I see a lot of elderly patients who have been put on 4 pills who come with hypotension and falls or simply don't feel well. I have to take them.off the drug one by one till I identify the culprit. Not a good idea. Better start gradually.
Would the pill be more beneficial than safer tadalafil?
The study utilized the United States Collaborative Network, which includes data from over 50 million men within the TriNetX global database. For the study, researchers evaluated more than 500,000 men aged 40 or older diagnosed with erectile dysfunction between February 2004 and February 2021. Outcomes in men prescribed tadalafil or sildenafil were compared to those diagnosed with erectile dysfunction who did not receive the medications. Key findings include:
Mortality: 34% reduction with tadalafil, 24% with sildenafil
Heart Attack: 27% reduction with tadalafil, 17% with sildenafil
Stroke: 34% reduction with tadalafil, 22% with sildenafil
Venous Thromboembolism: 21% reduction with tadalafil, 20% with sildenafil
Dementia: 32% reduction with tadalafil, 25% with sildenafil
If a drug class name includes the word “ blocker “, aren’t we wanting to attain the maximum blockade percentage of the targeted system ? No doubt that it is appropriate to combine blockers to achieve goals of therapy by impacting different sites of the pathophysiology and, common sense would have us believe that lower doses would cause less side effects, but, do they really? In my experience, the incidence of ACE angioedema, clinically significant hyperkalemia, cough and transient decrease in GFR, is not as common as reported. Individualized therapy is the standard and, once the goal is achieved by careful combination and titration, then one can consider the poly pill.
If a person has a bad reaction of any kind to the polypill how does one assess which drug is the culprit ? or is it the combination itself?
isn’t one drug at a time safer to begin with and only later once the patient is tolerating the regimen offer the polypill for convenience and long term compliance ?
I see the polypill as useful in some cases, but not in all. Old and/or fragile patients with multiple comorbidities need precision medicine, not a shotgun approach. That is the challenge and beauty of being a clinician and not just a drug dispenser.
It does sound like a great concept until you look under the hood. Polypill might not be the best regimen for CHF or cardiac pts but as one reader noted it seems ideal for HIV management. Great article.
We have been using poly pills in HIV for years. We call them fixed dose combination tablets. I'm not aware of RCTs Vs individual tablets but it's clear that patients love them.
Yes, when I started it was 3 pills in the morning and 2 at night, plus the co trimoxazole, perhaps TB Rx even fluconazole. The one tablet once a day for the HIV has been really helpful.
That's a great example of a successful polypill. I think what's different in the heart failure setting is the frequent need to titrate up and down the different components, which is not so much the case in HIV.
Yes, I completely agree. In South Africa we can procure 1 pill that can treat the vast majority of patients with HIV, which is quite different to heart failure
Dr. Mandrola, the most important of your concerns is that the polypill doesn't allow for optimization of the dosages of its component drugs. As both a patient and a (retired) prescriber, I'd prefer to take more pills and receive the dosages individualized to my needs.
In the current healthcare system where people have their health insurance for less than 2 years and change PCPs so many times I worry about the logistics of the polypill. I still see patients on DAPT years out from their stent placement or on a beta blocker for hypertension. I have to stop their ACE-I because they are also taking a peptide or supplement that's shooting their K sky-high. When I think about the percent of people who have a predictable enough healthcare journey to qualify for such a medication few people come to mind.
Speaking as a patient on those same four categories of pills, for the same condition (even with a heart function of 20%!) I would be most hesitant to subject myself to a one-size-fits-all dose for mere convenience. Yes, several dose combos would be available, but how many patients would fit into those same slots? As it is, my cardiologist had to tweak 3 out of 4 of my meds over a period of months to finally reach a highly satisfactory result for me — heart function now at 50%, and no real side effects. OK, a much lower bp, but no symptoms from that, either.
Can't comment on study structure, but trust what you say about it. But if I had a choice, I would take multiple pills over a polypill any day.
That being said, I have great sympathy for patients with no real understanding of medicine or pharmaceuticals. How do they even begin to take their meds properly, at the right time, with or without food, juggling side effects. Good grief, I have trouble enough managing my pill load (cardiac and cancer meds), and I was trained as a pharmacist!
There are already outcome measures that lead to Cardiology initiating one or more of the GDMT classes on hospital discharge or in clinic visits. There are many potential difficulties with low blood pressure, high potassium, dehydration, or kidney problems. Making it very easy to start all four at once sounds terrifying.
And yet your other point is undoubtedly true. If a person had the components titrated over time to a good combination, a single pill would really be great for patient convenience.
Both groups were on sacubitril and valsartan, and presumably many were on diuretics stronger than spironolactone. Or not ?
My experience with sacubitril-valsartan is that the incidence of clinically significant hypotension is quite high, leading to a need to reduce the other meds to counter it. A polypill would make such fine tuning more difficult.
I agree that a 3% difference in EF is physiologically and clinically meaningless. It would not be a reason for adopting this.
I also agree the KCCQ stuff must be taken with a lump of salt given open label design. OTOH, there would be no way to blind taking fewer pills vs more pills (1 poly pill vs 3 active pills…and adding 2 placebo pills in the “polypill” arm would literally defeat the purpose of the polypill). So I’m not sure if there is a way to get around that.
I wonder if this question might lend itself to non-inferiority design (assuming a very strict margin). The “benefit” of popping fewer pills every day might justify some tradeoff in efficacy.
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.
I see a lot of elderly patients who have been put on 4 pills who come with hypotension and falls or simply don't feel well. I have to take them.off the drug one by one till I identify the culprit. Not a good idea. Better start gradually.
Would the pill be more beneficial than safer tadalafil?
