Protocols Rationale and design of Triple AXEL: trial for early anticoagulation in acute ischemic stroke patients with nonvalvular atrial fibrillation Keun-Sik Hong1, Yun Jung Choi2, and Sun U. Kwon3* on behalf of Triple AXEL Investigators Rationale Patients with atrial fibrillation (AF) in the acute stage of ischemic stroke or transient ischemic attack (TIA) are at high risk of recurrent stroke, but the optimal anticoagulation strategy remains unclear due to the concern of intracranial bleeding. Novel oral anticoagulants compared to warfarin might be more safe and efficacious in patients suitable for early anticoagulation. Aims This trial is to evaluate the feasibility of early anticoagulation with rivaroxaban in acute ischemic stroke or TIA patients with nonvalvular AF. Design This is a randomized, open-label, blinded endpoint evaluation trial. Inclusion criteria are (1) nonvalvular AF, (2) presumed cardioembolic stroke or transient ischemic attack (TIA) confirmed by MRI within five-days from onset, and (3) mild to moderate stroke severity. We will randomize 196 patients to either rivaroxaban (10 mg once daily for five-days followed by 15 mg or 20 mg once daily) or dose-adjusted warfarin (coadministration of aspirin 100 mg per day until achieving international normalized ratio of 1·7). The study is registered in ClinicalTrials.gov (NCT02042534). Correspondence: Sun U. Kwon*, Stroke Center and Department of Neurology, University of Ulsan College of Medicine Asan Medical Center, 88 Olympic-ro Songpa-gu Seoul 138-736 Korea. E-mail: [email protected] 1 Department of Neurology, Ilsan Paik Hospital, Inje University, Goyang, Korea 2 Asan Medical Center, Clinical Trial Center, Seoul, Korea 3 Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea K. S. Hong and Y. J. Choi equally contributed to the current manuscript as co-first authors. Received: 5 June 2014 Accepted: 8 September 2014 Conflicts of interest: K. S. Hong is involved in the design and/or as a site investigator of multicenter clinical trials or observational study sponsored by Bayer Korea Ltd, Korea Otsuka, Norvartis Korea, and Pfizer Pharmaceuticals Korea Ltd, and received lecture honoraria or consultant fees from Pfizer Pharmaceuticals Korea Ltd, Sanofi-Aventis Korea, Bayer Korea Ltd, Boehringer Ingelheim Korea, and Boryung Pharm (modest). S. U. Kwon is a principal investigators of multicenter investigator-sponsored clinical trials sponsored by Korea Otsuka Pharmaceutical, Pfizer Korea, and Bayer Korea, and involved or supposed to be involved as a site investigators of multicenter clinical trials or observational studies sponsored by Boeringer-Ingelheim, Bayer, and Pfizer Korea, BMS, and received lecture honoraria or consultant fees from Pfizer Korea, Korea Otuska, Takeda, Sanofi-Aventis Korea, Bayer Korea, Boehringer Ingelheim Korea, BMS Korea and Daiichi Sankyo Korea. Funding: This study was supported by Bayer Korea Ltd. and grants of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C1061) and the Korea Healthcare technology R&D Project, Ministry of Health, Welfare & Family Affairs, Republic of Korea (HI10C2020). This is an investigator-initiated clinical trial, and the sponsor company (Bayer Korea Ltd.) is not involved in the study design (except for rivaroxaban dose selection), operations including selection and management of sites, data management, and writing this manuscript. DOI: 10.1111/ijs.12386
Study outcomes The primary endpoint is the composite of recurrent ischemic lesion and intracranial bleeding on MRI at four-weeks. Secondary endpoints are recurrent ischemic lesions, intracranial bleeding, major bleeding, major vascular events, four-week modified Rankin Scale score, and duration of hospitalization after randomization. Discussion The results of this proof-of-concept trial will guide go/no-go decision to a large phase 3 confirmatory trial. Key words: acute ischemic stroke, atrial fibrillation, NOAC, rivaroxaban, TIA, warfarin
Background In patients with atrial fibrillation (AF) and cardioembolic (CE) stroke, the risk of recurrent ischemic stroke is high shortly after the event. Because AF-related ischemic strokes are generally more disabling and more often fatal than other ischemic stroke subtypes, the prevention of recurrent cardiac embolism with adequate antithrombotic therapy is of great importance. However, brain tissue and vessels damaged by acute cerebral ischemia are prone to bleeding, and early anticoagulation might further increase the risk of intracranial bleeding. Long-term anticoagulation with warfarin is highly effective for preventing recurrent stroke (1), but the benefit of warfarin in acute setting has not been confirmed. In addition, warfarin therapy in acute ischemic