JAMA published a study showing major benefits of a pill given to patients after heart attack. Instead of celebration it has received serious criticism. Why?
I’ve often pondered why we accept as standard of care drugs or therapeutics that have single digit absolute risk benefit? That means 90% of patients get no benefit?? Most blockbuster drugs fall into this category
It does seem that patent-title and the rent-seeking that follows is the major driver of "research"
Western taxpayers fund basic research then the patentable bits are cherry picked and the government that taxes the people then stops them using things they paid to research unless they pay way over the odds because of an artificial shortage.
Agree with Dr Mandrola. If it were a pill from a western pharmaceutical co. the reaction might have been different. I’m not surprised by the components of the pill. Remember that foxglove, salix alba vulgaris and penicillium notatum among many, have given us wonder medications.
I’ll go you one further on PARADIGM: How do you know all the data was released? It is not uncommon for drug companies to cherry pick and, in studies where the “evidence” is marginal, there should be even greater concern that the numbers were bent.
Some oncologists switched cancer therapies for curable rectal cancer based on this PILOT STUDY of 14 patients. The media coverage was so intense that it reached my daughter’s Instagram feed.
It’s hard to balance enthusiasm for the possible with the reality of evidence based practices.
In reading through this checklist of what makes a good trial I couldn't help but think about how disastrous the Covid vaccine trials really were. So what you have here is a new drug candidate in an RCT with a pretty large number of participants. There's a reduction in heart conditions at one year on the drug and also a small reduction in all cause mortality, meaning less people died in the treatment arm from anything else. There's a low dropout rate of participants, which indicates that side effects of the drug are tolerable and it appears that this compound was a follow on from traditional Chinese approaches to angina. I think people put too much emphasis on understanding a mechanism of action in what remains very complicated processes within the human body. I wonder if the researchers extreme caution is due to a follow the money thing going on behind the scenes.
Is it perfect? Of course not. There's always limitations. But let's compare this to the Covid vaccine trials. There was a large N in the main adult trials, but followups for new variants have been conducted on as few as eight mice. There was no history of mRNA being used successfully. The reduction in Covid specific mortality was based on one extra Covid death in the placebo group. There's evidence of increased all cause mortality and very high drop out rates indicating intolerable side effects to treatment and evidence that Pfizer et al might have even hidden some bodies and didn't use the same compound in their end product. It boggles the mind that this was passed off for science when it was 100% marketing...
Well I agree that the skepticism is skewed a lot. But China is notoriously bad at doing reliable RCTs when it comes to anything traditionally Chinese, they are very biased in proving traditional medicine, even when it is not traditionally Chinese like acupuncture and homeopathy. Almost everything that comes from China that deals with traditional Chinese "medicine" tends to skew positive and are often great educational examples of cherrypicking and questionable research practices as the plausibility of those drugs is so far at the bottom that it is zero. So their excessive skepticism is completely justified. But your point that this kind of skepticism is often absent with "western" pharmaceutical RCTs for things that are almost equally implausible is also verg much justified. I think that first time positive trials with small effect sizes should always deserve a lot of skepticism, and probably all other first time RCTs as well. I didn't find the effect size of this RCT all that spectacular to begin with, the relative risk reduction seems nice but the absolute risk reduction like with so many cases is not spectacular at all. 36% reduction or 1.6% is a big difference when it comes to practical significance.
In various fields that I follow with some consistency, the PRC is flooding the market with questionable studies. The idea that anyone would take alleged data from the Chinese Communist Party at face value is most troubling. Research from an untrustworthy dictatorship should have a prominent asterisk beside it.
And drywall in supplements and the disappearance of the early reporters on social media of the Covid devastation in China . American companies fleeing Hong Kong . Cannot trust anything I am afraid
Yes. I actually watched them live on Tik Tok before TT became crazy. The videos were from overwhelmed hospitals, and lots of deaths. The citizen journalist disappeared. A google search can find his name. Those videos are gone. I wish I was smarter. I told my wife that there is this crazy virus and it looked like the contagion movie on TT. It was surreal. If i was smarter I would have cashed out my 401k........ They were the early days in wuhan
I am not a research cardiologist, but it only makes sense to me that trial results that are not replicable would keep a drug OFF the market; there’s obviously something amiss. I am also having difficulty with the two other examples: exhibit A seems a no-brainer. Exhibit B seems to show a marked difference in results. Am I reading it wrong? Where can one see the trial info? RE: undertsanding the mechanism of function…..how about that acetaminophen? And was or was not chemical analysis used to determine the actual functional susbstances in the treatment; using a term like ‘insect parts’ just smacks of the sort of write-ups that the latest ‘wonder’ treatments get in click-bait ads. No knowledge of a substance means no proprietary ownership, sure to condemn it in this country.
