Warfarin, Aspirin, and Intracranial Vascular Disease
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《新英格兰医药杂志》
The Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) Trial, funded by the National Institute of Neurological Disorders and Stroke and reported by Chimowitz et al.1 in this issue of the Journal, was a careful comparison of these two therapies in patients with cerebrovascular events attributed to intracranial atherosclerosis. The WASID Trial, in concert with other, smaller studies,2,3 clearly shows that symptomatic intracranial atherosclerotic stenosis is a marker of extremely aggressive vascular disease. Ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke occurred within two years in approximately 22 percent of the patients, whether they were treated with high-dose aspirin (1300 mg per day) or warfarin. In addition, the probability of ischemic stroke at two years did not differ between the two treatment groups: it was 0.20 among patients treated with aspirin and 0.17 among those treated with warfarin. Stroke in patients with intracranial atherosclerosis can occur by multiple mechanisms. In the WASID Trial, 73 percent of the recurrent cerebrovascular events occurred in the territory of the index vessel, defined as one having at least 50 percent stenosis. Stroke in this population probably also occurred because of hypertensive vascular disease and the risk of embolism from the aortic, cardiac, and cerebrovascular sources associated with systemic atherosclerosis.
The outcome data from WASID clarify some but not all the relevant issues. The use of a nonstandard, large dose of aspirin and the absence of evidence tying the dose of aspirin to a benefit in stroke prevention make it difficult to choose an antiplatelet regimen and a dose in clinical practice. The occurrence of more deaths due to cancer, congestive heart failure, diabetes, and even cardiac causes in the warfarin-treated group than in the aspirin-treated group stands out as incongruous with the results of previous warfarin studies involving tens of thousands of patients with vascular disease.4 The lenient classification of bleeding disorders as major hemorrhage, some of which do not carry the same level of disability as stroke, also contributed to a higher rate of "major hemorrhage" among warfarin-treated patients than in previous studies. Given that there was no significant difference in the primary end point between the two treatment groups, the study was appropriately stopped because of safety considerations. The results of this trial may appear to a cursory reader to represent an open-and-shut case; the authors conclude, "Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis." If only the practice of medicine were so simple.
The WASID Trial was an intention-to-treat, comparison trial of the administration of aspirin at a dose of 1300 mg per day and warfarin with a target international normalized ratio (INR) of 2.0 to 3.0. The target INR turned out to be not so easy to achieve. In this study, the patients receiving warfarin were within their INR goal only about 63 percent of the time, and approximately 28 percent of the patients dropped out of the warfarin-treated group. As compared with published data, 63 percent as a percentage of time in the target range is not bad.5 In prior studies, the time in the target range correlated with clinical outcomes,6 and seemingly it did so in WASID as well. Even considering only the patients who received treatment, the rate of ischemic stroke was 25 per 100 patient-years with a subtherapeutic INR — a rate that was reduced to 5 per 100 patient-years with a therapeutic INR. The rate of major cardiac events was 10.8 per 100 patient-years with a subtherapeutic INR and was reduced to 0.4 per 100 patient-years with a therapeutic INR. These data suggest that anticoagulation within the therapeutic range is associated with a striking reduction in the risk of cerebrovascular and cardiovascular events. Unfortunately, it is extremely difficult, if not impossible, to achieve a consistent therapeutic INR with warfarin in a population study or in routine practice. The optimal scheme for INR testing and warfarin dose adjustment has not been definitively determined. Why do we instruct patients who are taking warfarin to check their INR once a month? The percentage of time in the target range in studies of warfarin ranges from 40 percent to 92 percent,5 the latter in a patient self-test study with checks occurring every four days.7
The negative findings of the WASID Trial are clearly an indictment of the shortcomings of long-term warfarin use, but the INRs when the events occurred suggest that therapeutic anticoagulation can be very beneficial. How should the treating physician change his or her practice on the basis of the findings of this study? Clearly, the data indicate that long-term warfarin use with an expected time in the INR target range of less than 63 percent is not efficacious for all patients with symptomatic intracranial stenoses. However, the WASID data do not necessarily suggest that all patients with symptomatic intracranial stenosis should be treated with aspirin during all phases of their disease and be left to face the 22 percent two-year risk of ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke that the WASID Trial predicts.
