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

Norman Swan.

Today, a warning about a potentially dangerous drug interaction that some

people with what's called atrial fibrillation might have.

Success in Western Australia reducing the rate of preterm births, but it's hard
work.

A calculator for success with IVF.

And the media who have been full of the thunderstorm asthma event in
Melbourne two weeks ago, thousands of people turning up in emergency
departments, intensive care admissions and several deaths. One reason for the
impact is thought to be that too many people with asthma don't recognise that
their condition is worse than it is and are on the wrong treatment. Basically
throughout Australia there is a cohort of people who live with unacceptable
asthma symptoms. Someone who studied this is Matthew Peters who is
professor of respiratory medicine at Macquarie University in Sydney. Welcome to
the Health Report.

Matthew Peters: Good evening Norman.

Norman Swan: I should just say that Matthew is speaking to us via Skype from
Vienna where he is at a conference. Just before we get to this unacceptable level
of symptoms in the community, what do we know about the causes of this huge
event? Is it simply pollen?

Matthew Peters: It's a combination of circumstances, including pollen. You need

a build-up of pollen, so typically in Australia it's grass pollen because that is
carried on breezes. So a number of days of pollen build-up, and then preceding
the thunderstorm typically there are winds and downdraughts. They take the
pollen up into the cloud base, simply because there's distilled water, the larger
pollen particles are broken up into much smaller pollen particles, and the smaller
ones are then dispersed in the storm, and these smaller ones are of a sufficiently
small calibre to penetrate deep into the airways and establish an asthma
reaction.
Norman Swan: And it's a true asthma reaction?

Matthew Peters: No question, and probably electrical forces contribute as well,

it's a very complex milieu.

Norman Swan: So tell us about this group of people with unacceptable asthma
symptoms, and what asthma symptoms are we talking about here?

Matthew Peters: We are talking about wheeze, breathlessness, chest tightness,

general incapacity to consistently go around your tasks of daily life without
breathlessness. The ones we worry most about are those which are disturbing
during the small hours of the morning or on waking because they are good
markers of poor asthma control. Of course frequent use of Ventolin or a blue
puffer is a marker again of poor asthma control that can generally be much
improved with good care.

Norman Swan: So when you talk about Ventolin or salbutamol, you're talking
about what's called a reliever, it doesn't treat the asthma, it just opens up the
airways?

Matthew Peters: That's it, yes. It's a temporary stopgap solution but
unfortunately relied on by too many people in our community as the core
treatment for their asthma.

Norman Swan: Indeed this week, in fact this morning new statistics have come
out to show that there were 3 million prescriptions for Ventolin in the last 12
months. So that's a lot of people sucking on Ventolin.

Matthew Peters: Despite all our efforts, it's still very heavily used and we just
have had for decades better ways to manage asthma, we haven't been able to
effectively and consistently roll out.

Norman Swan: Although asthma deaths have gone down in Australia.

Matthew Peters: And that's one of the really fascinating things. So we've
dramatically reduced asthma deaths in our community, but we haven't got good
current symptom control improved to the same degree, and it's one of the
conundrums. There clearly are people in the community at risk of dying from
asthma. One presumes they are taking enough of their core asthma treatment to
avert very severe asthma and deaths in the majority of cases, but are still
tolerating a level of asthma symptom control that we think they don't need to
tolerate and does still put them at risk of some significant asthma crises.

Norman Swan: So what other numbers? What proportion?

Matthew Peters: The core number that we worry about is people who by
standard criteria have poorly controlled asthma, so we know around 25% of all
people in Australia with asthma, surveyed well, have uncontrolled asthma
symptoms and are not taking a regular asthma preventer, or if you like a solution
puffer for their asthma. So that's one group of 25%. Separately there is 20% who
report that they are using their core asthma treatment or preventer, but they still
have poorly controlled asthma.

Norman Swan: As typified by the sort of symptoms that you were talking about a
moment ago.

Matthew Peters: Correct.

