Linden 2007.

Study characteristics
Methods	Method of randomisation not clear (no stratification factors were used due to large sample size)
Participants	3114 women (aged 21.9 to 76.9 years) with high‐risk stage I or II breast cancer treated with doxorubicin and cyclophosphamide. Also, if less than a mastectomy was performed, women received external beam radiation therapy (39% of the women in the low peak dose group and 38% of women in the high peak dose group; location of the tumour nm; dose nm). No prior anthracycline therapy; no prior cardiac radiotherapy; no prior cardiac dysfunction
Interventions	Doxorubicin (infusion duration nm) with a peak dose of either 54 mg/m2 (N = 1590; cumulative anthracycline dose nm; the planned cumulative dose was 324 mg/m2) or 81 mg/m2 (N = 1524; cumulative dose nm; the planned cumulative dose was 324 mg/m2)
Outcomes	Heart failure (i.e. clinical heart failure defined as congestive heart failure grade 3 or 4 according to SWOG criteria) OS (defined as time from registration to time of death due to any cause) Adverse effects other than cardiac damage (according to SWOG criteria)
Notes	Although the cumulative anthracycline doses women in both treatment groups received were not documented, the authors of this study have stated that women in both groups received identical total doses of chemotherapeutic agents. Length of follow‐up nm (median follow‐up for women still alive at the time of analysis is 7.2 years). The study was supported in part by the US Public Health Service Cooperative Agreement grants, but no information on the influence of funders was provided.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	It was stated that this was a randomised study, but no further information on the methods of randomisation was provided
Allocation concealment (selection bias)	Unclear risk	It was stated that this was a randomised study, but no further information on the methods of randomisation was provided
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): overall survival	Low risk	No information on blinding of outcome assessors was provided, but since this is not applicable for overall survival we judged this as a low risk of bias
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	Low risk	Almost all women (99.3%) were included in the analysis of clinical heart failure
Incomplete outcome data (attrition bias): overall survival	Unclear risk	Not documented how many women were included in the analysis of overall survival
Incomplete outcome data (attrition bias): adverse effects other than cardiac damage	Low risk	Almost all women (99.3%) were included in the analysis of adverse effects other than cardiac damage
Selective reporting (reporting bias)	Low risk	There was no reference to a protocol provided in the manuscript (and we did not search for it), but all expected outcomes were reported
Other bias	Unclear risk	Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): no (all items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: unclear (not reported)