n=8 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Left Ventricular Ejection Fraction (LVEF) Baseline	61.1 percent Interval 59.7 to 64.9	59.0 percent Interval 57.2 to 60.4	61.9 percent Interval 60.0 to 65.0
Left Ventricular Ejection Fraction (LVEF) 12 Month	58.4 percent Interval 57.4 to 59.3	60.4 percent Interval 59.1 to 61.9	59.7 percent Interval 56.9 to 62.3
Left Ventricular Ejection Fraction (LVEF) 24 Month	61.7 percent Interval 57.3 to 62.3	61.7 percent Interval 59.4 to 62.5	60.3 percent Interval 58.0 to 62.6

PRIMARY outcome

Timeframe: 12 months

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

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.

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=13 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Treatment Adherence as Measured by Pill Count	93 percent of prescribed doses Interval 0.0 to 99.4	—	—

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=11 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care n=8 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Adverse Events Grade 4 and Higher	1 Participants	0 Participants	1 Participants
Adverse Events Grade 5	1 Participants	0 Participants	1 Participants
Adverse Events Grade 2 and Higher	11 Participants	8 Participants	47 Participants
Adverse Events Grade 3 and Higher	6 Participants	2 Participants	15 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=11 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care n=8 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Diastolic Function (E/e') by Echocardiogram Baseline	7.86 ratio Interval 6.89 to 8.6	6.85 ratio Interval 6.07 to 7.78	7.64 ratio Interval 6.54 to 8.7
Diastolic Function (E/e') by Echocardiogram 12 Month	8.22 ratio Interval 7.65 to 9.18	8.24 ratio Interval 6.79 to 8.82	7.06 ratio Interval 6.46 to 8.45
Diastolic Function (E/e') by Echocardiogram 24 Month	8.25 ratio Interval 7.05 to 8.67	7.90 ratio Interval 7.2 to 8.68	7.04 ratio Interval 6.43 to 7.99

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=11 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care n=8 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Ventricular-arterial Coupling Measured by Echocardiogram 12 Month	0.83 ratio Interval 0.64 to 0.94	0.88 ratio Interval 0.84 to 0.89	0.82 ratio Interval 0.71 to 0.93
Ventricular-arterial Coupling Measured by Echocardiogram Baseline	0.76 ratio Interval 0.62 to 0.83	0.84 ratio Interval 0.68 to 0.95	0.71 ratio Interval 0.58 to 0.92
Ventricular-arterial Coupling Measured by Echocardiogram 24 Month	0.83 ratio Interval 0.78 to 0.94	0.78 ratio Interval 0.74 to 0.89	0.82 ratio Interval 0.71 to 0.96

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=11 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care n=8 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Cardiac Strain Measurements by Echocardiogram Baseline GLS	-20.7 percent Interval -21.8 to -20.2	-20.5 percent Interval -23.0 to -20.1	-21.8 percent Interval -22.9 to -20.6
Cardiac Strain Measurements by Echocardiogram 12 Month GLS	-21.1 percent Interval -22.6 to -20.0	-20.0 percent Interval -21.6 to -19.4	-21.3 percent Interval -23.2 to -19.8
Cardiac Strain Measurements by Echocardiogram 24 Month GLS	-22.0 percent Interval -22.9 to -20.3	-22.1 percent Interval -25.3 to -20.2	-21.3 percent Interval -22.6 to -20.0
Cardiac Strain Measurements by Echocardiogram Baseline GCS	-29.0 percent Interval -34.4 to -24.3	-24.4 percent Interval -27.5 to -22.7	-27.9 percent Interval -30.6 to -23.4
Cardiac Strain Measurements by Echocardiogram 12 Month GCS	-24.3 percent Interval -25.3 to -22.9	-26.2 percent Interval -30.1 to -23.6	-25.2 percent Interval -28.2 to -21.9
Cardiac Strain Measurements by Echocardiogram 24 Month GCS	-25.0 percent Interval -27.9 to -22.5	-24.7 percent Interval -29.7 to -22.3	-27.2 percent Interval -31.1 to -23.3

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=11 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care n=8 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Frequency of Individuals With Cardiac Dysfunction	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: up to 24 months

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.

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=11 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care n=8 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
High-sensitivity Troponin (hsTnT) Level Baseline	6.1 ng/L Interval 4.7 to 7.3	8.0 ng/L Interval 6.4 to 8.4	5.7 ng/L Interval 4.1 to 8.0
High-sensitivity Troponin (hsTnT) Level 12 Month	7.4 ng/L Interval 6.4 to 8.0	6.2 ng/L Interval 4.2 to 8.7	7.2 ng/L Interval 5.6 to 9.4
High-sensitivity Troponin (hsTnT) Level 24 Month	7.0 ng/L Interval 5.6 to 8.0	6.0 ng/L Interval 4.7 to 7.3	6.4 ng/L Interval 5.3 to 8.2

SECONDARY outcome

Timeframe: up to 24 months

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.

