Excellente review, but it should be noted that in the Deliver trial, Dapagliflozin significantly reduced the total number of hospitalizations for any cause. https://www.jacc.org/doi/10.1016/j.jacc.2022.12.026
Excellent review.As a investigator and author in the DIG trial, and at one of the largest site .In my job as an educator of Fellows,Residents and Students there are several things to learn from the DIG trial and was just discussed with my CCU team n rounds last week.
First the Inclusion criteria were picked due to the knowledge that DIGOXIN was felt to be beneficial in the HFrEF population with Afib, LVEF<20% and Class4 CHF when the study was designed in the late 80's and 90's.That is why the trial was done in the way it was.
Second-the Paper, when originally submitted was meant to include only the primary outcome (which it did not meet) but due to editorial review, comments and approvals , the secondary endpoint of Hospitalization were added to the final manuscript.
However, as you state, it should not be tossed out, because not only is important for mortality to be affected but also quality of life,an this includes being able not to have our patients hospitalized.I think you make a great point comparing it to the Empagliflozin data, sometime it is all in the details and who is pushing the agenda and guidelines.
Finally, you are very correct, the incidence of Dig toxicity is low from what it was in the 80's and 90's and this was mainly due to the algorithm decided for the trial and its validation one first 500 or so patients with level monitoring that changed the way digoxin was ordered.
However, intravenous digoxin in hypotensive patients with rapid afib (especially if we can't give amiodarone) is a crucial tool for inpatient cardiologists. I don't need an RCT to know it is safe and effective. But be very careful with loading dosages and monitor dig levels carefully.
A systematic review (which some consider the highest form of evidence) of observational studies on digitalis from 2017 found
-In patients already taking digoxin, mortality was not higher in digoxin users, however, the risk of death was related to dig levels: for every 0.5 ng/ml increase in dig level, the risk of death rose by 19 percent and if dig level was >1.2 ng/ml the death rate increased by 56 percent.
–Patients not taking digoxin before the trial who began taking it over the course of the study had a 78 percent increase in the risk of death from any cause and a four-fold increased risk of sudden death after starting digoxin use. Most sudden deaths occurred within six months after digoxin was started.
–Risk of death with initiation of digoxin was increased in patients with and without heart failure.
But we know that these observational studies are hopelessly confounded no matter how much they attempt to account for differing variables and the RCT is what we should rely on.
I used digoxin extensively throughout my decades of practice. I tried some of the newer drugs as they came out but almost always came back to the digoxin. None of the newer drugs ever showed me that they managed atrial flutter/fibrillation or congestive heart failure any better than digoxin. I think the scare talk about digitalis toxicity harked back to the days when digitalis leaf was used and it was very difficult to know what dose the patient was getting. I never saw digitalis toxicity with the standard dose tablets of digoxin. We would simply tailor the dose or frequency to the particular patient's renal function and clinical response. When compared to the newer drugs it's efficacy was at least equal and frequently better. Side effects were practically nonexistent and it was much, much cheaper.
This posting reminds me of a woman, about age 65, once referred to me (a general internist) in desparation by her family doctor. Having enjoyed power and respect as an elementary school teacher in charge of her own classroom, she had little tolerance for doctors telling her what to do. Also, she had been unable to tolerate heart-rate controlling drugs (various beta-blockers, calcium channel antagonists) and was unwilling to try any others.
When I met her, she could barely walk from waiting room to examining room, and turned out to be (quietly) in frank pulmonary edema with very fast heart rate and ECG proof of atrial fibrillation, but no valvular disease. At my suggestion to try digoxin, in which I thought I might interest her as an "entirely different older drug that few people still know how to use", my friendly South Africa-trained cardiologist colleague agreed to admit her to a CCU - perhaps the first time in recent memory that anyone was admitted to be "digitalized."
This treatment worked like hot damn to slow her heart rate, bringing her out of pulmonary edema and back to independent function. She was never willing to try anything else, and insisted that digoxin had saved her life (I agreed). Over some years she never lost her crustiness, but she did lose a great deal of weight and at least 10 years later was thriving. This was almost certainly not an accident, iin my opinion.
