914
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
SANTARPIA G et al.
FOCUS REVIEWS ON ARRHYTHMIA
Clinical Significance of Non-Vitamin K Antagonist Oral Anticoagulants in the Management of Atrial Fibrillation Giuseppe Santarpia, MD, PhD; Antonio Curcio, MD, PhD; Gerolamo Sibilio, MD; Ciro Indolfi, MD
Atrial fibrillation (AF) is the most commonly observed rhythm disorder in clinical practice. It is associated with a high risk of thromboembolic stroke and increased cardiovascular mortality. Vitamin K antagonists (VKAs), the only oral anticoagulants used for thromboembolic prophylaxis in AF patients over the past 60 years, have been effective in reducing thromboembolic stroke, compared with placebo and aspirin, in this group of patients. However, VKAs have a very narrow therapeutic window, so regular monitoring of the therapeutic effect is obligatory for their use. The need for regular assessment of blood anticoagulation often causes dissatisfaction and reduces patients’ quality of life. Non-VKA oral anticoagulants (NOACs), such as dabigatran, a direct thrombin inhibitor, and 3 factor Xa inhibitors, namely rivaroxaban, apixaban, and edoxaban, have been developed in recent years and have increased the armamentarium available to the physician for thromboprophylaxis in non-valvular AF (NVAF) patients. This review describes the characteristics of NOACs, analyzing aspects related to their use in the thromboprophylaxis of NVAF patients. It also discusses how to optimize NOAC therapy in specific clinical conditions, such as renal or liver impairment, and concomitant assumption of drugs potentially interfering with NOACs action. Finally, it focuses on NOACrelated bleeding management in the setting of non-cardiac surgery or radiofrequency catheter ablation of NVAF. (Circ J 2015; 79: 914 – 923) Key Words: Atrial fibrillation; Coagulation; Hemorrhage; Oral anticoagulation; Stroke
D
espite recent improvements in pharmacologic and electrical therapies, atrial fibrillation (AF) still remains the most common supraventricular tachyarrhythmia encountered in daily clinical practice. It affects 1–2% of the general population and its incidence increases in older patients.1 The disease is frequently asymptomatic, but associated with a 2-fold increase in mortality, a 3-fold increase in congestive heart failure and a 5-fold increase in the risk of thromboembolic events, leading to frequent hospitalizations and worsened quality of life.2 Although the use of antiarrhythmic medications leads to a significant improvement in symptoms,3 assessment of thromboembolic risk and the use of adequate anticoagulation is mandatory in the proper therapeutic management of AF.4,5
Physiopathology of Thromboembolism and Anticoagulants in AF The association between AF and thromboembolic risk is widely recognized and the genesis of thrombus formation in AF is multifactorial. All the anatomical and physiopathological features of the triad of events necessary for thrombus for-
mation, described 150 years ago by Rudolph Virchow,6 are present in AF. In fact, AF is often characterized by endocardial damage, from dilatation of the atria,7 blood slowdown and stasis,8 related to the anatomy of the atria, and abnormal changes in blood constituents, including platelet activation,9 as well as inflammation10 and changes in growth factor.11 For these reasons, AF can favor a prothrombotic and hypercoagulable state. Warfarin, a VKA, is the most commonly used agent among the OACs used for thromboembolic prophylaxis in AF patients. Its effectiveness is proven by 64% relative risk reduction of stroke compared with placebo,12 and it also shows superior results to aspirin13 and to aspirin plus clopidogrel.14 However, VKAs have some faults: (a) it takes time (days) to achieve a satisfactory therapeutic effect; (b) intricate superimposition with parenteral anticoagulants; (c) narrow therapeutic window; (d) significant interaction with several drugs and food, making regular monitoring of the therapeutic effect obligatory. For these reasons, a review found that up to 65% of patients at risk were not taking OACs, and the international normalized ratio (INR) was out of range in a further 19% of patients.15 Thus, the impetus for the development of the nonvitamin K antagonist oral anticoagulants (NOACs), such as
