The worst part of the story is the EP docs foisting responsibility for discussing the patient's death with the family on the house staff. Inexcusable. Of course they were preoccupied with their very important work of trying to suppress inducible VT.
I was happy that I was able to remember the issue at all ! My memory is sometimes as is normal for a 75 year old but I still love Medicine. It will be 50 years ago next yr since my Northwestern MD. I am retired many years but still continue my License and CME . I just completed the Harvard Internal Med course for Specialists ( but I was an FP LMD ) . If you or your Dad have not read “ The Lost Art of Healing “. by Bernard Lown MD, it was fabulous. Hope that you and your Dad are happy and doing well .
This is the lesson of CAST: It is the poster trial of why we should ultimately judge a study by patient-oriented outcomes vs non-patient based results such as lab values, electrophysiologic numbers, etc. (This refers to large 'landmark' studies, not bench science.) The hired gun subject matter expert is sure to state with a furrowed brow and measured delivery how the latest drug improves LFTs, lipid profile, or heart attacks, but is offended when confronted with the counter-assertion to please provide evidence of all-cause benefit for patients. Ya know, those people we are supposed to help.
Across every domain of medicine, this lesson is pervasive, or should be. Just a few examples of a long list:
Vaccines - Anyone in the queue for Lymerix or Rotashield?
Screening - PSA is a slam dunk to help the patient live longer? Right? or maybe this evidence is lacking...
NSAID - Vioxx anyone?
Chol med - gemfibrozil reduces triglycerides and chol, but - ahem -increases all-cause mortality
Erothropoetin - Yes, the patient faces increased cancer risk, but at least their blood count is higher.
Yes, that is also what my father (Guenter Breithardt) told me. It was speculated that propafenone (with intrinsic beta blocker activity) might have led to different (less negative) results. We will never know...(?)
"I would argue that the HERS and WHI trials are far more important. They showed that the observational data suggesting cardiac benefits from hormone replacement therapy were wrong."
So, a reduced death rate in women 50-60 y/o on estrogen means there are no cardiac benefits? WHI suffered from a very wide age distribution in women started on HT, something that basically almost never happened in the real world, at least not in the world inhabited by OBGs as am I. There is an optimum age to give HT, and an age beyond which other measures should be considered. Clarifying the difference is important. Making blanket statements is not helpful. Even Joanne Munson changed her views on the WHI results as more detailed analysis showed who benefited and who didn't from HT.
This was an amazing story and my heart bleeds not just for the 35 year old patient that died but for the intern who may have been emotionally scarred believing that she killed him. The patient died of his cardiomyopathy - in the setting of appropriately heroic measures to try to save him - from trying to suppress his VT in the first place to the final events at the code. The CAST trial, not yet out when this story unfolded, studied antiarrhythmic therapy in ischemic heart disease. This patient's cardiomyopathy may have been ischemic but at age 35 possibly not. CAST also focused on PVC prevention, not suppression of recurrent VT. The attending had a "feeling" that the drug killed him but clearly did not possess the full picture. He missed an opportunity to help his intern understand the full spectrum of serious disease - never mind that she did not make the decision to give the Encainide even if she was the one who wrote the order.
From an accuracy standpoint, you are correct that CAST looked at PVC suppression not VT suppression, demonstrating that I should not rely on my memory thirty years after the fact. Thank you for pointing out my error. From an interpretation standpoint, though, it pretty much ended choosing medications for VT based on EP-guided evidence of inducibility suppression.
Also from an interpretation standpoint, I don't think many people would think that a strategy that increases mortality in people with ischemic cardiomyopathy should be used in people with other forms of cardiomyopathy, particularly when there's even less observational evidence of benefit in those other forms. These are obviously judgment calls, but I can't recall anyone with any form of CM being managed this way in decades.
As I tried to convey in the piece, there was no attending involved in any of these discussions. As for responding to Cara's belief that she had killed Bill, I think you can make reasonable guesses as to what I said at the time.
You never forget your first. And CAST was, as far as I know, the first medical reversal and “biologic plausibility” faceplant in the…ahem…face of a rigorous test of causation.
Unfortunately, while the Bill’s of the world paid the price for that lesson, it’s still a lesson that hasn’t been fully learned by the academic and guideline-writing committee. And imo, that’s to the detriment of everyone, including any subsequent and future Bill’s.
I wonder what socioeconomic, (non)family oriented, spirituality or lack thereof, academic, moral philosophy, and jurisprudence influences have on people who want to become doctors. How their minds were formed and impacted led them to medicine is interesting. I look back and wonder why I wanted to become a nurse. It was to care for those who were in a medical crisis (big or small), ease their discomfort, and heal them. Then nursing life threw me curve balls, fast balls, sliders and change-ups. My patients had the audacity to die, even with all the work I had done and was doing. I never saw death as a failure though. It wasn't a bad thing, the wrong thing, something to chew on as to what I should have/could have done differently to save this person's life. 99.99% of the time - nothing. It happens. It is ok. I don't feel a need for an autopsy or an M&M conference. My patient was meant to go. I did nothing wrong nor did I miss something. Why do doctors see death as a failure and wrongful?