stroke has several disadvantages; (1) delayed onset of action; (2) excessive anticoagulation with warfarin loading in some patients, potentially resulting in intracranial bleeding (2,3); and (3) theoretical transient hypercoagulability during the early period of initiation (2,4). Currently, stroke guidelines do not recommend urgent anticoagulation in patients with acute ischemic stroke, including those with AF-related strokes (5), and the optimal time and strategy to initiate anticoagulation in acute setting remains controversial. Novel oral anticoagulants (NOACs) might be promising candidates for early anticoagulation because of their rapid onset of action, absence of transient hypercoagulability, and stable and predictable anticoagulation effect. Large trials of long-term anticoagulation therapy in patients with AF found that the risk of intracranial bleeding was lower with NOACs than with warfarin (6–9). However, since AF patients with acute ischemic stroke were excluded from those randomized trials, data on the safety and efficacy of NOACs in the acute stage of cerebral ischemia are not currently available. This proof-ofconcept trial (Acute stroke with Xarelto to reduce intracranial bleeding, recurrent embolic stroke, and hospital stay: Triple AXEL) aims to compare rivaroxaban vs. dose-adjusted warfarin for the safety and efficacy assessed by recurrent ischemic lesion and intracranial bleeding on magnetic resonance imaging (MRI) in patients with AF-related acute ischemic stroke or TIA who were considered suitable candidates for early anticoagulation.
© 2014 The Authors. International Journal of Stroke published by John Wiley & Sons Ltd Vol ••, •• 2014, ••–•• on behalf of World Stroke Organization. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
1
Protocols
K.-S. Hong et al.
The results will guide go/no-go decision to a phase 3 confirmatory trial.
from eligible patients or their legally authorized representatives will be obtained. The trial is registered in ClinicalTrials.gov (NCT02042534).
Methods Design This is a phase 2, multicenter (12 institutions in South Korea), randomized, open label, blinded endpoint evaluation (PROBE) trial to compare the safety and efficacy of rivaroxaban vs. warfarin in patients with acute ischemic stroke or TIA due to presumed AF-related cardioembolism. The study is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and was approved by local institutional review boards and Korean Ministry of Food and Drug Safety [Tracking number: 30078]. Written informed consent
Study population The detailed inclusion and exclusion criteria are outlined in Table 1. The principal inclusion criteria are (1) nonvalvular AF documented by electrocardiogram (ECG) including paroxysmal AF, (2) a presumed CE ischemic stroke or TIA within five-days of stroke onset, and (3) a stroke of mild to moderate severity (acute ischemic lesion on DWI less than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere). Key exclusion criteria include (1) significant hemorrhagic transformation within the ischemic
Table 1 Inclusion and exclusion criteria Inclusion criteria 1. Acute presumed cardioembolic stroke of mild to moderate severity or TIA that fulfills the following criteria (1) Ischemic stroke or TIA with acute ischemic lesion confirmed by DWI (2) Randomization within five-days after symptom onset (3) Mild to moderate stroke severity defined by acute ischemic lesion on DWI less than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere 2. Persistent or paroxysmal AF documented by one of followings (1) AF documented by 12-lead ECG or Holter within 30 days before randomization (2) Prior history of AF confirmed by the review of medical record 3. Age ≥19 years 4. Written informed consent Exclusion criteria 1. Significant hemorrhagic transformation (parenchymal hematoma type I or type II by the ECASS definition) 2. Mechanical heart valve requiring warfarin therapy 3. Stroke or TIA caused by presumed small vessel occlusion defined as 100 mmHg 13. Malignancy or other serious medical conditions with a life expectancy
Study outcomes The primary endpoint is the composite of recurrent ischemic lesion and intracranial bleeding on MRI at four-weeks. Secondary endpoints are recurrent ischemic lesions, intracranial bleeding, major bleeding, major vascular events, four-week modified Rankin Scale score, and duration of hospitalization after randomization. Discussion The results of this proof-of-concept trial will guide go/no-go decision to a large phase 3 confirmatory trial. Key words: acute ischemic stroke, atrial fibrillation, NOAC, rivaroxaban, TIA, warfarin
