I don’t think the reanalysis added anything. Those inclined to be sceptical would already regard the evidence for use to be weak, due to lack of any mortality benefit. It’s easy to hint about theoretical harms, bias, and tell a story about how difficult it was to get the data. But that’s not science. Legitimate researchers can almost always obtain the full datasets and study reports of approved drugs, so I sense there is also exaggeration to put a darker context on the situation.
Dr Mandrola: how did you get started, and then skilled, at critical appraisal?
You had mentioned in one of your podcast episodes that you had not been so interested in research for the first decade or so of practice. What was your inspiration and how did you get started? I'm assuming that at first your critical appraisal skills were on par with that of the average physician.
"It's hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions." - Original paper's author
Debunking a paper you don't agree with is easy. You just say that it is "fundamentally flawed". Done
of course we are measuring LDL - the " taxi" , not cholesterol. Those who hold of the cholesterol theory of heart desease hold that the size of the LDL particles matters , small is a problem, not big ,so what was checked. When we don't feel bound to follow Big Pharma protocols and narratives that push statins, we realize that cholesterol is not a problem , unless you have damaged arteries cholesterol cannot get in , cholesterol is a " marker" , not the " maker ".
"It is really hard to understand how this much cholesterol reduction, and MI and stroke reduction, and reduction in the need for stents or bypass, does not improve survival."
Now, I havent opened the dataset and dusted off my book of epidmiologic statistics yet to thoroughly comb through for myself - but feel strongly data is inconclusive and further studies are needed. I would be curious to perform additional studies evaluating the same all cause mortality and potential association to vaccination/booster status... and potential for secondary systemic autoimmune deficiencies or disorders that could be impacting the new(er) trials?
We are scientists, we are healthcare, and we are nurses. It is our responsibility to save our nation from ourselves, and preserve professional integrity.
The elephant lurking unremarked in the corner of the room is, of course, the possibility (some would say probability) that the cholesterol theory of heart disease is hogwash.
If you have devoted an incredible amount of time, thought , and energy to making a trial as perfect as possible including utilizing the premier CEC in a blinded fashion for adjudication I can empathize with the investigators concern about sharing the CSRs.
Once the CSRs are handed out the trial investigators have no assurance (as there was with the initial CEC) that the investigators would have the same level of integrity, diligence, consistency and honesty.
That being said, I wish, as you say, that "practice-changing" studies were reviewed by qualified and unbiased experts. Fortunately, in cardiology we have you to keep investigators honest!
Thanks for your comments on this study. When I first heard this story I wondered how this independent group came up with different adjudication of the deaths. I thought that perhaps the first group adjudicating the cause of death was somehow biased.
Dr. Sabatine does a great job of explaining why there might be differences. And Steve Nissen points out
“The cardiovascular outcomes in the FOURIER trial were adjudicated by the clinical events committee [CEC] at the TIMI Group,” Nissen told TCTMD. “The CEC members were blinded to treatment assignment. The CEC at TIMI is one of the world’s most experienced adjudication teams, and their process has been audited by many external groups. I have great confidence in the integrity of the TIMI group and find it inconceivable that bias was present in their adjudication.”
So while I'm all in favor of transparency and independent review I don't think this particular paper should change our appropriate use of PCSK9 inhibitors. I've been a slow adopter due to cost concerns and other factors but for many of my patients I feel they have been life saving.
"It is really hard to understand how this much cholesterol reduction, and MI and stroke reduction, and reduction in the need for stents or bypass, does not improve survival."
First, define how "reduction in the need for stents or bypass" is calculated, precisely.
I will posit that an EF of 55% with two arterial restrictions exceeding 70% is an ordinary finding. A further bold, yet uncontroversial, assertion is that there are no approved pharmaceutical interventions for reducing arterial plaque.
Now consider the pivot away from revascularization in response to drug trials, even when the degree of arterial occlusion clearly indicates intervention is required.
Finally, consider the everyday practice of cardiology, and its dependence on echocardiogram in discovery of arterial restriction.
Now explain why CT and MRI reveal arterial restrictions that have been missed by years of periodic echocardiogram testing.
Occam's Razor can only be properly applied when all of the situational attributes are taken into consideration.
1) as a layman I am curious and suspicious that the FDA will not release the CSR data to serious doctors, scientists, and reporters for independent evaluation; 2) when Sabatine rolls out the 'disinformation' charge, it is an immediate flag that signals concern about his intererst/ability to argue the RIAT analysis. It appears to all boil down to a disagreement on how to classify various adverse events and deaths. For the benefit of your readers, could you please request a response from the RIAT authors to Sabatine? I ask because when I forwarded the RIAT findings to my cardiologist, he sent back the above referenced article. Surely the lipogenic community is getting hot under the collar about ANY criticism. Thank you.
I don’t think the reanalysis added anything. Those inclined to be sceptical would already regard the evidence for use to be weak, due to lack of any mortality benefit. It’s easy to hint about theoretical harms, bias, and tell a story about how difficult it was to get the data. But that’s not science. Legitimate researchers can almost always obtain the full datasets and study reports of approved drugs, so I sense there is also exaggeration to put a darker context on the situation.
