Thromb Haemost 2019; 119(01): 066-076
DOI: 10.1055/s-0038-1676519
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Predictors of Over-Anticoagulation in Warfarin Users in the UK General Population: A Nested Case–Control Study in a Primary Health Care Database

Mar Martín-Pérez
1   Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, Spain
,
David Gaist
2   Department of Neurology, Odense University Hospital, Odense, Denmark
3   Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
,
Francisco J. de Abajo
4   Clinical Pharmacology Unit, University Hospital Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
5   Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain
6   Pharmacoepidemiology Group, Ramón y Cajal Health Research Institute (IRYCIS), Madrid, Spain
,
Luis A. García Rodríguez
1   Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, Spain
› Author Affiliations
Funding None.
Further Information

Publication History

06 July 2018

18 October 2018

Publication Date:
31 December 2018 (online)

Abstract

Background Many patients on warfarin therapy often present with supratherapeutic international normalized ratio (INR) levels, resulting from the influence of several patient-specific factors, which have been associated with adverse outcomes.

Objective This article aims to identify risk factors for over-anticoagulation (INR levels ≥4) in a cohort of patients taking warfarin.

Methods A cohort of warfarin users aged 18 to 85 years from January 2005 to April 2013 was identified in The Health Improvement Network U.K. primary care database (N = 12,506). A random date was assigned to all patients within their eligible person-time (index date), and a nested case–control analysis was performed with individuals presenting a first episode of INR level ≥4 after the index date used as cases (N = 699) and patients with non-supratherapeutic INR values (≤3) as controls (N = 9,798). Using unconditional logistic regression models, odds ratios with 95% confidence intervals were calculated adjusted for potential confounders. Two sensitivity analyses were performed with alternative definitions of over-anticoagulation (INR levels ≥5 or > 3).

Results Among the factors examined, the strongest predictors of over-anticoagulation were warfarin indication (in particular, valvular atrial fibrillation and valve replacement), renal failure (with the risk increasing steeply with decreasing estimated glomerular filtration rate), cancer, anaemia, respiratory infections treated with antibiotics, chronic obstructive pulmonary disease treated with β2-agonists, polypharmacy (≥10 medications), low socio-economic status and residency in rural areas. Similar results were obtained when supratherapeutic levels were defined as INR ≥5 or, alternatively, as INR > 3.

Conclusion Predictors of supratherapeutic INR levels found in this study might help physicians identify patients where closer INR monitoring is warranted.

Authors' Contributions

F.J. de Abajo, D. Gaist, L.A. García Rodríguez and M. Martín-Pérez substantially contributed to the concept and design of the article; acquired, analysed and interpreted data; drafted and critically reviewed the article for important intellectual content; and approved the version to be published.


