Friday, August 29, 2014

A Line CAST Too Far: An Evaluation of the Contraindications of Class Ic Antiarrhythmics

Flecainide and propafenone are the only Class Ic antiarrhythmic drugs (AADs) available in the United States. These agents block the fast sodium channels within cardiomyocytes, thereby decreasing the rate of rise and magnitude of the action potential. This causes a slowing of conduction velocity, without increasing the effective refractory period. While these agents are particularly useful for atrial fibrillation (AF) and atrial flutter, utilization remains low because their contraindications exclude many patients who would otherwise be candidates for therapy. In particular, the Class Ic AADs are contraindicated in patients with structural heart disease, and those with previous myocardial infarction. The latter is often extrapolated to include any degree of coronary artery disease (CAD). As a result, these agents are commonly reserved for patients with lone AF.

So why is this such a bummer? The reasons are primarily two-fold. Despite the modest effects achieved with antiarrhythmics as a class, the Class Ic AADs achieve some of the highest rates of successful cardioversion and subsequent maintenance of sinus rhythm (1). Second, the Class Ic agents do not exhibit some of the dose-limiting toxicities associated with other common antiarrhythmics, making them an invaluable addition to our armamentarium for rhythm control. In particular, while QT prolongation is a major concern with other AADs, the Class Ic agents do not significantly prolong the QT interval (2). While their contraindications are no mystery to those familiar with antiarrhythmic therapy, perhaps they should be. A deeper dive into the history behind these established contraindications may cause the astute clinician to be a bit skeptical.

Where did these contraindications originate from? It seems that they have been somewhat broadly extrapolated from the initial Cardiac Arrhythmia Suppression Trial (CAST I) (3). This trial sought to evaluate the safety and long-term outcomes of flecainide and encainide for suppression of premature ventricular contractions (PVCs) in patients with a recent myocardial infarction (MI). The investigators hypothesized that suppressing these PVCs would improve long-term survival after MI. Ultimately the study was terminated early because of a 2.6-fold increased risk of arrhythmic death when compared to placebo. Before delving further, it is important to note, that this trial had nothing to do with rhythm control for supraventricular arrhythmias – an indication for which the Class Ic AADs would be most sought for today.

So what type of patient population was studied? Indeed, this is a tough question to answer from reading just the final publication, since little demographic information is available. Upon further digging, it becomes clear that the overall population studied resembles only a tiny fraction of those lumped into the vague designations of “structural heart disease” or “coronary artery disease”. Specifically, rigorous inclusion criteria were enforced for entry into the CAST trial; those suffering an MI had to have subsequent PVCs and/or non-sustained ventricular tachycardia completely suppressed during open-label titration with one of the study drugs. Not surprisingly, only 60% of total patients screened met inclusion criteria for randomization (4). Thus, patients who met eligibility criteria likely represent a minority of all patients suffering an MI. Further, while the inclusion criteria stipulated maximum thresholds for ejection fraction, the average ejection fraction of all patients in the study was much lower, at just above 30% (5). Clearly, the CAST trial enrolled a much more specific population than those who might be excluded from these agents today.

Issues regarding concurrent drug therapy also question the applicability of the study to contemporary practice, as less than 30% of these patients were taking beta blockers, despite what is now a class IA recommendation for beta blockers in this population (6). In fact, about 40% of patients in the study received nondihydropyridine calcium channel blockers (diltiazem or verapamil) (3); a class IIIB negative recommendation for these agents in heart failure with reduced ejection fraction (6). Indeed, a considerable number of deaths in the study were attributed to cardiogenic shock and asystole, causing one to wonder whether the study drugs were solely to blame.

Moreover, virtually no information is provided regarding the distribution of baseline demographics among the study arms (i.e. time from MI to study enrollment, concurrent medications, ejection fraction), causing a whole host of concerns about potential confounders skewing outcome results. Finally, where is the literature supporting harm with propafenone in these patients? Propafenone seems to be guilty by association.

While the aforementioned contraindications for flecainide and propefanone are often applied universally for all indications, it is interesting to note that their own FDA-approved labels are rather circumspect with regard to this, stating, “The applicability of the CAST results to other populations…is uncertain” (7, 8). Thus, while their use for supraventricular arrhythmias is still shunned in the presence of structural heart disease, world literature reveals a mere 0.4% incidence of proarrhythmic effects when used for paroxysmal atrial fibrillation (7).

