Norman Swan: Hello, and welcome to this week's Health Report with me,

Norman Swan. Today, foretelling the future when you can still change your
destiny. A statistical spat which could affect your opinion of your local hospital.
Assessing stroke care in Australia. And multi-vitamins and your heart.

According to one estimate, over 8 million Australians buy vitamins or

supplements in any six-month period. 16% of the population report taking a multi-
vitamins in the previous 24 hours. So it's big business, and you imagine for it to
be so common that people think they are getting some benefit.

One reason people take multi-vitamins is to protect their heart, but the evidence
for a cardiovascular prevention is the thin, to say the least, and it has not been
made any more substantial by a paper reporting the results of a large long-term
trial. The lead author is Susanne Rautiainen of the Karolinska Institutet in
Stockholm. Welcome to the Health Report.

Susanne Rautiainen: Thank you.

Norman Swan: Just tell us about this trial, because it was into male doctors,
wasn't it?

Susanne Rautiainen: Yes. So it was among male physicians in the US.

Norman Swan: So what did they do?

Susanne Rautiainen: So they were recruited, and in this trial a commonly used
multi-vitamin was tested for over 10 years to see whether those who were
randomised taking a multi-vitamin compared to placebo had any reduced risk of
cardiovascular disease.

Norman Swan: And it wasn't a small trial, it was about 15,000 of them.

Susanne Rautiainen: Yes, exactly.

Norman Swan: And these were male doctors, aged 50 years or over?

Susanne Rautiainen: Yes.

Norman Swan: And what was in the multi-vitamin capsule?

Susanne Rautiainen: So it was basically a wide spread of vitamins and minerals
in low doses, and typically obtained from the usual diet. It wasn't high doses, it
was a commonly used multi-vitamin, low dose, that is aiming to mirror the diet
that was tested. This type of supplement, especially in the US and in Sweden, I
don't know in Australia, but that's the most common used dietary supplement in
the general population.

Norman Swan: And what were the outcomes you were looking for?

Susanne Rautiainen: It was primarily testing cancer and cardiovascular disease

prevention. But what we have done in our study was looking at cardiovascular
disease and whether a baseline nutritional status could explain the results.

Norman Swan: So you were looking at heart attacks, strokes, death from
cardiovascular disease, that sort of thing.

Susanne Rautiainen: Yes, exactly, so we combined heart attacks and strokes

and cardiovascular disease death.

Norman Swan: And before we get to those results, were there any results on the
cancer, or is that still to report?

Susanne Rautiainen: Yes, the overall results on cancer has been recorded but
the baseline nutritional status and additional information, that's an ongoing study.

Norman Swan: And did they find any results on cancer, before we get…?

Susanne Rautiainen: Yes, so there was a modest reduction in cancer incidence,

but no effect on cardiovascular disease.

Norman Swan: So there is no effect on cardiovascular disease, and then one of

the criticisms of the study was that baseline nutritional status, in other words if
somebody had poor nutritional status they might get an extra benefit, and that
was one of the things that you looked at in this particular study.

Susanne Rautiainen: Yes, because intuitively you would think that if you have a
poor diet, if you don't get enough vitamins and minerals from your diet you would
benefit from a multi-vitamin, so that's what we tried to figure out in this study. So
all these men filled in a questionnaire at baseline asking about the wide range of
foods they were consuming and then we looked in several ways to see
whether…among groups of men, having a poor diet, whether this multi-vitamin
actually added any benefit on cardiovascular disease reduction. And we did not
see any evidence at all that the baseline diet would explain the lack of effect from
a multi-vitamin on cardiovascular disease risk.

Norman Swan: You found some interactions with other vitamins, vitamin B6,
vitamin D and vitamins B12. What were those interactions?

Susanne Rautiainen: Yes, so when we do these kind of studies we do a lot of

comparisons and we do a lot of statistical tests. So this could be just a cause of
multiple comparisons, that's what we talk about in research. When we do a lot of
different comparisons, we could get these false positive results that when we see
this effect, we can't really…we really need to interpret this with caution because
we are doing a lot of comparisons, so we do not put any weight into those results
because overall when we are looking at, we see…the overall interpretation is that
basically diet is not explaining…baseline diet is not explaining the lack of effect
on heart disease.