Supplementary Material

 
  • References

  • 1 Bourgeois S, Jorgensen A, Zhang EJ. , et al. A multi-factorial analysis of response to warfarin in a UK prospective cohort. Genome Med 2016; 8 (01) 2
  • 2 Johnson JA, Caudle KE, Gong L. , et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther 2017; 102 (03) 397-404
  • 3 Merli GJ, Tzanis G. Warfarin: what are the clinical implications of an out-of-range-therapeutic international normalized ratio?. J Thromb Thrombolysis 2009; 27 (03) 293-299
  • 4 Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6, Suppl): 160S-198S
  • 5 Jacobs LG. Warfarin pharmacology, clinical management, and evaluation of hemorrhagic risk for the elderly. Cardiol Clin 2008; 26 (02) 157-167
  • 6 Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med 1994; 121 (09) 676-683
  • 7 Hylek EM, Regan S, Go AS, Hughes RA, Singer DE, Skates SJ. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med 2001; 135 (06) 393-400
  • 8 Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (3, Suppl): 287S-310S
  • 9 Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120 (11) 897-902
  • 10 Wittkowsky AK, Devine EB. Frequency and causes of overanticoagulation and underanticoagulation in patients treated with warfarin. Pharmacotherapy 2004; 24 (10) 1311-1316
  • 11 Abdel-Aziz MI, Ali MA, Hassan AK, Elfaham TH. Factors influencing warfarin response in hospitalized patients. Saudi Pharm J 2015; 23 (06) 642-649
  • 12 Berg TM, O'Meara JG, Ou NN. , et al. Risk factors for excessive anticoagulation among hospitalized adults receiving warfarin therapy using a pharmacist-managed dosing protocol. Pharmacotherapy 2013; 33 (11) 1165-1174
  • 13 Demirkan K, Stephens MA, Newman KP, Self TH. Response to warfarin and other oral anticoagulants: effects of disease states. South Med J 2000; 93 (05) 448-454
  • 14 Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998; 279 (09) 657-662
  • 15 Clark NP, Delate T, Riggs CS. , et al; Warfarin-Associated Research Projects and Other Endeavors Consortium. Warfarin interactions with antibiotics in the ambulatory care setting. JAMA Intern Med 2014; 174 (03) 409-416
  • 16 Fang MC, Go AS, Hylek EM. , et al. Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc 2006; 54 (08) 1231-1236
  • 17 Froom P, Miron E, Barak M. Oral anticoagulants in the elderly. Br J Haematol 2003; 120 (03) 526-528
  • 18 Marie I, Leprince P, Menard JF, Tharasse C, Levesque H. Risk factors of vitamin K antagonist overcoagulation. QJM 2012; 105 (01) 53-62
  • 19 Keeling D, Baglin T, Tait C. , et al. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol 2011; 154: 311-324
  • 20 Brigden ML, Kay C, Le A, Graydon C, McLeod B. Audit of the frequency and clinical response to excessive oral anticoagulation in an out-patient population. Am J Hematol 1998; 59 (01) 22-27
  • 21 Freixa R, Blanch P, Ibernón M. , et al. Identification of factors responsible for oral over-anticoagulation in outpatients with heart disease [in Spanish]. Rev Esp Cardiol 2003; 56 (01) 65-72
  • 22 Jaakkola S, Nuotio I, Kiviniemi TO, Virtanen R, Issakoff M, Airaksinen KEJ. Incidence and predictors of excessive warfarin anticoagulation in patients with atrial fibrillation-the EWA study. PLoS One 2017; 12 (04) e0175975
  • 23 Nelson WW, Wang L, Baser O, Damaraju CV, Schein JR. Out-of-range INR values and outcomes among new warfarin patients with non-valvular atrial fibrillation. Int J Clin Pharm 2015; 37 (01) 53-59
  • 24 Panneerselvam S, Baglin C, Lefort W, Baglin T. Analysis of risk factors for over-anticoagulation in patients receiving long-term warfarin. Br J Haematol 1998; 103 (02) 422-424
  • 25 Martín-Pérez M, Gaist D, de Abajo FJ, Rodríguez LAG. Population impact of drug interactions with warfarin: a real-world data approach. Thromb Haemost 2018; 118 (03) 461-470
  • 26 Blak BT, Thompson M, Dattani H, Bourke A. Generalisability of The Health Improvement Network (THIN) database: demographics, chronic disease prevalence and mortality rates. Inform Prim Care 2011; 19 (04) 251-255
