We have basically 5 different mechanisms to reduce blood pressure: Diuretics: Renal volume depletion; ACE Inhibitors: Vasoconstrictor synthesis inhibition; ARBs: Angiotensin receptor antagonism; Calcium Channel Blockers: Vascular smooth-muscle vasodilation; Beta-Blockers: Sympathetic cardiac suppression.
My gut feeling is that the polypill or even giving multiple pills is a sign that cardiologists (and certainly PCPs) don't care about or understand the underlying biological mechanisms. It encourages thinking that just meets the NUMBER. It replaces treatment of cause for treatment of symptom.
Yes it's complicated and often multi-factorial but if polypill further encourages symptom treatment that may not be progress.
I'm drawn to Dylan's line:
"Johnny's in the basement mixing up the medicine" and the pharmacists of 100 plus years ago making elixirs for sale to treat symptoms without understanding the underlying biological mechanisms and causes.
As always I like your write-ups - and I certainly agree that a 3% different in EF is meager. But the difference in very patient oriented outcome - ED visits and hospitalizations is substantial - 37 vs 86 per 100 patients years - unfortunately, hard to know what that means in English - but feels pretty good.
If we threw every paper reporting an industry sponsored RCT in the garbage, there would be precious little progress made in understanding what drugs work on whom, because it’s so expensive to run RCTs, especially because of the regulatory compliance involved. However, these reports require painstakingly careful review of their strengths and weaknesses and wide dissemination of the problems associated with their conclusions. (Thank you, John!)
I do disagree with John’s concern about “highly selected patients”. For a first RCT, it is critical for patients to be as ideal as possible in order for the results to be interpretable. Later, inclusion criteria can be loosened to determine applicability to a wider population. I wonder whether compounding pharmacies will have a role in producing polypills with patient-specific doses of the multiple components.
I have no experience with the polypill. It is so sad that these patients have to be on 4 medications in the first place. It seems reasonable to be able to titrate each pill. Do these patients improve? Are they able to come off of one or more of these medicines?
Perhaps a polypill could be considered after each of the components doses have been titrated and side effects excluded. Cost and poor experimental design questions are essential, but risking the polypill in a general polpulation would be intrepid to the verge of temerity. Non rare complications include, edema from calcium channel blockers, and cough from Ace Inhibitors and exacerbating ( or causing for the first time) Raynaud's.
Whereas Occam’s razor concept was used to hone in on a specific clinical diagnosis, it is evident that ALL clinical diagnoses require multi-pronged interventions for optimal effects.
Whereas the best combinations of agents can indeed be tested in RCTs, the individualized optimization of doses is going to need physician input and interval monitoring.
I get the potential importance of the polypill concept. But to use EF as the primary endpoint immediately calls into question the clinical importance of this study. Some patients with EF’s of 20% look like they are at death’s door and others look like they’re ready for a jog.
The concept behind polypill is PROFIT. Last year combination medicines cost Medicare more than $800 million more than for the same individual medications. Big Pharma patents these polypills. Who would have guessed???? Dr Mandrola did not mention who sponsored that polypill trial of selected indigent patients. Read this conflict of interest statement and ask, "Do we need to look any further?"
Conflict of interest statement
Competing interests: A.P. has received research funding (to the institution) from American Heart Association, Applied Therapeutics, Roche, Ultromics, Gilead Sciences, Bayer and AstraZeneca; has received honoraria as an advisor, consultant or speaker for Tricog Health Inc., Lilly, Rivus, Roche Diagnostics, Axon Therapies, Edward Lifesciences, Science37, Novo Nordisk, Bayer, Medical AI, AstraZeneca, Baylor Scott and White Research Institute, Boehringer Ingelheim, iRhythm Technologies, Tourmaline Bio, Merck, Sarfez Pharmaceuticals, Ultromics, Kardigan, Tenax Pharma, Alnylam, Abbott, Kilele Health, Anumana, Acorai, Novartis and Antlia Biosciences. A.P. is a coinventor on a Polypill for Heart Failure US provisional patent application (63/912,172) filed November 2025. N.K. has received consultant fees from Heart Test Laboratories, Tricog Health, Idorsia Pharmaceuticals and Science37. M.W.S. reports nonfinancial support from Merck, honoraria outside the present study from Idorsia and Otsuka, is an advisor for AccurKardia, is on the executive board for descendantsDNA and is the founder of ReCODE Medical. A.C. has received grant funding outside the present study from Novo Nordisk, Lilly USA and Sarfez Pharmaceuticals. Z.L.C. reports grants from AstraZeneca and personal fees from Abiomed, Vectorious, Kestra Medical Technologies, Reprieve Cardiovascular, WhiteSwell and Lexicon Pharmaceuticals. D.K.G. has received honoraria as an advisor to Novo Nordisk and research support from the NHLBI (R01HL153607, R01HL145293, R01HL133860). M.T.H. has served as a consultant for Imricor Medical Systems Inc. T.J.W. is named as a coinventor on a Polypill for Heart Failure US provisional patent application (63/912,172) filed November 2025 and another application related to technologies for producing combination pills. The other authors declare no competing interests.