Norman Swan: Just to explain the interaction…in other words, you had an
increased risk of cardiovascular events with those vitamins?

Susanne Rautiainen: Yes, so that's why you need to be a little bit careful when
you do these type of studies…

Norman Swan: So you don't want to create panic that they are increasing their
risk of heart disease.

Susanne Rautiainen: No, because you are doing so many subgroup analyses,
you are splitting the men into different groups, so this is something that could just
be just a causal that are doing a lot of these different comparisons.

Norman Swan: And just finally, male doctors aren't necessarily typical of the
general population, is this the applicable beyond male doctors?

Susanne Rautiainen: Yes, so that's also one of the criticisms of this study, that
these men on average had a healthy diet on average. We could see that when
we were comparing results to a national study in the US, that they had higher
intakes of fruits and vegetables for example.

Norman Swan: So if somebody wanted to convince themselves that they were

going to get benefits, they would just say they could just ignore this trial, but what
you're saying is buyer beware, it's not necessarily showing much benefit.

Susanne Rautiainen: I would interpret the results that if you have a diet…you
have high intake of fruits and vegetables, fibre, nuts…a multi vitamins would
probably not add any additional benefit.

Norman Swan: Save your money.

Susanne Rautiainen: Yes, exactly.

Norman Swan: And we will wait for the cancer results to come out to see
whether or not that works too. Thank you very much indeed for your time.
Susanne Rautiainen is in the Institute of Environmental Medicine at the
Karolinska Institutet in Stockholm.

And you're listening to the Health Report here on RN, ABC news and CBC radio
across Canada. I'm Norman Swan.

Staying with risk factors for heart disease, your risk factors for heart disease in
midlife may predict how gummed up your brain will be 20-odd years down the
road. Gummed up, that is, with a gunky substance called amyloid, which is part
of the brain pathology leading to Alzheimer's disease. Rebecca Gottesman was
one of the researchers. She is associate professor of neurology and
epidemiology at Johns Hopkins University's School of Medicine in Baltimore.

Rebecca Gottesman: Thank you, thanks for having me.

Norman Swan: I thought this was a done deal, that we knew that if you had
coronary risk factors in midlife it stuffed up your brain in late life. But clearly there
was more work to be done.

Rebecca Gottesman: Well, we did know from studies, including my own, as well
as other studies done by other terrific groups, that vascular risk factors, heart risk
factors, as you mentioned, are associated with bad outcomes in terms of both
your cognition as well as stroke and other bad effects on the brain. What we
didn't really understand, and I think that this paper at least makes an attempt to
try to explain a little bit better, is how that happens. So if we know that heart risks
increase the risk of dementia, what we haven't understood is is it just that you
happen to have two things going on in your brain, you have Alzheimer's type
changes and you have vascular type changes, that your cognition might be
worse and you might be more likely to be given a diagnosis of dementia? Or is it
that the vascular changes are actually doing something in the brain that triggers
Alzheimer's neuropathology? In our study, where we used PET imaging, looking
at amyloid deposition in the brain, specifically suggests that there may be a direct
effect of these vascular risk factors on the Alzheimer's pathology.

Norman Swan: So PET is like a nuclear scan which shows the brain in action, it
shows the metabolism of the sugar in the brain actively, so unlike an MRI which
is more static, a PET is more dynamic.

Rebecca Gottesman: Exactly, and specifically with PET you can look not only at
sugar in the brain, as you mention, but other types of markers. So in this
particular study we looked at a specific marker called florbetapir, which we think
binds to amyloid in the brain. And the leading hypothesis of Alzheimer's is that
amyloid builds up to lead to Alzheimer's. So in this particular study we can inject
this isotope through an IV when people are getting a PET scan and it binds to the
parts of the brain where there is amyloid specifically. And these were people who
didn't have dementia in this particular study, but we found that a number of them
still had higher levels of amyloid than would be considered normal.

Norman Swan: So tell us a bit more about the study. Who did you study and
what did you do?