I have concluded that no synthetic drugs or vitamins are safe, especially in the long term. Trials are meaningless when the chemicals in the drugs are akin to poisons. Read the labels and the MSDS sheets and be amazed.
In my residency, one cardiologist told me “oxygen is overused in this hospital and it’s the fault of the residents.” I thought what the heck. An Infectious disease specialist told me a really good way to handle the death of a patient – when in doubt explain to the family that sometimes we don’t know why the patient died, but an autopsy is always helpful to possibly answer those questions that I may have as a doctor about what I could do differently or you may have as a family member about what you or the patient could’ve done differently.
We have to be careful not to eat our young. The patient had a potentially fatal condition. Otherwise nobody would’ve been considering him for a heart transplant.
Feb 16·edited Feb 16Liked by Adam Cifu, MD, David Rind
Very nice article. The CAST trial and proarrhythmic effects of class I antiarrhythmic drugs is one of the most interesting things I’ve been involved in. In my 4-year term on the FDA Cardio-renal Advisory Committee we evaluated the evidence from CAST in recommending drug labeling. The story is more interesting than people think. The entire saga was detailed in Thomas J Moore’s book Deadly Medicine. Moore points out that there were very significant warning sings during the development program. This includes rare trials on large apes with worrisome findings. I recommend the book to anyone who wants to take a really deep dive into the saga. There are also interesting statistical issues. CAST had an interim monitoring plan with one-sided stopping boundaries as the cardiologists were absolutely certain that there could only be a mortality benefit, with no chance of harm. I think the original statistical test was one-sided, and it was statisticians who pushed that to change. And in retrospect a Bayesian design would have stopped earlier, either with evidence of harm or even stronger evidence of inefficacy (which includes harm).
The worst part of the story is the EP docs foisting responsibility for discussing the patient's death with the family on the house staff. Inexcusable. Of course they were preoccupied with their very important work of trying to suppress inducible VT.
Thank you for this. I'm appalled at how many people accept observational evidence as if it proves causality just because it's from a big database.
I was happy that I was able to remember the issue at all ! My memory is sometimes as is normal for a 75 year old but I still love Medicine. It will be 50 years ago next yr since my Northwestern MD. I am retired many years but still continue my License and CME . I just completed the Harvard Internal Med course for Specialists ( but I was an FP LMD ) . If you or your Dad have not read “ The Lost Art of Healing “. by Bernard Lown MD, it was fabulous. Hope that you and your Dad are happy and doing well .
Respectfully
Gerald M Casey MD
This is the lesson of CAST: It is the poster trial of why we should ultimately judge a study by patient-oriented outcomes vs non-patient based results such as lab values, electrophysiologic numbers, etc. (This refers to large 'landmark' studies, not bench science.) The hired gun subject matter expert is sure to state with a furrowed brow and measured delivery how the latest drug improves LFTs, lipid profile, or heart attacks, but is offended when confronted with the counter-assertion to please provide evidence of all-cause benefit for patients. Ya know, those people we are supposed to help.
Across every domain of medicine, this lesson is pervasive, or should be. Just a few examples of a long list:
Vaccines - Anyone in the queue for Lymerix or Rotashield?
Screening - PSA is a slam dunk to help the patient live longer? Right? or maybe this evidence is lacking...
NSAID - Vioxx anyone?
Chol med - gemfibrozil reduces triglycerides and chol, but - ahem -increases all-cause mortality
Erothropoetin - Yes, the patient faces increased cancer risk, but at least their blood count is higher.
Wasn’t it discussed later that the use of Flecanide with a Beta Blocker might have overcome the pro arrhythmia results ?
Gerald M Casey MD
Yes, that is also what my father (Guenter Breithardt) told me. It was speculated that propafenone (with intrinsic beta blocker activity) might have led to different (less negative) results. We will never know...(?)
"I would argue that the HERS and WHI trials are far more important. They showed that the observational data suggesting cardiac benefits from hormone replacement therapy were wrong."
So, a reduced death rate in women 50-60 y/o on estrogen means there are no cardiac benefits? WHI suffered from a very wide age distribution in women started on HT, something that basically almost never happened in the real world, at least not in the world inhabited by OBGs as am I. There is an optimum age to give HT, and an age beyond which other measures should be considered. Clarifying the difference is important. Making blanket statements is not helpful. Even Joanne Munson changed her views on the WHI results as more detailed analysis showed who benefited and who didn't from HT.
