Month: April 2019

Atrial Fibrillation

by empharmd, posted in EM PharmD Core

Discussions of drug therapy in atrial fibrillation (Afib) are often centered on the ongoing debate of rate versus rhythm control strategy.[1,2] From the numerous publications including the AFFIRM, RACE, and corresponding meta-analyses, neither strategy has been proven clearly beneficial when compared to the other.[3-6] While the nuances of these studies, and the interventions in question, are hotly debated topics, their discussion revolves around outpatient Afib management. Any attempt at extrapolation of these data to acute management of Afib is flawed since these studies did not include patients in the extremes of acute Afib. Rather, these data examined the chronic treatment strategies of Afib. It’s not that this isn’t a valid discussion, it is simply the wrong context for the ED.

The debate of rate versus rhythm control in the emergency department shares some similarities, but also, important differences to the aforementioned clinical context. When considering rate or rhythm control in acute Afib in the ED, the patient’s clinical status generally guides, if not dictates, the treatment pathway. Patients who are hemodynamically unstable (further defined below) self select into the rhythm control pathway with electrical cardioversion. Whereas patients who are stable, generally receive a ventricular rate control strategy while the underlying cause of Afib is identified. While this is simply a generalization, it roughly accounts for the vast majority of patients presenting to EDs.

But the debate persists with each camp promoting their respective risks versus benefits.[1,2] In the rhythm control proponents, the argument centers on the need to convert Afib to normal sinus since Afib is an abnormal rhythm, which lowers quality of life further worsened by rate control drugs (beta-blockers and calcium channel blockers), causes structural and electrical cardiac remodeling, and anticoagulation carries a 4-9% risk of bleeding.[7] The rate control camp contends that electrical or pharmacological cardioversion itself carries a risk of thromboembolic event and should not be performed since a TEE is often not feasible to rule out the presence of a clot in the left atrium and/or therapeutic anticoagulation has not been achieved. Furthermore, the options for pharmacologic rhythm control are fraught with serious adverse events that patients rarely tolerate and will end up on rate control anyways. Ultimately, the debate rages on, but does it necessarily apply to the management of Afib with RVR in the ED?

In this chapter, we will examine the drug therapies for patients with Afib presenting to the emergency department. Rather than centering the discussion on rate versus rhythm and which is superior, we will examine patient cases that are most common in the ED and tie in the most common clinical scenarios encountered as a result of Afib.

66 year old male presents via EMS for palpitations that have been coming and going for a week (history of hypertension, diabetes, COPD). On the monitor, the patient appears to be in atrial fibrillation with a rate of 155 bpm, blood pressure of 110/80 mmHg, normal temp, 100% on room air. After an EKG confirms Afib with rapid ventricular response (RVR), the physician orders an initial bolus of diltiazem followed by an infusion. What’s the best dose for this patient?

Acute rate control

There are three main strategies for acute rate control of Afib with RVR in the ED: non-dihydropyridine calcium channel blockers (CCB), beta-blockers (BB), and digoxin.[8-12] Despite Afib with RVR being one of the most commonly encountered arrhythmias in the ED, there is very little high quality evidence guiding pharmacotherapy. Our treatment strategies are guided by the current understanding of Afib with RVR and clinical experience. In Afib with RVR, the atrial conduction sends overwhelming depolarizations to the AV node with anywhere from three hundred to six hundred impulses every minute. The inherent refractory period of the AV node limits the number of depolarizations to the ventricle, however, given the sheer number of atrial depolarizations, the ventricular response becomes irregular. When this irregular ventricular rate increases to 150-170 beats per minute, an already compromised cardiac output from poor ventricular filling is exacerbated by the even shorter filling time and poor stroke volume. Hypoperfusion can occur, if the ventricular rate is not addressed in short order.

Before discussing the ideal agent to control ventricular rate, we must first understand the goal of therapy. With rate control strategies of Afib with RVR in the ED, the goal is to lower the ventricular rate to a sufficient degree such that adequate diastole takes place. While there is limited evidence specifically addressing patients in the ED for goal HR, a lenient strategy of a target ventricular rate of less than than 110 beats per minute versus a more strict control (between 80-110) seems reasonable.[13]

When considering the available drug therapy options, an ideal agent would work rapidly to slow the ventricular rate, be easily titratable and short duration of action, but without causing untoward adverse events with concomitant comorbid diseases. While some references discuss the left ventricular ejection fraction (LVEF) as an element to guide therapy, this information is rarely available in the ED.[12] If patients have a documented LVEF on record, it may help, however, it may not be representative of the current hemodynamics. Similarly, comorbid disease states such as asthma, or existing CHF, are considerations in drug selection, not relative contraindications.[8] This nuance of nomenclature should come with the understanding there has been a conscious discussion of the risks of treatment with the potential benefits. Nevertheless, an ideal agent is nothing but a fantasy, and we must select the best of the agents we have: CCBs, BBs, and digoxin.[8]

Non-dihydropyridine calcium channel blockers

Diltiazem and verapamil are the CCBs that are options for ventricular rate control of Afib in the ED. Categorized as class IV antiarrhythmic drugs in the Vaughan Williams classification, these agents increased refractoriness of nodal tissues.[9-11] If you recall the cardiac conduction cycles, and the flow of electrolytes during depolarization, you’ll notice that there are different patterns depending on the type of cardiac tissue in question. While muscle tissue electrical pathways follow the common “side profile of batman” pattern, nodal tissue has a different pattern.

Cardiac nodal tissue (SA and AV nodes) electrical conduction tissues are less negative at rest than non-pacemaker cells and they can also spontaneously depolarize due to slow calcium and sodium influx during phase 4. By blocking these L-type calcium channels, phase 4 is prolonged, thereby increasing the time between depolarizations. This improvement of refractoriness in the AV nodal tissue, decreases the number of depolarizations that make it through to the ventricles. There is also some slowing of the conduction of the depolarization through the ventricles. The end result is a prolonged diastole and improved cardiac output, despite the atrial still in fibrillation.

Controlling of this ventricular rate can be accomplished using CCBs including diltiazem and verapamil. These CCBs have primarily cardiac effects, and do not produce significant vasodilation at normal doses. With escalating doses, however, vasodilation can occur. The AHA support the use of CCBs in patients with Afib and heart failure with preserved ejection fraction (HFpEF), but recommend beta-blockers or digoxin in patients with heart failure with reduced ejection fraction (HFrEF).[8] It’s a common misconception that the guidelines do not recommend CCBs in HFrEF. This is not the case, the guidelines do not make any such statement. In patients with Afib with HFrEf, beta-blockers may be used with caution, or digoxin or amiodarone be selected. These recommendations come with the same level of evidence and strength of recommendation.