Norman Swan: And we've also had on the Health Report, but some time ago,
the research which suggests that when people…first of all people think they grow
out of asthma when they are adults, which in fact is not true, some grow out of it
as children, but you don't grow out of it when you're an adult.

Matthew Peters: If you have established asthma in adult life, spontaneous

resolution is extraordinarily rare.

Norman Swan: But there is research to suggest that when you are not feeling
too bad about your asthma, you think you haven't got it anymore, it's only when
you have an asthma attack you think you've got asthma.

Matthew Peters: Yes, and this is the problem of terminology, a nut we haven't
quite cracked, that some people would describe or some people living with
asthma would describe an asthma attack as when their Ventolin doesn't work or
relieve their symptoms as quickly as they would expect it to. Whereas we think
the very need for Ventolin is a marker of poor asthma control and is in itself an
asthma attack and something that we should worry about. So getting a common
language, common terminology, a common way of approaching the goals of
asthma care is something we are still striving to achieve.

Norman Swan: So in other words up to 40% or 50% of people with asthma are
on a bit of a knife edge and therefore when something like this thunderstorm
asthma event comes along, they are hit particularly hard.

Matthew Peters: Correct, and some of the 20% who have uncontrolled
symptoms despite using their regular puffer appropriately may have symptoms
for other reasons. They may report breathlessness because they are not as fit as
they'd like to be, but within that group there will be people with asthma who are
genuinely at risk because they might be using their inhaler but very badly. And
that in itself is a signal to some of the things that we can do, just simple attention
to detail in taking treatment regularly, in taking their inhalers with the correct
techniques so delivery is good and the effect is maximised.

Norman Swan: So just take us through the solutions here. So we've got all these
complicated terminologies like relievers, preventers and so on, what is the
evidence-based treatment for asthma that…you're using your blue puffer too
often, you've got these symptoms, what is the evidence-based treatment?

Matthew Peters: Well, at the very least, patients…I shouldn't call them patients,
that's not dogma…people living with asthma who have regular symptoms and are
on no regular preventer treatment or core asthma treatment should be taking one
that includes an inhaled steroid component. And just the administration of a
relatively tiny dose of inhaled steroid regularly virtually eliminates the risk of
asthma deaths and asthma crises, trips to hospital. So that's the core. That
should be taken in an inhalant the patient is familiar with, and they have good
technique, and one would expect that their symptoms—breathlessness, cough,
wheeze, chest tightness—will improve well. Where they don't improve well then
sometimes a long-acting form of Ventolin or similar needs to be added.

Norman Swan: Matthew, thank you very much indeed.

Matthew Peters: It's a great pleasure.

Norman Swan: Matthew Peters is professor of respiratory medicine at

Macquarie University in Sydney.
And you're listening to the Health Report here on RN, ABC news radio and CBC
radio across Canada.

A paper in the Canadian Medical Association Journal has issued a warning about
an interaction between a blood thinner called dabigatran, and two cholesterol
medications, statins, one of which, lovastatin, isn't used in Australia, but the
other, simvastatin, has been popular in the past. The interaction increases the
risk of a haemorrhage. The lead author on the paper was pharmacist and clinical
epidemiologist Associate Professor Tony Antoniou of the University of Toronto.
Dabigatran, by the way, is used to prevent stroke in people with what is called
atrial fibrillation.

Tony Antoniou: That's correct, it's a blood thinner that is used by patients mostly
with atrial fibrillation, which is a kind of irregular heart rhythm.

Norman Swan: And it has become quite popular. There's been a lot of
controversy about dabigatran because it is not reversible and there is no test to
really work out how well it's going.

Tony Antoniou: That's correct, yes, it has become…although the use of it has
been increasing quite a bit. I mean, during the period of our study, use of the
drug had increased 90-fold between 2012 and 2014. So despite some of the
concerns with the drug, its uptake was quite rapid.

Norman Swan: And what made you think that statins or at least these two statins
we are talking about, increase the risk of haemorrhage or might increase the risk
of haemorrhage?

