title: Risk of major bleeding at different PT-INR ranges in elderly Japanese patients with non-valvular atrial fibrillation receiving warfarin: a nested case-control study.
abstract: BACKGROUND
  Debate continues about the optimal anticoagulation level for elderly Japanese patients with non-valvular atrial fibrillation (NVAF) receiving warfarin. The Japanese Circulation Society guideline has recommended prothrombin time-international normalized ratios (PT-INR) of 1.6 - 2.6 for elderly patients and 2.0 - 3.0 for non-elderly patients, because previous observational studies indicated increased risk of bleeding when the ratio exceeded 2.6. We aimed to reappraise the relationship between PT-INR and the risk of major bleeding in elderly Japanese patients.
  
  
  METHODS
  From the electronic medical records, we selected a cohort of elderly (age ≥ 70 years) Japanese patients with NVAF who were prescribed warfarin for the prevention of thromboembolic diseases between November 2010 and March 2014 at Kanto Rosai Hospital. We identified those who developed major bleeding (cases). For each case, we randomly selected two matched controls by adopting a risk-set sampling method defined by calendar date, age, gender, length of warfarin administration, and the prescriber of warfarin. The risk of major bleeding in patients having PT-INR ≤ 1.49, 1.50 - 1.99, 2.00 - 2.49 (the reference), 2.50 - 2.99, and ≥ 3.00 were compared using the conditional logistic regression method. The study protocol was approved by the IRB before the study was begun.
  
  
  RESULTS
  Among the cohort of 806 elderly patients, we identified 32 cases and selected 64 matched controls. The overall incidence of major bleeding was 3.5 per 100 patient-years. The odds ratios (95 % confidence intervals) for the risk of developing major bleeding in patients with PT-INR ≤ 1.49 (n = 20), 1.50 - 1.99 (n = 32), 2.00 - 2.49 (n = 18), 2.50 - 2.99 (n = 10), and ≥ 3.00 (n = 16) were 1.0 (0.2, 5.9), 0.3 (0.1, 1.9), 1.0 (reference), 1.2 (0.2, 8.4), and 19.8 (2.0, 198.9), respectively, with a significant difference between ≥ 3.00 and reference.
  
  
  CONCLUSIONS
  Among elderly Japanese patients with NVAF, PT-INR 2.0 - 3.0 may be associated with a clinically permissible risk of major bleeding while PT-INR ≥ 3.00 a significant risk. Further studies are warranted to determine whether the risk of major bleeding is significantly lower for PT-INR 2.50 - 2.99 than for PT-INR ≥ 3.00.
authors.affiliation: Department of Hospital Pharmacy, Japan Labour Health and Welfare Organization Kanto Rosai Hospital, 1-1 Kiduki-Sumiyoshi, Nakahara, Kawasaki, Kanagawa 211-8510 Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohgushi
authors.affiliation: Department of Hospital Pharmacy, Japan Labour Health and Welfare Organization Kanto Rosai Hospital, 1-1 Kiduki-Sumiyoshi, Nakahara, Kawasaki, Kanagawa 211-8510 Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohtani
authors.affiliation: Department of Hospital Pharmacy, Japan Labour Health and Welfare Organization Kanto Rosai Hospital, 1-1 Kiduki-Sumiyoshi, Nakahara, Kawasaki, Kanagawa 211-8510 Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Nakayama
authors.affiliation: Department of Hospital Pharmacy, Japan Labour Health and Welfare Organization Kanto Rosai Hospital, 1-1 Kiduki-Sumiyoshi, Nakahara, Kawasaki, Kanagawa 211-8510 Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Asai
authors.affiliation: Department of Hospital Pharmacy, Japan Labour Health and Welfare Organization Kanto Rosai Hospital, 1-1 Kiduki-Sumiyoshi, Nakahara, Kawasaki, Kanagawa 211-8510 Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Cardiology, Japan Labour Health and Welfare Organization Kanto Rosai Hospital, 1-1 Kiduki-Sumiyoshi, Nakahara, Kawasaki, Kanagawa 211-8510 Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Namiki
authors.affiliation: Department of Public Health and Epidemiology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose Tokyo, 204-8588 Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Akazawa
authors.affiliation: Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose Tokyo, 204-8588 Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Echizen
keywords: Elderly patients; Japanese; Non-valvular atrial fibrillation; PT-INR; Warfarin
references.citation: Chest. 2008 Jun;133(6 Suppl):546S-592S
references.pmid: 18574273
references.citation: Circ J. 2015;79(11):2345-52
references.pmid: 26329097
references.citation: Lancet. 2010 Sep 18;376(9745):975-83
references.pmid: 20801496
references.citation: BMJ. 2002 Nov 9;325(7372):1073-5
references.pmid: 12424167
references.citation: Am J Med. 2011 Feb;124(2):111-4
references.pmid: 20887966
references.citation: N Engl J Med. 2013 Nov 28;369(22):2093-104
references.pmid: 24251359
references.citation: Thromb Res. 2012 Jul;130(1):21-6
references.pmid: 22137743
references.citation: Thromb Haemost. 1993 Mar 1;69(3):236-9
references.pmid: 8470047
references.citation: N Engl J Med. 1996 Aug 22;335(8):540-6
references.pmid: 8678931
references.citation: J Cardiol. 2015 Mar;65(3):175-7
references.pmid: 25169015
references.citation: N Engl J Med. 2011 Sep 8;365(10):883-91
references.pmid: 21830957
references.citation: Ann Intern Med. 1994 Jun 1;120(11):897-902
references.pmid: 8172435
references.citation: Intern Med. 2001 Dec;40(12):1183-8
references.pmid: 11813841
references.citation: Circ Cardiovasc Qual Outcomes. 2009 Jul;2(4):297-304
references.pmid: 20031854
references.citation: Nihon Rinsho. 2011 Nov;69 Suppl 9:567-71
references.pmid: 22724264
references.citation: Am J Epidemiol. 1976 Feb;103(2):226-35
references.pmid: 1251836
references.citation: N Engl J Med. 2011 Sep 15;365(11):981-92
references.pmid: 21870978
references.citation: Stroke. 1991 Aug;22(8):983-8
references.pmid: 1866765
references.citation: Eur Heart J. 2010 Oct;31(19):2369-429
references.pmid: 20802247
references.citation: N Engl J Med. 2009 Sep 17;361(12):1139-51
references.pmid: 19717844
references.citation: Circ J. 2014;78(8):1997-2021
references.pmid: 24965079
references.citation: JAMA. 2001 Jun 13;285(22):2864-70
references.pmid: 11401607