Diltiazem is commonly used in EDs for rate control give its extensive history in clinical experience. Traditional dosing is 0.25 mg/kg followed by 0.35 mg/kg, and a subsequent infusion rate between 5-15 mg/hr. More recent evidence suggests that lower bolus doses of 0.1 mg/kg or fixed 10 mg doses may achieve the same lenient rate control goals, without excessive adverse events.[14] Despite it’s relatively long half-life of approximately 4 hours, the onset of IV administration of diltiazem is 3 minutes. Diltiazem is metabolized hepatically by CYP-3A4 to numerous metabolites.

Verapamil is not commonly used in the ED as a result of concerns for more pronounced decreases in blood pressure compared to diltiazem. However, this is a misconception. This belief is held from a prospective, randomized, double-blind, crossover study in 17 men with Afib or atrial flutter.[15] Patients received either diltiazem or verapamil bolus (20 mg then 25 mg vs 5 mg then 10 mg, respectively) followed by infusions for 8 hours, with appropriate wash out and crossover procedures. There was no significant difference between systolic blood pressures after bolus dosing and during infusions with a mean change SBP of -9.7 +/- 11.5% for diltiazem and -2.9 +/- 7.7% for verapamil. Three (n=15) patients who received verapamil, and zero in the diltiazem (n=10) arm had hypotension. One patient in the verapamil group experienced clinically significant hypotension, seizures and EKG changes after the second verapamil bolus, but was discharged with no long term sequelae. It was noted this patient had an LVEF of 20%. Therefore, in this small, limited study, verapamil may cause more hypotension than diltiazem, but this is based on 3 adverse events.

Verapamil for Afib is dosed at 0.1 mg/kg (or 5 to 10 mg) over at least 2 minutes; if no response, an additional 10 mg bolus after 15 to 30 minutes may be given.[12] A continuous infusion of 5 mg/hour is the initial starting rate. Similar to diltiazem, verapamil has a rapid onset when given IV (~3-5 minutes) and a half-life of ~5 hours, with metabolites after hepatic CYP metabolism.

The threshold systolic blood pressure that is clinically defined as ‘unstable’ to hypotensive, necessitating a rhythm control strategy is poorly defined. Taking a single metric alone, without considering the complete clinical picture is a fundamentally flawed approach. Therefore, in patients with SBP in the 90-100’s, it may be reasonable to attempt to use CCB as a rate control strategy before electing for cardioversion. One complementary intervention is the use of push-dose pressors, namely phenylephrine, in this scenario. Bedside titration of intermittent phenylephrine boluses, may allow for adequate vascular support while the ventricular rate is controlled. Consistent with the paucity of evidence guiding therapies for Afib with RVR in the ED, this approach is reasonable under close supervision of experts.

As for which agent is preferred is a matter of uncertainty. The only head to head literature is the aforementioned study in 17 men.[15] Similarly, it is unclear from the available evidence whether CCBs or BBs are the preferred agents for rate control.

Beta-blocker

Beta-blockers slow cardiac conduction by binding to beta-1 receptors in cardiac nodal tissue, and cardiac muscle tissue.[9,10] In nodal tissue, BBs prevent the activation of a depolarization through the sympathetic nervous system. But in the event of a lack of sympathetic stimulation, BBs can decrease phosphorylation of L-type calcium channels through inhibition of cAMP activated protein kinase A. While the predominant mechanism in acute Afib depends on nodal tissue inhibition, decreasing intracellular calcium may also play a role.

The most commonly used BB for Afib in the ED is metoprolol. Metoprolol should be given in a dose of 2.5 to 5 mg every 5 minutes to a maximum of 15 mg.[9,10] Unlike diltiazem, there is no conversion to a continuous infusion. In such cases, either immediate release oral metoprolol could be used, or an infusion of esmolol. Similar to CCBs, caution should be taken in patients with HFrEF, but also patients with reactive airway disease (aka asthma). Esmolol and propranolol may be used in certain circumstances: propranolol in thyrotoxicosis or thyroid storm, and esmolol in circumstances where a 9 minute half-life is desired.[9,10]

In terms of clinical evidence comparing BBs to CCBs, there is limited head to head data. Two small studies have compared metoprolol to diltiazem in acute management of Afib. In one study, there was no difference in patient-oriented outcomes between the two agents.[16] The most recent comparison randomized patients in a double-blinded manner to metoprolol or diltiazem for Afib in the ED. This study demonstrated more rapid rate control with diltiazem than with metoprolol at 30 min (95.8% vs. 46.4%).[17] While these data support the common clinical practice of diltiazem use, more data is needed to confirm it’s role.

Digoxin

Digoxin is known to inhibit the sodium-potassium ATPase channel in cardiac myocytes, thereby leading to an increased calcium concentration in the cell, ultimately augmenting contractility as well as increasing the slope of phase 4 and increasing automaticity.[9,10] These effects, however, are not the intended mechanism by which digoxin is useful in Afib with RVR. Digoxin in this role inhibits calcium currents in AV nodal tissue and activation of acetylcholine-mediated potassium currents in the atrium causing a hyperpolarization, shortening of atrial action potential, and increases in AV nodal refractoriness.[9,10] This ultimately will permit ventricular diastole and promote improved perfusion.

Loading doses of digoxin are necessary for this effect to take place. The ‘loading dose’ is administered over numerous hours.[9,10] The typical dosing regimen for patients with normal renal function is a IV bolus of 0.5 mg followed by 0.25 mg IV every 6 hours until a total of 1 mg or 1.5 mg is achieved. This prolonged administration comes with a delayed onset of action and time to maximum efficacy. While the onset of some observed benefit is somewhere around 30 minutes, the maximal effect on rate control may not be seen for up to 24 hours. This, coupled with the low therapeutic index of digoxin, its renal dose adjustments, and drug interactions limit the use of digoxin for Afib in the ED.

