1
Oral Anticoagulant Use Around the Time of Atrial Fibrillation Ablation: A Review of the Current Evidence of Individual Oral Anticoagulant Use for Periprocedural Atrial Fibrillation Ablation Thromboembolic Prophylaxis ALEX B. GARTON, M.D.,∗ JOHN DUDZINSKI, D.O.,† and PETER R. KOWEY, M.D.∗ ,†,‡ From the ∗ Division of Cardiovascular Disease; †Department of Internal Medicine, Lankenau Medical Center, Wynnewood, Pennsylvania, USA; and ‡Jefferson Medical College, Philadelphia, Pennsylvania, USA
Oral Anticoagulant Use Around the Time of Atrial Fibrillation Ablation. Atrial fibrillation is the most common arrhythmia and ablation is becoming more prevalent as a treatment option. Appropriate treatment of atrial fibrillation mandates thromboembolic prophylaxis, and atrial fibrillation ablation periprocedural management of oral anticoagulation is paramount because of the unique susceptibility for thromboembolism that exists for a patient undergoing ablation. Uninterrupted warfarin therapy is the current standard approach for periprocedural atrial fibrillation anticoagulation. Novel oral anticoagulants, including direct thrombin and factor Xa inhibitors, are being used more frequently for thromboembolic prophylaxis in atrial fibrillation patients, but the best strategy for using novel oral anticoagulants in periprocedural anticoagulation is unknown. Optimal periprocedural anticoagulation management strategies with oral anticoagulants, limitations of using novel oral anticoagulants, and future directions in this field are discussed. (J Cardiovasc Electrophysiol, Vol. pp. 1-8) atrial fibrillation, atrial fibrillation ablation, novel oral anticoagulants, thromboembolic prophylaxis Introduction Atrial fibrillation (AF) is one of the most common cardiac conditions, accounting for a growing number of hospitalizations and health care expenditures. In 2005, an estimated 3 million people in the United States had AF, and that number will increase to 5.6 million by the year 2050.1 AF is a particular challenge to physicians because of an associated risk of thromboembolism. Ischemic stroke occurs in patients with nonvalvular AF at an average rate of 5% per year, which is 2–7 times higher than people without AF.2 Accordingly, treatment for AF includes reducing the risk of stroke, in addition to relieving symptoms. Radiofrequency catheter ablation has gained favor as a nonpharmacologic management option for AF since Ha¨ıssaguerre et al. showed that AF frequently originates from sleeves of atrial tissue invaginated in pulmonary veins. Pulmonary vein isolation, augmented by direct atrial ablation, has since proliferated.3 From 1990 to 2005, the number of AF ablations increased by 15% per year.4 Estimates are that between 20,000 and 50,000 AF ablations are performed yearly in the United States. The efficacy of AF ablation varies widely across series and is variable depending on definitions of success. According Dr. Kowey is a consultant/speaker for Boehringer-Ingelheim, Johnson & Johnson, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. Other authors: No disclosures. Address for correspondence: Alex B. Garton, M.D., Lankenau Medical Center, 100 East Lancaster Avenue, Medical Office Building East, Suite 558, Wynnewood, PA 19096, USA. Fax: 484-476-1658; E-mail: [email protected] Manuscript received 10 July 2014; Revised manuscript received 14 August 2014; Accepted for publication 27 August 2014. doi: 10.1111/jce.12546
to a survey collected from 182 centers performing AF ablation between 2003 and 2006, close to 70% of AF ablation patients were asymptomatic and no longer required antiarrhythmic medication. Another 10% of the patients became asymptomatic in the presence of previously used antiarrhythmic medication. Success rates have been higher with paroxysmal AF compared to persistent or longstanding AF.5 These success rates may be inflated due to the inherent biases of surveys. The Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial may provide a more precise success rate. The study is comparing drug therapy with AF ablation to determine which approach is better and under which circumstances is one option better than the other. The trial is currently enrolling patients at 134 sites to a target enrollment of 2,200 patients.6 Risk of thromboembolism during interruption of anticoagulation and as a result of damaged endocardium is a particular concern with AF ablation. A 2010 worldwide survey of centers performing AF ablation between 2003 and 2006 revealed that stroke or transient ischemic attack is a complication in up to 1% of all AF ablation procedures.5 The risk of a cerebrovascular event may be increased in patients over the age of 75 following the procedure, regardless of their rhythm, anticoagulation status, or CHADS2 score.7 Bleeding and vascular complications, the other major adverse outcomes of AF ablation, are the consequences of the prophylaxis for thromboembolism and the mechanics of the procedure itself. Life-threatening bleeding, like tamponade and hemothorax, carry a risk of approximately 1.3% with AF ablation.5 The novel oral anticoagulants (NOACs) present an advance in the care of AF patients. Three NOACs are currently approved for use, dabigatran, rivaroxaban, and apixaban, and one is under review by the FDA, edoxaban (Table 1). Progressively more AF patients are receiving the NOACs to
2
Journal of Cardiovascular Electrophysiology
Vol. No.
