Intern Emerg Med DOI 10.1007/s11739-015-1226-4
IM - REVIEW
Direct oral anticoagulants in the secondary prevention of stroke and transient ischemic attack in patients with atrial fibrillation Valentina Arnao1 • Giancarlo Agnelli2 • Maurizio Paciaroni2
Received: 8 November 2014 / Accepted: 3 March 2015 SIMI 2015
Abstract In patients with non-valvular atrial fibrillation (NVAF) and history of transient ischemic attack (TIA) or stroke, the rate of vascular events is higher in comparison to patients without history of stroke or TIA. A meta-analysis of direct oral anticoagulants (DOACs) studies, including only patients with history of stroke or TIA, report a significant reduction of 15 % in the rates of composite of stroke and systemic embolism in patients treated with DOACs, compared to those treated with warfarin. Furthermore, a reduction of 14 % for major bleeding, as well as a 56 % reduction for hemorrhagic stroke over a median follow-up of 1.8–2.0 years is reported. The combination of DOACs and antiplatelet agents carries the potential of additive benefits in patients with NVAF and other vascular diseases. However, the rate of major bleeding is higher among patients who receive concomitantly antiplatelet agents, compared to those taking only a single drug category. The risk of major bleeding seems to be higher among patients receiving dual antiplatelet agents, compared to those receiving a single antiplatelet drug. When NVAF is associated with an acute coronary syndrome requiring dual antiplatelet therapy (e.g. coronary angioplasty and stenting), DOACs plus this therapy should be considered. However, this therapy has to be administered for the shortest possible time, according to the patient’s haemorrhagic and thrombotic risks, and stent type. When NVAF is
& Maurizio Paciaroni [email protected] 1
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy
2
Stroke Unit, Division of Internal and Cardiovascular Medicine, University of Perugia, Santa Maria della Misericordia Hospital, Via G. Dottori 1, 06100 Perugia, Italy
associated with carotid stenosis, a single antiplatelet therapy should be considered. Regarding carotid revascularization, it seems preferable to treat these patients with endarterectomy, so to avoid dual antiplatelet therapy, which is generally administered after stenting. Keywords Medicine Non-valvular atrial fibrillation Stroke Secondary prevention
Introduction Non-valvular atrial fibrillation (NVAF) is the most common dysrhythmia in adults, and constitutes a major risk factor for stroke. About 15–20 % of all strokes are associated with NVAF [1]. Moreover, ischemic strokes in patients with NVAF are more often disabling and fatal, and occur at a later age compared to strokes in patients with sinus rhythm [2]. Direct oral anticoagulants (DOACs) provide an alternative to the traditional dose-adjusted anticoagulation with warfarin, the latter is based upon an international normalized ratio (INR) range of 2.0–3.0 have been shown to be at least as effective and safe as warfarin. This review evaluates the clinical use of DOACs in preventing stroke and systemic embolism in patients with NVAF and a history of transient ischemic attack (TIA), or stroke. Data for this review were identified by searching PubMed for single or combined terms including: nonvalvular atrial fibrillation, direct oral anticoagulants, stroke, secondary prevention, anticoagulation and ischemic heart disease, anticoagulation and carotid stenosis. Original research papers, clinical series, case reports and reviews were included. Our research covered all relevant data from January 2009 to August 2014.
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The mechanism of action for DOACs
DOACs safety and efficacy in secondary prevention of stroke and TIA
In patients with NVAF, oral anticoagulation with vitamin K antagonists has been the basis of antithrombotic therapy for more than 20 years as it reduces the risk of stroke by 64 % [3]. Vitamin K antagonists have many pharmacological limitations including slow onset and offset of action, a narrow therapeutic window requiring frequent coagulation monitoring, an unpredictable anticoagulant effect related to genetic factors, and numerous interactions with foods and medications. Several new oral anticoagulants have been made available over the last years. The direct oral anticoagulants most extensively evaluated in phase III trials have been the direct factor IIa (thrombin) inhibitor (dabigatran etexilate), and the direct inhibitors of factor Xa (rivaroxaban, apixaban and edoxaban). These agents offer potential advantages over vitamin K antagonists, such as rapid onset and offset of action, absence of an effect of dietary vitamin K intake on their activity, and fewer drug interactions. Routine coagulation monitoring is not necessary as DOACs are administered in fixed-oral daily doses despite differences in age, gender or body mass index (Table 1). Dabigatran is a pro-drug that is taken orally in a fixed dose, and is rapidly converted by CYP-independent esterases in a potent reversible direct competitive inhibitor of thrombin with a rapid onset of action, predictable and consistent anticoagulant effect, and half-life of 12–17 h; dabigatran is mostly excreted by the renal system [4]. Rivaroxaban directly inhibits factor Xa, and has a dual mode of elimination, by the kidneys and the liver [5]. Apixaban is an oral direct factor Xa inhibitor with rapid absorption, a 12 h half-life, and 25 % renal excretion [6]. Edoxaban is an oral, reversible, direct factor Xa inhibitor with a linear and predictable pharmacokinetic profile; edoxaban reaches maximum concentrations within 1–2 h after oral administration, and is eliminated by the kidneys up to 50 % [7].