Anticoagulation

Another interesting contrasting element of the discussion of rate versus rhythm control between outpatient and ED management is anticoagulation. In the outpatient/less acute realm, a limitation of rate control strategy is the need for systemic anticoagulation for the duration of the arrhythmia.[8] With this potential reduction in the risk of ischemic stroke, there to is an increase in risk of hemorrhage, which varies depending on the particular drug used, and patient specific factors. In acute Afib management, however, rhythm control strategies require immediate anticoagulation followed by a 4 month course. Although rate control strategies require anticoagulation, the timeline in which to initiate this therapy is not as urgent as establishing control of the ventricular rate. Most often, anticoagulant strategies are not determined until after the ED stay in patients receiving rate control.

Bottom line:

Diltiazem is commonly used in the ED for rate control, but verapamil, metoprolol and esmolol are all reasonable choices

Digoxin works, but tomorrow.

Anticoagulation is important, but also tomorrow.


Expanded rate control

Magnesium sulfate

Calcium gluconate for CCBs with low SBP

Rhythm control

Hemodynamically unstable patients are getting shocked. Hemodynamically unstable patients are those in whom there is the presence of end organ hypoperfusion i.e. presence of ischemic cardiac symptoms, altered mental status). [12] These unstable patients are candidates for electrical cardioversion with synchronized cardioversion irrespective of duration of dysrhythmia. Here the best drug therapy is sedation and analgesia, followed by anticoagulation.

44 year old male presents to the ED for palpitations that started today. He has no history of palpitations, and is otherwise healthy. His vital signs are all within normal limits, except for heart rate which is 168 bpm and an EKG shows Afib with RVR. Is flecainide a useful drug for this patient?

The discussion of rhythm control requires appropriate establishment of context. As briefly outlined previously, patients who are hemodynamically unstable presenting with Afib with RVR most often require rhythm control via electrical cardioversion.[9] Elective cardioversion, where patients are hemodynamically stable is a more complex discussion. If this rhythm control strategy is selected, patients undergoing electrical or antiarrhythmic drug therapy for Afib lasting at least 48 hours or for an unknown duration, they require anticoagulation with oral anticoagulation (warfarin or a DOAC) should be given for at least 3 weeks before cardioversion is performed.[9] This scenario is not one that would be managed by the ED. Nor would patients undergo a transesophageal echocardiogram (TEE) prior to cardioversion in the ED. Aggressive rhythm control protocols such as the Ottawa Aggressive protocol, rely on the relative low risk of thromboembolic risks and elect for rhythm strategies with oral propafenone or flecainide.[18,19] Recent evidence suggests supports this low risk of complications and that the risk of thromboembolic complications is 0.7% when cardioversion is performed without anticoagulation within 48 hours of Afib onset, which is consistent with previous evidence.[20,21]

Pharmacologic rate control

Although electrical cardioversion generally has a higher rate of successful restoration of sinus rhythm (~90%), pharmacologic strategies are often attempted first. While the rate of successful cardioversion is closer to 60% with drug therapy, successful cardioversion may be more likely if conducted within 7 days of onset of Afib.[9] Of the available antiarrhythmic agents, the Vaughn Williams class III agents (amiodarone, ibutilide and dofetilide), the class ICs (flecainide and propafenone), may be used for cardioversion of Afib.

In general, the IC agents should only be used for rhythm control in patients with ‘lone’ Afib. The concern, based on the CAST study, is that underlying ‘structural heart disease,’ hypertension, ischemia or heart failure may have an increased risk of mortality.[22] In patients with these risk factors, amiodarone or ibutilide are reasonable, and some resources suggest procainamide is an option as well.[12] However, the warnings generated from CAST extend to all Class I antiarrhythmics, including procainamide.[23] If procainamide is selected, CCBs or BBs may be given to prevent paradoxical increases in the ventricular rate (vagolytic response), with a target of 100 to 120 beats per minute.[12] However, this recommendation is inconsistent in the literature.[11]

Sodium channel blockers

Procainamide

As a Class Ia antiarrhythmic, procainamide blocks open sodium channels, slowing the velocity conduction. In addition to sodium channel blockade, procainamide also inhibits outward potassium flow and prolongs the action potential. Through decreased automaticity in nodal tissues, refractory periods are prolonged. These mechanisms are reflected on the EKG by prolonging the QRS and the QT intervals.

Procainamide has numerous complications with its use. It can cause peripheral vasodilation from it’s ganglion-blocking effects and based on the rate of IV administration. The dosing recommendations for procainamide must be viewed with the knowledge that this drug was once a component of ACLS. The loading dose of procainamide should be given at a rate between 20 to 50 mg/minute until one of the following criteria are met: a total of 17 mg/kg is given, the QRS increases by 50%, hypotension occurs, or the arrhythmia is controlled (ie sinus). At which point an infusion of 1-4 mg/hour may be initiated.

While procainamide itself is a potent sodium channel blocker, its metabolite, NAPA (N-acetyl procainamide), is a potassium channel blocker, with a longer half-life and can induce a Lupus-like syndrome. While these effects are more likely with long term use of procainamide is associated with one of the highest rates of successful cardioversion (~60%) among drug therapy options.[24]

Flecainide and Propafenone

Flecainide and propafenone belong to the class IC agents and are known as sodium channels antagonists with slow unblocking properties. The effects of flecainide are primarily attributed to these slow recovery times from blockade. In the atria, the desired location for action in Afib, flecainide performs better and prolongs potentials at fast rates better than at slower rates of conduction. Flecainide can also block open ryanodine (RyR2) receptors on the sarcoplasmic reticulum, thus preventing calcium dependent calcium release. The effects seen on the EKG are PR, QRS and QT prolongation.

The role of flecainide in Afib is as an oral loading dose protocol, known as ‘pill in the pocket.’ In selected patients, who are maintained on a CCB or BB, if they feel palpitations or other symptoms of Afib, they can take one 300mg dose of flecainide (200mg if they’re less than 70 Kg) and follow up with their cardiologist.[25] Similar protocols have been adapted for use in the ED, where after diagnosis of new onset Afib and initiation of a CCB or BB, an oral loading dose of flecainide (or propafenone, see below) can be given with a first dose of DOAC. After which, patients may be discharged with close follow up, rather than hospital admission.

Flecainide, as with all Class I antiarrhythmics, carries the warning of increased mortality in patients with structural heart disease. Thus, outside of expert consultation, should only be used in patients with ‘lone’ Afib.

