Atrial Fibrillation Roger Hefflinger, Pharm.D. Clinical Associate Professor Idaho State University COP Family Medicine Residency of Idaho

Transcription

1 Atrial Fibrillation 2016 Roger Hefflinger, Pharm.D. Clinical Associate Professor Idaho State University COP Family Medicine Residency of Idaho

2 Disclosures: The planners and presenter have disclosed no conflict of interest, including no relevant financial relationships with any commercial interests pertaining to this activity.

3 Objectives for Pharmacists and Prescribers: Analyze rationale for stroke risk stratification and options for anticoagulation Describe viable intravenous and oral ratecontrolling therapy options Recognize conditions in which chemical cardioversion should be considered

4 Objectives for Pharmacy Technicians and Nurses: Describe types of atrial fibrillation Identify anticoagulant therapy options for patients with atrial fibrillation List medications for atrial fibrillation with high risk for drug interactions and adverse effects

5 Atrial Fibrillation Guidelines

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7 What Controls SA Automaticity? Sympathetic tone Parasympathetic tone Hormones Steroids Thyroxine Electrolytes sodium, potassium, magnesium, chloride, phosphorus Tissue Hypoxia

8 Where does the Impulse go next? Atrial Myocardium Sodium dependent tissue AV Node Calcium Dependent tissue Adrenergic sensitive HIS Purkinje See SA node Ventricular Myocardium Ectopic focci and reentrant circuits primarily generated in sodium dependent tissue- Atrial myocardium

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10 Definition of Atrial Fibrillation Paroxysmal Atrial Fibrillation: AF that terminates spontaneously or with intervention within 7 days Episodes may recur with variable frequency Persistent Atrial Fibrillation: Continuous AF that is sustained > 7 days Long-Standing Persistent AF: Continuous AF > 12 months duration

11 Definition of Atrial Fibrillation Permanent Atrial Fibrillation: The term permanent AF is used when the patient and clinician make a joint decision to stop further attempts to restore and/or maintain sinus rhythm Acceptance of AF represents a therapeutic attitude on the part of the patient and the clinician than an inherent pathophysiologic attribute of AF. Acceptance of AF may change as symptoms, efficacy of therapeutic interventions and patient and clinician preferences evolve

12 Definition of Atrial Fibrillation Nonvalvular Atrial Fibrillation: AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair

13 Pathophysiology

14 Selected Risk Factors and Biomarkers for AF: Increasing Age, Hypertension, Diabetes Mellitus, Hyperthyroidism CHF, MI, Valvular heart disease, Cardiothoracic surgery Obesity, Sleep Apnea Smoking, Exercise, Alcohol Use European ancestry, Family History, Genetic Variants EKG: Left ventricular hypertrophy Echocardiographic: Left atrial enlargement Decrease LV fractional shortening Increased LV thickness Biomarkers: Increase CRP Increase BNP

15 What are our Goals of therapy? Thromboembolic Risk and Treatment: Risk Stratification Considerations in selecting Anticoagulants What are the factors that influence your selection of one drug over another? - rgh Rate Control: Recommendations Rhythm Control: Recommendations Prevent Thromboembolism Direct Current Cardioversion Pharmacologic Cardioversion Chemical Cardioversion Drugs to Maintain Sinus Rhythm

16 What are our Goals of therapy? Specific Patient Groups AF: Hypertrophic Cardiomyopathy AF Complicating Acute Coronary Syndromes Hyperthyroidism Pulmonary Disease Wolf-Parkinson Whit and Pre-Excitation Syndromes Heart Failure Familial (Genetic) AF Post operative Cardiac and Thoracic Surgery

17 Goal Number One- Thromboembolic Event Prevention Issues- Antiplatelet therapy enough? Anticoagulation therapy Acute- Un-fractionated Heparin Low molecular weight heparins Injectable Xa Inhibitors Chronic- Vitamin K antagonists- Coumadin with bridge or without? Thrombin Inhibitor Factor Xa inhibitors

18 It used to be easy! Risk Stratification <65 = ASA, ASA or Warfarin, >75 Warfarin

19 CHADS 2

20 Now Preferred = CHA 2 DS 2 -VASc

21 Thromboembolism Prevention: Selection of antithrombotic therapy should be based on the risk of thromboembolism irrespective of whether the AF pattern is paroxysmal, persistent or permanent Patients with nonvalvular AF with prior stroke, TIA, or a CHA 2 DS 2 -VASc score of 2 or greater, oral anticoagulants are recommended Warfarin (INR 2-3): Level A or Dabigatran, Rivoroxaban, Apixaban: Level B

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23 Vitamin K Antagonists Warfarin Coumadin

24 Warfarin Pharmacokinetics Food- no effects on absorption Protein Binding: 99% Extensive p-450 metabolism CYP2C9- primarily responsible for inactivation of more active s-warfarin T ½- 40 hours Terminal T-1/2- About 7 days