Direct oral anticoagulants have been compared to warfarin in patients with NVAF in four phase-III randomized trials (ARISTOTLE, RE-LY, ROCKET-AF and ENGAGE AFTIMI 48) [8–11]. A meta-analysis of these four trials reports a significant 11 % reduction in favor of DOACs, for both overall mortality and cardiovascular mortality. Furthermore, DOACs have been associated with a 19 % significant reduction in stroke and systemic embolism, compared to warfarin, over a median follow-up of 1.8–2.0 years. Moreover, DOACs have also been associated with a significant reduction of 14 % in intracranial bleedings. To date, a 13 % reduction in any stroke has been reported, which is not statically significant. A trend for more severe strokes has been observed with DOACs in both primary and secondary prevention [12]. The RE-LY, ROCKET AF and ARISTOTLE trials provide subgroup analysis for patients with history of stroke or TIA. Overall, 14,527 patients had history of previous stroke or TIA. The RE-LY study concludes that, in comparison to warfarin, 110 mg dabigatran is not inferior, and 150 mg dabigatran is superior in the prevention of stroke or systemic embolism. Furthermore, 110 mg dabigatran is associated with less major bleeding and 150 mg dabigatran has similar rates of major bleeding, compared to warfarin. The ROCKET AF trial reports that there is no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin is different in patients who had a previous stroke or TIA, and in those who had no previous stroke or TIA [13]. The subgroup analysis of the ARISTOTLE study reports that 5 mg apixaban twice daily is superior to warfarin for the prevention of stroke or systemic embolism in NVAF patients with previous stroke. The reductions in rates of cardiovascular death, disabling
Table 1 Vascular outcomes of AF patients with prior TIA or stroke in the randomised trials, from Ntaios 2012 modified [14] RE-LY Dabi 110
ROCKET AF Dabi 150
Warfarin
Rivaroxaban
ARISTOTLE Warfarin
Apixaban
Warfarin
Stroke or systemic embolism
55
51
65
179
187
73
98
Stroke
53
47
59
171
172
67
96
Ischemic/unknown stroke
52
43
41
151
144
57
68
Disabling/fatal stroke Hemorrhagic stroke
36 2
33 5
44 18
92 22
98 30
39 12
46 31
Cardiovascular death
45
73
70
192
194
72
76
Major bleeding
65
102
97
178
183
77
106
6
13
30
34
46
15
41
Intracranial bleeding
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or fatal stroke, and all- cause mortality with apixaban versus warfarin are similar in patients with and without previous stroke or TIA [6]. A meta-analysis of DOACs studies, including only patients with history of stroke or TIA, 7876 patients allocated to a DOACs and 6651 to warfarin, reports a significant reduction of 15 % in the rates of composite of stroke and systemic embolism in patients treated with DOACs, compared to those treated with warfarin. Furthermore, a reduction of 14 % for major bleeding, as well as a 56 % reduction for hemorrhagic stroke over a median follow-up of 1.8–2.0 years, is reported [14].
Atrial fibrillation in association with other vascular diseases In patients with NVAF and history of TIA or stroke, the rate of vascular events is higher in comparison to patients with NVAF without history of stroke or TIA. Additionally, patients with stroke or TIA might have ischemic heart disease or carotid atherosclerotic disease that can potentially increase the risk of recurrent vascular events. Finally, patients with prior stroke or TIA have an increased risk of major bleeding associated with anticoagulant therapy. Currently, there are no guidelines regarding an optimal therapeutic strategy for these patients. The coexistence of atrial fibrillation and ischemic heart disease In a consecutive series of 813 patients admitted for acute stroke, the rate of cardiovascular events (myocardial infarction or acute heart failure), in a time span observation of 8.7 days, is 6.5 %, and this is associated with increased mortality [15]. Cardiovascular events occur more frequently in patients with cardio-embolic stroke compared to other stroke types. Risk factors include high National Institute of Health Stroke Score (NIHSS) on admission, high blood glucose levels, and a recent history of angina or myocardial infarction. In patients with acute coronary syndrome, or undergoing percutaneous coronary intervention (PCI), aspirin plus clopidogrel is recommended to reduce the recurrence of vascular events. In patients with NVAF, the combination of oral anticoagulants and antiplatelet agents carries the potential of greater benefits, but also an increased risk of bleeding [16]. Up to 10 % of all patients undergoing PCI with stent implantation require chronic anticoagulation, therapy mostly due to atrial fibrillation [17]. In a post hoc analysis of RE-LY, Dans et al. [18] compared the efficacy and safety of two doses of dabigatran versus warfarin in subgroups of patients with and without concomitant antiplatelet treatment. Dabigatran
110 mg is not inferior to warfarin, regardless of whether or not patients use antiplatelet agents, and major bleeding is lower, compared to warfarin in both subgroups. Dabigatran 150 mg has a lower rate of recurrent stroke than warfarin among patients who do not receive antiplatelet agents, although there is a trend toward reduced benefit among patients who receive antiplatelet agents. The rate of major bleeding is higher among patients who use concomitant antiplatelet agents, compared to those without (4.4 versus 2.6 %, respectively). The risk of major bleeding is higher in patients who receive dual antiplatelet agents than in those who received a single antiplatelet agent, with the lowest risk for 110 mg dabigatran. In terms of rate, the risk of bleeding is reported to increase by 50 % when a single antiplatelet is added, and doubled in the case of dual-antiplatelet agents; the absolute rate of bleeding is lowest with 110 mg