Thank you for your thoughtful and insightful analysis of STRONG HF.
I want to make three points in response to your analysis:
1. The African enrolment is a strength, not a weakness.
You frequently noted that a large proportion of participants were recruited from Africa, implying this limits generalisability. I would argue the opposite: this is one of the trial’s most important contributions.
African populations have been systematically underrepresented in cardiovascular RCTs.(https://www.jacc.org/doi/10.1016/j.jacadv.2024.101383) As a result, the external validity of major HF and ACS guidelines for these populations is deeply uncertain, despite outcomes often being worse than in N. America/Europe.
If anything, STRONG-HF attempts to correct a structural imbalance in the evidence base. Trials that exclude large segments of the global CVD population are rarely criticised for limited external validity; trials that include them should not be.
2. “Poor standard of care” depends on your perspective
You suggest that the control group reflects a suboptimal level of care and that the population does not resemble the multimorbid octogenarian admitted daily to US hospitals. That is true if the implicit frame is a high-income health system.
But the control arm reflects the real-world standard of care in many lower- and middle-income settings. In those systems, heart failure patients are younger, less comorbid, and yet experience substantially higher mortality. The discomfort should not be that the trial lacks relevance to Boston or London. It should be that the younger patients in resource-constrained settings receive markedly inferior care.
3. The framing determines the conclusion
If the question is “what does this trial add for patients in well-resourced US centres” then the impact may be modest, operationally challenging, and not valid for many typical patients.
If the question is instead, “Can structured, rapid optimisation meaningfully reduce mortality in health systems where baseline care is weak?” Then the trial becomes a fundamentally different and more consequential study.
You may reasonably argue that the intensity of follow-up is difficult to replicate even in the US. I agree. But the trial demonstrates that structured implementation of guideline-directed therapy can produce substantial mortality reductions in settings where nihilism might otherwise prevail. That is not trivial.
I agree with Andrew on the chf trial. The population studied didn’t accurately reflect the average population we see in America…certainly not in my rural southeast population. I regularly see patients dc’d on GDMT who are significantly symptomatic within 7 days of dc. Hypotension, syncope, volume depletion, etc. I find patients to be too quickly up-titrated on sacubitril/valsartan and empagliflozin.
Really enjoyed this (I read transcript rather than listening).
Great insights by Dr. Foy re: Strong HF which I hadn’t realized. I was more in tune with the process issues (and hence performance biases) and how that translated to my work environment (or not). But I was not aware that “standard care” seemed rather suboptimal. And I hadn’t done the arithmetic to realize they screened a very select cohort (to explain why there were so few HFrEF exacerbations they apparently saw per enrolling hospital per year). This adds a whole other dimension to the external validity limitations of this study.
Of course, the guideline people have ignored all of this, and it’s 4 drugs for everybody all day every day.
Due respect to the SM crew touting baloxavir, I disagree. Deep dive: (https://tinyurl.com/23efmekb) published today. Baloxavir is exactly as good as the failed Tamiflu. A careful read shows almost entirely placebo effect. Moreover, it doesn't prevent flu—it reduces test positivity, not illness (https://tinyurl.com/54ywzrev). I'm a big fan, but think maybe the SM reading on baloxavir was a bit superficial—let the debates begin. Fun!
Although I agree baloxavir doesn't seem much better, I didn't come with the impression that they said it was (better).
Anyway, RECOVERY adapativr platform trial is now recruiting influenza hospitalized patients to both oseltamivir and baloxavir and hopefuly it will reach a higher amount of patients.
“This review does not provide reasonable evidence to support the vaccination of healthcare workers to prevent influenza in those aged 60 years or older resident in long term care institutions.”
“Reasons for the current gap between policy and evidence are unclear, but given the huge resources involved, a re-evaluation should be urgently undertaken.”
