Hrs.conferencearchives.com

SUMMER SELF STUDY PROGRAM
Drug Therapy for Stabilization of AF: From Foxglove to Tarantulas
Friday, May 16, 2008
Bramah N. Singh, MD, DSc, FRCP
Gerald V. Naccarelli, MD, FHRS

Current Drug Options for Atrial Fibrillation
L. Brent Mitchell, MD
Dr. Brent Mitchell discussed the magnitude of the clinical problem of atrial fibrillation. He reviewed
the epidemiology of atrial fibrillation using a graphical display comparing the total population of
the United States based on age to the population of people in the United States with atrial
fibrillation based on age taken from and article by Feinberg (Arch Int Med 1995;155:469). In this
article from 1995, there was an estimated 2.2 million people in the US with atrial fibrillation with a
median age of 75 years. The prevalence of atrial fibrillation was 2.3% in people older than 40
years of age and 5.9% in people older than 65 years of age. Approximately 70% of people with
atrial fibrillation were between 65 and 85 years of age. The baby boom generation is fast
approaching their 60s and there has been a drastic increase over the last 10-20 years in risk
factors contributing to atrial fibrillation in the general population (specifically diabetes, obesity and
high blood pressure), suggesting that the incidence of atrial fibrillation is likely to increase
significantly in the next 10 years. The likely treatment for the majority of patients with atrial
fibrillation will continue to be drug therapy.
Treatment goals for atrial fibrillation were discussed and Dr. Mitchell focused his musings
specifically on rate control of atrial fibrillation and pharmacologic options for rhythm control.
With regard to rate control of atrial fibrillation, conventional medications such as digitalis
preparations, beta adrenoceptor blockers, non-dihydropyridine centrally acting calcium channel
blockers, or amiodarone can be used. Conversion to sinus rhythm can also be a good strategy
for rate control of atrial fibrillation. AV nodal ablation and placement of a pacemaker can also be
considered when pharmacologic methods fail. A study comparing heart rate response in atrial
fibrillation using different AV nodal blocking agents alone and in combination (digoxin, diltazem,
atenolol, digoxin plus atenolol, and digoxin plus diltiazem) demonstrated that digoxin alone does
not offer good control of heart rate in atrial fibrillation at rest or with exercise. Diltiazem offers
improved control of heart rate at rest and decreased the exercise rate of atrial fibrillation. Atenolol
markedly slowed the resting rate and prevented a significant increase with exercise which could
decrease exercise tolerance. The combination of diltiazem or atenolol with digoxin futher slowed
the resting rate in atrial fibrillation and the maximal exercise rate.
Strategies for conversion of atrial fibrillation to sinus rhythm were then reviewed. Pharmacologic
options include membrane–stabilizing drugs including sodium cannel blocking agents, either
Class IA (quinidine, procainamide, disopyramide) or Class IC (flecainide, propafenone) or
potassium channel blocking agents that are Class III (sotalol, dofetilide, ibutilide, amiodarone).
For acute termination of atrial fibrillation or atrial flutter, meta-analysis by McNamara et al in
1993, indicated that ibutilde had an odds ratio (OR) of 31 for acute termination of the atrial
arrhythmia, while flecainide (OR 13), dofetilide (OR 6.7), propafenone (OR 3.9), amiodarone (OR
3.2), Quinidine (OR 2.9) were all better than placebo. Digoxin, calcium channel blockers, and
beta-blockers did not have efficacy in acute termination of atrial fibrillation or flutter. Interestingly,
sotalol also did not show efficacy for acute termination of atrial fibrillation.
For secondary prevention of atrial fibrillation or flutter, which is the use of a drug to prevent
recurrence once the patient is back in sinus rhythm, Amiodarone had the best odds ratio for
prevention of recurrence (6.8) while flecainide (4.3), propafenone (3.0), disopyramide (2.9),
quinidine (2.7), and sotalol (2.5) also demonstrated efficacy.
With regard to drugs that prolong repolariztion as an anti-arrhythmic effect (Class IA and Class
III), excessive QT prolongation might lead to ventricular proarrhythmia and torsade de pointes.
Ibutilide may have a 3.6-9% incidence of torsade depending on the dose used. Pretreatment with
intravenous magnesium (2-3 grams) prior to infusion of ibutlide may decease the incidence of
torsade.
Intravenous amiodarone when given as a standard dose (5 mg/kg over 30 minutes then 1200 mg
over 24 hours) did not show efficacy over placebo in terminating atrial fibrillation. However, with
high dose amiodarone (125 mg /hr infused to a maximum of 3 gms), there was a statistically
significant improvement in cardioversion to sinus rhythm at the 24 hour mark. Using oral
amiodarone at 30 mg/kg, there was a significantly earlier termination of atrial fibrillation/flutter
than placebo. For persistent atrial fibrillation,amiodarone performed significantly better than
placebo and sotalol after cardioversion for prevention of recurrence.