Propafenone

Propafenone shares many mechanistic similarities with flecainide: they are Class IC agents, and both are known as sodium channels antagonists with slow unblocking properties and potassium channel blocking properties. While flecainide is a racemic mixture with no significant difference, the enantiomers of propafenone share similarities in sodium channel properties, but differ in that S-propafenone has beta-blocking activity (it shares some similarities with propranolol), and R-propafenone blocks RyR2 channels.

Propafenone can induce a paradoxical increase in ventricular response in some Afib patients, which is why some recommend patients should be taking a CCB or BB prior to initiation. As a substrate of CYP2D6 and subject to significant first pass metabolism, there are numerous drug interactions possible with propafenone.

For pill in the pocket oral loading doses, propafenone should be given as the immediate release product at a dose of 600 mg (450 mg if the patient is less than 70 kg).[26] Consistent with flecainide, and as with all Class I antiarrhythmics, propafenone carries the warning of increased mortality in patients with structural heart disease. Thus, outside of expert consultation, should only be used in patients with ‘lone’ Afib.

Amiodarone

Amiodarone is commonly thought of as a Class III antiarrhythmic pertaining to its potassium channel blocking activity. However, it actually possesses therapeutically relevant properties of all classes: sodium channel blocking, calcium channel blocking, and adrenergic blocking effects. This ‘broad spectrum’ antiarrhythmic, so to speak, can be used for a wide range of arrhythmias. For Afib, the recommended dose is different from what is commonly (possibly erroneously) given: 3-5 mg/kg IV over 15-20 minutes.[12] That equates to a dose of roughly 250-400 mg for the average 80 Kg adult (much higher than the 150 mg IV for ventricular arrhythmias for patients with a pulse). The reason for therapeutic failures of amiodarone in this setting is often a result of the incorrect dose being administered.

While amiodarone can be used in every case where Class I agents are ‘contraindicated’ (despite it too having sodium channel blocking properties), amiodarone comes with significant adverse events, drug interactions and therapeutic considerations. Since amiodarone is insoluble in water, it is suspended in polysorbate 80 which itself can cause hypotension and hypersensitivity reactions. Furthermore, since it is insoluble in water, further dilution in dextrose may cause precipitation, and an in-line filter is recommended for administration.

Amiodarone is roughly 37% iodine by weight. Thus, it can have significant impact on thyroid function, can cause corneal deposits, discoloration of soft tissues, but also affords amiodarone a huge volume of distribution. The numerous adverse events of amiodarone impact every organ system to some degree. Similar to the list of adverse events, amiodarone is a potent CYP inhibitor, PGP inhibitor, yielding many drug interactions. Yet, it has a long history of clinical experience and still commonly used today.

Dofetilide and Ibutilide

Dofetilide and ibutilide are class III antiarrhythmics.[27,28] Each agent exerts a dose-dependent block on the rapid component of the delayed rectifier potassium current, prolonging repolarization. The role of these agents is limited in the ED setting due to complications with the initiation of the drugs. With dofetilide, the QTc must be less than 440 msec and renal impairment with GFR less than 60 mL/min requires dose adjustments. Furthermore, serum electrolytes should be followed (particularly potassium and magnesium) and replaced as needed – ideally prior to initiation of dofetilide. The risks of not following these recommendations is torsades de pointe. As for ibutilide, similar considerations should be made prior to initiation.

Dofetilide is only available as an oral agent, where ase ibutilide only available as a parenteral agent. The role of either agent in the ED is limited, if not entirely absent.

Bottom line:

Rhythm control in the ED is not rhythm control for chronic management of Afib

For unstable patients, drugs are not the answer – DC cardioversion

For otherwise stable patients, oral loading dose of Ic agents, procainamide infusion or amiodarone loading are reasonable options.

  1. Stiell IG et al. Managing Recent-Onset Atrial Fibrillation in the Emergency Department. Ann emerg Med 2011; 57 (1): 31 – 2.
  2. Decker WW et al. Selecting Rate Control for Recent-Onset Atrial Fibrillation. Ann Emerg Med 2011; 57(1): 32 – 3.
  3. The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–1833.
  4. Van Gelder  IC, Hagens VE, Bosker  HA, et al. The Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–1840.
  5. de Denus  S, Sanoski  CA, Carlsson  J, Opolski G, Spinler  SA. Rate vs rhythm control in patients with atrial fibrillation: A meta-analysis. Arch Intern Med 2005;165:258–262
  6. Roy  D, Talajic  M, Nattel S,  et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–2677
  7. Weigner MJ, Caulfield TA, Danias PG, Silverman DI, Manning WJ. Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours. Ann Intern Med. 1997 Apr 15;126(8):615-20.
  8. January  CT, Wann LS, Alpert  JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol, 2014;64:e1–e76
  9. Knollmann BC, Roden DM. Antiarrhythmic Drugs. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2189&sectionid=170271275. Accessed January 18, 2019.
  10. Harvey RD, Grant AO. Agents Used in Cardiac Arrhythmias. In: Katzung BG. eds. Basic & Clinical Pharmacology, 14e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2249&sectionid=175217302. Accessed January 18, 2019.
  11. Sanoski CA, Bauman JL. The Arrhythmias. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146057036. Accessed January 19, 2019.
  12. Yealy D, Kosowsky JM: Dysrhythmias, in Marx JA, Hockberger RS, Walls RM, et al (eds): Rosen’s Emergency Medicine: Concepts and Clinical Practice, ed 8. St. Louis, Mosby, Inc., 2010, (Ch) 79: p 1034-63.
  13. Van Gelder IC, et al; RACE II Investigators. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010 Apr 15;362(15):1363-73
  14. Lee J, et al. Low-dose diltiazem in atrial fibrillation with rapid ventricular response.Am J Emerg Med. 2011 Oct;29(8):849-54.
  15. Phillips BG, Gandhi AJ, Sanoski CA, Just VL, Bauman JL. Comparison of intravenous diltiazem and verapamil for the acute treatment of atrial fibrillation and atrial flutter.Pharmacotherapy. 1997 Nov-Dec;17(6):1238-45.
  16. Demircan C, et al. Comparison of the effectiveness of intravenous diltiazem and metoprolol in the management of rapid ventricular rate in atrial fibrillation.Emerg Med J. 2005 Jun;22(6):411-4.
  17. Fromm C, et al. Diltiazem vs. Metoprolol in the Management of Atrial Fibrillation or Flutter with Rapid Ventricular Rate in the Emergency Department.J Emerg Med. 2015 Aug;49(2):175-82.
  18. Alboni  P, Botto  GL, Baldi N,  et al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med 2004;351:2384–2391
  19. Stiell IG, et al. Association of the Ottawa Aggressive Protocol with rapid discharge of emergency department patients with recent-onset atrial fibrillation or flutter. CJEM. 2010 May;12(3):181-91
  20. Nuotio I, Hartikainen JEK, Grönberg T, Biancari F, Airaksinen KEJ. Time to Cardioversion for Acute Atrial Fibrillation and Thromboembolic Complications. JAMA. 2014;312(6):647–649
  21. Weigner MJ, Caulfield TA, Danias PG, Silverman DI, Manning WJ. Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours.Ann Intern Med. 1997 Apr 15;126(8):615-20.
  22. Echt DS, et al. Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo: The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781-788
  23. Procainamide. In: Lexi-comp online. Accessed 1/21/2019 at http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7556#f_warnings-and-precautions
  24. Stiell IG, Clement CM, Symington C, Perry JJ, Vaillancourt C, Wells GA. Emergency department use of intravenous procainamide for patients with acute atrial fibrillation or flutter. Acad Emerg Med. 2007 Dec; 14(12):1158-64
  25. Flecainide. In: Lexi-comp online. Accessed 1/21/2019 http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6916
  26. Amiodarone. In: Lexi-comp online. Accessed 1/21/2019 http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6332?hl=Antiarrhythmic%20Agent,%20Class%20III
  27. Dofetilide. In: Lexi-comp online. Accessed 1/21/2019 http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6780?hl=Antiarrhythmic%20Agent,%20Class%20III
  28. Ibutilide. In: Lexi-comp online. Accessed 1/21/2019 http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7067?hl=Antiarrhythmic%20Agent,%20Class%20III

