Ileana L. Piña, MD, MPH; Paul J. Hauptman, MD


December 09, 2011

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Ileana L. Piña, MD, MPH: Hello. I am Ileana Piña from Montefiore Einstein in New York and this is my blog. I am happy to tell you that I am at Scientific Sessions 2011 for the American Heart Association, and that is the buzz that you may be hearing in the background.

I have with me today Paul Hauptman, who is not only a good friend but a wonderful professional from Saint Louis University and part of the "heart failure mafia," as I like to call us. Welcome, Paul, and thank you for joining us.

Paul J. Hauptman, MD: Thank you, Ileana.

Dr. Piña: You and I were having a very friendly dinner conversation. You told me about a very interesting case of a patient you saw, and it stirred a whole conversation about digoxin. Now that we have dronedarone not doing well, clinicians are left with amiodarone, about which many are still leery, or beta-blockers, which you and I love for our heart failure patients. However, our primary care colleagues are sometimes, especially in the elderly, a little bit hesitant to bump it up because they are afraid of bradycardia and hypotension. We are left with digoxin, a drug that 45%-50% of the patients are still taking. I can't remember the last time I started digoxin de novo on a heart failure patient. What are your thoughts about digoxin today?

Dr. Hauptman: It is an excellent question. The trends are suggesting continued downward use of digoxin in heart failure. We published a paper a number of years ago, from the ADHERE registry, when only about 25% of patients admitted with acute decompensated heart failure were on digoxin.[1] A little bit worrisome is the fact that older patients -- who are more likely to be on digoxin -- are at risk for digoxin toxicity.

Dr. Piña: Is digoxin safe in the older patients?

Dr. Hauptman: It is a little unclear. Practices die hard. In congestive heart failure, you could really look at digoxin as a fourth-line or maybe even fifth-line agent. The patient must be on optimal medical therapy: an angiotensin-converting enzyme (ACE) inhibitor, beta blocker, diuretic, and probably an aldosterone antagonist. As a fifth-line agent for patients who are still symptomatic, digoxin has a role.

What we don't know is how often it is used in atrial fibrillation. Is it going up? Is it going down? That is something that we have to explore. It is a little bit concerning because in the days of heart rate control being in favor, it could be that more digoxin is being used.

Dr. Piña: Tell me and our readers about your patient, because I thought it was very interesting.

Dr. Hauptman: Sure. It struck me as being a very typical case in a general medical service. We were called on the cardiology consult service to see an elderly patient who was not feeling well. She had a long history of heart failure, was felt to potentially be near end-stage heart failure, and was in the hospital, nauseated, not feeling well, with worsening renal function, and so we were called in to comment on heart failure management.

I was struck by her symptoms. She could not eat. She was miserable, and there were some subtle mental status changes as well. So I asked the team to get a digoxin level, and it came back a 1.9 ng/mL.

Dr. Piña: Is she a tiny lady?

Dr. Hauptman: No, she is of average size, but no question, smaller size with lower lean body mass puts you at risk, as does worsening renal function (which she had), and her concomitant medications were another major risk factor. Amiodarone or verapamil to control heart rate can increase digoxin levels.

Dr. Piña: Or medications for blood pressure control.

Dr. Hauptman: Cyclosporine and the azoles (itraconazole, fluconazole) will also raise digoxin levels. So not only was she digoxin-toxic, but we decided to take a pretty aggressive posture. Given her renal function, I estimated that it would take 3-5 days for her digoxin level to fall demonstrably.

Dr. Piña: Considering the kinetics, yes.

Dr. Hauptman: We therefore opted to administer a digoxin antibody. What is interesting about that is that you don't really need to use the conventional 20 vials. There is an algorithm. You enter the patient's digoxin level and body weight. For this patient, we used 2 vials, which was relatively inexpensive in that setting.

Dr. Piña: Two vials is not a lot at all.

Dr. Hauptman: By the next day, she was eating. She was no longer nauseated.

Dr. Piña: That is fabulous.

Dr. Hauptman: Digoxin toxicity is an underrecognized condition in the elderly in a general medical service. Frankly, in many of the elderly patients I see, I try to take them off digoxin because their risk for toxicity outweighs the potential benefit of the drug.

Dr. Piña: Yes, but to go back to what is happening right now, there is a lot of focus on atrial fibrillation. We have seen the JAMA paper[2] from one of the big cohort groups finding that the incidence of atrial fibrillation in women was linked to mortality, so clinicians are waking up and saying "wait a minute." This isn't a benign thing that is happening now.

