It's time to rethink the role of digoxin

It doesn't look like a very hazardous plant. Tall, with pink-purple flowers, foxglove can grow like a weed. But just as weeds spread and persist, so has the legend of prescribing digoxin.

It all started--as many things do in medicine—with a good idea. I remember reading my first cardiac physiology book, don't you? As a Connecticut guy, the legendary text was Physiology of the Heart by Dr Arnold Katz. Inside those pages is where I first learned that blocking the Na-K exchanger led to a rise in intracellular sodium, which in turn (via a Na-Ca exchanger) led to higher intracellular calcium. This had to be a good thing because more calcium meant more vigorous contraction of the heart muscle. And if that wasn't enough goodness, for patients with AF, digoxin somehow exerted a vagal effect (slowing) on AV node conduction.

For controlling the ventricular rate of atrial fibrillation, digoxin became a no-brainer. Enhanced contractility and a slower ventricular rate—what's not to like?

This isn't old thinking; it's ancient thinking—and it has persisted for nearly a half-century. Some current estimates have at least a third of patients with AF on digoxin. To this day, I still see "dig" mistakenly used as a rhythm-control drug.

If I had a favorite theme to write about it, it would be how new information proves old thinking incorrect. That's why I want to meander a bit about this newest analysis of the role of digoxin in patients with AF. (Great coverage by Sue Hughes.)

Ten years after the landmark AFFIRM trial told us that rhythm control was no better than rate control in asymptomatic patients with AF, its trove of clinical data continues to bear fruit. Seriously, AFFIRM has taught us so much.

Most recently, University of Kentucky researchers published a post hoc analysis of AFFIRM data. As surprisingly few studies have been done on digoxin and AF, the researchers aimed to determine the relationship between mortality and digoxin in a real-world cohort. The AFFIRM data are well suited for this sort of analysis, as nearly 70% of all patients in the study were exposed to digoxin. (Of note: my previous group in Louisville participated in AFFIRM. We are solidly real world.)

The results were eye-opening. Patients treated with digoxin had a 41% higher mortality rate. This finding persisted after control of comorbidities and propensity scores, across gender, and in both patients with and without heart failure. The study is available for free at the European Heart Journal. Basically, in this asymptomatic cohort, there was nothing good about being on digoxin.

A quick note on methodology. Although this was an after-the-fact analysis, the investigators used rigorous statistical methods, including the consideration of many covariates and matching propensity scores. These sorts of maneuvers are necessary when analyzing data from a clinical trial designed to compare something else. The investigators clearly state that AFFIRM did not randomize patients to digoxin therapy, so confounding is always possible. That's an important point.

So let's ask: Do these striking findings make sense?

First, we know that digoxin is a drug with a very narrow therapeutic window. Like all ion-active antiarrhythmic drugs, digoxin excess can cause both brady- and tachyarrhythmia. I don't have to tell you about this because examples of dig-toxic rhythms still populate board exams.

Second, the pharmacokinetics (I hate using that word) of digoxin presents many challenges. It has a long half-life, slow onset of action, and numerous drug interactions and is excreted by the kidneys. Since many patients with AF take other meds and have other diseases, this is a real problem.

Third, no trial has ever shown that digoxin reduces mortality. There have been negative trials, neutral trials, or those that show improved secondary outcomes, like improved quality of life or hospitalizations, for instance, but outcome-wise, digoxin remains solidly in the dubious category.

Fourth, in looking at the largest trial of digoxin, it was clear that digoxin benefit was seen only when levels were monitored closely and kept at low levels. I can attest that in the real world achieving this sort of exquisite control is challenging. It's one thing to control dig levels in a clinical trial, with an army of extenders at your disposal; it's yet another to do it in the real world.

My bottom line:

We have recently learned that an aggressive rate-control strategy in AF offers little benefit over a more lenient strategy. This makes it less imperative to pour rate-controlling AF medicines into our patients. It lessens the need for digoxin. (As a concept, this also aligns well with my bias to a less-is-more approach to all things medical.)

