Challenging the superiority of amiodarone for rate control in Wolff-Parkinson-White and atrial fibrillation.

The objective of this review is to explore and challenge the superiority of amiodarone for rate control in Wolff-Parkinson-White syndrome and concomitant atrial ﬁbrillation (WPW-AF). The current recommendation for pharmacological treatment of this condition is amiodarone. A review of the past 25 years of literature ﬁnds several studies that identify a small risk of ventricular ﬁbrillation secondary to amiodarone administration for rate control in WPW-AF. Additionally, the literature supports the safe and effective use of procainamide for rate control in WPW-AF. This review concludes that amiodarone is not superior to procainamide in rate control for WPW-AF, and may be dangerous.


Introduction
We present a case of a patient with Wolff-Parkinson-White (WPW) syndrome and concomitant atrial fibrillation (AF) to demonstrate and discuss the controversy surrounding its treatment. The current recommendation for pharmacological treatment is amiodarone. In this article, we challenge its efficacy, as well as discuss the evidence behind procainamide use (Table 1).

Case presentation
A 39-year-old man presented to the Emergency Department (ED), complaining of 8 h palpitation and fluttering discomfort in his chest. The patient had a history of intermittent palpitations, but stated that he typically could meditate to help alleviate these symptoms. He reported that the palpitations typically occurred at times of stress or exertion. Approximately 3 years prior, he had been diagnosed with Wolff-Parkinson-White syndrome. Cardiac and stress testing were conducted without any further abnormalities or need for angiography.
The patient presented with the following vital signs: blood pressure 92/37 mmHg, pulse 209 beats/min (bpm), respiratory rate 24 breaths/min, and pulse oximeter 100%, although it is unclear if the patient was on supplemental oxygen. The patient was neither on any medications, nor had any follow-up since the WPW diagnosis. He stated that he had been doing well, with the exception of the intermittent bouts of palpitations. He denied dizziness, lightheadedness, or pain. The family history was non-contributory. He smoked cigars but denied cigarettes. The patient used marijuana, but denied cocaine.
He was alert and oriented and the skin was warm and dry. There was no jugular venous distension. He was tachycardic, but there was no wheezing, rales or increased work of breathing, and he denied shortness of breath and cough.
The rhythm strip demonstrated a wide-complex ventricular response between 200 and 220 bpm, occasionally dropping to 180-190 ( Fig. 1) Given the known WPW syndrome, this was interpreted as AF. The systolic blood pressure intermittently dipped to 60-80 mmHg, despite IV fluids. The chest X-ray study was normal. Although 150 mg of IV amiodarone was administered, he remained tachycardic, at 200-210 bpm. The blood pressure continued to be labile, with a systolic blood pressure of 60-110 mmHg.
The patient was not initially cardioverted, as he had been symptomatic for 8 h, and tolerated the moderate hemodynamic compromise. Procainamide, though effective to simultaneously block the AV node and accessory pathway, was not chosen due to its more potent negative inotropic effect relative to amiodarone. The SBP, though stable, hovered in the low 1990s. Procainamide was not immediately available in the ED within 15 min, and the patient's blood pressure was low; had this not been the case, it could have been used instead.
Lidocaine has little to no negative inotropy, but is contraindicated in AF with WPW, as it slows AV conduction, but can facilitate antegrade conduction along the accessory pathway [11], resulting in increased rate, hypotension, or ventricular fibrillation [10]. Furthermore, the use of two sequential antidysrhythmic agents in the same patient is not recommended; synchronized cardioversion is the preferred treatment. The cardiology consultant also recommended amiodarone over procainamide through phone consultation.
Given lack of improvement with antidysrhythmic therapy, we began synchronized cardioversion (all with a The patient was bag-valve-mask ventilated, intubated, and cardiopulmonary resuscitation was begun. He then received a 200 J defibrillation without resolution. We administered 1 mg of IV epinephrine (1:10,000) and defibrillated a second time at 300 J. He reverted to a widecomplex tachycardia at 140-160 bpm. The troponin level returned elevated at 0.22 lg/l (reference rate 0.00-0.09 lg/l), and he was started on heparin. Initial pertinent laboratory values were normal magnesium 2.0 mg/dl (reference range 1.3-2.7 mg/dl), myoglobin 59 ng/ml (reference range 0-110 ng/ml), sodium 136 mmol/l (reference range 135-147 mmol/l), potassium 3.8 mmol/l (reference range 3.5-5.5 mmol/l), chloride 103 mmol/l (reference range 99-109 mmol/l), bicarbonate 25 mmol/l (reference range 20-31 mmol/l), calcium 9.3 mg/dl (reference range 8.7-10.4 mg/dl), and mildly elevated bun/creatinine ratio of 22/1.41 mg/dl (reference range 6-20/0.70-1.30 mg/dl). No further troponin or cardiac enzyme levels were recorded during this episode. As per the admitting cardiologist's recommendations, a 17 mg/kg loading dose of IV procainamide was given at 30 mg/min, followed by a drip at 2 mg/min. He converted to a normal sinus rhythm, rate 76 with Q-waves in the inferior leads of unclear chronicity, and no acute ST-T wave changes (Fig. 2). Repeat electrocardiogram displayed a sinus bradycardia, rate 54 bpm with inferior Q-waves, intraventricular conduction delay, and non-specific ST-T wave changes (Fig. 3). As the AF episode concluded, the vital signs were recorded at: blood pressure 84/55 mmHg, pulse 67 bpm and respirations 14 breaths/min. An echocardiogram showed normal left ventricular chamber size, wall thickness and motion, with an ejection fraction of 50%. Mild left atrial enlargement, normal mitral and aortic valves, normal right heart, and mild tricuspid regurgitation were also recorded. The patient was admitted to the hospital, and subsequently underwent electrophysiology study, ablation of an accessory pathway (AP) without complications, and cardiac catheterization revealing no significant coronary disease. The patient recovered and was discharged on hospital day 6.

