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Rate Control in Atrial Fibrillation: Critically Important, Underappreciated

This article discusses the importance and underappreciation of rate control in the treatment of atrial fibrillation (AF), including goal setting, monitoring, and the consequences of uncontrolled rapid rates. It also explores the association between heart rate in AF and adverse outcomes such as mortality and cardiovascular hospitalization.

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Rate Control in Atrial Fibrillation: Critically Important, Underappreciated

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  1. Rate Control in Atrial Fibrillation:Critically Important, Underappreciated Renee M. Sullivan, MD Brian Olshansky, MD Division of Cardiology University of Iowa

  2. Treatment of AF is Not New “Of all the stomachic remedies, the one whose effects have appeared most constant and the most prompt in many cases, is quinine mixed with a little rhubarb. Long and rebellious palpitations have ceded to this febrifuge seconded with a light purgative.” Jean-Baptiste de Senac Paris, 1749

  3. 75-yo Female in Clinic Recent-Onset Atrial Fibrillation (AF) • History - fatigue, dyspnea for 2 weeks • Past history - hypertension • Physical: pulse -110, BP-115/70 • Lungs – clear • Heart – irregular rate, no murmur or gallop • Extremities - no edema • EKG – AF rate 130 new since one month ago • Plan – control rate, anticoagulate, cardiovert How do you control the rate?

  4. AF - Uncontrolled Rate A Common Problem

  5. Rate Control in AF What are the issues? • Does rate control matter? Why? When? • What is the goal for rate control? • What is the endpoint for rate control? • How is it best to control the rate? • How is rate control monitored? Optimal management approach is unclear Best rate is undefined

  6. Consequences of Rapid Rate • Symptoms – dyspnea, fatigue, palpitations • Impaired quality-of-life • Poor exercise tolerance • Hemodynamic compromise and heart failure • Cardiomyopathy • Ischemia • Risk of death

  7. Goals of Rate Control What goal is most important? • Control rate (rest and/or exercise) • Alleviate symptoms • Improve functionality and quality-of-life • Optimize hemodynamics • Reduce risk of cardiomyopathy • Decrease hospitalizations, frequent care • Prevent complications • Reduce drug switches • Improve survival Therapies may help one but not another

  8. First Detected Paroxysmal(Self-terminating) Persistent(Not self-terminating) Permanent Rate Control ApproachVaries by AF Classification ACC/AHA/ESC Guidelines Fuster V. Circulation 2006;114:700-752

  9. Heart Rate and Mortality 25 Men Also true in AF?? 20 Age: 40-80 years Follow-up: 12 years N=4756 15 Women All-Cause Mortality (%) 10 5 0 <60 70-80 80-90 >90 60-70 Resting Heart Rate (bpm) Mensink GB. Eur Heart J 1997;18:1404-1410

  10. Heart Rate and Mortality Is Faster Rate in AF also Associated with Increased Mortality? Healthy Men Coronary Artery Disease All-cause Non-sudden death from MI Sudden death from MI 24,913 patients Followed 14.7 years 5,713 patients Followed 23 years Relative Risk Hazard Ratio Heart rate (bpm) Jouven X. N Engl J Med 2005;352:1951– 8 Diaz A. Eur Heart J 2005;26:967–74 Fox K. J Am Coll Cardiol 2007;50:823-30 Heart rate (bpm)

  11. Heart Rate - Adverse Outcomes Results from BEAUTIFUL – Patients with CAD CV Death Admission for heart failure Admission for MI Coronary revascularization Also true for patients with AF?? Fox K. Lancet 2008;372:817-821

  12. Rapid Rate in AF–A Risk for Death? Many parameters of importance but does rapid heart rate in AF increase mortality? Kowey P. J Am Coll Cardiol 2004;43:1209-10

  13. Heart Rate in AF and Outcomes Time to CV Hospitalization or Death Time to Death No difference between those achieving or not achieving the AFFIRM heart rate goals Cooper HA. Am J Cardiol 2004;93:1247-53

  14. 77 patients with AF at baseline in PRIME II Rate “low” (<80) or “high”(>80) NYHA Class III or IV Includes only patients in neurohormonal substudy Heart Rate in AF and Survival Patients with chronic heart failure Rienstra M. Int J Cardiol 2006;109:95-100

  15. Why Control Rate? To reduce symptoms Symptoms vary by patient age and AF type Levy S. Circulation 1999;99:3028

  16. Rapid Rates in AF Physiologic Consequences • Diastolic and systolic dysfunction-> pulmonary congestion, heart failure • Hypotension, poor cardiac output -> reduced end-organ perfusion -> ischemia, renal dysfunction • Autonomic adjustments -> increased afterload and contractility

