Atrial Fibrillation and Ventricular Arrhythmias

1. Atrial Fibrillation and Ventricular Arrhythmias Ibrahim Sales, Pharm.D. Assistant Professor of Clinical Pharmacy King Saud University isales@ksu.edu.sa

2. Supraventricular Arrhythmias • Supraventricular arrhythmia • Sinus Bradycardia • AV Nodal Block • Atrial fibrillation • Paroxysmal Supraventricular Tachycardia (PSVT) • Ventricular arrhythmia • Ventricular Premature depolarization • Ventricular tachycardia • Ventricular fibrillation • Torsades de Pointes

3. Atrial Fibrillation • The most common sustained arrhythmia encountered in clinical practice • Rapid & disorganized conduction in atria leading to loss of mechanical contraction • "irregularly irregular" appearance on ECG • HR of 120–180 usually observed because AV node unable to block all atrial impulses

4. Classification of AF • Paroxysmal (self-terminating) : • episodes terminate spontaneously in less than seven days, • usually less than 48 hours. • Persistent AF : • fails to self-terminate within 7 days. • Episodes may eventually terminate spontaneously, or they can be terminated by cardioversion. ACC/AHA/European Society of Cardiology

5. Classification of AF • Permanent AF • arrhythmia lasts for more than one year and cardioversion either has not been attempted or has failed. • "Lone" AF: • describes paroxysmal, persistent, or permanent AF in individuals withoutstructural heart disease (usually young patients, <60 yrs)

6. Classification of AF • Nonvalvular AF: • Not caused by valvular disease, prosthetic heart valves, or valve repair • Recurrent atrial fibrillation: • ≥ 2 episodes of atrial fibrillation

7. Causes of AF • Hypertensive heart disease  • Coronary disease  • Valvular heart disease  • Heart failure • Hypertrophic cardiomyopathy • Congenital heart disease • pulmonary embolism • COPD • Obstructive sleep apnea • Hyperthyroidism  • Alcoholism (Holiday Heart Syndrome) • Surgery: CABG 30-40% • Inflammation and infection • Medications: theophylline, bisphosphonate

8. Clinical implications of AF Am Fam Physician. 2011 Jan 1;83(1):61-68

9. Goals of Therapy • Disease specific goals of therapy • Control ventricular rate • Preventing thromboembolic events • Restore sinus rhythm • Maintain sinus rhythm • Global goals: • Reduce mortality • Improve QOL • Decrease hospitalization and ER visits • Optimize the cost effectiveness of treatment

10. Approach to therapy of AFib • Evaluate the need for acute treatment • By starting a rate control drug • Contemplate restoration of SR taking into consideration the risks • restoring and maintaining SR may not be a desirable goal for all patients • Consider thromboembolic prophylaxis with appropriate antithrombotic drug based on stroke risk

11. Rate control vs. rhythm Control • Overall Conclusion: • No significant difference in overall mortality between rate-control and rhythm-control strategies • Anticoaugulant (AC) need is similar in both groups

12. Rate control Strategy • At least as effective as rhythm control strategy for preventing stroke and death in atrial fibrillation • Fewer adverse events than rhythm control strategy • Rhythm control with AAD maybe considered if patient remained symptomatic despite adequate ventricular rate control • Target HR: • Lenient resting HR< 110 bpm vs. strict rate control, resting HR< 80 BPM, have similar cardiovascular outcomes • Therefore, target a resting heart rate of < 110 bpm AAD: anti-Arrhythmic Drugs

13. Rate control Strategy • Drugs for long-term rate control • Beta blocker (oral) • metoprolol50-200 mg/day, propranolol 80-240 mg/day) • Non-dihydropyridine(oral) • diltiazem120-360 mg/day, verapamil 120-360 mg/day) • Digoxin (oral) • AF with HF, LVD (LVEF < 40%) or for sedentary individuals • not recommended as monotherapy to control ventricular rate in patients with paroxysmal atrial fibrillation

14. Rate control Strategy • Amiodarone (oral) • when other medical therapy has failed to control heart rate adequately • AF with pre-excitation • preferred drugs for rate control are oral propafenone or amiodarone • combination therapy with any of digoxin, beta blocker, or non-DHP-CCB may be used to control heart rate at rest and with exercise

15. Rhythm control strategy • Recommended in patients with symptomatic AF despite rate control • Pharmacologic rhythm control strategy associated with more hospitalizations and adverse events without apparent benefit compared to rate control strategy in AF • Rate control should be continued throughout rhythm control approach

16. Rhythm control strategy • Cardioversion with DCC • DCC is useful to start rhythm control strategy for atrial fibrillation • Pretreatment with amiodarone, flecainide, ibutilide, propafenone or sotalol before DC cardioversion may increase success rate and prevent recurrent atrial fibrillation • Pharmacological cardioversion: • Success rate lower than DC • Selection of agent: • If the AF is ≤7 days duration: • Dofetilide, flecainide, ibutilide, propafenone or, to a lesser degree, amiodarone (preferred if structural heart dz) • If the AF is >7 days duration • dofetilide or, to a lesser degree, amiodarone or ibutilide

