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Direct Oral Anticoagulants in Atrial Fibrillation Georg Noll, Sarah Noll, David Hürlimann
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Direct Oral Anticoagulants in Atrial Fibrillation
Georg Noll1, Sarah Noll2, David Hürlimann1
1
Heart Clinic Hirslanden Zurich, 2University of Zurich, Switzerland
Address for correspondence: Georg Noll, MD Herzklinik Hirslanden Witellikerstrasse 40 CH-8032 Zurich/Switzerland [email protected]
Abstract Atrial fibrillation (AF) is a frequent and clinically relevant disease that is associated with stroke, other thromboembolic events and mortality. Traditionally antithrombotic therapy encompassed vitamin K antagonists (VKA) and aspirin. Randomized controlled trials have demonstrated a 64% reduction in thromboembolic events and 26% reduction in mortality while a 22% reduction of stroke and a non-significant 19% reduction in mortality were observed for aspirin. This article focusses on the major clinical trials for direct oral anticoagulants including dabigatran, rivaroxaban, apixaban and edoxaban in the clinical setting of atrial fibrillation.
Furthermore special patient groups, the issue of concurrent coronary artery disease, cardioversion, AF ablation and cost-effectiveness are discussed.
Introduction Atrial fibrillation (AF) is the most frequent sustained arrhythmia 1. The prevalence in the general population is estimated to be 1-2% 2. Lifetime risk for the development of AF is about 25% in men and women
3, 4
. Its prevalence increases with age. Therefore, an
increase of 50% during the next 50 years has been predicted
1, 5, 6
. Epidemiologic data
show that atrial fibrillation AF is associated with increased rates of stroke, other thromboembolic events and mortality
7, 8, 9
. The risk of stroke is 5 times higher in patients with AF
and thrombo-embolic events due to AF are more severe and recurrence is more frequent 10
. AF is also associated with an increased rate of hospitalisations and cognitive
dysfunction may be due to repetitive embolic events. Left ventricular dysfunction is also often present in patients with AF. This can either be the cause or the consequence of AF. Conditions which are associated with and may further promote AF are cardiovascular risk factors such as aging, hypertension, diabetes and obesity, cardiovascular (valvular and coronary heart disease, congenital heart defects) and chronic renal and lung diseases
11.
The antiarrhythmic management of AF comprises either rhythm or rate control depending on the situation and the hemodynamic condition. Furthermore, antithrombotic therapy has to be established in patients at significant risk of thrombo-embolic events. Based on cohort data and non-warfarin arms of clinical trials echocardiografic and clinical risk factors associated with the risk for thromboembolic events have been identified. These are age, hypertension, diabetes, and structural heart disease. For risk stratification different assessment tools have been developed such as CHADS2 and more recently CHA2DS2VASc Scores 5, 12, 13.
Antithrombotic Therapy Six large randomized trials using vitamin K antagonists (VKA) mainly for primary prevention demonstrated consistently a reduction of thrombo-embolic events of 64%
14
. In
a metaanalysis mortality was significantly reduced by 26%. There was no significant increase in intracerebral hemorrhage. Aspirin has been tested in several trials. A metaanalysis demonstrated a 22% reduction of stroke by aspirin compared to control. Looking at asprin-only studies, a non-significant 19% reduction in stroke and no effect on mortality was seen
14
. The reduction of stroke
was mainly driven by the SPAF-1 trial Stroke prevention in atrial fibrillation investigators 15, which was stopped early and therefore the effect may be overestimated. Therefore, the effect of aspirin on stroke in AF patients is modest and probably due to its effect on frequently present vascular disease in these patients. Aspirin did not reduced the risk of stroke and thromboembolic event in a prospective randomized trial of low-risk patients, but a tendency of increased bleeding complication was noted 16. In patients unsuitable for VKA antagonist, addition of clopidogrel was compared to aspirin allone in the large ACTIVE A trial. The combination of clopidogrel and aspirin reduced the rate of thromboembolic events by 19% but the risk of bleeding was significantly higher in the group with dual antiplatelet therapy
17
. However in the ACTIVE-W study, compared to warfarin the
combination therapy was clearly inferior (annual thromboembolic event rate 5.60% vs 3.93%) and the bleeding risk was increased by 22% 18.
