Treatment of Atrial Fibrillation WS 2024 PDF

Treatment of Atrial Fibrillation Jodi L. Taylor, PharmD, BCCCP, FASHP  Recent Guidelines and Statements 2023 ACC/AHA/ACCP/HRS Guidelines for the Diagnosis and Management of Atrial Fibrillation Circulation 2023: doi:10.1161/CIR.0000000000001193 2022 CHEST Guideline: Perioperative Mana...

Treatment of Atrial Fibrillation Jodi L. Taylor, PharmD, BCCCP, FASHP  Recent Guidelines and Statements 2023 ACC/AHA/ACCP/HRS Guidelines for the Diagnosis and Management of Atrial Fibrillation Circulation 2023: doi:10.1161/CIR.0000000000001193 2022 CHEST Guideline: Perioperative Management of Antithrombotic Therapy CHEST 2022; doi:10.1016/j.chest.2022.07.025 2020 ACC Expert Consensus Decision Pathway for Anticoagulation and Antiplatelet Therapy in Patients with Atrial Fibrillation or VTE Undergoing PCI or with ASCVD J Am Coll Cardiol 2020; doi:10.1016/j.jacc.2020.09.011 2019 ACC/AHA/HRS Focused Update of the 2014 Guideline for the Management of Patients with Atrial Fibrillation Circulation 2019;140:e125-e151 2014 ACC/AHA/HRS Guideline for the Management of Patients with Atrial Fibrillation Circulation 2014;130:e199-267  Learning Objectives Recognize common mechanisms and agents associated with drug-induced atrial fibrillation (AF). State the diagnostic study that identifies AF. Design appropriate pharmacological treatment regimens for acute and chronic management of AF (for rate, anticoagulation, rhythm, including device-related) from a patient case. Relate appropriate route of drug administration based on hemodynamic state of the patient. Distinguish drugs that can and cannot be given to a patient with pre-excitation. Distinguish appropriate and inappropriate agents for pharmacological conversion of AF. Describe appropriate patient safety considerations for pill-in-the-pocket strategy. State rate control goals. Calculate CHA2DS2VASc and HAS-BLED scores from a patient case (point tables NOT given on exam). Relate modifiable risk factors for bleeding and strategies to minimize bleeding risk. Outline appropriate use of bridging therapy in AF patients. Contrast Valvular AF (EHRA Type 1) with Non-Valvular AF (EHRA Type 2). Recognize lifestyle and risk factor modifications identified for AF patients by the AHA.  Atrial Fibrillation Facts AF is the most The AF incidence and AF is associated with a common sustained AF is associated bad prevalence increases decreased quality of cardiac arrhythmia in outcomes. in some populations. life. the U.S. Estimated 50 Increased rates of 37% lifetime risk million people death, stroke, and in those  55 affected thromboembolic years worldwide events $28.4 billion Increased rates of Men have higher annual US heart failure and incidence healthcare costs hospitalizations Caucasians have higher incidence Joglar JA, et al. Circulation. 2023;149:e1-e156 https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_atrial_fibrillation.htm Accessed 11/1/19. Chung MK, et al. Circulation. 2020;141:e750 AF Prevalence by Social Demographic Index SDI represented as geometric mean of 3 common indicators: ▪ Income per capita ▪ Mean educational achievement  15 yrs ▪ Total fertility rate < 25 yrs Joglar JA, et al. Circulation. 2023;149:e1-e156 Image from https://www.cdc.gov/heartdisease/atrial_fibrillation.htm. Accessed 11/10/2023.  Atrial Fibrillation (AF) AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of mechanical function ▪ The atria contract irregularly and chaotically ▪ Contraction coordination between the atria and ventricles is lost Diagnosis: > 30 seconds of heart rhythm with no discernible repeating P waves and irregular RR intervals on ECG NEJM Video in Clinical Medicine: ECG can be seen here: https://www.nejm.org/doi/full/10.1056/NEJMvcm1400705 An animation of AF can be seen here: https://watchlearnlive.heart.org/index.php?moduleSelect=atrfib Hindricks G, et al. Eur Heart J 2020; doi:10.1093/eurheartj/ehaa612 Atrial Fibrillation: ECG Normal Sinus Rhythm No distinct P waves The atrial rate is variable and > 300 bpm Absolutely irregular RR intervals (ventricular response) Atrial Fibrillation  Many drugs contribute to development of AF through common mechanisms: Adrenergic stimulation Vagal stimulation Direct cardiotoxicity Changing atrial conduction, refractoriness, or automaticity Coronary vasoconstriction/ischemia Electrolyte disturbances Van der Hooft CS. J Am Coll Cardiol 2004;44:2117  Agents Implicated in Drug-Induced AF or Atrial Flutter Albuterol Alcohol Alendronate Caffeine Dobutamine Fluoxetine Ipratropium Levosimendan Methylprednisolone Milrinone Mitoxantrone Paclitaxel Theophylline Others Tisdale JE, Miller DA, eds. Drug-Induced Diseases: Prevention, detection, and management, 3rd ed. 2018. Tisdale JE, et al. Circulation 2020;142:e214  The first detection of AF is usually heralded by one of the