Additional objectives are:
3) Whether there are positive (or negative) interactions between the effects of more intense BP and more intense LDL-C lowering. This will be tested by using a 3×2 factorial design, and suitable interaction tests. Since all the patients will also receive nonrandomized antiplatelet therapy unless contraindicated (or anticoagulant therapy if with atrial fibrillation or other indications), and those with diabetes mellitus will be treated in such a way as to keep HbA1C at values no higher than 7%, the ESH-CHL-SHOT trial is designed to investigate the optimal treatment strategies and targets for preventing recurrent stroke in hypertensive patients with a previous stroke or TIA, with the hypothesis that optimal treatment may reduce stroke incidence by over 50%.
4) Investigating the effects of more or less intense BP and LDL-C lowering on cognitive decline in elderly patients with a previous stroke or TIA. This objective will be tested by administering the Montreal Cognitive Assessment (MoCA) Test to all patients. Quantitative evaluation of the MoCA score will provide a measurable index of cognitive decline in the various arms of the trial.
5) Investigating the effects of more or less intense BP and LDL-C lowering on the development of dementia in elderly patients with a previous stroke or TIA. This objective will be tested by administering the IQCODE to a patient informant.
6) Investigating the effects of more or less intense BP and LDL-C lowering on development and progression of cerebral small vessel disease (WML, MB and lacunae). This will be investigated quantitatively in a selective cohort of patients enrolled by sites able to use a common protocol of MRI. Central reading of MRI with volumetric analysis of the lesions(hyperintensities) will provide quantitative measures of MRI changes in the various arms of the trial.
7) Investigating the role of ambulatory blood pressure compared with clinic blood pressure in predicting recurrent stroke as well as other cardiovascular outcomes. ESH-CHL-SHOT is the first large outcome trial in which all patients will have ambulatory BP monitored at yearly intervals, thus avoiding the insufficient statistical power of previous trials in which only a proportion of patients had data on ambulatory BP. Ambulatory BP tracing will be read centrally providing reliable measures of 24-h BP at various times during follow-up in the various arms of the trial.
8) Investigating for the first time in a prospective way the role of short-term (within 24 hours) and long-term (between consecutive visits over 4 years) BP variabilities. This will be made possible through the extensive use of ambulatory BP monitoring (allowing easy measurement of within 24-hour variability) and repeated clinic BP measurements at short intervals of 3 months (15 to 20 measurements for patients over the duration of the trial). Variability measures will be calculated centrally.
9) Providing a cost/benefit analysis comparing the cost of intense combined lowering of both BP and LDL-C (more drugs and additional exams) with the benefit of potential reduction in incidence of fatal and nonfatal strokes and cardiovascular outcomes, thus providing useful information to National Health Systems in European countries as well as in China for the best use of economic resources in preventing stroke.
ESH-CHL-SHOT is a prospective, multinational, multicentre, comparative, randomized trial, with a 3 x 2 factorial design: A) three different SBP targets (group 1: < 145 to 135 mmHg; group 2: < 135 to 125 mmHg; group 3: < 125 mmHg); B) two different LDL-C targets (group A: 2.8 to 1.8 mmol/l; group B: < 1.8 mmol/l).