HOT 1998.

Study characteristics
Methods	Multicentre, 3 × 2 factorial design, ITT strategy. PROBE trial. All participants in the HOT trial were randomly assigned to achieve 3 therapeutic goals (DBP ≤ 90 mmHg, ≤ 85 mmHg, or ≤ 80 mmHg) and to receive aspirin (acetylsalicylic acid) 75 mg daily or placebo under double‐blind conditions. Participants were randomized on the basis of the following baseline variables: age, sex, previous antihypertensive therapy, smoking, previous MI, previous other CHD, previous stroke, and diabetes mellitus. Follow‐up: 3.3–4.9 years (mean 3.8 years)
Participants	3232 men and women aged 50–80 years (mean 62 years) with essential hypertension. Required DBP ≥ 100 mmHg and ≤ 115 mmHg on 2 occasions, at least 1 week apart. Exclusion criteria included: malignant or secondary hypertension; stroke or MI within 12 months before randomization; decompensated CHF; serious disease affecting survival during the next 2–3 years; requirement for BB, ACEI, or diuretic treatment for reasons other than hypertension; requirement for antiplatelet or anticoagulant treatment; and diabetes requiring insulin. Baseline characteristics of 3232 participants (% or mean): men/women: 53%/47%; age: 62 years; SBP: 174 (SD 15) mmHg; DBP: 106 (SD 3) mmHg; diabetes: 12%; current smoker: 16%; and ethnic group: white: 92%, non‐white: 8%. Previous cardiovascular condition: IHD: 95%; stroke: 7%. Countries: Argentina, Austria, Belgium, Canada, Denmark, East Asia, Finland, France, Germany, Great Britain, Greece, Hungary, Israel, Italy, Mexico, Norway, South East Asia, Spain, Sweden, Switzerland, Netherlands, and the USA.
Interventions	Standard target: DBP ≤ 90 mmHg Lower target: DBP ≤ 85 mmHg or ≤ 80 mmHg
Outcomes	Primary outcomes: pooled major cardiovascular events (non‐fatal MI, non‐fatal stroke, or cardiovascular death) and target blood pressures or DBP achieved during treatment. Secondary outcomes: target DBP and specific outcomes, such as total or cardiovascular mortality, fatal and non‐fatal CHD, and stroke and hospitalization.
Funding sources	Astra AB (Sweden), Astra Merck Inc. (USA), Teva (Israel), Hoechst (Argentina)
Declarations of interest	Not reported
Notes	Silent MIs were documented by ECG at randomization and final visit. Blood pressures achieved at end of the trial: standard target: DBP 85 (SD 5) mmHg; lower target: DBP 82 (SD 5) mmHg. A private repository provided individual participant data from people with hypertension with established CVD that were used in this Cochrane Review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization was computer‐generated based on communications by fax between investigators and the Study Coordinating Centre" (pp. 1755–62). Comment: the randomization procedure was a version of the Pocock‐Simon randomization (Pocock SJ, 1975) Protocol, section 7.3.
Allocation concealment (selection bias)	Low risk	Quote: "The randomization was computer‐generated based on communications by fax between investigators and the Study Coordinating Centre" (pp. 1755–62; and protocol, section 7.3).
Blinding of participants and personnel (performance bias) All outcomes	High risk	The study design was not compatible with blinding of participants and personnel.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "An Independent Clinical Event Committee evaluated all events (masked)" (pp. 1755–62; and protocol, section 7.2).
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "14% of the ECG could not be obtained leading to uncertainty on silent myocardial infarctions. On the other hand, no significant differences among targets have been detected" (Clinical Study Report, p. 23, pp. 1755–62, Figure 1).
Selective reporting (reporting bias)	Low risk	The database showed all required results (study protocol, sections 3.1 and 3.2).
Other bias	Unclear risk	Subgroup of participants with basal CVD not predefined.