dabigatran, compared to 150 mg dabigatran or warfarin. Following a double blind, placebo-controlled design, the ATLAS ACS-2 TIMI 51 study group randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 or 5 mg of rivaroxaban or placebo. All patients were to receive standard medical therapy, including low-dose aspirin; they were also to receive a thienopyridine (either clopidogrel or ticlopidine) according to the national or local guidelines: 14,292 patients received a dual antiplatelet therapy (aspirin and thienopyridine). Rivaroxaban significantly reduces the primary efficacy end point (a composite of death from cardiovascular causes, myocardial infarction, or stroke), compared to placebo, with respective rates of 8.9 and 10.7 % [hazard ratio 0.84, 95 % confidence interval (CI) 0.74–0.96, P = 0.008], with significant improvements for both doses. When compared to placebo, rivaroxaban increases the rate of intracranial hemorrhage (0.6 versus 0.2 %, P = 0.009) even if previous ischemic stroke or transient ischemic attack in patients who are taking both aspirin and a thienopyridine is an exclusion criterion [19]. The combination of DOACs and antiplatelet agents increases the risk of major bleedings, but in patients with a history of ischemic heart disease and NVAF, this combination is necessary, making it preferable to a single antiplatelet therapy. In the case of recent coronary angioplasty and stenting, the dual antiplatelet therapy should be carefully chosen, balancing the risk of thrombosis and thromboembolism with the risk of hemorrhage associated with the administration of multiple antithrombotic drugs and with accurate stratification of the patients [20]. Clopidogrel should be added to aspirin for a minimum of 1 month after the implanting of a bare-metal stent, and for a minimum of 3 months after implanting an eluting coronary stent [21]. Ticagrelor and prasugrel belong to a new generation of P2Y12 inhibitors that demonstrate an improved reduction in mortality, myocardial infarction,
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and stroke in comparison to clopidogrel. However, the main drawback of these agents is that they are associated with an higher risk of major bleeding in comparison to clopidogrel. Therefore, ‘‘the triple therapy’’, including the newer generation of P2Y12 inhibitors seems to be even more hazardous than triple therapy including clopidogrel [17]. The coexistence of atrial fibrillation and carotid stenosis High-grade stenosis of the extracranial carotid artery is diagnosed in 12 % of the patients with NVAF treated with vitamin K antagonists for stroke prophylaxis. High-grade stenosis of the extracranial carotid artery is also seen in about 20 % of the patients with NVAF and acute stroke, despite an adequate treatment with vitamin K antagonists. In these patients, carotid atherosclerosis is an independent predictor for ischemic cerebral events [22, 23]. Several studies report that approximately 50 % of patients with AF have some degree of carotid stenosis [24]. There is no definitive evidence that antiplatelet therapy is beneficial in preventing stroke or the progression of stenosis in asymptomatic patients. Specifically, one randomised trial of aspirin versus placebo in patients with asymptomatic carotid stenosis fails to show any significant long-term protective effect [25]. Based on the pathophysiology mechanisms of NVAF and symptomatic carotid stenosis, it seems plausible that oral anticoagulants plus low dose aspirin might be beneficial for ischemic stroke prevention [26]. Furthermore, if revascularization is required, endarterectomy is preferred to stenting to avoid dual antiplatelet therapy. When carotid angioplasty and stenting are needed, the dual antiplatelet therapy must be initiated, but its duration must be as short as possible, in absence of safety data for prolonged treatment.
Timing for starting DOACs The four NVAF trials do not clearly indicate an optimal time to initiate therapy with NAOCs for secondary prevention of stroke, as patients with acute stroke were excluded from the DOACs trials. In the RE-LY trial, two reasons for exclusion were stroke within 14 days and severe stroke within 6 months. In ROCKET AF, patients with TIA within 3 days, acute stroke within 14 days and severe disabling stroke (modified Rankin score 4–5, inclusive) within 3 months of randomisation were excluded. In ARISTOTLE, patients with a previous intracranial hemorrhage or any stroke within 7 days before random assignment were excluded. Finally, in the ENGAGE AFTIMI-trial 48 patients with stroke within the previous
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30 days were excluded [11]. Only in ARISTOTLE, 47 patients had a previous stroke within 14 days before random allocation. Of these, 44 had a stroke between 7 and 14 days, 21 of whom were randomly assigned to apixaban and 23 to warfarin. There were no events (stroke or systemic embolism) among these 44 patients. The remaining three patients had a stroke within 7 days before random allocation [6]. Before beginning DOACs, physicians should carefully assess the risk of transformation of ischemic stroke, as well as the risk of recurrent ischemic stroke. Risk factors for haemorrhagic transformation include cardioembolism, large infarcts, thrombolytic treatment and a high level of fasting blood glucose [27]. Another consideration is that warfarin takes 4–5 days to achieve its full anticoagulant effect, while the anticoagulant effect of novel anticoagulants is immediate, within 2–3 h. Useful data in clinical practice is lacking from the literature, despite this, it might be advisable to start anticoagulant therapy after 7–14 days, considering prognostic factors described above. Finally, future randomised controlled trials are needed to evaluate for the efficacy and safety of DOACs in the early treatment of acute ischemic stroke.