Rebecca Gottesman: Sure. So the Atherosclerosis Risk in Community study, or

the ARIC study, has been going on now for nearly 30 years. It was initiated in
four community sites across the United States. This study started evaluating
nearly 16,000 people, almost 30 years ago, and has followed them over time,
collected important information about vascular risk factors, vascular markers,
followed them for cognitive function at a few earlier time points. And most
recently in 2011 to 2013, people had a more detailed cognitive assessment, and
a subset of people had brain MRIs, and then I recruited from that subset to do
these PET scans. So these are people who don't have dementia but were
recruited from the community 30 years ago, we have all of this longitudinal
information about them, and now we have this PET amyloid imaging on this
subset of 346 people, and in whom we can really look at the relationship.

Norman Swan: And what risk factors did you look at?

Rebecca Gottesman: So we focused on five risk factors, and a key point I want
to make is we looked at their status in middle age. So at the first visit in the ARIC
study, which is when people were 45 to 64 years old, because some evidence
has suggested that midlife risk factors are even more important for later life
dementia as opposed to risk factors later. So we looked at high blood pressure,
high cholesterol, diabetes, obesity and smoking status when people were middle-
aged. And we found that the more risk factors you had, the more amyloid you
had in your brain.

Specifically when we looked at the individual risk factors, the only one that was
associated with amyloid later was obesity, the other ones didn't have a separate
effect. But really the cumulative amount of these risk factors appeared to be most
important.

Norman Swan: I'm sorry, let me just get that straight about obesity. So obesity
was the one that counted later in life rather than in midlife, is that what you are
saying?

Rebecca Gottesman: No, so obesity was the one that when we looked at them
individually in midlife it had an effect by itself…

Norman Swan: Ah, I see, the rest were working together.

Rebecca Gottesman: Exactly. So hypertension, there was a suggestion of

increased risk, but statistically it didn't show an association with amyloid. Obesity
did, but just from midlife.

Norman Swan: Which ties in with essentially evidence-based practice now

where people say, look, your cholesterol doesn't matter that much by itself or
your blood pressure doesn't matter that much by itself, but it's your total risk
when you add up all the factors, that's what counts, your so-called absolute risk.
So in other words, what you're saying here is that your absolute risk, your total
risk of heart disease also affects your brain.

Rebecca Gottesman: Absolutely, and the problem is a lot of these risk factors
do go together. So it's not that common that someone just has one of them, so
it's pretty common that these co-occur, which means it's going to be common
that people have an elevated risk associated with that co-occurrence.

Norman Swan: There have been studies of amyloid in the brain which suggest
you can find people with a lot of amyloid in the brain and no dementia and no
cognitive problems, and there's still a lot of debate about whether amyloid really
matters much at all. Is this a stepping stone on the way to cognitive decline, or is
it just something else you've found?

Rebecca Gottesman: I think that's a great point and you're absolutely right. Our
study is an example of the fact people can have elevated amyloid and be non-
demented. So there are people in our study who had mild cognitive impairment
but no one who had dementia. We also had people who were totally normal and
some of those had elevated amyloid. So amyloid is but one factor in the pathway
of things that leads to Alzheimer's, and it may just be a marker of the other things
that have happened.

Regardless, I think these data suggest the importance of looking decades earlier
than the amyloid changes. So we know that in Alzheimer's disease part of the
reason that treatment attempts have been unsuccessful to date and that there is
no known way to prevent or treat Alzheimer's is because we are probably looking
at people a little bit too late. So we are looking at them when they already have
amyloid in the brain or there is already tau accumulating in the brain.

Norman Swan: Which is the other piece of gunk…

Rebecca Gottesman: Exactly, the other a big factor. So there has been an
emphasis in the Alzheimer's community at looking at people before clinical
disease, and our data suggests that if vascular risk factors are playing an
important role you really need to look decades before you start having even
amyloid changes. But you're absolutely right, figuring out how tau fits in, and
other changes in the brain, inflammatory changes et cetera, there is likely many
things going on. I still think this is probably a piece of the puzzle, not a solution to
the puzzle, but I do think it's an important part in understanding what is
happening in Alzheimer's.