Received March 18, 2015; accepted March 19, 2015; released online April 2, 2015 Division of Cardiology, Department of Medical and Surgical Sciences, “Magna Graecia” University, Catanzaro (G. Santarpia, A.C., C.I.); Division of Cardiology, Santa Maria delle Grazie Hospital, Pozzuoli (G. Sibilio); and URT-CNR, Consiglio Nazionale delle Ricerche, Catanzaro (C.I.), Italy Mailing address: Ciro Indolfi, MD, Chief, Department of Medical and Surgical Sciences, and Director, URT Consiglio Nazionale delle Ricerche (CNR), Magna Graecia University, Catanzaro 88100, Italy. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-15-0319 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, May 2015
NOACs in AF
915
dabigatran a direct thrombin inhibitor, and 3 factor Xa inhibitors, namely rivaroxaban, apixaban, and edoxaban. Their therapeutic use for prevention of cardio-embolic complications was validated in recent large phase III trials, demonstrating their non-inferiority, and superiority in some cases, to warfarin.16–19 Use of NOACs is currently recommended by guidelines for stroke prevention in patients with non-valvular AF (NVAF).4,5 They have a predictable anticoagulant effect, and do not require routine blood monitoring, which makes them an attractive alternative to VKAs.
Table 1. Thromboembolic Risk Scores CHADS2
CHA2DS2-VASc
ongestive heart failure/LV C dysfunction
1
1
Hypertension
1
1
Age ≥75 years
1
2
Diabetes mellitus
1
1
Stroke/TIA/thromboembolism
2
2
Vascular disease
–
1
Age 65–74 years
–
1
Sex category (ie, female)
–
1
Maximum score
6
9
Risk factors
Thromboembolic Risk Stratification and Recommendation for Anticoagulant Therapy
CHADS2 score includes history of congestive heart failure, arterial hypertension, age ≥75 years, diabetes mellitus and history of stroke (2 points). The acronym CHA2DS2-VASc score considers history of congestive heart failure, arterial hypertension, age >65 years (age ≥75 years=2 points), diabetes mellitus, history of stroke (2 points), vascular disease and sex category. LV, left ventricular; TIA, transient ischemic attack.
In the clinical evaluation of patients with NVAF, the estimation of thromboembolic risk is very important, because not all patients with NVAF need to receive anticoagulation therapy. There are some conditions in which the risks may outweigh the potential benefits, in light of the fact that the average annual frequency of major bleeding during warfarin therapy ranges from 1.3% to 7.2%.20 The most commonly risk scores used to stage the thromboembolic risk in AF patients are the CHADS2 and CHA2DS2-VASc scores (Table 1). The 2012 focused update of the guidelines of the European Society of Cardiology4 recommends oral anticoagulation therapy (NOACs or VKAs) in all NVAF patients >65 years or showing a moderate or high thromboembolic risk, quantified by a CHA2DS2VASc ≥1. In very low risk patients with a CHA2DS2-VASc=0 (ie, aged 90%/60%
6.5%
48–72 h/72–96 h/36–48 h
2–3 h
36–42 h/120–200 h/8–14 h
14–17 h
Metabolism/ elimination
Via CYP450, Renal 90%/mainly hepatic/renal 60%, fecal 30%
Via P-gp transporter/80% renal excretion
Drug interaction
400 known interactions