Future direction For the secondary prevention of further vascular events after TIA or minor stroke of presumed arterial origin, there is sufficient evidence to conclude that vitamin K antagonists in any dose are not more efficacious than antiplatelet therapy, and that medium and high intensity anticoagulation with an INR of 2.0–4.5 leads to a significant increase in major bleeding complications [28]. Moreover, there is no evidence that treatment with low intensity anticoagulation leads to a higher bleeding risk than treatment with antiplatelet agents: RR 1.27 (95 % CI 0.79–2.03). Regarding clinical randomised trials, they show that DOACs reduce intracranial major bleedings, compared to warfarin. For this reason, results from ongoing trials on interventional treatment in secondary prevention of stroke having a non-cardioembolic origin, comparing antiplatelet therapy to DOACs, are being awaited. These include the ‘‘TRACE trial (NCT01923818)’’ [29] a randomised, double-blind controlled comparing rivaroxaban plus aspirin in the first 30 days to aspirin alone for the treatment of highrisk patients with acute non-disabling cerebrovascular events; the ‘‘DATAS (NCT01924135)’’ [29] trial, an openlabel single arm study enrolling patients with TIA or minor stroke, treated with dabigatran for 30 days; ‘‘ADANCE (NCT01924325)’’, an open-label trial comparing apixaban versus dual-antiplatelet therapy (clopidogrel and aspirin) in
Intern Emerg Med
acute non-disabling cerebrovascular events [29]. Concerning patients with nonvalvular AF who undergo PCI with stent, the ongoing open-label randomised, controlled, multicenter ‘‘PIONEER AF PCI study (NCT01 830 543)’’, is investigating the safety of two different rivaroxaban treatment regimens and vitamin K treatment. In this trial, various combinations of dual anti-platelet therapy, lowdose aspirin or clopidogrel, prasugrel or ticagrelor are used. The ongoing-trial ‘‘REDUAL-PCI’’ is comparing a dual antithrombotic therapy (DAT) regimen including dabigatran (110, or 150) plus clopidogrel or ticagrelor (De-DAT) with a triple antithrombotic therapy (TAT) combination of warfarin plus clopidogrel or ticagrelor plus ASA B100 mg q.d. (warfarin-TAT) in patients with Atrial Fibrillation who undergo a PCI with stenting [29]. Concerning the specific antidote for the DOA, an approach using a monoclonal antibody and a modified recombinant form of factor Xa are being developed [30, 31]. Further studies will be necessary to determine an optimal timing for initiating anticoagulation after ischemic stroke.
Conclusions On the basis of this review, we suggest the following management principles for patients with NVAF and a history of stroke or TIA: • • •
•
•
•
In patients with NVAF, DOACs; For secondary prevention of stroke should be considered; When NVAF is associated with history of ischemic heart disease, DOACs plus a single antiplatelet therapy should be considered, even though there is a reported increase in the risk of bleeding associated with this therapy; When NVAF is associated with acute coronary syndrome that requires dual antiplatelet therapy (e.g. coronary angioplasty and stenting), DOACs plus this therapy should be considered. However, this therapy has to be administered for the shortest time possible, according to the patient’s haemorrhagic and thrombotic risks and stent type; When NVAF is associated with carotid stenosis, DOACs plus a single antiplatelet therapy should be considered. In the case of carotid revascularization, it seems preferable to treat these patients with endarterectomy, so to avoid dual antiplatelet therapy, which is generally administered to patients treated with carotid stenting; The four reviewed trials do not clearly indicate an optimal time to initiate therapy with DOACs for secondary prevention of stroke.
Conflict of interest Arnao V.: no disclosures. Agnelli G. reports receiving personal fees from Boeringher Ingelheim, Sanofi, Daiichi Sankyo and Bayer. Paciaroni M. received honoraria as a member of the speaker bureau of Sanofi, Astra Zeneca, Boeringher Ingelheim and Bayer. Ethical Statement The study ‘‘Direct oral anticoagulants in the secondary prevention of stroke and transient ischemic attack in patients with atrial fibrillation’’ by Arnao V., Agnelli G., Paciaroni M., was approved by the ethic committees of S. Maria della Misericordia hospital University of Perugia. This study was reviewed by the institutional review board and arbitrated as not systematic research. Animals and humans are not directly involved with the study. Informed consent Informed consents for participants was not required per our IRB.