I Have Andexanet Issues, 2: A Formulary Toolkit

by empharmd, posted in Classic EM PharmD, EM PharmD Blog

Zahra Nasrazadani, PharmD, BCPS

Emergency Medicine Clinical Pharmacist

Salina Regional Health Center


A few months ago, Kristina Kipp wrote her inaugural EMCrit article enumerating her (extremely justified) concerns with the data we had available at the time regarding andexanet alfa…or should I say “coagulation factor Xa (recombinant), inactivated-zhzo”(1)? Since then—and in a somewhat perverse order of operations—the drug has been rolled out in a second-generation release and later, the New England Journal of Medicine published the final results from Portola’s ANNEXA-4 trial (2). Essentially, the results revealed what most of us expected to see. There is no need to re-adjudicate the conclusions Dr. Kipp reached in her manifesto to righteous cynicism. Now, the question becomes— what do we do with this information? My recommendation is the same that I brought to our Pharmacy and Therapeutics Committee: keep the drug off of formulary, at least for now. What follows is a compendium of the strategies I found useful at our institution, compiled in one convenient article for your viewing pleasure.

A Review

First, I’d strongly encourage you to read Dr. Kipp’s original post on the subject of andexanet last June (3). It covers a lot of the bedrock clinical concerns that we should be keeping at the forefront of our opposition.

Andexanet’s primary mechanism of action is via binding and sequestration of Factor Xa inhibitors—specifically apixaban and rivaroxaban—to reverse their anticoagulant effects. The sequestered anticoagulants are unable to perform their Xa-inhibitory functions and anti-Xa levels decline quickly; they then recover and possibly rebound around an hour after the drug’s two-hour infusion is completed (4,5). What does that mean? Well, we still don’t know. Measuring anti-Xa levels is a fairly common surrogate endpoint for determining hemostasis, yet our ANNEXA-4 authors conclude that “there is no significant relationship between hemostatic efficacy and reduction in anti-factor Xa activity during andexanet treatment,” based on the analyzed data. Therefore, all hemostatic efficacy endpoints were determined clinically by an adjudication committee whose “members were blinded to the extent possible in a single arm cohort study.” And although that tricky little detail has been widely pulled into the light of day for scrutiny, it really cannot be over-emphasized: ANNEXA-4 had no comparator group. More to come on that point in a bit. Let’s dig into the persuasive bits.

Clinical Evidence

So what do we use instead of andexanet? This isn’t a problem to be solved—our normal standard of care is already firmly in place and quite effective. Although off-label, prothrombin complex concentrate (in the US, usually of the 4-factor variety, 4F-PCC) has been a handy little workhorse for this purpose.

If you’re crafting your formulary, start with an evaluation of the way your institution utilizes 4F-PCC. How many patients do you reverse annually overall? How about specific to the direct oral anticoagulants (DOACs) in question, apixaban and rivaroxaban? You’ll need this data to assign hard numbers to pharmacoeconomic analysis, but you also can’t establish a starting point for this conversation without knowing your current state of affairs. Look at the pertinent metrics: hemostasis, dose, subsequent thrombotic events, etc. Is your institution using the the drug-reference-recommended 50 units/kg dose? Ours implemented a lower dose regimen at 25 units/kg a couple of years ago and we’ve found our in-house results to be consistent with the published literature on the matter, which is to say: it works. Because dose-finding studies weren’t performed to bring this drug to market, many studies have attempted to do some post-market analysis with promising results at much lower doses.

A 2016 executive summary of antithrombotic reversal recommendations from the Neurocritical Care Society and the Society of Critical Care Medicine recommends 50 units/kg for DOAC reversal (6). The following year, the UPRATE trial found that a 25 unit/kg dose was sufficient to achieve 69% anticoagulant reversal with a low rate of embolic events at 2.4% (7). When evaluating intracranial hemorrhage in 2018, Schulman et al found similar efficacy and safety with this low dose (8). Whichever dosing strategy your institution chooses, you have clinical support for doing so. The 2016 reversal guideline above, paired with the American College of Cardiology expert consensus in late 2017 both provide formal support for utilization of 4F-PCC in DOAC reversal (9). If you worry that these guidelines don’t include andexanet references because it came to the market after their publication, the American Heart Association has you covered. In early 2019, their journal, Stroke, published a summary of current approaches and included both andexanet and 4F-PCC as treatment choices for DOAC reversal (10).