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=11 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care n=8 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
N-terminal Pro B-type Natriuetic Peptide (NTproBNP) Level Baseline	88.4 ng/L Interval 57.1 to 100.1	54.8 ng/L Interval 43.2 to 74.3	98.4 ng/L Interval 35.5 to 161.6
N-terminal Pro B-type Natriuetic Peptide (NTproBNP) Level 12 Month	126.8 ng/L Interval 23.2 to 143.9	32.6 ng/L Interval 19.6 to 82.7	52.0 ng/L Interval 25.3 to 108.9
N-terminal Pro B-type Natriuetic Peptide (NTproBNP) Level 24 Month	81.7 ng/L Interval 54.9 to 110.5	53.9 ng/L Interval 33.6 to 91.6	46.6 ng/L Interval 30.1 to 113.5

SECONDARY outcome

Timeframe: up to 24 Months

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.

Outcome measures

Outcome measures
Measure	Elevated Risk / Carvedilol n=11 Participants Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Elevated Risk/Usual Care n=8 Participants Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 Participants Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Left Ventricular Mass Baseline	110.6 g Interval 87.0 to 124.9	95.3 g Interval 87.2 to 103.6	98 g Interval 84.5 to 120.0
Left Ventricular Mass 12 Month	92.2 g Interval 75.4 to 103.6	98.4 g Interval 90.2 to 138.0	94.5 g Interval 84.2 to 112.2
Left Ventricular Mass 24 Month	80.2 g Interval 65.6 to 91.9	96.9 g Interval 85.8 to 120.8	97.8 g Interval 90.0 to 108.5

Adverse Events

Elevated Risk / Carvedilol

Serious events: 1 serious events

Other events: 11 other events

Deaths: 1 deaths

Elevated Risk/Usual Care

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Low Risk / Non-randomized

Serious events: 1 serious events

Other events: 47 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Elevated Risk / Carvedilol n=11 participants at risk Patients determined to be elevated risk and randomized to carvedilol (elevated risk/carvedilol arm) initiated carvedilol at a dose of 3.125 mg twice daily on the evening of the first cancer therapy cycle and continued for 12 months. Dose adjustments were based on tolerability and targeted parameters as determined by the study physician, and carvedilol was titrated to maximum tolerated dose by the participant or to a SBP of 110-120mmHg or heart rate (HR) of 50-55 beats per minute. Titration steps were predefined at doses of 6.25 mg, 12.5 mg, and up to 25 mg twice daily. Clinical, echocardiographic, and biomarker data were collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9 12 and 24 months.	Elevated Risk/Usual Care n=8 participants at risk Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 participants at risk Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
General disorders Disease Progression	9.1% 1/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	0.00% 0/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	0.00% 0/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.
Cardiac disorders Cardiac Arrest	0.00% 0/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	0.00% 0/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	2.0% 1/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.

Other adverse events

Other adverse events
Measure	Elevated Risk / Carvedilol n=11 participants at risk Patients determined to be elevated risk and randomized to carvedilol (elevated risk/carvedilol arm) initiated carvedilol at a dose of 3.125 mg twice daily on the evening of the first cancer therapy cycle and continued for 12 months. Dose adjustments were based on tolerability and targeted parameters as determined by the study physician, and carvedilol was titrated to maximum tolerated dose by the participant or to a SBP of 110-120mmHg or heart rate (HR) of 50-55 beats per minute. Titration steps were predefined at doses of 6.25 mg, 12.5 mg, and up to 25 mg twice daily. Clinical, echocardiographic, and biomarker data were collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9 12 and 24 months.	Elevated Risk/Usual Care n=8 participants at risk Patients with elevated risk who were randomized to the Elevated Risk/Usual Care arm were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.	Low Risk / Non-randomized n=49 participants at risk Patients who did not meet the threshold for elevated risk were not randomized, but were followed with clinical, echocardiographic, and biomarker data collected at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Vascular disorders Hypertension	81.8% 9/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	37.5% 3/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	61.2% 30/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.
General disorders Fatigue	36.4% 4/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	50.0% 4/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	46.9% 23/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.
Investigations Ejection Fraction Decreased	0.00% 0/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	0.00% 0/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	16.3% 8/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.
Investigations Electrocardiogram T Wave Abnormal	0.00% 0/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	0.00% 0/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	16.3% 8/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.
Vascular disorders Thromboembolic Event	0.00% 0/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	12.5% 1/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	12.2% 6/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.
Nervous system disorders Dizziness	0.00% 0/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	0.00% 0/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	8.2% 4/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.
Vascular disorders Hypotension	0.00% 0/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	0.00% 0/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	6.1% 3/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.
Cardiac disorders Myocardial Infarction	0.00% 0/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	0.00% 0/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	6.1% 3/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.
Nervous system disorders Pre-Syncope	9.1% 1/11 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	12.5% 1/8 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.	2.0% 1/49 • 24 months Adverse Events were assessed and graded according to the CTCAE v5.0. At each visit, patients were assessed for grade 2 and higher targeted adverse events (bradycardia, fatigue, and hypotension) as well as cardiovascular events and events ending in death using chart review and patient interview. All SAEs and AEs collected as part of the study and consistent with reporting requirements are reported.

Additional Information

Bonnie Ky, MD, MSCE

University of Pennsylvania

Phone: 215-573-6606

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place