Digoxin, digoxout: an appraisal of digoxin immune fab

Preface: The inspiration for this topic came from an exchange on Twitter between @PharmERToxGuy, @DavidJuurlink, and I, representing one of the things I love most about #hcsm -- the opportunity for dialogue across diverse backgrounds and practice settings. In this particular case, we debated the appropriate use of digoxin immune fab (DigiFab^®), which was certainly challenging to do in segments of 140 characters or less. Below I have outlined a more detailed rationale for why I advocate its conservative use in the management of digoxin toxicity.

My reasons for advocating the conservative use of digoxin immune fab (DigiFab^®) are unrelated to its efficacy, as it is undoubtedly the most effective antidote for digoxin toxicity. Instead, I contend that in many cases, it is an unnecessary and overly aggressive -- if not a costly -- approach to a scenario that may be just as effectively managed by thoughtful monitoring and supportive therapy. While it can be challenging to predict whether patients might require fab therapy at a later time, I believe a more judicious approach can be made possible by considering the severity of toxicity, the circumstances in which it occurred, and whether fab administration would substantially alter the clinical course of the patient.

Digoxin toxicity is difficult to characterize as a result of heterogeneity in the literature (e.g., study methods, definitions for toxicity) and how use of digoxin has evolved over time (i.e., patient populations, indications, dosing, target concentrations). As an example, a patient with a ventricular arrhythmia and serum digoxin concentration of 10.0 ng/mL in 1994 and one with symptomatic bradycardia and a serum digoxin concentration of 2.0 ng/mL in 2014 are both classified as having digoxin toxicity (and both cases often characterized simply as a dysrhythmia), although the severity of their presentations is vastly different. These and similar challenges may explain in part some of the discrepancies in the literature, as some studies demonstrate a decline in the prevalence of digoxin toxicity while others claim it has not changed [1-3].

What has changed considerably over the last several decades is how digoxin is used. In the late 1980s and early 1990s, it was not uncommon for the vast majority of patients with heart failure to be receiving digoxin therapy -- as many as 9 out of 10 in some studies [4]. Today those numbers are substantially fewer, as digoxin therapy is often reserved for those patients with advanced symptomatic disease. When it is used in this population, a lower serum concentration (i.e., 0.5 - 0.9 ng/mL) is targeted, ameliorating many of the more severe adverse effects observed in the setting of elevated concentrations in the past [5,6]. Additionally, patients with heart failure are likely to be on concomitant therapies (e.g., beta blockers, aldosterone antagonists, implantable defibrillators and other devices) that may confer protection from some of the more severe forms of digoxin toxicity or prevent it altogether (e.g., less hypokalemia as a result of aldosterone antagonist use). Similar trends, including a decline in overall digoxin use and reservation for only the most advanced cases, have also been observed in the atrial fibrillation population, where lenient rate control targets have obviated the need for digoxin in many patients [7-9].

Whether or not these differences impact the number of patients presenting with digoxin toxicity, they likely influence how, and perhaps more importantly, why patients present. In my practice setting, digoxin toxicity often manifests as a result of something more problematic (i.e., renal impairment as a result of worsening heart failure, emergence of underlying conduction abnormalities) rather than the consequence of a drug-drug interaction or acute overdose. In these latter cases, fab administration may be a reasonable approach for preventing hospital admission. However, for the 4 out of every 5 patients with digoxin toxicity who require hospitalization either way, fab administration may not confer substantial benefit over what would be provided by monitoring and symptomatic support [3].

Patients with worsening heart failure often require days of clinical evaluation whether or not they have signs or symptoms consistent with digoxin toxicity (which can often mimic those of worsening heart failure). Furthermore, complete digoxin withdrawal may actually worsen outcomes in this population [6, 10]. In the case of renal impairment, digoxin immune fab may not be an ideal strategy if renal impairment is advanced or does not improve substantially, as it too requires renal clearance and is not removed by hemodialysis. Although an earlier review substantiates fab use in patients with mild to moderate renal impairment, several limitations make it difficult to derive similar conclusions when renal impairment is severe [11]. Although manifestations of digoxin toxicity may initially improve in this latter population, recrudescent toxicity may occur days to weeks later as digoxin redistributes from peripheral tissues, a phenomenon that has been well-documented in the literature [12, 13]. For patients on chronic digoxin therapy, this may occur even in the absence of severe renal impairment. In these scenarios, fab use may provide clinicians with a false sense of security, resulting in less frequent monitoring or premature discharge when the patient should be observed for recrudescent toxicity or worsening signs and symptoms of heart failure.