As pharmacists, we’re often not thinking about the risk of litigation, and certainly it’s not looming over us the way it is for physicians. They need to know that your formulary recommendations aren’t putting them at increased risk just as much as they need to know about clinical risk to your mutual patients. By providing guideline-level evidence to support your formulary choice, you’ll be able to assuage some of this concern. Use the evidence cited above to show them that they will not be failing to meet the standard of care by choosing to make andexanet unavailable, and that’s an important fact as well as key phrasing and framing for your argument.

So far, what we’ve done is assess our status quo and build evidentiary support for 4F-PCC in DOAC reversal. If you’re sports-minded, this is called defense and it’s not enough to win an argument. You also need to develop some offense. It’s the difference between “what we’re doing is good” and “the alternative is demonstrably bad.” Andexanet was approved and delivered to market via the FDA’s Accelerated Approval Program. As such, Portola is not required to assess meaningful, patient-centered outcomes. They need only “fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint” (1). Ostensibly, this explains away the lack of a comparator group. Although much has been said about ANNEXA-4’s significant limitations, it bears repeating that this study also utilized exclusion criteria such that they limited the study only to the healthiest patients. They chose subjects that could feasibly be managed without reversal of their anticoagulants. Although I believe andexanet should be kept off of your formulary, you may be faced with a physician or physician group that insists on the drug’s availability. If you simply can’t avoid purchasing this drug, it is in our patients’ best interest to insist that the same exclusion criteria be implemented as restrictions on andexanet’s use. It has not been studied in the sickest bleeding patients and still experienced a surprisingly high all-cause mortality rate at 30 days. As Dr. Justin Morgenstern notes, “if [andexanet] is given in a population of patients you don’t expect to die, 14% will die” (11).

As a reminder, exclusion criteria include: patients needing surgery within 12 hours, intracranial hemorrhage with a Glasgow Coma Score of less than 7, hematoma volume greater than 60 mL, expected survival less than one month, thrombotic event in the two weeks prior to enrollment, or receipt of warfarin, dabigatran, or various blood products (PCC, recombinant factor VIIa, whole blood, plasma) within the prior 7 days. Doesn’t that list sound very much like the patients for whom you’d most want and need a reversal agent? The surgeons at your institution think so, too. And although those exclusion criteria are extensive, ANNEXA-4 also didn’t enroll patients with “visible, musculoskeletal, or intra-articular bleeding.” They also didn’t permit discretionary doses of andexanet beyond the approved bolus and two-hour infusion. To enforce all of these parameters at your institution, you’ll need to frame utilization of andexanet as analogous to alteplase in ischemic stroke. Work through the checklist, determine your patient’s eligibility, and try to make your electronic health record pull its weight. It quickly becomes cumbersome and unrealistic but we have no idea what andexanet would do to those excluded patient populations so it is essential to protect them.

Although we’ve talked quite a bit about clinical considerations already, we haven’t even tackled hemostatic efficacy yet. So, does andexanet alfa work? The answer is that we actually still don’t know. Patient’s in the ANNEXA-4 trial were assessed for hemostasis at 12 hours after the end of their andexanet infusion. To be included, their last DOAC dose had to have been no more than 18 hours prior to treatment. So, let’s say a patient took their DOAC precisely 18 hours ago, then received a 15-30 minute bolus of andexanet, and then a 2 hour infusion. Study subjects could be as much as 20.5 hours out from their last DOAC dose when the 12-hour clock starts ticking, which means they are 32.5 hours out at the first analyzed assessment of hemostasis. With half-lives of 12 hours and 5-9 hours for apixaban and rivaroxaban, respectively, there is no appreciable drug still on board when this assessment was performed for at least some percentage of patients. By choosing a chronologically distant endpoint, the authors of ANNEXA-4 aren’t asking a meaningful question in the first place.

So, we have an off-label agent that works well and has lots of available evidence, plus the backing of expert guidelines to support its use. And we have another agent with one poorly-designed study and no useful outcome measures. So we’ve established some solid defense and a key piece of offense: our cherry-picked patient population—that explicitly was only included when expected survival was greater than one month—actually generated a number needed to harm of approximately 7. On to the next.

Pharmacoenonomic considerations

When andexanet alfa was initially released to selected sites, before we even knew much about its efficacy, everyone seemed to know that this drug was expensive. In healthcare, much of the cost of our interventions is woefully lacking transparency. Drug pricing charts circulated rampantly in the FOAMed Twittersphere painted an impossible picture in the order of tens of thousands of dollars. Now that any institution can order andexanet, we can confirm the rumors by querying our wholesaler. At the time of writing, andexanet is $22,000 per package of four 200mg vials. Any hospital wishing to keep andexanet in stock should keep three flats on hand at all times in order to be adequately stocked to administer the high-dose regimen, which is an 800mg bolus plus a 8 mg/min infusion for 2 hours, which totals 960mg. At a cumulative dose of 1760mg, that is a $66,000 out-of-pocket expense; accountant friends might chime in with something about cash flow. And depending on how often you are reversing DOAC bleeds, it’s possible you’ll be throwing nearly $70K in the garbage when it outdates. Remember the good old days when we thought 4F-PCC was costly?

The pharmacoeconomic angle is perhaps the easiest piece of this discussion to make compelling. For my institution, our annual cumulative 4F-PCC expenditure was less than the cost of treating just two high-dose andexanet patients. If you take this information to your P&T Committee, know that you won’t just be speaking to physicians. In general, these decision-making bodies also include administrators and various C-suite types. They speak the language of dollars, whereas we tend to speak the language of pharmacokinetics and chemistry. Know your audience and tailor a piece of your presentation to the more financially-minded individuals in the room. Consider also the payment structure for the vast majority of anti-coagulated patients—that is, predominantly Medicare recipients. Patient stays are reimbursed based on their assignment into a diagnosis-related group (DRG). In 2016, the average covered charge for an intracranial hemorrhage ranged from $26,728 to $53,754. GI bleeds were covered from $20,910 to $50,999, with the actual dollar amount depending on the ICD-10 code that is applied to each patient. And although these are the “covered charges,” the actual Medicare payouts range from $4,485 to $13,097, again depending on the diagnosis (12). Now, I’m no accountant, but the very fact that this is not the language I normally speak is what necessitates our involvement in the financials. We’re looking at massive sums that, when not fully covered, become the responsibility of the patient. The details are extremely complicated so these dollar signs don’t perfectly account for all of the moving parts, but the gap between what’s paid and what’s incurred is not one that can be spanned by minor adjustments. These numbers are simply staggering.