Norman Swan: So does it shine a light on the cause of Alzheimer's?

Rebecca Gottesman: I think that it shines a light on the vascular risk factors as
maybe having a direct impact on Alzheimer's. And I'm not going to say this tells
us that the cause of Alzheimer's is vascular disease because it certainly doesn't.
But I do think it gives important information that it may directly affect the
pathology that leads to Alzheimer's, as opposed to just being another bystander,
that if you happen to have both your cognition will be worse.

Norman Swan: There is a gene that increases your risk of Alzheimer's disease,
and it's related to vascular risk factors and it's called ApoE4. Did you do any sub-
studies on this group of people for their ApoE4 status, to see whether that further
boosted their deposition of amyloid?

Rebecca Gottesman: We did. So our studies have certainly verified the fact in
this cohort that having an E4 allele, that particular type of the ApoE gene does
increase risk, as we would expect. It also increases the amount of amyloid. So in
other studies it increased risk of dementia, and in this particular ARIC PET study
that I've been describing, it increased risk of amyloid.

We looked specifically at that exact question, to see how having an ApoE4 gene
changed the way vascular risk affected amyloid. And we didn't find a statistical
difference in people who were carriers of an E4 gene and those who weren't.
Both groups had an elevated risk associated with more vascular risk factors.
There is sort of a hint that maybe people who were gene carriers had an even
higher risk, but statistically we didn't have enough power to show that difference,
so we can't say with confidence that the combination—vascular risk factors and
having ApoE4 allele and this increased genetic risk—increases your risk that
much more. But the data do suggest that there might be something there with
that particular combination.

Norman Swan: So if you were in your 70s, is there any point to changing your
risk factors than if you are looking to protect your brain, given that there is very
little evidence that it has an impact?
Rebecca Gottesman: I still think that there is, and obviously the jury is still a little
bit out on at what age it becomes maybe dangerous to treat some of these, so
hypertension being an example. In the US there was a set of guidelines for
hypertension treatment that initially said you don't need to treat people as
aggressively above aged 60, and most people agreed that that was maybe too
low of a…

Norman Swan: That's almost childhood in the current environment.

Rebecca Gottesman: And the SPRINT trial, which was a big trial, it showed us
that it's actually very important to treat blood pressure aggressively. There's a
part of the SPRINT trial which we don't know the results of yet which will look at
cognition specifically in association with that tighter blood pressure control. But I
think there are other ways in which vascular risk factors can adversely affect the
brain, stroke being one example, and, related to stroke, silent strokes. And we
know that hypertension for example is a very strong risk factor for stroke, and we
know stroke can also affect cognition. So that alone is compelling enough
information, arguing that you need to really treat blood pressure and cholesterol
and diabetes, et cetera, stop smoking, control your weight, even if you are in your
70s. Our study data don't clearly show that amyloid itself can be effected, but it's
probably because it is in some ways too late, that the amyloid changes have
already happened if they are going to happen.

Norman Swan: And I suppose the proof of the pudding is in the eating, given
that in countries around the world where risk factors are going down in the
general population, European countries, Britain, a little bit of evidence from
America, that dementia rates seem to be falling, that the disaster scenario is not
necessarily playing out.

Rebecca Gottesman: Absolutely, and so that's further evidence supporting this

general idea that risk factors are associated with dementia; as risk factors go
down, dementia goes down. The problem is our population is ageing, so there
are more people that we are concerned about who are surviving other diseases
related to vascular disease, but may develop these other chronic diseases,
including kidney disease and certainly dementia. But you're absolutely right, rates
appear to be going down, but I still think it's not something that we have solved
completely, and I think people don't necessarily think as seriously about their risk
factor status when they are middle aged or even younger.

Norman Swan: Rebecca Gottesman, thank you very much for joining us on
the Health Report.

Rebecca Gottesman: Thank you for having me, have a terrific day.

Norman Swan: Rebecca Gottesman is associate professor of neurology and

epidemiology at Johns Hopkins University's School of Medicine in Baltimore.

