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.
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SUMMARY OF CURRICULUM VITAE Born : April 22 1940 Medical Studies : University of Madrid 1957 - 1964 Internship : Hospital Puerta de Hierro. Madrid. Spain. 1964 - 1965 Resident in Cardiothoracic Surgery : Clínica Puerta de Hierro. Madrid. Spain. 1966 - 1970. Fellowship: Stanford University Medical Center. 1970 (Jan-June) Fellowship: New York University Medical Center. July 1970 -June 1971. Instruc