TABLE 1 Novel Oral Anticoagulants Drug Mechanism of action Major trial Trial results when compared with warfarin
Half-life Time to Cmax Nonbleeding adverse effect Dose adjustment
Drug interactions
Dabigatran Direct thrombin inhibitor RE-LY 150 mg bid reduced stroke with similar major hemorrhage rate. 110 mg bid had noninferior stroke rate with lower major hemorrhages 12–17 hours 1 hour Dyspepsia
Rivaroxaban
Apixaban
Edoxaban
Factor Xa inhibitor
Factor Xa inhibitor
Factor Xa inhibitor
ROCKET-HF Noninferior for stroke with similar overall bleeding but less intracranial and fatal bleeding
ARISTOTLE Reduced stroke, caused less bleeding, and had lower mortality
ENGAGE AF-TIMI 48 Noninferior for stroke with less bleeding and cardiovascular death
5–13 hours 2–4 hours None
12 hours 3–4 hours None
8–11 hours 1 hour None
75 mg bid for CrCl 15–30 mL/minute
15 mg daily for CrCl 15–50 mL/minute
30 mg daily for CrCl 30–50 mL/minute, wt ࣘ60kg, or concomitant verapamil, quinidine, or dronedarone use
Avoid P-gp inducers. Reduce dose to 75 mg bid if CrCl 30–50 and taking dronedarone or ketoconazole
Avoid combined P-gp and strong CYP3A4 inhibitors or inducers
2.5 mg bid for those with 2 of following: ࣙ80 years old, wt ࣘ60 kg, SCr ࣙ1.5 mg/dL Avoid combined P-gp and strong CYP3A4 inhibitors or inducers
Avoid P-gp inducers
Dabigatran, rivaroxaban, and apixaban: bid, twice daily dosing; Cmax = maximum concentration after 1 dose; CrCl = creatinine clearance; wt = weight; SCr = serum creatinine; P-gp = P-glycoprotein.35-39
prevent thromboembolism associated with AF. Results from the PINNACLE-AF registry revealed that during the fourth quarter of 2012, 14.9% of patients with nonvalvular AF and a CHADS2 score of ࣙ2 were treated with an NOAC, compared to 44.3% being treated with warfarin.8 The increased use of both NOACs and AF ablation in the treatment of patients with AF mandate a safe and effective periprocedural protocol for using these relatively new medicines. New protocols for the use of NOACs for AF ablation periprocedural anticoagulation are being explored to minimize adverse outcomes with AF ablation. This article will discuss various strategies that have been explored, and will attempt to define the current state of knowledge. Current Guidelines The recently released 2014 AHA/ACC/HRS guideline for the management of patients with AF has produced new recommendations with regard to AF ablation.2 One section of the guideline specifically addressed periprocedural anticoagulation to reduce the risk of thromboembolism. It mostly referred to the 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of AF for guidance. That statement did make several recommendations with regard to NOAC therapy including initiation of a direct thrombin or factor Xa inhibitor after ablation as an alternative postprocedure anticoagulation strategy, and systemic anticoagulation with a direct thrombin or factor Xa inhibitor may be used for at least 2 months following an AF ablation procedure.9 The recent guideline also addressed anticoagulation in the setting of cardioversion, a category into which AF ablation sometimes falls since cardioversion frequently occurs during the procedure. Patients in AF for 48 hours or longer, and those
