Optimal Anticoagulation for Patients With Atrial Fibrillation　— Benefits for Reducing Stroke Severity —

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder.¹ The prevalence of AF increases with age, and as such, AF is a serious issue in the aging population.^2–4 In patients with AF, thrombus formation in the left atrium (LA) can occasionally cause stroke and systemic embolism. Among the potential embolic sources, nonvalvular AF is currently the most frequent cause of cardioembolic stroke.

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In high-risk patients with AF, an embolus originating from the thrombus in the left appendage and/or LA may be transported with high flow through a large artery, especially towards the brain, and occlude the artery at the site of anatomical narrowing. A fibrin-rich thrombus generated in the LA secondary to AF is mostly larger than a platelet-rich thrombus. Additionally, there is poor development of collateral flow following sudden occlusion of an artery. As a consequence, blood flow in the brain is significantly and extensively reduced in the territory distal to the occluded artery following cardioembolic stroke. An infarction caused by cardioembolism typically shows cortical and subcortical lesions with clear margins, regional or scattered lesions in one vascular territory, or multiple lesions in multiple vascular territories. Thus, cardioembolic strokes cause the most severe neurological deficits compared with strokes that have other etiologies, such as atherothrombotic, lacunar, and other uncommon types.

Prevention of stroke secondary to AF is important for reducing the burden of post-stroke disability in the aging population.⁴ Oral anticoagulants (OACs) are highly effective for preventing stroke or systemic embolism in patients with AF; for example, warfarin reduces the incidence of stroke by 64%.⁵ In addition to these prophylactic effects, the appropriate use of warfarin may mitigate the severity of ischemic stroke.⁶ It has been reported that severe stroke was less frequent in 602 patients with an onset prothrombin time-international normalized ratio (PT-INR) ≥1.5 than in those with a PT-INR <1.5, even after adjusting for potential confounding factors (Figure).⁷ A similar association was found between the onset PT-INR and severe disability at 3 months, whereas there were no differences in poor functional outcome between patients with a PT-INR of 1.50–1.99 and those <1.50.

Figure.

Association between PT-INR at onset and clinical outcomes in patients with acute ischemic stroke. (A) Odds ratios (OR) and 95% confidence intervals (CI) of severe neurological deficits at 3 months and (B) poor functional outcome at 3 months, are shown according to the intensity of anticoagulation with warfarin. National Institutes of Health Stroke Scale (NIHSS) on admission ≥10 was regarded as severe neurological deficit. Poor functional outcome was defined as a modified Rankin scale ≥4 at 3 months. (Adapted with permission from Nakamura A, et al.⁷) PT-INR, prothrombin time-international normalized ratio.

There are a number of explanations for the relationship between the intensity of anticoagulation and stroke severity. Increased anticoagulation therapy may produce a smaller or more fragile embolus compared with insufficient anticoagulation. Alternatively, under increased fibrinolytic activity, the occluded artery may reopen before irreversible brain damage occurs, either by spontaneous lysis of the thrombus or migration of the thrombus to a distal position. Ay et al demonstrated that admission PT-INR correlated with infarct volume on diffusion-weighted imaging in patients with acute ischemic stroke under warfarin use.⁸ In that study, a PT-INR <2.0 was associated with a 3.5-fold greater lesion volume compared with a PT-INR ≥2.0. Further, the median lesion volume was significantly smaller in patients with a PT-INR ≥1.6 than in those with a PT-INR <1.6. Recently, in a study of 68 stroke patients with nonvavular AF, Matsumoto et al also reported that infarct size was smaller in patients with a PT-INR >1.6 compared with those with a PT-INR <1.6.⁹ This relationship was also examined in a larger population of 180 cardioembolic patients with nonvalvular AF, which is reported in this issue of the Journal.¹⁰ Warfarin control at a PT-INR ≥2.0 was effective in reducing the infarct volume, although there were no differences in infarct volume between a PT-INR 1.60–1.99 and a PT-INR<1.60.

