Does a change in angiotensin II formation caused by antihypertensive drugs affect the risk of stroke? A meta-analysis of trials according to treatment with potentially different effects on angiotensin II

Background Stroke prevention by anti hypertensive therapy is believed to be related to the fall in blood pressure (BP). Experimental data have documented that activation of non-AT, receptors of angiotensin II may exert anti-ischaemic mechanisms in the brain. The present meta-analysis of various randomized clinical trials attempts to relate stroke risk to angiotensin II formation during anti hypertensive therapy. Methods Primary and secondary stroke prevention was examined in 26 prospective, randomized clinical trials including 206 632 patients without heart failure, in whom a total of 7108 strokes occurred. The trials were selected because a difference in angiotensin II generation was expected between the two treatment arms on the basis of the drugs' pharmacodynamic effects, and allowed 36 evaluations of the relative risk of stroke. Findings In placebo-controlled trials, stroke risk was significantly higher with angiotensin II-decreasing than increasing drugs, but systolic BP decreased less in the former. Compared with an active therapy having a neutral effect on angiotensin II formation, stroke risk was also higher with angiotensin-clecreasing drugs than with angiotensin-increasing drugs, whereas BP decrease was comparable with both drug classes. When angiotensin II-decreasing drugs were directly compared with angiotensin II-increasing drugs in the same trials, stroke risk was significantly increased. On-treatment systolic BP was minimally and significantly higher with angiotensin II-decreasing drugs, but not large enough to explain the excess in stroke risk. Conclusion Within the limitations of the methodology, our meta-analysis supports the hypothesis that angiotensin II-decreasing drugs are less stroke protective than angiotensin II-increasing drugs, although this difference is not entirely explained by their smaller BP-lowering effect.