[Could angiotensin II type I receptor antagonists have a superior beneficial effect than that of angiotensin II converting enzyme inhibitors with respect to the risk of cerebrovascular accident?].
In contrast with the expected results, the Captopril Prevention Project study has found that the relative risk of stroke was greater by 25% in patients treated with ACEI than in patients receiving the conventional diuretics +/- betablockers regimen (Hanson et al. ISH Amsterdam, June 98). This difference persisted after adjustment for the initial differences of blood pressure levels between the groups after randomisation. This does not mean that ACEI would worsen the risk of stroke when compared to a placebo, since a potent protective effect of diuretics and betablockers on the relative risk of stroke has long been demonstrated. Nonetheless, these results suggest that for a similar blood pressure lowering effect, conventional therapy is more effective than ACEI to prevent stroke. This finding, in discrepancy with the current prevailing opinion that ACEI have emerged as the most effective preventive treatment to reduce cardiovascular morbidity, is regarded as surprising by the investigators. However, a number of animal experimental data may help to envisage the complete inhibition of angiotensin II formation as a two-edged sword, because of the multiplicity of its receptors mediating different, and even opposite effects. In a series of experimental studies in mammals, the group of Fernandez has provided a bundle of observations suggesting that angiotensin II contributes to early reperfusion following acute ischemia by enabling the recruitment of pre-existing collateral vascularisation, an effect mediated via the stimulation of non-AT1 receptors (possibly AT2). Indeed, the worsening of stroke in the gerbil after incomplete ligation of the carotid by pre-treatment with ACEI had been demonstrated by these authors (J Cerebral Blood Flow Metab, 1988; 24:937), and they further show that pre-administration of losartan significantly reduced the ischemic brain damage and the mortality induced by the abrupt ligation of one carotid, but that this preventive effect of losartan was abolished if enalapril was co-administrated (J Cardiovasc Pharmacol 1994; 24:937). The first available clinical data on stroke risk with ACEI reported in the CPP study, showing a less effective prevention of stroke with ACEI than diuretics supports the hypothesis that similar mechanism may also prevail in humans, and lead us to propose to discuss the rationale for a large multicentric trial aiming to compare the protective effect of ARAT1 and ACEI on the risk of recurrence of stroke.
Fournier
A
A
Service de néphrologie, médecine interne, neurologie et pharmacologie, CHU d'Amiens.
Achard
J M
JM
Mazouz
H
H
Pruna
A
A
Hottelart
C
C
Rosa
A
A
Fernandez
L
L
Andrejak
M
M
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012307:Risk Factors; D020521:Stroke / Q000517:prevention & control*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2