25 Mechanism of Vitamin K Antagonists Protein C Protein S Factor VII Factor IX Factor X Factor II

26 Gut absorption- Binding GI bacteria- K Warfarin Interactions Diet changes Liver metabolism Protein displacement

27 2009 FDA Warfarin Labeling Change CYP2C9 and VKORC1 Polymorphisms The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles, CYP2C9*2 and CYP2C9*3, result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively. Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9, and *11 alleles in Caucasians. Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle through inhibition of VKOR, a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (e.g., 1639G>A) have been associated with variable warfarin dose requirements. VKORC1 and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements. CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the initial dose of warfarin

28 Genetic testing does it help? 2007 FDA Coumadin warning of genetic mutations 2009 made the dosing recommendation changes;

29 Signal Interaction Everything interacts with Warfarin

30 Think/Pair/Share Discuss with the person on your right: What are the potential advantages and disadvantages of using warfarin as an anticoagulant? Discuss with the person on your left: When do you anticipate the major potential drug interactions with warfarin to present? What should you do about it?

31 Direct Thrombin Inhibitor: Dabigatran Pradaxa Dabigatran etexilate mesylate is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation 150 mg BID Renal Dosing: CrCl no change CrCl consider decreasing to 75 BID CrCl mg BID CrCl <15- Dosing recommendations can not be provided

32 Pharmacokinetics Xa Inhibitors Abixaban Eliquis 50% Bioavailable Food Delays Tmax 1 hour 87% Protein Bound Metabolism 3A4, Pgp = Look for inhibitors Not Dialyzable Rivoroxaban Xarelto % Bioavailable Food- no effect 10 mg 15, 20 mg WITH food Evening Meal Inc Bioava Metabolism 3A4, Pgp Inhibitors increase AUC T ½ 5-9 hours Longer in elderly NOT dialyzable

33 Factor Xa Inhibitors: 2015 January 9 th 2015 Edoxaban Savaysa ENGAGE AF-TIMI 48 (ClinicalTrials.gov number, NCT ) 21,105 Afib- CHADs score 2.8 Low dose edoxaban- 30 mg/day High dose edoxaban- 60 mg/day Standard warfarin 3.5 years Primary endpoint- Thromboembolic event Percent Renal elimination- 50% T ½- Normal GFR- 12 hours T ½ GFR<30-17 hours Liver 3A4 substrateminimal Time to peak 1-2 hours Effects food- minimal N Engl J Med 2013;369:

34 Edoxaban Savaysa Afib: N Engl J Med 2013;369:

35 Atrial Fibrillation: SE Stroke Systemic Embolism Major Bleeding Intracranial hemorrhage All Cause Mortality

36 Anticoagulation Renal Recommendations:

37 Fresh Frozen Plasma Reversing Agents? Human Prothrombin Complex Concentrate: Kcentra Recombinant active Factor VIIa: Prothrombin Complex Concentrate:

38 Xa Inhibitor Reversing Agent: Antidote Andexanet Alpha Annexa Portola Rx Coming Soon????

39 Think/Pair/Share Work with the person on your right: What are the advantages and potential disadvantages of the Novel Oral Anticoagulants?

40 Goal of Therapy Two: Rate Control Control of the ventricular rate using a beta blocker or non-dihydropyridine calcium channel antagonist is recommended for patients with paroxysmal, persistent or permanent AF. Intravenous administration of a BB or CCB is recommended to slow the ventricular heart rate in the acute setting. In patients experiencing AF related symptoms during activity, the adequacy of the heart rate control should be assed during exertion.

41 What is the desired heart rate? A heart rate control (resting heart rate <80 beats per minute strategy is reasonable for symptomatic management of AF. A lenient rate-control strategy (resting heart rate < 110 bpm) may be reasonable as long as patients remain asymptomatic and left ventricular systolic function is preserved

42 Beta Adrenergic Blocking Medications:

43 Limitations BB Blood pressure reduction Adrenergic blockade Decrease exercise ability Shortness of breath NOT contraindicated in COPD or Asthma Caution- may want to rate control with different class Tartrate Succinate

44 Calcium Channel Antagonists Diltiazem 0.25 mg/kg loading dose ( ) then in 20 minutes if needed 0.35 mg/kg (25 mg) then Continuous infusion (5-10mg/hour) then PO IR mg Q 6 hours then SR QD Verapamil 5-10 mg IV then repeat in minutes then IR mg Q 6 hours then SR QD

45 Limitations NDPCCB Nondihydropyridine calcium channel antagonists should not be used in patients with decompensated HF as these may lead to further hemodynamic compromise. (Level of Evidence: C) Negative Inotropes Blood pressure reduction Statin interactions: Lovastatin, Simvastatin (NMT mg) others caution

46 BB vs CCB vs Dig vs BB + Dig vs CCB + Dig

47 CCB or BB NOT Appropriately Controlling Rate: Digitalize Loading dose normal sized adult about 1 mg ½ dose first time 0.5mg over 5 minutes 6 hours later: ¼ dose 0.25mg over 5 minutes 6 hours later: ¼ dose 0.25mg over 5 minutes 6 hours later Maintenance dose PO mg Check level in 5-7 days

48 STILL not to adequate rate control: Rate and Cardioversion considerations: Amiodarone: mg IV over 1 hour 50mg/hour for 24 hours then PO: mg a day or mg a day

49 Think/Pair/Share Work with the person on your left: What are the advantages and disadvantages of the various medications used for rate control?

