HDPAL 2014.

Study characteristics
Methods	Study design Parallel RCT Study dates Duration of follow‐up: 12 months Time frame: August 2005 to September 2013
Participants	Study characteristics Setting: single‐centre (4 dialysis units affiliated with Indiana University) Country: USA Inclusion criteria: ≥ 18 years; ESKD treated with chronic HD dialysed 3 times/week for at least 3 months with hypertension and LV hypertrophy Exclusion criteria: patients with ongoing atrial fibrillation; BMI ≥ 40 kg/m2; history of missing one or more HD treatments in the previous month; known drug abuse; severe chronic obstructive airway disease; stroke or MI within the previous 6 months or known contraindication to atenolol or lisinopril Baseline characteristics Number (analysed/randomised): intervention group 1 (58/100); intervention group 2 (46/100) Mean age ± SD (years): intervention group 1 (52.2 ± 11.7); intervention group 2 (53.1 ± 13.5) Sex (M/F): intervention group 1 (73/27); intervention group 2 (58/42) Dialysis type: HD Mean dialysis vintage ± SD (years): intervention group 1 (4.2 ± 4.4); intervention group 2 (3.9 ± 4.2) Comorbidities CVD: intervention group 1 (100/100); intervention group 2 (100/100) Diabetes: not reported Hypertension: intervention group 1 (100/100); intervention group 2 (100/100) Depression (clinician diagnosis): not reported
Interventions	Intervention classification Pharmacological intervention Indication: study reporting fatigue Intervention group 1 Atenolol 25 mg 3 times/week, and the dose was doubled every 2 to 4 weeks up to a maximum dose of 100 mg Intervention group 2 Lisinopril 10 mg 3 times/week, and the dose was doubled every 2 to 4 weeks up to a maximum dose of 40 mg Co‐interventions All subjects were on thrice‐weekly dialysis
Outcomes	Outcomes reported Fatigue outcome measures used: validation data available (fatigue was reported as an adverse event using a questionnaire) Adverse events (including fatigue, vascular access, hypertension and depression) Questionnaire (20 questions were preceded by the following stem: ‘Over the last week, how frequently have you found yourself bothered by the following symptoms?’ The symptoms were as follows: fatigue or tiredness, chest pain, abdominal pain, cold hands or feet, dizziness on standing, muscle cramps, diarrhoea, nausea, vomiting, dry cough, upper respiratory infection or common cold, shortness of breath, headaches, persistent dizziness, numbness in hands or feet, decreased sex drive, decreased ability to have sex, drowsiness or sleepiness, depression or feeling sad and nightmares. The responses were constantly, frequently, sometimes, rarely or never. Never was coded as 0, rarely as 1, sometimes 2, frequently 3 and constantly as 4) (administered at baseline prior to any administration of the drug and subsequently at monthly intervals over the duration of the trial) Serious adverse events: assessed until the end of treatment Cardiovascular events (MI, stroke): assessed until the end of treatment Cardiovascular hospitalisation: assessed until the end of treatment All‐cause hospitalisation: assessed until the end of treatment Cardiovascular death: assessed until the end of treatment Death: assessed until the end of treatment Pulse pressure: assessed at baseline, 3, 6 and 12 months Heart rate: assessed at baseline, 3, 6 and 12 months Change in aortic pulse wave: assessed at 6 months Change of left ventricular hypertrophy assessed at baseline, 6 and 12 months ECG Post dialysis weights (monitored monthly): assessed at baseline, 3, 6 and 12 months HRQoL KDQOL: assessed at the beginning and end of the trial BP (DBP and SBP) (recorded monthly twice daily): assessed at baseline, 3, 6 and 12 months Self‐inflating automatic oscillometry device
Notes	Additional information Funding: National Institutes of Health NIDDK 2R01‐DK062030‐10 Conflicts of interest/disclosures: none Trial registration identification number: NCT00582114 A priori published protocol was reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from Georgianos 2015: "Randomization was performed using a random permuted block design, and computer‐generated random sequence was used for allocation concealment." Comment: A computer‐generated random sequence is considered as low risk of bias. No imbalance between intervention groups was apparent
Allocation concealment (selection bias)	Low risk	Quote from Agarwal 2014: "Subjects were randomised in a 1:1 ratio to either atenolol or lisinopril using concealed opaque envelopes, using a random permuted block design. A permuted block design was chosen to avoid imbalance in assignment to the study drugs over time. Random sequence was generated by a statistician using a computer program and study technicians opened these envelopes after confirming eligibility with the principal investigator." Comment: There was no reason to suspect that the statistician had knowledge of the forthcoming allocation. However, It was not reported if envelopes were numbered
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote from Agarwal 2014: "The Hypertension in Hemodialysis Patients Treated with Atenolol or Lisinopril (HDPAL) was a randomised, open‐label, parallel group, active control, single‐centre trial that compared the safety and efficacy of ACE‐inhibitor‐based therapy with β‐ blocker‐based treatment, each administered three times weekly after dialysis." Comment: An open‐label study is considered as high risk of bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote from Agarwal 2016: "To accurately capture the adverse effects of atenolol and lisinopril in the HDPAL trial, we used a structured questionnaire." Quote from Agarwal 2014: "An independent data and safety monitoring board reviewed the safety data and the study progress on an annual basis." Comment: An independent data and safety monitoring board reviewed outcomes. The outcomes were assessed with an appropriate measure, without differences between groups (fatigue was reported as an adverse event). It was not stated if the independent data and safety monitoring was blinded to the treatment assigned. However, objective and subjective outcomes were assessed. It was not stated if the interviewer was blinded to the treatment allocation to evaluate fatigue
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote from supplementary Figure 1 in Agaewal 2014: "Reasons for removal by PI: Four subjects refused to perform home blood pressure monitoring repeatedly, one had pain with home BP measurements and one was excluded following a stroke. Reasons for withdrawal of consent was as follows. Atenolol: not feeling well, light‐headed, BP too low, changed mind, wanted original medications, worry about BP, study medication made the subject sick Lisinopril: dizziness, headaches, high BP, fear of stroke, tired of taking BP, tired of participating (n= 4), no reason offered (n= 3), refused home BP monitoring, did not want study medication (n=2), wanted to go back on metoprolol." Comment: As reported in Figure 1, 58/100 in the intervention group 1 (Atenolol) and 46/100 in the intervention group 2 (Lisinopril) completed the study (> 5% lost to follow‐up, with differences between groups). Some reasons for discontinuations appeared to be related with the intervention
Selective reporting (reporting bias)	Low risk	Protocol was published. Fatigue was reported in accordance with a pre‐specified analysis plan, using multiple eligible outcome measurements (scales, time points). Fatigue was reported in a format that was not extractable for meta‐analysis. All outcomes that should be addressed (fatigue, cardiovascular disease, and death) were reported. Fatigue was reported but not extractable
Other bias	High risk	Quote from Agarwal 2014: "We terminated the trial on the unanimous recommendation of the independent data safety monitoring board which found a clear signal for cardiovascular safety on an annual monitoring meeting after complete randomisation. At their annual meeting, the committee also noted that the lisinopril group experienced an increase in the following: all‐cause serious adverse events, all‐cause hospitalisation rates, hypertension and hyperkalaemia." Comment: There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups. Funding was unlikely to influence the data analysis and authors did not report conflicts of interest. However, the study was terminated early