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KOKUBO Y

EDITORIAL

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp

New Oral Anticoagulants (NOAC) Studies in the Ideal and the Real World – Needs of Prospective Observational Studies – Yoshihiro Kokubo, MD, PhD

T

he anticoagulant warfarin has been conventionally used for prophylaxis of cerebral infarction (cardioembolism) with atrial fibrillation (AF). The prescription rate of warfarin increased after 2000 in particular. In fact, warfarin was used in 87% of patients with AF in the J-RHYTHM registration study at Japanese institutions.1 That registry study demonstrated that a PT-INR=1.6–2.6 is a safe and effective target for preventing thromboembolic events in nonvalvular AF (NVAF) patients in Japan, particularly those aged ≥70 years’ although INR=2.6–2.99 is also effective, it is associated with a trend toward an increased risk of major hemorrhage. Warfarin has been the gold standard of stroke prevention for patients with AF. However, it is associated with many limitations: high risks of drug-drug (vitamin K) and drug-food (such as natto [traditional Japanese fermented soybeans]) interactions, long half-life, complicated induction and interruption, and the need for frequent PT-INR monitoring.

Article p 1018 Recently, new oral anticoagulants (NOACs) have been used as alternatives to warfarin anticoagulation in NVAF. A randomized trial, RE-LY,2 evaluated 110 mg and 150 mg twicedaily doses of dabigatran in such patients. Compared with warfarin, both doses of dabigatran were associated with similar and lower rates of stroke and systemic embolism, and with lower and similar rates of major hemorrhage, respectively. The randomized, double-blind ARISTOTLE clinical trial showed that apixaban was superior to warfarin in preventing stroke or systemic embolism in AF patients, caused less bleeding, and resulted in lower mortality.3 The ROCKET-AF double-blind clinical trial showed that rivaroxaban was not inferior to warfarin in the prevention of subsequent stroke or systemic embolism in AF patients.4 A randomized double-blind, double-dummy trial found that 2 different once-daily regimens of edoxaban were not inferior to warfarin with respect to the prevention of stroke or systemic embolism in AF patients and were associated with significantly lower rates of bleeding and cardiovascular disease mortality.5 A systematic review and meta-analysis of subgroups showed that NOACs were generally associated with a lower risk of intracranial bleeding than warfarin, although no more effective than warfarin for prevention of ischemic stroke and systemic embolic event in the overall

Table.  Main Exclusion Criteria Common to 4 Major Clinical Trials of Oral Anticoagulants Common exclusion criteria   Acute stroke, moderate or severe mitral stenosis, severe renal failure, high risk of bleeding. Other exclusion criteria   Acute coronary syndrome, coronary revascularization, active endocarditis, use of dual antiplatelet therapy, other indications for anticoagulation therapy, an inability to adhere to study procedures, severe stroke 70%. The estimation of stroke risk matched well with the CHADS2 score estimate in 87% of cases; however, estimated bleeding risk matched in only 64% of cases, and with an apparent overestimation in 26%. According to the European Primary Care Cardiovascular Society, NOACs are at least as safe as warfarin.13 The NOAC guidelines also have more reliable methods of determining stroke and bleeding risks, to guide treatment choice and improve management of risk factors better; for instance, the exclusion of low-dose aspirin as an option for most patients, the use of good therapeutic control if warfarin is used, and the availability of a range of new rapid-onset, short-acting, anticoagulants with few interactions and no monitoring requirements.13 The ORBIT-AF was an out-patient registry conducted for AF patients14 and showed that two-thirds of patients with AF who were previously not recommended for oral anticoagulants were newly recommended under the 2014 guidelines. It is also important for patients with asymptomatic or untreated AF to consult a doctor. A person with a high risk of AF should undergo electrocardiography regularly. However, the present Japanese medical examination does not include electrocardiography and no risk chart to predict incident AF as a substitute for an electrocardiogram. Quite recently, a Japanese cohort study showed that hypertension is a risk for incident AF.15 Compared with normal blood pressure and normal weight, systolic prehypertension with overweight is associated with increased risk of incident AF (P for interaction=0.04). We hope that an AF prediction tool such as the Framingham Heart Study will be available in Japan as soon as possible.

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Acknowledgments I thank Dr Masatoshi Koga for his useful discussion.

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Sources of Funding This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Nos. 25293147 and 26670320), and Intramural Research Fund of the National Cerebral and Cardiovascular Center (22-1-2).

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Disclosures/Conflict(s) of Interest

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None.

References

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. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139 – 1151. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981 – 992. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883 – 891. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093 – 2104. Gomez-Outes A, Terleira-Fernandez AI, Calvo-Rojas G, Suarez-Gea ML, Vargas-Castrillon E. Dabigatran, Rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: A systematic review and meta-analysis of subgroups. Thrombosis 2013; 2013: 640723. JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013): Digest version. Circ J 2014; 78: 1997 – 2021. National Clinical Guideline Centre (UK). Atrial Fibrillation: The Management of Atrial Fibrillation. London: National Institute for Health and Care Excellence (UK); 2014 June. PubMed PMID: 25340239. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: Executive summary: A report of the ACC/AHA Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130: 2071 – 2104. Toyoda K, Arihiro S, Todo K, Yamagami H, Kimura K, Furui E, et al. Trends in oral anticoagulant choice for acute stroke patients with nonvalvular atrial fibrillation in Japan: The SAMURAI-NVAF Study. Int J Stroke 2015 January 12, doi:10.1111/ijs.12452. Saji N, Kimura K, Aoki J, Uemura J, Sakamoto Y. Intracranial hemorrhage caused by non-vitamin K antagonist oral anticoagulants (NOACs): Multicenter retrospective cohort study in Japan. Circ J 2015; 79: 1018 – 1023. Patel AD, Tan MK, Angaran P, Bell AD, Berall M, Bucci C, et al. Risk stratification and stroke prevention therapy care gaps in canadian atrial fibrillation patients. Am J Cardiol 2015; 115: 641 – 646. Hobbs FR, Taylor CJ, Jan Geersing G, Rutten FH, Brouwer JR. European Primary Care Cardiovascular Society (EPCCS) consensus guidance on stroke prevention in atrial fibrillation (SPAF) in primary care. Eur J Prev Cardiol 2015 February 20, doi:10.1177/ 2047487315571890. O’Brien EC, Kim S, Hess PL, Kowey PR, Fonarow GC, Piccini JP, et al. Effect of the 2014 Atrial Fibrillation Guideline Revisions on the proportion of patients recommended for oral anticoagulation. JAMA Intern Med 2015 March 2, doi:10.1001/jamainternmed.2015.13. Kokubo Y, Watanabe M, Higashiyama A, Nakao YM, Kobayashi T, Watanabe T, et al. Interaction of blood pressure and body mass index with risk of incident atrial fibrillation in a Japanese urban cohort: The Suita Study. Am J Hypertens 2015 April 6, doi:10.1093/ajh/hpv038.

  1. Inoue H, Okumura K, Atarashi H, Yamashita T, Origasa H, Kumagai

Circulation Journal  Vol.79, May 2015

New Oral Anticoagulants (NOAC) Studies in the Ideal and the Real World - Needs of Prospective Observational Studies.

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