The study utilized the United States Collaborative Network, which includes data from over 50 million men within the TriNetX global database. For the study, researchers evaluated more than 500,000 men aged 40 or older diagnosed with erectile dysfunction between February 2004 and February 2021. Outcomes in men prescribed tadalafil or sildenafil were compared to those diagnosed with erectile dysfunction who did not receive the medications. Key findings include:
Mortality: 34% reduction with tadalafil, 24% with sildenafil
Heart Attack: 27% reduction with tadalafil, 17% with sildenafil
Stroke: 34% reduction with tadalafil, 22% with sildenafil
Venous Thromboembolism: 21% reduction with tadalafil, 20% with sildenafil
Dementia: 32% reduction with tadalafil, 25% with sildenafil
https://www.utmb.edu/news/article/utmb-news/2024/11/19/study-finds-erectile-dysfunction-medications-associated-with-significant-reductions-in-deaths--cardiovascular-disease--dementia
How does it benefit the pharma? I mean that's pretty much all that one needs to know, methinks. Color me jaded.
If a drug class name includes the word “ blocker “, aren’t we wanting to attain the maximum blockade percentage of the targeted system ? No doubt that it is appropriate to combine blockers to achieve goals of therapy by impacting different sites of the pathophysiology and, common sense would have us believe that lower doses would cause less side effects, but, do they really? In my experience, the incidence of ACE angioedema, clinically significant hyperkalemia, cough and transient decrease in GFR, is not as common as reported. Individualized therapy is the standard and, once the goal is achieved by careful combination and titration, then one can consider the poly pill.
If a person has a bad reaction of any kind to the polypill how does one assess which drug is the culprit ? or is it the combination itself?
isn’t one drug at a time safer to begin with and only later once the patient is tolerating the regimen offer the polypill for convenience and long term compliance ?
I see the polypill as useful in some cases, but not in all. Old and/or fragile patients with multiple comorbidities need precision medicine, not a shotgun approach. That is the challenge and beauty of being a clinician and not just a drug dispenser.
It does sound like a great concept until you look under the hood. Polypill might not be the best regimen for CHF or cardiac pts but as one reader noted it seems ideal for HIV management. Great article.
We have been using poly pills in HIV for years. We call them fixed dose combination tablets. I'm not aware of RCTs Vs individual tablets but it's clear that patients love them.
I recall asking patients to take 3 Saquinavir caplsues every 6 hours plus AZT and 3TC twice a day. That’s was Guideline.
It got “better” when Saquinavir was changed to 2 Indinavirs every eight hours.
Oh and one DS Trimethoprim Sulfa Monday Wednesday and Friday, too.
Fixed combo is a godsend for these patients.
Yes, when I started it was 3 pills in the morning and 2 at night, plus the co trimoxazole, perhaps TB Rx even fluconazole. The one tablet once a day for the HIV has been really helpful.
That's a great example of a successful polypill. I think what's different in the heart failure setting is the frequent need to titrate up and down the different components, which is not so much the case in HIV.
Yes, I completely agree. In South Africa we can procure 1 pill that can treat the vast majority of patients with HIV, which is quite different to heart failure
Dr. Mandrola, the most important of your concerns is that the polypill doesn't allow for optimization of the dosages of its component drugs. As both a patient and a (retired) prescriber, I'd prefer to take more pills and receive the dosages individualized to my needs.
In the current healthcare system where people have their health insurance for less than 2 years and change PCPs so many times I worry about the logistics of the polypill. I still see patients on DAPT years out from their stent placement or on a beta blocker for hypertension. I have to stop their ACE-I because they are also taking a peptide or supplement that's shooting their K sky-high. When I think about the percent of people who have a predictable enough healthcare journey to qualify for such a medication few people come to mind.
Speaking as a patient on those same four categories of pills, for the same condition (even with a heart function of 20%!) I would be most hesitant to subject myself to a one-size-fits-all dose for mere convenience. Yes, several dose combos would be available, but how many patients would fit into those same slots? As it is, my cardiologist had to tweak 3 out of 4 of my meds over a period of months to finally reach a highly satisfactory result for me — heart function now at 50%, and no real side effects. OK, a much lower bp, but no symptoms from that, either.
Can't comment on study structure, but trust what you say about it. But if I had a choice, I would take multiple pills over a polypill any day.
That being said, I have great sympathy for patients with no real understanding of medicine or pharmaceuticals. How do they even begin to take their meds properly, at the right time, with or without food, juggling side effects. Good grief, I have trouble enough managing my pill load (cardiac and cancer meds), and I was trained as a pharmacist!
Spot on
There are already outcome measures that lead to Cardiology initiating one or more of the GDMT classes on hospital discharge or in clinic visits. There are many potential difficulties with low blood pressure, high potassium, dehydration, or kidney problems. Making it very easy to start all four at once sounds terrifying.
And yet your other point is undoubtedly true. If a person had the components titrated over time to a good combination, a single pill would really be great for patient convenience.
Both groups were on sacubitril and valsartan, and presumably many were on diuretics stronger than spironolactone. Or not ?
My experience with sacubitril-valsartan is that the incidence of clinically significant hypotension is quite high, leading to a need to reduce the other meds to counter it. A polypill would make such fine tuning more difficult.
Poly pills always more expensive and often not covered
I agree that a 3% difference in EF is physiologically and clinically meaningless. It would not be a reason for adopting this.
I also agree the KCCQ stuff must be taken with a lump of salt given open label design. OTOH, there would be no way to blind taking fewer pills vs more pills (1 poly pill vs 3 active pills…and adding 2 placebo pills in the “polypill” arm would literally defeat the purpose of the polypill). So I’m not sure if there is a way to get around that.
I wonder if this question might lend itself to non-inferiority design (assuming a very strict margin). The “benefit” of popping fewer pills every day might justify some tradeoff in efficacy.
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.