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IM - REVIEW
Direct oral anticoagulants in the secondary prevention of stroke and transient ischemic attack in patients with atrial fibrillation Valentina Arnao1 • Giancarlo Agnelli2 • Maurizio Paciaroni2
Received: 8 November 2014 / Accepted: 3 March 2015 SIMI 2015
Abstract In patients with non-valvular atrial fibrillation (NVAF) and history of transient ischemic attack (TIA) or stroke, the rate of vascular events is higher in comparison to patients without history of stroke or TIA. A meta-analysis of direct oral anticoagulants (DOACs) studies, including only patients with history of stroke or TIA, report a significant reduction of 15 % in the rates of composite of stroke and systemic embolism in patients treated with DOACs, compared to those treated with warfarin. Furthermore, a reduction of 14 % for major bleeding, as well as a 56 % reduction for hemorrhagic stroke over a median follow-up of 1.8–2.0 years is reported. The combination of DOACs and antiplatelet agents carries the potential of additive benefits in patients with NVAF and other vascular diseases. However, the rate of major bleeding is higher among patients who receive concomitantly antiplatelet agents, compared to those taking only a single drug category. The risk of major bleeding seems to be higher among patients receiving dual antiplatelet agents, compared to those receiving a single antiplatelet drug. When NVAF is associated with an acute coronary syndrome requiring dual antiplatelet therapy (e.g. coronary angioplasty and stenting), DOACs plus this therapy should be considered. However, this therapy has to be administered for the shortest possible time, according to the patient’s haemorrhagic and thrombotic risks, and stent type. When NVAF is
& Maurizio Paciaroni [email protected] 1
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy
2
Stroke Unit, Division of Internal and Cardiovascular Medicine, University of Perugia, Santa Maria della Misericordia Hospital, Via G. Dottori 1, 06100 Perugia, Italy
associated with carotid stenosis, a single antiplatelet therapy should be considered. Regarding carotid revascularization, it seems preferable to treat these patients with endarterectomy, so to avoid dual antiplatelet therapy, which is generally administered after stenting. Keywords Medicine Non-valvular atrial fibrillation Stroke Secondary prevention
Introduction Non-valvular atrial fibrillation (NVAF) is the most common dysrhythmia in adults, and constitutes a major risk factor for stroke. About 15–20 % of all strokes are associated with NVAF [1]. Moreover, ischemic strokes in patients with NVAF are more often disabling and fatal, and occur at a later age compared to strokes in patients with sinus rhythm [2]. Direct oral anticoagulants (DOACs) provide an alternative to the traditional dose-adjusted anticoagulation with warfarin, the latter is based upon an international normalized ratio (INR) range of 2.0–3.0 have been shown to be at least as effective and safe as warfarin. This review evaluates the clinical use of DOACs in preventing stroke and systemic embolism in patients with NVAF and a history of transient ischemic attack (TIA), or stroke. Data for this review were identified by searching PubMed for single or combined terms including: nonvalvular atrial fibrillation, direct oral anticoagulants, stroke, secondary prevention, anticoagulation and ischemic heart disease, anticoagulation and carotid stenosis. Original research papers, clinical series, case reports and reviews were included. Our research covered all relevant data from January 2009 to August 2014.
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The mechanism of action for DOACs
DOACs safety and efficacy in secondary prevention of stroke and TIA
In patients with NVAF, oral anticoagulation with vitamin K antagonists has been the basis of antithrombotic therapy for more than 20 years as it reduces the risk of stroke by 64 % [3]. Vitamin K antagonists have many pharmacological limitations including slow onset and offset of action, a narrow therapeutic window requiring frequent coagulation monitoring, an unpredictable anticoagulant effect related to genetic factors, and numerous interactions with foods and medications. Several new oral anticoagulants have been made available over the last years. The direct oral anticoagulants most extensively evaluated in phase III trials have been the direct factor IIa (thrombin) inhibitor (dabigatran etexilate), and the direct inhibitors of factor Xa (rivaroxaban, apixaban and edoxaban). These agents offer potential advantages over vitamin K antagonists, such as rapid onset and offset of action, absence of an effect of dietary vitamin K intake on their activity, and fewer drug interactions. Routine coagulation monitoring is not necessary as DOACs are administered in fixed-oral daily doses despite differences in age, gender or body mass index (Table 1). Dabigatran is a pro-drug that is taken orally in a fixed dose, and is rapidly converted by CYP-independent esterases in a potent reversible direct competitive inhibitor of thrombin with a rapid onset of action, predictable and consistent anticoagulant effect, and half-life of 12–17 h; dabigatran is mostly excreted by the renal system [4]. Rivaroxaban directly inhibits factor Xa, and has a dual mode of elimination, by the kidneys and the liver [5]. Apixaban is an oral direct factor Xa inhibitor with rapid absorption, a 12 h half-life, and 25 % renal excretion [6]. Edoxaban is an oral, reversible, direct factor Xa inhibitor with a linear and predictable pharmacokinetic profile; edoxaban reaches maximum concentrations within 1–2 h after oral administration, and is eliminated by the kidneys up to 50 % [7].
