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

No love lost for labetalol infusions: risks of prolonged use

This entry has been moved.

The trouble with diltiazem infusions

This post has been updated, and moved to a new blog at the following URL: 
http://blogs.pharmacy.umaryland.edu/atrium/2016/03/18/the-trouble-with-diltiazem-infusions/

Desensitization in patients with an aspirin allergy

After tweeting about an aspirin desensitization we performed last week, I have received several requests for our approach in patients with aspirin allergies, as well as the protocol that we use to desensitize those in whom we feel therapy is clinically indicated.

Given the time and resources required for a desensitization (e.g., drug preparation, admission to an intensive care unit, frequency of monitoring, etc.), the most important initial steps are determining if aspirin is indicated (and no other reasonable alternatives exist), and whether the patient has a history of a true type I hypersensitivity reaction (e.g., anaphylaxis) to aspirin.  In the case of the former, all of our aspirin desensitizations have been performed for the purpose of providing dual antiplatelet therapy in the setting of an acute coronary syndrome (ACS), often with coronary stent placement. For patients with stable coronary disease (or for those in whom monotherapy may mitigate excess bleeding risk), clopidogrel monotherapy may serve as a suitable alternative to aspirin; based on the results of the CAPRIE trial, clopidogrel is associated with comparable rates of both ischemic and bleeding outcomes compared to aspirin [1]. Unfortunately, the number of patients for whom this would be a reasonable strategy is quite small, making aspirin desensitization necessary in the majority of cases.

If aspirin is clinically indicated, a thorough interview of the patient should be performed to determine the type of allergic reaction experienced. In many cases, the reported allergy is not a type I hypersensitivity reaction, or it is simply an adverse effect (e.g., gastritis) that has been mislabeled as an allergy. If the history is unclear, or if the patient provides any information that might be concerning (e.g., a rash occurred but unsure whether swelling or wheals were involved, unsure about timing related to exposure, etc.), I usually err on the side of caution.

At our institution, we transfer patients undergoing aspirin desensitization to the cardiac intensive care unit, where they can receive frequent monitoring of vital signs and observation for adverse reactions. We use the procedure described by Wong, et al. [2] to reach a target dose of 325 mg over a 3-hour period. For the doses preceding 81 mg, we compound a liquid formulation by crushing an 81 mg chewable tablet and mixing it with a sufficient quantity of sterile water to create a 1 mg/mL solution.  Additionaly, we compound two batches in case the patient vomits up a dose.

The desensitization is then performed as follows:

1. Pre-medicate with oral diphenhydramine 25 mg and famotidine 20 mg.
2. Check vital signs at baseline and every 20 minutes thereafter.
3. At 20 minute intervals, administer the following doses of aspirin:
   [Time 00:00] 0.1 mg (0.1 mL)
   [Time 00:20] 0.3 mg (0.3 mL)
   [Time 00:40] 1 mg (1 mL)
   [Time 01:00] 3 mg (3 mL)
   [Time 01:20] 10 mg (10 mL)
   [Time 01:40] 20 mg (20 mL)
   [Time 02:00] 40 mg (40 mL)
   [Time 02:20] 81 mg (one 81 mg tablet)
   [Time 02:40] 162 mg (two 81 mg tablets)
   [Time 03:00] 325 mg (one 325 mg tablet)
   
4. After the last dose of the desensitization, a normal administration time (i.e., every 24 hours) may be resumed.
5. If an allergic reaction is observed at any time, rescue medications (intravenous diphenhydramine, epinephrine) should be administered.

We target an initial dose of 325 mg because this is the standard loading dose at our institution for patients presenting with ACS (some institutions use 162 mg for this purpose); however, after achieving this dose during the desensitization process, we then administer a maintenance dose of 81 mg daily.

Acknowledgement: Special thanks to Abigail Miller Cook, PharmD, BCPS, with whom I collaborated on the above process at our institution; Abbie is currently a clinical pharmacy specialist at Loyola University Medical Center in Chicago, IL.

References

1. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996 Nov 16;348(9038):1329-39.
2. Wong JT, Maclean JA, Bloch KJ, et al. Rapid oral challenge-desensitization for patients with aspirin-related urticaria-angioedema. J Allergy Clin Immunol. 2000 May;105(5):997-1001.

Azithromycin in patients with cardiovascular disease

In a study published in the New England Journal of Medicine earlier this week, investigators observed an increased risk of sudden cardiac death associated with the macrolide antibiotic azithromycin (Zithromax^®) [1]. Azithromycin is considered a first-line option in the management of several types of upper respiratory tract infections and is one of the most widely-prescribed antibiotics in the US.  The results of the trial by Ray, et al prompted the US Food & Drug Administration (FDA) to issue a safety alert addressing the use of azithromycin in patients with cardiovascular disease and further investigation is currently underway.

Using electronic medical records and prescription-use data from patients enrolled in the Tennessee Medicaid program, investigators found a small but statistically significant increase in the risk of cardiovascular death (hazard ratio 2.88, 95% CI 1.79 - 4.63, p < 0.001) when azithromycin (5-day course) was compared to no antibiotic therapy, a result that was significant both in terms of sudden cardiac death as well as other types of cardiovascular death.  When compared to amoxicillin, the risk of cardiovascular death associated with azithromycin was similarly increased (hazard ratio 2.49; 95% CI 1.38 to 4.50; p = 0.002).

