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Antihypertensive agents and prevention of dementia - Editorial
  It is plausible that some of these drugs cut dementia risk
Published 12 January 2010, doi:10.1136/bmj.b5409 BMJ 2010;340:b5409
Colleen J Maxwell, associate professor, David B Hogan, professor and Brenda Strafford Foundation chair in geriatric medicine 1 Departments of Community Health Sciences and Medicine, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1 Research, doi:10.1136/bmj.b5465
About 36 million people worldwide have a form of dementia such as Alzheimer's disease. If survival, prevention, or treatment do not improve dramatically, this number could double over the next 20 years.1 In the search for interventions to delay or prevent this condition, vascular risk factors have attracted attention. Various studies have shown an association between mid-life hypertension (especially if untreated) and the likelihood of developing dementia,2 3 raising the possibility that antihypertensives might offer an effective form of prevention.
In the linked study (doi:10.1136/bmj.b5465), Li and colleagues report on the possible role of angiotensin receptor blockers in reducing the risk of dementia and slowing progression.4
Several prospective cohort studies show an association between pharmacotherapy for hypertension and a lower risk of cognitive decline or incident dementia (in people under 75 years).3 5 Patients with Alzheimer's disease treated with antihypertensives seem to have better cognitive outcomes.6 With a few exceptions,5 these observational studies assessed only baseline drug exposure and did not examine the duration of treatment or changes over time. Other concerns include limited study duration, selective loss to follow-up, and confounding by indication. In addition, failure to have a long enough latency period before the diagnosis of dementia when assessing drug exposure can lead to a protopathic bias. This means that early unrecognised disease manifestations such as a reduction in blood pressure, apathy, or impaired cognition may reduce the likelihood of starting or continuing treatment and may result in a spurious protective effect.
Cell based research and animal models suggest several biological mechanisms by which antihypertensives might be neuroprotective. In addition to lowering blood pressure and reducing vascular pathology, certain agents may have an effect on the neuropathology of Alzheimer's disease.7 Biological plausibility, however, does not equate to clinical effectiveness. If there is a protective effect, it is unclear whether this results from a reduction in blood pressure or, at least in part, some other mechanism. If the first scenario is true, we should focus on lowering blood pressure by whatever effective means, but if the second is true we should be careful in our choice of agent.
Randomised controlled trials of antihypertensives in later life that have cognition as an outcome show mixed results. Only the Systolic Hypertension in Europe (Syst-Eur) study showed a significantly lower incidence of dementia with active treatment.8 Other trials found no overall benefit, although some subgroups (such as patients with mild cognitive impairment at baseline or recurrent stroke) had improved outcomes. Common criticisms include their relatively short duration, enrolment of low risk (from a cognitive standpoint) subjects, treatment of cognition as a secondary outcome, unbalanced numbers of dropouts, and contamination. Meta-analyses have yielded equivocal results.9 10 Therefore, although results have been promising, the case remains open as to whether treatment of hypertension in later life delays or prevents dementia.
In the linked prospective cohort study of older (over 65), mostly (98%) male, subjects, Li and colleagues found significantly lower hazard rates for incident dementia with angiotensin receptor blockers than with the angiotensin converting enzyme inhibitor lisinopril (hazard ratio 0.81, 95% confidence interval 0.73 to 0.90) and other cardiovascular drugs (0.76, 0.69 to 0.84).4 In patients with pre-existing Alzheimer's disease, the use of an angiotensin receptor blocker was associated with a lower risk of admission to a nursing home. Both classes of drugs had protective effects that may be additive with concurrent use.
The reason that angiotensin receptor blockers might be superior to angiotensin converting enzyme inhibitors is that the two receptors have complex and non-identical mechanisms of action. For example, they act differently on type 1 and 2 angiotensin receptors, which are both present in the brain. Stimulation of type 1 receptors causes vasoconstriction, whereas stimulation of type 2 receptors reportedly leads to vasodilatation, neuronal differentiation, apoptosis, and axonal regeneration. Angiotensin converting enzyme inhibitors inhibit both receptors, but angiotensin receptor blockers selectively inhibit type 1 receptors. This could translate to improved cerebral blood flow and an enhanced neuroprotective effect. Open label trials of angiotensin receptor blockers suggest beneficial effects on cognition, but two randomised controlled trials (SCOPE and PRoFESS) showed no significant benefit in either the rate of cognitive decline or incident dementia with angiotensin receptor blockers.11
Li and colleagues tackled some of the limitations common to observational studies. Similar drug classes were used as comparators, to provide some control for confounding by indication. The comparison with lisinopril seems straightforward, but the cardiovascular comparator contained a broad range of agents with similarly diverse indications. Important confounders such as a family history of dementia, education, and severity of disease were not considered. Although the authors excluded people who presented with dementia in the year before the start of treatment, disease could have been misclassified at baseline and during follow-up, and the potential of protopathic bias with selective initiation or discontinuation of particular antihypertensives remains. Study duration from the standpoint of outcomes was relatively short at four years. As with all studies of this nature, association does not prove causation, and the absence of changes in blood pressure during follow-up further clouds interpretation. The non-random allocation of treatment is also a serious problem. Racial and ethnic disparities in the use of antihypertensives such as angiotensin receptor blockers have been shown among American veterans,12 and the ethnic origin of most study subjects was not reported. The results may not be generalisable to women, because women comprised only 2% of the cohort.
The public health implications of finding an effective way of preventing dementia are immense, but further work is needed to verify the usefulness of antihypertensives in general and angiotensin receptor blockers in particular.
Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: (1) No financial support for the submitted work from anyone other than their employer; (2) No financial relationships with commercial entities that might have an interest in the submitted work; (3) No spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work; (4) No non-financial interests that may be relevant to the submitted work.
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