Direct oral anticoagulants (DOAC) VKA have been proven to effectively reduce thromboembolic events in patients with AF, but these drugs have several disadvantages such as slow onset of action, food and drug interactions and a need for monitoring. Therefore, direct oral anticoagulants (DOAC) have
been developed and tested in large clinical trials compared to the gold standard warfarin. The DOAC can be divided into the two groups of either direct thrombin or factor Xa inhibitors. These durgs have been tested for different indications such as perioperative prophylaxis of deep vein thrombosis after orthopedic surgery and for the treatment of venous thormboembolism. Efficacy and safety of DOAC have been investigated in four large randomized trials compared to warfarin in patients with non-valvular AF (Table 1). All these studies were primarly designed as non-inferiority trials. In addition, apixaban has also been compared to aspirin in patients not eligible for VKA.
Dabigatran Dabigatran directly and reversibly inhibits both free and fibrin-bound thrombin. Two different (blinded) dosages of the drug (110 and 150 mg bid) were compared with openlabeled adjusted-dose warfarin in the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) study in patients with atrial fibrillation at risk for stroke
19.
18113 patients
with a mean CHADS2 score of 2.1 were enrolled. The rate of primary outcome (systemic embolism or stroke) was 1.69% per year for warfarin, as compared with 1.11% per year for dabigatran at dose of 150 mg bid (relative risk, 0.66; 95% CI, 0.53 to 0.82; p < 0.001 for superiority) and 1.53% per year for dabigatran at a dose of 110 mg twice daily (relative risk with dabigatran, 0.91; 95% CI, 0.74 to 1.11; p < 0.001 for non-inferiority.) Compared with warfarin (3.36% per year), however, the risk of major bleeding was 2.71% per year for dabigatran at a dose of 110 mg (p = 0.003), but similar (3.11% per year) for dabigatran at a dose of 150 mg (p = 0.31). Thus, the higher dose of dabigatran showed advantage concerning thromboembolic events whereas the lower dose was better than warfarin concerning bleeding (Figure 1). Intracranial bleeding was significantly reduced in both groups treated with dabigatran compared to warfarin (relative risk reduction 69% with 110 mg bid, 60% with 150 mg bid, Figure 1). In the Long-term Multicenter Extension of
Dabigatran Treatment In Patients with Atrial Fibrillation (RELY-ABLE) 48% of the patients randomized to dabigatran in RE-LY continued double blind medication
20
. During the
follow-up of 28 months similar rates of thromboembolic events and death occurred in both groups whereas bleeding was more frequent in patients treated with the higher dose of dabigatran (HR 1.26, CI 1.04-1.53).
Rivaroxaban Rivaroxabin is an oral, direct acting, reversible factor Xa inhibitor. In the Rivaroxaban Once Daily Oral Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study Rivaroxaban 20 mg (15 mg od in patients with creatinine clearance 30-49 ml/min) once daily was compared to warfarin
21
. Rivaroxaban was non-inferior to warfarin for the prevention of stroke and
systemic embolism (Figure 1), but was not better than warfarin according to the intentionto-treat analysis. The rate of major and clinically relevant minor bleeding of rivaroxaban and warfarin was comparable. However, rivaroxaban treatment was associated with increased major gastrointestinal bleeding, but intracranial hemorrhage and fatal bleeding were significantly lower in rivaroxaban treated patients (Figure 1).
Apixaban In the Apixaban Versus Aspirin to Reduce the Risk of Stroke (AVERROES) trial patient with AF not suitable or unwilling to receive VKA for different reasons were randomized to receive the direct factor Xa inhibitor apixaban 5 mg twice daily or Aspirin (81-324 mg per day)
22.
The rate of stroke or systemic embolism was significantly lower in patient treated
with apixaban compared to aspirin (relative risk reduction 55%). Bleeding, including intracranial hemorrhage as well as myocardial infarction were comparable in both groups. There was no significant heterogeneity for treatment efficacy on ischemic stroke and
bleeding depending on CHADS2/CHA2DS2VASc Scores
23 24
. Secondary analysis showed
significant 20% lower rate of hospitalisations for the apixaban treated patients 25. Apixaban was also tested against warfarin in the ARISTOTLE (Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial
26
. In the group
receiving apixaban 5 mg bid (2.5 mg bid in patients age >80 years, body weight 133 umol/L) stroke and thromboembolic events were significantly less frequent then in patient randomized to warfarin (Figure 1). Apixaban was also associated with less major bleeding, intracranial bleeding and lower mortality (Figure 1). The effect of apixaban was independent of stroke and bleeding risk
27
. The treatment effect of apixaban
(vs warfarin) was not influenced by prior VKA use 28.