Dr Miller -- Spot on point! Before reading any study, always review the conflict of interest statements. As soon as you see industry funding, throw the article into the trash.
Every day providers in primary care hear from people who are concerned about how many pills they are taking (supplements they choose to take don’t count to them), how confused they are about what to take and when, etc. If you could get the dosage right, and it’s covered by insurance, adherence would improve. I don’t know if adherence would improve outcomes, but that’s more a test of GDMT.
Is a polypill better than a number of individual pills? In concept, I would think that it certainly is. Dr. Mandrola, you raise important practical concerns, chief being that with a polypill, it is difficult or not possible to adjust component doses to the individual's needs.
I see an added concern which I would imagine necessitates a far larger trial than ~100 people per arm: Even with an RCT there is a confounding effect, a bias that is difficult to adjust for with a small open-label trial. Some (maybe many) of the people in the trial may be particularly health conscious and therefore more than willing to take quite a number of pills per day. Other than taking their meds, what else are these people doing to address their cardiac health? Only a far larger trial will smooth the effects on the results across the 2 arms. Another issue is cost. For people who are uninsured, total cost per day will be a factor, quite possibly an important one. Is a polypill less costly than several individual pills? Again, only a far larger trail will address the effect on the results.
I would think that this trail is an important early step but in my view, it is far too small to address the confounding effects.
We have basically 5 different mechanisms to reduce blood pressure: Diuretics: Renal volume depletion; ACE Inhibitors: Vasoconstrictor synthesis inhibition; ARBs: Angiotensin receptor antagonism; Calcium Channel Blockers: Vascular smooth-muscle vasodilation; Beta-Blockers: Sympathetic cardiac suppression.
My gut feeling is that the polypill or even giving multiple pills is a sign that cardiologists (and certainly PCPs) don't care about or understand the underlying biological mechanisms. It encourages thinking that just meets the NUMBER. It replaces treatment of cause for treatment of symptom.
Yes it's complicated and often multi-factorial but if polypill further encourages symptom treatment that may not be progress.
I'm drawn to Dylan's line:
"Johnny's in the basement mixing up the medicine" and the pharmacists of 100 plus years ago making elixirs for sale to treat symptoms without understanding the underlying biological mechanisms and causes.
As always I like your write-ups - and I certainly agree that a 3% different in EF is meager. But the difference in very patient oriented outcome - ED visits and hospitalizations is substantial - 37 vs 86 per 100 patients years - unfortunately, hard to know what that means in English - but feels pretty good.
If that’s true, I think it’s huge. ED physicians spend a lot of time getting people diuresed and back on their meds.
If we threw every paper reporting an industry sponsored RCT in the garbage, there would be precious little progress made in understanding what drugs work on whom, because it’s so expensive to run RCTs, especially because of the regulatory compliance involved. However, these reports require painstakingly careful review of their strengths and weaknesses and wide dissemination of the problems associated with their conclusions. (Thank you, John!)
I do disagree with John’s concern about “highly selected patients”. For a first RCT, it is critical for patients to be as ideal as possible in order for the results to be interpretable. Later, inclusion criteria can be loosened to determine applicability to a wider population. I wonder whether compounding pharmacies will have a role in producing polypills with patient-specific doses of the multiple components.
I have no experience with the polypill. It is so sad that these patients have to be on 4 medications in the first place. It seems reasonable to be able to titrate each pill. Do these patients improve? Are they able to come off of one or more of these medicines?
Perhaps a polypill could be considered after each of the components doses have been titrated and side effects excluded. Cost and poor experimental design questions are essential, but risking the polypill in a general polpulation would be intrepid to the verge of temerity. Non rare complications include, edema from calcium channel blockers, and cough from Ace Inhibitors and exacerbating ( or causing for the first time) Raynaud's.