Direct oral anticoagulants have been compared to warfarin in patients with NVAF in four phase-III randomized trials (ARISTOTLE, RE-LY, ROCKET-AF and ENGAGE AFTIMI 48) [8–11]. A meta-analysis of these four trials reports a significant 11 % reduction in favor of DOACs, for both overall mortality and cardiovascular mortality. Furthermore, DOACs have been associated with a 19 % significant reduction in stroke and systemic embolism, compared to warfarin, over a median follow-up of 1.8–2.0 years. Moreover, DOACs have also been associated with a significant reduction of 14 % in intracranial bleedings. To date, a 13 % reduction in any stroke has been reported, which is not statically significant. A trend for more severe strokes has been observed with DOACs in both primary and secondary prevention [12]. The RE-LY, ROCKET AF and ARISTOTLE trials provide subgroup analysis for patients with history of stroke or TIA. Overall, 14,527 patients had history of previous stroke or TIA. The RE-LY study concludes that, in comparison to warfarin, 110 mg dabigatran is not inferior, and 150 mg dabigatran is superior in the prevention of stroke or systemic embolism. Furthermore, 110 mg dabigatran is associated with less major bleeding and 150 mg dabigatran has similar rates of major bleeding, compared to warfarin. The ROCKET AF trial reports that there is no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin is different in patients who had a previous stroke or TIA, and in those who had no previous stroke or TIA [13]. The subgroup analysis of the ARISTOTLE study reports that 5 mg apixaban twice daily is superior to warfarin for the prevention of stroke or systemic embolism in NVAF patients with previous stroke. The reductions in rates of cardiovascular death, disabling
Table 1 Vascular outcomes of AF patients with prior TIA or stroke in the randomised trials, from Ntaios 2012 modified [14] RE-LY Dabi 110
ROCKET AF Dabi 150
Warfarin
Rivaroxaban
ARISTOTLE Warfarin
Apixaban
Warfarin
Stroke or systemic embolism
55
51
65
179
187
73
98
Stroke
53
47
59
171
172
67
96
Ischemic/unknown stroke
52
43
41
151
144
57
68
Disabling/fatal stroke Hemorrhagic stroke
36 2
33 5
44 18
92 22
98 30
39 12
46 31
Cardiovascular death
45
73
70
192
194
72
76
Major bleeding
65
102
97
178
183
77
106
6
13
30
34
46
15
41
Intracranial bleeding
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or fatal stroke, and all- cause mortality with apixaban versus warfarin are similar in patients with and without previous stroke or TIA [6]. A meta-analysis of DOACs studies, including only patients with history of stroke or TIA, 7876 patients allocated to a DOACs and 6651 to warfarin, reports a significant reduction of 15 % in the rates of composite of stroke and systemic embolism in patients treated with DOACs, compared to those treated with warfarin. Furthermore, a reduction of 14 % for major bleeding, as well as a 56 % reduction for hemorrhagic stroke over a median follow-up of 1.8–2.0 years, is reported [14].
Atrial fibrillation in association with other vascular diseases In patients with NVAF and history of TIA or stroke, the rate of vascular events is higher in comparison to patients with NVAF without history of stroke or TIA. Additionally, patients with stroke or TIA might have ischemic heart disease or carotid atherosclerotic disease that can potentially increase the risk of recurrent vascular events. Finally, patients with prior stroke or TIA have an increased risk of major bleeding associated with anticoagulant therapy. Currently, there are no guidelines regarding an optimal therapeutic strategy for these patients. The coexistence of atrial fibrillation and ischemic heart disease In a consecutive series of 813 patients admitted for acute stroke, the rate of cardiovascular events (myocardial infarction or acute heart failure), in a time span observation of 8.7 days, is 6.5 %, and this is associated with increased mortality [15]. Cardiovascular events occur more frequently in patients with cardio-embolic stroke compared to other stroke types. Risk factors include high National Institute of Health Stroke Score (NIHSS) on admission, high blood glucose levels, and a recent history of angina or myocardial infarction. In patients with acute coronary syndrome, or undergoing percutaneous coronary intervention (PCI), aspirin plus clopidogrel is recommended to reduce the recurrence of vascular events. In patients with NVAF, the combination of oral anticoagulants and antiplatelet agents carries the potential of greater benefits, but also an increased risk of bleeding [16]. Up to 10 % of all patients undergoing PCI with stent implantation require chronic anticoagulation, therapy mostly due to atrial fibrillation [17]. In a post hoc analysis of RE-LY, Dans et al. [18] compared the efficacy and safety of two doses of dabigatran versus warfarin in subgroups of patients with and without concomitant antiplatelet treatment. Dabigatran
110 mg is not inferior to warfarin, regardless of whether or not patients use antiplatelet agents, and major bleeding is lower, compared to warfarin in both subgroups. Dabigatran 150 mg has a lower rate of recurrent stroke than warfarin among patients who do not receive antiplatelet agents, although there is a trend toward reduced benefit among patients who receive antiplatelet agents. The rate of major bleeding is higher among patients who use concomitant antiplatelet agents, compared to those without (4.4 versus 2.6 %, respectively). The risk of major bleeding is higher in patients who receive dual antiplatelet agents than in those who received a single antiplatelet agent, with the lowest risk for 110 mg dabigatran. In terms of rate, the risk of bleeding is reported to increase by 50 % when a single antiplatelet is added, and doubled in the case of dual-antiplatelet agents; the absolute rate of bleeding is lowest with 110 mg