Edoxaban To test non-inferiority of edoxaban another direct factor Xa ihibitor compared to warfarin 21105 patients were included into the ENGANGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial
29
. They were randomized to receive either edoxaboan 30 mg or 60 mg once a
day or warfarin. For both doses of edoxaban significant non-inferiority was demonstrated in comparison to warfarin for the primary endpoint of stroke or systemic thromboembolic events (Figure 1). In the group treated with the higher dose 60 mg per day dosage significant superiority of edoxaban could be demonstrated. The rate of major bleeding and intracranial hemorrhage was significantly lower in both edoxaban groups (Figure 1). The rate of cardiovascular mortality was also lower in edoxaban treated patients. Total mortality was reduced compared to warfarin only in the low dose group (HR 0.87; 0790.96).
Special Patient Groups, Subgroup-Analyses
A substantial number of patients entering the studies already had a history of a cerebrovascular event (Table 1). The efficacy and safety of all four DOAC was independent of prior stroke or TIA 30. Heart failure is a risk factor for AF and stroke; thromboembolic events increase with the severity of heart failure and seem to be similar in preserved and impaired systolic function 31, 32, 33
. The presence of heart failure (in 32% - 63% of the study populations) was
associated with an increased rate of stroke but it did not impact on the results in any of the studies 34, 35, 36, 29. Data of a large registry indicate that chronic kidney disease substantially increases the risk of thromboembolism and bleeding in patients with AF
37
. Warfarin, but not aspirin
treatment was associated with a decreased risk fo stroke and thromboembolism, whereas warfarin and aspirin increased the risk of bleeding. The predictive value of impaired renal function was analyzed in ROCKET AF and validated in the ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) cohort
38
. It could be demonstrated that creatinine
clearance below 60 ml per minute is the second most important predictor of stroke and systemic embolism. Severe renal failure was an exclusion criterium for all trials. Kindey function impairment (GFR als low as 30 ml/min) did not influence the results in all trials 39. At baseline, 29-40% of patients were taking aspirin. Aspirin use did not influence the results except for the low-dose group in ENGAGE AF, where warfarin was better than edoxaban on thromboembolic events, but there was no interaction concerning bleeding in this subgroup. Subanalyses of the ARISTOTLE population revealed that high-sensitive troponin T (hsTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are independently associated with an increased risk for stroke and cardiovascular mortality (and also of bleeding for NT-proBNP)
40 41
. The efficacy of apixaban compared to warfarin was
independend of the levels of these markers. HsTnT and NT-proBNP may be used for risk stratification in AF patients in the future.
Switching Prior warfarin use did not influence the effect of DOAC on efficacy and safety in most studies. In ROCKET AF warfarin-experienced patients switched to rivaroxaban exhibited a slight increase in major and clinically relevant bleeding during the inital phase of the trial 42. In ENGAGE AF, there was an interaction for the primary endpoint in both edoxaban groups favouring patients previously treated with warfarin. For bleeding this interaction was not apparent. After trial termination patients on DOAC were switched to warfarin. In ROCKET AF therapeutic anticoagulation was reached after a mean of 13 days in rivaroxaban assigned patients compared to 3 days in patients receiving warfarin
43
. During this period increased
rate of thromboemblic events were seen in ROCKET AF but not in ENGAGE
43 44
. These
data indicate careful monitoring of thomboplastin time when switching patients from NOAC to VKA. Overall, quality of warfarin therapy according to center average time in therapeutic range was analyzed in ROCKET AF, ARISTOTLE, and ENGAGE
45
. It did not affect the results
on primary endpoint and bleeding (ENGAGE AF, ARISTOTLE).
Coronary artery disease Subgroup analysis for patients with prior myocardial infarction did not influence the effects of rivaroxaban or edoxaban on thromboembolic events. However there was an interaction concerning bleeding. In the original publication of RE-LY myocardial infarction as an endpoint was more frequent compared to warfarin in RE-LY (low dose) including more events this difference was no more significant
46
19
. In an update
whereas no effects were
seen in the trials using factor Xa inhibitors. Subsequent metaanalyses including other dabigatran trials suggested a possible association of myocardial infarction with the use of dabigatran compared to warfarin
47,
48
. A large-scale cohort study in Denmark
demonstrated an increased risk of myocardial infarction and coronary events in patients early after switching from warfarin to dabigatran compared to continued warfarin therapy 49
. The mechanisms by which dabigatran may increase the risk of myocardial infarction is
not clear. Warfarin however has been shown to be successful in secondary prevention after myocardial infarction 50, 51, 52.