Trivalent vaccine did not provide any protection for hospitalization. “On the contrary, we found a threefold increased risk of hospitalization in subjects who did get the TIV vaccine.” https://pubmed.ncbi.nlm.nih.gov/22525386/
Last year’s study of working-aged adults showed that the vaccine was associated with a higher risk of influenza during the 2024-2025 respiratory viral season, “suggesting that the vaccine has not been effective in preventing influenza this season.”
another great fortnite in medicine. Loved it! once again, I am so happy to have Andrew as part of the team. I love his explanations and his nuance stance on many of these issues. also John, I appreciated your emergency gathering about LDL treatment in the younger population. I saw you get trashed on X. like you, I learned a lot from the discussion. thanks for doing it
LDL is not one entity, and statins preferentially increase the proportion of small dense LDL. Our cholesterol hypothesis is probably wrong.
“Our study suggests that statin therapy—whether or not recipients have coronary artery disease—does not decrease the proportion of small, dense LDL among total LDL particles, but in fact increases it, while predictably reducing total LDL cholesterol, absolute amounts of small, dense LDL, and absolute amounts of large, buoyant LDL.”
Mortality is a pretty hard end point. “Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review”
We should ask why, despite the widespread use of statins, that our CV mortality remains high, and our dementia rates are outpacing our life expectancies. Brains need fat; hence the benefits of a ketogenic diet in children with refractory seizures.
1. Give us a written copy of the podcast. who wants to waste An hour looking for the pearls that you guys are good at.
2. Tom Jefferson and Carl Henegan nailed Tamiflu and congeners years back. It’s fixed science. Your symptoms might get better in 6 days instead of 7 but 30% of miserable side effects.
3. Bunus point. Why don’t you put a red asterisk by all Pharma funded papers?
You can get an auto-generated transcript in podcast app by clicking on the ellipsis (3 dots)….”transcript” is one of the dropdown menu options. It’s not perfect, there are voice recognition typos, and there is no indication of who is speaking. But it gets the job done for me. (I much prefer reading to listening).
Thank you for your thoughtful and insightful analysis of STRONG HF.
I want to make three points in response to your analysis:
1. The African enrolment is a strength, not a weakness.
You frequently noted that a large proportion of participants were recruited from Africa, implying this limits generalisability. I would argue the opposite: this is one of the trial’s most important contributions.
African populations have been systematically underrepresented in cardiovascular RCTs.(https://www.jacc.org/doi/10.1016/j.jacadv.2024.101383) As a result, the external validity of major HF and ACS guidelines for these populations is deeply uncertain, despite outcomes often being worse than in N. America/Europe.
If anything, STRONG-HF attempts to correct a structural imbalance in the evidence base. Trials that exclude large segments of the global CVD population are rarely criticised for limited external validity; trials that include them should not be.
2. “Poor standard of care” depends on your perspective
You suggest that the control group reflects a suboptimal level of care and that the population does not resemble the multimorbid octogenarian admitted daily to US hospitals. That is true if the implicit frame is a high-income health system.
But the control arm reflects the real-world standard of care in many lower- and middle-income settings. In those systems, heart failure patients are younger, less comorbid, and yet experience substantially higher mortality. The discomfort should not be that the trial lacks relevance to Boston or London. It should be that the younger patients in resource-constrained settings receive markedly inferior care.
3. The framing determines the conclusion
If the question is “what does this trial add for patients in well-resourced US centres” then the impact may be modest, operationally challenging, and not valid for many typical patients.
If the question is instead, “Can structured, rapid optimisation meaningfully reduce mortality in health systems where baseline care is weak?” Then the trial becomes a fundamentally different and more consequential study.
You may reasonably argue that the intensity of follow-up is difficult to replicate even in the US. I agree. But the trial demonstrates that structured implementation of guideline-directed therapy can produce substantial mortality reductions in settings where nihilism might otherwise prevail. That is not trivial.
I agree with Andrew on the chf trial. The population studied didn’t accurately reflect the average population we see in America…certainly not in my rural southeast population. I regularly see patients dc’d on GDMT who are significantly symptomatic within 7 days of dc. Hypotension, syncope, volume depletion, etc. I find patients to be too quickly up-titrated on sacubitril/valsartan and empagliflozin.
Really enjoyed this (I read transcript rather than listening).
Great insights by Dr. Foy re: Strong HF which I hadn’t realized. I was more in tune with the process issues (and hence performance biases) and how that translated to my work environment (or not). But I was not aware that “standard care” seemed rather suboptimal. And I hadn’t done the arithmetic to realize they screened a very select cohort (to explain why there were so few HFrEF exacerbations they apparently saw per enrolling hospital per year). This adds a whole other dimension to the external validity limitations of this study.
