Hypertension is a major risk factor for cerebrovascular events both for cerebral infarction and transient ischemic attacks (TIAs; 1-4). The higher the blood pressure level, the greater the incidence of stroke events (5). The ability of antiplatelet drug therapy to reduce the risk of stroke has been demonstrated in numerous trials (6). In the report of the Antiplatelet Trialists' Collaboration, reduction in vascular events with antiplatelet therapy as secondary prevention were statistically significant in both normotensive and hypertensive patients. However, the patients in the Antiplatelet Trialists' Collaboration study were a rather heterogeneous group of patients with a variety of antiplatelet-therapy regimens. Very few single studies have evaluated whether or not antiplatelet therapy is equally effective in patients with different levels of blood pressure (7,8).
The first European Stroke Prevention Study (ESPS I) recruited 1,306 patients with TIA or stroke in a single center in Kuopio, Finland. We performed a subgroup analysis based on these Finnish patients to evaluate the efficacy of antiplatelet therapy in the secondary prevention of stroke in patients with increased blood pressure at entry into the study.
SUBJECTS AND METHODS
The ESPS was a randomized, double-blind, placebo-controlled European multicenter study with the participation of 16 centers in six countries. The aim of the ESPS was to investigate whether the combination of dipyridamole (DP; Persantin), 75 mg, 3 times a day, and acetylsalicylic acid (ASA), 330 mg, 3 times a day, is more effective than placebo for the secondary prevention of stroke or death in patients with previous ischemic cerebral lesions. The study design and main results of this study were previously published (7). Of the 2,500 patients included, 1,306 (52%) patients were recruited by the University Hospital of Kuopio, 652 patients in the treatment group and 654 patients in the placebo group (Table 1).
All the patients included in this study had had a recent (<90 days) transient ischemic attack (TIA) or stroke. TIA was defined as a neurologic ischemic disorder with clinical deficits resolving fully within 24 h. A vascular event was classified as stroke if the neurologic deficit persisted for >1 day. The treatment lasted 24 months, with follow-up visits every 3 months.
A physician measured blood pressure at entry with the patient seated after at least a 20-min rest. Disappearance of the Korotkoff sounds was recorded as diastolic blood pressure. For statistical analyses, the average of two recordings (both arms) was used. Mean time for first visit with blood pressure measurement after stroke or TIA was 40.4 days in placebo group and 47.9 days in the treatment group (no statistical difference). This excludes the possibility that high blood pressure values in some patients could have been the result of acute stress reaction after brain infarction or TIA. The patients with systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥85 mm Hg were included in the study and classified into subgroups (Table 2). The numbers of patients receiving antihypertensive drugs (β-blockers, diuretics, vasodilators, and other antihypertensive drugs) were similar in both treatment groups. Table 3 shows mean values of blood pressure during follow-up. There was no statistical difference between the treatment groups at any evaluated time point. As well, there was no tendency to blood pressure changes during the study period.
The results were analyzed by the intention-to-treat analysis. The end point was the occurrence of stroke during the 2 years of follow-up. No differences were found between the treatment group and the placebo group with respect to age, sex, qualifying event, arterial territory, blood pressure, ischemic heart disease, previous myocardial infarction, diabetes, alcohol consumption, or smoking habits (data not shown).
Data analyses were conducted with the SPSS programs (SPSS for Unix, Release 4.0). Student's t test for independent samples and χ2 test were used to compare baseline data. The efficacy of antiplatelet treatment was analyzed by survival analysis (9; survival in this context means freedom from stroke), and the significance test was based on Lee-Desu statistics (10).
The mean (SD) age among 1,306 patients (717 men, 589 women) was 62.5 (10.2) years. A history of hypertension was present in 517 (39.6%) patients. During the 2-year follow-up, 148 patients had a fatal or nonfatal stroke. The incidence of stroke was reduced by 48.8% (p = 0.0001) in the treatment group compared with the placebo group.
The effect of systolic blood pressure at entry on the occurrence of stroke in patients with ASA+DP and placebo treatment is shown in Fig. 1a. The reduction of stroke in the treatment group compared with the placebo group was evident at all levels of increased systolic blood pressure (end-point reduction, 55.2-68.2%), and differences were statistically significant in all subgroups except for one (systolic blood pressure, ≥180 mm Hg; n = 235; end-point reduction, 53.7%; p = 0.0548).