Finally, as I alluded to in several instances above, digoxin immune fab may not be the most cost-effective strategy in a given patient. Notably, many cost-effectiveness analyses are a decade or more older, making them subject to the same limitations as the epidemiological studies described above. Given the financial woes of today's health care environment, cost-effectiveness should be a factor in determining whether a therapy is indicated, especially when less expensive alternatives exist or if the therapy is unlikely to alter the long-term outcome of the patient. Otherwise, we endanger our ability to use these more expensive therapies in patients who have no alternatives.  In the US, a single vial of digoxin immune fab costs between $1200-1500 (or more), and most patients require multiple vials based on their body weight and/or serum digoxin concentration. Unless hospitalization can be substantially shortened or avoided altogether, the cost of fab therapy may quickly outpace reimbursement. For example, the average reimbursement for a drug overdose at my institution runs about $6500, whereas a heart failure admission runs around $8300 [14].

That being said, the following are situations where I would definitely recommend the use of digoxin immune fab:

• Ventricular arrhythmias, accelerated junctional rhythms
• Life-threatening bradyarrhythmias unresponsive to chronotropic agents (and when temporary pacing is not readily available)
• Acute mental status changes
• Acute overdose

I generally avoid recommending fab on the basis of a specific serum digoxin concentration alone, as these are often open to interpretation (e.g., timing of ingestion, laboratory draw). Furthermore, a toxic concentration is any concentration that results in clinically meaningful adverse sequelae in a given patient. A serum digoxin concentration of 2.0 ng/mL resulting in a ventricular arrhythmia is toxic and requires emergent treatment, while a patient with a serum concentration of 4.0 ng/mL and no adverse sequelae requires close observation but emergent therapy is not warranted.

Outside the indications outlined above, the strategy I most commonly recommend for managing digoxin toxicity is to simply facilitate urine output (e.g., intravenous fluids), provide supportive therapy when necessary, and monitor closely should a need for fab arise. If the patient has symptomatic bradycardia, this may require intermittent use of a chronotropic agent. Although atropine is often recommended in this scenario, its half life makes it less than ideal for counteracting a drug that may require hours to days to clear. Instead, I prefer the use of a dopamine infusion in this setting, as it may be turned on or off (or titrated) based on patient need. Importantly, dopamine and other catecholamine-based therapies should be monitored closely so as not to exacerbate other rhythm disturbances commonly associated with digoxin toxicity.

Peer review: Special thanks goes to Jo Ellen Rodgers, PharmD, FCCP, BCPS (AQ Cardiology), a clinical associate professor at the University of North Carolina Eshelman School of Pharmacy, and Jonathan Cicci, PharmD, BCPS, a clinical pharmacy specialist in cardiology at the University of North Carolina Health Care for their review of this entry.

References

1. Haynes K, Heitjan D, Kanetsky P, Hennessy S. Declining public health burden of digoxin toxicity from 1991 to 2004. Clin Pharmacol Ther. 2008 Jul;84(1):90–4.
2. Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but crucial complication to recognize. Am J Med. 2012 Apr;125(4):337–43. 
3. See I, Shehab N, Kegler SR, Laskar SR, Budnitz DS. Emergency Department Visits and Hospitalizations for Digoxin Toxicity: United States, 2005-2010. Circ Heart Fail. 2013 Dec 3; 
4. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987 Jun 4;316(23):1429–35. 
5. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA J Am Med Assoc. 2003 Feb 19;289(7):871–8. 
6. Ahmed A, Gambassi G, Weaver MT, Young JB, Wehrmacher WH, Rich MW. Effects of discontinuation of digoxin versus continuation at low serum digoxin concentrations in chronic heart failure. Am J Cardiol. 2007 Jul 15;100(2):280–4. 
7. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5;347(23):1825–33. 
8. Hohnloser SH, Crijns HJGM, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009 Feb 12;360(7):668–78. 
9. Van Gelder IC, Groenveld HF, Crijns HJGM, Tuininga YS, Tijssen JGP, Alings AM, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010 Apr 15;362(15):1363–73. 
10. Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993 Jul 1;329(1):1–7. 
11. Wenger TL. Experience with digoxin immune Fab (ovine) in patients with renal impairment. Am J Emerg Med. 1991 Mar;9(2 Suppl 1):21–23; discussion 33–34. 
12. Rajpal S, Beedupalli J, Reddy P. Recrudescent digoxin toxicity treated with plasma exchange: a case report and review of literature. Cardiovasc Toxicol. 2012 Dec;12(4):363–8. 
13. Hazara AM. Recurrence of digoxin toxicity following treatment with digoxin immune fab in a patient with renal impairment. QJM Mon J Assoc Physicians. 2013 Sep 27; 
14. Medicare C for, Baltimore MS 7500 SB, Usa M. Medicare Provider Charge Data Overview [Internet]. 2013 [cited 2013 Dec 24]. Available from: http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Medicare-Provider-Charge-Data/index.html