Tony Antoniou: We thought about that because there was some previous
research that had been done by others that was basic pharmacology type
research that suggested that those two statins in particular, lovastatin and
simvastatin, had some properties that could increase the amount of
dabigatran that was absorbed by our bodies, and thereby then increase the risk
of bleeding. So what we were interested in examining was whether those findings
from those other researchers could translate into something important at the
population level.

Norman Swan: So what did you do in this study?

Tony Antoniou: So what we did was we used Ontario's administrative health
records, and we started off by looking at all people who were 66 years of age and
older who had been prescribed dabigatran between May 2012 and March 2014.
And then we just basically looked at people who had had either a stroke or
people who had been admitted to hospital, had an emergency department room
visit for bleeds. And then we took a look to see if there was a difference in the
risk of either of these outcomes according to the type of statin that patients were
prescribed.

Norman Swan: And why did you look at stroke?

Tony Antoniou: We also looked at stroke because there is some evidence also
that those same two statins, lovastatin and simvastatin, could actually interfere
with the way dabigatran is activated or turned on, so that it would be a less
effective blood thinner and therefore also then increase the risk of stroke
potentially. So we actually did two separate studies.

Norman Swan: Remembering of course that it is treating atrial fibrillation, which

is the top chamber of your heart where a clot can gather because it's not beating
properly.

Tony Antoniou: That's correct. So the clot can gather or form in the heart and
then travel to the brain and cause a stroke. So we were thinking that if these two
drugs decreased or interfered with the activation of dabigatran to its active form,
they could interfere with its ability to prevent a clot, and so these patients might
also be at higher risk for stroke.

Norman Swan: What did you find?

Tony Antoniou: We actually found that there was no influence of lovastatin and
simvastatin at all on the risk of stroke compared with other statins. But in contrast
we found that being treated with simvastatin and lovastatin increased the risk of
bleeding by about 40% or so relative to patients receiving one of the other
statins.

Norman Swan: When you say major bleeding, what are we talking about here?
Tony Antoniou: Yes, that's an important question because we define major
bleeding as any episode of a bleed that results in either hospital admission or an
emergency department room visit for bleeding. About two-thirds, 70% of the
bleeds we found were from the stomach, so they were gastrointestinal bleeds,
with a much smaller minority being brain bleeds.

Norman Swan: And did anybody die as a result?

Tony Antoniou: We didn't actually look at if anybody died actually, so I couldn't

answer that question if there were any deaths from the bleeds.

Norman Swan: And you looked at the other statins and you found that this risk
did not exist.

Tony Antoniou: Yes, so we did this using those statins as the reference group
or the control group because those statins don't have the same properties as
lovastatin and simvastatin. So we wouldn't expect them to behave in the same
way when it comes to the way dabigatran is handled by the body.

Norman Swan: I'm doing this story because it's an important public health
message. Today there's been a release in Australia of the top 10 drugs by
numbers and by cost and so on. And the top statins in Australia are atorvastatin,
trade name Lipitor, and rosuvastatin, trade name Crestor, and while simvastatin
and lovastatin were popular a few years ago, they are not anymore, or
simvastatin in particular I should say. Is it the same in Canada, that they are not
very popular drugs anymore?

Tony Antoniou: Simvastatin is still used occasionally, but I would say the same
is true up here. Atorvastatin and rosuvastatin have probably eclipsed the use of
those other two drugs for managing most patients.

Norman Swan: The core message here is that if you are on dabigatran and you
are on a statin, just check what statin it is just in case it is one of these two,
simvastatin or lovastatin.

Tony Antoniou: I think that would be the core message. I think first not to do
anything without consulting your physician obviously. But for people who are on
dabigatran, I think our findings suggest that preferential use of one of the other
statins should probably be considered to derive the same benefits from statins
while minimising the risk of a bleed.

Norman Swan: Tony Antoniou, thank you for joining us on the Health Report.

Tony Antoniou: Thank you very much for your time and your interest.

Norman Swan: Pharmacist and clinical epidemiologist, Associate Professor

Tony Antoniou is at the University of Toronto. And remember, the interaction
does just seem to be with simvastatin, and if you are living in Canada, lovastatin,
not the other statins, and talk to your GP about it.

