Vardan 1987.

Methods	Randomized, double‐blind, placebo‐controlled trial (parallel arms). Wash‐out period = 2 weeks. USA
Participants	DBP 91 to 104 mmHg. Mean age not given. Males 65.7%. Baseline BP was 142.9/97.3 mmHg in the treatment group and 144.9/96.8 mmHg in the control group
Interventions	Chlorthalidone 15 mg (N = 71) or 25 mg/d (N = 75) or placebo (N = 76) Trial duration = 12 weeks
Outcomes	Mean standing and supine SBP and DBP (at weeks 2, 4, 8 and 12); pulse rate; body weight, ECG, hematology, urinalysis, serum biochemistry; liver function tests
Notes	A sample size calculation was not provided. The study included elderly (60 years or older) patients with isolated systolic hypertension only (i.e. SBP 160 to 219 mmHg and DBP < 90 mmHg). A step‐up protocol was used wherein poor response (i.e. BP goal not reached) after 4 weeks led to a doubling of drug dosage from 1 to 2 capsules of chlorthalidone per day; poor response in patients receiving placebo led to a simulated randomization with a doubling of placebo capsules. Therefore with increasing and/or changing medication, BP results were taken from the first 4 weeks of the study only. The study authors stated that there were no statistically significant differences (P value = NS) across treatment groups in baseline SBP and DBP. Gender and race were available for all patients combined into one group therefore P values could not be calculated. We determined that baseline biochemical levels were not statistically significant between treatment groups. Mean ± SEM for BP data at 4, 8 and 12 weeks useful. Not all patients received potassium supplementation. Mortalities and SAEs were not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"The patients were then randomly allocated in double‐blind fashion to receive the 15‐mg or 25‐mg chlorthalidone preparation or the placebo..." (left column, bottom line of p.485). No further information given
Allocation concealment (selection bias)	Unclear risk	Not stated by study authors
Blinding (performance bias and detection bias) All outcomes	Low risk	"The patients were then randomly allocated in double‐blind fashion to receive the 15‐mg or 25‐mg chlorthalidone preparation or the placebo in identical tablet forms to be taken once a day throughout the trial period of 12 weeks." (left column, bottom line of p.485)
Incomplete outcome data (attrition bias) All outcomes	Low risk	The study authors did not state whether the primary efficacy analysis was based on an intention‐to‐treat (ITT) or per‐protocol technique Exclusions: 27,199 patients were screened; 2130 of these were included in the first baseline clinic visit. 1579/2130 (74%) of patients were excluded from the study during the 3 baseline clinic visits following screening, but prior to randomization Attrition: 5/71 (7%) and 9/75 (12%) patients receiving chlorthalidone 15 mg and 25 mg doses, respectively, and 6/76 (8%) patients receiving placebo withdrew from the study. Reasons included: 12 patients for "unacceptable side effects", 5 ‐ "further elevation in blood pressure" and 3 ‐ "protocol violations" WDAEs: 12 patients withdrew due to adverse events (referred in the study as "unacceptable side effects"). The specific reasons in the chlorthalidone 15 mg group were 3/71 (4%) patients: 1 ‐ "rash, drowsiness, depression, weakness, sleep disturbances", 1 ‐ "nausea" and 1 ‐ "rash with pruritus"; in the chlorthalidone 25 mg group were 7/75 (9%) patients: 1 ‐ "rash with pruritus", 1 ‐ "painful eyes, headache, cramps, nausea", 1 ‐ "light‐headedness, diplopia", 1 ‐ "coryza, pruritus, flu symptoms", 1 ‐ "palpitations, light‐headedness", 1 ‐ "headache" and 1 ‐ "hypokalemia". In the placebo group were 3/76 (4%) patients: 1 ‐ "headache, edema, tinnitus" and 1 ‐ "rash, periorbital edema, choking, swollen, ulcerated uvula"
Selective reporting (reporting bias)	High risk	ECG, hematology, urinalysis and liver function were measured, but not reported on in the study. Pulse rate was measured, but not reported. Baseline for body weight was not shown. Endpoint BP was expressed as mean ± SE (standard error of the mean), not as change from baseline to endpoint. SE was given for biochemical data, not SD. Reporting of baseline patient demographics and characteristics was incomplete, i.e. mean age and medical history were not shown. Mortalities and SAEs were not documented Total AEs: 22.5% (16/71), 32% (24/75) and 19.7% (15/76) of patients from the CTD 15 mg and 25 mg and placebo groups, respectively. The 3 to 4 most commonly reported AEs in each treatment group were mentioned
Industry sponsorship	High risk	Supported by Boehringer Ingelheim Pharmaceuticals Inc.