Strong P-gp inhibitors: ↑↑↑ NOAC exposure - ketoconazole Controindicated - itraconazole association - cyclosporine - tacrolimus - dronedarone Mild-moderate P-gp inhibitors: ↑ NOAC exposure - ketoconazole - amiodarone Use association - quinidine with caution - verapamil - clarithromycin P-gp inducers: ↓ NOAC exposure - rifampicin Controindicated - phenytoin association - carbamazepine - Hypericum perforatum
Dosage in NVAF
According to INR (INR 2–3)
150 mg twice daily
Dose monitoring
INR values
If required with thrombin time
Rivaroxaban
Apixaban
Edoxaban
Target
Factor Xa
Factor Xa
Factor Xa
Oral bioavailability
80–100%
50%
62%
2–4 h
3–4 h
1–2 h
Time for peak effect Plasm half-life Metabolism/ elimination Drug interaction
5–13 h
12 h
10–14 h
Via CYP450, Via P-gp transporter/35% renal excretion
Via CYP450, Via P-gp transporter/27% renal excretion
Via CYP450, Via P Gp transporter/50% renal excretion
Strong CYP3A4 and P-gp inhibitors: ↑↑↑ NOAC exposure *Azole-antimycotics - ketoconazole Controindicated - itraconazole association - voriconazole - posaconazole *HIV protease inhibitors *Dronedarone
Strong CYP3A4 and P-gp inhibitors: ↑↑↑ NOAC exposure Azole-antimycotics - ketoconazole - itraconazole Controindicated - voriconazole association - posaconazole HIV protease inhibitors
CYP3A4 inducers: ↓ NOAC exposure - rifampicin - phenytoin Use association - carbamazepine with caution - phenobarbital - Hypericum perforatum
CYP3A4 inducers: ↓ NOAC exposure - rifampicin - phenytoin Use association - carbamazepine with caution - phenobarbital - Hypericum perforatum
CYP3A4 inducers: ↓ NOAC exposure - rifampicin Use association with caution
Dosage in NVAF
20 mg daily
5 mg twice daily
60 mg daily
Dose monitoring
–
–
–
CYP450, cytochrome P 450; CYP3A4, cytochrome P 450 3A4; INR, international normalized ratio; NOAC, non-vitamin K antagonist oral anticoagulant; P-gp, P-glycoprotein.
with increased risk of bleeding and the presence of 2 risk markers (age ≥80 years, body weight ≤60 kg, creatinine ≥1.5 mg/dl) were treated with the lower dose of apixaban 2.5 mg twice daily. The results of this trial documented that apixaban was superior to warfarin in preventing stroke or
systemic embolism; in addition, it caused less bleeding than warfarin and resulted in lower mortality. Edoxaban has recently been examined by a randomized multicenter trial named ENGAGE-TIMI 48,19 in which 21,105 NVAF patients with moderate-high risk were randomized to receive 60 mg
Circulation Journal Vol.79, May 2015
918
SANTARPIA G et al.
Table 4. Efficacy and Safety Randomized Trials Comparing NOACs and Warfarin in Patients With NVAF RE-LY (dabigatran) No. of patients Study population
Study design Dosage
ROCKET-AF (rivaroxaban)
ARISTOTLE (apixaban)
ENGAGE AF-TIMI 48 (edoxaban)
18,113
14,264
18,201
21,105
Patients with NVAF CHADS2 score ≥1 (mean 2.1) Mean age: 72 years
Patients with NVAF CHADS2 score ≥2 (mean 3.5) Mean age: 73 years
Patients with NVAF CHADS2 score ≥1 (mean 2.1) Mean age: 70 years
Patients with NVAF CHADS2 score ≥2 (mean 2.8) Mean age: 72 years
Double-blind randomized, non-inferiority trial
Double-blind randomized, non-inferiority trial
Double-blind randomized, non-inferiority trial
Double-blind randomized, non-inferiority trial
150 mg (110 mg) twice daily
20 mg (15 mg) once daily
5 mg (2.5 mg) twice daily
60 mg (30 mg) once daily
Control drug
Warfarin (INR 2–3) TTR 64%
Warfarin (INR 2–3) TTR 55%
Warfarin (INR 2–3) TTR 62%
Warfarin (INR 2–3) TTR 68.4%
Primary efficacy outcome
Stroke (ischemic or hemorrhagic) or systemic embolism
Stroke (ischemic or hemorrhagic) or systemic embolism
Stroke (ischemic or hemorrhagic) or systemic embolism
Stroke (ischemic or hemorrhagic) or systemic embolism
Principal safety endpoint
Major bleeding
Composite of major and non-major bleeding
Major bleeding
Major bleeding
Efficacy of dabigatran 110 mg vs. warfarin (0.91; 95% CI, 0.74–1.11; P
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
SANTARPIA G et al.
