NO SKIPPED BEATZ: A PRACTICAL REVIEW OF THE ANTI-ARRHYTHMIX

Transcription

1 NO SKIPPED BEATZ: A PRACTICAL REVIEW OF THE ANTI-ARRHYTHMIX feat. Lance Ray, Pharm.D., BCPS ADJUNCT ASSOCIATE PROFESSOR OF PHARMACOTHERAPY UNIVERSITY OF NORTH TEXAS COLLEGE OF PHARMACY

2 Get Rhythm Learning Objectives: (Pharmacists) 1. Summarize the pathophysiology of arrhythmias and describe how different antiarrhythmic drug classes aim to control these rhythm disturbances 2. Describe various acute and long-term evidence-based approaches to therapy for atrial fibrillation 3. Identify various treatment strategies for other common supraventricular-, ventricular-, and brady-arrhythmias Learning Objectives: (Technicians) 1. Identify the common uses for anti-arrhythmic drugs while reviewing basic arrhythmia pathophysiology 2. Describe the concept of rate versus rhythm control in atrial fibrillation 3. Identify scenarios when electrical cardioversion are indicated for normal rhythm restoration ACPE description: We will briefly review the pathophysiology of common arrhythmias and how various agents aim to control them both in the acute and long-term setting. Landmark-trials and adverse effects will be profiled for common drugs.

3 Review Nerve conduction SA node - Atrial pacemaker AV node - Speed bump [correct] pathway to conduct to ventricles Muscle contraction unique cells (automaticity) Refractory period Important for impulse termination if absent vicious loop(s)

4 Why do arrhythmias occur? Ion channel conduction disturbance Myocardial infarction (MI) Ischemia myocardial scarring Cardiovascular disease Ventricular hypertrophy Hypertension RAAS activation Genetic mutation/ polymorphism Increased sympathetic tone Hyperthyroidism Exercise Metabolic disturbances Diabetes Obesity Oxidative stress Age Smoking Alcohol use Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. 2011

5 Most common type of arrhythmia Atrial Fibrillation by far

6 A Epidemiology of AF Prevalence: % of population 4% of population over age 60 (Increases with age) Comorbidities: CHF (increases with severity) 4% AF in NYHA class I 50% AF in NYHA class IV Go AS et al. Heart Disease and Stroke statistics 2013 update. Report from AHA. Circulation 2013;127:e6-e245 Lloyd-Jones DM, et al. Framingham Heart Study. Circulation. Aug ;110(9):1042-6

7 Projected AF incidence assuming no increase in age-adjusted AF incidence assuming continued increase in incidence rates Circulation vol. 114 no

8 Concept of Re-entry Indefinite loop of impulse conduction? Impulse travels too quick or? extra impulse generated or? Shortened refractory period Can occur anywhere in the cardiac conduction system Atrium AFib (multiple foci), Atrial flutter (one focus) Ventricle VT (usually triggered by a PVC) AV node AVNRT PSVT

9 AF begets AF - Electrical remodeling occurs - Important to treat promptly

10 Re-entry We need to either - SLOW CONDUCTION Velocity (to a point that impulse dies out) or - PROLONG REFRACTORINESS (to block impulse) All anti-arrhythmic drugs do one or both of these Pharmacotherapy: A Pathophysiologic Approach. 9 th ed.

11 Vaughan-Williams Class I Slows conduction II III Prolongs refractory period IV

12 Arrhythmias Asymptomatic Incidental finding Life-threatening Emergency Anti-arrhythmic drugs can be pro-arrhythmic

13 Clinical History of Anti-arrhythmics 1950s lidocaine, quinidine 1980s surge of new anti-arrhythmic drugs (AAD) 1990s and on general decline in use Declined use for two reasons: 1. Toxicities with AADs (drug-interactions, proarrythmic!) 2. Technical advances in non-pharmacological therapy Catheter ablation of re-entry loops (Afib, Aflutter) Implantable cardioverter-defibrillators (ICD) (VT/VF)

14 Classification of Antiarrhythmics Vaughn Williams Most frequently used classification system Limitations multiple mechanisms may exist for a drug/class Does not incorporate clinical indication (AF, VT) makes difficult to summarize classes Class Pharmacologic MOA Clinical MOA notes I Na + channel block Rhythm Class Ia, Ib, Ic II β-block Rate All B-blockers III K + channel block Rhythm Multiple MOAs IV Ca ++ channel block Rate Non-DHP CCB V Digoxin / adenosine ~rate / other Drugs not related

15 Class I AADs Ia Ib Ic Quinidine (PO) Disopryamide (PO) Procainamide (IV) Lidocaine (IV) Mexilitine (PO) Flecainide (PO) Propafenone (PO) CCV = chemical cardioversion SR = sinus rythm Clinical use/comments: - Supraventricular and ventricular arrhythmias - Little use of oral agents - Procainamide for immediate AF CCV - Limited to life-threatening ventricular arrhythmias - Most potent Na + blocking effects - First-line agents within Class I for Maintenance of SR for AF/AFlutter - Or life-threatening refractory ventricular arrhythmias AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76 Pharmacotherapy: A Pathophysiologic Approach. 9 th ed.

