Use of Antiarrhythmic Drugs for AF Who, What and How? Dr. Marc Cheng Queen Elizabeth Hospital

Transcription

1 Use of Antiarrhythmic Drugs for AF Who, What and How? Dr. Marc Cheng Queen Elizabeth Hospital

2 Content i. Rhythm versus Rate control ii. Anti-arrhythmic for Rhythm Control iii. Anti-arrhythmic for Rate control

3 Classification of AF 1.Paroxysmal AF <7days 2.Persistent AF 7 days 3.Long standing persistent AF 1 year 4.Permanent AF

4 Rhythm Control Rate Control Prevention of thrombolism

5 Rate vs Rhythm control

6 Results Rhythm vs. Rate control Trials

7 AFFIRM 4,060 patients with recurrent AF to rate control (using digoxin, beta blocker, and/or calcium channel blockers) vs rhythm control with the most effective antiarrhythmic drug All patients were initially anticoagulated At five years, 35 percent of patients were in SR in rate control group compared to 63 percent of patients in SR with rhythm control The most frequently used initial antiarrhythmic drugs were amiodarone (38%) and sotalol (31%). N Engl J Med. 2002;347:

8 AFFIRM There was an almost significant trend toward a decrease in the rate of occurrence of the primary end point (all- cause mortality) with rate control (21.3% versus 23.8% percent, HR 0.87, 95% CI ). There was no difference between the two groups in the incidence of cardiac death, arrhythmic death, or deaths due to ischemic or hemorrhagic stroke N Engl J Med. 2002;347:

9 RACE 522 patients with recurrent persistent AF or atrial flutter less than one year in duration who had required one to two cardioversions within the prior 2 years. Randomly assigned to rate control using the same AV nodal blocking drugs as used in AFFIRM or to rhythm control. Initial therapy for rhythm control was sotalol. If AF recurred within six months, antiarrhythmic drug therapy was changed The primary end point was a composite of cardiovascular death, admission for heart failure, thromboembolic event, severe bleeding, pacemaker implantation, or severe side effects from N Engl J Med. 2002;347: antiarrhythmic drugs.

10 RACE After 2.3 years, significantly fewer patients were in SR in the rate control group (10 vs 39%) There was an almost significant trend toward a lower incidence of the primary end point with rate control (17.2 versus 22.6 % with rhythm control, HR 0.73, 90% CI ) There was no difference in cardiovascular mortality (6.8 versus 7%). N Engl J Med. 2002;347:

11 AF-CHF

12 AF-CHF

13 What about in clinical practice?

14 Appropriate anti-thrombotic therapy Clinical evaluation Paroxysmal Persistent Permanent Long-standing persistent Rhythm control symptomatic Rate control failed rhythm control

15 Rhythm control

16 Pharmacological Rhythm Control increase the likelihood of a successful electrical cardioversion, to maintain SR after cardioversion, or for long-term antiarrhythmic therapy. preferred in those for whom the risk of DC cardioversion procedural sedation is high. lower rates of successful conversion compared to electrical cardioversion disadvantages- prolonged telemetric monitoring to detect sinus node dysfunction, atrioventricular (AV) block, proarrhythmic response, and conversion of AF to atrial flutter. The various antiarrhythmic agents used for rhythm control of AF include class IA, class IC, class III and multichannel blockers.

17 Vaughan-Williams Classification

18 Disopyramide, Quinidine, Procainamide (Class IA) sodium channel-blocking drugs uncommonly used now because other agents have greater efficacy and fewer side effects. Quinidine is predominantly eliminated by hepatic metabolism Disopyramide- excreted 60% by renal route; negative inotropic effects. The other major adverse effects are related to anticholinergic side effects such dry mouth and urinary retention. All are associated with a small incidence of torsades de pointes. IV procainamide is also still used in patients who present with pre-excited AF and a stable hemodynamic response.