following: Irregular pulse Symptoms Ischemic stroke or TIA Image from https://www.heart.org/-/media/data-import/downloadables/ Accessed 11/1/19  Clinical Evaluation of AF Patient Interview Symptomatology Onset Frequency, duration, precipitating and relieving factors Previous response to pharmacologic agents Presence of underlying heart disease or other reversible conditions Home medications 12-lead ECG Verify rhythm Wave morphology Clinical Pearl: A QT interval and a corrected QT Pre-excitation interval [QTc] are available on EKG reports. The QTc Bundle Branch Block is calculated based on the R-R interval and the QT Prior MI interval to adjust for changes in the cardiac cycle. QTc  Clinical Evaluation of AF Echocardiography (Transthoracic or Transesophageal) Valvular heart disease LA & RA size LV size & function LV hypertrophy Pericardial disease Laboratory Tests TSH, T4 Serum creatinine Electrolytes Liver function tests Pregnancy test  OLD Classification of AF Paroxysmal Persistent Long-standing Permanent Usually < 48 > 7 days Persistent AF Accepted, no hours duration for > 1 year longer Requires attempting to cardioversion restore NSR Clinical Conundrum: Classification of AF does not impact your decision to provide or withhold anticoagulation (ACC/AHA). Classification of AF can be used to aid in risk assessment for those with non-sex CHADSVASc of 1 (ESC). Camm AJ, et al. Eur Heart J 2010;31:2369  NEW AF Stages 1 2 3 4 At Risk Pre-AF AF Permanent AF Presence of Evidence of Paroxysmal Persistent AF Long-standing Successful AF No further modifiable structural or AF (3A) (3B) persistent AF ablation (3D) attempts to and non- electrical (3C) control modifiable findings AF that is AF that is Freedom rhythm after risk factors further intermittent continuous AF that is from AF after discussion predisposing and and sustains continuous percutaneous between to AF terminates for > 7 days for > 12 or surgical patient and within  7 or requires months in intervention clinician days of onset intervention duration to eliminate AF  Staging: AF 1 and AF 2 AF1 AF2 Modifiable Risk Factors Structural Findings Obesity Atrial enlargement Lack of fitness Valve disease Hypertension Hypertrophic cardiomyopathy Sleep apnea Left ventricular hypertrophy Alcohol Diabetes Electrical Findings Nonmodifiable Risk Factors Frequent atrial ectopy Genetics Short bursts of atrial tachycardia Male sex Atrial flutter Age Prolonged PR interval Joglar JA, et al. Circulation. 2023;149:e1-e156 Therapeutic Considerations in AF Acute Prevention of Chronic Progression Treatment Treatment Acute Management of AF Is my patient hemodynamically stable? Rhythm Control Pursued in selected patients Anticoagulation Must be considered in all patients Rate Control Must be addressed in all patients  Acute Management of AF Hemodynamic changes seen in AF patients can be due to: ▪ Loss of coordinated contraction ▪ High ventricular rates ▪ Irregularity of the ventricular response ▪ Decrease in myocardial blood flow Some experts suggest that heart rates < 150 bpm are unlikely to cause symptoms of instability, but individualized assessment is critical!! Signs/Symptoms: – Hypotension – Ischemic chest discomfort – Acutely altered mental status – Pulmonary edema/acute heart failure – Signs of shock – Decreased urinary output Link MS, et al. Circulation. 2015; 132:S444-S464 Acute Management of AF Is my patient hemodynamically stable? Rhythm Control Pursued in selected patients Anticoagulation Must be considered in all patients Rate Control Must be addressed in all patients  Acute Rate Control Consider likelihood of therapeutic success with PO administration: Ability to Integrity of GI Perfusion of GI Swallow or Tract Tract Access GI Tract Stable patient with intact, accessible and perfused GI Tract Oral Administration is an option… Everyone else… Parenteral Administration  Acute Rate Control Options No decompensated HF present: ▪ BB or NDHP-CCB preferred ▪ Digoxin second-line Calcium Beta Channel ▪ Amiodarone third-line blockers Blockers (non-DHP) Decompensated HF present: ▪ Amiodarone preferred ▪ DO NOT USE NDHP-CCB Risk of inadvertent Digoxin Amiodarone cardioversion! Consider the addition of IV magnesium for those in AF with RVR. All are available in IV and PO formulations  Pre-excitation syndrome occurs when an alternate “electrical pathway” exists in the heart that bypasses the AV node. Results in earlier activation of the ventricles Encompasses many different syndromes (i.e. Wolff-Parkinson-White, Lown- Ganong-Levine, etc.) AF with If you block the AV nodal pathway, you promote propagation of the electrical signal through the accessory pathway. Pre-Excitation Can lead to an increase in HR. Agents to avoid: adenosine, non-DHP CCBs, BB, digoxin OK to use: procainamide, ibutilide Acute Management of AF Is my patient