Of course, the guideline people have ignored all of this, and it’s 4 drugs for everybody all day every day.
Due respect to the SM crew touting baloxavir, I disagree. Deep dive: (https://tinyurl.com/23efmekb) published today. Baloxavir is exactly as good as the failed Tamiflu. A careful read shows almost entirely placebo effect. Moreover, it doesn't prevent flu—it reduces test positivity, not illness (https://tinyurl.com/54ywzrev). I'm a big fan, but think maybe the SM reading on baloxavir was a bit superficial—let the debates begin. Fun!
Although I agree baloxavir doesn't seem much better, I didn't come with the impression that they said it was (better).
Anyway, RECOVERY adapativr platform trial is now recruiting influenza hospitalized patients to both oseltamivir and baloxavir and hopefuly it will reach a higher amount of patients.
Speaking of the flu, here are some truths you won’t see on MSM. BTW, the circulating strain H3N2 is likely made worse by the shots.
“In immunogenicity studies, repeated vaccination blunts the hemagglutinin antibody response, particularly for H3N2.”
https://pubmed.ncbi.nlm.nih.gov/28562111/
“The unexpected findings of lower effectiveness with repeated vaccination and no protection given household exposure require further study.” https://pmc.ncbi.nlm.nih.gov/articles/PMC3693492/
“This review does not provide reasonable evidence to support the vaccination of healthcare workers to prevent influenza in those aged 60 years or older resident in long term care institutions.”
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005187.pub5/full
“Reasons for the current gap between policy and evidence are unclear, but given the huge resources involved, a re-evaluation should be urgently undertaken.”
https://pmc.ncbi.nlm.nih.gov/articles/PMC1626345/
Trivalent vaccine did not provide any protection for hospitalization. “On the contrary, we found a threefold increased risk of hospitalization in subjects who did get the TIV vaccine.” https://pubmed.ncbi.nlm.nih.gov/22525386/
Last year’s study of working-aged adults showed that the vaccine was associated with a higher risk of influenza during the 2024-2025 respiratory viral season, “suggesting that the vaccine has not been effective in preventing influenza this season.”
https://www.medrxiv.org/content/10.1101/2025.01.30.25321421v3
Thanks
another great fortnite in medicine. Loved it! once again, I am so happy to have Andrew as part of the team. I love his explanations and his nuance stance on many of these issues. also John, I appreciated your emergency gathering about LDL treatment in the younger population. I saw you get trashed on X. like you, I learned a lot from the discussion. thanks for doing it
LDL is not one entity, and statins preferentially increase the proportion of small dense LDL. Our cholesterol hypothesis is probably wrong.
“Our study suggests that statin therapy—whether or not recipients have coronary artery disease—does not decrease the proportion of small, dense LDL among total LDL particles, but in fact increases it, while predictably reducing total LDL cholesterol, absolute amounts of small, dense LDL, and absolute amounts of large, buoyant LDL.”
https://pmc.ncbi.nlm.nih.gov/articles/PMC2929871/
Mortality is a pretty hard end point. “Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review”
https://bmjopen.bmj.com/content/6/6/e010401
We should ask why, despite the widespread use of statins, that our CV mortality remains high, and our dementia rates are outpacing our life expectancies. Brains need fat; hence the benefits of a ketogenic diet in children with refractory seizures.
I think you guys have lost your mojo.
1. Give us a written copy of the podcast. who wants to waste An hour looking for the pearls that you guys are good at.
2. Tom Jefferson and Carl Henegan nailed Tamiflu and congeners years back. It’s fixed science. Your symptoms might get better in 6 days instead of 7 but 30% of miserable side effects.
3. Bunus point. Why don’t you put a red asterisk by all Pharma funded papers?
You can get an auto-generated transcript in podcast app by clicking on the ellipsis (3 dots)….”transcript” is one of the dropdown menu options. It’s not perfect, there are voice recognition typos, and there is no indication of who is speaking. But it gets the job done for me. (I much prefer reading to listening).
Thanks, Steve
love these discussions.