Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Stroke Notes reduction with ARB, beyond blood pressure control. In the fol- lowing deliberations, we would like to put forward what we think is an attractive hypothesis for such a mechanism. The trend towards stroke reduction may be attributed to the ability of ARBs to mildly inhibit platelet activity. In fact, platelets contain angiotensin II receptors within their surface membranes [2] and, therefore, ARBs may affect platelet activity directly tar- geting these specific receptors. Indeed, in vitro data strongly sug- gest antiplatelet properties of not only the prodrugs from the ARB class, but their principal metabolites as well [3]. Moreover, these results have been confirmed in a small randomized study suggest- ing ex vivo platelet inhibition by ARBs in patients with mild to moderate hypertension [4]. Treatment with valsartan (80–360 mg/day) over 9 weeks resulted in a consistent inhibition of ade- nosine diphosphate-induced conventional platelet aggregation, and prolonged closure time by the PFA-100 Platelet Analyzer. In addition, therapy with ARB has been associated with a downreg- ulation of the expression of numerous platelet surface receptors such as glycoprotein Ib, glycoprotein IIb/IIIa activity, vitronectin receptor, p-selectin, LAMP-1, and CD40-ligand. It will be critical to know whether the minuscule, yet poten- tially appealing stroke reduction signal observed in ONTARGET will translate into significant stroke prevention in such a mega- trial as PRoFESS [5]. These data are expected soon, and will be critical for the comprehension of better ways to prevent recidivat- ing strokes. The focus is on maintaining the optimal balance be- tween the utilization of blood pressure-lowering medications and platelet inhibitors to protect such high-risk patients from repeat- ed vascular events. The recently published ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was a phase IV randomized study which enrolled 25,620 high-risk patients with coronary heart disease or diabetes plus additional risk factors, who were over the age of 55 years of age but did not have evidence of heart failure [1]. Patients were randomized to receive either the ACE-inhibitor ramipril (10 mg/day), the angio- tensin receptor blocker (ARB) telmisartan (80 mg/day), or their combination. The mean duration of follow-up of the study was 55 months. The primary composite outcome was the time to the first event of cardiovascular death, myocardial infarction (MI), stroke, or hospitalization for heart failure. It occurred in 16.5% of pa- tients treated with ramipril, in 16.7% of those treated with telmis- artan, and in 16.3% of patients randomized to combination ther- apy ( table 1). The ONTARGET investigators conclude that telmis- artan was equivalent to ramipril in high-risk patients with vascular disease or diabetes. The combination of the two drugs was associated with more adverse events without an increase in clinical outcomes benefit. Even though the evidence presented in table 1 reveals a level of nonsignificance for the difference of the various outcome mea- sures among the three treatment arms, the incidence of strokes may deserve further scrutiny. In absolute numbers, there were 405 strokes (4.7%) in the ramipril arm, compared with 369 strokes (4.3%) in the telmisartan arm. In the combination group, there were 373 strokes (4.4%). In fact, this finding represents an 8.5% stroke reduction with ARB when compared with the ACE inhibi- tor. Considering the straight-forward and robust study design of ONTARGET and its long follow-up over 4 years, we suspect that this mild trend towards a decrease in strokes does not represent a random play of chance. Furthermore, when those antihyperten- sive agents were used in combination, the trend towards fewer strokes remains consistent, representing a 6.4% risk reduction as compared to monotherapy with the ACE inhibitor, despite the more potent antihypertensive effect. Since there is a lack of asso- ciation between the degree of blood pressure lowering and the incidence of strokes, the ONTARGET data may point to other distinct underlying mechanism(s) responsible for the mild stroke Published online: October 21, 2008 © 2008 S. Karger AG, Basel 1015–9770/08/0265–0563$24.50/0 Accessible online at: www.karger.com/ced Cerebrovasc Dis 2008;26:563–564 DOI: 10.1159/000164555 Telmisartan and Stroke Reduction in the ONTARGET Trial: Benefit beyond Blood Pressure Lowering? Victor L. Serebruany a , Dan Atar b , Dan F. Hanley a a HeartDrug TM Research Laboratories, Johns Hopkins University, Towson, Md., USA; b Aker University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway Table 1. ONTARGET key outcomes Outcome Ramipril (n = 8,576) % Telmisartan (n = 8,542) % Combination (n = 8,502) % CV death/MI/stroke/ CHF hospitalization 16.5* 16.7 16.3 CV death/MI/stroke 14.1 13.9 14.1 MI 4.8 5.2 5.2 Stroke 4.7 4.3 4.4 CHF hospitalization 4.1 4.6 3.9 CV death 7.0 7.0 7.3 Any death 11.8 11.6 12.5 Renal impairment 10.2 10.6 13.5 * All nonsignificant among groups. CV = Cardiovascular; CHF = congestive heart failure.