Sotalol or Class I anti-arrhythmic agents have a one year efficacy for maintenance of sinus
rhythm of 40% while amiodarone has a one year efficacy of approximately 65%. If drugs are used
sequentially, atrial fibrillation can be prevented in approximately 82% of patients.
showed no difference in all cause mortality based on a strategy of rate control
vs. rhythm control for atrial fibrillation. Rate control patients had fewer hospitalizations than
rhythm control patients and fewer anti-arrhythmic drug adverse events. However, with regard to
survival, multivariate analysis showed worse survival associated with coronary artery disease,
congestive heart failure, diabetes, smoking, mitral regurgitation, use of digoxin, and use of anti-
arrhythmic drugs. A survival benefit was seen in those with normal left ventricular function, use of
warfarin, and in sinus rhythm.
Clinical Evaluation of Drug Therapy of Atrial Fibrillation
Richard L. Page, MD, FHRS
Dr. Richard Page reviewed the goals of anti-arrhythmic drug treatment of atrial fibrillation which
include reduction or elimination in atrial fibrillation events, reduction of elimination of symptoms
associated with atrial fibrillation, reduction of atrial fibrillation burden, and assurance that the anti-
arrhythmic drug is safe. A reduction in stroke risk or need for warfarin is not a goal of anti-
arrhythmic drug therapy as each patient should be evaluated for stroke risk based on clinical
parameters, not based on whether or not an anti-arrhythmic drug will be used. Anti-arrhythmic
medications have not been shown to reduce risk of stroke.
Traditional approaches to measure the effect of an anti-arrhythmic drug rely on a reduction in
symptomatic episodes or a prolongation of the time to recurrence of symptomatic atrial fibrillation.
To illustrate this, Dr. Page reviewed the development of Azimilide, a Class III drug that blocks I Ks
and I Kr channels and was felt to have a low incidence of torsades de pointes. Unfortunately,
torsades was noted during clinical testing and the drug had a variable efficacy for atrial fibrillation
which resulted in the termination of further development of Azimilide for treatment of atrial
fibrillation. In contrast, trials of d,l-sotalol for treatment of atrial fibrillation showed that, for patients
with symptomatic recurrences of atrial fibrillation, Sotalol did prolong the time to recurrence. However, it did not appear to be better than placebo at terminating an acute episode of atrial fibrillation. As such it was approved by the FDA for prevention of recurrent atrial fibrillation but not for acute treatment of atrial fibrillation. Finally, Dofetilide was studied for acute termination of atrial fibrillation and found to have efficacy over placebo and in a follow-up of these patients, it prolonged the time to recurrence and reduced the number of recurrences and received approval by the FDA for acute and chronic therapy of atrial fibrillation. Because of meta-analysis of Quinidine mortality and results of the CAST trial raised questions about the safety of anti-arrhythmic drugs, there has been increased attention to drug safety evaluations in treatment of atrial fibrillation. Sotalol was studied in post-infarction patients and did not demonstrate increased mortality. Azimilide did a post-infarction study (ALIVE) that showed no increased mortality. Dofetilide was evaluated in a post-infarction study (Diamond MI) and in a congestive heart failure population (Diamond CHF) and did not show increased mortality. Amiodarone was evaluated in a heart failure study (CHF-STAT) and showed no increase in mortality. Silent atrial fibrillation, defined as asymptomatic atrial fibrillation, can pose risk for stroke if not recognized or evaluated. In patients with a history of atrial fibrillation, significantly more asymptomatic episodes of atrial fibrillation can be recorded using Holter monitors compared to symptomatic recurrences with an event recorder. Once anti-arrhythmic drugs are used to control atrial fibrillation, the drug may make it more difficult for the patient to be aware of recurrences. In a study of patients with a history of atrial fibrillation receiving a pacemaker with software for recognition of atrial fibrillation, atrial fibrillation was documented in 46% of patients with an ECG but in 88% of patients by the device. In patients with > 48 hours of atrial fibrillation in an episode, 38% were asymptomatic during the event. Drug therapy did not influence the duration of asymptomatic atrial fibrillation. In the SOPAT Trial, 1033 patients with symptomatic atrial fibrillation were evaluated on Quinidine in combination with two doses of Verapamil and compared to Sotalol and placebo. Transtelephonic monitor recordings were obtained daily and with symptoms to assess efficacy of therapy. The higher dose of Quinidine with Verapamil reduced symptoms but this was due to a higher incidence of episodes of asymptomatic atrial fibrillation. Symptoms of atrial fibrillation appeared related to the heart rate in atrial fibrillation not the therapy. In placebo patients, 63% of atrial fibrillation recurrences were symptomatic compared to 33% of recurrences in drug treatment patients. When analyzed based on heart rate during recurrent atrial fibrillation, symptoms were related to higher heart rates during