SY 08-2 HYPERTENSION MANAGEMENT FOR SECONDARY PREVENTION OF STROKE

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Abstract

Stroke is known to frequently recur in patients with a history of cerebrovascular disease, and the control of hypertension is extremely important for the treatment of those patients. The robust relationship between the recurrent cerebrovascular disease and blood pressure control has been demonstrated in large-scale clinical studies. The antihypertensive drug therapy significantly reduces the recurrence rate of all types of cerebrovascular disease, incidences of myocardial infarction and all vascular events. Evidence suggests that any class of antihypertensive drugs including diuretics, Ca channel blockers, ARBs, and ACE inhibitors are shown to be similarly effective for the secondary prevention of stroke, except in some small study such as MOSES. Thus, most of the benefit obtained from drugs can be ascribed to a decrease in blood pressure.

Then, how far should blood pressure be lowered? Target of blood pressure control has been somewhat controversial, since an excessive reduction of blood pressure might exacerbate cerebral ischemia in the area perfused by cerebral artery with a significant stenosis. In fact, some Japanese clinical study has shown that in patients with impaired perfusion demonstrated by PET-CT, the risk of recurrent stroke was high when the systolic blood pressure was <130 mmHg. In those without impaired perfusion, this risk may be high at a high blood pressure level. In the study involving patients with carotid artery stenosis, the risk of cerebrovascular disease significantly increased in a group in which the systolic blood pressure decreased to 140 mmHg among patients with symptomatic, 70% or greater stenosis of the bilateral carotid arteries (accounting for 2 to 3%), whereas there was no increase in this risk even when the systolic blood pressure decreased to 140 mmHg in patients with 70% or greater unilateral carotid artery stenosis. In the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Study, among patients with symptomatic intracranial artery stenosis, the blood pressure level was not associated with the risk of ischemic cerebrovascular disease in those with marked (70% or greater) stenosis. Thus, in the presence of obstruction of a main trunk of the cerebral arteries or marked stenosis, management matched to individual patients is suggested to be necessary.

There have been very few studies which have primarily investigated the optimum blood pressure level in the secondary prevention of stroke. The sub-analysis of the large clinical trial, PROGRESS, indicated that the incidences of cerebral hemorrhage and cerebral infarction were lower in patients in whom blood pressure was controlled at a lower level (a systolic blood pressure of about 120 mmHg). In the Bleeding with Antithrombotic Therapy (BAT) Study in Japan, 4,009 patients taking antithrombotic drugs for the prevention of recurrent cerebrovascular or heart disease were prospectively enrolled, and hemorrhagic events were investigated over 19 months. The results suggest that the incidence of cerebral hemorrhage is lower when the blood pressure immediately before/after onset is lower, suggesting that blood pressure should be reduced to <130/80 mmHg.

In the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial, a randomized comparative study was conducted in patients with chronic-phase lacunar infarction by dividing them into two groups: a group with a systolic blood pressure of <130 mmHg (aggressive therapy group) and that with a systolic blood pressure of 130–149 mmHg (standard therapy group), with a mean follow-up of approximately 4 years. The mean systolic blood pressure difference after 1 year between the two groups was 11 mmHg. The incidence of cerebral infarction/hemorrhage showed no significant difference, whereas cerebral hemorrhage was significantly lower in its incidence in patients with a lower systolic blood pressure.

We have been conducting a multicenter, randomized, open-label study (RESPECT study; Clinical Trials.gov Identifier: NCT01198496) since 2010, in which hypertensive patients with a history of strokes are randomly assigned to either a standard therapy group (£140/90 mmHg; if having current DM/CKD/MI, £130/80 mmHg) or a strict therapy group (BP lowering target: £120/80 mmHg). The patients were treated with stepwise multi-drug therapy using an angiotensin-receptor antagonist, diuretic, calcium channel blocker and additional other classes of drug if necessary. The recurrent stroke rates in both groups will be compared from various aspects, and whether strict BP management is useful for the prevention of recurrent strokes will be verified. The first interim analysis of this study has been recently performed.

At present, in the JSH2014 Guidelines, the target of blood pressure control for patients with chronic-phase cerebral infarction is established as <140/90 mmHg. In particular, an excessive decrease in blood pressure should be avoided in patients with marked stenosis of the bilateral carotid arteries or occlusion of a main trunk of the cerebral arteries. However, the Guidelines recommend that a lower level (<130/80 mmHg) should be targeted in patients with lacunar infarction or those taking antithrombotic drugs (excluding those with 50% or greater stenosis/occlusion of the carotid artery or a main trunk of the cerebral arteries). If the patient complains of dizziness, light headedness, tiredness, a heavy feeling of the head, numbness, weakness, loss of energy or exacerbation of neurological signs or symptoms during treatment, these may be symptoms of cerebral circulatory insufficiency due to a decrease in blood pressure, and a decrease in the dose or change in the type of antihypertensive drug is necessary. Particular caution is needed in patients with occlusion of a main trunk of the cerebral arteries (especially in the vertebral-basilar artery system), because dysautoregulation of the cerebral circulation may persist for 3 months or more.

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