EDITORIAL
Combined antithrombotic therapy of potential value in acute atrial fibrillation related stroke
See paper by Abdul-Rahim et al. on page 1048.
The article by Abdul-Rahim et al. [1] from VISTA provides potentially quite important information. In atrial fibrillation related acute stroke, we are confronted with the very real concern about early recurrent stroke. On the other hand, we also clearly want to avoid hemorrhagic complications of our therapy so we must be diligent in weighing the potential benefits versus risks in the best interest of our patients. Studies of acute stroke in atrial fibrillation have not necessarily shown benefit from acute anticoagulant therapy [2]. However, we recognize that the magnitude of risk for recurrent cerebral embolus reflects cumulative risk in terms of the presence or absence of cardiomyopathy, ventricular or atrial thrombus, associated hypercoagulability, prior cerebral embolus and other potential factors. Additionally, we know from the International Stroke Trial [3] and the Chinese Antiplatelet Stroke Trial [4] that early initiation of antiplatelet therapy with aspirin can potentially improve outcome. We also know from studies such as the Stroke Prevention in Atrial Fibrillation [5] and other pooled data [6] that anticoagulant therapy is clearly superior to antiplatelet therapy for the prevention of stroke in non-valvular atrial fibrillation. Therefore, at least theoretically, it would make sense that combined antithrombotic therapy could have a dual benefit and possibly justify the potential risk of a bleeding complication. A commonly faced dilemma is the patient who presents with mild to moderate acute ischaemic stroke, is found to be in atrial fibrillation, who may or may not have received tissue plasminogen activator depending upon their time of presentation, and is now having watchful waiting in terms of when the optimal time is to address the anticoagulant issue for protection against further cerebral embolus. This paper supports the approach of combined antithrombotic therapy within 1 day of the event, on average, with antiplatelet therapy and within 2 days of the event, on average, with anticoagulant therapy. The study is non-randomized and not controlled which makes its value subject to interpretation. The practicality of the take home message may be
© 2014 EAN
improved by factoring in the recognition that certain patients are more likely to have hemorrhagic transformation of their initial infarcts associated with clinical worsening. Contributing factors may include larger infarcts, older patients with patients 80 years of age and beyond having increasing concerns over anticoagulant therapy, and chronic suboptimal blood pressure control. An approach for those worrisome patients with moderate or larger infarcts, whose functional status is such that they may benefit from early initiated combined antithrombotic therapy, would be to repeat a non-contrast computed tomography brain scan roughly 72 h out from the event to ensure no obvious hemorrhagic transformation of the infarct. Assuming no hemorrhage, the issue at hand becomes whether or not so-called ‘bridging’ therapy with intravenous unfractionated heparin should be initiated first. Theoretically, this would be to ensure that clinical deterioration is not pending as a complication of anticoagulant therapy. Hallevi et al. [7] looked at bridging with either enoxaparin or heparin versus no bridging in a retrospective study of anticoagulation after cardioembolic stroke. They reported no clear advantage of bridging versus early initiation of warfarin. They observed a 10% risk of symptomatic hemorrhagic transformation in the enoxaparin group. However, there might have been a selection bias toward early warfarin for those patients deemed most likely not to be at risk for hemorrhagic conversion. Abdul-Rahim et al. [1] make mention of how patients receiving intravenous tissue plasminogen activator may have had less likelihood of hemorrhagic transformation as this agent may serve as a ‘stress test’ for hemorrhagic conversion risk as well as the routine need for follow-up computed tomography brain scan which can serve as a ‘safety measure’ prior to proceeding with anticoagulant therapy. The theoretical advantage of heparin bridging in higher risk patients would be the ability for rapid reversal of the anticoagulant effect with protamine sulfate. On the other hand, despite success in being better able to reverse the effects of warfarin within a reasonable amount of time, there is clearly not such
1027
EUROPEAN JOURNAL OF NEUROLOGY
doi:10.1111/ene.12588
1028
EDITORIAL
rapid reversal available as with heparin and the newer oral anticoagulants are of even greater concern in terms of the ability to address bleeding complications in a timely fashion. Once it is established that anticoagulant therapy is safe for the patient, usually within several days, oral anticoagulant therapy can be initiated as the heparin is tapered and discontinued. I am aware that this more cautious approach could be viewed as controversial and may well extend hospital stay and initial expense. However, this might well be in the best interest of the patient along with the observation that we tend to remember the complications of our therapy much more than the ‘saves’ and this would appear to be a case in point.
2.
3.
4.
5.
R. E. Kelley Department of Neurology, Tulane University School of Medicine, New Orleans, LA, USA
6.
(e-mail: [email protected])
References 1. Abdul-Rahim A, Fulton RL, Frank B, et al. Association of improved outcome in acute ischaemic stroke patients
7.
with atrial fibrillation who receive early antithrombotic therapy: analysis from VISTA. Eur J Neurol 2015; 22: 1048–1055. Berge E, Abdelnoor M, Nakstad PH, Sandset PM; on behalf of the HAEST Study Group. Low molecular weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355: 1205–1210. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–1581. CAST(Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–1649. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation. Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: 687–691. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: an analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449–1457. Hallevi H, Albright KC, Martin-Schild S, et al. Anticoagulation after cardioembolic stroke: to bridge or not to bridge? Arch Neurol 2008; 65: 1169–1173.
