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Print version ISSN 1807-5932

Clinics vol.67 no.6 São Paulo  2012 



Warfarin doses for anticoagulation therapy in elderly patients with chronic atrial fibrillation



Antonio de Padua Mansur; Julio Yoshio Takada; Solange Desiree Avakian; Celia M.C. Strunz

Faculdade de Medicina da Universidade de Sao Paulo, Heart Institute (InCor), Sao Paulo/SP, Brazil




OBJECTIVE: Anticoagulation is a challenge for the prophylaxis of thromboembolic events in elderly patients with chronic atrial fibrillation. Stable anticoagulation is defined as the time within >70% of the therapeutic range. However, the dosage required to achieve stable anticoagulation remains unknown. The aim of this study was to analyze the warfarin dose necessary for the maintenance of stable oral anticoagulation therapy in elderly patients.
METHODS: We analyzed 112 consecutive outpatients with atrial fibrillation who were >65 years of age, had received anticoagulation therapy with warfarin for more than 1 year and had a stable international normalized ratio between 2.0 and 3.0 for >6 months. The international normalized ratio was measured in the central laboratory using the traditional method.
RESULTS: The patients were stratified according to the following age groups: <75 or >75 years and <80 or >80 years. The mean daily doses of warfarin were similar for patients <75 or >75 years (3.34+1.71 versus 3.26 +1.27 mg/ day, p = 0.794) and <80 or >80 years (3.36+ 1.49 versus 3.15 + 1.23 mg/day, p = 0.433). In 88 (79%) patients, the daily warfarin dose was between 2 and 5 mg/day; in 13 (11%) patients, the daily warfarin dose was <2.0 mg/day; and in 11 (10%) patients, the daily warfarin dose was >5.0 mg/day. The correlation between the daily warfarin dose and the international normalized ratio was 0.22 (p = 0.012).
CONCLUSION: Stable anticoagulation was achieved in 80% of patients who received doses of 2 to 5 mg/day of warfarin, and the mean daily dose was similar across the age groups analyzed.

Keywords: Warfarin; Anticoagulation; Elderly; Chronic Atrial Fibrillation.




Chronic atrial fibrillation (AF) is more prevalent in the elderly population and serves to increase the risk of thromboembolic events. Oral anticoagulation therapy with warfarin is highly effective for the prevention of thromboem-bolic events (1,2). However, only half of the patients with AF are within the therapeutic range of anticoagulation, whereas the other half does not use oral anticoagulants (3) or are inadequately anticoagulated (4). Currently, oral anticoagulation therapy with warfarin requires regular control of the levels of anticoagulation based on an international normalized ratio (INR) between 2 and 3 (INR2-3) (5). It is known that elderly patients are more likely to experience both throm-boembolic events and bleeding, even when they are within the therapeutic range of anticoagulation (6). For example, intracranial bleeding occurs more frequently in very elderly patients (>85 years) and those with an INR value >3.5 (7). According to this increased bleeding risk in the elderly, physicians may tolerate nontherapeutic INR levels or prescribe lower doses of warfarin than the nonelderly would receive, which leads to a bias that favors inadequate and ineffective anticoagulation (8). Previous studies have demonstrated the efficacy and safety of chronic oral anticoagulation with warfarin in elderly patients by adopting an INR range between 2 and 3 (INR2-3). Patients with AF who remained within the INR2-3 therapeutic range for more than 70% of the anticoagulationtimehadnearlyan80% reduction in the risk of stroke (9). However, the average warfarin dose used in these studies is unknown, especially the mean dose in patients with INRs within the ideal range. Therefore, the current study aimed to analyze the average warfarin dose for anticoagulation in patients with chronic, stable INR2-3 scores. By providing a definition of the appropriate dose for these patients, we aim to provide health professionals with the safest warfarin dose, thus reducing the risk of bleeding and adjusting the dynamics of the laboratory analysis for anticoagulation.