The narrow therapeutic window and need for drug level monitoring are the practical limitations for its use. That said, I have tended to use it still in pts with AF and HFrEF (where a common alternative, amiodarone, also has onerous monitoring requirements).
This is a great reminder to not dismiss dig entirely. I think, 26 years on from the trial, I still harbor some biases against it (for not reducing mortality); yet accept newer drugs which similarly don’t do so. This realization of my own cognitive dissonance is disquieting but useful.
I was rather surprised to learn that Dig was 1st approved for human use by the FDA in 1998. In Veterinary Medicine, we were using it in the 1970s in dogs with valvular CHF. It can be quite helpful for dogs but as in people the margin of safety is narrow & it is a bit tricky, especially since many of our heart failure patients weight 5-20 lbs. Alas, it has also fallen out of favor in VM.
I endorse your viewpoint. Somehow Digoxin is out-of-common-use now, largely because of other less toxic molecules with proven efficacy and safety. However Tab. Digoxin 0.0625mg/d with monitoring of S. Digoxin levels must be continued. Please beware a drug may be highly effective in clinical trials but may carry poor effectiveness in common use. Earlier we were using 0.25mg/d of Digoxin and toxicities were commonly encountered.
Digoxin in small doses, 0.0625 mg, works very well for rate control in combination with other drugs in atrial fibrillation and as an adjunct in heart failure treatment. Thanks for the review.:))
Digoxin and a dedicated cardiologist enabled my mother to reach 79 after developing heart valve damage in her 20s and heart valve replacement surgery in her early 70s.
Still waiting for the healthy heart herb trial or the HHH study that proves herbs are far better than any drugs for heart health. That is along with lifestyle changes and the elimination of not so healthy habits and actions. Of course, that study will never happen because it would bust the false heart protocols to smithereens and put tens of thousands of medicos out on the streets.
Your detailed objective reviews of the literature are priceless. For digoxin your observation that studies with unfavorable outcomes have common characteristics. They are prospective with the digoxin arm having sicker patients and the dosages used were too high. The outcome,then as expected is sicker patients developing dig toxicity. I have noticed this pattern of science unfortunately in our current FDA approval process. HHS terminated the FDA Unapproved Drug Initiative in November 2020 for multiple reasons one being the pattern of older drugs being shown in a bad light in comparison to newer patented alternatives. Indeed digoxin would fall in to this category of drugs in use prior to June 25, 1938 when the FDA was created by Congress. HHS found this element of the FDA Modernization Act resulted in exclusion of generics in lieu of costly alternatives. I first noticed this pattern when a new and very expensive expensive IV anti emetic medication Zoltan was introduced and the tried and true anti emetic droperidol was given a black box warning for prolonged QT syndrome. More recently strange biases emerged with the COVID pandemic. Early in the pandemic there were two fraudulent studies published in the Lancet and NEJM. These were touted by NIH and CDC government public health officials as the end of HCQ as a treatment for COVID on the very day the articles appeared on the pre print server with no peer review.. One demonstrated the inexpensive medication HCQ did not demonstrate efficacy and the other demonstrated unexpected severe toxicities. Both studies were retracted for fraudulent data. Indeed one week of peer review revealed the studies were entirely falsified. At the time Prodromos at U Illinois reviewed all the HCQ literature presumably searching for any patterns of bias or worse yet fraud. Of the 43 published reports 25 reported efficacy for HCQ 15 showed no improvement and 3 demonstrated negative efficacy. Fortunately no additional fraudulent papers were found. Their conclusions were that HCQ was consistently effective in unbiased studies. 11 studies treated early by design and they all demonstrated efficacy. The studies with no benefit or negative efficacy were studies where treatment was given late in doses that were known to be toxic and late in the disease that is more than 48 hours after hospital admission with most already in the ICU on ventilators. HCQ total drug treatment acquisition costs were $20 with Remdesivir costing $3100. My point here is there may be times where unexplained biases in the literature can be explained. I now analyze the potential for financial biases in the medical industrial complex before I conduct literature reviews routinely. Freedom of Information documents reveal from 2010-2020 $350M in royalty payments were received by NIH employees. Remarkably there is no requirement for disclosure revealing who paid how much to whom. We know NIH employees Fauci received 23 royalty payments and NIH Director Collins received 14 royalty payments and Clifford Lane 8 royalty payments in this period. We are not permitted to know how much was paid and which companies or drugs were subject to royalty payments. I have formally recommended all such payments be fully disclosed. I know you work very hard with your reviews. The presence of royalty payments to key officials is pertinent to implicit biases in study design. The NIH awards $30B per year to roughly 56,000 researchers per year. The refusal of NIH to provide transparency on $350M in royalty payments to its employees makes me suspicious of NIH studies having a higher rate of unintentional or intentional biases in study design.