recurrences. Finally, the ATHENA trial was reviewed. In this trial, the hypothesis that Dronedarone used to treat atrial fibrillation would prolong the time to first cardiovascular hospitalization or death in moderate to high risk patients with atrial fibrillation was tested. Patients randomized to Dronedarone (400 mg BID) or placebo had paroxysmal/persistent atrial fibrillation with either age >75 or age >70 + one risk factor (hypertension, diabetes, prior stroke/TIA, left atrial size >50 mm, or left ventricular ejection fraction< 40%). Dronedarone decreased the incidence of cardiovascular hospitalization and death compared to placebo (Hazard Ratio = 0.76, p< 0.001). The secondary endpoint of cardiovascular mortality was also reduced in the Dronedarone group (Hazard Ratio = 0.71, p = 0.03). In summary, clinical evaluation of drug therapy of atrial fibrillation includes the assessment of the treatment goal which is a reduction of symptomatic recurrences of atrial fibrillation. In addition, drug safety must be evaluated. Atrial fibrillation burden which includes assessment of asymptomatic and symptomic recurrences should be measured. Clinical trial design determines the labeling of drugs. Finally, new endpoints of a decrease in cardiovascular hospitalizations and mortality may be considered as clinically relevant endpoints in the future. New Ion Channel Blocking Drugs
Katherine Murray, MD
Dr. Murray reviewed new, investigational ion channel blocking drugs under development to treat
atrial fibrillation (AF). She noted that an improved understanding of the channels involved in atrial
versus ventricular depolarization and repolarization has allowed for the development of agents
that can more specifically target the atrium, with fewer effects on the ventricle. In particular, Dr.
Murray notes that the IKur and IKAch channels are specifically found within atrial and not ventricular
tissue, and so are particularly appealing drug targets for AF. She described atrial remodeling
during AF, which involves shortening of the atrial action potential, which impacts the effectiveness
of drugs on remodeled atrium. She then described the major classes of new drugs under
development for AF as well as examples of each: atrial specific (vernakalant), multiple ion
channel (dronedarone, azimilide, tedisamil), Na channel (ranolazine), gap junction modifiers
(rotigaptide) and stretch activated channel (GsMtx4).
Dr. Murray noted that the IV form of vernakalant (RD 1235) has received provisional FDA
approval, while the oral formulation is still in Phase 2 clinical trials and not yet approved.
Vernakalant blocks multiple channels, including INa, IKur, ITO, and IKAch, with minimal effects on IKr
at clinical doses. Vernakalant causes an atrial selective increase in action potential duration, with
minimal effects on hemodynamics and ventricular repolarization. Several clinical studies (CRAFT
and ACT I, II and III) have been performed on IV Vernakalant. These studies have shown
approximately 60% efficacy in conversion of short-duration AF (3-48 hours), but considerably
lower efficacy (approximately 24%) of conversion AF of longer duration (3-7 days). Adverse
events were uncommon, but included hypotension, complete AV block and cardiogenic shock. In
summary, IV vernakalant is reasonably effective at converting recent onset AF, much less
effective at converting AF of longer duration, and has a low incidence of side effects, while oral
vernakalant is in earlier development.
Moving on to dronedarone: this is an investigational drug which has not been FDA approved and
has Class I, II, III and IV anti-arrhythmic properties similar to amiodarone, although there are
differences in potency of the 2 agents on cardiac ion channels which might affect efficacy and
safety of the 2 drugs. Structurally, dronedarone is similar to amiodarone, but does not contain
iodine. Multiple clinical trials have been performed with dronedarone, including EURIDIS,
ADONIS, ANDROMEDA and ATHENA (the results of the ATHENA trial were presented at HRS
2008). Overall, these trials showed that dronedarone is significantly more effective than placebo
at preventing recurrence of AF, and also reduces the ventricular rate during AF. Dronedarone has
not been compared to amiodarone in a head-to-head fashion, but according to Dr. Murray it is
likely that amiodarone is more effective at preventing AF recurrence compared to dronedarone
based on a comparison of separately published data from the 2 agents. Dronedarone has been
shown to decrease the combined endpoint of hospitalization/death in patients with AF. From a
safety perspective, dronedarone appears to have less toxicity than amiodarone: dronedarone has
not been associated with thyroid disease, although lung disease has been rarely seen.
Dronedarone does prolong the QT interval, but has not been associated with polymorphic
ventricular tachycardia. On a cautionary note, Dr. Murray mentioned that dronedarone was
associated with increased mortality compared to placebo in the ANDROMEDA trial of patients
with heart failure (but not in the other trials of non-heart failure patients). In summary,
dronedarone is likely to be safer but potentially less efficacious than amiodarone in preventing
recurrence of AF, and its use may be restricted in heart failure patients due to concern of
increased mortality.