A paper published in the prestigious American Journal of Obstetrics and

Gynaecology has revealed an 8% reduction in preterm births from a preterm birth
prevention initiative in Western Australia. 8% doesn't sound like a lot but it is
when you consider the impact that preterm birth has on community health,
particularly in disadvantaged populations. One of the people involved in
pioneering this initiative is Professor John Newnham of King Edward Memorial
Hospital and the Women and Infants Research Foundation in Perth. Welcome to
the Health Report, John.

John Newnham: Good afternoon Norman, thank you.

Norman Swan: What do we know about the causes of preterm birth?

John Newnham: Well, preterm birth just describes birth at an age before 37
completed weeks, so it's really a timing definition. The causes are multiple, there
are multiple causes of preterm birth, and they differ at the different ages. So it's
the range between 20 weeks and 37 weeks. The very early ones we think are
more often related to inflammation and infection, and later on they are more
related to just spontaneous early onset of labour, which we don't understand, and
sometimes because doctors have pulled babies out early for one reason or
another.

Norman Swan: Yes, we've talked about that on the Health Report before, there
is an iatrogenic element to preterm birth. But you focused on hormones here?

John Newnham: No, we focused on the whole range. So the initiative that we
launched two years ago had six primary interventions, of which two or three were
the major areas of work. So firstly we concentrated on the length of the cervix in
mid pregnancy. So we now know that if you measure the length of the cervix in
mid pregnancy at the time of your routine mid pregnancy ultrasound scan, which
in Australia is done at 18 weeks gestation, the length of the cervix predicts
heavily when you are going to deliver. So a very short or shortened cervix
predicts early birth, and a long cervix predicts a later term birth. And we now
have a relatively simple treatment that can markedly reduce that risk.

Norman Swan: How reliable is that number, because women can be short,
women can be tall, and presumably their cervix varies according to their body
shape and size.

John Newnham: There's a small influence on the woman's height, but as a

general rule we have a strong cut-off. So on an internal scan, a measurement of
25 millimetres is our cut-off, and under that the risk of preterm birth goes up
dramatically.

Norman Swan: Simply because the cervix is unlikely to hold the baby as the
baby gets larger?

John Newnham: No, as you start getting uterine activity, of course for which
there are no symptoms, the woman is not aware of it, it starts pulling the cervix
up and thinning it, which normally occurs towards term and in labour, but in mid
pregnancy in women at risk of going into preterm labour, this starts happening
silently much earlier.

Norman Swan: So what do you do about it?

John Newnham: Well, we've got several options available to us. The first thing is
you need to know it's there, so that the woman can have this discussed with her.
We have vaginal progesterone treatment which is a natural hormone available in
a pessary, one pessary, one tablet basically in the vagina each night, and that
reduces the risk of preterm birth by about a half.

Norman Swan: And it's safe for the baby?

John Newnham: We believe it's safe to the baby. It has been in

use…progesterone has been in use for about 50 years one way or another. We
need better safety data going well into childhood, but at the moment it's natural
vaginal progesterone and we are operating on the assumption at the moment
that it's safe.

Norman Swan: And also if the cervix is super-short, then there are surgical
interventions that you can do.

John Newnham: Yes. So if the cervix is very short, if it's surprisingly short, we
have available to us, as we have had for quite a long time, the idea of surgically
closing the cervix.

Norman Swan: And then women with a history of preterm birth can get
progesterone on a regular basis, that's one of your other interventions.

John Newnham: Yes, so women who have had a previous preterm birth before,
in particular an early one, whether it be spontaneous labour or if the membrane
has ruptured, if we prescribe this progesterone treatment starting at 16 weeks of
pregnancy, our evidence is that that will halve the risk of recurrence.

Norman Swan: And you've got a warning for doctors; don't deliver a baby under
38 weeks unless you really have to.

