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Evidence of the beneficial effects of BP lowering, however, does not answer all major practical problems physicians are faced with when treating individuals to prevent stroke or stroke recurrence or, more broadly, cardiovascular disease.

Unfortunately, after completing the milestone placebo-controlled trials in the last 30 years of the past century, clinical trials have mostly been focused on comparing the benefits of different antihypertensive regimens, with the intent to show specific benefits of new agents or, vice versa, the superiority of the older ones.

There is no doubt that these comparative trials have led to useful information, but – as it has recently been remarked– 46 trials in more than 230 000 patients have probably been too many to end up with the conclusion of current guidelines that the benefits of antihypertensive treatment mainly relies upon BP lowering per se whatever the agents administered.

The large number of trials comparing different drug regimens were mostly originated and sponsored by pharmaceutical companies which had the (legitimate) interest to show efficacy and safety of their drugs often on the request of regulatory authorities. As a consequence of this, however, a number of issues, concerning treatment strategies rather than drug preferences, though quite relevant to medical practice, have not been investigated by trials, and answers to these questions have been left to experts’ opinion or “wisdom” (often diverging) rather than being based on evidence

The Stroke in Hypertension Optimal Treatment trial, promoted by the European Society of Hypertension and the Chinese Hypertensive League (ESH-CHL-SHOT), aims to address the medically and socially important problem of optimizing prevention of stroke recurrence. On the basis of the most recent (2008) guidelines for the management of stroke and TIA by the European Stroke Organization, it is clear that optimal treatment strategies for preventing recurrent stroke are not firmly established: while it is agreed that antiplatelet therapy should be recommended to all patients without contraindications, the lowest level to which BP should be brought with further significant benefit is unknown, the benefit of lowering LDL-C to the same level as in myocardial infarction is unclear, as well as the existence of positive or negative interactions between intense BP and intense LDL-C reductions.

Accordingly the major objectives of the ESH-CHL-SHOT trial are to clarify the following questions, which are also relevant to broader aspects of antihypertensive and lipid-lowering therapies:

1) Whether in patients with a recent stroke or TIA (1 to 6 months) lower BP targets (< 125 mmHg SBP) are more effective in preventing recurrent stroke (as well as other cardiovascular outcomes and death) than higher targets, or whether at the lowest BPs the benefits are reduced (similarly or differently for strokes and CHD events, for ischaemic and haemorrhagic strokes). To investigate this question the patients will be randomized to three different SBP targets since only comparison of three targets can prove or disprove the existence of a J-curve. Group 1 will be randomized to SBP targets corresponding to those that have been shown to be associated with benefits in previous trials on elderly hypertensives: SBP < 145 to 135 mmHg (average target 140 mmHg) (14, 15). Group 2 will be randomized to a SBP target < 135 to 125 mmHg (average target 130 mmHg). Group 3 will be randomized to a SBP target < 125 mmHg (average target 120 mmHg). This part of the trial will also help clarifying the unknown issue as to whether elderly hypertensives are benefited by SBP lowering below the current targets of 150-140 mmHg.

2) Whether a more intense LDL-C reduction to levels often recommended in patients post-MI is more beneficial than a less intense one also in post-stroke/TIA patients. To investigate this question the patients will be randomized to two different LDL-C targets (group A: LDL-C 2.8 to 1.8 mmol/l; group B: LDL-C < 1.8 mmol/l). Possible differences between patients with a previous ischaemic or cardioembolic stroke, and differences in type of recurrent stroke (ischaemic or haemorrhagic) will be assessed. In order to achieve objectives 1-2 statistical calculations indicate that 7500 patients should be enrolled and followed up for four years to accrue 925 validated recurrent strokes.

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