hemodynamically stable? Rhythm Control Pursued in selected patients Anticoagulation Must be considered in all patients Rate Control Must be addressed in all patients  Acute Rhythm Control Why Cardioversion How? Cardioversion? Symptoms present Chronic Drugs Electricity HD unstable rhythm despite due to RVR control will adequate be pursued rate control Electrical cardioversion is called “Direct Current Cardioversion” or DCC for short. HD = hemodynamic; RVR = rapid ventricular response  Cardioversion How? Pharmacological Cardioversion Drugs Electricity Pros Cons Patients with normal LV function: ▪1st line: IV amiodarone, ibutilide ▪2nd line: procainamide Patients with HFrEF: ▪IV amiodarone  Patient-Initiated Pharmacological Cardioversion “Pill-in-the-Pocket, or PIP” An oral dose of flecainide or propafenone can be used as a “pill-in-the-pocket” strategy to restore NSR (Class IIa, LOE B) Initial conversion must be done in a monitored setting Telemetry monitoring for at least 6 hours after first dose Efficacy: Conversion to normal sinus rhythm (NSR) Safety: ventricular tachycardia, post-conversion pauses, bradycardia, drug- induced hypotension Concomitant Beta-blocker or non-DHP CCB must be administered January CT, et al. Circulation 2014;130:e199  Patient-Initiated Pharmacological Cardioversion “Pill-in-the-Pocket, or PIP” Inclusion Criteria Exclusion Criteria Outcomes Randomized patients with Structural heart disease present Significant reduction in symptomatic, paroxysmal AF [EF < 50%, active ischemic heart health care utilization disease, LVH] Adverse event rate of 16% Sustained AF episodes [lasting at least 2 hours] Abnormal conduction parameters Non-efficacy rate of 19% [QRS, PR, pre-excitation] AF episodes occur less frequently than once per month Sinus node dysfunction or AV block present AF episodes cannot have disabling or severe symptoms Hypotension Patients must be able to comply Previous intolerance of study drugs with directions Original trial did not enroll patients > 75 years of age (mean patient age 53 years) Future consideration: How will mobile EKG monitoring change utilization of PIP? Andrare JG, et al. Heart Rhythm 2018;15:9 Alboni P, et al. N Engl J Med 2004;351:2384 Kirchhof P, et al. N Engl J Med 2023;389:1167  Cardioversion How? Direct Current Cardioversion (DCC) Drugs Electricity Pros Cons ▪Immediate DCC is recommended when RVR does not respond promptly to stabilization attempts in the presence of ongoing myocardial ischemia, symptomatic hypotension, or heart failure. ▪DCC is contraindicated in patients with digitalis toxicity! Acute Management of AF Is my patient hemodynamically stable? Rhythm Control Pursued in selected patients Anticoagulation Must be considered in all patients Rate Control Must be addressed in all patients  Antithrombotic Therapy for Cardioversion There is an increased risk of thromboembolism following cardioversion with the highest risk in the first 72 hours. Majority of thromboembolic complications occur within 10 days of cardioversion. You JJ, et al. Chest. 2012;141:e531S  TEE-Guided Approach (AF duration > 48 hrs) TEE  TTE The mandatory 3-week anticoagulation period for elective cardioversion can be shortened if Transesophageal Echocardiogram (TEE) shows no thrombus in the left atrium and left atrial appendage. The most consistent predictor of ischemic stroke on TEE is moderate-severe LV Systolic dysfunction Left atrial spontaneous echo-contrast, complex aortic plaque, or low left atrial appendage velocities (≤ 20 cm/s) on TEE are also independent predictors of stroke and Lip GY, et al. Chest 2018;154:1121 thromboembolism. TTE = transthoracic echocardiogram Image from https://www.froedtert.com/arrhythmia-program/atrial-fibrillation/left-atrial-appendage-laa-closure  TEE-Guided Approach (AF duration > 48 h) TEE after Anticoagulation Options for TEE-guided therapeutic AC strategy: ▪ IV UFH ▪ LMWH at full VTE treatment doses NO Thrombus Thrombus ▪ DOAC ▪ Warfarin* CV (must be No CV *TEE scheduled for 5 days later and only performed if INR is in therapeutic range prior to study within 24 hr) OAC 4-12 wks CV=cardioversion; AC=anticoagulation; OAC=oral anticoagulant Therapeutic Considerations in AF Acute Prevention of Chronic Treatment Progression Treatment  Chronic AF Management Lifestyle and RF Modification (LRFM) for all patients Obesity Physical inactivity Unhealthy alcohol consumption Smoking Diabetes Hypertension Stroke Risk must be assessed in all patients; treat when indicated CHA2DS2-VASc Symptom management must be addressed in all patients AF Burden Rate control Rhythm control Joglar JA, et al. Circulation. 