Because of the nature of the trial, in which investigators have to adapt therapies to the SBP and LDL-C targets to which patients are randomized, a double-blind design is impossible. Therefore the trial is designed as a Prospective, Randomized, Open, Blind Endpoint evaluation (PROBE) trial (72), where all outcomes (cardiovascular, neurological and cognitive) are to be blindly evaluated by Independent Event Adjudicating Committees.
Population at study
The trial is to be conducted on 7500 subjects, aged 65 years and above, of either gender, having presented a stroke or transient ischaemic attack (TIA) 1 to 6 months previously.The number of patients to be included (7500 patients for a mean treatment follow-up of 4 years) has been calculated to provide sufficient statistical power to answer the two main questions under investigation. The planned number of 7500 patients should be recruited during 24 months by about 250 units. 2500 patients are to be enrolled and followed-up in Europe (23 countries) and 5000 in China. The trial will also include an additional number of patients with a qualifying haemorrhagic stroke randomized to the BP lowering arm only.
The sequence is generated by the Statistical Centre. Assignment is to be made automatically when the patient’s data are entered into the electronic clinical research form (eCRF).
Antihypertensive: Patients under antihypertensive treatment should have it increased or decreased, and untreated patients should have it instituted to achieve the SBP target within 3 months. Investigators may follow a therapy algorithm based on ESH/ESC or Chinese guidelines, but are free to individualize it. Lipid-lowering: Patients previously untreated with a statin will be assigned a statin (compound freely chosen by the investigator among those registered in his/her country); patients already under statin therapy will be maintained under that statin or switched to another statin according to the investigator’s judgement. The compound to be used and the initial dose will be chosen dependent on baseline and target LDL-C. Doses should be changed to achieve the allocated target within 3 months. In addition all patients will be given nonrandomized antiplatelet (if necessary anticoagulant) therapy by their investigators according to evidence-based guidelines.
Primary: Time to stroke (fatal and non-fatal). Secondary: Time to 1) First major cardiovascular event; 2) Coronary events; 3) All cause death; 4) Cardiovascular death; 5) Hospitalized heart failure; 6) New onset atrial fibrillation; 7) Ischaemic stroke; 8) Haemorrhagic stroke; 9) Stroke + TIA; 10) Cognitive decline/Dementia. Tertiary: 1) Disability; 2) Depression; 3) White matter lesions and microbleeds (MRI); 4) Organ damage. Adverse experiences will also be reported and evaluated.
All data should be entered by investigators into an eCRF on the trial website, where data will be checked at the two Coordinating Centres. In addition to medical history and examination, the following measurements will be obtained at screening (S) or randomization (R) and specific times during follow-up: 1) SBP, DBP, HR by a validated, automatic oscillometric device with data output into the eCRF (S/R, monthly until SBP target, and then every 3 months); 2) 24-h ambulatory BP with validated device and fixed protocol (S, SBP target, and yearly intervals); 3) T-C, HDL-C, LDL-C, TG (S, monthly until LDL-C target, and then every 6 months); 4) routine blood tests and urine analysis (S, and at yearly intervals); 5) 12-lead ECG, (S, after 1 and 3-years and study end); 6) cognition: Montreal Cognitive Assessment test, IQ CODE and Disability Assessment for Dementia score (S, after 1 year and study end or primary outcome); 7) disability: modified Rankin score and Barthel index (S and yearly intervals); 8) Depression: 15-item Geriatric Depression scale (S, year one and study end or primary endpoint); 9) Brain imaging (CT or preferably MRI) at screening, and study end or primary endpoint.