19 Flecanide (Class IC) extremely effective for the conversion of AF of < 24 to 48 hours of duration. should not be used in patients with structural heart disease (with left ventricular systolic dysfunction or coronary artery disease) can acutely revert recent-onset AF within 6 hours (67%-92% of patients). A single, large oral dose mg pill-in-the-pocket approach is mainly to facilitate conversion of recent-onset and paroxysmal episodes of AF. peak plasma levels are reached 2 to 4 hours after an oral dose and has a long half-life 12-24hours mainly metabolized by the liver (70%) SE: metallic taste, dizziness, and visual disturbance

20 Flecanide (Class IC) preexisting scar or ischemia, promote the development of reentry and VT by slowing the conduction velocity Use of simultaneous AV node blockade is recommended Regular ECG monitoring is recommended, as an increase in QRS duration of 25% on therapy compared with baseline is a sign of potential risk of pro-arrhythmia.

21 Propafenone (Class IC) more effective in paroxysmal as opposed to persistent AF negative inotropic and chronotropic effects owing to its β receptor blocking and calcium channel-blocking properties Metabolized by the liver. The elimination half-life is 6 or 7 hours. well tolerated as effective as flecainide in suppressing AF recurrences recommended as a frontline rhythm-control drug in patients without structural heart disease and also for patients with hypertension but without substantial LVH

22 Dofetilide (Class III) indicated for the conversion of AF and atrial flutter to SR and also to maintain SR after cardioversion Recommend dofetilide as a first-line antiarrhythmic drug for AF in patients post myocardial infarction and with congestive heart failure. causes dose-dependent, selective QT-interval prolongation mainly eliminated via renal excretion (80%); half-life of 8 to 10 hours requires initializing the drug therapy in hospital with ECG monitoring for the first five doses or for a minimum of 12 hours post cardioversion, whichever is greater. can provoke NSVT & torsades de pointes side effects: headache, chest pain, dizziness, nausea, rash, flu-like symptoms, and diarrhea.

23 Sotalol (Class III) as effective as class IA and IC agents in suppressing AF recurrences recommended as a first-line therapy in patients with AF and underlying CAD also used in the long-term rhythm control as a second-line treatment for patients with AF and none or minimal structural heart disease. bioavailability of about 90% to 100%. It is not metabolized but excreted unchanged by the kidneys For recent onset AF, sotalol is found to be less effective in converting to SR than quinidine (60% vs. 20%) produces a dose-related prolongation in the QT interval side effects: include fatigue, bradycardia and torsades de pointes (<2% if maximal dose is 160 mg twice daily. Not used in if the QTc > 525 ms)

24 Amiodarone (Class III) Not approved by the FDA for the treatment of AF Amiodarone is the most effective (65%) oral agent in preventing AF recurrences with better efficacy than propafenone, sotalol, and dronedarone in active comparator trials Reserved as an alternative agent for treatment of AF due to its extracardiac side effects, except in patients with clinical heart failure or hypertension with substantial left ventricular hypertrophy. multichannel blocker; no clinically significant negative inotropic effect. a highly lipophilic and a large volume of distribution, resulting in a delayed onset of action and a long elimination half-life.

25 Amiodarone (Class III) Conversion rate with use of IV amiodarone is in the range of 64% to 85%. The conversion rates with oral amiodarone at 24 hours vary from 27% to 87% depending upon the duration of AF. The most frequent cardiovascular side effect is dose-related bradycardia, QT prolongation but a very low incidence of torsades de pointes. Serious end-organ toxicity includes pulmonary fibrosis and druginduced hepatitis, hypo or hyperthyroidism. Other side effects include photosensitivity, alopecia, insomnia, corneal deposits, and optic neuritis. Its potential for long-term end-organ toxicity has limited the drug to mainly a secondary option for preventing AF recurrences