2023;149:e1-e156  Shared Decision Making (SDM) “The use of evidence-based decision aids might be useful to guide stroke reduction therapy treatment decisions throughout the disease course to improve engagement, decisional quality, and patient satisfaction.” ACC Colorado Program Mayo Clinic Ottawa Hospital Patient Stanford Guide to Stroke for Patient Centered Anticoagulation Choice Decision Aids link Prevention link Decisions link Decision Aid link Link to external tools Application with Booklets Application for use videos, FAQs, Videos during clinician visit knowledge check, Visuals to quantify and worksheet to stroke risk after guide patient- calculation clinician discussion Joglar JA, et al. Circulation. 2023;149:e1-e156  Chronic AF Management Lifestyle and RF Modification (LRFM) for all patients Obesity Physical inactivity Unhealthy alcohol consumption Smoking Diabetes Hypertension Stroke Risk must be assessed in all patients; treat when indicated CHA2DS2-VASc Symptom management must be addressed in all patients AF Burden Rate control Rhythm control Joglar JA, et al. Circulation. 2023;149:e1-e156  Lifestyle and Risk Factor Modification (LRFM) Weight loss for BMI > 27 who have AF; target 10% weight loss Obesity Moderate to vigorous exercise training for those with AF; target 210 minutes per week Physical Fitness Those with AF who smoke cigarettes should be strongly advised to quit and should receive GDMT for cessation Tobacco Use Patients with AF seeking a rhythm-control strategy should minimize or eliminate alcohol consumption Alcohol Intake In patients with AF, recommending caffeine abstention to prevent AF episodes is of no benefit Caffeine intake Caffeine abstention may reduce symptoms in those who report caffeine triggers or worsens AF symptoms Optimal BP control is recommended Hypertension In patients with AF, it may be reasonable to screen for OSA Sleep apnea  Chronic AF Management Lifestyle and RF Modification (LRFM) for all patients Obesity Physical inactivity Unhealthy alcohol consumption Smoking Diabetes Hypertension Stroke Risk must be assessed in all patients; treat when indicated CHA2DS2-VASc Symptom management must be addressed in all patients AF Burden Rate control Rhythm control Joglar JA, et al. Circulation. 2023;149:e1-e156  Antithrombotic Therapy in AF ESSENTIAL component of AF treatment 15-20% of all ischemic strokes occur in AF patients AF independently increases risk of ischemic stroke by 4-5 fold De Biase L, et al. Circulation 2010;121:2550 January CT, et al. Circulation 2014;130:e199 Singer DE, et al. Chest 2008; 133: 546S  Chronic Antithrombotic Therapy in AF CHA2DS2VASc HAS-BLED SAMeTT2R2 Chronic management of Estimates Identifies Predicts anticoagulation in AF annual patients likelihood based on risk stroke risk with high of achieving assessments! bleed risk good TTR Individualized risk assessments change over time and should be completed on a regular basis! Risk assessments should be documented! TTR=time in therapeutic range Other tools to estimate risk include ATRIA, GARFIELD-AF, and HEMORR2HAGES.  Additional Risk Factors not included in CHA2DS2-VASc: Higher AF burden/long duration Persistent/permanent vs. paroxysmal BMI  30 HCM Poorly controlled HTN eGFR < 45 ml/hr Proteinuria (> 150 mg/24hr) aVascular Enlarged LA volume ( 73 ml) or disease = CAD, PVD, aortic plaque diameter ( 4.7 cm) Camm AJ, et al. Eur Heart J 2010; 31: 2369 Joglar JA, et al. Circulation. 2023;149:e1-e156  CHA2DS2VASc Risk Assessment Component Definition C = CHF The presence of signs and symptoms of either right (elevated CVP, hepatomegaly, dependent edema) or left (exertional dyspnea, cough, fatigue, orthopnea, PND, cardiac enlargement, rales, gallop rhythm, pulmonary venous congestion) ventricular failure or both confirmed by non-invasive or invasive measurements demonstrating objective evidence of cardiac dysfunction H = HTN A resting blood pressure > 140 mmHg systolic and/or > 90 mmHg diastolic on at least two occasions or current antihypertensive pharmacologic treatment A = Age Age > 75 years → 2 points Age 65 – 74 years → 1 point D = DM Fasting plasma glucose level > 126 mg/dL or treatment with oral hypoglycemic agent and/or insulin Lip GY, et al. Chest 2010;137:263  CHA2DS2VASc Risk Assessment Component Definition S2 = CVA/TIA/TE Stroke defined as a focal neurologic deficit of sudden onset as diagnosed by a neurologist, lasting > 24 hours and caused by ischemia. TIA defined as a focal neurological deficit of sudden onset as diagnosed by a neurologist lasting < 24 hours. TE defined as either ischemic stroke, peripheral embolism, or pulmonary embolism. Peripheral embolism defined as a thromboembolism outside the brain, heart, eyes and lungs. Lip GY, et al. Chest 2010;137:263  CHA2DS2VASc Risk Assessment Component Definition V = Vascular Disease (Prior MI, PAD, Coronary artery disease (prior MI, angina pectoris, PCI, or CABG) or Aortic Plaque) PVD defined as intermittent claudication, previous surgery or percutaneous intervention on the abdominal aorta or lower