  • 27 Lewis JD, Schinnar R, Bilker WB, Wang X, Strom BL. Validation studies of the health improvement network (THIN) database for pharmacoepidemiology research. Pharmacoepidemiol Drug Saf 2007; 16 (04) 393-401
  • 28 Cannegieter SC, Rosendaal FR, Wintzen AR, van der Meer FJ, Vandenbroucke JP, Briët E. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333 (01) 11-17
  • 29 Hirsh J, Dalen J, Anderson DR. , et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 (1, Suppl): 8S-21S
  • 30 Rouaud A, Hanon O, Boureau AS, Chapelet G, de Decker L. Comorbidities against quality control of VKA therapy in non-valvular atrial fibrillation: a French national cross-sectional study. PLoS One 2015; 10 (03) e0119043
  • 31 Fitzmaurice DA, Blann AD, Lip GY. Bleeding risks of antithrombotic therapy. BMJ 2002; 325 (7368): 828-831
  • 32 Lee A, Crowther M. Practical issues with vitamin K antagonists: elevated INRs, low time-in-therapeutic range, and warfarin failure. J Thromb Thrombolysis 2011; 31 (03) 249-258
  • 33 Limdi NA, Limdi MA, Cavallari L. , et al. Warfarin dosing in patients with impaired kidney function. Am J Kidney Dis 2010; 56 (05) 823-831
  • 34 Limdi NA, Beasley TM, Baird MF. , et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20 (04) 912-921
  • 35 Bonde AN, Lip GYH, Kamper AL. , et al. Renal function, time in therapeutic range and outcomes in warfarin-treated atrial fibrillation patients: a retrospective analysis of nationwide registries. Thromb Haemost 2017; 117 (12) 2291-2299
  • 36 Szummer K, Gasparini A, Eliasson S. , et al. Time in therapeutic range and outcomes after warfarin initiation in newly diagnosed atrial fibrillation patients with renal dysfunction. J Am Heart Assoc 2017; 6 (03) 6
  • 37 Miners JO, Yang X, Knights KM, Zhang L. The role of the kidney in drug elimination: transport, metabolism, and the impact of kidney disease on drug clearance. Clin Pharmacol Ther 2017; 102 (03) 436-449
  • 38 Palareti G, Legnani C, Lee A. , et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000; 84 (05) 805-810
  • 39 Reddy U, Mallepaddi NR, Chevassut TJ. High INR on warfarin. BMJ 2015; 350: h1282
  • 40 del Campo M, Roberts G. Changes in warfarin sensitivity during decompensated heart failure and chronic obstructive pulmonary disease. Ann Pharmacother 2015; 49 (09) 962-968
  • 41 Verstuyft C, Robert A, Morin S. , et al. Genetic and environmental risk factors for oral anticoagulant overdose. Eur J Clin Pharmacol 2003; 58 (11) 739-745
  • 42 Jaffer A, Bragg L. Practical tips for warfarin dosing and monitoring. Cleve Clin J Med 2003; 70 (04) 361-371
  • 43 DeRemer CE, McMichael B, Young HN. Warfarin patients with anemia show trend of out-of-range international normalized ratio frequency with point-of-care testing in an anticoagulation clinic. J Pharm Pract 2018; 897190018768114
  • 44 Wood J. Rural Health and Healthcare: A North West perspective; 2004. Available at: www.nwpho.org.uk/reports/ruralhealth.pdf . Accessed October 15, 2018
  • 45 Penning-van Beest FJ, Geleijnse JM, van Meegen E, Vermeer C, Rosendaal FR, Stricker BH. Lifestyle and diet as risk factors for overanticoagulation. J Clin Epidemiol 2002; 55 (04) 411-417
  • 46 Baron JA, Mann J, Stukel T. Effect of weight loss on coagulation factors VII and X. Am J Cardiol 1989; 64 (08) 519-522
  • 47 Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation. Thromb Haemost 2001; 86 (02) 569-574
  • 48 Witt DM, Delate T, Clark NP. , et al; Warfarin Associated Research Projects and other EnDeavors (WARPED) Consortium. Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood 2009; 114 (05) 952-956
  • 49 Garcia DA, Regan S, Crowther M, Hylek EM. The risk of hemorrhage among patients with warfarin-associated coagulopathy. J Am Coll Cardiol 2006; 47 (04) 804-808
  • 50 Narum S, Solhaug V, Myhr K, Johansen PW, Brørs O, Kringen MK. Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system. Br J Clin Pharmacol 2011; 71 (02) 254-262