In an era where beta blockers are easily available and inexpensive, I see little role for the widespread use of digoxin. It's time to let go of ancient thinking. (As an aging bike racer, I can assure you that things change over decades.)

In selected cases where the benefits of digoxin may outweigh its burdens, I'd lean strongly toward the lowest dose, and I'd make a commitment to monitoring of drug levels—with a goal of 0.5–0.8.

A final caveat: It is the personal (and anecdotal experience) of this blogger that IV-digoxin remains useful for the acute and short-term control of rapidly conducting atrial tachyarrhythmias, especially in hospitalized patients with low blood pressure.

It's a pretty plant, but we must be careful with it.

JMM

PS. Here is a nice review on digoxin: Gheorghiade M, Van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation 2006; 113:2556-2564. Available here.

Your comments

	It's time to rethink the role of digoxin
	# 1 of 7	December 3, 2012 12:00 (EST)
	John Mandrola	Sorry about that. In my neck of the woods, "UK" refers to University of Kentucky. I'll fix the error.
	# 2 of 7	December 3, 2012 12:00 (EST)
	John Mandrola	As always Ken, your comments are excellent. I worried about this post, for the reasons you set out. In a 800-1000 word post, it's difficult to touch on the nuances of each study. (Another reason why I am glad you take the time to comment.) Agree on all aspects. The post-hoc analysis was just that. It has statistical limitations. Also, the strict versus lenient rate-control debate isn't as clear as I implied. Patients with AF don't often follow a simple protocol. They vary a lot.   But the big picture remains the same. Digoxin remains a difficult drug to use. Its narrow therapeutic window and significant potential for toxicity combined with its complete lack of positive outcome data should give clinicians pause. Hopefully, that message comes through.
	# 3 of 7	December 3, 2012 12:00 (EST)
	MR	"...Most recently, UK researchers published a post-hoc analysis of AFFIRM data...." With due respect, I would like to mention that the researchers were not from UK but primarily from US and many from Kentucky.
	# 4 of 7	December 3, 2012 12:00 (EST)
	Ken Grauer, MD	John- I agree with your post, "It's Time to Rethink the Role of Digoxin" - and also with your words of caution, "It's a pretty plant, but we must be careful with it" - though not necessarily with your path to these accurate conclusions. I totally agree with your caveat and personal anecdotal experience: "IV Digoxin remains useful for the acute and short-term control of rapidly conducting atrial tachy-arrhythmias, esp. in hospitalized patients with low BP". During my years of practice - my anecdotal experience was the same. The post-hoc analysis of the AFFIRM Trail by UK researchers is problematic - despite the seemingly large increase in mortality. Mortality from Dig was not a primary end point of this retrospective analysis - plus NO Dig levels were required - NO monitoring of renal function was required - there was NO check on compliance - and "HF" was loosely defined as EF <40%. So while the conclusion of this study might be true - in NO WAY does this study prove it. It can't given the above methodologic flaws. Similarly - I have trouble with the Van Gelder NEJM study finding "lenient" vs "strict" rate control didn't matter - since to me a non-inferiority assessment of "resting rate <110/min" vs "resting rate <80/min plus moderate exercise rate <110/min" simply looks at two ends of the spectrum without allowance for individualized middle ground rate control. I realize objective and prospective analysis of an "individualized rate control regimen" would be a nightmare to study - but I don't think one should generalize the subject of rate control to "all or none" which is what (to me) this NEJM article does. I believe the entity of tachycardia-related cardiomyopathy (from persistent uncontrolled rapid AFib) is real - so hard to believe that some attenuation of rate (even if it doesn't achieve resting heart rate < 80/min) is not beneficial, at least in some subsets of patients. All of the above said - the reason why I have shared the views you state here is simply because the newer generation of physicians just don't have (and won't get) the experience needed using Digoxin to be able to master the intricacies of that drug. Though my specialty was not cardiology - I cared for hundreds of patients (in-hospital and out-of-hospital) in my family medicine practice who have been on Dig, or who I started on Dig. It was the "bread and butter" of my cardiology rotation during residency. Though possessing a very narrow "therapeutic window" - mastery of