extremity vessels, abdominal or thoracic surgery, arterial and venous thrombosis. Aortic Plaque S = Sex category Female sex Lip GY, et al. Chest 2010;137:263  Risk Categories by CHA2DS2VASc Score Low Risk for Stroke Non-sex CHA2DS2VASc Score of 0 Stroke risk reduction (oral anticoagulant) not recommended Aspirin monotherapy for prevention of stroke is not recommended Intermediate Risk for Stroke Non-sex CHA2DS2VASc Score of 1 Stroke risk reduction (oral anticoagulant) therapy is reasonable (COR 2a, LOE A) Monotherapy ASA or DAPT as an alternative to anticoagulation is not recommended (COR 3, LOE B-R) High Risk for Stroke Non-sex CHA2DS2VASc Score > 2 Stroke risk reduction therapy (oral anticoagulant) is recommended (COR 1, LOE A) Monotherapy ASA or DAPT as an alternative to anticoagulation is not recommended (COR 3, LOE B-R) January CT, et al. Circulation 2019;140:e125  Intermediate Risk and Therapy Selection Look for other indications for anticoagulation Step 1 Mechanical heart valves Moderate-severe mitral stenosis Others Assess benefit v. risk Step 2 Annual thrombotic risk of 0.6 – 1.3% What is the patient’s bleeding risk (HAS-BLED estimate)? Shared decision-making Step 3 “Shared decision-making should occur after a discussion of absolute risks and relative risks of stroke and bleeding as well as the patient’s values and preferences” Sulzgruber P, et al. Eur Heart J 2019;40:3010  HAS-BLED for Bleeding Risk Component Definition Points Hypertension SBP > 160 mmHg 1 Abnormal kidney function Dialysis, history of renal transplant, or SCr > 2.2 mg/dL 1 Abnormal liver function Cirrhosis or [total bilirubin > 2 x ULN + AST/ALT > 3 x ULN] 1 Stroke History of stroke 1 Bleeding Previous bleed history or disposition to bleed 1 Labile INR Unstable/high INRs or TTR < 60% 1 Elderly Age > 65 years 1 EtOH Alcohol abuse 1 Drugs Concomitant use of drugs (antiplatelets, ASA, NSAIDs) 1 Note: HTN in CHADSVASc gets a point regardless of BP control. HTN ULN=upper limit of normal in HAS-BLED only gets a point for uncontrolled BP. TTR=time in therapeutic range  Intermediate Risk and Therapy Selection Non-Sex CHA2DS2VASc = 1 HASBLED > 2 HAS-BLED < 2 Look for additional No therapy favored individual thrombosis RF Intermediate Risk = Non-sex CHADSVASc 1 Sulzgruber P, et al. Eur Heart J 2019;40:3010 Appropriate Use of HAS-BLED HAS-BLED is used to increase the frequency of follow-up and draw attention to modifiable risk factors for bleeding Score > 3 warrants more frequent review/follow-up HAS-BLED score should not solely be used to decide if a patient receives anticoagulation  Assessing Bleeding Risk For all patients with AF, HAS-BLED score should be used to address modifiable bleeding risk factors Risk should be assessed, score re-calculated, and documented at every patient contact Modifiable Potentially Modifiable Uncontrolled blood pressure Frailty INR control Management strategy (follow-up) Concomitant drug therapy Anemia Excessive alcohol intake Reduced platelet counts/function Avoidance of hazardous Renal impairment hobbies/occupations Avoidance of bridging therapy Appropriate choice and dose of OAC  Other Bleeding Considerations Falls Home evaluation to reduce risks, physical therapy, walking aids, neurological assessment 295 falls needed to outweigh the ischemic stroke reduction benefit Cognitive impairment Only withhold if no caregiver present to guarantee medication adherence Regular Medication Review Medic Alert Bracelet Intensive Counseling for OTC medication selection Man-Son-Hing M, et al. Arch Intern Med 1999;159:677  Oral Anticoagulants (OAC) for Stroke Prevention DOACs are recommended over VKA. Exceptions: severe rheumatic mitral stenosis, mechanical heart valve Patients on VKA with low time in therapeutic range (TTR, 60 ml/min Every Q 6months Monitoring CrCl 30-59 ml/min Every 3 months recommendations for CrCl  30 ml/min Every 1-2 months kidney, liver, and anemia Liver Child-Pugh A (mild) Every 6 months exist for patients on DOAC therapy. Minimal intervals Child-Pugh B (moderate) Every 3 months for monitoring change Child-Pugh C (severe) Every 1-2 months based on the degree of RBC (Hgb/Hct) HAS-BLED 0-2 Every 6 months dysfunction/risk. HAS-BLED  3 Every 3 months DOAC Contraindications Mechanical Heart Valves Moderate to Severe Mitral Stenosis Hepatic disease associated with Rivaroxaban contraindicated with Child-Pugh Class B coagulopathy and clinically relevant bleeding All other DOACs contraindicated with Child-Pugh Class C  DOAC Dosing Intentional consideration needs to be given to dosing of DOACs! ▪ Different dosing for AF vs. other indications ▪ Different dosage reduction recommendations between agents Agent Stroke Prevention in AF Treatment of DVT/PE Prevention of DVT/PE Apixaban 5 mg PO BID 10 mg PO BID x 7 days, then 5 mg PO BID 2.5 mg PO BID (Eliquis) Dabigatran 