Beta blockers and angiotensin modulators form the cornerstone of heart failure management in the general population. The benefit of these inexpensive agents is ill-defined in HER2-positive breast cancer patients with known cardiac-related comorbidities who are treated with trastuzumab, which is the gold standard targeted therapy in this patient population plus a known cause for reversible cardiotoxicity in many patients. We sought to determine if being on these cardiovascular medications up-front to exposure to targeted therapy prevents the decline in LVEF in patients with known cardiac-related comorbidities. Adhered to the PRISMA statement for pooled-analysis. Selection criteria: Clinical trials involving patient cohorts already on cardioprotective medications when treated with trastuzumab. Search strategy: PubMed, the Cochrane Library, Google Scholar, Web of Science, and Scopus databases from 1998 to 2013, plus www.asco.org and www.clinicaltrials.gov. Outcome measure: Decline in LVEF >10% of baseline per ECHO or MUGA while on beta blocker +/− angiotensin modulator (ACEi or ARB), plus trastuzumab. Statistical analysis: Dedicated pooled-analysis statistical software (BioStat Inc., NJ, USA). From 218 articles, 6 clinical trials (n = 329) were selected with extractable data. Patients on beta blocker +/− angiotensin modulator tended to be older and heavily pretreated with chemotherapy. Being on cardioprotective medications during trastuzumab therapy was beneficial for stability of LVEF in patients at above-average risk for cardiotoxicity [mean odds ratio (OR): 0.664, 95%CI 0.44 to 0.99; random effects model p = 0.05 versus fixed effect model p = 0.004]. Statistical analyses revealed robustness of our analysis for comorbidity index (p < 0.05). Evidence to support the up-front use of beta blockers as a cardioprotective strategy in breast cancer patients at highest risk for cardiotoxicity secondary to targeted therapy has yet to be fully investigated in a randomized clinical trial -- the results of the MANTICORE 101 clinical trial are pending. However, our hypothesis-generating analysis suggests that use of a beta blocker +/− angiotensin modulator while receiving targeted therapy blunts the decline in LVEF in breast cancer patients with known cardiac risk factors or comorbidities. Although our analysis only represents a statistical signal of possible clinical benefit, further investigation is warranted.