dabigatran, compared to 150 mg dabigatran or warfarin. Following a double blind, placebo-controlled design, the ATLAS ACS-2 TIMI 51 study group randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 or 5 mg of rivaroxaban or placebo. All patients were to receive standard medical therapy, including low-dose aspirin; they were also to receive a thienopyridine (either clopidogrel or ticlopidine) according to the national or local guidelines: 14,292 patients received a dual antiplatelet therapy (aspirin and thienopyridine). Rivaroxaban significantly reduces the primary efficacy end point (a composite of death from cardiovascular causes, myocardial infarction, or stroke), compared to placebo, with respective rates of 8.9 and 10.7 % [hazard ratio 0.84, 95 % confidence interval (CI) 0.74–0.96, P = 0.008], with significant improvements for both doses. When compared to placebo, rivaroxaban increases the rate of intracranial hemorrhage (0.6 versus 0.2 %, P = 0.009) even if previous ischemic stroke or transient ischemic attack in patients who are taking both aspirin and a thienopyridine is an exclusion criterion [19]. The combination of DOACs and antiplatelet agents increases the risk of major bleedings, but in patients with a history of ischemic heart disease and NVAF, this combination is necessary, making it preferable to a single antiplatelet therapy. In the case of recent coronary angioplasty and stenting, the dual antiplatelet therapy should be carefully chosen, balancing the risk of thrombosis and thromboembolism with the risk of hemorrhage associated with the administration of multiple antithrombotic drugs and with accurate stratification of the patients [20]. Clopidogrel should be added to aspirin for a minimum of 1 month after the implanting of a bare-metal stent, and for a minimum of 3 months after implanting an eluting coronary stent [21]. Ticagrelor and prasugrel belong to a new generation of P2Y12 inhibitors that demonstrate an improved reduction in mortality, myocardial infarction,
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and stroke in comparison to clopidogrel. However, the main drawback of these agents is that they are associated with an higher risk of major bleeding in comparison to clopidogrel. Therefore, ‘‘the triple therapy’’, including the newer generation of P2Y12 inhibitors seems to be even more hazardous than triple therapy including clopidogrel [17]. The coexistence of atrial fibrillation and carotid stenosis High-grade stenosis of the extracranial carotid artery is diagnosed in 12 % of the patients with NVAF treated with vitamin K antagonists for stroke prophylaxis. High-grade stenosis of the extracranial carotid artery is also seen in about 20 % of the patients with NVAF and acute stroke, despite an adequate treatment with vitamin K antagonists. In these patients, carotid atherosclerosis is an independent predictor for ischemic cerebral events [22, 23]. Several studies report that approximately 50 % of patients with AF have some degree of carotid stenosis [24]. There is no definitive evidence that antiplatelet therapy is beneficial in preventing stroke or the progression of stenosis in asymptomatic patients. Specifically, one randomised trial of aspirin versus placebo in patients with asymptomatic carotid stenosis fails to show any significant long-term protective effect [25]. Based on the pathophysiology mechanisms of NVAF and symptomatic carotid stenosis, it seems plausible that oral anticoagulants plus low dose aspirin might be beneficial for ischemic stroke prevention [26]. Furthermore, if revascularization is required, endarterectomy is preferred to stenting to avoid dual antiplatelet therapy. When carotid angioplasty and stenting are needed, the dual antiplatelet therapy must be initiated, but its duration must be as short as possible, in absence of safety data for prolonged treatment.
Timing for starting DOACs The four NVAF trials do not clearly indicate an optimal time to initiate therapy with NAOCs for secondary prevention of stroke, as patients with acute stroke were excluded from the DOACs trials. In the RE-LY trial, two reasons for exclusion were stroke within 14 days and severe stroke within 6 months. In ROCKET AF, patients with TIA within 3 days, acute stroke within 14 days and severe disabling stroke (modified Rankin score 4–5, inclusive) within 3 months of randomisation were excluded. In ARISTOTLE, patients with a previous intracranial hemorrhage or any stroke within 7 days before random assignment were excluded. Finally, in the ENGAGE AFTIMI-trial 48 patients with stroke within the previous
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30 days were excluded [11]. Only in ARISTOTLE, 47 patients had a previous stroke within 14 days before random allocation. Of these, 44 had a stroke between 7 and 14 days, 21 of whom were randomly assigned to apixaban and 23 to warfarin. There were no events (stroke or systemic embolism) among these 44 patients. The remaining three patients had a stroke within 7 days before random allocation [6]. Before beginning DOACs, physicians should carefully assess the risk of transformation of ischemic stroke, as well as the risk of recurrent ischemic stroke. Risk factors for haemorrhagic transformation include cardioembolism, large infarcts, thrombolytic treatment and a high level of fasting blood glucose [27]. Another consideration is that warfarin takes 4–5 days to achieve its full anticoagulant effect, while the anticoagulant effect of novel anticoagulants is immediate, within 2–3 h. Useful data in clinical practice is lacking from the literature, despite this, it might be advisable to start anticoagulant therapy after 7–14 days, considering prognostic factors described above. Finally, future randomised controlled trials are needed to evaluate for the efficacy and safety of DOACs in the early treatment of acute ischemic stroke.