150 mg PO BID (UFH/LMWH x 5 – 10 days), then 150 mg PO 110 mg PO post-op, then 220 mg PO (Pradaxa) BID daily Edoxaban 60 mg PO daily (UFH/LMWH x 5 – 10 days), then 60 mg PO NOT INDICATED (Savaysa) daily Rivaroxaban 20 mg PO daily 15 mg PO BID x 21 days, then 20 mg PO daily 10 mg PO daily (Xarelto) Dosing information does not include full FDA-approved indication or adjustments for geriatrics, organ function and/or body weight. https://dailymed.nlh.nih.gov  VKA Therapy Warfarin (Coumadin®, Jantoven®) Reduced pro-coagulant activity of vitamin K dependent clotting factors II, VII, IX and X Reduced anticoagulant activity of protein C & S Two Isomers, R & S R – 45 hour half-life, 1A2 & 3A4 metabolism, but less extensive than S isomer S – 29 hour half-life, 3 x as potent as R isomer, 2C9 metabolism (major), 3A4 metabolism Warfarin is dosed once daily and doses are individually titrated to achieve a therapeutic INR Goal: 2.5, Range 2 – 3 Usual starting dose is 5 mg 5 – 7 days until “steady state” INR Not uncommon to check daily in hospitalized patients (dose scheduled for 6 PM) Therapeutic Conundrum: Warfarin “loading” at initiation of therapy Curriculum foreshadowing: We will talk about pharmacogenomic considerations with warfarin dosing in Pharmacotherapy V  INR Monitoring INR values outside of the therapeutic range place your patient at risk for harm!! Fuster V, et al. Circulation 2006;114:e257  Rosendaal method TTR Calculate total change in INR between two consecutive measurements Calculate percent of total change that would fall within the goal INR range ∆ INR tot = 2.6 – 1.8 = 0.8 ∆ INR in range = 2.6 – 2.0 = 0.6 % TTR = 0.6 / 0.8 = 75% TTR < 65% requires intervention. Optimal TTR is > 70%. TTR=time in therapeutic range Rosendaal FR, et al. Thromb Haemost 1993;69:236  SAMe-TT2R2 for TTR Prediction Letter Risk Factor Defined Points Score 0-2 Likely to achieve good TTR on VKA S Sex (female) 1 therapy A Age ( 2 Me Medical History (> 2 from: HTN, DM, CAD/MI, PAD, 1 Less likely to achieve good TTR and CHF, CVA, Pulmonary disease, hepatic or renal may require disease) Alternative therapy T Treatment (interacting drugs) 1 More frequent INR checks Intensive education/counseling T Tobacco use (within 2 years) 2 Referral to a specialty clinic R Race (non-Caucasian) 2 Maximum Score 8 Clinical conundrum… Does this score also identify those likely to struggle with DOAC adherence???  Bridging Therapy for Planned Procedures 1. Stop VKA prior to procedure, usually 5 days prior 2. Start full-dose LMWH, usually 3 days prior to procedure 3. Have procedure! Clinical Pearl: Not all procedures require 4. Resume VKA and LMWH post procedure interruption of AC. 5. Stop LMWH once INR therapeutic x 2 consecutive draws VKA=warfarin; LMWH=low molecular weight heparin; AC=anticoagulant  The BRIDGE Study Inclusion Criteria:  18 years 1884 Patients Confirmed, chronic AF undergoing elective procedure On warfarin at least 3 months INR in range Planned procedure requiring warfarin 950 No Bridge 934 Bridge interruption Therapy Therapy Exclusion Criteria: 0.4% TE 0.3% TE Mechanical heart valve 1.3% Major 3.2% Major CVA, TIA, or systemic embolism in bleeding bleeding previous 12 weeks Mean CHADS score was 2.4 & 2.3 Major bleeding in previous 6 weeks CrCl < 30 ml/min Bridging does not reduce the risk of PLT < 100 thromboembolism, but it does increase Cardiac, cranial or spinal surgery the risk of bleeding in some patients. planned Douketis JD, et al. N Engl J Med 2015;373:823  Do I Bridge? Does the patient have a mechanical heart valve? Yes No CHEST 2018 Low Risk = No Bridging We will discuss in Valvular Heart Disease lecture! High Risk = No recommendation DOAC = No Bridging AHA 2019 *High-risk patients: TIA or CVA in last 3 Use balance of risks of stroke and bleeding and duration of interruption to decide months, prior periop CVA, CHADSVASc  7 or CHADS2 score 5 or 6 CHEST 2022 Generally, no Bridging. Bridging is suggested for high-risk patients*. January CT, et al. Circulation. 2019;139:e125 Lip GY, et al. CHEST. 2018;154:1121 Douketis JD, et al. CHEST. 2023;162:e207  Valvular AF: Historical Perspective: RE-ALIGN Trial Aortic or Mitral Mechanical Valve Trial terminated prematurely due Replacement to excess thromboembolic and bleeding events in dabigatran group Surgery in Surgery in past 7 days last 3 months Dabigatran Warfarin Dabigatran Warfarin Eikelboom JW, et al. N Engl J Med 2013;369:1206 Valvular Heart Disease: Historical Perspective After the RE-ALIGN trial, DOAC phase III trials excluded patients with: Mechanical prosthetic heart valves Moderate to severe mitral stenosis (usually of rheumatic origin) Inconsistent definitions and unclear labeling have led to the development of a new categorization Evaluated Heartvalves, Rheumatic or Artificial (EHRA) EHRA Type 1 Refers to patients with