Dr. Murray then described other investigational drugs for AF. These include ranolazine, a drug
developed as an anti-anginal agent, which reduces intracellular Ca and Na overload. In addition
to its anti-anginal effects, ranolazine appears to be effective at reducing atrial and ventricular
arrhythmias (including AF). Gap junction modifiers including rotigaptide (a peptide which
increases gap junction conductance) have shown effectiveness in reducing AF duration in animal
models. Another agent, GsMtx-4 (derived from tarantula toxin) inhibits stretch-activated channels
and has also shown effectiveness in animal models of AF. Dr. Murray concludes her talk by
mentioning multiple other pathways that may be targets for investigational AF drugs, all with the
goal of improving efficacy and safety compared to currently available agents.
Novel Targets to Treat and Prevent Atrial Fibrillation
Frederico Lombardi, MD
Dr. Lombardi reviewed the strategies for drug therapy of AF that do not directly target ion
channels. He noted that, in addition to changes in ion channels and action potential
characteristics that other forms of remodeling take place in the atria including atrial dilation,
inflammation and fibrosis, which may predispose to AF. These processes involve activation of a
variety of pathways, including the renin-angiotensin-aldosterone (RAAS) system, mitogen-
activated protein kinases (MAPK), and stretch-activated currents, which may serve as targets for
AF therapies. Available agents that may be used to target these pathways include angiotensin
converting enzyme inhibitors (ACE-I), angiotensin-receptor blockers (ARB), statin drugs,
glucocorticoids and polyunsaturated fatty acids (PUFA) from a variety of sources, including fish.
ACE-I/ARB
Dr. Lombardi noted that numerous studies involving treatment with ACE-I and/or ARB compared
to placebo have examined the incidence and/or recurrence of AF (often as a seondary endpoint),
including the TRACE, Val-HeFT, LIFE and CHARM studies. Many of these individual studies, as
well as a meta-analysis of available studies, suggest that these agents are effective in reducing
AF recurrence and incidence, although this effect tends to be most pronounced in patients with
heart failure. Another study has demonstrated that the addition of either an ACE-I (perindopril) or
an ARB (losartan) to amiodarone is more effective than amiodarone alone at reducing the
recurrence of AF in patients with lone AF. The ONTARGET study found similar effectiveness of
an ACE-I (ramipril) compared to an ARB (telmisartan) in reduction of AF, with no significant
additive benefit of combining the agents.
Statins
Dr. Lombardi then described the role of statins in the prevention of AF. He emphasized that
individual studies as well as meta-analysis have demonstrated a reduction in AF (both incidence
and recurrence) with statin drugs. In regard to events such as myocardial infarction and stroke,
multiple studies have demonstrated that higher statin doses are more effective than lower doses
in reducing these events. Surprisingly, the PROVE-IT and A to Z studies did not show a similar
effect of statin dose on prevention of AF, and low dose statins appeared as effective as high dose
statins in regard to AF. It is therefore possible that the mechanism of statins in prevention of AF
may differ from their mechanism in prevention of myocardial infarction and stroke.
Inflammation
Dr. Lombardi moved to the discussion of the role of inflammation in AF. C-Reactive Protein (a
marker of inflammation) has been found to be predictive of AF recurrence after cardioversion in
one study (surprisingly, atrial size was not predictive of AF recurrence in this study). In further
support of the inflammatory hypothesis, multiple studies have demonstrated that glucocorticoids
can reduce the incidence of AF after cardiac surgery, presumably via their anti-inflammatory
properties.
PUFAs/Fish
Dr. Lombardi concluded his talk with a discussion of the role of omega 3 PUFAs (oils derived
from fish and other sources) and dietary fish in the prevention of AF. He noted that this is
controversial, as some studies have demonstrated a link between PUFA/fish intake and reduction
in AF, while other studies have shown no such link. One possible explanation for this controversy
stems from animal data, which suggests that PUFA may prevent atrial fibrosis and AF associated
with congestive heart failure but not AF associated with atrial tachycardia. It is therefore possible
that PUFA could be effective in preventing AF in some clinical scenarios but not in others.
Randomized studies comparing high dose PUFA to placebo have demonstrated a reduction in AF
incidence after cardiac surgery (in one study) and in the first year after myocardial infarction (in another study). Dr. Lombardi ended his talk by emphasizing the importance of inflammation and fibrosis in the maintenace of AF, and the targeting of these pathways in addition to ion channels in order to most effectively treat AF.

Source: http://hrs.conferencearchives.com/heartrhythm2008/107/cme/017_Summary.pdf