16 Class I ADRs Ia Ib Ic Quinidine (PO) Procainamide (IV) Disopryamide (PO) Lidocaine (IV) Mexilitine (PO) Flecainide (PO) Propafenone (PO) Major Individual ADRs Hemolytic anemia, GI upset Hypotension Anti-cholinergic symptoms (Vagolytic effect = HR) Acute liver injury, Bronchospasm, AV block Class effect QTc, TdP, Heart failure, ventricular arrhythmias Dizziness, sedation, confusion, blurred vision Dizziness, Heart failure, Ventricular arrhythmia Contraindicated in SHD CYP 2D6 substrates SDH = Structural Heart Disease TdP = torsades de pointes AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76 Pharmacotherapy: A Pathophysiologic Approach. 9 th ed.

17 Summary of Class I agents Use has greatly declined No new FDA approvals for class in 20 years Many patients do not tolerate and must discontinue therapy ( 20 30%) Most pro-arrhythmic of all Vaughan Williams Classes (limits use to younger/healthier patients)

18 Class III Amiodarone Sotalol Clinical use Most (?best) evidence in AF rhythm control IV is first line agent in acute VT/VF Both utilized in supraventricular OR ventricular arrhythmias Dronedarone Ibutilide (IV) Dofetilide (PO) Only approved for AFib Used for acute chemical cardioversion AF/Atrial flutter sinus rhythm Long term maintenance of sinus rythym

19 Amiodarone is unique most commonly used AAD Displays actions of ALL Classes (I, II, III and IV) Predominantly class III Non-selective β-blocking, Ca ++ blocking effects Low-pro-arrhythmic effect IV therapy (acute indications for ACLS VT / VF) slow onset with PO: loading regimen Long half-life 60 days Adverse effects Drug interactions Inhibits MOST CYPs

20 Amiodarone - ADRs Associated with chronic therapy cumulative doses Close monitoring Adverse Effect Monitoring Treatment Hyper/hypothyroidism (2 30%) Pulmonary fibrosis ( risk w/ cumulative dose) Routine thyroid function tests Annual CXR Thyroid/anti-thyroid supplement or DC DC therapy LFT abnormalities (15 25%) transient Routine LFTs Lower dose/dc Optic neuropathy (1 2%) Routine eye exams DC therapy Photosensitivity (25 75%) Use sun-block Preventative Blue-gray skin discoloration (1-3%) DC therapy TdP (<1%), bradycardia, hypotension Routine ECGs Dose adjustment Q J Med 2011; 104: Am J Med ;706 Pharmacotherapy: A Pathophysiologic Approach. 9 th ed.

21 Amiodarone Drug-Drug Interactions P-glycoprotein (P-gp) inhibitor Can increase digoxin levels by 2x Empirically reduce digoxin by 50% Inhibitor of CYP2C9, 2C19, 3A4, 2D6 warfarin (can elevate levels 0 200%) Depends on amiodarone maintenance dose Empirically reduce warfarin dose by ~30% 400mg QD 40% 300mg QD 35% 200mg QD 30% 100mg QD 25% Chest. 2002;121(1):19-23

22 Dronedarone: Amiodarone without Iodine Dronedarone (Multaq ) (FDA approved in 2009) paroxysmal or persistent AF Similar properties (all 4 class effects) Non-iodinated Less organ toxicity than amiodarone Methylsulfonyl addition less lipophilic Only PO available Increased mortality in heart failure patients vs placebo Black Box Warning: NHYA Class IV or II-III w/ recent decompensation ANDROMEDA Study - NEJM 2008; 358: Dronedarone vs amiodarone Dronedarone less effective for rhythm control in AF than amiodarone Less adverse effects and less all-cause mortality than amiodarone $$$ J Am Coll Cardiol. 2009;54(12):

23 Dronedarone CYP450 2D6 and 3A4 inhibitor Citalopram and TCAs are contraindicated Many other drugs: use caution P-gp inhibitor increases levels of digoxin, rivaroxaban, dabigatran

24 Sotalol Non-selective B-Blocker with K + -blocking properties (Class II and III) Clinical use: Maintain sinus rhythm in AF As effective as Class I agents but less toxicity In general less effective than amiodarone but also less toxicity As effective as amiodarone in patients with ischemic heart disease/cad Avoid in HF Niche use long-term rhythm control pts w underlying CAD Clinical use: recurrent or sustained VT SAFE-T Investigators. N Engl J Med 2005;352: AFFIRM Investigators. N Eng J Med 2002;347: Pharmacotherapy: A Pathophysiologic Approach. 9 th ed.