Future direction For the secondary prevention of further vascular events after TIA or minor stroke of presumed arterial origin, there is sufficient evidence to conclude that vitamin K antagonists in any dose are not more efficacious than antiplatelet therapy, and that medium and high intensity anticoagulation with an INR of 2.0–4.5 leads to a significant increase in major bleeding complications [28]. Moreover, there is no evidence that treatment with low intensity anticoagulation leads to a higher bleeding risk than treatment with antiplatelet agents: RR 1.27 (95 % CI 0.79–2.03). Regarding clinical randomised trials, they show that DOACs reduce intracranial major bleedings, compared to warfarin. For this reason, results from ongoing trials on interventional treatment in secondary prevention of stroke having a non-cardioembolic origin, comparing antiplatelet therapy to DOACs, are being awaited. These include the ‘‘TRACE trial (NCT01923818)’’ [29] a randomised, double-blind controlled comparing rivaroxaban plus aspirin in the first 30 days to aspirin alone for the treatment of highrisk patients with acute non-disabling cerebrovascular events; the ‘‘DATAS (NCT01924135)’’ [29] trial, an openlabel single arm study enrolling patients with TIA or minor stroke, treated with dabigatran for 30 days; ‘‘ADANCE (NCT01924325)’’, an open-label trial comparing apixaban versus dual-antiplatelet therapy (clopidogrel and aspirin) in
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acute non-disabling cerebrovascular events [29]. Concerning patients with nonvalvular AF who undergo PCI with stent, the ongoing open-label randomised, controlled, multicenter ‘‘PIONEER AF PCI study (NCT01 830 543)’’, is investigating the safety of two different rivaroxaban treatment regimens and vitamin K treatment. In this trial, various combinations of dual anti-platelet therapy, lowdose aspirin or clopidogrel, prasugrel or ticagrelor are used. The ongoing-trial ‘‘REDUAL-PCI’’ is comparing a dual antithrombotic therapy (DAT) regimen including dabigatran (110, or 150) plus clopidogrel or ticagrelor (De-DAT) with a triple antithrombotic therapy (TAT) combination of warfarin plus clopidogrel or ticagrelor plus ASA B100 mg q.d. (warfarin-TAT) in patients with Atrial Fibrillation who undergo a PCI with stenting [29]. Concerning the specific antidote for the DOA, an approach using a monoclonal antibody and a modified recombinant form of factor Xa are being developed [30, 31]. Further studies will be necessary to determine an optimal timing for initiating anticoagulation after ischemic stroke.
Conclusions On the basis of this review, we suggest the following management principles for patients with NVAF and a history of stroke or TIA: • • •
•
•
•
In patients with NVAF, DOACs; For secondary prevention of stroke should be considered; When NVAF is associated with history of ischemic heart disease, DOACs plus a single antiplatelet therapy should be considered, even though there is a reported increase in the risk of bleeding associated with this therapy; When NVAF is associated with acute coronary syndrome that requires dual antiplatelet therapy (e.g. coronary angioplasty and stenting), DOACs plus this therapy should be considered. However, this therapy has to be administered for the shortest time possible, according to the patient’s haemorrhagic and thrombotic risks and stent type; When NVAF is associated with carotid stenosis, DOACs plus a single antiplatelet therapy should be considered. In the case of carotid revascularization, it seems preferable to treat these patients with endarterectomy, so to avoid dual antiplatelet therapy, which is generally administered to patients treated with carotid stenting; The four reviewed trials do not clearly indicate an optimal time to initiate therapy with DOACs for secondary prevention of stroke.
Conflict of interest Arnao V.: no disclosures. Agnelli G. reports receiving personal fees from Boeringher Ingelheim, Sanofi, Daiichi Sankyo and Bayer. Paciaroni M. received honoraria as a member of the speaker bureau of Sanofi, Astra Zeneca, Boeringher Ingelheim and Bayer. Ethical Statement The study ‘‘Direct oral anticoagulants in the secondary prevention of stroke and transient ischemic attack in patients with atrial fibrillation’’ by Arnao V., Agnelli G., Paciaroni M., was approved by the ethic committees of S. Maria della Misericordia hospital University of Perugia. This study was reviewed by the institutional review board and arbitrated as not systematic research. Animals and humans are not directly involved with the study. Informed consent Informed consents for participants was not required per our IRB.
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