Cardioversion and AF ablation The experience of cardioversion under DOAC is limited. The published data on dabigatran, rivaroxaban and apixaban indicate that the risk for thromboembolic events following cardioversion is low and comparable to warfarin
53, 54, 55, 56
. Three metaanalyses
have been published including 10 to 14 studies of different design mostly retrospective comparing dabigatran with warfarin in the setting of AF ablation
57, 58, 59
. In the smallest
study including 1501 patients, the primary combined endpoint of neurological events and bleeding showed a trend in favor of warfarin, due to a numerical increase of periprocedural neurologic events in dabigtran treated patients
57
. Metaanalyses including more patients
showed a small, but not significant trend of more thromboembolic complications with comparable rates of bleeding favoring dabigatran for minor bleeding
58 59
. This is in line
with the observation of a non-randomized prospective comparison of cerebral MRI after AF ablation. In patients treated with dabigatran (n=30) new microthromboemolism was detected in 26.7% of patients compared to 10% in the warfarin treated patients (n=180) 60. Further randomized trials are needed to demonstrate safety and efficacy of DOAC in patients undergoing AF ablation.
Comparison of DOAC-Trials Several metaanalyses and comparisons of the different DOAC in AF have been performed 61, 62, 63
. Comparison of data on non-ischemic stroke in RE-LY, ROCKET AF, and
ARISTOTLE demonstrate comparable effect of warfarin but superiority on intracranial bleeding
62
. Sardar et al. analyzed the subset of patients with prior stroke or TIA in RE-LY,
ROCKET AF and ARISTOTLE
64
. They could not find superiority of DOAC compared to
warfarin in secondary prevention concerning stroke or mortality, but a significant lower rate of intracranial hemorrhage. An indirect comparison of a subset of high risk patients (CHADS2 3) in RE-LY, ROCKET AF, and ARISTOTLE suggest similar efficacy of high dose dabigatran by rivaroxaban and apixaban but apixaban seems to be superior concerning bleeding
63.
In line with other analysis, a network metaanalysis also showed a
benefit of DOAC on stroke, ischemic stroke and mortality compared to VKA
65
. The
analysis of Cochrane Collaboration confirmed these data 66.
Cost-effectiveness Several papers have been published on cost-effectiveness of DOAC compared to warfarin for different health care systems cost-effectiveness
70.
67, 68, 69
. Time in therapeutic range importantly influences
A recent review on cost-effectiveness models published emphazises
the difficulty of this topic due to the lack of head-to-head comparisons of NOAC 71.
Percutaneous and surgical exclusion of left atrial appendage Small series of surgical amputation and obliteration without long-term follow-up have been reported. Percutaneous left atrial appendage occlusion devices have been tested and are effective for stroke prevention in atrial fibrillation, with proven reductions in thromboembolic events in comparison with placebo and non- inferiority with warfarin therapy 72, 73, 74. This
promising novel therapy should be further tested in large randomized trials with long-term follow up.
Patient benefit Evidence of four major clinical trial indicate that DOAC are associated with a decrease in total and cardiovascular mortality, stroke and systemic embolism
61
. In addition, there is a
trend in the reduction of major bleeding and a consistent significant important reduction of incracranial bleeding. Therefore guidelines recommend to consider anticoagulants, such as dabigatran, apixaban, and rivaroxaban for patients with non-valvular AF due to better efficacy, safety and convenience profile compared with VKA. Further trials are needed to clarify the safety profile of each o DOACs in different populations such as patients with chronic kidney disease, coronary artery disease and very elderly patients
75 76
. In addition,
data are lacking for the management of patients with acute stroke. At present thrombolysis in patients with stroke under DOAC is not recommended
77.
Interestingly, recent analyses
indicate that in an anticoagulated population the majority of deaths are not related to thromboembolic events or anticoagulation
78
. Therefore other interventions have to be
identified to further reduce mortality.
