European Journal of Clinical Pharmacology © by Springer-Verlag 1979
Europ. J. clin. Pharmacol. 15, 319-322 (1979)
Factors Affecting Warfarin Requirements A Prospective Population Study P. A. Routledge, P. H. Chapman, D. M. Davies, and M. D. Rawlins Department of Pharmacological Sciences,WolfsonUnit of Clinical Pharmacology, Universityof Newcastleupon Tyne and Department of Clinical Pharmacology, ShotleyBridge General Hospital, Co. Durham, U. K.
Summary. In 228 ambulatory patients receiving treatment with warfarin, there was a progressive decline in the dose required to produce an equivalent degree of anticoagulant control with increasing age from the third decade onwards. However, the relationship between age and dose was significant only in patients receiving warfarin after episodes of venous thromboembolism or because of coronary artery disease. Patient weight was also related to warfarin requirements, although it was less important a determinant than age.
Key words: warfarin, anticoagulation; age, sex, weight
Elderly patients receiving oral anticoagulant therapy have a greater risk of bleeding (Peyman, 1958; Husted and Andreasen, 1976) than younger patients. Moreover, the elderly require lower doses of oral anticoagulants to produce comparable degrees of anticoagulation (O'Malley et al., 1977; Husted and Andreasen, 1977). The following study was performed to assess the relative contributions of age, sex and weight to warfarin dosage requirements, and to observe the influence of the disease, for which anticoagulant therapy was given, on these variables.
Patients and Methods All patients attending the anticoagulant outpatient clinic at Shotley Bridge General Hospital over a 12 month period were considered for inclusion in the study. Any patient with clinical or biochemical evidence of liver disease or cardiac failure, or who was
receiving a drug known to interact with warfarin, was excluded. Patients' anticoagulant requirements were noted after a minimum of 14 days warfarin treatment and when "therapeutic" control of blood coagulation had been achieved (prothrombin ratio of 1.8 to 2.5). In 211 patients, seven successive doses of warfarin (prescribed after the prothrombin ratio had reached the "therapeutic" range) was recorded, together with the corresponding prothrombin ratios. In 17 other patients (who received warfarin for a shorter period) only 3-6 (mean 4.5) prescribed warfarin doses, together with the corresponding prothrombin ratios, were available. However, none of these patients received warfarin for a period shorter than 6 weeks. Patients' weight and the indication for anticoagulant therapy was also recorded. The prothrombin ratio was performed by the hospital laboratory using Thrombokinase (Geigy) and was calculated by dividing the one stage prothrombin time for the patient's plasma by the equivalent time for undiluted control plasma (normally 15 seconds). Patients were divided into 6 age groups according to their date of birth. Group 1 contained all patients born during or before 1900; group 6 represented those patients born during, or after 1941; groups 2-5 included those patients born during the decades 1901-1910, 1911-1920, 1921-1930 and 1931-1940 respectively. Patients were also classified into 4 diagnostic groups according to the indication for anticoagulation:
Diagnostic Group A (50 patients) contained those patients given warfarin for severe unstable angina, following myocardial infarction, or after coronary artery bypass surgery. Diagnostic Group B (88 patients) contained patients given warfarin because of valvular heart disease, 0031-6970/79/0015/0319/$01.00
320
P. A. Routledge et al.: Factors Affecting Warfarin Requirements
60--
n-228
8 -
m
m
1
50--
No. of patients
6
40--
-
-t 30
~= 4
20--
22 10--
0
L
I
I
I
I
I
t
I
2
4
6
8
10
12
14
Daily Warfarin dosage (rag)
1=14 6 0.05) in the anticoagulant requirements of males and females, and the present study confirms this. However, in five of the six age groups the mean warfarin reqiairement of males was higher than females, possibly reflecting the slight influence of weight on anticoagulant requirements since at all ages males were significantly heavier than females (p < 0.05). Eccles (1975) was unable to demonstrate a significant relationship between weight and warfarin dosage requirement in his patient population. Amongst our much larger group weight was a significant, though small, determinant of dose.