If the dronedarone data are worrisome, more and more doctors are not going to put their patients on dronedarone. They are going to go back to digoxin because it's an old drug. It's cheap -- about 10 cents per tablet. When I have used it, I have lowered the doses considerably, 0.125 mg, and you worry about maybe ' seeing more digoxin toxicity.

Dr. Hauptman: That is a concern. There is a way around that: I use 0.125 mg in most patients and even 0.0625 mg. In some patients, we give 0.125 mg on Monday, Wednesday, and Friday. There was a period of time when we didn't check levels. Now I am going back to checking levels again. Anywhere from 6 to 12 hours post-dose, we will check the level. The data are pretty clear, at least in heart failure, that if the level is less than 0.9 ng/mL, you're probably safe. You are probably getting the biggest bang for your buck, in terms of the effect of digoxin, at least in heart failure patients. The risk for toxicity and potential for increased mortality are much reduced.

There is a gradient of less than 0.9 ng/mL. Between 0.9 and 1.2 ng/mL is probably a neutral effect. We learned from the digoxin study that if the level is more than 1.2 ng/mL, the mortality rate may actually be greater than if the patient is on placebo.

Dr. Piña: What about women? We saw that Harlan Krumholz paper years ago in the New England Journal of Medicine[3] about digoxin toxicity in women, specifically, from the digoxin trial.

Dr. Hauptman: Right. The confounder was digoxin level. Kirk Adams[4] had a very nice paper that came out after the Krumholz analysis, which more or less explained that phenomenon. It wasn't gender, per se; it was digoxin level.

The paper had some limitations because the digoxin level wasn't available for all patients in the digoxin study. For the cohort that had a digoxin level performed approximately 30 days after the initiation of the study, it was pretty clear that it was the digoxin level, not the gender, at play.

Dr. Piña: As women, in particular, get older and start to lose body mass, there isn't a lot of room for error. You said 0.9-1.2 ng/mL would be neutral. What about for women?

Dr. Hauptman: If you maintain a patient at less than 0.9 ng/mL, you may be getting some of the therapeutic benefit of digoxin, which, interestingly enough, is really more of a very weak sympatholytic agent.

Dr. Piña: That's right; it's vagal.

Dr. Hauptman: That's correct. Those effects predominate at the lower dose levels, so you are relatively safe there. However, if the condition of the patient changes, you have to be cognizant of that fact. If the renal function worsens, or if the patient, for whatever reason, is not taking anything by mouth but is managing to still take their pills, that is setting a patient up for toxicity.

Dr. Piña: A good lesson for our primary care audience is that if they have a patient on digoxin and the pulse rate has now become almost regular, that may be an early sign of digoxin toxicity. Or if the patient suddenly goes into a tachycardia that can't be identified, that paroxysmal atrial tachycardia should still be considered a marker of digoxin toxicity.

Dr. Hauptman: Absolutely. It's a guarantee that I can stump our fellows when I ask them to explain the differential when a patient who has longstanding atrial fibrillation suddenly has a regular pulse. They always think the patient has converted into sinus rhythm, but it can be a junctional rhythm and it can be a manifestation of digoxin toxicity. Some of the signs and symptoms can be rather subtle.

Dr. Piña: As in your patient.

Dr. Hauptman: That's right. In her case it was the nausea, not feeling well, and mental status that was a bit off.

Dr. Piña: Anorexia is common in our field, but putting it all together, it's important to get a digoxin level. It's not that expensive.

Dr. Hauptman: If viewers and readers want to understand digoxin toxicity, they should read the initial description by William Withering.[5] It is a beautiful description of digoxin toxicity because he did not know how much extract of the foxglove to give, and so in his description, he would give more until the patients had some kind of symptoms. He was able to document the visual changes and a whole host of other symptoms that patients developed. He realized, "I have pushed the dose too hard."

Dr. Piña: He also documented heart failure so beautifully in his description of a patient who couldn't breathe and whose pulse was irregular. It is a great story. I want to thank you for joining us.

Dr. Hauptman: My pleasure.

Dr. Piña: For my audience, I want you to couple this with the atrial fibrillation interview that I did with Bruce Wilkoff recently, "Atrial Fibrillation: Putting This Jigsaw Puzzle Together". Hopefully, this interview will complement that one, because it was all about atrial fibrillation. This meeting will have sessions about atrial fibrillation, and I want to keep it in the thoughts of our primary care audience.

Having said that, thank you for joining me today. I am Ileana Piña signing off from Orlando. Have a great day.


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