There’s a famous quote from the screenwriter William Goldman on the limits of knowledge about the movie business:
“Nobody knows anything. Not one person in the entire motion picture field knows for a certainty what's going to work. Every time out it's a guess and, if you're lucky, an educated one.”
That quote applies better than we’d like to think when it comes to medicine.
We certainly have some knowledge about the human body and doctors definitely know a lot of information about the risks and benefits of different medical treatments.
But certainty about what we know is hard to come by. And things happen all the time that are useful for reminding us about the limits of our understanding of a system as complex as the human body.
The impetus to talk about the limits of our knowledge is a recent study looking at a traditional Chinese medicine compound called Tongxinluo.
The study itself and the editorial response to the study are interesting windows into the scientific method and the progression of knowledge.
Tongxinluo is a compound use in traditional Chinese medicine that seems to improve outcomes after a heart attack
Tongxinluo is a traditional Chinese medicine compounded ingredient composed of powders and extracts from multiple plant and insect products:
“Tongxinluo is a mixture of ingredients extracted, concentrated, and freeze-dried from 7 plant and 5 animal products, including the dried bodies of cockroaches, centipedes, leeches, cicadas, and scorpions.”
The fact that Tongxinluo is composed of a variety of inputs makes studying it challenging - we don’t know which ingredient or combination of ingredients is responsible for the effect (which leads to confusion about proportions of ingredients and the scalability of widely prescribing a substance like this).
In 2006, the Cochrane Collaboration actually did a review of Tongxinluo and found that the quality of evidence at that time was not high enough to comment on its effectiveness or safety profile.
That makes sense - it’s expensive to study heart disease outcomes in a high quality way, and the financial incentives aren’t there for a traditional Chinese medicine compound.
But for a compound to be used for hundreds of years and continue to be investigated and used, it makes me suspect that there’s been enough experiential success that it’s worth further study before we just dismiss it as not having benefit because no one has shown it to have a benefit.
This is the old “absence of evidence is not evidence of absence” argument, but at some point, you have to actually generate evidence.
Enter the CTS-AMI Trial - a high quality study demonstrating the effectiveness of Tongxinluo in patients after a heart attack
This study took about 3800 patients who had a type of heart attack called a STEMI and randomized half of them to receive Tongxinluo and half to receive placebo.
These were sick patients - they just had a heart attack, after all - but they weren’t the sickest patients. These patients weren’t in shock, didn’t have heart failure, and only about 20% had diabetes.
Only about half of them were placed on beta blockers as well as ACE inhibitors or ARBs, which are considered standard of care after a heart attack.
More than 90% of patients received statins and two antiplatelet medications.
CTS-AMI showed an improvement in 30 day outcomes, which was driven by a reduction in cardiac death and a reduction in heart attacks:
There’s a trend towards a reduction in death from any cause that just barely missed statistical significance. And it seems like the reduction in death from cardiovascular disease persists up to a year:
All in all, a pretty impressive finding for a new compound - I am both impressed and surprised!
Does one study like this change practice? It depends on who you ask
Am I ready to prescribe Tongxinluo to every post heart attack patient? Absolutely not, but I’m certainly intrigued.
No single study should completely revolutionize your clinical practice unless you’re more gullible than you should be, but new research certainly changes assumptions about how likely this treatment is to be effective when it’s studied further.
It’s certainly worth noting that patients weren’t well treated with beta blockers and ACE inhibitors or ARBs - only half were on them.
I would be really interested to test Tongxinluo as an additive agent on top of the current standard of care rather than instead of the current standard.
The editorials published alongside the article also comment on the lack of clarity regarding the active ingredient or mechanism of action as well as concern about the generalizability to a non-Chinese population.
The isolated ingredient argument is an interesting one that reflects a difference in the traditional reductionist approach to the scientific method versus a more holistic one.
The holistic argument - the synergistic effect of the ingredients together is what has the impact
The counter - maybe some of the substances in Tongxinluo have all of the beneficial effect and other parts of it are either neutral or actively harmful
It’s impossible to sort out these arguments right now, but more study may provide insight there.
There’s precedent for isolating a traditional Chinese medicine ingredient applied to Western medicine
The malaria drug artemisinin was originally isolated from qinghaosu, an herb used in traditional Chinese medicine, and its discovery won the Nobel Prize in 2015.
So the desire to take a holistic or traditional treatment and isolate the active ingredient has precedent and is going to be the natural next step that almost all doctors want to take here before they prescribe Tongxinluo to any post heart attack patient.
But it’s worth thinking about Tongxinluo in the context of a recent study publicized at the European Society of Cardiology meeting earlier this year, looking at another traditional Chinese medicine, qiliqiangxin, that showed an improvement in outcomes for heart failure patients.
There is a huge amount about biology that we don’t know.
And the way that traditional approaches to disease treatment (like Chinese medicine or Ayurveda) are often dismissed by Western doctors wholeheartedly is probably throwing out the baby with the bathwater.
Just because we don’t understand the biology doesn’t mean that we should ignore a trial
When I read about the CTS-AMI trial and the somewhat dismissive reaction to it, the first place that my mind went was to the biology of triglyceride lowering and fish oil.
A few months ago I wrote about how our current understanding of the mechanisms of disease can lead us to be overly confident about the impact of an untested therapy and put the cart before the horse when it comes to results from a to-be-published study:
Don't fall in love with the biology
The point in that piece was that we can’t assume a trial is going to be positive because it fits with our current understanding of how the science “should” work.
For a treatment to be useful, it has to show a real benefit, not a theoretical benefit.
The converse is also true - when a treatment is shown to have a real benefit, we shouldn’t dismiss it because it doesn’t also have a theoretical benefit.
Sometimes the science starts with understanding the mechanism and developing the treatment.
But in the case of Tonglinxuo, I wonder whether things will go in the opposite direction - development of treatment, followed by a better understanding of the biology.