VHD needing OAC therapy with VKA (DOAC contraindicated) Mechanical prosthetic heart valve Moderate – severe mitral stenosis EHRA Type 2 Refers to patients with VHD needing OAC with either VKA or DOAC All other native valve stenoses and insufficiencies, mitral valve repair patients, bioprosthetic valve replacements, and transaortic valve interventions (TAVI) Steffel J, et al. Eur Heart J 2018;39:1330 Ensuring Adherence to OAC Therapy Patient Education Family Involvement Predefined follow-up schedule Aligning dosing regimen with daily schedule Technology aids  Contraindication to OAC? Is this a short-term problem that can be addressed/mitigated or is this a long-term problem? Long-Term CI Short-Term CI Severe bleeding due to a Bleeding in a system that is treatable nonreversible cause Bleeding related to isolated trauma Spontaneous CNS bleed due to a Bleeding related to procedural nonreversible cause complication Serious bleeding related to recurrent falls when cause of falls is not felt to be treatable For those with long-term contraindications to OAC or high risk of both stroke and bleeding, left atrial appendage occlusion (LAAO) can be considered. CI= contraindication  LAA Closure Devices WATCHMAN® → WATCHMAN FLX® Device 2019 ACC/AHA Focused Update: “Percutaneous LAA occlusion may be considered in patients with AF at increased risk of stroke who have contraindications to long-term anticoagulation.” COR IIb, LOE B-NR Saw J, et al. JACC Cardiovasc Interv 2019;12:1067 Aminian A, et al. JACC Cardiovasc Interv 2019;12:1003 Reddy VY, et al. Circulation 2013;127:720. CMS Requirement: CHADSVASc > 3 Reddy VY, et al. J Am Coll Cardiol 2017;70:2964 Kabra R, et al. JAMA Network Open. 2019;2(10):e1914268.  WATCHMAN FLX® Post-operative Plan DOAC (Apixaban or Rivaroxaban) + Low dose Aspirin x 45 days post-procedure DAPT (ASA 75-81mg) x 6 months ASA 75-81 mg for life (or until LAA is permanently closed) PINNACLE FLX trial. Kar S, et al. Circulation 2021;143:1754  Other LAA Closure/Exclusion Options Block LAA Opening: Amplatzer Amulet Wavecrest Clamp off LAA: Lariat Atriclip Sierra Lakkireddy D, et al. Circulation. 2021. doi:10.1161/CIRCULATIONAHA.121.057063 Image from: https://citoday.com/articles/2018-may-june/the-spectrum-of-devices-for-percutaneous-left-atrial-appendage-occlusion. Accessed 10/20/22  Chronic AF Management Lifestyle and RF Modification (LRFM) for all patients Obesity Physical inactivity Unhealthy alcohol consumption Smoking Diabetes Hypertension Stroke Risk must be assessed in all patients; treat when indicated CHA2DS2-VASc Symptom management must be addressed in all patients AF Burden Rate control Rhythm control Joglar JA, et al. Circulation. 2023;149:e1-e156  Rate vs. Rhythm Control Initial approach was to choose between the two strategies. Superiority/non-inferiority assessed in MANY clinical trials with no definitive evidence for improved outcomes, QOL, or mortality with one approach over another. Maybe also Image from https://www.heart.org/-/media/data-import/downloadables/ Accessed 11/1/19  Early Rhythm Control Recent investigations have focused on impact of early rate control selection. Inclusion Criteria: Intervention: Rhythm control n=2789 Early AF (dx  1 yr) included antiarrhythmic drugs, > 75 years ablation, and cardioversion Additional criteria initiated early after Rhythm Usual Care ensuring CHADSVASc >2 randomization. All patients received anticoagulation and rate control. Primary Outcome: Composite of death, stroke, or serious AE from rhythm control therapy. Kirchhof P, et al. N Engl J Med 2020;383:1305  Early Rhythm Control Trial stopped early in favor of early rhythm control: More first primary-events in usual care (5.0 per 100 person-years) vs. early rhythm control (3.9 per 100 person-years). No difference in mortality, LV function, cognitive function, symptom scores, or quality-of-life scores. Kirchhof P, et al. N Engl J Med 2020;383:1305  Selecting Rate Control Goals: RACE II Trial Primary Composite Outcome: n=614 Death from CV causes, hospitalization for HF, stroke, systemic bleeding, and life-threatening arrhythmic events Follow-Up Duration: Min 2 yrs, Max 3 yrs Lenient Control Strict Control Exclusion Criteria: HR < 110 bpm HR < 80 bpm Paroxysmal AF Outcome Rate 12.9% Outcome Rate 14.9% Known CI to either HR goal or negative chronotropic drugs Inclusion Criteria: Unstable HF Permanent AF  12 months HF admission in previous 3 months Age  80 years CVA Mean resting HR > 80 bpm PPM, ICD or resynchronication therapy Current use of OAC if indicated (ASA if not) SSS or AV conduction disorder Untreated hypothyroidism or < 3 months euthyroidism 65% of HF patients were NYHA Class I. Inability to walk or bike Van Gelder IC, et al. Am Heart J. 2006;152:420 Van Gelder IC, et al. N Engl J Med 2010;362:1363 SSS=sick sinus syndrome; PPM=permanent