Background In patients with atrial fibrillation (AF) and cardioembolic (CE) stroke, the risk of recurrent ischemic stroke is high shortly after the event. Because AF-related ischemic strokes are generally more disabling and more often fatal than other ischemic stroke subtypes, the prevention of recurrent cardiac embolism with adequate antithrombotic therapy is of great importance. However, brain tissue and vessels damaged by acute cerebral ischemia are prone to bleeding, and early anticoagulation might further increase the risk of intracranial bleeding. Long-term anticoagulation with warfarin is highly effective for preventing recurrent stroke (1), but the benefit of warfarin in acute setting has not been confirmed. In addition, warfarin therapy in acute ischemic stroke has several disadvantages; (1) delayed onset of action; (2) excessive anticoagulation with warfarin loading in some patients, potentially resulting in intracranial bleeding (2,3); and (3) theoretical transient hypercoagulability during the early period of initiation (2,4). Currently, stroke guidelines do not recommend urgent anticoagulation in patients with acute ischemic stroke, including those with AF-related strokes (5), and the optimal time and strategy to initiate anticoagulation in acute setting remains controversial. Novel oral anticoagulants (NOACs) might be promising candidates for early anticoagulation because of their rapid onset of action, absence of transient hypercoagulability, and stable and predictable anticoagulation effect. Large trials of long-term anticoagulation therapy in patients with AF found that the risk of intracranial bleeding was lower with NOACs than with warfarin (6–9). However, since AF patients with acute ischemic stroke were excluded from those randomized trials, data on the safety and efficacy of NOACs in the acute stage of cerebral ischemia are not currently available. This proof-ofconcept trial (Acute stroke with Xarelto to reduce intracranial bleeding, recurrent embolic stroke, and hospital stay: Triple AXEL) aims to compare rivaroxaban vs. dose-adjusted warfarin for the safety and efficacy assessed by recurrent ischemic lesion and intracranial bleeding on magnetic resonance imaging (MRI) in patients with AF-related acute ischemic stroke or TIA who were considered suitable candidates for early anticoagulation.
© 2014 The Authors. International Journal of Stroke published by John Wiley & Sons Ltd Vol ••, •• 2014, ••–•• on behalf of World Stroke Organization. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
1
Protocols
K.-S. Hong et al.
The results will guide go/no-go decision to a phase 3 confirmatory trial.
from eligible patients or their legally authorized representatives will be obtained. The trial is registered in ClinicalTrials.gov (NCT02042534).
Methods Design This is a phase 2, multicenter (12 institutions in South Korea), randomized, open label, blinded endpoint evaluation (PROBE) trial to compare the safety and efficacy of rivaroxaban vs. warfarin in patients with acute ischemic stroke or TIA due to presumed AF-related cardioembolism. The study is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and was approved by local institutional review boards and Korean Ministry of Food and Drug Safety [Tracking number: 30078]. Written informed consent
Study population The detailed inclusion and exclusion criteria are outlined in Table 1. The principal inclusion criteria are (1) nonvalvular AF documented by electrocardiogram (ECG) including paroxysmal AF, (2) a presumed CE ischemic stroke or TIA within five-days of stroke onset, and (3) a stroke of mild to moderate severity (acute ischemic lesion on DWI less than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere). Key exclusion criteria include (1) significant hemorrhagic transformation within the ischemic
Table 1 Inclusion and exclusion criteria Inclusion criteria 1. Acute presumed cardioembolic stroke of mild to moderate severity or TIA that fulfills the following criteria (1) Ischemic stroke or TIA with acute ischemic lesion confirmed by DWI (2) Randomization within five-days after symptom onset (3) Mild to moderate stroke severity defined by acute ischemic lesion on DWI less than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere 2. Persistent or paroxysmal AF documented by one of followings (1) AF documented by 12-lead ECG or Holter within 30 days before randomization (2) Prior history of AF confirmed by the review of medical record 3. Age ≥19 years 4. Written informed consent Exclusion criteria 1. Significant hemorrhagic transformation (parenchymal hematoma type I or type II by the ECASS definition) 2. Mechanical heart valve requiring warfarin therapy 3. Stroke or TIA caused by presumed small vessel occlusion defined as 100 mmHg 13. Malignancy or other serious medical conditions with a life expectancy
