posted on Thursday, 25th October 2018
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In July 2018, the Lancet published an important article about
the health benefits of aspirin by an international team led by
Peter Rothwell of Oxford. It contained important new information
yet it received little media attention. The reason, I think, was
that it was complicated. The authors noted that the benefits of
long term aspirin in prevention of heart attacks and strokes were
not as great as some early work would have suggested and they set
out to investigate the effects of dose, age and gender. The idea is
that we can use these combined historical data to estimate the best
dose for a person of a particular size, age and gender. The general
accepted wisdom is that even a little aspirin is enough to
permanently inactivate platelets, even though the drug is broken
down as soon as it reaches the liver in the circulation from the
gut. A reanalysis of more than 117,000 people who took part in 10
clinical trials revealed a complicated story. The low dose now
commonly used of between 75 and 100mg per day was only effective in
smaller people and was not protective in larger or heavier people.
This seemed to be an effect of body size rather than a result of
being simply overweight as it was found to relate to height as well
as weight. Using a full size aspirin tablet of 325mg or more
reversed the effect; there was a protective effect among people
over 70kg (11st) whereas the smaller people, more often female, did
worse on the bigger doses than the control group, that is that
cardiovascular events were slightly more common among aspirin
takers than among people not taking aspirin. The take home message
was that the cardiovascular benefits of aspirin are dose dependent
but that you can have too much of a good thing. Spreading a larger
dose over a twice daily dose seemed to be beneficial.
The second part of the study looked at cancer rates in the five
trials where this was possible (we must remember that these trials
did not involve people with Lynch Syndrome, more about this later).
Again, there was evidence of a dose effect. First, they looked at
the 20 year influence on colorectal cancer. The 75-100mg dose was
protective against colorectal cancer only in those who were under
70kg whereas the 325mg group saw protection up to 80kg also.
This fits with our report in 2015 that the risk of cancer was
increased in the CAPP2 study in people who were overweight and that
this effect was reduced by those who were in the 600mg aspirin
treatment group.
Finally, they looked at the short-term cancer rates and found
that there was no overall short term effect on either incidence or
mortality. Rumour has it the Oxford team will be publishing a more
detailed analysis of the cancer data.
What does this all mean for CaPP3? First, it reinforces the case
for our trial. Clearly there is still much to learn about the
optimal dose of aspirin. CaPP3 will help target the groups who will
benefit most and identify the best dose. As I mentioned above, the
trials included in this analysis consisted of a random set of the
general population, whose lifetime risk of bowel cancer is much
less than for a person with Lynch Syndrome. The effects on
cardiovascular risks are relatively small so there are no major
ethical concerns for people in the target group for CaPP3
recruitment, namely adults with Lynch Syndrome. In absolute terms,
the effects of body size and age are relatively small, which is why
they have taken so long to be discussed, so we should not change
the design of CaPP3 at this late stage when we are close to the end
of recruitment. The case for the CaPP3 trial continuing is
increased as we need to know more about how to choose the right
dose and duration.
John Burn
August 2018
posted on Monday, 4th June 2018
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Welcome to the CaPPtain's blog. I'm feeling in
Churchillian mood; we have now consented 1305 people in the UK to
take part in CaPP3. Our four international partners are all
now recruiting. Finland have 63, Australia have 81, Israel
have 2 and Pamplona in Spain have just started and have randomised
4 people. This gives us a grand total of 1455 recruits.
To paraphrase Winston, as we approach our minimum target of 1500,
is that this is not the end, nor is it the beginning of the end but
it is perhaps, the end of the beginning!
Please pass on our thanks to all the people who have agreed to
test the three aspirin doses. Thanks also to the recruiters
too numerous to name here, to the Trial Steering Committee and the
Data Monitoring Committee, to my co-investigators and our central
office led by Gill Borthwick who are constantly at work to keep the
wheels on the trial. We expect to pass the first recruitment
milestone in the autumn with 1500 international recruits. But will
ask to be allowed to keep recruiting in the UK until the end of
2018, when hopefully we will have the 1500 UK recruits. A
major reason for this is that our drop-out rate has been higher
than expected. In CAPP2 we had a 20% withdrawal, but in CaPP3
we are running at 26% withdrawal before the two year follow
up. The design change to allow us to invite people to remain
on their respective doses in the open phase will, to some extent,
make up for the loss of power, but it would be good to think about
what factors are influencing people to withdraw.
The famous "confetti" produced by the blister packed aspirin in
the blinded phase is often discussed on the Lynch Syndrome Facebook
page, but we can't do anything about that as it's part of the
original design. The size of the packets is also an issue we
can't change. We are open to suggestions from any and all of
the CaPP community on how we can help to keep people in the study
and taking their tablets at least until the 2 year mark. It
would be a great shame if we went to all this trouble only to be
criticised for lacking the statistical power to decide which is the
best dose. It is worth reminding ourselves, that this is a
once in a lifetime opportunity to get a meaningful answer which
will influence the use of aspirin to prevent cancer for many years
to come. If you are talking with a participant who is
thinking of stopping, please talk through with them their reasons,
especially if in relation to an adverse event. It may be that
a short break to allow for external issues to be resolved will
allow the participant to restart. We realise that some participants
find it difficult taking pills every day, or often don't remember
to take their evening dose. Discuss with them ways of remembering
to take their pills, or suggest that they are taken once a day.
This is vital to being able to make best use of the
data we collect in coming years.
It is also important to be clear that we can continue to collect
information even if a person doesn't want to continue taking the
tablets. We think that taking aspirin for even a short time
may have a useful effect, but we can only prove this if we retain
the ability to follow up people who have been randomised. For
the reader unfamiliar with the way trials are analysed, great
importance is attached to an analysis called "Intention to Treat".
This means we have to look at all the data and include all the
people who started the trial. If we lose access to the
medical data, the whole trial is weakened.
But let's end on a positive note. We are doing the biggest
genetically targeted therapeutic prevention randomised trial ever
attempted and we are going to make our ambitious recruitment
target. We are keeping the issue of aspirin as a cheap
practical means of cancer prevention in the consciousness of
clinicians and regulators. Cancer Research UK have awarded a
£5million Catalyst grant to a research consortium led by Professor
Jack Cuzick, of which we are a key member. This will allow us to
dig deeper into the mechanism of aspirin effect and explore ways to
minimise adverse effects and target aspirin prevention more
effectively.
Thank you all again for your hard work and support.
John Burn
June 2018