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Prof. Guido Grassi
Recent evidence indicates that blood pressure lowering interventions exert protective cerebrovascular effects. These effects are clear in secondary prevention of stroke, in which blood pressure reductions via Ace-inhibitors have been shown to reduce stroke recurrence.
Stroke is the third leading cause of morbidity and mortality worldwide, and it is associated with a high rate of physical and intellectual disability . Patients who suffered a first transient ischemic attack (TIA) or ischemic stroke are at high risk of any vascular event, the most frequent ones being myocardial infarction and stroke recurrence. The availability of safe and effective treatments against recurrent stroke is thus of great clinical importance. However, the available therapeutic strategies at present only consist in 1) administration of antiplatelet drugs, which have been shown to be effective in reducing the risk of recurrent stroke by about 30% , 2) administration of anticoagulants , and 3) carotid endarterectomy . These options cannot be regarded as entirely satisfactory, because only patients with ischemic cerebrovascular disease can benefit and the administration of antiplatelet or anticoagulant drugs is indicated only in relatively small groups of subjects, i.e. those with atrial fibrillation and tight carotid artery stenosis.
Several diseases and/or risk factors are involved in stroke occurrence. These include diabetes, hypercholesterolemia, cigarette smoking, aortic atheroma, alcohol consumption and obesity . It is also well established, however, that high blood pressure is a risk factor of major importance for the first cerebrovascular event  and can drastically be reduced (30 to 50%) with blood pressure lowering agents  The “blood pressure”-related risk also plays a key role in the recurrence of stroke, the risk increasing proportionally with the raise in systolic and diastolic blood pressure values .
No conclusive data are available on the ability of blood pressure lowering agents to exert a protective effect against stroke recurrence. This is because a meta-analysis of four clinical trials conducted with diuretics or Beta-blockers showed a positive trend in the two trials involving hypertensive patients, but was inconclusive in either hypertensive or normotensive patients .
The Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS)  was primarily aimed at determining whether the administration of a blood pressure lowering regimen in patients with a history of a recent cerebrovascular disease could reduce the recurrence of stroke. The study was conducted in 172 Centers of 10 different countries and involved more than 6000 patients who were followed for an average follow-up time of between 4-5 years and underwent, according to a double-blind design, either placebo or an ACE-inhibitor (perindopril 4mg/day) administration, given as monotherapy or combined with a diuretic (indapamide 2.5mg/day). The primary endpoint was total stroke recurrence. Secondary endpoints included fatal or disabling strokes, major vascular events and disability.
The main results of the study can be summarized as follows. First, active treatment, which decreased systolic and diastolic blood pressure by 9 mmHg and 4 mmHg respectively, reduced the risk of the recurrence of stroke (on average –28%). Second, the reduction was more marked in patients with a history of hemorrhagic stroke (-50%) and was also observed in combination with antiplatelet treatment. Finally the benefits were not limited to hypertensive patients. Three major advances in the study were 1) the demonstration of marked protection against the recurrence of hemorrhagic stroke (all previous interventions in this regard having proved unsuccessful), 2) the substantial risk reduction in virtually all patients subgroups and 3) the treatment-induced reduction in both less and more severe or disabling strokes.
One final result of the Progress Study should be mentioned, namely the effect of treatment on cognitive function and occurrence of dementia. Because this latter frequent complication of recurrent stroke has been shown to be reduced by about 30%, the study results further strengthen the vasoprotective properties of the blood pressure reduction in patients with a previous stroke.
The results of the Progress Study suggest that blood pressure reduction should be pursued in the great majority of patients with cerebrovascular disease without fear of inducing cerebral under perfusion, even if blood pressure is normal and “on-treatment” values are relatively low. They also show that the favorable effects of the blood pressure lowering intervention are obtained by interfering with the renin-angiotensin-aldosterone system via perindopril administration. It is thus likely that the beneficial effects of treatment depend not only on the blood pressure reduction “per se” but also on the positive cerebrovascular effects of the renin-angiotensin blockade.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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Prof. G. Grassi Monza - Milan, Italy Vice-Chairman of the ESC Working Group on Hypertension and the Heart
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