Table heading Table 1: Baseline characteristics and annual event rates in AF patients treated with DOAC
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Direct Oral Anticoagulants in Atrial Fibrillation Georg Noll, Sarah Noll, David Hürlimann
PII: DOI: Reference:
www.elsevier.com/locate/enganabound S0037-1963(14)00017-1 http://dx.doi.org/10.1053/j.seminhematol.2014.04.001 YSHEM50773
To appear in: Semin Hematol
Cite this article as: Georg Noll, Sarah Noll, David Hürlimann, Direct Oral Anticoagulants in Atrial Fibrillation, Semin Hematol , http://dx.doi.org/10.1053/j.seminhematol.2014.04.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Direct Oral Anticoagulants in Atrial Fibrillation
Georg Noll1, Sarah Noll2, David Hürlimann1
1
Heart Clinic Hirslanden Zurich, 2University of Zurich, Switzerland
Address for correspondence: Georg Noll, MD Herzklinik Hirslanden Witellikerstrasse 40 CH-8032 Zurich/Switzerland [email protected]
Abstract Atrial fibrillation (AF) is a frequent and clinically relevant disease that is associated with stroke, other thromboembolic events and mortality. Traditionally antithrombotic therapy encompassed vitamin K antagonists (VKA) and aspirin. Randomized controlled trials have demonstrated a 64% reduction in thromboembolic events and 26% reduction in mortality while a 22% reduction of stroke and a non-significant 19% reduction in mortality were observed for aspirin. This article focusses on the major clinical trials for direct oral anticoagulants including dabigatran, rivaroxaban, apixaban and edoxaban in the clinical setting of atrial fibrillation.
Furthermore special patient groups, the issue of concurrent coronary artery disease, cardioversion, AF ablation and cost-effectiveness are discussed.
Introduction Atrial fibrillation (AF) is the most frequent sustained arrhythmia 1. The prevalence in the general population is estimated to be 1-2% 2. Lifetime risk for the development of AF is about 25% in men and women
3, 4
. Its prevalence increases with age. Therefore, an
increase of 50% during the next 50 years has been predicted
1, 5, 6
. Epidemiologic data
show that atrial fibrillation AF is associated with increased rates of stroke, other thromboembolic events and mortality
7, 8, 9
. The risk of stroke is 5 times higher in patients with AF
and thrombo-embolic events due to AF are more severe and recurrence is more frequent 10
. AF is also associated with an increased rate of hospitalisations and cognitive
dysfunction may be due to repetitive embolic events. Left ventricular dysfunction is also often present in patients with AF. This can either be the cause or the consequence of AF. Conditions which are associated with and may further promote AF are cardiovascular risk factors such as aging, hypertension, diabetes and obesity, cardiovascular (valvular and coronary heart disease, congenital heart defects) and chronic renal and lung diseases
11.
The antiarrhythmic management of AF comprises either rhythm or rate control depending on the situation and the hemodynamic condition. Furthermore, antithrombotic therapy has to be established in patients at significant risk of thrombo-embolic events. Based on cohort data and non-warfarin arms of clinical trials echocardiografic and clinical risk factors associated with the risk for thromboembolic events have been identified. These are age, hypertension, diabetes, and structural heart disease. For risk stratification different assessment tools have been developed such as CHADS2 and more recently CHA2DS2VASc Scores 5, 12, 13.
Antithrombotic Therapy Six large randomized trials using vitamin K antagonists (VKA) mainly for primary prevention demonstrated consistently a reduction of thrombo-embolic events of 64%
14
. In
a metaanalysis mortality was significantly reduced by 26%. There was no significant increase in intracerebral hemorrhage. Aspirin has been tested in several trials. A metaanalysis demonstrated a 22% reduction of stroke by aspirin compared to control. Looking at asprin-only studies, a non-significant 19% reduction in stroke and no effect on mortality was seen
14
. The reduction of stroke
was mainly driven by the SPAF-1 trial Stroke prevention in atrial fibrillation investigators 15, which was stopped early and therefore the effect may be overestimated. Therefore, the effect of aspirin on stroke in AF patients is modest and probably due to its effect on frequently present vascular disease in these patients. Aspirin did not reduced the risk of stroke and thromboembolic event in a prospective randomized trial of low-risk patients, but a tendency of increased bleeding complication was noted 16. In patients unsuitable for VKA antagonist, addition of clopidogrel was compared to aspirin allone in the large ACTIVE A trial. The combination of clopidogrel and aspirin reduced the rate of thromboembolic events by 19% but the risk of bleeding was significantly higher in the group with dual antiplatelet therapy
17
. However in the ACTIVE-W study, compared to warfarin the
combination therapy was clearly inferior (annual thromboembolic event rate 5.60% vs 3.93%) and the bleeding risk was increased by 22% 18.