This was an amazing story and my heart bleeds not just for the 35 year old patient that died but for the intern who may have been emotionally scarred believing that she killed him. The patient died of his cardiomyopathy - in the setting of appropriately heroic measures to try to save him - from trying to suppress his VT in the first place to the final events at the code. The CAST trial, not yet out when this story unfolded, studied antiarrhythmic therapy in ischemic heart disease. This patient's cardiomyopathy may have been ischemic but at age 35 possibly not. CAST also focused on PVC prevention, not suppression of recurrent VT. The attending had a "feeling" that the drug killed him but clearly did not possess the full picture. He missed an opportunity to help his intern understand the full spectrum of serious disease - never mind that she did not make the decision to give the Encainide even if she was the one who wrote the order.
From an accuracy standpoint, you are correct that CAST looked at PVC suppression not VT suppression, demonstrating that I should not rely on my memory thirty years after the fact. Thank you for pointing out my error. From an interpretation standpoint, though, it pretty much ended choosing medications for VT based on EP-guided evidence of inducibility suppression.
Also from an interpretation standpoint, I don't think many people would think that a strategy that increases mortality in people with ischemic cardiomyopathy should be used in people with other forms of cardiomyopathy, particularly when there's even less observational evidence of benefit in those other forms. These are obviously judgment calls, but I can't recall anyone with any form of CM being managed this way in decades.
As I tried to convey in the piece, there was no attending involved in any of these discussions. As for responding to Cara's belief that she had killed Bill, I think you can make reasonable guesses as to what I said at the time.
Painful and illuminating reading. Thank you.
You never forget your first. And CAST was, as far as I know, the first medical reversal and “biologic plausibility” faceplant in the…ahem…face of a rigorous test of causation.
Unfortunately, while the Bill’s of the world paid the price for that lesson, it’s still a lesson that hasn’t been fully learned by the academic and guideline-writing committee. And imo, that’s to the detriment of everyone, including any subsequent and future Bill’s.
I wonder what socioeconomic, (non)family oriented, spirituality or lack thereof, academic, moral philosophy, and jurisprudence influences have on people who want to become doctors. How their minds were formed and impacted led them to medicine is interesting. I look back and wonder why I wanted to become a nurse. It was to care for those who were in a medical crisis (big or small), ease their discomfort, and heal them. Then nursing life threw me curve balls, fast balls, sliders and change-ups. My patients had the audacity to die, even with all the work I had done and was doing. I never saw death as a failure though. It wasn't a bad thing, the wrong thing, something to chew on as to what I should have/could have done differently to save this person's life. 99.99% of the time - nothing. It happens. It is ok. I don't feel a need for an autopsy or an M&M conference. My patient was meant to go. I did nothing wrong nor did I miss something. Why do doctors see death as a failure and wrongful?
I have concluded that no synthetic drugs or vitamins are safe, especially in the long term. Trials are meaningless when the chemicals in the drugs are akin to poisons. Read the labels and the MSDS sheets and be amazed.
Geez this sounds like what happened with those rush vaccines for Covid and the (now found out) issues with them that were known from the get go.
So who is to take responsibility for the deaths?
In my residency, one cardiologist told me “oxygen is overused in this hospital and it’s the fault of the residents.” I thought what the heck. An Infectious disease specialist told me a really good way to handle the death of a patient – when in doubt explain to the family that sometimes we don’t know why the patient died, but an autopsy is always helpful to possibly answer those questions that I may have as a doctor about what I could do differently or you may have as a family member about what you or the patient could’ve done differently.
We have to be careful not to eat our young. The patient had a potentially fatal condition. Otherwise nobody would’ve been considering him for a heart transplant.
Very nice article. The CAST trial and proarrhythmic effects of class I antiarrhythmic drugs is one of the most interesting things I’ve been involved in. In my 4-year term on the FDA Cardio-renal Advisory Committee we evaluated the evidence from CAST in recommending drug labeling. The story is more interesting than people think. The entire saga was detailed in Thomas J Moore’s book Deadly Medicine. Moore points out that there were very significant warning sings during the development program. This includes rare trials on large apes with worrisome findings. I recommend the book to anyone who wants to take a really deep dive into the saga. There are also interesting statistical issues. CAST had an interim monitoring plan with one-sided stopping boundaries as the cardiologists were absolutely certain that there could only be a mortality benefit, with no chance of harm. I think the original statistical test was one-sided, and it was statisticians who pushed that to change. And in retrospect a Bayesian design would have stopped earlier, either with evidence of harm or even stronger evidence of inefficacy (which includes harm).
I also really enjoyed the article. And yes, Thomas J Moore's Deadly Medicine is an excellent read.
Thanks for writing this Dr. Rind