Belfast, Northern Ireland - There is no convincing evidence that lowering blood pressure prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent previous cerebrovascular disease, according to a new systematic review of the field [1].

But the authors say that because of considerable differences among the trials included in the review, a high rate of patient dropout, and the fact that many control subjects received antihypertensive drugs, they were unable to reach a reliable conclusion, and therefore cannot rule out the possibility that antihypertensive therapy reduces later dementia in these patients.

The review, published in the April 19, 2006 issue of the Cochrane Database of Systematic Reviews, was conducted by a team from Queen's University (Belfast, Northern Ireland), led by Dr Bernadette McGuinness.

They note that hypertension is a direct risk factor for vascular dementia and that recent studies have suggested that hypertension also has an impact on the prevalence of Alzheimer's disease. They therefore set out to evaluate all published data looking at whether the treatment of hypertension lowers the rate of cognitive decline in patients with hypertension but no history of stroke or transient ischemic attacks.

The researchers found three suitable randomized double-blind placebo-controlled trials—Syst Eur, SCOPE, and SHEP—which together comprised 12 091 hypertensive subjects with an average age of 72.8 years.

Mean blood pressure at entry across the studies was 170/84 mm Hg. All trials instituted a stepped-care approach to hypertension treatment, starting with a calcium-channel blocker, a diuretic, or an angiotensin receptor blocker.

The combined result of the three trials was that there was no significant difference between treatment and placebo in the incidence of dementia. Blood-pressure reduction resulted in an 11% relative risk reduction of dementia in patients with no previous cerebrovascular disease, but this effect was not statistically significant.

Syst Eur did show a benefit from antihypertensive treatment in the prevention of dementia, but this was not seen in either SCOPE or SHEP. In addition, the two trials reporting a change in Mini-Mental State Examination did not indicate a benefit from antihypertensive treatment.

The researchers point out that many problems arose when they analyzed the data for this review.

One difficulty was that many patients left the double-blind treatment in all three studies—to receive open-label antihypertensive treatment for ethical reasons, because an end point had been reached, or because they died or were lost to follow-up. Because these losses did not occur randomly (they were probably related to treatment), they bias the results of this analysis, researchers explain.

The bias might be reduced by analyzing one-year data, but the true cognitive effects might not be seen over such a short time period, they note. Individual patient data would be required to be certain about the outcomes in each study; there also might be an advantage to extending the length of follow-up to be certain of the true incidence of cognitive decline, they add.

"If one were to look at the evidence from cross-sectional, longitudinal, and observational studies along with the [randomized controlled trials], there is moderately strong evidence . . . to support the view that hypertension in midlife, especially if not treated effectively, negatively affects cognition and contributes to the development of dementia and Alzheimer's in later life," the authors write. It is proposed that high blood pressure in middle age can cause a long-term cumulative effect, which leads to increased severity of atherosclerosis and more vascular comorbidities in later life. There is less evidence from these studies that the same negative effect on cognition is present for hypertension in later life, they note.

The authors suggest that future research should focus on analysis of the studies using individual patient data, although this would be time-consuming and expensive. They also say that other trials should investigate different classes of drugs, given that in Syst Eur it was speculated that dementia prevention was facilitated by the neuroprotective role of the calcium-channel blocker nitrendipine. But, they point out, future trials must be head to head, because placebo-controlled trials can no longer be justified, and they would have to have very long follow-up periods to be certain of the true incidence of dementia.