Dr Mandrola: how did you get started, and then skilled, at critical appraisal?
You had mentioned in one of your podcast episodes that you had not been so interested in research for the first decade or so of practice. What was your inspiration and how did you get started? I'm assuming that at first your critical appraisal skills were on par with that of the average physician.
Was the placebo in the trial inert?
"It's hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions." - Original paper's author
Debunking a paper you don't agree with is easy. You just say that it is "fundamentally flawed". Done
of course we are measuring LDL - the " taxi" , not cholesterol. Those who hold of the cholesterol theory of heart desease hold that the size of the LDL particles matters , small is a problem, not big ,so what was checked. When we don't feel bound to follow Big Pharma protocols and narratives that push statins, we realize that cholesterol is not a problem , unless you have damaged arteries cholesterol cannot get in , cholesterol is a " marker" , not the " maker ".
"It is really hard to understand how this much cholesterol reduction, and MI and stroke reduction, and reduction in the need for stents or bypass, does not improve survival."
Now, I havent opened the dataset and dusted off my book of epidmiologic statistics yet to thoroughly comb through for myself - but feel strongly data is inconclusive and further studies are needed. I would be curious to perform additional studies evaluating the same all cause mortality and potential association to vaccination/booster status... and potential for secondary systemic autoimmune deficiencies or disorders that could be impacting the new(er) trials?
We are scientists, we are healthcare, and we are nurses. It is our responsibility to save our nation from ourselves, and preserve professional integrity.
Thank you, again, for your clear writing.
The elephant lurking unremarked in the corner of the room is, of course, the possibility (some would say probability) that the cholesterol theory of heart disease is hogwash.
If you have devoted an incredible amount of time, thought , and energy to making a trial as perfect as possible including utilizing the premier CEC in a blinded fashion for adjudication I can empathize with the investigators concern about sharing the CSRs.
Once the CSRs are handed out the trial investigators have no assurance (as there was with the initial CEC) that the investigators would have the same level of integrity, diligence, consistency and honesty.
That being said, I wish, as you say, that "practice-changing" studies were reviewed by qualified and unbiased experts. Fortunately, in cardiology we have you to keep investigators honest!
Interesting to see this! I funded the RIAT Initiative several years ago while at Arnold Ventures.
Brilliant! Thank you!
John,
Thanks for your comments on this study. When I first heard this story I wondered how this independent group came up with different adjudication of the deaths. I thought that perhaps the first group adjudicating the cause of death was somehow biased.
But this is not the case as this excellent TCTMD article (https://www.tctmd.com/news/study-alleges-mortality-miscount-fourier-trial-timi-group-disagrees) reveals.
Dr. Sabatine does a great job of explaining why there might be differences. And Steve Nissen points out
“The cardiovascular outcomes in the FOURIER trial were adjudicated by the clinical events committee [CEC] at the TIMI Group,” Nissen told TCTMD. “The CEC members were blinded to treatment assignment. The CEC at TIMI is one of the world’s most experienced adjudication teams, and their process has been audited by many external groups. I have great confidence in the integrity of the TIMI group and find it inconceivable that bias was present in their adjudication.”
So while I'm all in favor of transparency and independent review I don't think this particular paper should change our appropriate use of PCSK9 inhibitors. I've been a slow adopter due to cost concerns and other factors but for many of my patients I feel they have been life saving.
Dr. P
Thank you! So clearly written. Whenever I hear anyone say “…but the research shows…” I make this face 😏.
We need pharma-Snopes !
"It is really hard to understand how this much cholesterol reduction, and MI and stroke reduction, and reduction in the need for stents or bypass, does not improve survival."
First, define how "reduction in the need for stents or bypass" is calculated, precisely.
I will posit that an EF of 55% with two arterial restrictions exceeding 70% is an ordinary finding. A further bold, yet uncontroversial, assertion is that there are no approved pharmaceutical interventions for reducing arterial plaque.
Now consider the pivot away from revascularization in response to drug trials, even when the degree of arterial occlusion clearly indicates intervention is required.
Finally, consider the everyday practice of cardiology, and its dependence on echocardiogram in discovery of arterial restriction.
Now explain why CT and MRI reveal arterial restrictions that have been missed by years of periodic echocardiogram testing.
Occam's Razor can only be properly applied when all of the situational attributes are taken into consideration.
More grist for the mill not to trust the results of “peer reviewed” research.
It seems you struck a nerve with the researchers AND the clinical events committee at TIMI: https://www.tctmd.com/news/study-alleges-mortality-miscount-fourier-trial-timi-group-disagrees
1) as a layman I am curious and suspicious that the FDA will not release the CSR data to serious doctors, scientists, and reporters for independent evaluation; 2) when Sabatine rolls out the 'disinformation' charge, it is an immediate flag that signals concern about his intererst/ability to argue the RIAT analysis. It appears to all boil down to a disagreement on how to classify various adverse events and deaths. For the benefit of your readers, could you please request a response from the RIAT authors to Sabatine? I ask because when I forwarded the RIAT findings to my cardiologist, he sent back the above referenced article. Surely the lipogenic community is getting hot under the collar about ANY criticism. Thank you.