Very, very interesting. I've been using the CMS "dollars for docs" database when reading papers in medical journals. But it never occurred to me that royalty payments to NIH employees would not be open to the same scrutiny. And if there could be conflict of interest for doctors, whether clinicians or researchers, the scale of such a conflict caused by royalty payments seems so much greater.
Thank you for this article. I trained in the early 90’s and still use digoxin as well. It is quite useful, acts more rapidly than amiodarone, and is well tolerated. It requires attention from the physician which in my experience is in short supply with the advent of the hospitalist system. I would second the request above for afib primer.
Thanks for another nice analysis. In case you happen to read this, I have a request. Since more and more folks are wearing smart watches with ECG's, could you write a basic primer on AFib, including your recommendations? I can read the guidelines but would like to know your thoughts. You've written quite a few articles on the topic that include looking at trials, but maybe you could summarize them.
Excellente review, but it should be noted that in the Deliver trial, Dapagliflozin significantly reduced the total number of hospitalizations for any cause. https://www.jacc.org/doi/10.1016/j.jacc.2022.12.026
Excellent review.As a investigator and author in the DIG trial, and at one of the largest site .In my job as an educator of Fellows,Residents and Students there are several things to learn from the DIG trial and was just discussed with my CCU team n rounds last week.
First the Inclusion criteria were picked due to the knowledge that DIGOXIN was felt to be beneficial in the HFrEF population with Afib, LVEF<20% and Class4 CHF when the study was designed in the late 80's and 90's.That is why the trial was done in the way it was.
Second-the Paper, when originally submitted was meant to include only the primary outcome (which it did not meet) but due to editorial review, comments and approvals , the secondary endpoint of Hospitalization were added to the final manuscript.
However, as you state, it should not be tossed out, because not only is important for mortality to be affected but also quality of life,an this includes being able not to have our patients hospitalized.I think you make a great point comparing it to the Empagliflozin data, sometime it is all in the details and who is pushing the agenda and guidelines.
Finally, you are very correct, the incidence of Dig toxicity is low from what it was in the 80's and 90's and this was mainly due to the algorithm decided for the trial and its validation one first 500 or so patients with level monitoring that changed the way digoxin was ordered.
Stop and think! Always thoughtful and sensible, thank you Dr. Mandrola.
As always I greatly appreciate Dr. Mandrola''s observations.
The use of foxglove to treat dropsy is a fascinating and instructive chapter in the history of medicine.(https://theskepticalcardiologist.com/2015/07/11/foxglove-equipoise/)
I've been questioning for the last 10 years whether the death knell has sounded for digoxin in heart failure.(https://theskepticalcardiologist.com/2021/02/13/the-false-allure-of-natural-treatments-and-the-lessons-learned-from-foxglove/)
However, intravenous digoxin in hypotensive patients with rapid afib (especially if we can't give amiodarone) is a crucial tool for inpatient cardiologists. I don't need an RCT to know it is safe and effective. But be very careful with loading dosages and monitor dig levels carefully.
A systematic review (which some consider the highest form of evidence) of observational studies on digitalis from 2017 found
-In patients already taking digoxin, mortality was not higher in digoxin users, however, the risk of death was related to dig levels: for every 0.5 ng/ml increase in dig level, the risk of death rose by 19 percent and if dig level was >1.2 ng/ml the death rate increased by 56 percent.
