Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

80th Scientific Sessions of the American Heart Association

Orlando, Florida / November 4-7, 2007

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia seen in clinical practice and its incidence is increasing as the population ages. The most important potential complication of AF is stroke, for which AF is responsible for 15% to 20% of all occurrences. AF occurs in up to 40% of patients following cardiac surgery and is frequently associated with prolonged hospitalization as well as the development or exacerbation of congestive heart failure, as was noted by Dr. Peter Kowey, Chair, Cardiovascular Service, Lankenau Hospital, Wynnewood, Pennsylvania.

Current antiarrhythmic agents used in the management of AF block various ionic channels indiscriminately. More importantly, they lack selectivity for atrial tissue and, as a consequence, may induce life-threatening arrhythmias in ventricular tissue. As discussed by Dr. Kowey, ibutilide is indicated for conversion of AF to sinus rhythm in patients who develop AF after cardiac surgery, but as is the case with other antiarrhythmic agents, “Ibutilide has no atrial specificity and is associated with torsades de pointes, which is its principal liability.” Tedisamil is another antiarrhythmic agent currently being evaluated for the treatment of AF. To date, this agent has proven effective for AF termination with a positive dose response, but 0.5% to 0.6% of recipients experience torsades de pointes as well, noted Dr. Kowey.

The mixed sodium/potassium channel blocker vernakalant selectively blocks ion channels in the heart that are active during AF episodes. Its effect on termination of acute AF or atrial flutter (AFL) was evaluated in non-surgical patients with recent-onset or long-term AF or AFL in a trilogy of studies called ACT (Atrial Fibrillation Conversion Trial). The combined outcomes of ACT I and III (575 total patients; both studies completed before ACT II) indicated that 51.5% of patients receiving the novel antiarrhythmic were converted to sinus rhythm vs. 3.8% of placebo controls, at a mean time to conversion of 11 minutes. No torsades de pointes was reported in either of these trials.

ACT II

Dr. Kowey presented findings from ACT II, an international, double-blind, placebo-controlled study that included 190 patients in normal sinus rhythm prior to coronary artery bypass graft (CABG), valvular surgery or both, who then developed sustained AF (three to 72 hours) or AFL 24 hours to seven days after surgery. At study entry, 93% of patients had AF, while 6% had AFL (1% had neither). Patients were randomly assigned in a 2:1 ratio to receive a 10-minute infusion of vernakalant 3 mg/kg (n=107) or placebo (n=54). If AF or AFL persisted for 15 minutes despite the initial infusion, a second 10-minute infusion of 2 mg/kg or placebo was given.

The primary efficacy measure—conversion to sinus rhythm for at least 1 minute within 90 minutes of the first exposure—was achieved by 45% of the patients assigned to active treatment and 15% assigned to placebo (P=0.0002). Of the patients who converted to sinus rhythm with the antiarrhythmic, median time to conversion was 12 minutes with 75% converting to sinus rhythm after a single dose. Among patients with AF alone, conversion to sinus rhythm occurred in 47% of the vernakalant group vs. 14% of the placebo group (P=0.0001), with the median time to conversion again being 12 minutes. However, vernakalant was not effective in converting AFL to normal sinus rhythm. At 24 hours, 60% of vernakalant responders were still in sinus rhythm, as was 57% of the same group at seven days.

Adverse Events

In the first 24 hours after study drug administration, adverse events were reported in 32% of placebo controls and in 38% of the vernakalant group, of which 2% were serious: one patient experienced a complete atrioventricular block and one had hypotension (2/102). Bradycardia did occur more frequently in the first 24 hours following vernakalant administration (14%) compared with placebo (4%), which Dr. Kowey partially attributed to the superior conversion rate with the antiarrhythmic.

Unlike other antiarrhythmic agents used for the treatment of AF, vernakalant caused no excess ventricular arrhythmias in ACT II and it did not provoke any episodes of torsades de pointes, although it was associated with a transient prolongation of the QT interval, observed Dr. Kowey. There were no deaths in either group.

“My own belief is that the effect of this drug to terminate arrhythmias may lie in its sodium channel-blocking effect rather than a potassium effect. I believe that the potassium effect may be important for maintenance of sinus rhythm,” Dr. Kowey told the audience. An oral formulation of vernakalant is now being studied for chronic sinus rhythm maintenance.

AFFIRM: Sinus Rhythm or Rate Control

AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) established that a rate-control primary treatment strategy was comparable to a rhythm-control strategy on outcomes in patients with persistent AF; however, it represented a highly select subgroup of patients with minimally symptomatic to asymptomatic AF, according to Dr. Jeremy Ruskin, Cardiac Arrhythmia Services, Massachusetts General Hospital, Boston. Furthermore, “AFFIRM did not demonstrate that normal sinus rhythm and rate control are equivalent,” he pointed out. Being in sinus rhythm was associated with a significant 46% reduction in mortality compared with staying in AF (P<0.001). The lack of a survival benefit with antiarrhythmic drugs in AFFIRM may be a function of their adverse effects offsetting any benefit from restoration of sinus rhythm. Dr. Ruskin stated that many patients with AF require treatment directed toward maintenance of normal sinus rhythm. “Antiarrhythmic drugs don’t work in 100% of patients but patients always do better when in sinus rhythm,” he explained.

Atrial Fibrillation Guidelines

Until such time as new pipeline antiarrhythmics prove to be useful in helping convert AF to sinus rhythn, physicians can be guided in their therapeutic goals and treatment decisions by guidelines developed by international experts (J Am Coll Cardiol 2006;48(4):854-906). As presented by Dr. Eric Prystowsky, Director, Clinical Electrophysiology Laboratory, St. Vincent Hospital, Indianapolis, Indiana, physicians first need to decide if their goal is short- or long-term. A patient who develops AF for the first time after cardiac surgery, for example, usually only requires treatment for four to six weeks, whereas someone who has had a history of recurrent AF episodes may require long-term therapy. “In addition, one must take into account concomitant medical problems that may affect the occurrence of AF, medications used or both,” Dr. Prystowsky added. It is critical for treating physicians to decide whether to adopt a rate-control or sinus-control strategy, as well as the most appropriate course of antithrombotic therapy.

Ablation can also be offered as first-line treatment in some circumstances, provided the electrophysiologic laboratory has substantial expertise in the technique and patients who categorically refuse antiarrhythmic drug treatment clearly would have no other option but ablation.

As for his own approach in deciding whether to aim for rhythm or rate control, Dr. Prystowsky noted that for rate strategy, “I prefer to evaluate serial 24-hour heart rhythm trends in the presence of a patient’s normal daily activities, with the goal of achieving a mean heart rate of approximately 70 to 80 bpm and minimal to no mean hourly rates greater than 100 bpm.” In essence, he added, such a heart rate plot should mimic what physicians see in sinus rhythm in a similarly-aged patient.

For rhythm control, Dr. Prystowsky aims to reduce or eliminate symptomatic episodes of AF as best as possible. “One does not have to eliminate all such episodes for success,” he remarked, “but a marked reduction should occur so that the patient has an overall increase in quality of life.”

Note: At the time of printing, vernakalant is not available in Canada.