Dig therapeutics and ongoing patient-involved follow-up can minimize the incidence of Dig toxicity. It just requires time and effort. Alas, in my last few years of teaching - I'd find even senior residents able to count on the fingers of one hand the number of patients they started on Dig. Without thorough appreciation of how to use this drug - it is DANGEROUS. The clinical reality is that in 2012 - the experience needed to attain competency in using Dig has become elusive. It is for that reason that I no longer think of it as a drug that should be used in the non-cardiologist's armamentarium. In closing - in addition to being a "pretty plant" - the foxglove gave us art (What could be more classic than Van Gogh's portrait of his personal physician Dr. Gachet - with all wavy yellow-lines suggesting Van Gogh lived his later years in a Dig-toxic state from use of that drug in attempt to control his depression and seizures - GO TO: https://www.dropbox.com/s/sz8qibk79efl4kg/DIGoxin-Van%20Gogh-Dr%20Gachet-Dig_Tox.jpg ). The other major continuing use of Digoxin in 2012 - is that our collection of Dig-Toxic arrhythmias (albeit mainly of tracings from years past ... ) - still serves well for teaching the new generation much about arrhythmia interpretation from our fascinating array of Dig-toxic arrhythmias.
	# 5 of 7	December 7, 2012 10:14 (EST)
	Will Clementi	Pharmacokinetics This article about digoxin and "real world" data is more concerning than the drug itself. Does the analysis say that digoxin is toxic or that the prescribers do not know how to use it? It seems to me that when a physician states there are many drug interactions and digoxin is cleared from the kidneys chiefly is concerning in and of itself. And this statement is in fact some evidence that the excess mortality is due to poor monitoring and not the drug itself because pharmacokinetics are poorly understood by prescribers. Cardiologists trained today do not know digoxin from digitoxin and confuse the two. It remains concerning that prescribing of cardiac medications will rely on real world data and not uniformly prospective studies to make swiping conclusions about a drug or device. And that because of complex numerical methods cardiologist will assume any conclusion is valid. This is an example of that method and the failure of it. Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 6 of 7	December 12, 2012 04:44 (EST)
	james young	Difficulty of Use of Digoxin The author has pointed out that safe and effective use of Digoxin is difficult, and perhaps too difficult for widespread use by clinicians not adequately versed in its pitfalls. Optimum safety requires assiduous monitoring of renal function, digoxin levels, and levels of potassium and magnesium. Awareness of drug interactions is also critical,and these relate not only to pharmacokinetics, but also synergistic and antagonistic effects on its mode of action and desired effects on AV conduction and inotropy. Perhaps more importantly use should be restricted to situations where it is more efficacious. In this regard, the drug is more useful for volume overload as opposed to pressure overload, and useful for systolic dysfuction-particularly with LV or RV enlargement, and not useful for diastolic dysfunction. Probably countless patients have been intoxicated with digoxin over the years while being treated inappropriately for CHF due to diastolic dysfunction or aortic stenosis and other similar lesions. Another example would be inflow obstruction due to mitral stenosis. I agree with the author that use of the IV drug has been helpful in the management of hypotensive patients with rapid atrial fibrillation. ( although often modifying the use of catecholamines is key.) Severe and refractory cases of congestive heart failure due to very low ejection fraction remains an indication, as well, as an adjunct to optimal use of diuretics, vasodilators, beta blockers, and ACE inhibitors. Awareness of drug inteactions Author's disclosure (Dec 12, 2012) I have no relevant disclosures to make in connection with this topic.
	# 7 of 7	January 4, 2013 09:17 (EST)
	D. Davis	Use Digixon with Caution Digoxin Must Be Used With Caution Digoxin may place more stress on the heart of a patient with HF. A negative effect results when digoxin is used because the medicine slows the heart when it needs oxygen exchange but is somewhat restrained due to fluid retention. Administering digoxin can result in a toxic-like reaction. The heart rate is reduced just when it needs oxygen. Use it with caution. Author's disclosure (Jan 4, 2013) I have no relevant disclosures to make in connection with this topic.

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