From the headlines: azithromycin and the risk of fatal arrhythmias

Azithromycin (Zithromax®) made headlines again last week after the US Food & Drug Administration (FDA) issued a safety alert to warn patients and prescribers of an increased risk of fatal arrhythmias associated with its use.  As outlined in a previous blog entry from May, this latest announcement is the result of an investigation by the FDA following an analysis originally published by the New England Journal of Medicine [1], which found an increased risk of sudden cardiac death associated with azithromycin use. At the time, the reason for this increased risk was unknown, but many suspected it was due to QT interval prolongation, a cardiac conduction abnormality already well-described with other macrolide antibiotics. In its latest alert, the FDA warns that azithromycin be avoided in patients with known risk factors for sudden cardiac death, such as a history of arrhythmias or existing QT interval prolongation, hypokalemia, hypomagnesemia, or concomitant antiarrhythmic drug therapy.

For providers looking for more information about azithromycin use in patients with cardiovascular disease, please see this previous entry, which outlines alternative management strategies in at-risk patients.

References

1. Ray WA, Murray KT, Stein CM, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 May 17;366(20):1881-90.

Adjunct antiarrhythmic therapy in refractory ventricular tachycardia: lidocaine versus procainamide

Few management decisions are more controversial at my institution than which antiarrhythmic agent to select in patients with ventricular tachycardia (VT) that remains refractory to first-line therapies (e.g., amiodarone, maximally-tolerated doses of beta blockers) or in whom these therapies are contraindicated.  In many patients with advanced structural heart disease, lidocaine and procainamide are the only two remaining options. While some renewed enthusiasm for procainamide has emerged as of late -- in part a result of its re-appearance in the advanced cardiac life support algorithm for VT [1] -- much of the evidence to support procainamide is derived from studies evaluating its use as monotherapy.  When used alone, procainamide appears to be more effective than lidocaine in a heterogenous patient population [2,3].  However, for a growing number of patients with refractory VT, the challenge facing clinicians is rarely which agent to utilize first (as this is unquestionably amidoarone [4,5]) -- it is which agent to use as adjunct therapy, a scenario where minimal to no data exists to guide clinical decision-making.

Although many clinicians prefer procainamide for this purpose, I hope to make a case for at least attempting a trial of lidocaine, and why I often favor it as the initial adjunct antiarrhythmic to select in patients with advanced structural heart disease and refractory VT.

First, several disadvantages of using procainamide in this patient population are worth highlighting. From a pharmacokinetic standpoint, procainamide has a large volume of distribution, requiring that patients receive a considerable loading dose (i.e., 17 mg/kg) to produce a therapeutic effect. Moreover, procainamide and its active n-acetyl metabolite (NAPA) have a longer half-life than lidocaine -- about 3 and 5-8 hours, respectively, in patients with normal metabolic function.  These times may be prolonged by as much as five-fold in patients with hepatic and/or renal impairment, conditions that are common in patients with end-stage heart failure.  If toxicities (i.e., negative inotropy, hypotension) do emerge following the administration of procainamide, they may persist for extended periods of time, which is especially problematic in patients with compromised baseline hemodynamics. Although monitoring serum concentrations of procainamide and NAPA may ameliorate these risks, few medical centers still perform these tests and the turnaround time for referral assays may take up to a week to produce results. Finally, oral procainamide is no longer available in the US, so in patients for whom a more permanent solution (e.g., cardiac transplantation,  ventricular assist device implantation, VT ablation) is not available, procainamide does not represent a long-term management strategy.