322 None of the previous studies on warfarin dosage requirements in relation to age have included an investigation of the effect of the disease for which anticoagulants were being used. Our data suggests that the influence of age is greater for patients with venous thromboembolic disease (Group D) and coronary artery disease (Group A) than for our patient population as a whole. The lack of correlation between dose requirement and age in patients with valvular heart disease or peripheral arterial disease may be partly attributable to the narrow age ranges in these categories (44 and 35 years respectively) as compared to age ranges of 51 and 61 years respectively for patients with "coronary artery disease" or venous thromboembolism. However, this explanation alone is unlikely to account for the marked difference in the regression coefficients of age and dose requirement between the diagnostic groups. It is possible that factors associated with the disease states of patients with valvular heart disease and peripheral arterial disease may have been of sufficient magnitude to have masked the effects of age. The cause of the age-related sensitivity to warfarin is unclear. Shepherd et al. (1977) found no significant difference in the plasma clearance of warfarin after a single dose between 13 patients aged less than 40 years and 13 others aged over 65 years. Protein binding of warfarin did not change with age either. However, in 6 patients aged less than 37 years there was a greater depression of clotting factor synthesis at equivalent plasma warfarin concentra-
P. A. Routledge et al.: Factors AffectingWarfarin Requirements tion than in 6 patients aged over 62 years. These findings indicate that pharmacodynamic factors may be more important than pharmacokinetic factors in the age-related variation in warfarin sensitivity.
References Eccles, J. T.: Control of warfarin therapy in the elderly. Age Ageing 4, 161-165 (1975) Husted, S., Andreasen, F.: Problems encountered in longterm treatment with anticoagulants. Acta Med. Scand. 200, 379-384 (1976) Husted, S., Andreasen, F.: The influenceof age on the response to anticoagulants. Br. J. Clin. Pharmacol. 4, 559-565 (1977) O'Malley, K., Stevenson, I.H., Ward, C.A., Wood, A.J.J., Crooks, J.: Determinants of anticoagulant control in patients receivingwarfarin. Br. J. Clin. Pharmacol. 4, 309-314 (1977) Peyman, M. A.: The significanceof haemorrhage during the treatment of patients with the coumarin anticoagulants. Acta Med. Scand. (Suppl.) 339, 1-62 (1958) Shepherd, A. M. M., Hewick, D. S., Moreland, T. A., Stevenson, I. H.: Age as a determinant of sensitivityto warfarin. Brit. J. Clin. Pharmacol. 4, 315-320 (1977) Toohey, M.: Clinical trial of phenylindanedione as an anticoagulant. Brit. IVied.J. 21, 650-652 (1953) Received: June 8, 1978 in revised form: December 4, 1978 accepted: December 20, 1978 Prof. Dr. M. D. Rawlins Wolfson Unit of Clinical Pharmacology Claremont Place Newcastle upon Tyne/England
Europ. J. clin. Pharmacol. 15, 319-322 (1979)
Factors Affecting Warfarin Requirements A Prospective Population Study P. A. Routledge, P. H. Chapman, D. M. Davies, and M. D. Rawlins Department of Pharmacological Sciences,WolfsonUnit of Clinical Pharmacology, Universityof Newcastleupon Tyne and Department of Clinical Pharmacology, ShotleyBridge General Hospital, Co. Durham, U. K.
Summary. In 228 ambulatory patients receiving treatment with warfarin, there was a progressive decline in the dose required to produce an equivalent degree of anticoagulant control with increasing age from the third decade onwards. However, the relationship between age and dose was significant only in patients receiving warfarin after episodes of venous thromboembolism or because of coronary artery disease. Patient weight was also related to warfarin requirements, although it was less important a determinant than age.
Key words: warfarin, anticoagulation; age, sex, weight
Elderly patients receiving oral anticoagulant therapy have a greater risk of bleeding (Peyman, 1958; Husted and Andreasen, 1976) than younger patients. Moreover, the elderly require lower doses of oral anticoagulants to produce comparable degrees of anticoagulation (O'Malley et al., 1977; Husted and Andreasen, 1977). The following study was performed to assess the relative contributions of age, sex and weight to warfarin dosage requirements, and to observe the influence of the disease, for which anticoagulant therapy was given, on these variables.