26 Dronedarone (Class III) amiodarone dronedarone

27 Dronedarone (Class III) currently approved to reduce the risk of hospitalization in patients in SR with a history of paroxysmal or persistent AF patients contraindicated in patients with permanent AF or patients with advanced or recent CHF exacerbations. The most common adverse reactions are gastrointestinal (up to 10%), with nausea and diarrhea. Baseline and periodic hepatic serum enzymes, especially during the first 6 months of treatment, is recommended

28 Dronedarone (Class III) Similar to amiodarone, can interact with simvastatin and may increase the risk of myositis not as effective as amiodarone in suppressing AF recurrences and should not be used in patients with permanent AF demonstrated safety in patients with coronary artery disease and has been shown to reduce cardiovascular hospitalizations in paroxysmal and persistent AF patients.

29 NEJM. 2007;357:

30 J Cardiovac Electrophysiol. 2010;21;597

31 ANDROMEDA Study NEJM 2008;35:

32 ANDROMEDA Study NEJM 2008;35:

33 PALLAS Trial NEJM 2011;365:

34 PALLAS Trial NEJM 2011;365:

35 Ibutilide (Class III) molecular structural similarities to sotalol improves the efficacy of DC cardioversion and lower the cardioversion energy requirement more effective in conversion of atrial flutter than AF not available for oral use because of extensive first-pass metabolism. more effective for AF conversion than sotalol and class LA agents such as procainamide

36 Ibutilide (Class III) converts about 35% of persistent AF episodes and 45% of atrial flutter within 45 minutes of infusion a potent ventricular proarrhythmic drug and can result in polymorphic or monomorphic ventricular tachycardia (VT) similar to other class III agents. recommended that subjects be observed with continuous ECG monitoring for at least 4 hours after the ibutilide infusion or until the QTc interval has returned to baseline. Pre-treatment with high doses of intravenous magnesium appears to minimize the risk of ibutilide-induced torsades de pointes and increase the conversion efficacy.

37 Vernakalant a new multichannel-blocking antiarrhythmic drug approved by the European Commission for the rapid conversion of recentonset AF to SR (< 7 days duration for patients not undergoing surgery, and < 3 days duration for postcardiac surgery patients) effective for the conversion of AF, particularly if administered within 7 days of arrhythmia onset similar to ibutilide in terms of rapid onset of action but is ineffective in the conversion of atrial flutter. currently available for parenteral use only

38 Vernakalant The average conversion rate of AF to SR is 50%. A significant advantage is a rapid effect, with the median to conversion ranging between 8 and 14 minutes Vernakalant (51.7%) has superior efficacy compared with amiodarone (5.2%) for acute conversion of recent onset AF The major side effects of vernakalant include altered taste, sneezing, parasthesias, nausea, and pruritus. The main adverse cardiac effects of vernakalant are cardiac arrhythmias, complete AV block, and cardiogenic shock

39 Ranolazine an antianginal drug that reduces myocardial ischemia by its effects on the late inward sodium current This unique property of inactivating sodium channel increases atrial refractoriness and inhibits triggered activity In small case series, ranolazine has been found effective in suppressing AF in patients with resistant AF and also converting patient with AF using a pill-in-the-pocket approach MERLIN trial, ranolazine reduced the development of supraventricular arrhythmias, including AF

40 Ranolazine The efficacy or safety of drug synergy with ranolazine in combination with dronedarone was explored further in the HARMONY trial The combination of ranolazine and dronedrone proved to be more effective than either drug alone. Phase III trials are planned to better understand the safety and efficacy of this combination.

