Angiotensin receptor blockers & Alzheimer's

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advancedatheist
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Angiotensin receptor blockers & Alzheimer's

Post by advancedatheist » Thu Sep 08, 2011 11:54 am

Something to consider if you have a family history of Alzheimer's, or you learn you have genetic risk factors for the disease:

Angiotensin Receptor Blocker Use May Decrease the Incidence and Progression of Alzheimer’s Disease and Dementia in Older Men but the Strength of the Evidence Is Questionable

Multiple longitudinal studies suggest that elevated blood pressure (BP) in midlife is associated with deterioration of cognitive function later in life, and prospective, randomized, placebo-controlled studies have suggested that treatment of hypertension may reduce the incidence and severity of dementia. Whether certain antihypertensive agents provide additional benefits independent of their BP-lowering ability in reducing the incidence and progression of dementia in general, and Alzheimer’s disease (AD) in particular, has been the subject of considerable debate. A few studies in both humans and animals have suggested that angiotensin receptor blockers (ARBs) may preserve cognitive function independent of and in addition to their effects on BP. The current prospective, observational study analyzed information from the Veteran’s Administration (VA) healthcare system decision support database in a large population with uniform healthcare coverage. It asked whether, as compared to the angiotensin converting enzyme inhibitor (ACEI) lisinopril or other cardiovascular (CV) disease medications, use of ARBs is associated with a decrease in the incidence and progression of dementia and AD.

Investigators identified patients who as of October 2002 were 65 years of age or older from a database of over 7.3 million people. Patients were divided into those who did (progression analysis) or did not yet (incidence analysis) have a diagnosis of AD or dementia as of October 2002. In each of these groups, 3 different cohorts were analyzed and compared: (1) those taking ARBs (overall sample size of more than 11,500 patients), (2) those taking the ACEI lisinopril (overall sample size of more than 91,000 patients), and (3) those taking other CV drugs (excluding ARBs, ACEIs, and statins) as defined by VA formulary classification (more than 696,000 patients). Drug use from any of those 3 classes was determined based on a “drug possession ratio” of at least 80% and no exposure to other study drug classes during an index period of 6 months from October 2002. Drug use after entry into the study was in no way restricted by the investigators and was completely at the discretion of the treating physicians. For patients with a known history of dementia or AD at study entry (progression analysis), the primary endpoints evaluated were time to admission to a nursing home and death. For patients without a known history of dementia or AD at study entry (incidence analysis), time to diagnosis of either condition were the primary endpoints. Data on endpoints were collected over a 5-year time span (fiscal year 2002–2006).

Since raw BP data were not in the VA decision support database at the time of this study, the investigators determined mean BP for each cohort on the basis of a subsample from the VA health systems vertically integrated service network. To account for potential confounding variables, multiple statistical models including various CV risk factors as covariates (including age, history of stroke, hypertension, known CV disease, known renal disease, and diabetes) were employed.

For the incident analysis, data from about 800,000 patients were available. Overall, the mean age of the cohort was approximately 74 years, and the participants were overwhelmingly male (98%). At baseline, patients in the ARB or lisinopril groups had a lower incidence of known CV disease and stroke, but a higher incidence of diabetes than the CV drug comparator group. Mean BP was determined to be similar regardless of drug class. As compared to both lisinopril and the CV comparator group, the ARB group was associated with an approximately 20% decrease in the incidence of both AD and dementia, a result that did not change after including hypertension and renal insufficiency as covariates.

For the progression analysis, 12,574 patients (476 in ARB group, 3227 in lisinopril group, and 8871 in CV comparator group) with a preexisting diagnosis of AD and 44,601 patients (1920 in ARB group, 12,064 in lisinopril group, and 30,617 in CV comparator group) with a preexisting diagnosis of dementia were available for analysis. The characteristics of the patients with a preexisting diagnosis of AD and dementia were similar. Using multiple different Cox proportional hazards models, patients in the ARB group had significantly lower rates (20%–50% reduction) of admission to nursing homes and death than those in either the lisinopril or CV disease medication use comparator groups.

Further analysis suggested that there was a clear dose-dependent relationship between ARB use and incident dementia; the risk of incident dementia decreased with increasing ARB dose. Among individual ARBs, use of candesartan was associated with the greatest reductions in the incidence of dementia. In addition, the use of both an ARB and an ACEI was associated with lower rates of incident AD, incident dementia, and disease progression than ARBs or ACEIs alone.