with an unknown duration, should receive anticoagulation for at least 3 weeks prior to, and 4 weeks after, cardioversion. This is a Class I recommendation with warfarin, level of evidence B, and a Class IIb recommendation, level of evidence C, for an NOAC. A transesophageal echocardiogram demonstrating no identifiable thrombus in the left atrium or left atrial appendage can obviate the need for 3 weeks of anticoagulation prior to cardioversion. The European Heart Rhythm Association also published an executive summary practice guide on the use of NOACs in patients with nonvalvular AF in April 2013. This guide specifically addresses use of NOACs surrounding elective surgical procedures (Table 2) but fails to give specific guidelines surrounding AF ablation.10 AF ablation: Periprocedural Anticoagulation Management Strategies Warfarin Bridging a patient undergoing AF ablation with unfractionated heparin or low molecular weight heparin periprocedurally was the initial management option of choice. However, recent studies indicate that uninterrupted anticoagulation with warfarin is preferred. In 2007, an observational study found that continuation of warfarin through pulmonary vein ablation without administration of enoxaparin was safe and effective in preventing thromboembolism.11 Later, a nonrandomized study of just over 3,000 patients found that uninterrupted anticoagulation with warfarin, with an INR ࣙ 1.8, was not associated with increased bleeding.12 Then, a multicenter study that included nearly 6,500 patients found that continuation of therapeutic warfarin during radiofrequency ablation, with a goal INR ࣙ 2, reduced the risk of periprocedural stroke/TIA without increasing the risk of hemorrhagic events.13 Other retrospective studies have found the same,
Garton et al.
Oral Anticoagulant Use Around the Time of Atrial Fibrillation Ablation
3
TABLE 2 Last Intake of Drug Before Elective Surgical Intervention Dabigatran
Rivaroxaban
CrCl
Low risk (h)
High risk
ࣙ80 mL/minute 50–80 mL/minute 30–59 mL/minute 15–30 mL/minute
Oral Anticoagulant Use Around the Time of Atrial Fibrillation Ablation: A Review of the Current Evidence of Individual Oral Anticoagulant Use for Periprocedural Atrial Fibrillation Ablation Thromboembolic Prophylaxis ALEX B. GARTON, M.D.,∗ JOHN DUDZINSKI, D.O.,† and PETER R. KOWEY, M.D.∗ ,†,‡ From the ∗ Division of Cardiovascular Disease; †Department of Internal Medicine, Lankenau Medical Center, Wynnewood, Pennsylvania, USA; and ‡Jefferson Medical College, Philadelphia, Pennsylvania, USA
Oral Anticoagulant Use Around the Time of Atrial Fibrillation Ablation. Atrial fibrillation is the most common arrhythmia and ablation is becoming more prevalent as a treatment option. Appropriate treatment of atrial fibrillation mandates thromboembolic prophylaxis, and atrial fibrillation ablation periprocedural management of oral anticoagulation is paramount because of the unique susceptibility for thromboembolism that exists for a patient undergoing ablation. Uninterrupted warfarin therapy is the current standard approach for periprocedural atrial fibrillation anticoagulation. Novel oral anticoagulants, including direct thrombin and factor Xa inhibitors, are being used more frequently for thromboembolic prophylaxis in atrial fibrillation patients, but the best strategy for using novel oral anticoagulants in periprocedural anticoagulation is unknown. Optimal periprocedural anticoagulation management strategies with oral anticoagulants, limitations of using novel oral anticoagulants, and future directions in this field are discussed. (J Cardiovasc Electrophysiol, Vol. pp. 1-8) atrial fibrillation, atrial fibrillation ablation, novel oral anticoagulants, thromboembolic prophylaxis Introduction Atrial fibrillation (AF) is one of the most common cardiac conditions, accounting for a growing number of hospitalizations and health care expenditures. In 