Follow up br During a median cardiac follow
During a median cardiac follow-up of 11 (IQR, 9 to 18) months, a median of 5 MUGA scans were performed in each group (P ¼ 0.35). There was no significant difference in the number of trastuzumab cycles (Table 1) or cardiac follow-up 155
The mean final LVEF was significantly lower in the control group (61.1 8.1% vs 64.4 6.5%, P ¼ 0.026). The median absolute change in LVEF in the statin group was 0% (IQR e5% to þ3%; P ¼ 0.27), compared with an absolute decline of 6% (IQR e10% to e1% P < 0.001) in the control group. After adjustment for baseline LVEF and potential confounders (age, cardiovascular risk factors, cardiovascular medications, BMI, cancer stage, and anthracycline exposure), the difference observed in final LVEF between the 2 groups remained statistically significant (Table 2). No interaction was noted between the presence of coronary artery disease or diabetes and statin use on the differences in LVEF (Table 2). There was a higher incidence of cardiotoxicity (LVEF decline
not reach statistical significance in unadjusted analysis (P ¼ 0.1). However, upon adjusted analysis, statin treatment was independently associated with a lower risk of cardiotox-icity (odds ratio [OR] 0.32, 95% CI, 0.10-0.99, P ¼ 0.049) although with wide confidence intervals (Table 3). Trastu-zumab interruption was almost twice as frequent in the control patients (9.3%) than in patients treated with statins (4.7%), but this was not statistically significant (P ¼ 0.49). Adjusted analysis was not performed owing to the limited number of events.
Subgroup analysis by anthracycline exposure is summa-rized in Figure 1). The benefit of statins in preventing a Linezolid in LVEF was similar in those who did and did not receive anthracycline treatment.
We demonstrate that statin exposure (moderate- to high-intensity doses) is associated with lower declines in LVEF in women receiving trastuzumab therapy for HER2þ breast cancer. Patients who were on statins during cancer therapy had higher LVEF at end of treatment and smaller change in LVEF during treatment. This benefit persisted after adjusting for confounders including the use of anthracyclines and other known potentially protective cardiac medications. The magnitude of benefit was similar in patients who did and did not receive anthracycline therapy before trastuzumab. Although the difference in final LVEF between statin-treated and nontreated groups was modest, the magnitude of benefit was similar to that shown with other primary prevention studies in patients receiving cardiotoxic cancer therapies.9,13,14 Furthermore, statin-treated patients had a lower risk for car-diotoxicity as defined by CREC; however, the confidence interval around the OR was wide.
Mechanism of cardioprotection
The mechanism by which statins protect against trastuzumab-induced cardiotoxicity is unknown. However, oxidative stress and endothelial dysfunction are hypothesized
Canadian Journal of Cardiology
Volume 35 2019 Table 1. Baseline characteristics
All patients Control Statins
Postmenopausal, n (%)
Median statin dose, mg (range, % within statin group)
Previous medications, n (%)
Anthracyclines, n (%)
5-FU, fluorouracil; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; ER, estrogen receptor; IQR, interquartile range; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; MUGA, multigated acquisition scan; PR, pro-gesterone receptor; SD, standard deviation.
to play an important role in the pathophysiology of trastuzumab-induced cardiotoxicity.15,16 Neuregulin (NRG-
1) is a protein released by coronary microvasculature and myocardial endothelial cells in response to stress. It binds to the transmembrane HER4, which, in turn, dimerizes with HER2 to activate critical cell-survival pathways. The
Table 2. Adjusted final LVEF and LVEF change
inhibition of HER2 signalling by trastuzumab results in accumulation of reactive oxygen species (ROS) within car-diomyocytes, which leads to apoptosis and myocardial dysfunction.16 Moreover, NRG-1/ErbB2 signalling regulates myocyte-myocyte and myocyte-matrix interactions, which are essential for maintenance of sarcomeric structure.17
The estimates and P value were derived from analysis of covariance with adjustment for baseline LVEF (only for final LVEF), age, body mass index, car-diovascular risk factors (diabetes, hypertension, coronary artery disease), cancer stage (early or metastatic), cardiovascular medications (angiotensin converting enzyme inhibitor, angiotensin II receptor blocker, b-blocker), and anthracycline-based therapy. When interaction terms for coronary artery disease, diabetes, and statins were include the magnitude of difference for mean final LVEF and LVEF change remained similar and statistically significant. The interaction terms were not significant. For mean final LVEF: coronary artery disease*statin, P ¼ 0.14; diabetes*statin, P ¼ 0.69. For LVEF change: coronary artery disease*statin, P ¼ 0.20; diabetes*statin, P ¼ 0.88.