This observational study of older men in the VA healthcare system suggests that use of an ARB is associated with a reduced risk of incident dementia and AD as compared with the ACE inhibitor lisinopril and other drugs used to treat CV disease. In addition, among those with preexisting dementia or AD, ARB use is associated with a reduced risk of disease progression. 1


Comment
Dementia is a common and serious health problem that affects at least 33 million people worldwide. While the pathophysiology and classification of dementia is complex, there is increasing evidence that both in the case of AD and other forms of dementia CV disease risk factors play an important role in the development and progression of cognitive decline. This study suggests that use of a specific class of CV medications, ARBs, can lead to a decrease in the incidence and progression of both AD and dementia as compared to both the ACEI lisinopril, independent of BP reduction, as well as other CV medications often used for similar indications.

This study’s primary strength is its large sample size and the use of clinical meaningful endpoints (particularly in the progression analysis). It also, however, has some very significant limitations, including a relatively short follow-up period for the conditions in question (only 5 years), data collection from only one healthcare delivery system—the VA with its paucity of women in the cohort, limited information on the initial indications for the use of these medications, and lack of good BP data on the entire cohort. Most importantly, the observational study design used is subject to considerable potential treatment bias and important confounding variables that may not have been accounted for in the analyses. Indeed, the statistical models employed did not take into account a number of potential confounding variables, including: disease severity, indications for use of these medications, education level, socioeconomic status, previous intolerance to other drug classes, and family history of stroke or dementia. There may also be a host of other potential confounding variables that may not be easy to identify. Unfortunately, there is little information provided here or elsewhere about what types of patients end up taking an ARB instead of an ACEI, either in the VA or in other settings. Indeed, the consistency of the findings in this paper—similar reductions in the endpoints of progression and incidence, similar reductions when compared to lisinopril or to other CV disease medications, similar reductions regardless of the other covariates included in the model, and similar reductions in both AD and in overall dementia (where the pathophysiology may vary considerably) actually suggest a systemic treatment bias or confounding variable associated with ARB use. In fact, the Study on Cognition and Prognosis in the Elderly (SCOPE) trial, with its methodological flaws, is a prospective randomized controlled antihypertension intervention trial that studied the cognitive effects of an ARB (candesartan) in older patients and demonstrated no clear evidence that its use reduced the rate of cognitive decline or the incidence of dementia as compared to placebo on a background of open-label treatment of BP. And, while the present observational study suggests that use of an ARB and ACEI results in lower rates of incident AD, dementia, and disease progression than either agent when used alone, the recent results from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) found that using these 2 agents together was associated with more hypotension, syncope, and worsening renal function.

So, based on these important limitations, it appears clear that these results should not change our choice of antihypertensive medication in a patient with or at risk for AD and other forms of dementia. Before we completely ignore these data, however, it is important to note that this study adds to a small but growing amount of hypothesis-generating information suggesting that agents that block the renin-angiotensin-aldosterone system (RAAS), and ARBs in particular, are deserving of more careful study as relates to cognitive decline. There are a number of animal studies that have implicated the RAAS in the development of β-amyloid plaques characteristic of AD. And, interestingly, in the present analysis, use of candesartan, which is purported to have the greatest brain penetration of the ARBs, appeared to have a more beneficial effect than seen with ARBs associated with less brain penetration.

If in fact, blockade of the RAAS is helpful in reducing cognitive decline, whether or not ARBs would provide an advantage over ACEIs remains a subject of debate. Based on the way they interact with the RAAS cascade, ACEIs and ARBs have very different effects on the production of angiotensin II and subsequent activation of the angiotensin II type 2 receptor and other potential receptors found in the brain. In this current analysis, the ACEI chosen as a comparator was lisinopril, which actually has relatively little brain penetration. Other ACEIs, like perindopril and captopril, have been purported to have greater brain penetration. Whether the results of the present VA retrospective analysis would have been different had these other ACEIs rather than lisinopril been used is unknown.

Emerging research suggests that the RAAS may be involved in the incidence and progression of AD and dementia. Whether there is a beneficial treatment effect for RAAS blockade, and specifically for ARBs over ACEIs, remains unclear. Further research will be needed to clarify these issues. In the meantime, the choice of antihypertensive medication should not be guided by these largely hypothetical constructs and observational studies. Instead, pending further clinical trial research, the focus in patients with or at risk for AD and dementia should remain on overall BP control and aggressive treatment of other CV risk factors.


Reference
1
Li NC, Lee A, Whitmer RA, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465.
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