25 Sotalol ADRs: Generally well-tolerated (<15% discontinue due to ADRs) Fatigue, bradycardia, dyspnea, dizziness, Possibility of TdP, initiation in-hospital preferred Renally eliminated Must be renally adjusted No CYP450-mediated drug interactions Black Box warning - QTc Betapace AF renal adjustments CrCl >60 ml/min: Give q12hr CrCl ml/min: Give once daily CrCl <40 ml/min: Contraindicated Formulations of sotalol Can be used for ventricular tachycardias Betapace AF (specifically indicated for AF) Same drug better labeling (?)

26 AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76 Pharmacotherapy: A Pathophysiologic Approach. 9 th ed. Less commonly used Class III Ibutilide (Corvert ) - IV One-time dose for immediate chemical cardioversion (CCV) Dofetilide (Tikosyn ) PO Long-term therapy in specific patients Must be initiated in hospital (minimum 3 days) Highest risk of TdP since pure K+ channel blockade Eliminate other risk factors for TdP before therapy Correct low serum [Mg++] and [K+] ensure baseline QTc < 440 ms

27 Dofetilide Black Box warning: To minimize the risk of induced arrhythmia, patients initiated or re-initiated on TIKOSYN should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. TIKOSYN is available only to hospitals and prescribers who have received appropriate TIKOSYN dosing and treatment initiation education. Safe for patients with structural heart disease DIAMOND Study 59% conversion rate vs 34% in placebo 79% kept in SR at one year vs 42% placebo TdP occurrence of up to 3% (majority in first 3 days) 125mg 500mg PO q12h Titration algorithm Circulation. 2001; 104: Tikosyn package insert. 3/2015

28 Dofetilide initiation algorithm Determine baseline QTc ( 440 ms) Eliminate drug interactions Replace K and Mg Estimate CrCl from Tikosyn REMS Treatment Guidleline

29 Class II and IV (rate control agents) Drugs do nothing to underlying arrhythmia Most AF symptoms associated with RVR Rapid Ventricular Response Block AV node = control ventricular response = RATE CONTROL Patient is still technically in Afib Sinus pacemaker (SA node) Atrio-ventricular node (AV node) - Delay switch to allow ventricular filling speed bump - Only proper nerve conduction pathway to ventricle

30 Class II Beta-Blockers Decrease adrenergic tone primarily in SA/AV nodes conduction velocity, refractoriness, automaticity Clinical use: Slows ventricular response to Afib (RATE control) Additional properties Possible effects on electrical conduction Mortality benefits - post-mi and CHF

31 Acute rate control Which beta-blockers? virtually any Esmolol or Metoprolol available IV Chronic rate control (PO) Metoprolol Carvedilol (with HF) Atenolol Propranolol (non-selective and lipophilic) toxicity Most commonly used

32 Class IV Verapamil and Diltiazem Specifically affect calcium channels in SA and AV node Decrease heart rate rate control in AF and Atrial flutter

33 Class V - Digoxin Rate control via multiple mechanisms Narrow therapeutic index ( ng/ml) toxicity > 2.4 ng/ml Clinical fit: little use for rate control (third line agent) More effective, more rapid and less toxic drugs available Can be useful in patients with AF and HF no increased survival data for either AF or CHF indication TREAT-AF Study (2014) Retrospective cohort of newly diagnosed AF patients in VA system (n = 122,465) Digoxin use associated with 26% higher mortality rate (p < 0.001) at ~ 5 years Unfavorable kinetics J Am Coll Cardiol. 2014;64: Pharmacotherapy: A Pathophysiologic Approach. 9 th ed. AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76

34 1. Circulation. 2015;132: , Take away points I rhythm control - rarely used anymore II rate control in AFib (better evidence than class IV) 1 III rhythm control amiodarone most commonly used, beware of toxicities IV rate control in AFib V digoxin rate control little utility No magic bullet Class I and III (rhythm control) falling out of fashion 1. Better therapies exist Conversion of rhythm with DCC Catheter ablation 2. Long term control of Rate > Rhythm [AFFIRM Trial]