FOCUS REVIEWS ON ARRHYTHMIA
Clinical Significance of Non-Vitamin K Antagonist Oral Anticoagulants in the Management of Atrial Fibrillation Giuseppe Santarpia, MD, PhD; Antonio Curcio, MD, PhD; Gerolamo Sibilio, MD; Ciro Indolfi, MD
Atrial fibrillation (AF) is the most commonly observed rhythm disorder in clinical practice. It is associated with a high risk of thromboembolic stroke and increased cardiovascular mortality. Vitamin K antagonists (VKAs), the only oral anticoagulants used for thromboembolic prophylaxis in AF patients over the past 60 years, have been effective in reducing thromboembolic stroke, compared with placebo and aspirin, in this group of patients. However, VKAs have a very narrow therapeutic window, so regular monitoring of the therapeutic effect is obligatory for their use. The need for regular assessment of blood anticoagulation often causes dissatisfaction and reduces patients’ quality of life. Non-VKA oral anticoagulants (NOACs), such as dabigatran, a direct thrombin inhibitor, and 3 factor Xa inhibitors, namely rivaroxaban, apixaban, and edoxaban, have been developed in recent years and have increased the armamentarium available to the physician for thromboprophylaxis in non-valvular AF (NVAF) patients. This review describes the characteristics of NOACs, analyzing aspects related to their use in the thromboprophylaxis of NVAF patients. It also discusses how to optimize NOAC therapy in specific clinical conditions, such as renal or liver impairment, and concomitant assumption of drugs potentially interfering with NOACs action. Finally, it focuses on NOACrelated bleeding management in the setting of non-cardiac surgery or radiofrequency catheter ablation of NVAF. (Circ J 2015; 79: 914 – 923) Key Words: Atrial fibrillation; Coagulation; Hemorrhage; Oral anticoagulation; Stroke
D
espite recent improvements in pharmacologic and electrical therapies, atrial fibrillation (AF) still remains the most common supraventricular tachyarrhythmia encountered in daily clinical practice. It affects 1–2% of the general population and its incidence increases in older patients.1 The disease is frequently asymptomatic, but associated with a 2-fold increase in mortality, a 3-fold increase in congestive heart failure and a 5-fold increase in the risk of thromboembolic events, leading to frequent hospitalizations and worsened quality of life.2 Although the use of antiarrhythmic medications leads to a significant improvement in symptoms,3 assessment of thromboembolic risk and the use of adequate anticoagulation is mandatory in the proper therapeutic management of AF.4,5
Physiopathology of Thromboembolism and Anticoagulants in AF The association between AF and thromboembolic risk is widely recognized and the genesis of thrombus formation in AF is multifactorial. All the anatomical and physiopathological features of the triad of events necessary for thrombus for-
mation, described 150 years ago by Rudolph Virchow,6 are present in AF. In fact, AF is often characterized by endocardial damage, from dilatation of the atria,7 blood slowdown and stasis,8 related to the anatomy of the atria, and abnormal changes in blood constituents, including platelet activation,9 as well as inflammation10 and changes in growth factor.11 For these reasons, AF can favor a prothrombotic and hypercoagulable state. Warfarin, a VKA, is the most commonly used agent among the OACs used for thromboembolic prophylaxis in AF patients. Its effectiveness is proven by 64% relative risk reduction of stroke compared with placebo,12 and it also shows superior results to aspirin13 and to aspirin plus clopidogrel.14 However, VKAs have some faults: (a) it takes time (days) to achieve a satisfactory therapeutic effect; (b) intricate superimposition with parenteral anticoagulants; (c) narrow therapeutic window; (d) significant interaction with several drugs and food, making regular monitoring of the therapeutic effect obligatory. For these reasons, a review found that up to 65% of patients at risk were not taking OACs, and the international normalized ratio (INR) was out of range in a further 19% of patients.15 Thus, the impetus for the development of the nonvitamin K antagonist oral anticoagulants (NOACs), such as
