Aspirin and prevention-who knows best?
As the UK descends into hysteria around petrol and pasties, I have been reflecting for the last week on Peter Rothwell’s recent Lancet papers about cancer prevention and the role of aspirin. Basically, daily low-dose aspirin not only prevents development of new cancer, but also the spread of cancer. Aspirin is one of the oldest drugs in the drug cabinet of hospital wards and GP surgeries, but we continue to discover more about its roles in medicine. As new evidence appears on the horizon, the information and guidelines for practising doctors and their patients still continues to change. There are inevitably time delays in how quickly new information filters through healthcare settings and broader society, and how it is interpreted by both the patient and the doctor.
Aspirin has several different uses which are proven by large bodies of evidence, including as a painkiller, prevention of cardiovascular disease in people at risk (primary prevention) and people with known cardiovascular disease (secondary prevention) and now for prevention of cancer. I always love to refer back to the Hippocratic Oath, and so we have to weigh aspirin’s harms with these many benefits. The main harm with aspirin is bleeding, particularly people who have a tendency towards bleeding anyway, e.g. individuals with history of gastric ulcers.
Interestingly, as the new data is emerging about the long-term preventive effects on cancer, the use of aspirin for two other indications is in decline due to evidence of not that much good when weighed against the risk of bleeding. First, most doctors do not recommend low-dose aspirin for primary prevention of cardiovascular disease, largely due to available data from meta-analyses showing that it does not change mortality in diabetics or non-diabetics. Second, in patients with atrial fibrillation, a heart rhythm problem which increases risk of stroke, aspirin is no longer recommended, yet most guidelinesaround the world still include it. So while we can recommend aspirin for long-term cancer prevention, we may not be able to recommend it in healthy individuals for long-term stroke prevention.
Evidence-based medicine is following a moving target of diseases and treatments and so the evidence is also always changing, even for drugs as old as aspirin. So for newer drugs, you can begin to imagine how little we know. The challenge is to keep all people, both doctors and patients up-to-date with all available evidence and guidelines. However, we know that this is difficult, given that both doctors do not always follow guidelines and people do not generally like to take tablets. Notably, most news reports covering the “aspirin and cancer” story advised people to go and see their doctor before starting the drug. Fergus Walsh, of the BBC, quoted a notable academic, “Doctors were good at treating disease, but when it came to preventing ill-health then people had to make their own judgements”. I agree. I wonder whether people have as much chance of making the “right decision” themselves. And before you ask, I do not take an aspirin a day yet, but I did start cycling to work again this week. One preventive step at a time.
Inseparable bedfellows: serendipity and research
On the train-ride back from the Joint Annual Medical Research Society/Academy of Medical Sciences/Royal College of Physicians Clinician Scientists in Training Day, I was feeling inspired about basic science research, which does not happen often enough to epidemiologists like me. Every year they invite young researchers to present their findings and invite eminent speakers to encourage the next generation to stick with research. It is rare to go to a meeting where scientists from all disciplines from genetics and haematology to cardiology and epidemiology all present their work, but this meeting works.
I heard about some genuine “bench to bedside” research, from MRI scans to gauge neural function in intensive care patients to novel treatments for liver cirrhosis and metastatic breast cancer. The overall Young Investigator Prize winner was a very deserving Tamir Rashid from Cambridge. His research group has firstly produced stem cells from skin cells, which raises the possibility of not needing donor cells or embryonic cells in future. They have then developed new technology to correct the error in the genetic code in a form of liver cirrhosis (alpha-1 antitrypsin deficiency) using stem cells with the correct code. Finally, they have shown that these cells restored liver function in humans and the therapy is about to be tested in a clinical trial. This is a brilliant example of “bench to bedside” research starting with a hypothesis, testing in animal models and then developing a strategy of treating disease in humans, later to be tested in a trial. But how does research like this happen?
In plenary speeches, Professor Sir John Tooke and Professor Andrew Hattersley repeatedly stressed four important aspects of successful clinical research: good mentors, collaboration, serendipity and patient involvement. Professor Charles Warlow, the eminent stroke researcher, has written that “Good luck should be exploited, and very often barriers can be not just overcome but put to good use as well”.
Turning to Pubmed or to Google, we find countless examples of serendipity in scientific discovery and research. Luck has been important in the development of drugs, whether for cardiovascular diseases, malaria or depression. One of the most fascinating examples of good fortune and medical discovery in my own area of cardiology is the accidental injection of the right coronary artery by Mason Soanes in 1958 which led to the development of coronary angiography, and most of the advances in modern cardiology in the last half-century.
The social scientists refer to healthcare organisations and research organisations as complex adaptive systems(CASs) and as such, serendipity will always play a major role. A recent study looked at researchers' perspectives on “how high impact publications are developed and why they are consistently produced by a small group of researchers”. Interestingly, the researchers consistently found five factors: (1) rules of thumb; (2) these rules of thumb were reinforced by positive feedback from peers and mentors; (3) good communication skills allowing researchers to provide feedback to their peers, thus closing a positive feedback loop; (4) curiosity, open-mindedness and motivation; and (5) randomness and serendipity. The study found, unsurprisingly, that some researchers were better than others at capitalising this randomness. So the message for aspiring researchers, from the available evidence, is to be in the right place at the right time,stick with it if you get lucky, and don't forget to talk to your research team!
Are placebos as good as 'real' antidepressant drugs?
The National Health Service in the United Kingdom spends over 300 million pounds per year on antidepressants (475 million USD).
Last Sunday night the research was discussed in a CBS 60 Minutes report. During her interview, reporter Lesley Stahl challenged Kirsch: "You're saying if (patients taking antidepressants) took a sugar pill, they'd have the same effect?"
Kirsch replied: "They'd have almost as large an effect, and whatever difference it would be, would be clinically insignificant."
Stahl was incredulous. "But people are getting better taking antidepressants, I know them. We all know them."
"People get better when they take the drug, but it's not the chemical ingredients of the drugs that are making them better. It's largely the placebo effect," Kirsch replied.
Kirsch’s research raises many provocative questions. If placebos appear to cure depression, is depression a real disease? How can a sugar pill cure depression? If sugar pills work as well as drugs and have fewer side effects, why not use them?
Nobody doubts that depression can be very serious. (And any patient taking or considering antidepressant medication should consult a qualified practitioner before making treatment decisions.) Instead, it means placebos are particularly good at curing depression. This can be achieved through several mechanisms. The sugar in the pill can influence insulin levels and induce a cascade of physiological effects. Moreover the doctor’s friendly manner, also part of the placebo, has been shown to make mildly depressed patients feel better.
The reason placebos aren’t prescribed is doctors deem them to be unethical. This is because (among other reasons) doctors should only prescribe treatments that are proven to be effective. But effectiveness is often established by demonstrating superiority to placebos; so to prove they are effective, then need to be more effective than themselves, which is impossible. Moreover, as Stahl noted, the ‘real’ drugs have known and serious side effects. So not prescribing placebos might be even less ethical.
Whatever the answers to these difficult questions, surely we can come up with an answer to the placebo ethics dilemma that costs less than 300 million pounds per year. More research, please!