John Newnham: Yes, so we also had a major push across Western Australian
starting in mid-2014 to make sure that no one delivered a baby before 38 ½
weeks at least without a solid medical or pregnancy indication to do so. So social
delivery or unnecessary delivery before that time is something we were working
very heavily against. What we've done which has been unique is that instead of
targeting just doctors, we targeted the doctors, the midwives, all healthcare
professionals and the women and the families of Western Australia through a
print and social media campaign.

Norman Swan: And smoking?

John Newnham: Yes, smoking is a major risk factor for preterm birth. The
smoking rate in pregnancy in Western Australia and Australia has fallen down to
about 12%, but we've got a lot of work to do because in Aboriginal Australians
the smoking messages have not worked and their smoking rate in pregnancy sits
at about 50%. It's been unchanged the last 20 years. That's an area in which
we've got more work to do in the future.

Norman Swan: And you've got one preterm birth delivery clinic that is
specialising in this area for the state.

John Newnham: Yes, so we only had one tertiary level perinatal centre in
Western Australia, that's at King Edward Memorial Hospital, and we started a
dedicated clinic. The clinic is heavily based on measuring the length of the cervix
and providing appropriate treatment. It's not a big clinic. We aim to provide a
backstop, a final point of referral for very complicated cases…

Norman Swan: But essentially if you're living in Geraldton you'd expect the
obstetrician or the GP to manage this in Geraldton.

John Newnham: Well, a lot of women will either call and we'll give them a
management plan over the telephone with instructions for the doctors out there,
or they will come down for one or two visits and they'll go back home with their
management plan.

Norman Swan: Now, these great plans often fall over in implementation. This
sounds like a massive project.

John Newnham: Well, it was, but it was done by a small number of people. So
the most important thing we needed to do was to get the message out across all
of Western Australia. Western Australia is ideal for this, it's a medical island, with
desert to the right and ocean to the left. We have one tertiary level centre, so
everybody knows each other, everybody relates to each other. So we put
together an outreach team consisting of myself, a junior obstetrician, our chief
ultrasound imaging person, and one or two of our specialty midwives, and we
over a period of 15, 16 months did a lap of Western Australia, we travelled more
than 14,000 kilometres and we ran the evening workshops. More than 500
healthcare practitioners attended these workshops in their own hospital, so that
we knew that everybody knew exactly what this plan was.

Norman Swan: So can it work in New South Wales or Victoria where big
hospitals don't talk to each other and compete with each other?
John Newnham: Well, we hope to spread this out. And now we've demonstrated
in Western Australia that it has worked, we hope now to spread this out over into
eastern Australia, and that's my work for 2017.

Norman Swan: And it's affordable?

John Newnham: Well, it's actually very cheap. So the dedicated new clinic was
funded by the Minister for Health on a block grant, and the business case that we
presented to the Minister showed that the entire clinical service would be paid in
a year by just preventing two early preterm births. So that's very easy to
demonstrate. Then the outreach program actually doesn't cost very much money,
but it was funded by philanthropy, so the McCuskers and Nicola and Andrew
Forrest, and all through the Women and Infants Research Foundation funded it,
but actually it does not cost much money. The media helped. We won prizes in a
thing called the Orange Seed Competition, and so the West did a lot of free
advertising for us. And we use social media of course, which is free.

Norman Swan: So we look forward to the national spread. John Newnham,

congratulations, and thank you for joining us on the Health Report.

John Newnham: Thank you very much Norman.

Norman Swan: John Newnham is founder and chair of the WA Preterm Birth
Initiative, and executive director of the Women and Infants Research Foundation
in Perth.

Work done at the University of Aberdeen in Scotland has developed for modern
IVF treatment what we think is quite a reliable predictor of the chances of a live
birth. A very controversial topic. On the line from Aberdeen is the lead author of
this paper, Dr David McLernon, who is a research fellow in medical statistics.
Welcome to the Health Report.

David McLernon: Hi Norman, nice to speak to you.

Norman Swan: What are the elements of the prediction here?

David McLernon: Okay, so what we did was we developed two novel online
calculators. The first one uses information from the couple that's available before
they actually start IVF, such as the age of the woman and the diagnosis of their
fertility problem. We use that to predict their overall chance of having a baby over
an entire package of IVF treatment.

