Syst‐Eur 1991.

Methods	Randomised double‐blind placebo‐controlled multi‐site study conducted in ambulatory community‐based patients from referral clinic in Europe (23 countries across Western and Eastern Europe, mainly from Finland, Bulgaria, the Russian Federation, Belgium, Italy, Israel, UK, France, Estonia, Lithuania, Spain, Poland, and Romania)
Participants	4695 participants; 66.8% female; age range ≥ 60; mean 70.3 years; race: not reported; male 31% Mean blood pressure at entry: 174/86 mmHg Pre‐existing risk factors: myocardial infarction 1.2%; stroke 3.5%; smoking 7.3% BP target: reduce systolic by > 20 mmHg or < 150 mmHg Inclusion criteria: SBP 160 to 219 mmHg and DBP < 95 mmHg Exclusion criteria: hypertension secondary to a disorder that needed specific medical or surgical treatment; retinal haemorrhage or papilledema; congestive heart failure; dissecting aortic aneurysm; serum creatinine concentration at presentation of 180 micromols/L or more; history of severe nosebleeds, stroke, or myocardial infarction in the year before the study; dementia; substance abuse; any disorder prohibiting a sitting or standing position; any severe concomitant cardiovascular or non‐cardiovascular disease Follow‐up: 2.5 years; average follow‐up: 2 years (median)
Interventions	Treatment Step 1 ‐ nitrendipine 10 mg daily, 10 mg BID, 20 mg BID Step 2 ‐ enalapril 5 mg, 10 mg, 20 mg daily in evening and/or hydrochlorothiazide 12.5 to 25 mg/d in morning Control ‐ placebo
Outcomes	Mortality, stroke, CHD, CHF, systolic BP, diastolic BP
Notes	Percentage not on assigned therapy at study end (2 years) including open follow‐up and losses to follow‐up: placebo group 27%, treatment group 18% Percentage receiving nitrendipine fell from 80% in year 1 to 50% in year 4 Difference in blood pressure at end of study (Treatment ‐ Control) systolic/diastolic: ‐10.1/‐4.5 mmHg at 2 years Information was obtained for subgroups from publications using individual patient data from the INDANA database Data on mortality, cardiovascular mortality and morbidity (does not include TIA), cerebrovascular mortality and morbidity, and CHD mortality and morbidity are available for 60 to 79 years and 80 years or older subgroups from the INDANA database (Gueyffier 1999)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “randomized to double‐blind treatment with active medication or placebo by means of a computerized random function” Randomisation was stratified by centre, sex, and previous cardiovascular complications. Group allocation determined by computerised random function Comment: randomisation was properly done
Allocation concealment (selection bias)	Low risk	Quote: "all bottles with study medication are identified by a unique number, allowing persons with access to the code to distinguish between placebo and active medication.....The responsible officer at the RDDC is instructed by the Coordinating Office whether the patient should receive placebo or active medication. The officer then writes the patient identification number on the labels of the bottles with the study medications and ships a one‐year supply to the local investigator. Under no circumstances is the officer at the RDDC allowed to disclose a patient's code. The physician, who proposed the patient for entry into the trial, receives the patient's identification number and a sealed envelope with patient's code from the Coordinating Office. This envelop will be collected at the end of study, and can only be opened in a medical emergency that cannot be dealt otherwise. The investigator verifies whether the patient identification number on the label of each medicine bottle corresponds with the number given by the Coordinating Office" Comment: allocation of treatment was concealed via proper methods
Blinding of participant and personnel (performance and detection bias)	Low risk	Quote: "Sys‐Eur is conducted as a double‐blind placebo controlled multicentre trial" "In the active treatment, tablets with 20 mg nitrendipine, 10 mg enalapril, and 25 mg hydrochlorothiazide were used. The matching placebos in the control patients do not contain any active substance" "Placebo tablets were identical to the study drugs, with a similar schedule" Comment: both patients and physicians were unaware of treatment provided
Blinding of outcome assessment	Low risk	Quote: "the endpoint committee, which was unaware of the patients’ treatment status, identified all major endpoints by reviewing the patients’ files and other source documents, or by requesting detailed written information from the investigators, or by both approaches" "All other events were checked at the coordinating office by doctors who were unaware of the treatment‐group status" Comment: outcome assessment was carried out in an independent manner, and outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "in patients who do not continue to attend clinics (non‐supervised open follow‐up), the following information is obtained by writing, telephone or personal contact either from the patients themselves or where appropriate, their General Practitioner, family members, or via office of vital statistics: vital status, if deceased cause of death, information on current medical treatment; and the incidence of non‐morbid fatal events" "Patients without any report within the year before the trial stopped were counted as lost to follow‐up" Comment: follow‐up as complete as possible; losses to follow‐up: 2% at 2 years
Selective reporting (reporting bias)	Low risk	Comment: all fatal and non‐fatal cerebrovascular and cardiovascular outcomes were reported
Industry sponsorship bias	High risk	Quote: "the trial was sponsored by Bayer AG, Wuppertal, Germany. The National Fund for Scientific Research, Brussels, Belgium, provided additional support. The study medication was donated by Bayer AG and Merck Sharpe & Dohme Inc, West Point, Pa. The Syst‐Eur trial, initiated by Antoon Amery, MD, who died on November 2, 1994, was a concerted action of the BIOMED Research Program sponsored by the European Union. The trial was carried out in consultation with the World Health Organization, International Society of Hypertension, European Society of Hypertension, and World Hypertension League" Comment: conflict of interest was not declared