The incidence of stroke events by diastolic blood pressure is shown in Fig. 1b. Differences between the treatment group and the placebo group were similarly statistically significant at all levels of increased diastolic blood pressure (end-point reduction, 47.3-82.1%; p value <0.0001-0.003). There was a trend toward higher end-point reduction percentages in the subgroups of patients with the highest diastolic blood pressure readings (Fig. 1c).
The major finding of this study based on ESPS I data was that the effect of antiplatelet therapy in ischemic stroke and TIA patients is independent of blood pressure level at entry to the study. Furthermore, antiplatelet treatment seemed to be most effective in patients with high blood pressure, especially in those patients with high diastolic pressure readings.
Antiplatelet treatment produced similar proportional reductions in patients with diastolic blood pressure <90 mm Hg and ≥90 mm Hg in the Antiplatelet Trialists' Collaboration study (6). Our study represents an attempt to study the influence of hypertension in more detail to the response to antiplatelet treatment in the secondary prevention of stroke. There are sources of possible errors in this type of subgroup analysis. No differences were found between the treatment group and the placebo group with respect to risk factors for stroke, but the patients were not stratified a priori for their blood pressure level, and it was difficult to exclude the unbalanced distribution of risk factors.
Blood pressure is without doubt the most powerful risk factor for stroke. Even a casual blood pressure reading is highly predictive of a subsequent stroke (5). Our analysis is based on a single blood pressure value obtained during clinical examination at entry, and diastolic pressure in particular was strongly associated with the risk of a subsequent stroke. This is in accordance with previous reports (2,11,12).
One reason for this positive treatment effect with ASA+DP could be the existence of a hypercoagulable state in hypertension, which may partly explain the increased risk of stroke (13-16). Essential hypertension is associated with decreased fibrinolytic activity and enhanced platelet activity, as evidenced by high plasma levels of plasminogen activator inhibitor (PAI-1) and β-thromboglobulin (16). An increase in the platelet aggregatory response to adrenaline and adenosine diphosphate has been found in hypertensives (13,14) as well as an enhanced sensitivity of their platelets to arachidonic acid (17).
The degree of platelet activation has been shown to correlate with the levels of diastolic blood pressure (14), which could be related to our results concerning the trend toward higher stroke-reduction percentages in those patients with the highest diastolic blood pressures. In the ESPS I study, which included a total of 2,500 patients, the effect of diastolic blood pressure on the response to ASA+DP treatment was complex; among stroke patients, the efficacy of the treatment was slightly better for those with a baseline diastolic blood pressure of ≥90 mm Hg, whereas among TIA patients, the opposite was the case (7).
There is evidence that antihypertensive therapy may lower indices of platelet activation, such as β-thromboglobulin in essential hypertension (18-20), and a reduction in the susceptibility to platelet aggregation is one of the aims of modern antihypertensive therapy. In this study, most of the hypertensives were taking β-blockers or diuretics as antihypertensive therapy. The inhibitory effect of β-blockers on platelet aggregation depends on the pharmacologic properties of the blocker, whereas diuretics probably do not have any effect on platelet function (18,19).
It is not known whether this high dose of ASA combined with DP can modify blood pressure in hypertensive patients. In one short study with 150 mg DP administered orally 3 times daily, a decrease in circulating renin-angtotensin system activity was found in hypertensive patients without any concomitant change in blood pressure level (21). There is, however, evidence that ASA can be used at any dose without having an effect on blood pressure values (22,23).
As regards efficacy in stroke prevention, there is increasing evidence that the dose of ASA does not seem to be of importance and should be based on patient tolerance, which is better with lower doses of ASA (6,24). In addition, recent data indicate that DP may be combined with a low dosage of ASA for stroke prevention in patients with TIA or stroke (25). We believe that the results of our study could be extrapolated to the treatment with lower doses of ASA used in the clinical practice.
In conclusion, a combination of ASA and DP seems to be an effective treatment in hypertensive subjects in the secondary prevention of stroke. In this study, risk reduction was highest in those patients with the highest diastolic pressure. Considering the limited value of this subgroup analysis, further follow-up studies based on hypertensive subjects are needed to confirm this result. Although patients with high blood pressure readings responded well to antiplatelet drugs, the significance of effective control of hypertension should not be underestimated.
Acknowledgment: We thank Pirjo Halonen, M.Sc., for her assistance in statistical analysis. This study was partly supported by the Aarne and Aili Turunen Foundation.
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