Concluding, on the basis of the WASID data, that there is no reason to obtain images of the intracranial vessels to diagnose this high-risk condition does not seem warranted, especially since the study did not address management of the commonly unstable, acute phase of symptomatic intracranial stenosis. Indeed, the Kaplan–Meier curves (Fig. 2 and 3 in the article) show an almost immediate rise in the probability of the primary end point after enrollment, and much of this early rise seems to be due to ischemic stroke. Delay in quickly achieving a therapeutic level of anticoagulation in high-risk patients might have contributed to the failure of warfarin. A practice of initially treating high-risk patients with a rapidly and consistently active anticoagulant, such as low-molecular-weight heparin, followed by a transition to antiplatelet therapy after an asymptomatic period might prevent the accumulation of early adverse events (Figure 1). What approach should be taken when a patient has symptoms each time anticoagulation is discontinued or the INR drops below the therapeutic level? The WASID data show that warfarin is not superior to 1300 mg of aspirin in a population study. Because the result may well be related to the inadequate time in the INR target range with warfarin, as opposed to a general ineffectiveness of anticoagulation, it does not preclude a trial of very carefully regulated anticoagulation in patients who continue to have recurrent ischemic events in the territory of the index vessel, despite antiplatelet therapy.
Figure 1. Recurrent Artery-to-Artery Emboli from a Vertebral Source.
A 58-year-old man had five nonstereotyped neurologic events over a two-month period, including posterior headache, nausea, vomiting, gait unsteadiness, vertigo, tingling of the right arm and leg, blurring of the vision, and diplopia. A computed tomographic angiogram (Panel A) shows bilateral, calcified vertebral stenoses (arrows) below a patent basilar artery (BA). RVA denotes right vertebral artery, and LVA left vertebral artery. Magnetic resonance images show multiple embolic infarcts due to distal embolism from the vertebral artery stenosis as bright lesions (arrows) in the parietal and occipital lobes (Panels B and C, respectively) and cerebellum (Panel D).
Is there a better way to ensure that anticoagulation remains therapeutic? New drugs that quickly achieve stable therapeutic anticoagulation or point-of-care INR testing with ultrafrequent adjustments in the warfarin dose may be worthy of study in this population, given its high rate of events. Given the known beneficial effects of antiplatelet agents on atherosclerotic risk and the inadequate time in the target range with warfarin, is it time to halt studies of warfarin alone, without concomitant antiplatelet agents, in patients with atherosclerotic disease? Finally, it should be mentioned that intracranial angioplasty is a procedure that has not been tested in a randomized, double-blind clinical trial, but it is not infrequently performed in patients who continue to have ischemic symptoms despite "optimal" medical therapy.8 The WASID data do not indicate that failure of aspirin therapy is a reason to refer patients for intracranial angioplasty. A trial of interventional treatment as compared with medical treatment that includes anticoagulation still seems warranted.
We will learn an enormous amount from the WASID data. The patients and the investigators deserve a great deal of credit for participating in and carrying out this very difficult study. The messages at this point are that symptomatic intracranial atherosclerosis is a mark of aggressive vascular disease, that aspirin is an imperfect therapy, and that anticoagulation looks very promising but is difficult to achieve.
Source Information
From the Stroke Service, Massachusetts General Hospital, Boston.
References
Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005;352:1305-1316.
Thijs VN, Albers GW. Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy. Neurology 2000;55:490-497.
Wong KS, Li H. Long-term mortality and recurrent stroke risk among Chinese stroke patients with predominant intracranial atherosclerosis. Stroke 2003;34:2361-2366.
Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 2003;41:Suppl S:62S-69S.
Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl:204S-233S.
Samsa GP, Matchar DB. Relationship between test frequency and outcomes of anticoagulation: a literature review and commentary with implications for the design of randomized trials of patient self-management. J Thromb Thrombolysis 2000;9:283-292.
Horstkotte D, Piper C, Wiemer M. Optimal frequency of patient monitoring and intensity of oral anticoagulation therapy in valvular heart disease. J Thromb Thrombolysis 1998;5:S19-S24.
SSYLVIA Study Investigators. Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA): study results. Stroke 2004;35:1388-1392.(Walter J. Koroshetz, M.D.)
The outcome data from WASID clarify some but not all the relevant issues. The use of a nonstandard, large dose of aspirin and the absence of evidence tying the dose of aspirin to a benefit in stroke prevention make it difficult to choose an antiplatelet regimen and a dose in clinical practice. The occurrence of more deaths due to cancer, congestive heart failure, diabetes, and even cardiac causes in the warfarin-treated group than in the aspirin-treated group stands out as incongruous with the results of previous warfarin studies involving tens of thousands of patients with vascular disease.4 The lenient classification of bleeding disorders as major hemorrhage, some of which do not carry the same level of disability as stroke, also contributed to a higher rate of "major hemorrhage" among warfarin-treated patients than in previous studies. Given that there was no significant difference in the primary end point between the two treatment groups, the study was appropriately stopped because of safety considerations. The results of this trial may appear to a cursory reader to represent an open-and-shut case; the authors conclude, "Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis." If only the practice of medicine were so simple.
The WASID Trial was an intention-to-treat, comparison trial of the administration of aspirin at a dose of 1300 mg per day and warfarin with a target international normalized ratio (INR) of 2.0 to 3.0. The target INR turned out to be not so easy to achieve. In this study, the patients receiving warfarin were within their INR goal only about 63 percent of the time, and approximately 28 percent of the patients dropped out of the warfarin-treated group. As compared with published data, 63 percent as a percentage of time in the target range is not bad.5 In prior studies, the time in the target range correlated with clinical outcomes,6 and seemingly it did so in WASID as well. Even considering only the patients who received treatment, the rate of ischemic stroke was 25 per 100 patient-years with a subtherapeutic INR — a rate that was reduced to 5 per 100 patient-years with a therapeutic INR. The rate of major cardiac events was 10.8 per 100 patient-years with a subtherapeutic INR and was reduced to 0.4 per 100 patient-years with a therapeutic INR. These data suggest that anticoagulation within the therapeutic range is associated with a striking reduction in the risk of cerebrovascular and cardiovascular events. Unfortunately, it is extremely difficult, if not impossible, to achieve a consistent therapeutic INR with warfarin in a population study or in routine practice. The optimal scheme for INR testing and warfarin dose adjustment has not been definitively determined. Why do we instruct patients who are taking warfarin to check their INR once a month? The percentage of time in the target range in studies of warfarin ranges from 40 percent to 92 percent,5 the latter in a patient self-test study with checks occurring every four days.7
The negative findings of the WASID Trial are clearly an indictment of the shortcomings of long-term warfarin use, but the INRs when the events occurred suggest that therapeutic anticoagulation can be very beneficial. How should the treating physician change his or her practice on the basis of the findings of this study? Clearly, the data indicate that long-term warfarin use with an expected time in the INR target range of less than 63 percent is not efficacious for all patients with symptomatic intracranial stenoses. However, the WASID data do not necessarily suggest that all patients with symptomatic intracranial stenosis should be treated with aspirin during all phases of their disease and be left to face the 22 percent two-year risk of ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke that the WASID Trial predicts.