17. Rhythm control strategy • Thromboembolic prophylaxis during cardioversion: • for AF of known duration < 48 hours • immediate cardioversion indicated without delay for anticoagulation if hemodynamic instability • starting anticoagulation (with LMWH or IV UFH at full venous thromboembolism treatment doses) before cardioversion suggested if possible

18. Rhythm control strategy • for atrial fibrillation of ≥ 48 hours or of unknown duration • initial therapeutic anticoagulation recommended with either: • Option 1: Therapeutic anticoagulation (adjusted-dose vitamin K antagonist [VKA] therapy to target INR range 2-3, LMWH at full venous thromboembolism treatment doses, or dabigatran) for at least 3 weeks before cardioversion

19. Rhythm control strategy • Option 2: Transesophagealechocardiography (TEE)-guided approach with initial anticoagulation (LMWH or IV heparin) then cardioversion within 24 hours of confirmation of no thrombus • less hemorrhagic complications, but trend toward increased mortality • Post-cardioversionanticoagulation recommended for ≥ 4 weeks

20. Rhythm control strategy • Maintenance of NSR • Intermittent antiarrhythmic drug therapy • “Pill in the Pocket” • AAD: • Also increase the risk of arrhythmia • torsades de pointes (TdP): a potential adverse effect with dofetilide and sotalol • ventricular tachycardia or conversion to atrial flutter with tachyarrhythmia is a potential adverse effect with flecainide and propafenone • The AAD associated with increased mortality include sotalol, quinidine, and possibly disopyramide

21. Rhythm control strategy • “Pill in the Pocket” • A transient outpatient therapy for reversion of NSR in paroxysmal AF • single oral high dose taken only when an episode of AF is recognized by the patient • Agents: propafenone600 mg, or flecainide 300 mg • Very strict patient criteria • Absence of: structural heart disease,sinus and AV node dysfunction, QT interval prolongation, Brugada syndrome • Presence of AV nodal blockade with a BB or CCB to prevent rapid AV conduction if atrial flutter occurs.

22. Recommended Antiarrhythmic Therapy in Patients with Recurrent Paroxysmal or Persistent Atrial Fibrillation:

23. Ablation Therapy • ablation of AV node or accessory pathway (and pacemaker implantation) • indicated when medical therapy fails to control heart rate or produces intolerable side effects • Catheter ablation, or surgical ablation in patients having cardiac surgery for other reasons • recommended for patients with symptomatic paroxysmal atrial fibrillation after failure of antiarrhythmic drugs • may improve quality of life and reduce hospital readmission rates

24. Antithrombotic Therapy

25. Thromboembolic Prophylaxis • Guidelines consistently agree that most patients with AF should receive antithrombotic therapy. • AT is recommended to patients with permanent, persistent, or paroxysmal atrial fibrillation, atrial flutter, and patients managed with rate or rhythm control strategy

26. Antithrombotic in Atrial Fibrillation • Return of SR restores effective contraction in the atria >> dislodge poorly adherent thrombi • Selection of the antithrombotic agent depend on the level of risk: • CHADS2 or CHA2DS2-VASc score for risk stratification

27. Stroke Risk Stratification • Have ONE of the following factors: • Prior ischemic stroke, TIA • Mitral valve stenosis • Prosthetic heart valve • Have ONLY one of the following factors: • Age > 75 y Or HTN Or DM Or moderately or severely impaired LV systolic function and/or HF • Age > 75 y With none of the conditions listed above in the high- or intermediate-risk categories High Risk Patients: • Have > 2 of the • Age > 75 y • HTN • DM • Moderately or severely impaired LVSD and/or HF OR Intermediate Risk Patients: Low-Risk Patients:

28. Recommendations About Antithrombotic Therapy

29. Stroke Risk Stratification • CHADS2 risk score predicts stroke risk • Helps predict stroke risk in AF patients and determine which antithrombotic (AT) is appropriate ACCP 9th edition, 2012 Guidelines for the Management of Patients With AF

30. Recommendation for AT in AF AC: Anticoagulation ACCP 9th edition, 2012 Guidelines for the Management of Patients With AF

31. CHA2DS2-VASc ACCP 9th edition, 2012 Guidelines for the Management of Patients With AF

32. Overview on Antithrombotic Therapies

33. Vitamin K antagonist: Warfarin • The most commonly used AC • Target INR of 2-3 in patients without mechanical heart valves • lower target INR of 2 (range 1.6-2.5) may be considered for patients ≥ 75 y/o or if at  risk of bleeding but without contraindications to oral anticoagulant therapy

34. Vitamin K antagonist: Warfarin • Starting dose 5-10 mg adjusted based on INR • No need to bridge patient with heparin when initiating warfarin in AF patients • Determine INR at least weekly during initiation and monthly when INR is stable. • suggests monitoring INR at least every 12 weeks rather than every 4 weeks when INR consistently stable