At least in the abstract, it doesn't say where the study was done, but China is implied. If so, the data deserve to be doubted: might have come from a wet market. But hey--there's little reason not to try it out. If it only takes 55 NTT to start seeing a positive effect, things should start to look pretty definite after ~ 1,000 patients. Beyond that, you're just decreasing the p value. If you ~don't~ see a difference by then, wet market.
But really, the origin(s) of the things comprising the "compound" are irrelevant. Comes from insects? So what? Lots of antibiotics come from molds, anticoagulants from leeches--which, I might add, are still in the USP [U. S. Pharmacopaeia--yes, really] and are used mostly by plastic surgeons, etc.
Our British colleagues noted the bias in studies involving traditional Chinese medicine. The Communist Party has put pressure on researchers to show the benefits of traditional Chinese medicines. Data sharing is needed.
I’ve often pondered why we accept as standard of care drugs or therapeutics that have single digit absolute risk benefit? That means 90% of patients get no benefit?? Most blockbuster drugs fall into this category
Thanks for putting it simply- Hardly a blockbuster if only 10% get any benefit ! Wild
Follow the money! Drug companies will not have huge profits.
It does seem that patent-title and the rent-seeking that follows is the major driver of "research"
Western taxpayers fund basic research then the patentable bits are cherry picked and the government that taxes the people then stops them using things they paid to research unless they pay way over the odds because of an artificial shortage.
Agree with Dr Mandrola. If it were a pill from a western pharmaceutical co. the reaction might have been different. I’m not surprised by the components of the pill. Remember that foxglove, salix alba vulgaris and penicillium notatum among many, have given us wonder medications.
I’ll go you one further on PARADIGM: How do you know all the data was released? It is not uncommon for drug companies to cherry pick and, in studies where the “evidence” is marginal, there should be even greater concern that the numbers were bent.
Some oncologists switched cancer therapies for curable rectal cancer based on this PILOT STUDY of 14 patients. The media coverage was so intense that it reached my daughter’s Instagram feed.
It’s hard to balance enthusiasm for the possible with the reality of evidence based practices.
Great nuanced take. I enjoyed reading this.
Hmmm. Now I'm wondering if I'd get any cardiovascular benefits from eating that bug on the floor over there...
In reading through this checklist of what makes a good trial I couldn't help but think about how disastrous the Covid vaccine trials really were. So what you have here is a new drug candidate in an RCT with a pretty large number of participants. There's a reduction in heart conditions at one year on the drug and also a small reduction in all cause mortality, meaning less people died in the treatment arm from anything else. There's a low dropout rate of participants, which indicates that side effects of the drug are tolerable and it appears that this compound was a follow on from traditional Chinese approaches to angina. I think people put too much emphasis on understanding a mechanism of action in what remains very complicated processes within the human body. I wonder if the researchers extreme caution is due to a follow the money thing going on behind the scenes.
Is it perfect? Of course not. There's always limitations. But let's compare this to the Covid vaccine trials. There was a large N in the main adult trials, but followups for new variants have been conducted on as few as eight mice. There was no history of mRNA being used successfully. The reduction in Covid specific mortality was based on one extra Covid death in the placebo group. There's evidence of increased all cause mortality and very high drop out rates indicating intolerable side effects to treatment and evidence that Pfizer et al might have even hidden some bodies and didn't use the same compound in their end product. It boggles the mind that this was passed off for science when it was 100% marketing...