© 2014 EAN
Combined antithrombotic therapy of potential value in acute atrial fibrillation related stroke
See paper by Abdul-Rahim et al. on page 1048.
The article by Abdul-Rahim et al. [1] from VISTA provides potentially quite important information. In atrial fibrillation related acute stroke, we are confronted with the very real concern about early recurrent stroke. On the other hand, we also clearly want to avoid hemorrhagic complications of our therapy so we must be diligent in weighing the potential benefits versus risks in the best interest of our patients. Studies of acute stroke in atrial fibrillation have not necessarily shown benefit from acute anticoagulant therapy [2]. However, we recognize that the magnitude of risk for recurrent cerebral embolus reflects cumulative risk in terms of the presence or absence of cardiomyopathy, ventricular or atrial thrombus, associated hypercoagulability, prior cerebral embolus and other potential factors. Additionally, we know from the International Stroke Trial [3] and the Chinese Antiplatelet Stroke Trial [4] that early initiation of antiplatelet therapy with aspirin can potentially improve outcome. We also know from studies such as the Stroke Prevention in Atrial Fibrillation [5] and other pooled data [6] that anticoagulant therapy is clearly superior to antiplatelet therapy for the prevention of stroke in non-valvular atrial fibrillation. Therefore, at least theoretically, it would make sense that combined antithrombotic therapy could have a dual benefit and possibly justify the potential risk of a bleeding complication. A commonly faced dilemma is the patient who presents with mild to moderate acute ischaemic stroke, is found to be in atrial fibrillation, who may or may not have received tissue plasminogen activator depending upon their time of presentation, and is now having watchful waiting in terms of when the optimal time is to address the anticoagulant issue for protection against further cerebral embolus. This paper supports the approach of combined antithrombotic therapy within 1 day of the event, on average, with antiplatelet therapy and within 2 days of the event, on average, with anticoagulant therapy. The study is non-randomized and not controlled which makes its value subject to interpretation. The practicality of the take home message may be
© 2014 EAN
improved by factoring in the recognition that certain patients are more likely to have hemorrhagic transformation of their initial infarcts associated with clinical worsening. Contributing factors may include larger infarcts, older patients with patients 80 years of age and beyond having increasing concerns over anticoagulant therapy, and chronic suboptimal blood pressure control. An approach for those worrisome patients with moderate or larger infarcts, whose functional status is such that they may benefit from early initiated combined antithrombotic therapy, would be to repeat a non-contrast computed tomography brain scan roughly 72 h out from the event to ensure no obvious hemorrhagic transformation of the infarct. Assuming no hemorrhage, the issue at hand becomes whether or not so-called ‘bridging’ therapy with intravenous unfractionated heparin should be initiated first. Theoretically, this would be to ensure that clinical deterioration is not pending as a complication of anticoagulant therapy. Hallevi et al. [7] looked at bridging with either enoxaparin or heparin versus no bridging in a retrospective study of anticoagulation after cardioembolic stroke. They reported no clear advantage of bridging versus early initiation of warfarin. They observed a 10% risk of symptomatic hemorrhagic transformation in the enoxaparin group. However, there might have been a selection bias toward early warfarin for those patients deemed most likely not to be at risk for hemorrhagic conversion. Abdul-Rahim et al. [1] make mention of how patients receiving intravenous tissue plasminogen activator may have had less likelihood of hemorrhagic transformation as this agent may serve as a ‘stress test’ for hemorrhagic conversion risk as well as the routine need for follow-up computed tomography brain scan which can serve as a ‘safety measure’ prior to proceeding with anticoagulant therapy. The theoretical advantage of heparin bridging in higher risk patients would be the ability for rapid reversal of the anticoagulant effect with protamine sulfate. On the other hand, despite success in being better able to reverse the effects of warfarin within a reasonable amount of time, there is clearly not such
1027
EUROPEAN JOURNAL OF NEUROLOGY
doi:10.1111/ene.12588
1028
EDITORIAL
rapid reversal available as with heparin and the newer oral anticoagulants are of even greater concern in terms of the ability to address bleeding complications in a timely fashion. Once it is established that anticoagulant therapy is safe for the patient, usually within several days, oral anticoagulant therapy can be initiated as the heparin is tapered and discontinued. I am aware that this more cautious approach could be viewed as controversial and may well extend hospital stay and initial expense. However, this might well be in the best interest of the patient along with the observation that we tend to remember the complications of our therapy much more than the ‘saves’ and this would appear to be a case in point.
2.
3.
4.
5.
R. E. Kelley Department of Neurology, Tulane University School of Medicine, New Orleans, LA, USA
6.
(e-mail: [email protected])
References 1. Abdul-Rahim A, Fulton RL, Frank B, et al. Association of improved outcome in acute ischaemic stroke patients
7.
with atrial fibrillation who receive early antithrombotic therapy: analysis from VISTA. Eur J Neurol 2015; 22: 1048–1055. Berge E, Abdelnoor M, Nakstad PH, Sandset PM; on behalf of the HAEST Study Group. Low molecular weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355: 1205–1210. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–1581. CAST(Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–1649. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation. Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: 687–691. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: an analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449–1457. Hallevi H, Albright KC, Martin-Schild S, et al. Anticoagulation after cardioembolic stroke: to bridge or not to bridge? Arch Neurol 2008; 65: 1169–1173.
© 2014 EAN