Warfarin has a narrow therapeutic range for reducing the risk of embolic events without increasing hemorrhagic risk. It is internationally accepted that a PT-INR <2.0 is associated with an increased risk of ischemic stroke, whereas hemorrhagic events occur more frequently in the range of PT-INR >3.0. However, the risk of intracranial hemorrhage during anticoagulation therapy may differ according to ethnic group.¹¹ Asian subjects are at higher risk of intracranial hemorrhage than Caucasians. Thus, the Japanese guidelines recommend a reduced anticoagulation intensity of PT-INR 1.6–2.6 for nonvalvular AF in patients >70 years old.^12–14 To maintain the optimal intensity of anticoagulation for AF patients receiving warfarin, clinicians continuously monitor PT-INR and adjust the dose of warfarin accordingly. Nevertheless, a PT-INR below the therapeutic range is not uncommon during AF management in clinical practice. In fact, under-dosing of warfarin is one of the major causes of ischemic stroke in patients with nonvalvular AF.¹⁵

Optimal anticoagulation therapy may be recommended not only to prevent stroke but also to improve clinical outcomes following stroke. However, there remain some unsolved questions. For example, what intensity of anticoagulation is associated with a reduced infarct volume or favorable outcome, and is this association independent of ethnicity, race, or age? Further, can similar effects be achieved using the direct OACs, which are becoming increasingly used in the clinic, although the intensity of anticoagulation varies according to the time from medication. Further studies are required to confirm the beneficial effects of appropriate anticoagulation with OACs on outcomes following cardioembolic stroke.

Sources of Funding

None.

References

• 1.   Verheugt FW, Granger CB. Oral anticoagulants for stroke prevention in atrial fibrillation: Current status, special situations, and unmet needs. Lancet 2015; 386: 303–310.
• 2.   Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, et al. Prevalence of atrial fibrillation in the general population of Japan: An analysis based on periodic health examination. Int J Cardiol 2009; 137: 102–107.
• 3.   Atarashi H, Inoue H, Okumura K, Yamashita T, Kumagai N, Origasa H, et al. Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: A report from the J-RHYTHM Registry. Circ J 2011; 75: 1328–1333.
• 4.   Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: A global burden of disease 2010 study. Circulation 2014; 129: 837–847.
• 5.   Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857–867.
• 6.   Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349: 1019–1026.
• 7.   Nakamura A, Ago T, Kamouchi M, Hata J, Matsuo R, Kuroda J, et al. Intensity of anticoagulation and clinical outcomes in acute cardioembolic stroke: The Fukuoka Stroke Registry. Stroke 2013; 44: 3239–3242.
• 8.   Ay H, Arsava EM, Gungor L, Greer D, Singhal AB, Furie KL, et al. Admission international normalized ratio and acute infarct volume in ischemic stroke. Ann Neurol 2008; 64: 499–506.
• 9.   Matsumoto M, Okazaki S, Sakaguchi M, Ohara N, Furukado S, Nagano K, et al. Preadmission therapeutic anticoagulation reduces cerebral infarct volume in patients with nonvalvular atrial fibrillation. Eur Neurol 2011; 66: 277–282.
• 10.   Matsumoto M, Sakaguchi M, Okazaki S, Hashikawa K, Takahashi T, Matsumoto M, et al. Relationship between infarct volume and prothrombin time-international normalized ratio in ischemic stroke patients with nonvalvular atrial fibrillation. Circ J 2017; 81: 391–396.
• 11.   Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 2007; 50: 309–315.
• 12.   Yasaka M, Minematsu K, Yamaguchi T. Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation. Intern Med 2001; 40: 1183–1188.
• 13.   Inoue H, Okumura K, Atarashi H, Yamashita T, Origasa H, Kumagai N, et al. Target international normalized ratio values for preventing thromboembolic and hemorrhagic events in Japanese patients with non-valvular atrial fibrillation: Results of the J-RHYTHM Registry. Circ J 2013; 77: 2264–2270.
• 14.   JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013): Digest version. Circ J 2014; 78: 1997–2021.
• 15.   Nakamura A, Kuroda J, Ago T, Hata J, Matsuo R, Arakawa S, et al. Causes of ischemic stroke in patients with non-valvular atrial fibrillation. Cerebrovasc Dis 2016; 42: 196–204.