35. Vitamin K antagonist: Warfarin • Limitation: • Narrow therapeutic index • Require frequent dose adjustments and monitoring • Significant drug-drug and drug-food interaction • time required to achieve its pharmacologic effect is dependant on the T½ of the coagulation proteins. • full antithrombotic effect achieved in 5 to 7 days after • Pregnancy Category X

36. Dabigatran (Pradaxa®) • Dabigatranetexilateis a selective, competitive, reversible direct thrombin inhibitor • Approved by FDA in 2010 for stroke prevention in atrial fibrillation • Approved in Canada & Europe for VTE prevention after hip and knee replacement surgery

37. Dabigatran (Pradaxa®) • Oral capsule • Rapid onset of action • Half-life 12-17 hours, dosed TWICE Daily • No routine monitoring required • No reversal antidote • dialyzable • No dietary/food interactions • SE: Bleeding, Dyspepsia (common, likely due to tartaric acid) • Cost: $$$ compared to warfarin

38. Dabigatran (Pradaxa®) • Renal elimination • CrCl>30 ml/min: • 150 mg orally twice daily • Outside US: 110 mg twice daily for age >75 or propensity for GI bleeding • CrCl 15-30 ml/min: • 75 mg orally, twice daily* • Metabolism: P-gp substrate • use with caution when administered concomitantly with P-gp inhibitors or inducers

39. Dabigatran (Pradaxa®)

40. Dabigatran (Pradaxa®)

41. Converting to and from Dabigatran • Warfarin to Dabiatran • D/c warfarin and start dabigatranwhen INR <2.0 • Dabigatran to Warfarin • CrCl >50 ml/min: start warfarin 3 days before d/c DabiCrCl31-50 ml/min: start warfarin 2 days before D/c dabigatran • CrCl15-30 ml/min: start warfarin 1 day before stopping dabigatran • CrCl<15 ml/min: no recommendation

42. Dabigatran (Pradaxa®) • Product Stability: • Once bottle is opened, manufacturer recommends that drug be used within 30 days. Keep bottle tightly closed • Manufacturer package insert indicates potency is maintained for 120 days after first opening bottle.

43. Dabigatran (Pradaxa®) • Contraindications: • Active pathologic bleeding • History of serious hypersensitivity reaction to dabigatran (e.g., anaphylaxis, anaphylactic shock) • Patients with mechanical prosthetic heart valves • Pregnancy Category C

44. Rivaroxaban (Xarelto®) • Direct factor Xa inhibitor • Approved by FDA in 2011 for prevention of stroke in non-valvular AF. • Also in treatment and prophylactic in DVT/PE and following knee- or hip-replacement surgery • No laboratory monitoring required • No dosage adjustment for gender, age, extreme body weight • No reversal • Half life 5-9 hours

45. Rivaroxaban (Xarelto®) • Dosing: • Oral tablet, once daily (cost $231.60 USA) • Primarily renal elimination • If CrCl> 50 ml/min: give 20 mg once daily with evening meal • If Crcl15-50 ml/min give 15 mg once daily with evening meal • Contraindicated for creatinine clearance < 15 mL/minute

46. Rivaroxaban (Xarelto®) • Contraindications: • Active pathologic bleeding • Severe hypersensitivity reaction to rivaroxaban • Pregnancy Category C • Lactation: Discontinue nursing or the drug • DI: Drugs Affecting and/or P-glycoprotein and CYP3A4 • Avoid using with itraconazole, ketoconazole, Antiretrovirals, HIV protease inhibitors, Carbamezapine, rifampin, phenytoin, St. John's wort

47. Apixaban (Eliquis®) • Direct factor Xa inhibitor • Approved by FDA in 2012 for risk reduction of stroke and systemic embolism in nonvalvular AF • No routine lab testing • No reversal • Half life 8-15 hours • Metabolized in liver via CYP3A4 and CYP independent mechanisms • Eliminated via multiple pathways

48. Apixaban (Eliquis®) • Dose: 5 mg tablet Twice daily • To switch from warfarin, stop warfarin, then start apixaban when INR <2 • Cost: (5 mg BID): $250.37 (USA) • Pregnancy Category B • Lactation: Discontinue nursing or the drug • May prolong PTT and INR in a concentration-dependent fashion

49. Stopping Pradaxa (dabigatran), Xarelto (rivaroxaban), or Eliquis (apixaban) in AF patients • Discontinuing new oral AC places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following discontinuation in clinical trials in patients with nonvalvular atrial fibrillation. • If anticoagulation must be discontinued for a reason other than pathological bleeding, coverage with another anticoagulant should be strongly considered.

50. Limitations of Novel AC • Irreversibility • Cost • Renal function • Not studied where CrCL<30mL/min • Lack of monitoring • No readily available test • No therapeutic interval • Long term safety not known • No data on use in pediatric population