Fountzilas 2008.

Study characteristics
Methods	Randomisations were performed at the HeCOG Data Office (balanced by centre and stratified according to menopausal status (premenopausal versus postmenopausal), hormonal receptor status (positive versus negative), and number of positive nodes (1 to 3 versus 4 or more)
Participants	1086 women (aged 22 to 79 years) with non‐metastatic node‐positive epithelial breast cancer (T1‐4/N1‐2/M0) treated with epirubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Also, radiotherapy was mandatory for all women with breast‐conserving surgery (35% of women in both treatment groups) or for those with 4 or more positive lymph nodes (52% of women in the high peak dose group and 51% of women in the low peak dose group), and/or tumour size 5 cm or larger (irrespective of the initial operation type; 11% of women in both treatment groups). Radiation dose was 50 to 55 Gy on the entire breast or chest wall followed by a 10 to 15 Gy boost on the area where the tumour was initially located (Fountzilas 2005). Location of the tumour was nm. Prior anthracycline therapy nm; prior cardiac radiotherapy nm; no prior cardiac dysfunction
Interventions	Epirubicin (infusion duration nm) with a peak dose of either 110 mg/m2 (N = 551; cumulative anthracycline dose nm; the planned cumulative dose was 330 mg/m2) or 83 mg/m2 (N = 535; cumulative anthracycline dose nm; the planned cumulative dose was 332 mg/m2)
Outcomes	Heart failure (i.e. clinical heart failure defined as mild congestive heart failure responsive to therapy (WHO grade 3)) Adverse effects other than cardiac damage (according to WHO criteria)
Notes	The data presented in this table are for the 1063 out of 1086 women (540 out of 551 women in the high peak dose group and 523 out of 535 in the low peak dose group); 14 women were excluded because they never started therapy and 9 women had incomplete treatment and toxicity data. However, we performed an intention‐to‐treat analysis. Although the cumulative anthracycline doses women in both treatment groups received were not documented, the authors of this study have stated that the median cumulative doses of all drugs were almost identical in both groups. Median length of follow‐up 40 months. No funding documented.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	It was stated that randomisation was performed at the HeCOG Data Office, but no further information on the method of randomisation was provided
Allocation concealment (selection bias)	Low risk	Randomisation was performed at the HeCOG Data Office
Blinding of participants and personnel (performance bias)	Unclear risk	No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case
Blinding of outcome assessment (detection bias): clinical heart failure	Unclear risk	No information on blinding of outcome assessors was provided for clinical heart failure
Blinding of outcome assessment (detection bias): adverse effects other than cardiac damage	Unclear risk	No information on blinding of outcome assessors was provided for adverse effects other than cardiac damage
Incomplete outcome data (attrition bias): clinical heart failure	Unclear risk	It was not documented in how many women clinical heart failure was assessed; at least 2.1% not analysed
Incomplete outcome data (attrition bias): adverse effects other than cardiac damage	Unclear risk	It was not documented in how many women adverse effects other than cardiac damage were assessed; at least 2.1% not analysed
Selective reporting (reporting bias)	High risk	There was no reference to a protocol provided in the manuscript (and we did not search for it), but not all expected outcomes were reported in a useful manner
Other bias	Unclear risk	Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): unclear (unclear if prior cardiotoxic treatment was balanced between treatment groups; the other items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: unclear (not reported)