pacemaker; ICD=implanted cardiac defibrillator  Rate Control: RACE-II Trial After 3 years, there was no statistically significant difference between groups. Considerations/Limitations: Lenient ▪ Noninferiority design ▪ 90% confidence interval for composite endpoint Control ▪ The majority of patients enrolled had preserved LV function. ▪ Resting HR average between groups only differed by 10 bpm. ▪ Only 67% of patients in strict control achieved rate control target. Resting HR < 110 Guideline Recommendations: VS. In patients with AF without HF, HR target should be guided by symptoms, aiming for resting HR < 100 to 110 bpm. Strict Control ORBIT-AF showed that increasing heart rate was associated with higher all-cause mortality and incident HF. Resting HR < 80 Populations that would benefit from a low HR goal include those with rate-related cardiac dysfunction, ICDs, cardiac resynchronization Van Gelder IC, et al. N Engl J Med 2010;362:1363 therapy, and tachy-brady syndrome. January CT, et al. Circulation 2014;130:e199  Beta blockers Especially useful in the presence of high adrenergic tone, can be safely used in combination with digoxin Drugs for Non-DHP CCB Should be avoided in HFrEF due to negative inotropic Long-Term effects Rate Control Digoxin Effective for control of resting HR but questionable during exercise; use caution in monitoring for drug interactions and adverse effects Renally eliminated Increased mortality at concentrations > 1.2 ng/mL  AV node ablation ▪ Selective catheter-mediated destruction of Non-pharmacological the AV node or Bundle of His to achieve complete heart block Rate Control ▪ Palliative, but irreversible ▪ Cardiac pacemaker placement afterwards  Patient-Tailored Therapy Rate control may be a reasonable How will strategy in elderly patients who permanent have an acceptable level of AF/symptoms symptoms. affect the patient? How successful is rhythm Rhythm control may be Is the drug control reasonable to ameliorate tolerable? symptoms, but should NOT result expected to be? in cessation of antithrombotic therapy, rate control therapy, or therapy of underlying heart disease.  ▪ In patients diagnosed with AF for < 1 year, rhythm control can reduce hospitalizations, stroke, and mortality. Rhythm Control ▪ Rhythm control can reduce AF progression and may reduce development of dementia or worsening cardiac structural abnormalities ▪ Strict control of risk factors and avoidance of triggers should be included as part of a rhythm control strategy. Joglar JA, et al. Circulation. 2023;149:e1-e156  Long-term Rhythm Control Therapeutic Options: Considerations when choosing an agent: Amiodarone (Cordarone®, Pacerone®) Dofetilide (Tikosyn®) Heart Disease Other Factors Dronedarone (Multaq®) Structural heart disease Allergies CAD Hepatic function Flecainide (Tambocor®) Prior MI Renal function HFrEF Cardiovascular profile (BP, Propafenone (Rhythmol®) Severe LV hypertrophy (LV HR) wall thickness  1.5 cm) Adverse effect profile Sotalol (Betapace AF®) Pharmacological options generally listed in alphabetical order. Therapeutic preference denoted by “first-line” or “second-line”.  AAR Selection Place in Heart Disease Absent Heart Disease Present Drug Requirements for Use Therapy Dofetilide ▪ No QT prolongation First-line Dofetilide ¶ Amiodarone ¥ ▪ No uncorrected hypokalemia Dronedarone ¥ Dofetilide ¶ ▪ No uncorrected hypomagnesemia Flecainide ¶¥ ▪ Proper renal dose selection Propafenone ¥ Sotalol ▪ No bradycardia Second-line Amiodarone ¥ Sotalol ¶ ▪ No QT prolongation ▪ No uncorrected hypokalemia Third-line Sotalol ¶ ▪ No uncorrected hypomagnesemia ▪ Proper renal dose selection ¶ Renal dysfunction considerations ¥ Hepatic dysfunction considerations Joglar JA, et al. Circulation. 2023;149:e1-e156 Antiarrhythmic Drug-Drug Interactions Drug Drug-Drug Interactions Dofetilide ▪ Renal cation transport system inhibitors (cimetidine, dolutegravir, ketoconazole, megestrol, prochlorperazine, trimethoprim, verapamil) ▪ Hydrochlorothiazide Amiodarone ▪ 2C9 ▪ 2D6 ▪ 3A4 ▪ P-gp Dronedarone ▪ 3A4 ▪ 2D6 ▪ P-gp Flecainide ▪ 2D6 Propafenone ▪ 2D6  Non-Pharmacological Rhythm Control Catheter ablation gaining in popularity due to favorable outcomes in clinical trials 2020 ESC Atrial Fibrillation Guidelines now recommend catheter ablation or Pulmonary Vein Isolation (PVI) as first-line rhythm control therapy in symptomatic paroxysmal (IIa) or persistent AF (IIb) Clinical Pearl: Watch for trials with highly selective patient populations whose outcomes are broadly applied to the general population! Peri-Catheter Ablation Stroke Risk Management Therapeutic OAC for at least 3 weeks prior to ablation or use TEE to exclude LA thrombus prior to ablation Performance of procedure without OAC interruption is recommended Hindricks G, et al. Eur Heart J 2020; doi:10.1093/eurheartj/ehaa612