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42 Rate control

43 Rate Control For older patients in AF with minimal symptoms, rate control combined with the appropriate anticoagulation strategy is NOT INFERIOR to pharmacologic rhythm control. AFFIRM- trend toward improved survival in the rate-control group vs. rhythm-control group(p= 0.08). No large-scale randomized trial has readdressed this question in the era of AF ablation. Rate Control avoids both procedures such as cardioversions and ablations and the long-term use of potentially toxic antiarrhythmia. initial rhythm-control strategy > periods of rapid ventricular rates requiring rate control

44 Rate Control The choice of medication should be guided by the patient s comorbidities, with specific reasons to include or exclude a particular drug. Medication classes that can be used include β adrenergic blockers, non-dihydropiridine calcium channel blockers, and digitalis glycosides. βblockers or CCB are recommended as first line agents in paroxysmal, persistent, or permanent AF. Data from the AFFIRM trial revealed that β-blockers were more effective in achieving adequate rate control compared with CCB when used as monotherapy or in combination with digoxin.

45 Rate Control Digoxin as monotherapy is not recommended, owing to the inability of the drug to control the ventricular rate during exercise. CCB are effective agents for rate control in either chronic or acute AF. They should be administered intravenously in the acute setting, and continued as an infusion after a bolus because of their short half-lives. IV β-blockers, esmolol, metoprolol, and propranolol are all effective in the acute setting. Particular care should be taken when using verapamil in combination with other AV nodal blocking agents, as the interaction may affect drug metabolism. For example, co-administration of verapamil and digoxin may dangerously increase serum digoxin levels.

46 Rate control goal The need for rate control in AF to prevent congestive heart failure and the possibility of a tachycardia induced cardiomyopathy is very well established. However, prior heart-rate targets for rate control were not evidence-based. The 2006 AHA/ACC/ESC guidelines stipulated the goal of rate control as a resting heart rate between bpm and 90 to 115 bpm during moderate exercise. AFFIRM- less than 80 bpm at rest and less than 110 bpm during a 6-minute walk test No difference in survival or quality-of-life outcomes in patients when divided by quartiles of resting and exercise heart rates. Retrospective analysis of the data from the RACE showed no difference in similar outcomes when patients were stratified to resting heart rate of less than or greater than 80 bpm.

47 RACE II NEJM 2010;362:

48 RACE II It was a prospective study to investigate strict versus lenient ratecontrol strategy in patients with permanent AF. The heart-rate target for patients in the strict rate-control arm was a resting heart rate of less than 80 bpm, and less than 110 bpm during moderate exercise. Patients in the lenient arm were treated to a heart rate goal of less than 110 bpm during rest. The lenient strategy proved to be equivalent in the composite end point of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events, over a follow-up of 2 to 3 years. In addition, the lenient strategy was more commonly achieved (97.7% vs. 67%P< 0.001) and resulted in fewer medical visits. NEJM 2010;362:

49 Rate control goal The guideline suggests 80 bpm or less at rest as a target for rate control (class Ia) persistently normal LV function and in the absence of symptoms, a more lenient target of less than 110 bpm is reasonable. (class li b)

50 Drug of choice for Longterm Rate control The choice of agent for rate control should be guided by the patient s other medical conditions. Patients with coronary artery disease, systolic dysfunction, or heart failure should be treated with β-blockers as a first choice. In patients with systolic dysfunction and heart failure, the combination of β-blocker and digoxin may be ideal. AF associated with high sympathetic tone, such as hyperthyroidismrelated, exercise-induced, or postoperative AF, should all be treated preferentially with β-blockers. Calcium channel blockers, with negative ionotropic properties should be avoided in patients with systolic dysfunction. β-blockers can be problematic in patients with bronchospasm and depression, and may exacerbate either condition.

51 Drug of choice for Longterm Rate control

52 Take home messages 3 cornerstones in AF management i) prevention of thromboembolism ii) rate control iii) rhythm control Rate control - elderly, asymptomatic Rhythm control- young, short duration AF, symptomatic

53 Take home messages Each strategy is a recognized and a useful treatment option for rhythm management with its own limitations. Recurrent AF in most instances is a chronic problem and often progressive. Reassessment of treatment will frequently be needed over a lifetime & it is not uncommon for patients to move back and forth between the 2 rhythm-management strategies. The challenge is to choose the right strategy at a particular moment in time and recognize when it needs to be changed.

54 Thank you