Listening to that interview in our Newcastle studios, Professor Chris Levi, a

neurologist at John Hunter Hospital, and a leading stroke researcher. So Chris,
just tell us briefly…it's not really the main reason I've got you on the program, but
what is the relationship between stroke and Alzheimer's rather than stroke and
vascular dementia?

Christopher Levi: Well, this is music to my years as a vascular neurologist,

Norman, because I think there is increasing evidence now of this spectrum of risk
in Alzheimer's disease, and vascular pathology in the brain and Alzheimer's
pathology very commonly coexist. And the vascular risk factors are solid
predictors of risk of dementia. And because there are things you can do about
them, and I really think it is important to be addressing them early, as your
previous speaker proposed, and that was very important data I think. But
because they are actually modifiable, hypertension particularly but also the other
vascular risk factors, they are one of the few important things that we can do to
keep not only our brains healthy from stroke but also to minimise risk of cognitive
impairment and dementia.

Norman Swan: You've often been on the program before talking about the
quality of stroke care in Australia. What's the story, for example…? I mean, you
were a great critic of the fact that many emergency departments in Australia
would not give clot busting for people suffering stroke due to a clot. What's the
situation now across Australia?

Christopher Levi: Well, there have been some improvements I think in our
implementation of stroke thrombolysis, although it's still a challenge because it's
very much a team game, and you rely on ambulance services and emergency
departments and hospitals to have their acute stroke teams all organised and all
working together and playing nicely together. There has only been a national
audit, so a fairly modest shift from somewhere in the order of 5% of all strokes up
to about 7%, 8% of all strokes now, when we know there is the potential to treat
up to 30%. So there's still a big evidence practice gap unfortunately and a lot of
work to do still.

But to give the emergency college credit, they have done their own review of this
area now, and I understand that review will be guiding policy and I think changing
some of the viewpoints or hopefully changing some of their viewpoints within the
College of Emergency Medicine.

Norman Swan: An important thing is being able to compare performance in

hospitals, and you are feeling a bit sore at the moment because in a report on
mortality rates, death rates from stroke, John Hunter, which you would consider
one of the better places to go if you had a stroke, came out as an outlier, with
increased levels of death rates, and you are also an author on a paper in
today's Medical Journal of Australia looking at stroke statistics. This is very
technical but it is quite important to people wanting to…well, you often don't get a
choice of hospital, but knowing that your local hospital is going to be okay if you
get taken there in an ambulance if you're having a stroke. Very briefly, tell us
what the story is. First of all this study that you've got in the Medical Journal of
Australia.

Christopher Levi: So the background to this is that we've been for some time,
particularly internationally but also in Australia, moving towards reporting of
outcomes for major conditions. And I think this is a very healthy thing, and the
clinicians welcome it and are all on board in terms of this process, and we are
probably going to move from broader reporting at hospital level down to reporting
in the future at levels of departments or even individual clinicians. And I think this
is now the way things are going in some of the international…

Norman Swan: Okay, so that's the context, let's jump to the deal.

Christopher Levi: So strokes are a heterogeneous condition, and all your

listeners will know, some strokes are relatively mild and some are incredibly
severe and some are so severe that unfortunately the person dies very rapidly.
So severity of the stroke is obviously a very important determinant of outcome.
And the challenge we have is that many of the administrative datasets that are
used to compile reports on comparative stroke outcomes, particularly stroke
death rates…a recent example in New South Wales is a report from the Bureau
of Health Information that people may have seen in the media, and as you
alluded to, some hospitals, including my own patch, have been reported as being
hospitals with poor performance or higher than expected mortality rates. And the
problem here is this data unfortunately is unreliable. And for the clinicians
involved, of course they are not credible. So it loses its value in terms of a tool to
look critically at performance. And why it's not credible is because it doesn't
actually use the key variable that's required to adjust and do valid comparisons,
and that is; what was the severity of the stroke patients presented to that hospital
compared to the other hospitals that it is being compared to?

Norman Swan: And if I'm right, if the paper in the Medical Journal of
Australia today shows that you can have an error rate of up to 25% if you don't
take that into account.