2005, an estimated 3 million people in the United States had AF, and that number will increase to 5.6 million by the year 2050.1 AF is a particular challenge to physicians because of an associated risk of thromboembolism. Ischemic stroke occurs in patients with nonvalvular AF at an average rate of 5% per year, which is 2–7 times higher than people without AF.2 Accordingly, treatment for AF includes reducing the risk of stroke, in addition to relieving symptoms. Radiofrequency catheter ablation has gained favor as a nonpharmacologic management option for AF since Ha¨ıssaguerre et al. showed that AF frequently originates from sleeves of atrial tissue invaginated in pulmonary veins. Pulmonary vein isolation, augmented by direct atrial ablation, has since proliferated.3 From 1990 to 2005, the number of AF ablations increased by 15% per year.4 Estimates are that between 20,000 and 50,000 AF ablations are performed yearly in the United States. The efficacy of AF ablation varies widely across series and is variable depending on definitions of success. According Dr. Kowey is a consultant/speaker for Boehringer-Ingelheim, Johnson & Johnson, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. Other authors: No disclosures. Address for correspondence: Alex B. Garton, M.D., Lankenau Medical Center, 100 East Lancaster Avenue, Medical Office Building East, Suite 558, Wynnewood, PA 19096, USA. Fax: 484-476-1658; E-mail: [email protected] Manuscript received 10 July 2014; Revised manuscript received 14 August 2014; Accepted for publication 27 August 2014. doi: 10.1111/jce.12546
to a survey collected from 182 centers performing AF ablation between 2003 and 2006, close to 70% of AF ablation patients were asymptomatic and no longer required antiarrhythmic medication. Another 10% of the patients became asymptomatic in the presence of previously used antiarrhythmic medication. Success rates have been higher with paroxysmal AF compared to persistent or longstanding AF.5 These success rates may be inflated due to the inherent biases of surveys. The Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial may provide a more precise success rate. The study is comparing drug therapy with AF ablation to determine which approach is better and under which circumstances is one option better than the other. The trial is currently enrolling patients at 134 sites to a target enrollment of 2,200 patients.6 Risk of thromboembolism during interruption of anticoagulation and as a result of damaged endocardium is a particular concern with AF ablation. A 2010 worldwide survey of centers performing AF ablation between 2003 and 2006 revealed that stroke or transient ischemic attack is a complication in up to 1% of all AF ablation procedures.5 The risk of a cerebrovascular event may be increased in patients over the age of 75 following the procedure, regardless of their rhythm, anticoagulation status, or CHADS2 score.7 Bleeding and vascular complications, the other major adverse outcomes of AF ablation, are the consequences of the prophylaxis for thromboembolism and the mechanics of the procedure itself. Life-threatening bleeding, like tamponade and hemothorax, carry a risk of approximately 1.3% with AF ablation.5 The novel oral anticoagulants (NOACs) present an advance in the care of AF patients. Three NOACs are currently approved for use, dabigatran, rivaroxaban, and apixaban, and one is under review by the FDA, edoxaban (Table 1). Progressively more AF patients are receiving the NOACs to
2
Journal of Cardiovascular Electrophysiology
Vol. No.
