Through electronic patient records baseline characteristics
Through electronic patient records, baseline characteristics were collected, including cardiovascular risk factors, cardiac disease history, cardiovascular medications, cancer-related variables (disease stage, estrogen-receptor status, progesterone-receptor status) and cancer-treatment history. For each patient, we calculated the cardiac risk score generated from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 study.10 Trastuzumab exposure time was defined as the period (months) between the first and the last trastuzumab dose in each patient. Cardiac follow-up was defined as the time (months) between the first and the last MUGA scans.
The primary outcome was the final LVEF, defined as the last LVEF value within follow-up period closest to the last trastuzumab treatment. We also assessed the following secondary outcomes: (1) change in LVEF, defined as the difference between the final LVEF and the LVEF on the pretreatment scans (baseline LVEF); (2) incidence of car-diotoxicity, defined as the proportion of patients meeting the Cardiac Review and Evaluation Committee (CREC) defini-tion for cardiotoxicity (LVEF decline 10% to < 55% without symptoms of heart failure or 5% drop to < 55% with symptoms11) in at least 1 MUGA scan; and (3) the incidence of trastuzumab interruption (at least 1 MK-467 inter-ruption attributed to LVEF reduction). The median number of MUGA scans between groups was compared to assess for ascertainment bias.
Continuous variables are reported as mean standard deviation (SD) or median and interquartile range (IQR) as appropriate. Two sample Students’ t-tests or ManneWhitney U test were used to compare the means of continuous variables between patients and controls based on the data distribution. Categorical variables were expressed as
Calvillo-Argüelles et al. Statins and Trastuzumab Cardiotoxicity
frequencies and percentages and were analyzed using Fishers exact test. Wilcoxon signed-rank test was used to compare the change in LVEF (as defined above) within each group. Analysis of covariance (ANCOVA) was used to assess the relationship between statin exposure status and the primary outcome after adjustment for the baseline LVEF and the following covariates: age, body mass index (BMI), cardiovas-cular risk factors (diabetes, hypertension, coronary artery disease), cardiovascular medications (angiotensin-converting enzyme inhibitors [ACEi], angiotensin II receptor blockers [ARBs], b-blockers), cancer stage (early or metastasic), and anthracycline therapy. Given the established atherosclerosis-related benefits of statins in patients with coronary artery disease or diabetes, we included interaction terms for diabetes and coronary artery disease with statins as covariates in the ANCOVA models. A logistic regression model was con-structed using cardiotoxicity (as defined above) as the outcome, treatment with statins as the predictor, and anthracycline exposure, number of cardiovascular risk factors (diabetes, hypertension, coronary artery disease, smoking), and the NSABP-31 cardiac risk score10 as confounders. An-alyses were performed using SPSS v.20 (IBM Corp, Armonk, NY). Statistical tests were 2-sided, and statistical significance was defined as P < 0.05.
We identified 525 consecutive women with HER2þ breast cancer receiving trastuzumab therapy between 2002 and 2013. Forty-three patients received statins (statin group) before and during cancer treatment; they were matched to 86 statin-unexposed controls. Mean age at cancer diagnosis was 62 9 years. Statin types and median doses used are sum-marized in Table 1. The majority (81.4%) of the patients were on moderate- to high-intensity statin therapy.12 Anthracyclines were used in 72 (56%) patients prior to tras-tuzumab exposure. The median trastuzumab exposure time for the whole cohort was 11.8 (IQR 11 to 12) months with no significant difference between statin-treated patients and controls. With the exception of tamoxifen use, cancer treatments did not differ between the groups. The median doxorubicin equivalent dose was 201.5 mg/m2 in the statin arm and 202.7 mg/m2 in the control group (P ¼ 0.24).
Patients in the statin group had a larger BMI and were more likely to have diabetes, hypertension, dyslipidemia, and coronary artery disease than controls. This higher cardiovas-cular risk profile was reflected in the higher frequency of other cardiovascular medications such as ACEi, ARBs, b-blockers, mineralocorticoid-receptor antagonists, and calcium-channel blockers (Table 1). Mean baseline LVEF was similar between the 2 groups (66.7 5.4% vs 66.0 7.0% in control and statin groups, respectively, P ¼ 0.57).