Christopher Levi: Unfortunately that's the fact, that you will misclassify up to
25% of hospitals as either being poorer performers or better performers, and the
clinicians are aware of this of course, and because it's a well published fact, and
we've emphasised that recently in Australian data and using the national acute
stroke registry that does allow analyses to be appropriately adjusted for stroke
severity. In Newcastle of course we conducted our own independent analysis
using that data and demonstrated to our clinicians to support their morale
and…and also to demonstrate to our local community that we are in fact not an
outlier, we are right on the national average.

Norman Swan: That was Chris Levi of John Hunter Hospital in Newcastle.

In our Melbourne studio is Jean-Frederic Levesque, who is chief executive of the

New South Wales Bureau of Health Information. You see, we occasionally
accept in New South Wales people down into Victoria! Welcome to the program.
So why don't you take this into account, this stroke severity, Jean-Frederic?

Jean-Frederic Levesque: Well, it's technically not possible at the moment to

have the actual measurement of the severity of the patient when they arrive at
the emergency department so that we integrate that into the analysis. But it's also
because…

Norman Swan: But the Stroke Foundation manages to do that for their stroke
registry.

Jean-Frederic Levesque: Well, in our analysis we consider the data for more
than 20,000 patients, all of New South Wales, 85 hospitals, we really have to
cover the entire range of contexts so that we can look at hospitals' results and
provide them back with the information that they need to say, okay, should we
look at how we provide care, should be look at how emergency department
services are provided and how quickly they are, and therefore we need to rely on
the currently available data for all patients, not just those that end up with bigger
hospitals, such as in the study that was published today.

Norman Swan: I should explain that the study was of hospitals which see a lot of
people with stroke. However, if there's potential error of 25% you're not
necessarily feeding back the right data to hospitals and they could be making
some of the wrong decisions.

Jean-Frederic Levesque: Well, what's important to consider here, Norman, is

that this study is an important study that really shows that for each patient,
severity is a strong predictor of mortality. And I agree with Professor Levi entirely
on that front. What's really important is to assess if hospitals are different with
regards to the average severity of patients that they get. And the international
evidence suggests that there is not a lot of variation on that front because
patients will tend to go to the closest hospital. Ambulances also know that time is
critical to treat stroke, and therefore will bring them to the closest hospital. But we
also do a lot of validation at the Bureau of Health Information, to ensure that even
though we don't have severity as a variable in our study, we can assess if we feel
patients are different. And sometimes we even merge hospitals that tell us that
easier cases go here, we receive more severe cases et cetera, and we do the
effort, we make the effort of pooling them together and seeing if the results are
any different, and we feed this information back. So our role is really to provide
the most accurate information and feedback to hospitals as possible.
Norman Swan: I'm not sure what the barrier is, because this could undermine
the reliability of your data, say, in other conditions, although myocardial
infarction, heart attack is probably easier. We haven't got a lot of time left, but are
you going to move towards assessing stroke severity? Because you've got a
couple of hospitals that are outliers in New South Wales, not that people
necessarily care listening elsewhere in Australia, but they are not necessarily
outliers in the true sense of the word, and therefore people lose confidence, and
they might lose confidence in your data too. How are you going to assess stroke
severity? Surely it's not such a hard thing to do in the emergency department?

Jean-Frederic Levesque: We welcome every improvement in the data available,

and with the improvements in electronic medical records, we will be able to
integrate that type of information with the other sources of data that we have that
are reliable all across the hospitals, in every hospital, and we will continue
alongside this to compare hospitals, comparing them with their peer groups.
Because big university hospitals should not vary that much in terms of the
severity of cases. They have the similar kind of infrastructure et cetera. All of our
reports are providing a lot of information that enables to go a bit further than just
saying is this a high mortality context or not, and all of the analysis that we
produce we feed back to clinicians through face-to-face meetings but also
through specific profiles that we give to them, and we also split all of the strokes
according to their ischaemic nature or haemorrhagic nature because we know
that these are different in severity as well. But if we can integrate more bedside
measures, we will be more than happy to assess if they can improve our
measurements of course.

Norman Swan: Jean-Frederic Levesque is chief executive of the Bureau of

Health Information in the New South Wales Department of Health.

I'm Norman Swan, this has been the Health Report, se