  17. Autonomic Response to AF * p<0.05 MSNA – muscle sympathetic nerve activity Grassi G. Acta Physiol Scand 2003;177:399-404

  18. CVP and Sympathetic Activity in AF and Sinus * p<0.05 Grassi G. Acta Physiol Scand 2003;177:399-404

  19. Tachycardia-Mediated Cardiomyopathy • AF is most common cause • Due to fast and/or irregular rates • 24 patients with NYHA Class III or IV heart failure, LVEF = 0.26 ± 0.09 • With rate or rhythm control, LVEF improved to 0.51 ± 0.05 • Despite improvement - 5 had rapid decline in EF with recurrent tachycardia, 3 had sudden death Nerheim P. Circulation 2004;110:247-252

  20. Irregularity of Rate • Irregular ventricular rhythm may worsen • Symptoms • Hemodynamics • Ejection fraction • AV nodal ablation with pacemaker implantation can regularize rhythm and control rate Narasimhan C. Cardiovasc Electrophysiol 1998;9:S146-50

  21. AF – Heart Rate Variation

  22. Irregular Rhythm Impairs Cardiac Output Daoud E. Am J Cardiol 1996;78:1433-1436

  23. Pharmacologic Options For Rate Control • Beta-adrenergic blockers • Ca2+ channel antagonists • Digoxin • Amiodarone • Dronedarone • Drug combinations • Antiarrhythmics (sotalol, propafenone) • Sinus rhythm may be best way to control rate

  24. Acute Rate Control • Goal - control rate within minutes to hours • If unstable, electrical cardioversion • Approach depends on AF duration, LV function, clinical presentation • Medications - diltiazem, verapamil, metoprolol, esmolol, amiodarone, digoxin (IV or oral) • AV junctional ablation (rare)

  25. Acute Rate Control Diltiazem IV may have the edge Siu C-W. Crit Care Med 2009; 37:2174 –2179

  26. Longstanding Rate Control A patient-centered approach • Begin with rate control at rest, in AF and in sinus • Consider drug T1/2 and metabolism and comorbidities, when choosing a drug • Long-acting drugs will minimize dosing • Some drugs have circadian absorption • Upward titration and addition of drugs yields the best rate control results

  27. Rate Control of AF Digoxin 0.25 mg Diltiazem 240 mg Atenolol 50 mg Dig 0.25 mg + diltiazem 240 mg Dig 0.25 mg + atenolol 50 mg P vsdigoxin 180 Mean VR 125  28 Mean VR 105  15p<0.02 160 Mean VR 102  29 p<0.03 Mean VR 93  26 p<0.005 140 Mean VR 82  9 p<0.0001 Ventricular Rate, bpm 120 100 80 N= 12 60 10 12 2 4 8 6 Time, min Farshi R. J Am Coll Cardiol 1999;33:304-310

  28. Titration of Medications • Medication dosage – review at every visit • If rate is slow, medication may need reduction • If rate is too fast, medication may need to be increased or added • Evaluate rate with rest and activity • Holter monitor • Event monitor • 6-minute walk

  29. β-Blockers • Can convert recent onset AF and decrease recurrence (especially postoperatively) • Decreases resting rate but blunts rate with exercise (may not be better than other options) • Can control rate but increase symptoms • May treat comorbidities • May cause hypotension, bradycardia • Consider β-blocker with ISA if tachy-brady syndrome

  30. Rate Control with b-Blockers Alone or in combination D - Digoxin CCB - Ca2+ Channel Blocker BB - b-Blocker Hilliard AA. Am J Cardiol 2008;102:704-708

  31. Ca2+ Channel Antagonists • Rate control with rest and exercise • First-line for acute management and patients with no heart disease • Negative inotrope and may cause hypotension and bradycardia • Can increase risk of death in select populations • Caution - heart failure, hypotension, 10 AV block, bradycardia, WPW syndrome

  32. Rate Control with Ca2+ Channel Antagonists Mean ventricular rate on 24 hour Holter monitor Ventricular rate at rest, 50 and 80% of maximum, and maximal workloads Lundstrom T. J Am Coll Cardiol 1990;16:86-90

  33. Digoxin Vagotonic inhibition of AV nodal conduction • More effective in the elderly • Good combined with other AV nodal blockers • Improves contractility • Does not convert AF (may do the opposite) • Less effective during exercise (maybe) • Narrow therapeutic range • Caution with renal dysfunction, hypokalemia