From a population of 2,000 individuals undergoing chronic oral anticoagulation with warfarin, mostly to prevent thromboembolic events in patients with AF, we selected 112 ambulatory elderly patients (>65 years) who had received consecutive anticoagulation therapy with warfarin for more than 1 year and who had been INR2-3 stable for >6 months. These patients were divided into two groups according to the following age categories: <75 or >75 years and <80 or >80 years. We included only patients with AF and excluded patients with renal disease (creatinine levels >2.0 mg/dL) and uncompensated hepatic cancer or known endocrine diseases. We also excluded patients who had bleeding or significant changes in their INR in the preceding six months. The tolerable INR range was 1.8 to 3.2. The control routine outpatient anticoagulation analysis consisted of periodic visits to the doctor every two months with concomitant INR analysis. The Ethics Committee of the Heart Institute (InCor) approved this study, and written informed consent was obtained from all participants. Coagulation measurements were made using an automated method in our clinical laboratory, and the INR value was calculated according to the plasma clotting time of the patient divided by the clotting time of a normal control, raised to the power of the International Sensitivity Index (ISI). The venous blood samples were collected in tubes containing sodium citrate 3.8%. The plasma was obtained by centrifugation at 3000 rpm for 15 minutes and then analyzed using the Tcoag Destiny MaxTM (Trinity Biotech, Ireland) automated equipment. Also, a specific kit (PT Tcoag TriniCLOT Excel S) containing thromboplastin extracted from rabbit brain tissue was used, and this method had an ISI of 1.2. Normal, abnormal, and normal pooled plasma internal controls (TRINICHECK CONTROL - Trinity Biotech) were prepared in the laboratory and tested daily to assess the reliability and efficiency of the laboratory procedures to generate valid results. The results were divided into the following three groups according to the INR value obtained: INR<2.0, insufficiently anticoagulated patients; INR>2.0 but <3.5, appropriately anticoagulated patients; and INR> 3.5, excessively anticoagulated patients.

Statistical analysis

Sample size was calculated based on the differences between the 0.5 mg dose of warfarin and the average 1.5 mg standard deviation for patients <75 or >75 years, which resulted in 46 individuals for each group. The categorical variables were analyzed using the X2 test, and continuous variables were analyzed using the unpaired Student's t-test. A simple linear regression was used to analyze the correlation between the INR versus the daily warfarin dose. p-values<0.05 were considered statistically significant. The statistical software used was the ''Primer of Biostatistics'' version 4.02 (10).



The mean age of the selected patients was 79.3 + 5.57 years with a range from 65 to 98 years. Of these, 47 (42%) patients were male, and 65 (58%) were female. Regarding patient distribution by age, 27 patients were 65 to 75 years of age, 69 patients were 76 to 85 years of age, and 16 patients were >85 years of age. The average daily warfarin dose to maintain INR2-3 were similar for patients <75 or >75 years (3.34 +1.71 versus 3.26 + 1.27 mg/day, p = 0.794) and patients <80 or >80 years (3.36 + 1.49 versus 3.15 + 1.23 mg/day, p = 0.433) (Table 1). To achieve INR2-3, 88 (79%) patients received daily warfarin doses of 2 to 5 mg; 13 (11%) patients received doses <2 mg/day, and 11 (10%) patients received doses >5mg/ day. The correlation between the daily warfarin dose and the INR value was 0.22 (p = 0.012) (Figure 1).






This study demonstrates that 80% of patients had INRs within the optimal oral anticoagulation range (2.0 to 3.0) after receiving warfarin doses of 2-5 mg/day, and the mean dose was similar for both elderly age groups analyzed (< 75 or >75 years and <80 or >80 years). Previous studies have demonstrated the importance of maintaining a stable INR value between 2.0 to 3.0 for reducing strokes and mortality in patients with AF. The INR value remained within the therapeutic range more than 70% of the time, and age has been shown not to prevent patients from maintaining INRs within the recommended anticoagulation range (9,11,12). The stability of the INR value resulting from these doses facilitated anticoagulation in elderly patients, as well as the frequency of laboratory control. Furthermore, these doses may result in a smaller number of patients with an inadequate INR value (<2.0) and, therefore, increased protection from thromboembolic events and major bleeding. A recent study on patients with stable anticoagulation, time within the therapeutic range > 70%, and effective INR2-3 values demonstrated daily doses similar to those observed in our study (6). These authors also showed progressive reduction in the warfarin dose with increasing age, as 43 mg/week for patients aged 41 to 50 years was reduced to 24 mg/week for the 81- to 90-year-old age group. However, disconcordant with our study, this dose reduction was statistically significant for the ten-year difference in the age group > 40 years. In our study, the mean warfarin dose was similar between the groups of elderly individuals (>65 years) for the threshold ages of 75 years or 80 years. Inadequate anticoagulation is frequent (13), and one recent study that presented a systematic review of several other studies showed that many patients with AF are either inadequately anticoagulated or do not receive anticoagulation therapy (14). In a previous study, patients with INRs between 1.5 and 1.9 had a higher recurrence of venous thromboembolism compared to patients with INRs between 2.0 to 3.0, and this range of INR values was also not associated with a reduced risk of clinically significant bleeding over a follow-up period of 2.4 years (15). As compared to the optimal range of anticoagulation (INR2-3), we observed a significantly increased risk of ischemic stroke in patients with INRs < 1.8 as well as a risk of hemorrhagic stroke in patients with INRs >3.5, regardless of age or a high CHADS2 score (16).