Discussion
The American Heart Association (AHA) 2005 Cardiopulmonary Resuscitation Guidelines tachycardia algorithm solely recommends amiodarone for termination of ventricular tachycardia due to WPW-AF [1]. In this case Recent studies support the small yet serious risk of ventricular fibrillation secondary to amiodarone administration for rate control in WPW-AF. The 1996 Boriani case report concludes that amiodarone may lead to prodysrhythmic events in WPW-AF. The case report recommends the use of class 1A or 1C antidysrhythmic drugs in place of amiodarone in WPW-AF [2]. Similarly, in 2005, Tijunelis and Herbert published a review article on amiodarone in WPW-AF, arguing against the further use of amiodarone. The review article, which searched published reports over the past 30 years, finds no controlled studies administering amiodarone in WPW-AF [9,16]. Furthermore, the review notes that out of ten patients with WPW-AF who had ventricular tachydysrhythmias after antidysrhythmic drug administration, seven of the cases involved IV amiodarone [16]. Fengler et al., in a case report, caution against the use of amiodarone as well, stating that IV amiodarone usage in WPW-AF is documented to cause ventricular rate acceleration leading to ventricular fibrillation [4]. Additionally, Schützenberger et al. [13] caution against the use of amiodarone in WPW-AF presenting a case report of an increased ventricular response secondary to accelerated conduction via the accessory pathway. Kappenburger et al. state in a study that though amiodarone is effective, it does not entirely prevent a rapid ventricular response in eight of ten patients with induced AF and a short effective refractory potential. The failure to prevent an increased ventricular response leads the study to call for the establishment of the safety of amiodarone in WPW-AF [5]. The findings support the notion that amiodarone may not be the safe pharmacological treatment of choice for rate control in WPW-AF [2,4,5,13,16].
This leads us to the question of procainamide and its effectiveness. A study of procainamide use by Li looked at 51 patients with WPW-AF. The study concludes that procainamide administration increases the antegrade effective refractory period and the intra-atrial conduction time significantly [6]. Schatz et al. support procainamide as the favored pharmacological treatment for patients with WPW-AF due to the ability to safely lengthen the effective refractory period [12]. Additionally, Fengler et al. [4] favor the use of procainamide in WPW-AF, stating procainamide prolongs the effective refractory period and slows antegrade and retrograde conduction in the AP. Procainamide has risks as well, including a significant side-effect profile, namely hypotension, QT-interval prolongation, and contraindications for patients with compromised cardiovascular function [3,4].
Sotalol's effectiveness in rate control in patients with WPW-AF also calls for exploration. Madrid et al. [7] document conversion to a normal sinus rhythm in 12 of 22 patients who were administered sotalol. Additionally, the study finds no serious side effects and concludes that sotalol may be safe and effective [7]. Although sotalol is currently not available in the United States, it provides a pharmacological therapy option that warrants further study.
Amiodarone's relatively benign side-effect profile likely plays a role in the AHA recommendations. However, it is unclear whether this endorsement takes into consideration that amiodarone can cause ventricular fibrillation in a small but significant number of cases [2,16], or that amiodarone is simply not efficacious in a number of wide-complex tachycardia cases [3,8]. Despite procainamide's potential for WPW-AF control, it has significant side effects, including hypotension [3,4]. This risk can be anticipated and mitigated with a slow infusion of procainamide plus an infusion of intravenous fluids. If hypotension continues, the infusion may be stopped, and the physician can move on to cardioversion. The small percentage of patients who go into ventricular fibrillation with amiodarone administration cannot be predicted or controlled by stopping an infusion. Therefore, the ability to stop a procainamide infusion upon recognition of undesirable side effects is an advantage over amiodarone.

Conclusion
Past studies paint an unclear picture of the clinical efficacy of amiodarone and procainamide in WPW-AF. None of the clinical studies noted above were formal, prospective, randomized, controlled trials. They had variable placebo and drug choices, significant variations in drug dosages and administration, and widely differing primary endpoints. Ultimately, we believe there is a strong need for a prospective, controlled trial of amiodarone versus procainamide for ventricular rate control in WPW-AF. Given this review, there is no available evidence that amiodarone is preferred over procainamide in rate control for WPW-AF, and may be dangerous.