Received March 18, 2015; accepted March 19, 2015; released online April 2, 2015 Division of Cardiology, Department of Medical and Surgical Sciences, “Magna Graecia” University, Catanzaro (G. Santarpia, A.C., C.I.); Division of Cardiology, Santa Maria delle Grazie Hospital, Pozzuoli (G. Sibilio); and URT-CNR, Consiglio Nazionale delle Ricerche, Catanzaro (C.I.), Italy Mailing address: Ciro Indolfi, MD, Chief, Department of Medical and Surgical Sciences, and Director, URT Consiglio Nazionale delle Ricerche (CNR), Magna Graecia University, Catanzaro 88100, Italy. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-15-0319 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, May 2015
NOACs in AF
915
dabigatran a direct thrombin inhibitor, and 3 factor Xa inhibitors, namely rivaroxaban, apixaban, and edoxaban. Their therapeutic use for prevention of cardio-embolic complications was validated in recent large phase III trials, demonstrating their non-inferiority, and superiority in some cases, to warfarin.16–19 Use of NOACs is currently recommended by guidelines for stroke prevention in patients with non-valvular AF (NVAF).4,5 They have a predictable anticoagulant effect, and do not require routine blood monitoring, which makes them an attractive alternative to VKAs.
Table 1. Thromboembolic Risk Scores CHADS2
CHA2DS2-VASc
ongestive heart failure/LV C dysfunction
1
1
Hypertension
1
1
Age ≥75 years
1
2
Diabetes mellitus
1
1
Stroke/TIA/thromboembolism
2
2
Vascular disease
–
1
Age 65–74 years
–
1
Sex category (ie, female)
–
1
Maximum score
6
9
Risk factors
Thromboembolic Risk Stratification and Recommendation for Anticoagulant Therapy
CHADS2 score includes history of congestive heart failure, arterial hypertension, age ≥75 years, diabetes mellitus and history of stroke (2 points). The acronym CHA2DS2-VASc score considers history of congestive heart failure, arterial hypertension, age >65 years (age ≥75 years=2 points), diabetes mellitus, history of stroke (2 points), vascular disease and sex category. LV, left ventricular; TIA, transient ischemic attack.
In the clinical evaluation of patients with NVAF, the estimation of thromboembolic risk is very important, because not all patients with NVAF need to receive anticoagulation therapy. There are some conditions in which the risks may outweigh the potential benefits, in light of the fact that the average annual frequency of major bleeding during warfarin therapy ranges from 1.3% to 7.2%.20 The most commonly risk scores used to stage the thromboembolic risk in AF patients are the CHADS2 and CHA2DS2-VASc scores (Table 1). The 2012 focused update of the guidelines of the European Society of Cardiology4 recommends oral anticoagulation therapy (NOACs or VKAs) in all NVAF patients >65 years or showing a moderate or high thromboembolic risk, quantified by a CHA2DS2VASc ≥1. In very low risk patients with a CHA2DS2-VASc=0 (ie, aged 90%/60%
6.5%
48–72 h/72–96 h/36–48 h
2–3 h
36–42 h/120–200 h/8–14 h
14–17 h
Metabolism/ elimination
Via CYP450, Renal 90%/mainly hepatic/renal 60%, fecal 30%
Via P-gp transporter/80% renal excretion
Drug interaction
400 known interactions