While there are some limitations with the use of any retrospective analysis, the findings do call into question the widely-held notion -- one that I believed until now -- that azithromycin is less cardiotoxic than other macrolides (clarithyomcin, erythromycin), where the risks of sudden cardiac death are fairly well-established.  Given the known association of these agents with QT prolongation and the types of deaths observed (i.e., sudden cardiac death), the most likely etiology is a disturbance in cardiac conduction that results in a fatal ventricular arrhythmia. Similar risks have been attributed to the respiratory fluoroquinolones levofloxacin and moxifloxacin, which further limits the antibiotic choices available in this patient population.

So, in light of this new evidence, how does one manage the risk of cardiovascular death associated with azithromycin?  It would be unreasonable to avoid azithromycin in all patients with cardiovascular disease; however, the results of the present study (not to mention the litigious nature of the current health care environment) should at least warrant a more careful consideration of the risks and benefits of azithromycin use.

Who is likely at risk?
The increased risk of sudden cardiac death observed in the present study likely does not apply to every patient with cardiovascular disease, especially those with milder forms (e.g., hypertension) or those who only have risk factors (e.g., dyslipidemia) for more advanced forms of cardiovascular disease.  Those at greatest risk likely include:

• Patients with a recent myocardial infarction, especially those with new-onset heart failure and those not receiving beta blockers (which  reduce the risk of ventricular arrhythmias and sudden cardiac death in this population)
• Patients with advanced heart failure, especially those who have not yet received an automatic implantable cardioverter-defibrillator (AICD)
• Patients with severe electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), which are often associated with the use of chronic high-dose diuretic therapy
• Patients taking anti-arrhythmic medications with known risk of QT prolongation and torsade de pointes (e.g., dofetilide, flecainide); for a list of drugs associated with QT prolongation (by risk category), please see this resource developed by the Arizona Center for Education on Research and Therapeutics

Alternative strategies in high-risk patients
If the risk of sudden cardiac death is thought to outweigh the benefit of azithromycin therapy in an individual patient, alternative antibiotics should be considered.  By far, the most common indication for azithromycin is in the management of community-acquired pneumonia (CAP), where it is recommended as monotherapy in patients with no risk factors for drug-resistant Streptococcus pneumoniae, or in combination with a beta lactam in patients with comorbidities and/or risk factors for drug-resistant pathogens (e.g., chronic disease, immunosuppression, recent antibiotic use, etc) [2].  Some alternatives to consider include:

• In the lowest risk population (i.e., minimal  structural heart disease and no additional co-morbidities) for whom azithromycin monotherapy would have been considered, doxycycline alone is a reasonable alternative
• For moderate risk patients, a combination beta lactam / beta lactamase inhibitor (e.g., amoxicillin/clavulanic acid) or second to third generation cephalosporin (cefuroxime, cefpodoxime) is likely adequate; for higher risk patients (i.e., in whom the addition of a macrolide would have been considered), addition of doxycycline is a reasonable alternative
• Azithromycin is often added as adjunct therapy in patients who are at risk for atypical pathogens (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella species), which include those with chronic pulmonary disease, long-term immunosuppression, residence in long-term care facilities, etc; in these patients, the addition of doxycycline is a reasonable alternative
• Alternatives are more limited in patients with penicillin allergies; if the allergy to penicillin is reported as "rash", "upset stomach" or similar mild reactions (i.e., not true Type I hypersensitivity reactions), use of a second or third generation cephalosporin (+/- doxycycline) is reasonable, as the reported cross-reactivity with penicillins is around 5-10% or less.  For true beta lactam allergies, options are further limited, as the respiratory fluoroquinolones (usually the first-line alternative in patients with penicillin allergies) have cardiotoxicities that are comparable to the macrolides; in these patients, monotherapy with doxycycline may be effective, but more thoughtful consideration as to risks and benefits of azithromycin or fluoroquinolone therapy is probably warranted, including whether additional monitoring (e.g., ambulatory ECG) should be performed
• When used as part of the management of CAP, some advocate the use of loading/higher doses of doxycycline (e.g., 200 mg twice daily for at least the first day) in order to achieve adequate serum concentrations early in the treatment course [3]; given the low toxicity profile of short doxycycline courses, this strategy is probably reasonable

While the increased risk of sudden cardiac death observed with azithromycin significantly limits the choice of antibiotics used for the management of CAP in the ambulatory care setting, reasonable alternatives exist for the vast majority of cases.  Also on the bright side, these findings should lead to a more careful evaluation of the risks and benefits of azithromycin therapy in this high-risk patient population, which many would argue is a step in the right direction anyway.

Acknowledgment: Thanks goes to Emily Heil, PharmD, BCPS, a clinical pharmacy specialist in infectious diseases at the University of Maryland Medical Center, who reviewed and made suggestions to the above recommendations.

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.
2. Mandell LA, Wunderink RG, Whitney CG, et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27-72.
3. Clin Infect Dis. 2003 Sep 15;37(6):870. Doxycycline for community-acquired pneumonia. Cunha BA.