–Patients not taking digoxin before the trial who began taking it over the course of the study had a 78 percent increase in the risk of death from any cause and a four-fold increased risk of sudden death after starting digoxin use. Most sudden deaths occurred within six months after digoxin was started.
–Risk of death with initiation of digoxin was increased in patients with and without heart failure.
But we know that these observational studies are hopelessly confounded no matter how much they attempt to account for differing variables and the RCT is what we should rely on.
AP
I used digoxin extensively throughout my decades of practice. I tried some of the newer drugs as they came out but almost always came back to the digoxin. None of the newer drugs ever showed me that they managed atrial flutter/fibrillation or congestive heart failure any better than digoxin. I think the scare talk about digitalis toxicity harked back to the days when digitalis leaf was used and it was very difficult to know what dose the patient was getting. I never saw digitalis toxicity with the standard dose tablets of digoxin. We would simply tailor the dose or frequency to the particular patient's renal function and clinical response. When compared to the newer drugs it's efficacy was at least equal and frequently better. Side effects were practically nonexistent and it was much, much cheaper.
This posting reminds me of a woman, about age 65, once referred to me (a general internist) in desparation by her family doctor. Having enjoyed power and respect as an elementary school teacher in charge of her own classroom, she had little tolerance for doctors telling her what to do. Also, she had been unable to tolerate heart-rate controlling drugs (various beta-blockers, calcium channel antagonists) and was unwilling to try any others.
When I met her, she could barely walk from waiting room to examining room, and turned out to be (quietly) in frank pulmonary edema with very fast heart rate and ECG proof of atrial fibrillation, but no valvular disease. At my suggestion to try digoxin, in which I thought I might interest her as an "entirely different older drug that few people still know how to use", my friendly South Africa-trained cardiologist colleague agreed to admit her to a CCU - perhaps the first time in recent memory that anyone was admitted to be "digitalized."
This treatment worked like hot damn to slow her heart rate, bringing her out of pulmonary edema and back to independent function. She was never willing to try anything else, and insisted that digoxin had saved her life (I agreed). Over some years she never lost her crustiness, but she did lose a great deal of weight and at least 10 years later was thriving. This was almost certainly not an accident, iin my opinion.
The narrow therapeutic window and need for drug level monitoring are the practical limitations for its use. That said, I have tended to use it still in pts with AF and HFrEF (where a common alternative, amiodarone, also has onerous monitoring requirements).
This is a great reminder to not dismiss dig entirely. I think, 26 years on from the trial, I still harbor some biases against it (for not reducing mortality); yet accept newer drugs which similarly don’t do so. This realization of my own cognitive dissonance is disquieting but useful.
I was rather surprised to learn that Dig was 1st approved for human use by the FDA in 1998. In Veterinary Medicine, we were using it in the 1970s in dogs with valvular CHF. It can be quite helpful for dogs but as in people the margin of safety is narrow & it is a bit tricky, especially since many of our heart failure patients weight 5-20 lbs. Alas, it has also fallen out of favor in VM.
Heart failure approval 1998. Initial approval in 1954 for rate control.
Not just in vet med, but during my early Rx days in the 70s. I'm confused...
I endorse your viewpoint. Somehow Digoxin is out-of-common-use now, largely because of other less toxic molecules with proven efficacy and safety. However Tab. Digoxin 0.0625mg/d with monitoring of S. Digoxin levels must be continued. Please beware a drug may be highly effective in clinical trials but may carry poor effectiveness in common use. Earlier we were using 0.25mg/d of Digoxin and toxicities were commonly encountered.
Digoxin in small doses, 0.0625 mg, works very well for rate control in combination with other drugs in atrial fibrillation and as an adjunct in heart failure treatment. Thanks for the review.:))
Digoxin and a dedicated cardiologist enabled my mother to reach 79 after developing heart valve damage in her 20s and heart valve replacement surgery in her early 70s.