  34. 100 80 60 40 20 0 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 Digoxin for Rate Control 160 Digoxin ns P=0.0001 P<0.0001 P<0.0001 Placebo 140 P<0.0001 120 100 P=NS Conversion Rate, % Heart Rate (bpm) 80 60 Placebo 40 Digoxin 20 P=0.003 0 Hours Hours The DAAF Trial Group. Eur Heart J. 1997;18:649-654

  35. AFFIRM Is Digoxin a Risk? Time-Dependent Covariates Associated With Survival Covariate P-Value Hazard Ratio 99% CI Sinus rhythm <0.0001 0.53 0.39-0.72 Warfarin use <0.0001 0.50 0.37-0.69 Digoxin use 0.0007 1.42 1.09-1.86 AAD* use 0.0005 1.49 1.11-2.01 HR <1.00: decreased risk of death. HR >1.00: increased risk of death. *Antiarrhythmic drug The AFFIRM Investigators. Circulation 2004;109:1509-1513

  36. Amiodarone Can help control rate as well as rhythm • Used IV acutely as second-line drug • Less hypotension than other drugs • Used in combination long term • Long half-life • Multiple toxicities

  37. Rate Control with Amiodarone Clemo HF. Am J Cardiol 1998; 81:594-598

  38. Dronedarone Can help control rate as well as rhythm • Slows rate effectively in AF • Shorter T1/2 than amiodarone and less toxicity • Reduces cardiovascular death and hospitalization1 • Higher risk of death with acute heart failure2 1 Hohnloser SH. N Engl J Med 2009;360:668-78 2 Kober L. N Engl J Med 2008;358:2678-87

  39. ERATO Trial Dronedarone Controls Rate in AF Rate control with drug combinations Rate control at rest Rate control with maximal exercise Rate control over time Davy J-M. Am Heart J 2008;156:527

  40. Drug Combinations • Potentially beneficial • Beta-blocker – digoxin • Beta-blocker – amiodarone • Potentially adverse • Dofetilide – verapamil • Verapamil – digoxin • Digoxin – amiodarone • Beta-blocker- amiodarone

  41. AFFIRM Rate Control • Randomized 2027 patients (paroxysmal/persistent) • Rate control defined as • Rate < 80 bpm at rest or < 110 bpm on 6-min walk • Mean rate < 100 bpm on 24-hour Holter with no rate >100% max predicted age-adjusted exercise rate • Any rate control drug could be used • AV junctional ablation in only a small minority • Drug switches helped rate control Olshansky B. J Am Coll Cardiol 2004;43:1201-8

  42. Drug Selection in AFFIRM Significant Variables • Gender • History of coronary disease • Congestive heart failure • Hypertension • Pulmonary disease • First episode of AF • Baseline heart rate Olshansky B. J Am Coll Cardiol 2004;43:1201-8

  43. AFFIRM - Rate Control • Overall rate control with first drug therapy • 70% with beta blockers (±digoxin) • 54% with calcium channel blockers (± digoxin) • 58% with digoxin alone • Over time, patients on Ca2+ channel blockers or digoxin were switched to other drug (p< 0.0001) p = 0.08 Olshansky B. J Am Coll Cardiol 2004;43:1201-8

  44. AFFIRM - Rate Control Olshansky B. J Am Coll Cardiol 2004;43:1201-8

  45. AFFIRM - Drug Crossovers Olshansky B. J Am Coll Cardiol 2004;43:1201-8

  46. AFFIRM – Reason to Stop Rate Controlling Drugs Olshansky B. J Am Coll Cardiol 2004;43:1201-8

  47. RACE Rate Control • Randomized 256 patients (persistent AF) • Rate control - resting rate < 100 bpm • Issues: • Rate control was lenient • No measure of heart rate with exercise • No mention of drug switches Rienstra M. Eur Heart J 2007;28:741-751

  48. Heart Rates AFFIRM vs RACE Not necessarily the same population or the same way to measure Van Gelder I. Europace 2006;8:935-42

  49. Does Rate Predict Outcome? AFFIRM vs RACE - “event-free survival” What endpoint matters? Van Gelder I. Europace 2006;8:935-42

  50. Heart Rate Considerations • More attention paid to rate in trials than practice • Rate control in AF may lead to issues in sinus • Tachy-brady syndrome • Profound bradycardia leading to pacemaker • What is the appropriate endpoint? • Heart rate? Symptoms? Hemodynamics? Hospitalizations? Death?

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