Clinicians can face a difficult choice in deciding what class of antihypertensive medication to prescribe for their patients. However, all medications used to treat hypertension are not equal in their effects on important cardiovascular outcomes. A review by De Caterina and Leone, which appeared in the May 15, 2010, issue of The American Journal of Cardiology, concluded that beta-blockers are associated with worse results in the prevention of stroke compared with the use of other antihypertensive medications. Moreover, beta-blockers may not prevent coronary artery disease when used to treat patients with hypertension. They fail to lower central blood pressure to the degree of other antihypertensive drugs, and they have negative metabolic effects, which might contribute to higher rates of cardiovascular disease.

Beta-blockers have also been associated with worsened cognitive outcomes compared with angiotensin II receptor blockers (ARBs). It is possible that both angiotensin-converting enzyme (ACE) inhibitors and ARBs can reduce the risk for incident dementia. The current study by Kehoe and colleagues examines this possibility in a large cohort of patients.

Study Synopsis and Perspective

Controlling blood pressure with an ARB rather than other antihypertensive agents may significantly reduce the risk for Alzheimer's disease (AD) and vascular dementia (VaD), suggest results of a large observational study from the United Kingdom.

In the study, the risk for AD was 53% lower in older adults prescribed an ARB compared with those prescribed other antihypertensive agents. The risk was 24% lower in those prescribed an ACE inhibitor.

Patrick G. Kehoe, PhD, coleader of the Dementia Research Group at Frenchay Hospital, Bristol, and colleagues report their study in the October issue of the Journal of Alzheimer's Disease.

Dr. Kehoe and colleagues say their findings support those of a recent study in a predominantly male population from the United States. In that study, reported previously by Medscape Medical News, men prescribed ARBs had a lower incidence and rate of progression of AD than those prescribed ACE inhibitors or other cardiovascular drugs.

The accumulating observational and biological evidence in favor of ARBs protecting against dementia "strengthens the need for them to be studied more rigorously in the future," Dr. Kehoe and colleagues conclude.

Although "interesting, these are not conclusive findings," coauthor Richard M. Martin, PhD, from the University of Bristol, notes in a statement. "We now need to do the clinical trials to properly test our observations."

Accumulating Evidence

The study was a nested case-control study within the UK general practice research database. It was designed to see whether ARBs and ACE inhibitors are more strongly associated with AD, VaD, and other dementias relative to other antihypertensive drugs such as calcium channel blockers, beta-blockers, or thiazide diuretics.

Although both ARBs and ACE inhibitors reduce angiotensin II signaling, "now believed to be involved in the pathobiology of AD, ARBs are unlikely to interrupt ACE-mediated [amyloid-beta] degradation," unlike ACE inhibitors, the researchers note in their article. "These mechanisms of action suggest that ARBs may have benefits over [ACE inhibitors] in the etiology of AD," they write.

Included in the analysis were 9197 patients, aged 60 years and older, who were diagnosed between 1997 and 2008 with probable or possible AD (n = 5797), VaD (n = 2186), or unspecified/other dementia (n = 1214). Each case patient was matched by age, general practice, and sex to up to 4 control patients (n = 39,166).

The researchers observed that patients ever prescribed either ARBs or ACE inhibitors were less likely to develop AD, VaD, or other dementia than patients ever prescribed other antihypertensive medications. The associations were stronger for ARBs than for ACE inhibitors.

Table. Dementia Outcomes With ARBs and ACE Inhibitors vs Other Agents

Outcome	ARBs, OR (95% CI)	ACE inhibitors, OR (95% CI)
Probable AD	0.47 (0.37 - 0.58)	0.76 (0.69 - 0.84)
Probable VaD	0.70 (0.57 - 0.85)	0.82 (0.75 - 0.91)
Unspecified/other dementia	0.62 (0.47 - 0.81)	0.85 (0.75 - 0.96)

OR, odds ratio; CI, confidence interval

These associations did not differ by age, comorbidities, or blood pressure, suggesting little confounding by observed comorbidities, the researchers say. There was also evidence of a dose–response relationship between ARBs and AD (P = .009).

In analyses restricted to patients exposed either to ARBs or ACE inhibitors as their only therapy, there was an inverse association of ARB sole therapy (OR, 0.63; 95% CI, 0.45 - 0.88), but not ACE inhibitor sole therapy (OR, 1.01; 95% CI, 0.91 - 1.12).

"Preaching to the People"

Reached for comment, Gustavo C. Román, MD, medical director of the Nantz National Alzheimer Center at the Methodist Neurological Institute in Houston, Texas, who was not involved in the study, said it "reaffirms the need to control blood pressure, and the sooner, the better."

Dr. Román said he has been "preaching to the people that you need to keep your blood pressure under good control because it really seems that vascular disease, and especially hypertension, opens the gate to the amyloid-beta changes, although the mechanism is not very clear.

"Whatever the mechanism, it has been demonstrated over and over that vascular disease, in particular hypertension, is a risk factor for the development of [AD]," he added.

The study was supported by the North Bristol National Health Service Trust. The authors and Dr. Román have disclosed no relevant financial relationships.

J Alzheimers Dis. 2011;26:699-708. Abstract