LAUSR

The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) showed the benefits of blood pressure (BP) lowering for secondary stroke prevention in stroke survivors for the first time after a long dispute in the last century [1] and triggered active hypertensive therapy for stroke patients globally in this century. A post hoc analysis of PROGRESS demonstrated that both the lowest risks of ischemic stroke and of hemorrhagic stroke were among the one-quarter of patients with the lowest achieved follow-up BP levels (median 112/72 mmHg), and that these risks increased progressively with higher follow-up BP levels in the large cohort of patients with previous stroke or transient ischemic attack [2]. A similar tendency for an increased risk of ischemic/hemorrhagic stroke by increased follow-up BP levels was reproduced in subsequent stroke trials (Fig. 1) [3]. Several trials sought to clarify the preventive effect against recurrent stroke by randomizing patients into two groups with different BP lowering targets. In patients with recent lacunar stroke in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, lowering systolic BP to <130 mmHg significantly reduced the risk of intracerebral hemorrhage (ICH) by 63% and insignificantly reduced the risk of ischemic stroke by 16% compared to lowering to 130–149 mmHg [4]. The Recurrent Stroke Prevention Clinical Outcome (RESPECT) Study, involving patients having a history of stroke within the previous 3 years showed similar results: lowering BP to <120/80 mmHg, relative to <140/90 mmHg, reduced the risk of ICH by 91% and that of ischemic stroke by only 9% [5]. These trials failed to demonstrate a significant reduction in the risk of any stroke as the primary outcome by intensive BP lowering, since the incidence of ischemic stroke was much higher than that of ICH for both trials. A meta-analysis of these two trials and two more small studies finally succeeded in showing a statistically significant 22% reduced risk for any stroke recurrence by lowering systolic BP to at least <130 mmHg [5]. In the present post hoc analysis of RESPECT, Kitagawa et al. examined the effect of intensive BP lowering on recurrent stroke subtype risk in patients with a history of ischemic stroke, accounting for 84% of the overall participants in RESPECT [6]. The major finding was that strict BP control aiming at <120/80 mmHg significantly reduced the risk of ICH. Patients assigned to intensive BP lowering did not develop ICH for a mean 3.9-year follow-up, whereas 0.39% of patients assigned to standard BP lowering developed ICH annually. It is less likely that the J-curve phenomenon exists between the follow-up BP levels and the risk of ICH relative to that of ischemic stroke, since possible cerebral hypoperfusion due to systemic hypotension rarely causes bleeding events. Most patients developing ischemic stroke took antithrombotic agents like the present RESPECT cohort, and higher BP levels during antithrombotic medication were associated with incidental ICH, as previous studies on secondary stroke prevention with antithrombotic therapy indicated [3, 4, 7]. A limitation of the analysis of the risk of ICH common to RESPECT and other previous studies is that the incidence of ICH was too low for detailed investigation. Another major finding of the RESPECT sub-analysis was that the risk of recurrent ischemic stroke was almost identical between two treatment groups with different BP lowering targets [6]. The unclear preventive effect against ischemic stroke relative to ICH by intensive BP lowering was similar to the main results of RESPECT and other published studies. Based on the present result, the lower goal of <120/80 mmHg compared to previous trials does not seem to be necessary for secondary prevention of ischemic stroke in patients with a history of ischemic stroke. However, there are several points of discussion regarding this second major finding. First, we usually assume that cerebral * Kazunori Toyoda [email protected]