“Poly-pills” are the future.
Whereas Occam’s razor concept was used to hone in on a specific clinical diagnosis, it is evident that ALL clinical diagnoses require multi-pronged interventions for optimal effects.
Whereas the best combinations of agents can indeed be tested in RCTs, the individualized optimization of doses is going to need physician input and interval monitoring.
I get the potential importance of the polypill concept. But to use EF as the primary endpoint immediately calls into question the clinical importance of this study. Some patients with EF’s of 20% look like they are at death’s door and others look like they’re ready for a jog.
The concept behind polypill is PROFIT. Last year combination medicines cost Medicare more than $800 million more than for the same individual medications. Big Pharma patents these polypills. Who would have guessed???? Dr Mandrola did not mention who sponsored that polypill trial of selected indigent patients. Read this conflict of interest statement and ask, "Do we need to look any further?"
Conflict of interest statement
Competing interests: A.P. has received research funding (to the institution) from American Heart Association, Applied Therapeutics, Roche, Ultromics, Gilead Sciences, Bayer and AstraZeneca; has received honoraria as an advisor, consultant or speaker for Tricog Health Inc., Lilly, Rivus, Roche Diagnostics, Axon Therapies, Edward Lifesciences, Science37, Novo Nordisk, Bayer, Medical AI, AstraZeneca, Baylor Scott and White Research Institute, Boehringer Ingelheim, iRhythm Technologies, Tourmaline Bio, Merck, Sarfez Pharmaceuticals, Ultromics, Kardigan, Tenax Pharma, Alnylam, Abbott, Kilele Health, Anumana, Acorai, Novartis and Antlia Biosciences. A.P. is a coinventor on a Polypill for Heart Failure US provisional patent application (63/912,172) filed November 2025. N.K. has received consultant fees from Heart Test Laboratories, Tricog Health, Idorsia Pharmaceuticals and Science37. M.W.S. reports nonfinancial support from Merck, honoraria outside the present study from Idorsia and Otsuka, is an advisor for AccurKardia, is on the executive board for descendantsDNA and is the founder of ReCODE Medical. A.C. has received grant funding outside the present study from Novo Nordisk, Lilly USA and Sarfez Pharmaceuticals. Z.L.C. reports grants from AstraZeneca and personal fees from Abiomed, Vectorious, Kestra Medical Technologies, Reprieve Cardiovascular, WhiteSwell and Lexicon Pharmaceuticals. D.K.G. has received honoraria as an advisor to Novo Nordisk and research support from the NHLBI (R01HL153607, R01HL145293, R01HL133860). M.T.H. has served as a consultant for Imricor Medical Systems Inc. T.J.W. is named as a coinventor on a Polypill for Heart Failure US provisional patent application (63/912,172) filed November 2025 and another application related to technologies for producing combination pills. The other authors declare no competing interests.
Dr Miller -- Spot on point! Before reading any study, always review the conflict of interest statements. As soon as you see industry funding, throw the article into the trash.
Oh my.
Every day providers in primary care hear from people who are concerned about how many pills they are taking (supplements they choose to take don’t count to them), how confused they are about what to take and when, etc. If you could get the dosage right, and it’s covered by insurance, adherence would improve. I don’t know if adherence would improve outcomes, but that’s more a test of GDMT.
Is a polypill better than a number of individual pills? In concept, I would think that it certainly is. Dr. Mandrola, you raise important practical concerns, chief being that with a polypill, it is difficult or not possible to adjust component doses to the individual's needs.
I see an added concern which I would imagine necessitates a far larger trial than ~100 people per arm: Even with an RCT there is a confounding effect, a bias that is difficult to adjust for with a small open-label trial. Some (maybe many) of the people in the trial may be particularly health conscious and therefore more than willing to take quite a number of pills per day. Other than taking their meds, what else are these people doing to address their cardiac health? Only a far larger trial will smooth the effects on the results across the 2 arms. Another issue is cost. For people who are uninsured, total cost per day will be a factor, quite possibly an important one. Is a polypill less costly than several individual pills? Again, only a far larger trail will address the effect on the results.
I would think that this trail is an important early step but in my view, it is far too small to address the confounding effects.
Too small. Too weak end points. Marginal supposed improvement. And, as usual, the comparator was essentially placebo.