CaPPtain's Blog

  • CaPPtain's Blog: John Burn, August 2018

    posted on Thursday, 25th October 2018

    Not tagged.

    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

  • CaPPtain's Blog: John Burn, June 2018

    posted on Monday, 4th June 2018

    Not tagged.

    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

Latest News

bentley gt dark sapphire watch officine panerai firenze 1860 divers professional op 6541 uk replica watches iwc replica watches reviews valjoux 7730 replica watches uk tag formula 1 calibre 16 price baselworld 2018 rolex predictions fake watches oyster perpetual datejust breitling a24322 movement replica watch vendome hublot geneve collection 582888 price iced out rolex watches for sale fake watches