150 patients will be prospectively consented/screened. Over the course of the study, 30 patients are expected to develop abnormal strain with a normal EF \> 53%. They will be randomized in 1:1 fashion to open label carvedilol vs. no treatment.
All consenting patients will receive a baseline echocardiogram and blood draw for biomarkers and genetic testing. Patients will be followed with echocardiograms at 3 month intervals for 12 months, until completion of trastuzumab/pertuzumab therapy.
Based on echocardiogram findings, patient will fall into four study arms (A, B, C, D). Patients in Arm A (normal EF and normal strain) and Arm D (decrease in EF \> 10%, to a value \<53%) will receive current standard of care treatment and will be followed in a registry arm. Arms B and C will comprise of 30 patients with normal EF who develop preclinical cardiac dysfunction, as defined as a change in global longitudinal strain of \> 15% from baseline strain) or \< -15% absolute longitudinal strain will be prospectively assigned 1:1 to receive prophylactic carvedilol (Arm B) vs. no treatment (Arm C). Prophylactic carvedilol will be initiated at the starting dose of 3.125 mg PO BID and titrated based on blood pressure and heart rate.
Patients will be seen every 3 weeks during the titration phase at their chemotherapy appointments. At each visit, vitals and symptoms will be assessed for dizziness and side-effects from carvedilol. If patient complains of dizziness or HR \< 50 bpm, or SBP \< 100 mmHg, then the dose titration should stop and the dose should be reduced to the dose at the last increased increment. If there is a \> 10% decrease in EF to a value \< 53% on the next echocardiogram, then standard heart failure therapy will be initiated (beta-blocker and/or ace-inhibitors) and chemotherapy will be held as per standard of care. If patients require other standard of care treatments for heart failure, such as diuretic therapy or aldosterone antagonists, then this will also be initiated. At this point, these patients will be considered to have met the study endpoint. However, if there is an improvement or no change in strain and EF, then patients will continue with cardiac surveillance with an echo at 3 month intervals. Patients who have been assigned to receive prophylactic carvedilol will continue treatment for duration of chemotherapy up to 1 year. Prophylactic carvedilol will be stopped at the completion of study.
A biomarker substudy will be conducted on 100 patients. These patients will have labs drawn every at ten time points, baseline and every 6 weeks for 12 months, and 1 year post-chemotherapy. A separate blood draw for generation of hiPSC and DNA testing would be done for 100 patients. The blood collection will coincide with the patient's chemotherapy infusions with trastuzumab. These biomarkers will allow for further characterization of patients at risk for developing CTRCD.
A "cardio-oncology" echocardiogram will include standard 2D M-mode and Doppler echocardiography, 2D strain imaging, and 3D LV volume. This data will be processed on-line or off-line within 24 hours of completion of the echocardiogram to determine randomization.