TABLE 1 Novel Oral Anticoagulants Drug Mechanism of action Major trial Trial results when compared with warfarin
Half-life Time to Cmax Nonbleeding adverse effect Dose adjustment
Drug interactions
Dabigatran Direct thrombin inhibitor RE-LY 150 mg bid reduced stroke with similar major hemorrhage rate. 110 mg bid had noninferior stroke rate with lower major hemorrhages 12–17 hours 1 hour Dyspepsia
Rivaroxaban
Apixaban
Edoxaban
Factor Xa inhibitor
Factor Xa inhibitor
Factor Xa inhibitor
ROCKET-HF Noninferior for stroke with similar overall bleeding but less intracranial and fatal bleeding
ARISTOTLE Reduced stroke, caused less bleeding, and had lower mortality
ENGAGE AF-TIMI 48 Noninferior for stroke with less bleeding and cardiovascular death
5–13 hours 2–4 hours None
12 hours 3–4 hours None
8–11 hours 1 hour None
75 mg bid for CrCl 15–30 mL/minute
15 mg daily for CrCl 15–50 mL/minute
30 mg daily for CrCl 30–50 mL/minute, wt ࣘ60kg, or concomitant verapamil, quinidine, or dronedarone use
Avoid P-gp inducers. Reduce dose to 75 mg bid if CrCl 30–50 and taking dronedarone or ketoconazole
Avoid combined P-gp and strong CYP3A4 inhibitors or inducers
2.5 mg bid for those with 2 of following: ࣙ80 years old, wt ࣘ60 kg, SCr ࣙ1.5 mg/dL Avoid combined P-gp and strong CYP3A4 inhibitors or inducers
Avoid P-gp inducers
Dabigatran, rivaroxaban, and apixaban: bid, twice daily dosing; Cmax = maximum concentration after 1 dose; CrCl = creatinine clearance; wt = weight; SCr = serum creatinine; P-gp = P-glycoprotein.35-39
prevent thromboembolism associated with AF. Results from the PINNACLE-AF registry revealed that during the fourth quarter of 2012, 14.9% of patients with nonvalvular AF and a CHADS2 score of ࣙ2 were treated with an NOAC, compared to 44.3% being treated with warfarin.8 The increased use of both NOACs and AF ablation in the treatment of patients with AF mandate a safe and effective periprocedural protocol for using these relatively new medicines. New protocols for the use of NOACs for AF ablation periprocedural anticoagulation are being explored to minimize adverse outcomes with AF ablation. This article will discuss various strategies that have been explored, and will attempt to define the current state of knowledge. Current Guidelines The recently released 2014 AHA/ACC/HRS guideline for the management of patients with AF has produced new recommendations with regard to AF ablation.2 One section of the guideline specifically addressed periprocedural anticoagulation to reduce the risk of thromboembolism. It mostly referred to the 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of AF for guidance. That statement did make several recommendations with regard to NOAC therapy including initiation of a direct thrombin or factor Xa inhibitor after ablation as an alternative postprocedure anticoagulation strategy, and systemic anticoagulation with a direct thrombin or factor Xa inhibitor may be used for at least 2 months following an AF ablation procedure.9 The recent guideline also addressed anticoagulation in the setting of cardioversion, a category into which AF ablation sometimes falls since cardioversion frequently occurs during the procedure. Patients in AF for 48 hours or longer, and those
with an unknown duration, should receive anticoagulation for at least 3 weeks prior to, and 4 weeks after, cardioversion. This is a Class I recommendation with warfarin, level of evidence B, and a Class IIb recommendation, level of evidence C, for an NOAC. A transesophageal echocardiogram demonstrating no identifiable thrombus in the left atrium or left atrial appendage can obviate the need for 3 weeks of anticoagulation prior to cardioversion. The European Heart Rhythm Association also published an executive summary practice guide on the use of NOACs in patients with nonvalvular AF in April 2013. This guide specifically addresses use of NOACs surrounding elective surgical procedures (Table 2) but fails to give specific guidelines surrounding AF ablation.10 AF ablation: Periprocedural Anticoagulation Management Strategies Warfarin Bridging a patient undergoing AF ablation with unfractionated heparin or low molecular weight heparin periprocedurally was the initial management option of choice. However, recent studies indicate that uninterrupted anticoagulation with warfarin is preferred. In 2007, an observational study found that continuation of warfarin through pulmonary vein ablation without administration of enoxaparin was safe and effective in preventing thromboembolism.11 Later, a nonrandomized study of just over 3,000 patients found that uninterrupted anticoagulation with warfarin, with an INR ࣙ 1.8, was not associated with increased bleeding.12 Then, a multicenter study that included nearly 6,500 patients found that continuation of therapeutic warfarin during radiofrequency ablation, with a goal INR ࣙ 2, reduced the risk of periprocedural stroke/TIA without increasing the risk of hemorrhagic events.13 Other retrospective studies have found the same,
Garton et al.
Oral Anticoagulant Use Around the Time of Atrial Fibrillation Ablation
3
TABLE 2 Last Intake of Drug Before Elective Surgical Intervention Dabigatran
Rivaroxaban
CrCl
Low risk (h)
High risk
ࣙ80 mL/minute 50–80 mL/minute 30–59 mL/minute 15–30 mL/minute
