P-210: Comparison of stroke-protective-effects (SPE) of AT1-receptor blockers (ARB). Importance of blood- pressure (BP) control and of the comparator effect on angiotensin (A)-II

The acute brain ischemia model by unilateral carotid ligation in the gerbil has shown that angiotensin II infusion accelerates recovery of blood flow in the ipsilateral brain and that preadministration of ACEI when compared to that of ARB was associated with a higher mortality rate. Furthermore ACEI co-administration with an ARB canceled the SPE of this latter. This suggests a SPE of non-AT1 receptor-activation since AII-formation is increased with ARB but decreased with ACEI. The clinical relevance of this mechanism has been strongly supported by LIFE trial which has shown that, at comparable BP, losartan compared to atenolol conferred a selective 25% greater SPE while the higher AT1-blockade evidenced by greater LVH regression did not lead to greater prevention of cardiac complications. Indeed the hypothesis that higher AT1-blockade was responsible for this selective cerebral protection would imply a higher density of plaques in cerebral than in coronary arteries; which is unlikely, given the twice higher initial prevalence of CHD versus stroke in this population. SCOPE also supports this non-AT1-mediated brain anti-ischemic effect by showing also a selective 23%greater SPE of candesartan ±thiazide versus a placebo± thiazides, betablocker and dihydropyridine (DHP). However SBP was 3 mmHg lower with candesartan and according to HOPE trial this lower BP could account for a 13% stroke risk decrease so that the BP-independent SPE of candesartan is only 10%. Lower SPE of candesartan compared to losartan cannot however be infered from these percentages because the comparator in SCOPE had a neutral effect on AII whereas in LIFE the comparator atenolol had an AII-suppressing effect, which accounts for the 25% lower SPE of atenolol than that expected from the BP-decrease this drug induced comparatively to placebo in MRC 1992 trial. Thus had candesartan been LDcompared to atenolol, its SPE would have actually been 35%, ie higher than that of losartan. Conclusion: BP-control and comparator-effect on AII are important in the evaluation of ARB-SPE.