These results confirm the lack of an effect of age on complications related to inadequate anticoagulation (17). Other studies have also shown that the stability of INR2-3 was independently linked to elderly patients (>70 years) (18,19), and other independent variables identified in these studies included the absence of heart failure, clinically significant associated diseases, and diabetes. The absence of a significant relationship between the INR value and warfarin dose stresses the importance of individual variability, and, therefore, the need to develop a safe, therapeutic treatment window for elderly patients. In our study, the correlation between the INR value and the daily dose of warfarin was statistically significant but low (r = 0.22, p = 0.012), and the therapeutic window consisted of a daily dose from 2 to 5 mg. The definition of a warfarin dose that results in stable anticoagulation could also be used to promote patient adherence to this treatment process. The consensus statement of the American Heart Association/ AmericanCollege of Cardiology/European Society of Cardiology recommends a monthly laboratory analysis of patients on oral anticoagulation with warfarin with stable INRs between 2 and 3 (20). However, laboratory analyses are typically conducted over longer periods, e.g., every two months for patients with stable anticoagulation. Thus, additional studies are needed to determine the appropriate frequency of control laboratory analysis for this group of patients, but in the absence of significant changes in feeding routines, medications, and complications related to new diseases, the period for control analysis may be further extended. Similarly, in stable patients, anticoagulation control can be performed by other health professionals, such as nurses and pharmacists, who are involved in medical supervision. This would likely further reduce the costs of anticoagulation, and the effectiveness of these procedures has been documented (21,22). Cost reduction while maintaining the efficacy of anticoagulation could also be obtained by caring for patients receiving anticoagulation in groups, instead of seeing each patient individually (23). Another option for patients with stable anticoagulation is self-control of the INR value for adjusting the warfarin dose (24).

INR2-3 was obtained in 80% of AF patients aged >65 years with stable chronic anticoagulation when these patients were given warfarin doses of 2 to 5 mg/day. The mean daily dose of warfarin was similar for the elderly age groups studied. Moreover, the doses of warfarin mentioned above can be used to provide safe anticoagulation for most patients, and stable anticoagulation will likely provide a significant cost reduction.



Mansur AP designed the study and was responsible for the patient data collection and manuscript writing. Takada JY designed the study and was responsible for the patient data collection and statistical analysis. Avakian SD designed the study and was responsible for the patient data collection and manuscript revision. Strunz CM designed the study and was responsible for manuscript revision.



1. Zimerman LI, Fenelon G, Martinelli Filho M, Grupi C, Atie J, Lorga Filho A, et al. Sociedade Brasileira de Cardiologia. Diretrizes Brasileiras de Fibrilacao Atrial. Arq Bras Cardiol 2009;92(6 supl.1):1-39.         [ Links ]

2. Stoddard MF, Singh P, Dawn B, Longaker RA. Left atrial thrombus predicts transient ischemic attack in patients with atrial fibrillation. Am Heart J. 2003;145(4):676-82,         [ Links ]

3. Mesas CE, Veloso HH, De Paola AA. Anticoagulation for atrial fibrillation: underutilization in a Brazilian tertiary outpatient clinic. Clin Cardiol. 2004;27(11):592-3.         [ Links ]

4. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-Analysis to Assess the Quality of Warfarin Control in Atrial Fibrillation Patients in the United States. J Manage Care Pharm. 2009;15(3):244-52.         [ Links ]