Direct oral anticoagulants (DOAC) VKA have been proven to effectively reduce thromboembolic events in patients with AF, but these drugs have several disadvantages such as slow onset of action, food and drug interactions and a need for monitoring. Therefore, direct oral anticoagulants (DOAC) have
been developed and tested in large clinical trials compared to the gold standard warfarin. The DOAC can be divided into the two groups of either direct thrombin or factor Xa inhibitors. These durgs have been tested for different indications such as perioperative prophylaxis of deep vein thrombosis after orthopedic surgery and for the treatment of venous thormboembolism. Efficacy and safety of DOAC have been investigated in four large randomized trials compared to warfarin in patients with non-valvular AF (Table 1). All these studies were primarly designed as non-inferiority trials. In addition, apixaban has also been compared to aspirin in patients not eligible for VKA.
Dabigatran Dabigatran directly and reversibly inhibits both free and fibrin-bound thrombin. Two different (blinded) dosages of the drug (110 and 150 mg bid) were compared with openlabeled adjusted-dose warfarin in the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) study in patients with atrial fibrillation at risk for stroke
19.
18113 patients
with a mean CHADS2 score of 2.1 were enrolled. The rate of primary outcome (systemic embolism or stroke) was 1.69% per year for warfarin, as compared with 1.11% per year for dabigatran at dose of 150 mg bid (relative risk, 0.66; 95% CI, 0.53 to 0.82; p < 0.001 for superiority) and 1.53% per year for dabigatran at a dose of 110 mg twice daily (relative risk with dabigatran, 0.91; 95% CI, 0.74 to 1.11; p < 0.001 for non-inferiority.) Compared with warfarin (3.36% per year), however, the risk of major bleeding was 2.71% per year for dabigatran at a dose of 110 mg (p = 0.003), but similar (3.11% per year) for dabigatran at a dose of 150 mg (p = 0.31). Thus, the higher dose of dabigatran showed advantage concerning thromboembolic events whereas the lower dose was better than warfarin concerning bleeding (Figure 1). Intracranial bleeding was significantly reduced in both groups treated with dabigatran compared to warfarin (relative risk reduction 69% with 110 mg bid, 60% with 150 mg bid, Figure 1). In the Long-term Multicenter Extension of
Dabigatran Treatment In Patients with Atrial Fibrillation (RELY-ABLE) 48% of the patients randomized to dabigatran in RE-LY continued double blind medication
20
. During the
follow-up of 28 months similar rates of thromboembolic events and death occurred in both groups whereas bleeding was more frequent in patients treated with the higher dose of dabigatran (HR 1.26, CI 1.04-1.53).
Rivaroxaban Rivaroxabin is an oral, direct acting, reversible factor Xa inhibitor. In the Rivaroxaban Once Daily Oral Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study Rivaroxaban 20 mg (15 mg od in patients with creatinine clearance 30-49 ml/min) once daily was compared to warfarin
21
. Rivaroxaban was non-inferior to warfarin for the prevention of stroke and
systemic embolism (Figure 1), but was not better than warfarin according to the intentionto-treat analysis. The rate of major and clinically relevant minor bleeding of rivaroxaban and warfarin was comparable. However, rivaroxaban treatment was associated with increased major gastrointestinal bleeding, but intracranial hemorrhage and fatal bleeding were significantly lower in rivaroxaban treated patients (Figure 1).
Apixaban In the Apixaban Versus Aspirin to Reduce the Risk of Stroke (AVERROES) trial patient with AF not suitable or unwilling to receive VKA for different reasons were randomized to receive the direct factor Xa inhibitor apixaban 5 mg twice daily or Aspirin (81-324 mg per day)
22.
The rate of stroke or systemic embolism was significantly lower in patient treated
with apixaban compared to aspirin (relative risk reduction 55%). Bleeding, including intracranial hemorrhage as well as myocardial infarction were comparable in both groups. There was no significant heterogeneity for treatment efficacy on ischemic stroke and
bleeding depending on CHADS2/CHA2DS2VASc Scores
23 24
. Secondary analysis showed
significant 20% lower rate of hospitalisations for the apixaban treated patients 25. Apixaban was also tested against warfarin in the ARISTOTLE (Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial
26
. In the group
receiving apixaban 5 mg bid (2.5 mg bid in patients age >80 years, body weight 133 umol/L) stroke and thromboembolic events were significantly less frequent then in patient randomized to warfarin (Figure 1). Apixaban was also associated with less major bleeding, intracranial bleeding and lower mortality (Figure 1). The effect of apixaban was independent of stroke and bleeding risk
27
. The treatment effect of apixaban
(vs warfarin) was not influenced by prior VKA use 28.