35 TREATMENT OF ATRIAL FIBRILLATION

36 General Approach to AF Acute treatment - Symptom control - Decrease ventricular rate Consider restoring sinus rhythm (cardioversion) - Risk vs benefit Prevent long-term complications - Thromboembolism - Recurrence of AF

37 Acute management Symptomatic AF Hemodynamically unstable Medical emergency electrical cardioversion (DCC) Stable or advanced age/comorbidities Rate control Preferred in stable AF patients AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76

38 Methods of Cardioversion Goal: to restore sinus rhythm Electrical shock Direct Current Cardioversion (DCC) Synchronized cardioversion Pharmacological (Chemical) Cardioversion Class I or Class III anti-arrhythmic New onset AF: spontaneous conversion rate ~60% at 24 hours (still cardiovert if unstable) Musco, S et al. Med Clin N Am. 92 (2008)

39 acute management of AF Initial rate control Intravenous class II or IV agent diltiazem (not with decomp CHF) metoprolol (not in asthma exac) IV Digoxin (second-line) slow onset, full effect at hours Initial Goal: HR < 100 Amiodarone if contraindications to above cardioversion can happen January et al. AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76

40 After initial rate / symptom control Cardioversion? Usually avoid cardioversion if: advanced age (> 65) multiple comorbidities recurrent AF (risks/challenges of maintaining sinus rhythm outweigh benefit) Vast majority of patients! January et al. AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76

41 Cardioversion Electrical success rates (~80 90 %) Requires procedural sedation (anesthesia) Pharmacological Lower rates of cardioversion (~60 70% among most agents) Direct current cardioversion (DCC) Class I or III anti-arrhythmic 1. January et al. AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76 Musco, S et al. Med Clin N Am. 92 (2008)

42 Rhythm Control Strategy Overview Rate control Ventricular rate, leave in AF Symptom control Beta Blocker Calcium Channel Blocker Digoxin Rhythm control Restore and maintain sinus rhythm Restore Electrical cardioversion Pharmacological cardioversion Maintain Pharmacologic Maintenance Class I or III anti-arrhythmic Catheter ablation

43 Pharmacologic Cardioversion (in ED and typically under direct cardiologist care) IV therapy agents Ibutilide Risk of TdP; pretreat with IV Magnesium sulfate Procainamide Hypotension, long infusion time Amiodarone Second line for pharmacologic conversion IV therapy usually converts within minutes to hours Oral therapy agents flecainide, propafenone, dofetilide Several contraindications AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76

44 So we ve successfully cardioverted But.at one year, AF recurrence is ~75 % if left untreated Even if treated, long-term rhythm control strategy reduces to 30 50% at 1 year! So we could forget about cardioversion and just alleviate symptoms by slowing heart rate Either one is be acceptable - highly depends on circumstance Lafuente-Lafuente C, et al. Arch Intern Med. 2006;166:

45 Long-term therapy RATE CONTROL OR RHYTHM CONTROL? LANDMARK TRIALS CAST CAST II AFFIRM RACE RACE-II PIAF STAF HOT-CAFE AF-CHF

46 Many agents lack favorable data Meta-analysis of quinidine therapy 6 randomized controlled trials reviewed (1980s) Quinidine vs placebo after cardioversion At 12 months: 50 % quinidine groups in SR 25% of control groups in SR Total mortality rate: Quinidine 2.9 % vs Control 0.8% (p<0.05) Quinidine effective at rhythm control but 3x more lethal Coplen SE et al. Circulation Oct;82(4):

47 AFFIRM Trial Largest, most pivotal AF trial to date n = 4060 (at 213 clinical sites) Intention to treat (ITT design) Baseline characteristics of patients Age 65 years No contraindications to anticoagulation or a rate or rhythm drug Other risk factors for stroke/death New AF patients randomized to receive Long-term rate control CCB, BB, or digoxin (chosen by treating physician to control resting HR 80 or 110 after 6 min walk ) Warfarin mandated Long-term rhythm control Oral Class I/III drugs (chosen by treating physician) most common amiodarone > sotalol > propafenone, procainamide N Eng J Med 2002;347:

48 AFFIRM Results Cumulative Mortality from Any Cause No significant difference in mortality Rhythm group: Trend towards increased mortality N Eng J Med 2002;347:

49 AFFIRM Trial Considerations Rate control not worse that rhythm control overall Possibly superior in: Elderly CAD no CHF Rhythm group: Higher % of TdP, cardiac arrest, hospitalization (p = 0.01) Higher % of drug-related side effects ( p<0.05) 62% maintained in sinus rhythm at 5 years Incidence of stroke similar in each group Limitations Multiple rate/rhythm drugs could be used in each group Selection bias Only applicable for age > 65 N Eng J Med 2002;347:

