Wednesday January 13 2010
It is too early to start using these drugs to treat dementia
“Millions of older people who take drugs for high blood pressure or heart problems can more than halve their risk of developing Alzheimer's disease and dementia,” The Guardian reported.
This large study assessed 800,000 people taking blood pressure drugs over a five-year period. People taking angiotensin receptor blockers (ARBs) were 25% less likely to be diagnosed with dementia compared to those on other blood pressure drugs.
The suggestion that this blood pressure drug might prevent dementia has important implications. However, the study has some limitations, including the fact that the people taking ARBs were less likely to have vascular disease and more likely to have diabetes than people on the other drugs.
Further randomised trials of these drugs, avoiding some of these limitations, can be expected. It is too soon to start taking ARBs specifically for the prevention or treatment of dementia.
Where did the story come from?
This study was carried out by Nien-Chen Li, a statistician from Boston University School of Public Health, and colleagues from other institutions in Massachusetts in the US, and Sweden. The research was supported by a grant from the Retirement Research Foundation and a donation from the Casten Foundation. The paper was published in the peer-reviewed British Medical Journal (BMJ).
What kind of research was this?
This prospective cohort study used data from the records of the Veterans Affairs health system, a health system providing care for about 4.5 million people annually in the US.
The aim was to assess whether certain drugs (ARBs, lisinopril or cardiovascular drugs) reduced the onset of Alzheimer’s disease or dementia in people who were disease free at the beginning of the study. It also aimed to determine whether the drugs reduced disease progression in people who already had the disease.
This was a non-randomised study (the participants were not randomly assigned a treatment) and, therefore, problems of bias are more likely despite the best attempts of the researchers to eliminate them. Potentially, the most problematic bias is that these drugs are used for different conditions, so the three groups could each be made up of people with a different spectrum of disease. For example, more people treated with ARBs and lisinopril had diabetes, as this is an indication for choosing this type of drug in people with high blood pressure. Also, more people treated with the comparator group of other cardiovascular drugs (for example, those that took beta-blockers) had cardiovascular disease.
The analysis was adjusted for these and other factors including age, stroke and hypertension. However, bias may not have been completely eliminated, and other factors, such as severity of disease and socioeconomic status, may have influenced the results.
To support their claim that ARBs have a special effect (as well as blood pressure reduction) the researchers examined whether the effect on blood pressure was the same for all the treated groups. They did not have these data for all patients, so blood pressure was measured in a separate sample. This showed that among about 2,000 people taking ARBs, the average blood pressure was 136/74 and this was similar in all groups. This means that the reduction in risk of dementia is unlikely to be due to the reduction in blood pressure alone. This supports the researchers’ theory that ARBs have a specific effect.
What did the research involve?
This study compared the rates of new-onset Alzheimer’s disease in people taking blood pressure drugs. The patients were split into three groups according to the type of blood pressure drug they were taking:
- the angiotensin converting enzyme (ACE) inhibitor, lisinopril, or
- other cardiovascular drugs (except statins, ARBs or ACE inhibitors).
The first part of the study looked at patients aged 65 and over without dementia but who had cardiovascular disease or high blood pressure. The patients were first tested between 2002 and 2003 to ensure that they did not have dementia. They were then followed from 2003 to 2006 and any diagnoses of dementia were measured, as well as how long the dementia took to develop. There were over 11,500 people in the ARBs group, more than 91,000 in the lisinopril group and more than 696,000 in the group of those taking other cardiovascular drugs (the cardiovascular comparator group). The researchers also investigated the disease progression in a group of patients who already had diagnosed dementia. They did this by measuring the time until they were admitted to a nursing home or until their death.
The researchers then analysed the data from the three groups over the four-year period, using models that took into account age, diabetes, stroke and cardiovascular disease. They reported results from both parts to the study as a hazard ratio (HR). This is a measure of relative risk used in studies that examine the time taken for an event (in this case dementia) to occur.
What were the basic results?
The researchers report that ARBs were associated with a reduced risk of developing dementia, and that they reduced the risk by 24% compared with the cardiovascular comparator (HR 0.76, 95% confidence interval [CI] 0.69 to 0.84). A reduction in risk of developing dementia was also present when ARBs were compared to lisinopril (HR 0.81, 95% CI 0.73 to 0.90).
In patients who already had Alzheimer’s disease, ARBs were associated with a significantly lower risk of admission to a nursing home (HR 0.51, 95% CI 0.36 to 0.72) and death (HR 0.83, 95% CI 0.71 to 0.97) compared with the cardiovascular comparator.
ARBs showed other additional effects when combined with other drugs. A combination of ARBs and ACE inhibitors was associated with a reduced risk of new cases of dementia compared with ACE inhibitors alone (HR 0.54, 95% CI 0.51 to 0.57). In those who already had dementia, this combination was associated with a reduced risk of admission to a nursing home (HR 0.33, 95%CI 0.22 to 0.49). Similar results were observed for Alzheimer’s disease for all comparisons.
How did the researchers interpret the results?
The researchers say that, “angiotensin receptor blockers are associated with a significant reduction in the incidence and progression of Alzheimer’s disease and dementia compared with angiotensin converting enzyme inhibitors or other cardiovascular drugs”. They note that their study was conducted in a predominantly male population.
This large and well-conducted study adds weight to the plausible theory that angiotensin receptor blockers can reduce the risk of Alzheimer’s disease and vascular dementia. However, it is too soon to start using these drugs in a targeted attempt at preventing or slowing dementia. Several cautions are raised by the researchers and in an editorial published in the BMJ:
- The people treated with ARBs were known to be different from those in the other groups in two important ways: their rates of diabetes and cardiovascular disease. As such, there may have been other differences between the groups, to the extent that the ARBs group was already less likely to develop dementia. For example the ARBs group may have had less severe vascular disease, or the other groups may have had more chance of having unrecognised early dementia.
- Taking the patients’ blood pressure was the only practical way of testing whether these drugs had different effects on blood pressure. Ideally, blood pressure would have been recorded for all patients in the study, and this would have strengthened the argument that ARBs were having a special effect. The sampling of a subgroup of patients from another recording system who have had their BP recorded may have been less accurate than directly recording the BP of the participants. For a long-term condition such as dementia, 48 months of follow-up is relatively short and longer studies will be needed.
- The results may not apply to women, as less than 2% of the people in the study were female.
Overall, this study raises an important possibility: that ARBs might be protective against dementia. However, further research confirming or refuting this in randomised trials is needed.