If you are making the case for keeping andexanet off of your formulary or applying rigorous restrictions, know that you aren’t alone. Get in communication with your group purchasing organization and find out how other institutions are handling this formulary decision. At the point where other massive and famous health systems are keeping andexanet off of their formularies (and they are), your hospital’s leaders are going to be reassured that they are making a decision somewhat multilaterally. Your purchasing organization is a wealth of information and is a valuable tool when making formulary decisions overall. For example, our institution’s purchasing group is conducting a survey of all participating hospitals regarding andexanet formulary decisions and will disseminate this information to members to bolster the conversations they know we’ll need to be having. Plus, your C-suite types are generally very compelled by this kind of information because they know other suits have thoroughly vetted their decision as well.

Scientific integrity

ANNEXA-4 sets a dangerous precedent if we allow it to do so. However, I don’t believe the study is wholly without merit. For one thing, it provides evidence for something many of us suspected all along: anti-Xa levels might not really mean much. For another thing, it is an excellent educational tool for learners of all varieties. This would be a great journal club article because it allows a student or resident to learn how to truly lay bare the “limitations” section of their presentation.

If you’ve been dying for the perfect illustration of the pitfalls of surrogate endpoints, now is your moment. Conversations about the importance of appropriate blinding are also warranted. The ANNEXA-4 authors offer a single line dedicated to justifying the total lack of comparator group: “At the time of study initiation, it was determined that a randomized, controlled trial would have logistic and ethical challenges, given the perceived risks of placebo assignment in this highly vulnerable population.” Even assuming we allow this assertion (but please don’t), they offer no explanation whatsoever as to why the comparator couldn’t have been the usual standard of care. Lacking this control group, the study is unable to reach conclusions about one of the most fundamental evidentiary concepts: statistical significance. Was the hemostasis achieved by andexanet significant? We can’t know. And that’s not just because of the lack of a comparator, but because they study also didn’t meet power. Importantly, the sample size of 350 patients required to meet power was determined, in part, by regulatory requirements that necessitated more patients in each DOAC group, beyond the initially planned 250 patients. Although the authors state that 250 patients would have been enough to meet power, the increased sample size suggests that the FDA disagreed. Ultimately, however, only 254 patients made it into the efficacy population and only 249 were included in analysis. So, by neither the first power calculation nor by the amended requirement was power met.

The line following the smoke and mirrors about unethical placebo groups is even more telling: “However, continued use of unapproved agents, despite a lack of rigorous clinical data, has changed the equipoise for a trial.” Again, the authors are setting up some fallacious arguments but also showing their hand. Use of 4F-PCC does have reasonably strong clinical data behind it (several examples of which they cite in their own references) but more importantly, no “rigorous clinical data” was collected by this trial. Additionally, this statement, when translated to plainer English, says, “off-label use of 4F-PCC showed us a money-maker niche so the balance of forces or interests has shifted.”

This is also a good moment to demonstrate the importance of reading the supplementary materials. There are all sorts of hidden gems lurking, and if your learners don’t already make a habit of deep-diving into the background and supporting literature when they present journal clubs, now is the time to enforce that practice. From the supplement, we learn that our hand-picked healthy patients were supposed to have been a very different group, but the exclusion criteria were extensively modified as the study progressed. Another noteworthy change includes adjusting the hemostatic efficacy assessment time from 24 hours to the 12 hours used in the study. The originally-planned 24-hour timeline would put the first assessment of hemostasis as far out as 44 hours from the last DOAC dose; this amendment was made “based on regulatory feedback.” The supplement also discloses the difference in hemostatic effect when comparing patients who received low versus high dose andexanet regimens. Although the statistical significance is unclear, high-dose patients numerically had poorer (or no) hemostasis than those who received low doses; we might interpret this to mean that patients who still had drug in circulation at the initiation of treatment were more poorly reversed than those patients in whom the DOAC dose was smaller and more chronologically distant. So, it seems we still have not answered the efficacy question.

TL;DR

Overall, this conversation covers a lot of ground. It’s intended to be a good spread of the variety of folks that are represented at your institution’s P&T. These are just some of the strategies that were useful at my specific institution. You may find yourself presenting the same information to more focused physician groups, like trauma or surgery sub-committees. Do some politicking in advance and assess who is already on your side or at least receptive to the conversation. Treat curbside questions about that new bleeding reversal drug as a golden opportunity to spread the good word of 4F-PCC and plant the seeds of well-placed skepticism at the ANNEXA-4 methods. Develop an elevator speech that hits the high points:

  • The drug likely doesn’t work, but we know with decent confidence how well 4F-PCC does.
  • For no added efficacy (and possibly risk of significant harm), you’re shouldering your patient with an unnecessary burden into the tens of thousands of dollars that is not picked up by insurance.
  • The drug is wholly untested in a clinically diverse group of sick patients so expect an extensive pre-andexanet checklist if added to formulary.
  • At least hold off until we get some good data. The phase 4 trial that began in January 2019 will compare andexanet to the usual standard of care and at least has the potential to yield meaningful results (projected to be completed in 2023, but still). (1)
  • Other massive institutions aren’t adding andexanet to their formularies (tailor this item to your available data).

Folks who insist on andexanet availability will make assertions based on what they hope the drug will accomplish. As you’ve seen, these are not founded in the data, so push back with confidence and diplomacy.