Concluding, on the basis of the WASID data, that there is no reason to obtain images of the intracranial vessels to diagnose this high-risk condition does not seem warranted, especially since the study did not address management of the commonly unstable, acute phase of symptomatic intracranial stenosis. Indeed, the Kaplan–Meier curves (Fig. 2 and 3 in the article) show an almost immediate rise in the probability of the primary end point after enrollment, and much of this early rise seems to be due to ischemic stroke. Delay in quickly achieving a therapeutic level of anticoagulation in high-risk patients might have contributed to the failure of warfarin. A practice of initially treating high-risk patients with a rapidly and consistently active anticoagulant, such as low-molecular-weight heparin, followed by a transition to antiplatelet therapy after an asymptomatic period might prevent the accumulation of early adverse events (Figure 1). What approach should be taken when a patient has symptoms each time anticoagulation is discontinued or the INR drops below the therapeutic level? The WASID data show that warfarin is not superior to 1300 mg of aspirin in a population study. Because the result may well be related to the inadequate time in the INR target range with warfarin, as opposed to a general ineffectiveness of anticoagulation, it does not preclude a trial of very carefully regulated anticoagulation in patients who continue to have recurrent ischemic events in the territory of the index vessel, despite antiplatelet therapy.
Figure 1. Recurrent Artery-to-Artery Emboli from a Vertebral Source.
A 58-year-old man had five nonstereotyped neurologic events over a two-month period, including posterior headache, nausea, vomiting, gait unsteadiness, vertigo, tingling of the right arm and leg, blurring of the vision, and diplopia. A computed tomographic angiogram (Panel A) shows bilateral, calcified vertebral stenoses (arrows) below a patent basilar artery (BA). RVA denotes right vertebral artery, and LVA left vertebral artery. Magnetic resonance images show multiple embolic infarcts due to distal embolism from the vertebral artery stenosis as bright lesions (arrows) in the parietal and occipital lobes (Panels B and C, respectively) and cerebellum (Panel D).
Is there a better way to ensure that anticoagulation remains therapeutic? New drugs that quickly achieve stable therapeutic anticoagulation or point-of-care INR testing with ultrafrequent adjustments in the warfarin dose may be worthy of study in this population, given its high rate of events. Given the known beneficial effects of antiplatelet agents on atherosclerotic risk and the inadequate time in the target range with warfarin, is it time to halt studies of warfarin alone, without concomitant antiplatelet agents, in patients with atherosclerotic disease? Finally, it should be mentioned that intracranial angioplasty is a procedure that has not been tested in a randomized, double-blind clinical trial, but it is not infrequently performed in patients who continue to have ischemic symptoms despite "optimal" medical therapy.8 The WASID data do not indicate that failure of aspirin therapy is a reason to refer patients for intracranial angioplasty. A trial of interventional treatment as compared with medical treatment that includes anticoagulation still seems warranted.
We will learn an enormous amount from the WASID data. The patients and the investigators deserve a great deal of credit for participating in and carrying out this very difficult study. The messages at this point are that symptomatic intracranial atherosclerosis is a mark of aggressive vascular disease, that aspirin is an imperfect therapy, and that anticoagulation looks very promising but is difficult to achieve.
Source Information
From the Stroke Service, Massachusetts General Hospital, Boston.
References
Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005;352:1305-1316.
Thijs VN, Albers GW. Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy. Neurology 2000;55:490-497.
Wong KS, Li H. Long-term mortality and recurrent stroke risk among Chinese stroke patients with predominant intracranial atherosclerosis. Stroke 2003;34:2361-2366.
Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 2003;41:Suppl S:62S-69S.
Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl:204S-233S.
Samsa GP, Matchar DB. Relationship between test frequency and outcomes of anticoagulation: a literature review and commentary with implications for the design of randomized trials of patient self-management. J Thromb Thrombolysis 2000;9:283-292.
Horstkotte D, Piper C, Wiemer M. Optimal frequency of patient monitoring and intensity of oral anticoagulation therapy in valvular heart disease. J Thromb Thrombolysis 1998;5:S19-S24.
SSYLVIA Study Investigators. Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA): study results. Stroke 2004;35:1388-1392.(Walter J. Koroshetz, M.D.)