VAS-COG: Lowering Angiotensin II May Raise Stroke Risk

SAN ANTONIO, July 16 -- Drugs that lower angiotensin II may increase the risk of stroke, contrary to conventional wisdom, an investigator asserted here.

A review of 26 clinical trials involving 206,632 patients revealed a consistent pattern of benefit with drugs that increase levels of angiotensin II compared with those that reduce angiotensin II (P=0.003), Albert Fournier, M.D., reported at the International Society for Vascular Behavioral and Cognitive Disorders.

Dr. Fournier, of University Hospital in Amiens, France, and colleagues did separate analyses of placebo-controlled trials, comparisons against angiotensin II-neutral drugs, and direct comparisons of angiotensin II-raising and angiotensin II-lowering agents.

"Classical and graphical meta-analysis of the large clinical trials that evaluated antihypertensive drugs in primary and secondary stroke prevention support the hypothesis that angiotensin II-increasing drugs are better for stroke prevention than are angiotensin II-decreasing drugs," said Dr. Fournier.

"Although [angiotensin II-raising] drugs decrease systolic blood pressure to a greater extent than angiotensin II-decreasing drugs," he said, "this blood pressure difference does not fully explain the better stroke prevention."

An abundance of data from experimental models of stroke suggests a protective effect from activation of receptors for angiotensin II and angiotensin IV, said Dr. Fournier. However, the hypothesis that angiotensin activation is cerebroprotective has not been specifically evaluated in clinical trials.

For the current analysis investigators grouped studies according to medications' effect on angiotensin II:

• Drugs that increase angiotensin II: diuretics, dihydropyridine calcium-channel blockers, short-acting non-dihydropyridine calcium channel blockers, and angiotensin Ireceptor blockers
• Drugs that decrease angiotensin II: beta-blockers, ACE inhibitors, and long-acting dihydropyridine calcium channel blockers
• Angiotensin-neutral drugs: alpha-blockers and the combination of a thiazide diuretic and a beta-blocker

The 26 trials excluded patients with heart failure, and a cumulative total of 7,108 strokes were reported in the studies.

Placebo-controlled trials demonstrated an overall hazard ratio for stroke of 0.67 for drugs that increase angiotensin II versus 0.87 for drugs that lower angiotensin II drugs.

In trials that involved active comparators with angiotensin II-neutral effects, drugs that decrease angiotensin II levels had a cumulative relative risk for stroke of 1.04. In contrast, angiotensin II-lowering drugs had a relative risk of 0.84 compared with the neutral agents.

Finally, in direct clinical comparisons, drugs that lower angiotensin II had a relative risk for stroke of 1.17 compared with drugs that increase angiotensin II levels.

Only one trial (a comparison of a beta-blocker and a thiazide diuretic) showed a stroke advantage for drugs that lower angiotensin II.

The remaining eight studies demonstrated a relative risk of 1.03 to 2.28 for drugs that decrease levels of angiotensin II.

The difference in stroke risk in clinical trials that compared angiotensin II-raising and angiotensin II-lowering drugs was statistically significant (P=0.003). A test for heterogeneity among the studies was not significant (P<0.07).