Dr John Mandrola practices cardiac electrophysiology in Louisville, KY. He finished training at Indiana University in 1996. His practice encompasses catheter ablation, including an eight-year experience with AF ablation, device implantation, and consultative EP. Outside of the EP lab, Dr Mandrola's two hobbies include competitive cycling and writing. He has maintained a medical, fitness, and cycling blog, Dr John M, for the past two years.
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It's time to rethink the role of digoxinDec 2, 2012 00:00 EST
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.
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.