And then there's a second calculator which then updates these predictions using
further information that's available after the first attempt such as the number of
eggs that were collected, and the number of embryos that were transferred.

Norman Swan: And of course what's called cryopreservation, because there is

increasing evidence which is not there in other predictors which is that frozen
embryos seem to do better than fresh embryos.

David McLernon: Yes, so we also included cryopreservation status of embryos.

There are quite a few trials going on globally at the minute to compare the effect
of fresh and frozen embryo transfers, and I think one or two of them have results
already that show that the live birth rates are no worse with frozen embryos.

Norman Swan: So just take us through some of these factors in your calculator.
So a woman's age, you compared a woman who is aged 31 versus 37.

David McLernon: Yes, that was only to present the results in a clear manner.
We used all women's ages…

Norman Swan: I'm sure, but this is an example so people can hook onto it. So if
you are 31 versus 37, your chances were 66% better just for being a bit younger.

David McLernon: Yes, but we all know that the effect of women's age on the
chances of having a baby decline from around the age of 30 onwards, and they
get worse from about 35 to 50.

Norman Swan: And duration of infertility pre-treatment also had a predictive

value.

David McLernon: Yes. So obviously the longer you've been trying to get
pregnant the more your chances of having a baby.

Norman Swan: What about post-treatment predictors? So the number of eggs

collected?
David McLernon: Yes, so we showed that the more eggs that you've collected in
your first IVF attempt increase your chances of having a baby. Up until around
13, 14 eggs and at that point then your chances actually stay quite steady with
further eggs that are collected.

Norman Swan: And having a frozen embryo makes a huge difference.

David McLernon: Yes…

Norman Swan: Almost doubles your chances.

David McLernon: Yes, it does, that's just a marker of the quality of the embryos
that the women have. So the more embryos you have that are top-quality, the
more chance of having enough left over after your fresh embryo transfer to
freeze to use later on.

Norman Swan: You illustrate this with a case study. So one is pre-treatment, a
30-year-old woman with two years of unexplained infertility. What are her
chances?

David McLernon: Okay, so we showed that her chance of having a baby after
the first complete cycle of IVF was 46%. Over three complete cycles it's 79%.
When they say complete cycle we are including all embryo transfers, that's about
one episode of ovarian stimulation.

Norman Swan: And the stage at which the embryos transferred also makes a
difference. So then if she has a fresh embryo cycle it drops considerably.

David McLernon: If she has a fresh embryo…?

Norman Swan: So her chances almost halve…you talk about when she has run
out of embryos and there's no freezing, then the chances drop quite dramatically.

David McLernon: Yes, that's because she hasn't got enough frozen embryos left
in order to carry on to increase her chances. It's all a cumulative effect that we
are measuring here with this model. So if you've only got one fresh embryo, your
chances, yes, are quite low.
Norman Swan: So what about the male partner? You've assumed that that's
constant, there's no problem with the male partner?

David McLernon: Yes, unfortunately the national data that we use from the
Human Fertilisation and Embryology Authority, which is the regulatory body for
IVF treatment in the UK, didn't include factors on the males, apart from perhaps
the actual diagnosis of infertility, if it was a male factor problem we were able to
include that information.

Norman Swan: And you didn't include intracytoplasmic sperm injection, which is
almost universal in the Australian context.

David McLernon: We actually did include that as well in the model…

Norman Swan: But it didn't make a difference?

David McLernon: In the post treated model, it showed that…ICSI is

intracytoplasmic sperm injection where they inject the sperm into the egg, we
showed it just marginally had a slightly lower effect compared to IVF.

Norman Swan: Interesting. So time will tell whether this applies to the Australian
context. Lots more questions to ask but unfortunately we have run out of time.
Thanks very much for joining us.

David McLernon: Okay, thanks.

Norman Swan: Dr David McLernon who is a research fellow in medical statistics

at the University of Aberdeen, my alma mater.

I'm Norman Swan, you've been listening to the Health Report. Please join me
next week.