  1. FDA Approval Letter – ANDEXXA. May 3, 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606693.pdf. Assessed on March 3, 2019.
  2. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with Factor Xa inhibitors. N Engl J Med 2019. DOI: 10.1056/NEJMoa1814051
  3. Kristina Kipp. EMCrit – I Have Issues with Andexanet by K. Kipp, PharmD. EMCrit Blog. Published on June 19, 2018. Accessed on March 3, 2019. Available at [https://emcrit.org/emcrit/issues-andexanet/ ].
  4. Ghadimi K, Dombrowski KE, Levy JH, Welsby IJ. Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Expert Rev Hematol 2016; 9: 115-22.
  5. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373: 2413-24.
  6. Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: executive summary. A statement for healthcare professionals from the Neurocritical Care Society and the Society of Critical Care Medicine. Crit Care Med 2016;44(1):2251-2257.
  7. Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017;130:1706-12.
  8. Schulman S, Gross PL, Ritchie B, et al. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemost 2018;118:842-51.
  9. Tomaselli GF et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Amer Coll Card 2017;70(24):3042-67.
  10. Bower MM, Sweidan AJ, Shafie M, et al. Contemporary reversal of oral anticoagulation in intracerebral hemorrhage. Stroke 2019;50:529-536.
  11. Justin Morgenstern, “Andexanet Alfa: More garbage science in the New England Journal of Medicine”, First10EM blog, February 11, 2019. Available at: https://first10em.com/andexanet-alfa/.
  12. National summary of inpatient charge data, FY2016, interactive dataset. Centers for Medicare and Medicaid Services. https://data.cms.gov/Medicare-Inpatient/National-Summary-of-Inpatient-Charge-Data-by-Medic/us23-4mx2

Dose Banding for Pediatric Medications

by Nadia I. Awad, posted in EM PharmD Core

If you go to any medication aisle of a store, you can find a wide selection of medications for pediatric patients. Everything from analgesics, cough and cold medications, and agents for gastrointestinal relief. Being a new parent myself, in learning the many ins and outs of infanthood, I did notice something that struck me as rather interesting, perhaps because of my background as an emergency medicine pharmacist, that called my attention.

On most over-the-counter medications for pediatric patients, particularly for oral liquid formulations, there is generally a single dose recommendation provided for any particular medication, given a weight range.  For example, this is the dosing range provided in the product labeling of ibuprofen for the branded formulation of Children’s Motrin® and Motrin Infant Drops®:

Yet, in the health-system setting, as we are so particular about ensuring that with documentation of the correct weight of the pediatric patient within the electronic medical record, we dose ibuprofen using a specific weight-based dose (generally 10 mg/kg/dose), rather than rely on this method for dosing the same medication.

Of course, from a practical standpoint, this makes the most sense, as our children are not regularly weighed when they are at home as opposed to obtaining an accurate weight when evaluated by a pediatrician in an inpatient or outpatient setting. But how many times have we heard of and/or been involved in situations where the weight was documented inaccurately (pounds versus kilogram) or the dosing of the medication prescribed was mg/kg/day instead of mg/kg/dose? You can also make the best pharmacotherapeutic recommendation for your sick pediatric patient, backed up by a complete and referenced in-house guideline for your team of providers (approved of course by the many committees at your institution), but the turnaround time in compounding the medication may not be all that feasible due to the individualization of the dose, limiting timely delivery and leading to potential delays in administration of therapy.

However, can this concept of dose banding, which is generally defined as dosing medications in patients based on a range (or ‘band’) of weights, with the dose generally falling within the middle of the band, be applied to the inpatient setting?

The concept of dose banding is not foreign in the inpatient setting. This strategy has been evaluated in pediatrics, particularly for antimicrobials and chemotherapeutic agents, and it has made headway in Europe over the past few years. In fact, the National Health Service (NHS) has actually advocated for the use of dose banding strategy for intravenous pediatric chemotherapeutic agents as a means to reduce drug waste, costs, and most importantly, errors in dosing these agents.1 Standardized doses have been proposed for these agents based on a band of predefined dose ranges with a given body surface area. Dose banding tables provided by the NHS are available here for a variety of chemotherapeutic agents, which can be used as a means to streamline chemotherapy for pediatric patients. In one evaluation of the effect of dose banding tables for chemotherapeutic agents, drug expenditures significantly decreased over the course of one year with this strategy,2 which can increase productivity within the department as a result of time freed for both extemporaneous compounding of the medication (as only standard doses would be required to be compounded) and clinical time, as errors are minimized and minimal intervention is needed in correcting the error (or worse, missing the error and treating the adverse reaction resulting from such an error later).

In addition, there was one evaluation conducted with prophylactic piperacillin-tazobactam in pediatric patients prior to surgery that also demonstrated minimal variations in the dosing recommendations of this agent when prescribed by a dose banding strategy relative to a mg/kg basis.3 In another evaluation of medications prescribed to pediatric patients in the emergency department, errors were minimized with dose banding strategies employed for a number of oral analgesic and antimicrobial therapies (our bread-and-butter classes of agents for this patient population in this acute setting).4

One may consider the pharmacokinetic implications (or lack thereof) with employing dose banding strategies for such agents. There are a number of evaluations that demonstrated minimal differences in pharmacokinetic parameters when dose banding strategies were used in pediatric patients versus dosing based on a mg/kg or mg/m2 basis.5-6 For some agents, a variance of 5% or less of the dose within the dose band versus standard mg/kg or mg/m2 dose may be acceptable.7 Of course, for agents with a narrow therapeutic index, one may not necessarily consider such a strategy to be utilized as a means to ensure that systematic toxicity is minimized with these particular agents while achieving the maximum therapeutic effect.

Overall, however, dose banding is an interesting concept that can make a multifaceted difference in the delivery of patient care, based on the numerous advantages highlighted above, and one that requires further evaluation for medications commonly used for the pediatric population in the inpatient setting.

References:

  1. Mayor S. National Health Service England introduces dose banding. Lancet Oncol 2016; 17(7):e271.
  2. Finch M, Masters N. Implications of parenteral chemotherapy dose standardisation in a tertiary oncology centre. J Oncol Pharm Pract 2018 [Epub ahead of print].
  3. Karande IS, Goff Z, Kewley J, et al. Dose-Banding of Intravenous Piperacillin-Tazobactam in Pediatric Surgical Inpatients. J Pediatr Pharmacol Ther 2017; 22(5):364-368.
  4. Al-Turkait A, Khan F. Can dose-banding help to reduce prescribing errors in a pediatric accident and emergency (A&E) department? Arch Dis Child 2015; 100(6):e1.26-e21.
  5. White-Koning M, Osborne C, Paci A, et al. Investigating the potential impact of dose banding for systemic anti-cancer therapy in the paediatric setting based on pharmacokinetic evidence. Eur J Cancer 2018; 91:56-67.
  6. Windscheif PM, Welsh R, Smith L, et al. Once daily gentamicin dose banding in newborns with signs of early onset neonatal sepsis (EONS), based on initial birth weight and gestational age. Arch Dis Child 2016; 101(9):e2.
  7. Plumridge RJ, Sewell GJ. Dose-banding of cytotoxic drugs: a new concept in cancer chemotherapy. Am J Health Syst Pharm 2001; 58(18):1760-1764.