Strong P-gp inhibitors: ↑↑↑ NOAC exposure - ketoconazole Controindicated - itraconazole association - cyclosporine - tacrolimus - dronedarone Mild-moderate P-gp inhibitors: ↑ NOAC exposure - ketoconazole - amiodarone Use association - quinidine with caution - verapamil - clarithromycin P-gp inducers: ↓ NOAC exposure - rifampicin Controindicated - phenytoin association - carbamazepine - Hypericum perforatum
Dosage in NVAF
According to INR (INR 2–3)
150 mg twice daily
Dose monitoring
INR values
If required with thrombin time
Rivaroxaban
Apixaban
Edoxaban
Target
Factor Xa
Factor Xa
Factor Xa
Oral bioavailability
80–100%
50%
62%
2–4 h
3–4 h
1–2 h
Time for peak effect Plasm half-life Metabolism/ elimination Drug interaction
5–13 h
12 h
10–14 h
Via CYP450, Via P-gp transporter/35% renal excretion
Via CYP450, Via P-gp transporter/27% renal excretion
Via CYP450, Via P Gp transporter/50% renal excretion
Strong CYP3A4 and P-gp inhibitors: ↑↑↑ NOAC exposure *Azole-antimycotics - ketoconazole Controindicated - itraconazole association - voriconazole - posaconazole *HIV protease inhibitors *Dronedarone
Strong CYP3A4 and P-gp inhibitors: ↑↑↑ NOAC exposure Azole-antimycotics - ketoconazole - itraconazole Controindicated - voriconazole association - posaconazole HIV protease inhibitors
CYP3A4 inducers: ↓ NOAC exposure - rifampicin - phenytoin Use association - carbamazepine with caution - phenobarbital - Hypericum perforatum
CYP3A4 inducers: ↓ NOAC exposure - rifampicin - phenytoin Use association - carbamazepine with caution - phenobarbital - Hypericum perforatum
CYP3A4 inducers: ↓ NOAC exposure - rifampicin Use association with caution
Dosage in NVAF
20 mg daily
5 mg twice daily
60 mg daily
Dose monitoring
–
–
–
CYP450, cytochrome P 450; CYP3A4, cytochrome P 450 3A4; INR, international normalized ratio; NOAC, non-vitamin K antagonist oral anticoagulant; P-gp, P-glycoprotein.
with increased risk of bleeding and the presence of 2 risk markers (age ≥80 years, body weight ≤60 kg, creatinine ≥1.5 mg/dl) were treated with the lower dose of apixaban 2.5 mg twice daily. The results of this trial documented that apixaban was superior to warfarin in preventing stroke or
systemic embolism; in addition, it caused less bleeding than warfarin and resulted in lower mortality. Edoxaban has recently been examined by a randomized multicenter trial named ENGAGE-TIMI 48,19 in which 21,105 NVAF patients with moderate-high risk were randomized to receive 60 mg
Circulation Journal Vol.79, May 2015
918
SANTARPIA G et al.
Table 4. Efficacy and Safety Randomized Trials Comparing NOACs and Warfarin in Patients With NVAF RE-LY (dabigatran) No. of patients Study population
Study design Dosage
ROCKET-AF (rivaroxaban)
ARISTOTLE (apixaban)
ENGAGE AF-TIMI 48 (edoxaban)
18,113
14,264
18,201
21,105
Patients with NVAF CHADS2 score ≥1 (mean 2.1) Mean age: 72 years
Patients with NVAF CHADS2 score ≥2 (mean 3.5) Mean age: 73 years
Patients with NVAF CHADS2 score ≥1 (mean 2.1) Mean age: 70 years
Patients with NVAF CHADS2 score ≥2 (mean 2.8) Mean age: 72 years
Double-blind randomized, non-inferiority trial
Double-blind randomized, non-inferiority trial
Double-blind randomized, non-inferiority trial
Double-blind randomized, non-inferiority trial
150 mg (110 mg) twice daily
20 mg (15 mg) once daily
5 mg (2.5 mg) twice daily
60 mg (30 mg) once daily
Control drug
Warfarin (INR 2–3) TTR 64%
Warfarin (INR 2–3) TTR 55%
Warfarin (INR 2–3) TTR 62%
Warfarin (INR 2–3) TTR 68.4%
Primary efficacy outcome
Stroke (ischemic or hemorrhagic) or systemic embolism
Stroke (ischemic or hemorrhagic) or systemic embolism
Stroke (ischemic or hemorrhagic) or systemic embolism
Stroke (ischemic or hemorrhagic) or systemic embolism
Principal safety endpoint
Major bleeding
Composite of major and non-major bleeding
Major bleeding
Major bleeding
Efficacy of dabigatran 110 mg vs. warfarin (0.91; 95% CI, 0.74–1.11; P
