Statistical analysis
The incidence and corresponding 95% confidence intervals (CIs) was
calculated by the number of patients experiencing cardiac toxicities
(LVEF decline or CHF) and total number of breast cancer patients treated
with anti-HER2 agents were extracted from the safety profiles of
included trials. Odds ratio (OR) and corresponding 95% CIs were used to
assessed the risk of cardiac toxicities associated with dual HER-2
blockade versus anti-HER-2 monotherapy. We used the Peto method to
calculate the ORs and 95% CIs because this method provided the best CI
coverage and was more appropriate method for meta-analysis when dealing
with low event
rates(<5%)[15]. To
determine the risk of cardiac toxicities associated with dual anti-HER2
blockade within particular groups, we also conducted the following
prespecified subgroup analyses: the treatment setting (neoadjuvant,
adjuvant and metastatic), the type of anti-HER2 therapies (dual HER2
blockade vs. trastuzumab; dual HER2 blockade vs. lapatinib), concomitant
treatment (none, chemotherapy and hormonal therapy). If Peto
OR>1, it reflected that more risk in dual HER2 blockade
group, and vice versa. A statistical test with a p -value less
than 0.05 was considered significant. To measure overall heterogeneity
across the included cohorts, we calculated theI 2 statistic, withI 2greater than 50% indicating high
heterogeneity. Sensitivity analysis using different statistical models
was performed to assess the stability of results. We assessed potential
publication bias by visual inspection of the symmetry of funnel plots
and with the Egger regression asymmetry test. All statistical analyses
were performed by using Version 2 of the Comprehensive MetaAnalysis
program (Biostat, Englewood, NJ) and Open Meta-Analyst software version
4.16.12 (Tufts University).