Leaving the question of being ethical or not up to the medical community is ridiculous. After the last 4 years, it does not deserve to decide what is ethical and what is not. I seriously doubt that most trials use a true placebo.
I'm glad you are writing these. Almost every intervention today that is just assumed to work, doesn't actually have proof that it works. Or there is proof it doesn't work.
Often the premise is 180 degrees from the truth. The so-called Serotonin Hypothesis, for instance, is flat wrong. Higher serotonin in the brain correlates with depression, anxiety and other mental illness. Lowering serotonin restores mental health in many cases.
"Second is that nearly everything we do in medicine should pass muster against a proper control arm. That might be a placebo, a sham procedure, or the standard of care. Blinding must be maintained in trials." Sage advice - yet, not to get too tangential, nearly all the vaccines made and placed on the children's schedule since the late 80's have not been RCT 'true' placebo evaluated - none - not a few mls of saline nor a sugar tablet - No joke (as Joe says) - now that's a fun fact
Thank you for this great review! When I was doing primary care internal medicine, I had great difficulty in dissuading my asymptomatic patients and their cardiologists from continuing to do annual sestamibi testing (presumably looking for a stentable lesion). I quoted from the Courage trials, and also referred them to the Choosing Wisely website recommendations for asymptomatic cardiac patients. I had several heated discussion with cardiologists regarding my objections to their annual tests, but in at least a few cases was able to get them to cut down on the frequency of their cardiac tests.
The first thing I do when I see a study I find out who is funding it. Maybe not in this case but even doctors have a conflict of interest. Sadly most people don't know the questions to ask when a medical issue stares them in the face.
Read the book "How We Do Harm" by Dr. Otis Brawley
Great to learn about the upcoming Orbita 2. Looking forward to it.
But more than just the specific findings of the study, was to show the need for sham control as a true placebo in interventional trials….and in particular when looking at “soft” endpoints. Clearly, and disturbingly, the lesson was not learned by the Triluminate investigators (I’m sure they aren’t the first, nor will they be the last). One’s impression of why this may have been so will likely hinge on where one sits on the skepticism-to-cynicism spectrum. At this point, I’m nearly full-scale deflection to the cynicism end.
I suspect that these results will not make a dent in these surgeries, just like othopedic surgeons continue to do surgery that is no more effective than placebo. I imagine it's difficult to conduct trials that involve sham surgeries with large numbers of participants, both because there is no financial incentive to fund such studies, and perhaps it's difficult to recruit patients who may not want to potentially receive a sham surgery, given that all surgeries involve risk, and a sham surgery has no benefit except placebo. Patients are equally conditioned as doctors to believe that surgery is an effective tool. I hope they can figure out exactly WHEN surgery IS actually useful!
Really can not wait until the #2 study is completed since most people have more than one vessel affected. Why should we be so surprised by the results of a placebo when seen in so many other examples in medicine yet when you look at MDs/DOs making huge $$ s from cardiac procedures their minds seek only more dollars rather than the truth. You only have to look at the total mess with the COVID death and disability vac to see the same results...money in their pockets blinds the credibility and ethics of MANY physicians. How curious it is that the supposed open minded career is so blinded by $$$$.
Although there was no statistical improvement in time to angina on the post procedure echocardiographic stress test, there apparently was an improvement in regional myocardial wall thickening/motion within the vascular distribution of the treated coronary vessel. Angina is subjective, improved echocardiographic wall motion/thickening is an objective finding. Is that not of clinical value? To extrapolate, if ORBITA-2 demonstrates improved LV global ejection fraction in those receiving multivessel treatment, even if no change in time to angina, might the conclusions be different?
Angina is subjective certainly, however the dubious nature of LV wall motion and EF assessment are also suspect with interobserver variability on echo of ~10% which is why ranges are often used. Additionally, data from revived-bcis2 would indicate in low EF patients there’s no definitive data for PCI. I’m not sure a small improvement in LV function is enough to warrant routine PCI unless clinical outcomes mirrored the LV function improvement. Hard clinical outcomes would be ideal, CV mortality, etc... I don’t believe orbita2 powered for CV outcomes only angina and QOL.
It is not unlike the management of claudication. There were numerous trials recommending anything from angioplasty/ with or without stent - to fem-pop bypass. Many of these interventions occluded with no change in symptoms, some made them worse. Current management is largely conservative without intervention. We only operate now for v severe claudication or critical ischaemia
I have the good fortune to be a collaborator on the ORBITA-2 team as a biostatistician. What ORBITA-2 has been able to do, like ORBITA, in the face of limited funding oppportunities, is pretty amazing. ORBITA-2 is also important because of its in-depth quantification of angina frequency and severity.
I look forward to your bringing the ISCHEMIA study results into the picture (I was one of the senior biostatisticians on ISCHEMIA). At some point I hope that we or another group will use ISCHEMIA results to quantify the extent to which patients in the invasive arm had better outcomes than patients in the optimal medical therapy arm, making use of patient utilities or clinical-severity-ordering of outcomes that breaks the ties in angina, hospitalization, MI, and death. A key challenge has been the quantification of the severity of MIs post-randomization. This is key to meeting the challenge of how to weigh the increase in peri-procedural MI in the invasive arm.
Leaving the question of being ethical or not up to the medical community is ridiculous. After the last 4 years, it does not deserve to decide what is ethical and what is not. I seriously doubt that most trials use a true placebo.
I'm glad you are writing these. Almost every intervention today that is just assumed to work, doesn't actually have proof that it works. Or there is proof it doesn't work.
