HSCSG 1974.

Methods	Randomized, double‐blind, placebo‐controlled trial conducted in USA with a six week drug run‐in phase.
Participants	452 ambulatory stroke survivors with mild to moderate hypertension, 80% African‐Americans, mean age 59 years, range < 75 years, 60% men. Baseline SBP/DBP 167/100 mmHg, pulse pressure 67 mmHg. 80% of participants had completed stroke in year before randomization. 16% had mixtures of completed stroke and TIA, and 4% had only TIAs. Inclusion criteria: SBP ≥ 140 to 220 mmHg and DBP 90 to 115 mmHg and stroke or TIA, or both, in previous year. Ambulatory, capable of long‐term attendance at treatment clinic, < 75 years of age and no concomitant disease that might be influenced adversely by prolonged treatment with drug or placebo. Follow‐up: 3 years
Interventions	Treatment: deserpidine 1 mg + methyclothiazide 10 mg Control: no treatment
Outcomes	Mortality, stroke, CHD, CHF, systolic BP, and diastolic BP
Notes	Definition of stroke used in the trial – “A marked increase in frequency of TIAs (twice the weekly pre‐randomization level of occurrence, and more than four per week), or a deterioration of more than eight points in the neurological score, also qualified as a stroke endpoint.” A stroke endpoint was defined by the same criteria used for entry into the study. It also was confirmed by a majority of a committee consisting of two members outside of the study and the Central Registry neurologist. The scoring system of residual deficits by the neurologist was based on a total of 100 points, allowed a maximum of 35 points for level of consciousness and mentation, 9 points for cranial nerve function, 30 points for motor system, 3 points for reflexes, 3 points for sensory function, and 20 points for 'health and performance' function. "The study was terminated earlier than planned when it became evident that further follow‐up would not significantly affect the results. All patients without endpoints were under observation for at least one year; the mean follow‐up period for all individuals including those with endpoints was 27.4 months, and for those not having endpoints, it was 38.6 months". " Forty‐nine who entered the drug trial were not subsequently randomized."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A prospective double‐blind co‐operative study was undertaken to determine the influence of treatment on the prognosis in stroke survivors with mild to moderate hypertension." If no intolerable side effects occurred, the patient was placed on a regimen of two tablets daily of randomized medication.” "To ensure that drug and placebo were balanced among groups with characteristics of possible prognostic importance, patients were divided into cells based on these characteristics, and drug or placebo was prescribed to maintain a balance within these cells. The characteristics for which this randomization was conducted were sex, race, diastolic blood pressure above or below 100 mm Hg, and the four stroke categories." "Although no effort was made to assure an equal distribution of drug‐treated and placebo‐treated patients within each clinic, the drug‐placebo ratio differed appreciably in only two of the ten clinics." "No statistically significant differences were noted in the frequency of abnormalities in the laboratory findings, ECGs, and chest X ray films between the drug and placebo groups." Comment: randomization was probably done. However, the method for random sequence generation was not mentioned. Baseline characteristics were well matched.
Allocation concealment (selection bias)	Low risk	Quote: "The biostatistical section was responsible for assignment of patients to drug or placebo regimens, distribution of medication by mail to the individual clinics, data preparation, coding, and analysis." “For use in an emergency, a sealed envelope held by a disinterested person at the local clinic identified the type of medication the patient was receiving." Comment: method of allocation concealment was not reported. Baseline characteristics were well matched.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "A prospective double‐blind cooperative study." "Neither the doctor nor the patient was aware of whether placebo or drug had been supplied. For use in an emergency, a sealed envelope held by a disinterested person at the local clinic identified the type of medication the patient was receiving." Comment: participants and treating physicians were blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "the report of the stroke event and the neurological findings were submitted to Central Registry for confirmation. A stroke endpoint was defined by the same criteria for entry into the study. It also was confirmed by a majority of a committee consisting of two members outside of the study and the Central Registry neurologist." "Similarly, any medical event justifying removal of the patient from the study was carefully reviewed and classified into cardiovascular and non‐cardiovascular categories. The events of a cardiovascular nature were confirmed by an outside cardiologist." Comment: outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "Five‐hundred and one patients were exposed to a pre‐randomization drug trial. Forty‐nine who entered the drug trial were not subsequently randomized." Of the 452 patients randomized, total withdrawals are not reported. "The study was terminated earlier than planned (3 years follow‐up) when it became evident that further follow‐up would not significantly affect the results. All patients without endpoints were under observation for at least one year; the mean follow‐up period for all individuals including those with endpoints was 27.4 months, and for those not having endpoints, it was 38.6 months." Comment: attrition rate was not mentioned and how data were analyzed was not reported.
Selective reporting (reporting bias)	Low risk	Comment: protocol was not available. Cerebrovascular and cardiovascular outcomes, blood pressure measurements, drug intolerance, laboratory measurements were reported.
Other bias	Low risk	This investigation was supported by grants from the National Institute of Neurological Diseases and Stroke.