Edoxaban To test non-inferiority of edoxaban another direct factor Xa ihibitor compared to warfarin 21105 patients were included into the ENGANGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial
29
. They were randomized to receive either edoxaboan 30 mg or 60 mg once a
day or warfarin. For both doses of edoxaban significant non-inferiority was demonstrated in comparison to warfarin for the primary endpoint of stroke or systemic thromboembolic events (Figure 1). In the group treated with the higher dose 60 mg per day dosage significant superiority of edoxaban could be demonstrated. The rate of major bleeding and intracranial hemorrhage was significantly lower in both edoxaban groups (Figure 1). The rate of cardiovascular mortality was also lower in edoxaban treated patients. Total mortality was reduced compared to warfarin only in the low dose group (HR 0.87; 0790.96).
Special Patient Groups, Subgroup-Analyses
A substantial number of patients entering the studies already had a history of a cerebrovascular event (Table 1). The efficacy and safety of all four DOAC was independent of prior stroke or TIA 30. Heart failure is a risk factor for AF and stroke; thromboembolic events increase with the severity of heart failure and seem to be similar in preserved and impaired systolic function 31, 32, 33
. The presence of heart failure (in 32% - 63% of the study populations) was
associated with an increased rate of stroke but it did not impact on the results in any of the studies 34, 35, 36, 29. Data of a large registry indicate that chronic kidney disease substantially increases the risk of thromboembolism and bleeding in patients with AF
37
. Warfarin, but not aspirin
treatment was associated with a decreased risk fo stroke and thromboembolism, whereas warfarin and aspirin increased the risk of bleeding. The predictive value of impaired renal function was analyzed in ROCKET AF and validated in the ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) cohort
38
. It could be demonstrated that creatinine
clearance below 60 ml per minute is the second most important predictor of stroke and systemic embolism. Severe renal failure was an exclusion criterium for all trials. Kindey function impairment (GFR als low as 30 ml/min) did not influence the results in all trials 39. At baseline, 29-40% of patients were taking aspirin. Aspirin use did not influence the results except for the low-dose group in ENGAGE AF, where warfarin was better than edoxaban on thromboembolic events, but there was no interaction concerning bleeding in this subgroup. Subanalyses of the ARISTOTLE population revealed that high-sensitive troponin T (hsTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are independently associated with an increased risk for stroke and cardiovascular mortality (and also of bleeding for NT-proBNP)
40 41
. The efficacy of apixaban compared to warfarin was
independend of the levels of these markers. HsTnT and NT-proBNP may be used for risk stratification in AF patients in the future.
Switching Prior warfarin use did not influence the effect of DOAC on efficacy and safety in most studies. In ROCKET AF warfarin-experienced patients switched to rivaroxaban exhibited a slight increase in major and clinically relevant bleeding during the inital phase of the trial 42. In ENGAGE AF, there was an interaction for the primary endpoint in both edoxaban groups favouring patients previously treated with warfarin. For bleeding this interaction was not apparent. After trial termination patients on DOAC were switched to warfarin. In ROCKET AF therapeutic anticoagulation was reached after a mean of 13 days in rivaroxaban assigned patients compared to 3 days in patients receiving warfarin
43
. During this period increased
rate of thromboemblic events were seen in ROCKET AF but not in ENGAGE
43 44
. These
data indicate careful monitoring of thomboplastin time when switching patients from NOAC to VKA. Overall, quality of warfarin therapy according to center average time in therapeutic range was analyzed in ROCKET AF, ARISTOTLE, and ENGAGE
45
. It did not affect the results
on primary endpoint and bleeding (ENGAGE AF, ARISTOTLE).
Coronary artery disease Subgroup analysis for patients with prior myocardial infarction did not influence the effects of rivaroxaban or edoxaban on thromboembolic events. However there was an interaction concerning bleeding. In the original publication of RE-LY myocardial infarction as an endpoint was more frequent compared to warfarin in RE-LY (low dose) including more events this difference was no more significant
46
19
. In an update
whereas no effects were
seen in the trials using factor Xa inhibitors. Subsequent metaanalyses including other dabigatran trials suggested a possible association of myocardial infarction with the use of dabigatran compared to warfarin
47,
48
. A large-scale cohort study in Denmark
demonstrated an increased risk of myocardial infarction and coronary events in patients early after switching from warfarin to dabigatran compared to continued warfarin therapy 49
. The mechanisms by which dabigatran may increase the risk of myocardial infarction is
not clear. Warfarin however has been shown to be successful in secondary prevention after myocardial infarction 50, 51, 52.