Anecdotally, in the patients with refractory VT that we have treated with procainamide, I have seen at least a third become hemodynamically unstable, many requiring the initiation of inotrope and/or vasopressor therapy and almost all requiring a reduction in their maintenance infusion (often not adequate enough to maintain suppression of the arrhythmia), if not discontinuation of the drug altogether.

Although lidocaine may be less effective as monotherapy, its use in conjunction with amiodarone has not been evaluated in clinical trials, and the combination may actually produce synergistic antiarrhythmic effects. Theoretically, the addition of lidocaine to amiodarone results in more pronounced blockade of sodium channels (given that lidocaine inhibits both open and inactivated channels) as well as prolongation of the effective refractory period. Furthermore, lidocaine demonstrates enhanced activity in depolarized myocardial cells, a characteristic that is common in ischemic tissue. Given the limited hemodynamic reserve in patients with advanced structural heart disease, the increased myocardial oxygen demand that results from prolonged periods of VT is likely to produce transient periods of ischemia where lidocaine may be especially useful.

From a pharmacokinetic standpoint, lidocaine has a smaller volume of distribution than procainamide, so smaller loading doses (i.e., 1-1.5 mg/kg) are required to produce a therapeutic response.  Moreover, the much shorter half-life of lidocaine (1-2 hours in patients with normal hepatic function) means that if a therapeutic effect is not observed soon after initiation (or if toxicities emerge), the drug is essentially eliminated from the body within hours.  While lidocaine may also produce adverse hemodynamic effects, these are more rare at the doses used clinically and are far less pronounced than those observed with procainamide.  Finally, if patients do respond to lidocaine and are not candidates for the advanced therapies mentioned above, the drug may be converted to oral mexiletine for chronic maintenance therapy.

In summary, there is little evidence to guide the management of patients with advanced structural heart disease and refractory VT who are already receiving amiodarone or other antiarrhythmic therapy.  Although procainamide appears to be more effective than lidocaine when used as monotherapy, no data exists to compare their adjunct use with amiodarone, a clinical scenario that is becoming more common in patients who are awaiting advanced therapies (or in whom these therapies are not viable). While the advantages of lidocaine in this scenario are largely theoretical (but reasonable based on existing data), it is the arguably the safer of the two drugs in this population, and the only one for which a long-term oral option exists. As a result, unless a more permanent solution for managing refractory VT is already known and imminent, I think it is reasonable to at least attempt a trial of lidocaine as the adjunct antiarrhythmic in most patients.

References

1. Neumar RW, Otto CW, Morrison, LJ, et al. 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science: Part 8: Adult Advanced Cardiovascular Life Support. Circulation. 2010;122:S729-S767.
2. Gorgels AP, van den Dool A, Wellens HJ, et al. Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Am J Cardiol. 1996 Jul 1;78(1):43-6.
3. Komura S, Chinushi M, Aizawa Y, et al. Efficacy of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Circ J. 2010 May;74(5):864-9.
4. Dorian P, Cass D, Barr A, et al. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med. 2002 Mar 21;346(12):884-90.
5. Somberg JC, Bailin SJ, Molnar J, et al; for the Amio-Aqueous Investigators. Intravenous lidocaine versus intravenous amiodarone (in a new aqueous formulation) for incessant ventricular tachycardia. Am J Cardiol. 2002 Oct 15;90(8):853-9.

Who would dare use dronedarone now?

For more on the dronedarone debacle, see this previous post.
Earlier this week, the US Food and Drug Administration (FDA) published an updated safety announcement for dronedarone (Multaq^®), a class III antiarrhythmic approved for use in patients with paroxysmal or persistent atrial fibrillation (AF). Their latest findings are based on the results of PALLAS [1], which found an increased risk of mortality and cardiovascular events among patients with permanent AF.  The prescribing label for dronedarone now contains the following recommendations:

• Dronedarone should not be used in patients with permanent AF.
• Providers should obtain ECGs every 3 months for patients taking dronedarone.  If a patient is in AF, they should be cardioverted to normal sinus rhythm or dronedarone should be discontinued.

These revisions follow warnings already contained in the dronedarone label which recommend that the drug not be used in patients with moderate to severe heart failure.