Often the premise is 180 degrees from the truth. The so-called Serotonin Hypothesis, for instance, is flat wrong. Higher serotonin in the brain correlates with depression, anxiety and other mental illness. Lowering serotonin restores mental health in many cases.
https://mattcook.substack.com/p/happy-to-horrified-the-lies-of-serotonin
"Second is that nearly everything we do in medicine should pass muster against a proper control arm. That might be a placebo, a sham procedure, or the standard of care. Blinding must be maintained in trials." Sage advice - yet, not to get too tangential, nearly all the vaccines made and placed on the children's schedule since the late 80's have not been RCT 'true' placebo evaluated - none - not a few mls of saline nor a sugar tablet - No joke (as Joe says) - now that's a fun fact
Thank you for this great review! When I was doing primary care internal medicine, I had great difficulty in dissuading my asymptomatic patients and their cardiologists from continuing to do annual sestamibi testing (presumably looking for a stentable lesion). I quoted from the Courage trials, and also referred them to the Choosing Wisely website recommendations for asymptomatic cardiac patients. I had several heated discussion with cardiologists regarding my objections to their annual tests, but in at least a few cases was able to get them to cut down on the frequency of their cardiac tests.
Wonderful.
Any thoughts on the recent trial of statins in HIV positive patient low to moderate risk?
The first thing I do when I see a study I find out who is funding it. Maybe not in this case but even doctors have a conflict of interest. Sadly most people don't know the questions to ask when a medical issue stares them in the face.
Read the book "How We Do Harm" by Dr. Otis Brawley
Great to learn about the upcoming Orbita 2. Looking forward to it.
But more than just the specific findings of the study, was to show the need for sham control as a true placebo in interventional trials….and in particular when looking at “soft” endpoints. Clearly, and disturbingly, the lesson was not learned by the Triluminate investigators (I’m sure they aren’t the first, nor will they be the last). One’s impression of why this may have been so will likely hinge on where one sits on the skepticism-to-cynicism spectrum. At this point, I’m nearly full-scale deflection to the cynicism end.
I suspect that these results will not make a dent in these surgeries, just like othopedic surgeons continue to do surgery that is no more effective than placebo. I imagine it's difficult to conduct trials that involve sham surgeries with large numbers of participants, both because there is no financial incentive to fund such studies, and perhaps it's difficult to recruit patients who may not want to potentially receive a sham surgery, given that all surgeries involve risk, and a sham surgery has no benefit except placebo. Patients are equally conditioned as doctors to believe that surgery is an effective tool. I hope they can figure out exactly WHEN surgery IS actually useful!
https://pubmed.ncbi.nlm.nih.gov/27402957/#:~:text=Narrative synthesis of results, based,reducing pain and improving disability.
Really can not wait until the #2 study is completed since most people have more than one vessel affected. Why should we be so surprised by the results of a placebo when seen in so many other examples in medicine yet when you look at MDs/DOs making huge $$ s from cardiac procedures their minds seek only more dollars rather than the truth. You only have to look at the total mess with the COVID death and disability vac to see the same results...money in their pockets blinds the credibility and ethics of MANY physicians. How curious it is that the supposed open minded career is so blinded by $$$$.
Dr. Mandrola,
Although there was no statistical improvement in time to angina on the post procedure echocardiographic stress test, there apparently was an improvement in regional myocardial wall thickening/motion within the vascular distribution of the treated coronary vessel. Angina is subjective, improved echocardiographic wall motion/thickening is an objective finding. Is that not of clinical value? To extrapolate, if ORBITA-2 demonstrates improved LV global ejection fraction in those receiving multivessel treatment, even if no change in time to angina, might the conclusions be different?
Angina is subjective certainly, however the dubious nature of LV wall motion and EF assessment are also suspect with interobserver variability on echo of ~10% which is why ranges are often used. Additionally, data from revived-bcis2 would indicate in low EF patients there’s no definitive data for PCI. I’m not sure a small improvement in LV function is enough to warrant routine PCI unless clinical outcomes mirrored the LV function improvement. Hard clinical outcomes would be ideal, CV mortality, etc... I don’t believe orbita2 powered for CV outcomes only angina and QOL.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32714-9/fulltext
thanks -- forgot the URL> Link added
Thank you for showing how good science is done.
It is not unlike the management of claudication. There were numerous trials recommending anything from angioplasty/ with or without stent - to fem-pop bypass. Many of these interventions occluded with no change in symptoms, some made them worse. Current management is largely conservative without intervention. We only operate now for v severe claudication or critical ischaemia
Doctors underestimate collateral perfusion. Our bodies mostly take care of themselves.
I have the good fortune to be a collaborator on the ORBITA-2 team as a biostatistician. What ORBITA-2 has been able to do, like ORBITA, in the face of limited funding oppportunities, is pretty amazing. ORBITA-2 is also important because of its in-depth quantification of angina frequency and severity.
I look forward to your bringing the ISCHEMIA study results into the picture (I was one of the senior biostatisticians on ISCHEMIA). At some point I hope that we or another group will use ISCHEMIA results to quantify the extent to which patients in the invasive arm had better outcomes than patients in the optimal medical therapy arm, making use of patient utilities or clinical-severity-ordering of outcomes that breaks the ties in angina, hospitalization, MI, and death. A key challenge has been the quantification of the severity of MIs post-randomization. This is key to meeting the challenge of how to weigh the increase in peri-procedural MI in the invasive arm.