Cardioversion and AF ablation The experience of cardioversion under DOAC is limited. The published data on dabigatran, rivaroxaban and apixaban indicate that the risk for thromboembolic events following cardioversion is low and comparable to warfarin
53, 54, 55, 56
. Three metaanalyses
have been published including 10 to 14 studies of different design mostly retrospective comparing dabigatran with warfarin in the setting of AF ablation
57, 58, 59
. In the smallest
study including 1501 patients, the primary combined endpoint of neurological events and bleeding showed a trend in favor of warfarin, due to a numerical increase of periprocedural neurologic events in dabigtran treated patients
57
. Metaanalyses including more patients
showed a small, but not significant trend of more thromboembolic complications with comparable rates of bleeding favoring dabigatran for minor bleeding
58 59
. This is in line
with the observation of a non-randomized prospective comparison of cerebral MRI after AF ablation. In patients treated with dabigatran (n=30) new microthromboemolism was detected in 26.7% of patients compared to 10% in the warfarin treated patients (n=180) 60. Further randomized trials are needed to demonstrate safety and efficacy of DOAC in patients undergoing AF ablation.
Comparison of DOAC-Trials Several metaanalyses and comparisons of the different DOAC in AF have been performed 61, 62, 63
. Comparison of data on non-ischemic stroke in RE-LY, ROCKET AF, and
ARISTOTLE demonstrate comparable effect of warfarin but superiority on intracranial bleeding
62
. Sardar et al. analyzed the subset of patients with prior stroke or TIA in RE-LY,
ROCKET AF and ARISTOTLE
64
. They could not find superiority of DOAC compared to
warfarin in secondary prevention concerning stroke or mortality, but a significant lower rate of intracranial hemorrhage. An indirect comparison of a subset of high risk patients (CHADS2 3) in RE-LY, ROCKET AF, and ARISTOTLE suggest similar efficacy of high dose dabigatran by rivaroxaban and apixaban but apixaban seems to be superior concerning bleeding
63.
In line with other analysis, a network metaanalysis also showed a
benefit of DOAC on stroke, ischemic stroke and mortality compared to VKA
65
. The
analysis of Cochrane Collaboration confirmed these data 66.
Cost-effectiveness Several papers have been published on cost-effectiveness of DOAC compared to warfarin for different health care systems cost-effectiveness
70.
67, 68, 69
. Time in therapeutic range importantly influences
A recent review on cost-effectiveness models published emphazises
the difficulty of this topic due to the lack of head-to-head comparisons of NOAC 71.
Percutaneous and surgical exclusion of left atrial appendage Small series of surgical amputation and obliteration without long-term follow-up have been reported. Percutaneous left atrial appendage occlusion devices have been tested and are effective for stroke prevention in atrial fibrillation, with proven reductions in thromboembolic events in comparison with placebo and non- inferiority with warfarin therapy 72, 73, 74. This
promising novel therapy should be further tested in large randomized trials with long-term follow up.
Patient benefit Evidence of four major clinical trial indicate that DOAC are associated with a decrease in total and cardiovascular mortality, stroke and systemic embolism
61
. In addition, there is a
trend in the reduction of major bleeding and a consistent significant important reduction of incracranial bleeding. Therefore guidelines recommend to consider anticoagulants, such as dabigatran, apixaban, and rivaroxaban for patients with non-valvular AF due to better efficacy, safety and convenience profile compared with VKA. Further trials are needed to clarify the safety profile of each o DOACs in different populations such as patients with chronic kidney disease, coronary artery disease and very elderly patients
75 76
. In addition,
data are lacking for the management of patients with acute stroke. At present thrombolysis in patients with stroke under DOAC is not recommended
77.
Interestingly, recent analyses
indicate that in an anticoagulated population the majority of deaths are not related to thromboembolic events or anticoagulation
78
. Therefore other interventions have to be
identified to further reduce mortality.
Table heading Table 1: Baseline characteristics and annual event rates in AF patients treated with DOAC
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