5. Blackshear JL, Baker VS, Rubino F, Safford R, Lane G, Flipse T, et al. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke prevention in atrial fibrillation III randomised clinical trial. Lancet. 1996;348(9028):633-8.         [ Links ]

6. Wieloch M, Sjalander A, Frykman V, Rosenqvist M, Eriksson N, Svensson PJ. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J. 2011;32(18):2282-9,         [ Links ]

7. Fang MC, Chang YC, Hylek EM, Rosand J, Greenberg SM, Go AS, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004;141(10):745-52.         [ Links ]

8. Chan PS, Maddox TM, Tang FM, Spinler S, Spertus JA. Practice-Level Variation in Warfarin Use Among Outpatients With Atrial Fibrillation (from the NCDR PINNACLE Program). American Journal of Cardiology. 2011;108(8):1136-40,         [ Links ]

9. Gallagher AM, Setakis E, Plumb JM, Clemens A, van Staa TP. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemostasis. 2011;106(5):968-77,         [ Links ]

10. Primer of Biostatistics, version 4.02. McGraw-Hill Companies, New York, 1996.         [ Links ]

11. White HD, Gruber M, Feyzi J, Kaatz S, Tse HF, Husted S, et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control - Results from SPORTIF III and IV. ArchInternMed. 2007;167(3):239-45,         [ Links ]

12. Morgan CL, McEwan P, Tukiendorf A, Robinson PA, Clemens A, Plumb JM. Warfarin treatment in patients with atrial fibrillation: Observing outcomes associated with varying levels of INR control. Thromb Res. 2009;124(1):37-41,         [ Links ]

13. Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart. 2005;91(4):472-7,         [ Links ]

14. OgilvieIM,NewtonN,WelnerSA,CowellW,LipGYH. Underuseof Oral Anticoagulants in Atrial Fibrillation: A Systematic Review. Am J Med. 2010;123(7):638-86,         [ Links ]

15. KearonC,GinsbergJS,Kovacs MJ,AndersonDR,Wells P,JulianJA,etal. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. New Engl J Med. 2003;349(7):631-9,         [ Links ]

16. Singer DE, Chang YC, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, et al. Should Patient Characteristics Influence Target Anticoagulation Intensity for Stroke Prevention in Nonvalvular Atrial Fibrillation? The ATRIA Study. Circ-Cardiovasc Qual. 2009;2(4):297-30.         [ Links ]

17. Parodi G, Marcucci R, Valenti R, Gori AM, Migliorini A, Giusti B, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA: the journal of the American Medical Association. 2011;306(11):1215-23,         [ Links ]

18. Witt DM, Delate T, Clark NP, Martell C, Tran T, Crowther MA, et al. Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood. 2009;114(5):952-6,         [ Links ]

19. Witt DM, Delate T, Clark NP, Martell C, Tran T, Crowther MA, et al. Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users. J Thromb Haemost. 2010;8(4):744-9,         [ Links ]

20. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curbs AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation - Executive summary. J Am Coll Cardiol. 2006; 48(4):854-906.         [ Links ]

21. Rudd KM, Dier JG. Comparison of Two Different Models of Anticoagulation Management Services with Usual Medical Care. Pharmacotherapy. 2010;30(4):330-8, phco.30.4.330.         [ Links ]

22. Hall D, Buchanan J, Helms B, Eberts M, Mark S, Manolis C, et al. Health Care Expenditures and Therapeutic Outcomes of a Pharmacist-Managed Anticoagulation Service versus Usual Medical Care. Pharmacotherapy. 2011;31(7):686-94,         [ Links ]

23. Griffin BL, Burkiewicz JS, Peppers LR, Warholak TL. International Normalized Ratio values in group versus individual appointments in a pharmacist-managed anticoagulation clinic. Am J Health-Syst Ph. 2009;66(13):1218-23,         [ Links ]

24. Watzke HH, Forberg E, Svolba G, Jimenez-Boj E, Krinninger B. A prospective controlled trial comparing weekly self-testing and self-dosing with the standard management of patients on stable oral anticoagulation. Thromb Haemostasis. 2000;83(5):661-5.         [ Links ]



Received for publication on November 17, 2011
First review completed on January 4, 2012
Accepted for publication on February 3, 2012



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