Well I agree that the skepticism is skewed a lot. But China is notoriously bad at doing reliable RCTs when it comes to anything traditionally Chinese, they are very biased in proving traditional medicine, even when it is not traditionally Chinese like acupuncture and homeopathy. Almost everything that comes from China that deals with traditional Chinese "medicine" tends to skew positive and are often great educational examples of cherrypicking and questionable research practices as the plausibility of those drugs is so far at the bottom that it is zero. So their excessive skepticism is completely justified. But your point that this kind of skepticism is often absent with "western" pharmaceutical RCTs for things that are almost equally implausible is also verg much justified. I think that first time positive trials with small effect sizes should always deserve a lot of skepticism, and probably all other first time RCTs as well. I didn't find the effect size of this RCT all that spectacular to begin with, the relative risk reduction seems nice but the absolute risk reduction like with so many cases is not spectacular at all. 36% reduction or 1.6% is a big difference when it comes to practical significance.
In various fields that I follow with some consistency, the PRC is flooding the market with questionable studies. The idea that anyone would take alleged data from the Chinese Communist Party at face value is most troubling. Research from an untrustworthy dictatorship should have a prominent asterisk beside it.
And drywall in supplements and the disappearance of the early reporters on social media of the Covid devastation in China . American companies fleeing Hong Kong . Cannot trust anything I am afraid
Yes. I actually watched them live on Tik Tok before TT became crazy. The videos were from overwhelmed hospitals, and lots of deaths. The citizen journalist disappeared. A google search can find his name. Those videos are gone. I wish I was smarter. I told my wife that there is this crazy virus and it looked like the contagion movie on TT. It was surreal. If i was smarter I would have cashed out my 401k........ They were the early days in wuhan
My thoughts, so far, are that you wrote a clear, scholarly and logical piece and are asking some very good questions !! Much appreciated !
I am not a research cardiologist, but it only makes sense to me that trial results that are not replicable would keep a drug OFF the market; there’s obviously something amiss. I am also having difficulty with the two other examples: exhibit A seems a no-brainer. Exhibit B seems to show a marked difference in results. Am I reading it wrong? Where can one see the trial info? RE: undertsanding the mechanism of function…..how about that acetaminophen? And was or was not chemical analysis used to determine the actual functional susbstances in the treatment; using a term like ‘insect parts’ just smacks of the sort of write-ups that the latest ‘wonder’ treatments get in click-bait ads. No knowledge of a substance means no proprietary ownership, sure to condemn it in this country.
Yes "insect parts" triggers my "spin" detector since the MSM "horse paste" (i,e. Ivermectin 5 minute hate )
I wonder if they look at how they made cochineal.
At least in the abstract, it doesn't say where the study was done, but China is implied. If so, the data deserve to be doubted: might have come from a wet market. But hey--there's little reason not to try it out. If it only takes 55 NTT to start seeing a positive effect, things should start to look pretty definite after ~ 1,000 patients. Beyond that, you're just decreasing the p value. If you ~don't~ see a difference by then, wet market.
But really, the origin(s) of the things comprising the "compound" are irrelevant. Comes from insects? So what? Lots of antibiotics come from molds, anticoagulants from leeches--which, I might add, are still in the USP [U. S. Pharmacopaeia--yes, really] and are used mostly by plastic surgeons, etc.
What's in a name? What's in a place of origin?
How long did we use aspirin for, before we knew it's mechanism of action? All we knew was that it worked and was relatively safe.
Our British colleagues noted the bias in studies involving traditional Chinese medicine. The Communist Party has put pressure on researchers to show the benefits of traditional Chinese medicines. Data sharing is needed.
Regulatory capture. Disclosure: I am an HFpEF patient, skeptical of "amazing new meds," and widow of an even more skeptical radiologist.
https://substack.com/app-link/post?publication_id=516896&post_id=138838196&utm_source=post-email-title&utm_campaign=email-post-title&isFreemail=true&r=27p4dj&token=eyJ1c2VyX2lkIjoxMzM4NjE3MzUsInBvc3RfaWQiOjEzODgzODE5NiwiaWF0IjoxNjk5OTAyNjE3LCJleHAiOjE3MDI0OTQ2MTcsImlzcyI6InB1Yi01MTY4OTYiLCJzdWIiOiJwb3N0LXJlYWN0aW9uIn0.AVDpTGiUWY6Ehqum2gqBJ-qcHLxjNy45nuLoOmeN-aA