50 Other Landmark Trials RACE, PIAF, STAF, HOT-CAFE All consistent with results of AFFIRM Not applicable to HF patients AF-CHF trial (2008) AF patients with LVEF < 35% and HF symptoms Results: No advantage with rhythm control in HF AF-CHF: N Engl J Med 2008;358:

51 Where are we now? It is acceptable to leave patients in AF and only control rate Rate vs rhythm Comparable mortality and stroke [AFFIRM] Class I drugs used in extreme caution post-mi (i.e. any SHD) [CAST Trial 1991]

52 So when DO we pursue a long-term rhythm strategy? (convert & keep in SR) When: Symptomatic patients despite rate control Unable to achieve HR 110 Younger patients or patients who prefer no long-term anticoagulation Pill-in-the-Pocket Patients who have had a safety trial of propafenone or flecainide can utilize a single-dose approach outpatient upon AF onset (IIa LOE B) Recent-onset AF, no drugcontraindications AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76

53 Preferred long-term rhythm control strategies Heart Failure Coronary Artery Disease only 1. amiodarone or dofetilide No SHD 1. sotalol or dofetilide or dronedarone (smaller subset of population) propafenone or flecainide or sotolol Hypertrophic cardiomyopathy Class Ia disopyramide! Amiodarone vs Sotalol two most-prescribed anti-arrhythmics Amiodarone: better at maintaining SR, good in HF, more widely prescribed, but more toxic Sotalol: AS effective in CAD, less side effects, but renally eliminated, (?advanced age) Both have AV nodal properties, limiting need for rate control (?) Above anti-arrhythmics ~50% at maintaining SR at 1 year (except amiodarone = %) SHD CAD, s/p MI, valve disease, LV dysfunction/lvh Therapy Vole 7; 4 p. 391 AFFIRM Investigators. N Eng J Med 2002;347:

54 2014 AHA/ACC AF Guidelines (for rhythm control)

55 There exist no one perfect anti-arrhythmic drug Benefit of maintaining SR Side effects of anti-arrhythmic drug Balance varies based on Patient factors Drug

56 Cathater ablation (see picture on next slide) What Radio-frequency ablation Cryo-ablation ( freezing ) How After reentry spot is located, high-frequency radiowaves burn a small area of tissue rendering it inactive. Difficult in AF many re-entrant pathways exist Post-care and recurrence of AF 20-50% recurrence at one year Majority within 3 months AAD added/continued for 3 months to reduce recurrence Higher success rate with multiple ablations Ganesan AN, J Am Heart Assoc Apr;2(2):e

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58 Catheter ablation Atrial Flutter First line therapy 90% effective (because.one re-entrant focus) AF Class I recommendation: Symptomatic paroxysmal AF Class II recommendation Afib refractory to medication Not able to tolerate AAD non-compliant w/ AAD Can be chosen as first line rhythm control method over AAD Advantages: avoid long-term use of AAD Risks thromboembolic events, cardiac tamponade, pulmonary vein stenosis (4.5% of patients) AHA/ACC/HRS Atrial Fibrillation Guideline. JACC 2014;64(21):e1-e76 Spector P, et al. Am J Cardiol 2009;104:

59 Treating AF Summary Class I agents are of little benefit in most patients Other anti-arrhythmics are falling out of favor also Its OK to leave patients in AF and just control rate! AFFIRM Trial No perfect anti-arrhythmic agent Toxic, pro-arrhythmic, and patient dependent! Newer non-pharmacological strategies emerging Catheter ablation

60 QUESTIONS? There are NO stupid questions..just stupid answers

61 Heart Block (AV block) AV node blocked in varying degrees speed bump (1 st degree) lane-change/detour (2 nd degree) road block (3 rd degree) Life-threatening severity Heart-Block ECG Tip: Focus on PR interval 1 st deg: long P-R interval (common and rarely symptomatic 2 nd deg (can be vaguely referred to as 2:1 block) Type I: progressively longer and longer P-R until QRS dropped Type II: regular P-R, then occasional dropped QRS 3 rd deg (P waves and QRS completely independent) i.e. P wave does not cause QRS i.e. no communication from atria to ventricle (inherent ventricular rate = HR = 40 bpm)

62 Treatment 1 st degree heart block usually incidental finding and asymptomatic 2 nd and 3 rd degree heart block Immediate: atropine and catecholamines (i.e. isoproterenol) Tanscutaneous pacing (temporary pacing) Remove AV node blocking agenst B-Blockers and non-dhp CCB contraindicated in heart-block Ventricular pacemaker necessary in 2 nd /3 rd degree