Still waiting for the healthy heart herb trial or the HHH study that proves herbs are far better than any drugs for heart health. That is along with lifestyle changes and the elimination of not so healthy habits and actions. Of course, that study will never happen because it would bust the false heart protocols to smithereens and put tens of thousands of medicos out on the streets.
Your detailed objective reviews of the literature are priceless. For digoxin your observation that studies with unfavorable outcomes have common characteristics. They are prospective with the digoxin arm having sicker patients and the dosages used were too high. The outcome,then as expected is sicker patients developing dig toxicity. I have noticed this pattern of science unfortunately in our current FDA approval process. HHS terminated the FDA Unapproved Drug Initiative in November 2020 for multiple reasons one being the pattern of older drugs being shown in a bad light in comparison to newer patented alternatives. Indeed digoxin would fall in to this category of drugs in use prior to June 25, 1938 when the FDA was created by Congress. HHS found this element of the FDA Modernization Act resulted in exclusion of generics in lieu of costly alternatives. I first noticed this pattern when a new and very expensive expensive IV anti emetic medication Zoltan was introduced and the tried and true anti emetic droperidol was given a black box warning for prolonged QT syndrome. More recently strange biases emerged with the COVID pandemic. Early in the pandemic there were two fraudulent studies published in the Lancet and NEJM. These were touted by NIH and CDC government public health officials as the end of HCQ as a treatment for COVID on the very day the articles appeared on the pre print server with no peer review.. One demonstrated the inexpensive medication HCQ did not demonstrate efficacy and the other demonstrated unexpected severe toxicities. Both studies were retracted for fraudulent data. Indeed one week of peer review revealed the studies were entirely falsified. At the time Prodromos at U Illinois reviewed all the HCQ literature presumably searching for any patterns of bias or worse yet fraud. Of the 43 published reports 25 reported efficacy for HCQ 15 showed no improvement and 3 demonstrated negative efficacy. Fortunately no additional fraudulent papers were found. Their conclusions were that HCQ was consistently effective in unbiased studies. 11 studies treated early by design and they all demonstrated efficacy. The studies with no benefit or negative efficacy were studies where treatment was given late in doses that were known to be toxic and late in the disease that is more than 48 hours after hospital admission with most already in the ICU on ventilators. HCQ total drug treatment acquisition costs were $20 with Remdesivir costing $3100. My point here is there may be times where unexplained biases in the literature can be explained. I now analyze the potential for financial biases in the medical industrial complex before I conduct literature reviews routinely. Freedom of Information documents reveal from 2010-2020 $350M in royalty payments were received by NIH employees. Remarkably there is no requirement for disclosure revealing who paid how much to whom. We know NIH employees Fauci received 23 royalty payments and NIH Director Collins received 14 royalty payments and Clifford Lane 8 royalty payments in this period. We are not permitted to know how much was paid and which companies or drugs were subject to royalty payments. I have formally recommended all such payments be fully disclosed. I know you work very hard with your reviews. The presence of royalty payments to key officials is pertinent to implicit biases in study design. The NIH awards $30B per year to roughly 56,000 researchers per year. The refusal of NIH to provide transparency on $350M in royalty payments to its employees makes me suspicious of NIH studies having a higher rate of unintentional or intentional biases in study design.
Very, very interesting. I've been using the CMS "dollars for docs" database when reading papers in medical journals. But it never occurred to me that royalty payments to NIH employees would not be open to the same scrutiny. And if there could be conflict of interest for doctors, whether clinicians or researchers, the scale of such a conflict caused by royalty payments seems so much greater.
Thank you for this article. I trained in the early 90’s and still use digoxin as well. It is quite useful, acts more rapidly than amiodarone, and is well tolerated. It requires attention from the physician which in my experience is in short supply with the advent of the hospitalist system. I would second the request above for afib primer.
Thanks for another nice analysis. In case you happen to read this, I have a request. Since more and more folks are wearing smart watches with ECG's, could you write a basic primer on AFib, including your recommendations? I can read the guidelines but would like to know your thoughts. You've written quite a few articles on the topic that include looking at trials, but maybe you could summarize them.