While these previous restrictions on the use of dronedarone have been largely interpreted as applying only to patients with systolic heart failure (due to their enrollment in the ANDROMEDA trial [2]), nearly 70% of the patients in PALLAS had heart failure to some degree and only one-fifth had systolic heart failure (e.g., left ventricular ejection fraction < 40%), leaving the remaining majority as having diastolic dysfunction. While an argument can be made that patients with permanent AF are quite different than those with paroxysmal or persistent AF, I still find it incredibly concerning that the drug was responsible for so many events (including deaths) in patients with preserved left ventricular function. Even more striking was how quickly the mortality event curves between dronedarone and placebo began to separate -- as early as one week and consistently thereafter.

Given the added restrictions included in this latest FDA announcement and the known risks already associated with dronedarone, I am left wondering which patients would actually benefit from this drug at all. I doubt many clinicians would attempt to make the argument that it is a safe alternative to amiodarone, especially given that the drug fails to show similar efficacy for maintaining normal sinus rhythm at even three months of therapy. Amiodarone may be associated with a number of problematic side effects, but it doesn't kill people.  With providers now being compelled to obtain ECGs every three months, it seems that the inconvenience, inefficacy, and risk of stroke, worsening heart failure, and death associated with dronedarone now seem to outweigh any conceivable benefits. Who would dare use it now?

References

1. Connolly SJ, Camm AJ, Hohnloser SH, et al; PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011 Dec 15;365(24):2268-76.
2. Køber L, Torp-Pedersen C, Carlsen J, et al; Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008 Jun 19;358(25):2678-87.

What to do about dronedarone?

In what has already been a tortuous journey, the fate of the antiarrhythmic drug dronedarone (Multaq^®) took another twist late last month when the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) issued a statement recommending the restriction of its use in patients with atrial fibrillation (AF). This announcement follows a similar release by the US Food & Drug Administration (FDA) earlier this summer, which recommended that patients taking dronedarone contact their provider to see if its continued use was warranted. Although the FDA's statement stops short of restricting dronedarone, it has left many clinicians in the US wondering what its status will be in the near future.

Dronedarone is a Vaughn-Williams Class III antiarrhythmic with structural and mechanistic similarities to amiodarone. However, several key differences in its structure were thought to provide it with similar efficacy compared to amiodarone but without many of the use-limiting toxicities, which can include injury to hepatic, thyroid, and lung tissue.

While earlier studies had demonstrated its efficacy in maintaining normal sinus rhythm in patients with AF, one of the first big hits to dronedarone came with the early termination of the ANDROMEDA trial, where the drug was associated with a twofold increase in the risk of death in patients with severe heart failure. Shortly thereafter, dronedarone was shown to reduce hospitalizations in high-risk patients with AF or atrial flutter, earning approval for its use here in the US. Questions remained regarding its efficacy compared to amiodarone, but this was all but settled in DIONYSOS, where dronedarone was shown to be far inferior to amiodarone for the maintenance of normal sinus rhythm (although associated with fewer serious side effects).

In addition to growing case reports that the drug may increase the risk of liver toxicity, more bad news came with the early termination of the yet-to-be-published PALLAS trial, which randomized patients with permanent AF to dronedarone or placebo and found that the drug doubled the risk of death, stroke, and hospitalization for heart failure. Both the FDA and EMA have since issued statements recommending against its use for this indication.

Although the EMA's statement recognizes dronedarone as still being an option for the maintenance of normal sinus rhythm in paroxysmal or persistent AF, it does suggest clinicians consider its use only after other alternatives have already been considered. Additionally, it recommends that patients initiating therapy with dronedarone have their lung and liver function monitored closely, with the latter being performed once monthly for the first six months of therapy.

So, what to do about its use here? Clearly, dronedarone should be avoided in patients with permanent AF or left ventricular dysfunction. However, it seems strange to me that the drug produced such profound increases in risk in PALLAS, yet was associated with a benefit in high-risk patients in ATHENA. My anecdotal experience is that the drug is not all that effective in the long-term. However, it seems a reasonable option for maintaining normal sinus rhythm in patients who have undergone an ablation and are unlikely to require antiarrhythmic drug therapy for an extended period of time. Otherwise, given its limited efficacy and growing reasons for concern, I'm just not sure the risks outweigh the benefits in the vast majority of patients with AF.