Let’s apply the potential ramifications here to a hypothetical 75-year-old male, whose atrial fibrillation has been well-maintained on propafenone for the past two decades. At a recent appointment, complaints of moderate, persistent chest pain lead to angiography, upon which a severe stenosis of the LAD was found. Although a stent was placed, he never actually infarcted, and his ejection fraction remains normal. On medical rounds, the patient is diagnosed with CAD, and the astute resident picks up on the apparent contraindication. The patient is switched to dronedarone and discharged. Two weeks later, the patient presents to the ED, and is now poorly controlled and symptomatic. In addition to failing therapy, an ECG reveals a prolonged QT interval greater than 50% from baseline. In this situation, after evaluating the risks of alternate therapy as compared to continued propafenone, it becomes clear that justifying such broadly extrapolated contraindications may lead to unnecessary risks. Herein applies the old adage, “If it ain’t broke, don’t fix it”.

Current contraindications to the Class Ic AADs have been over-extrapolated from the CAST study to encompass other patient populations and treatment indications that were not evaluated in the trial. This may result in the unnecessary exclusion of patients who may otherwise benefit from these drugs. Critically defining the studied population, and knowing the literature behind the label is crucial in helping the risk-averse clinician determine the most appropriate therapy.

  1. Naccarelli G, Wolbrette D, Khan M, et al. Old and new antiarrhythmic drugs for converting and maintaining sinus rhythm in atrial fibrillation: comparative efficacy and results of trails. Am J Cardiol 2003; 91[Suppl]:15D-26D.
  2. Hume JR, Grant AO. Chapter 14. Agents Used in Cardiac Arrhythmias. In: Katzung BG, Masters SB, Trevor AJ. eds. Basic & Clinical Pharmacology, 12e. New York, NY: McGraw-Hill; 2012. Accessed August 13, 2014.
  3. Echt D, Liebson P, Mitchell B, et al. Mortality and morbidity in patients receiving encainide, flecainide or placebo. The Cardiac Arrhythmia Suppression Trial (CAST). NEJM 1991; 324:781-788.
  4. Capone R, Pawitan Y, El-Sherif N, et al. Events in the cardiac arrhythmia suppression trial: baseline predictors of mortality in placebo treated patients. JACC 1991; 18: 1434-1438.
  5. Epstein A, Bigger T, Wyse G, et al. Events in the cardiac arrhythmia suppression trial:  mortality in the entire population enrolled. JACC 1991; 18:14-19.
  6. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:1495-1539.
  7. Flecainide (Tambocor) [package insert]. Northridge, CA: 3M Pharmaceuticals; 2006. 
  8. Propafenone (Rythmol) [package insert]. Rockford, IL: UDL Laboratories; 2010.

Adam Spaulding, PharmD, BCPS (@PharmERAtom)
Emergency Medicine Pharmacist
The Waterbury Hospital
Waterbury, Connecticut

Editorial note:
Many of the points discussed by the author related to the inclusion criteria and baseline demographics of patients enrolled in CAST were addressed by experts in the field of cardiac electrophysiology in an editorial published in a subspecialty journal of Circulation. This is another instance where dogmas related to pharmacotherapy get passed on to generations of clinicians and are taken for granted as part of the learning experience without many questions raised, and more often than not, can have a true impact on clinical practice when applied to direct patient care. One scenario where the dogma related to the contraindications of the class Ic antiarrhythmics can have an influence in our practice in the emergency department is the "pill-in-the-pocket" approach for managing patients with paroxysmal atrial fibrillation, where both flecainide and propafenone may be commonly used as single doses due to their rapid onset of action and overall tolerability relative to other antiarrhythmic agents. This can lead to some dire consequences in our patients, especially if we institute therapies that are considered to be both less efficacious and potentially more harmful. A true examination of why we do things the way that we do in emergency medicine based on commonly accepted facts (or misconceptions, in this case) may lead us to debunk more and more myths as time progresses, and can ultimately not only change practice but also prevent perpetuation of these dogmas to future clinicians being taught in the didactic setting. As the saying goes, "Half of everything that we know is wrong; we just don't know which half." I'd like to add to that statement: "...until we really investigate the facts."

--Nadia Awad, Pharm.D., BCPS (@Nadia_EMPharmD)

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