50 Goal of Therapy Three: Cardioversion: Direct Current Cardioversion: For patients with AF of 48 hours duration or longer or duration unknown- Anticoagulation is recommended for 3 weeks before and 4 weeks after cardioversion. (Electrical or Chemical) If needing urgent cardioversion and not anticoagulated a transesophageal echocardiography before cardioversion to look for left atrial thrombus

51 Chemical Cardioversion When and why did we stop trying to chemically cardiovert ALL patients with AF

52 Chemical Cardioversion: Class 1 Evidence A Recommendations: Flecainide, dofetilide, propafenone and intravenous ibutilide are useful for pharmacologic cardioversion of AF or atrial flutter, provided contraindications to the selected drug are absent Class 2a- Recommendation: Amiodarone orally is a reasonable option for cardioversion

53 What- PRN antiarrythmics Pill in the Pocket Propafenone or flecanide in addition to BB or NDPCCB is reasonable to terminate AF outside the hospital once this treatment has been observed to be safe in a monitored setting for selected patients

54 Pill in the Pocket Data: In-hospital administration of flecainide and propafenone in a single oral loading dose has been shown to be effective and superior to placebo in terminating atrial fibrillation 210 Patients, /- 5 months follow-up 165 pts (79%) had 619 events 569 events (92%) treated within 36 minutes Treatment successful in 534 episodes (94%) within 113 minutes N Engl J Med 2004;351:

55 Antiarrhythmics to Maintain Sinus Rhythm

56 Amiodarone Class 3: Phase 3 (Potassium channel blocker) Pharmacologic Cardioversion Guideline dose (Initial): 600 to 800 mg/day orally in divided doses until a total loading dose of 10 g Guideline dose (Maintenance): 200 mg orally daily Maintenance of Sinus Rhythm Guideline dose (Initial): 400 to 600 mg/day orally in divided doses for 2 to 4 weeks Guideline (Maintenance): 100 to 200 mg orally daily

57 Amiodarone Side Effects:

58 Dronedarone Multaq Exact MOA unknown Non-Iodinated amiodarone Important note: Strong CYP3A4 inhibitors (eg, ketoconazole) and Class I or III antiarrhythmics (eg, amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) must be discontinued prior to initiating dronedarone hydrochloride 400 mg BID with food 2x increased risk of heart failure and cardiovascular death

59 Flecanide Tambocor Class 1c (Sodium channel blocker) Flecainide has a long half-life (12 to 27 hours). Steady-state plasma levels in normal renal and hepatic function may not be achieved until 3 to 5 days of therapy at a given dose. Therefore, do not increase dosage more frequently than once every 4 days, because optimal effect may not be achieved during the first 2 to 3 days of therapy. Ventricular proarrythmic effects Facts and Comparisons

60 Sotolol Betapace Recommended Hospitalized: Initial dosage: Step 1: Prior to administration of the first dose, the QT interval must be determined using an average of 5 beats. If the baseline QT is greater than 450 msec (JT greater than or equal to 330 msec if QRS over 100 msec), use is contraindicated. Step 2: Prior to the administration of the first dose, the patient's CrCl should be calculated. Step 3: 80 mg twice daily (CrCl greater than 60 ml/minute); 80 mg once daily (CrCl 40 to 60 ml/minute); contraindicated (CrCl less than 40 ml/minute). Step 4: Administer the appropriate daily dose and begin continuous ECG monitoring with QT interval measurements 2 to 4 hours after each dose Step 5: If the 80 mg dose level is tolerated and the QT interval remains less than 500 msec after at least 3 days (after 5 or 6 doses if patient receives once-daily dosing), the patient can be discharged. Alternatively, during hospitalization, the dose can be increased to 120 mg twice daily and the patient followed for 3 days on this dose (followed for 5 or 6 doses if patient receives once-daily doses

61 Propafenone Rythmol Class 1c (sodium channel blocker) Chemical Cardioversion IV 2mg/kg may repeat with 1-2mg/kg in 6-8 hours Oral Cardioversion IR 150, 225, mg PO x once 150mg TID Oral Cardioversion ER 225, 325, BID increase every 3-5 days

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63 Conclusion: Anti-coagulate Vitamin K Antagonist- Warfarin Thrombin Inhibitor- Dabigatran Pradaxa Xa Inhibitors- Xarelto, Eliquis, Savaysa Rate Control BB, NDHPCCB, Dig, Amiodarone Chemical Cardioversion Amiodarone, Flecanide, Sotalol, Propafenone

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65 Questions