Patients and Methods All patients attending the anticoagulant outpatient clinic at Shotley Bridge General Hospital over a 12 month period were considered for inclusion in the study. Any patient with clinical or biochemical evidence of liver disease or cardiac failure, or who was
receiving a drug known to interact with warfarin, was excluded. Patients' anticoagulant requirements were noted after a minimum of 14 days warfarin treatment and when "therapeutic" control of blood coagulation had been achieved (prothrombin ratio of 1.8 to 2.5). In 211 patients, seven successive doses of warfarin (prescribed after the prothrombin ratio had reached the "therapeutic" range) was recorded, together with the corresponding prothrombin ratios. In 17 other patients (who received warfarin for a shorter period) only 3-6 (mean 4.5) prescribed warfarin doses, together with the corresponding prothrombin ratios, were available. However, none of these patients received warfarin for a period shorter than 6 weeks. Patients' weight and the indication for anticoagulant therapy was also recorded. The prothrombin ratio was performed by the hospital laboratory using Thrombokinase (Geigy) and was calculated by dividing the one stage prothrombin time for the patient's plasma by the equivalent time for undiluted control plasma (normally 15 seconds). Patients were divided into 6 age groups according to their date of birth. Group 1 contained all patients born during or before 1900; group 6 represented those patients born during, or after 1941; groups 2-5 included those patients born during the decades 1901-1910, 1911-1920, 1921-1930 and 1931-1940 respectively. Patients were also classified into 4 diagnostic groups according to the indication for anticoagulation:
Diagnostic Group A (50 patients) contained those patients given warfarin for severe unstable angina, following myocardial infarction, or after coronary artery bypass surgery. Diagnostic Group B (88 patients) contained patients given warfarin because of valvular heart disease, 0031-6970/79/0015/0319/$01.00
320
P. A. Routledge et al.: Factors Affecting Warfarin Requirements
60--
n-228
8 -
m
m
1
50--
No. of patients
6
40--
-
-t 30
~= 4
20--
22 10--
0
L
I
I
I
I
I
t
I
2
4
6
8
10
12
14
Daily Warfarin dosage (rag)
1=14 6 0.05) in the anticoagulant requirements of males and females, and the present study confirms this. However, in five of the six age groups the mean warfarin reqiairement of males was higher than females, possibly reflecting the slight influence of weight on anticoagulant requirements since at all ages males were significantly heavier than females (p < 0.05). Eccles (1975) was unable to demonstrate a significant relationship between weight and warfarin dosage requirement in his patient population. Amongst our much larger group weight was a significant, though small, determinant of dose.
322 None of the previous studies on warfarin dosage requirements in relation to age have included an investigation of the effect of the disease for which anticoagulants were being used. Our data suggests that the influence of age is greater for patients with venous thromboembolic disease (Group D) and coronary artery disease (Group A) than for our patient population as a whole. The lack of correlation between dose requirement and age in patients with valvular heart disease or peripheral arterial disease may be partly attributable to the narrow age ranges in these categories (44 and 35 years respectively) as compared to age ranges of 51 and 61 years respectively for patients with "coronary artery disease" or venous thromboembolism. However, this explanation alone is unlikely to account for the marked difference in the regression coefficients of age and dose requirement between the diagnostic groups. It is possible that factors associated with the disease states of patients with valvular heart disease and peripheral arterial disease may have been of sufficient magnitude to have masked the effects of age. The cause of the age-related sensitivity to warfarin is unclear. Shepherd et al. (1977) found no significant difference in the plasma clearance of warfarin after a single dose between 13 patients aged less than 40 years and 13 others aged over 65 years. Protein binding of warfarin did not change with age either. However, in 6 patients aged less than 37 years there was a greater depression of clotting factor synthesis at equivalent plasma warfarin concentra-
P. A. Routledge et al.: Factors AffectingWarfarin Requirements tion than in 6 patients aged over 62 years. These findings indicate that pharmacodynamic factors may be more important than pharmacokinetic factors in the age-related variation in warfarin sensitivity.
References Eccles, J. T.: Control of warfarin therapy in the elderly. Age Ageing 4, 161-165 (1975) Husted, S., Andreasen, F.: Problems encountered in longterm treatment with anticoagulants. Acta Med. Scand. 200, 379-384 (1976) Husted, S., Andreasen, F.: The influenceof age on the response to anticoagulants. Br. J. Clin. Pharmacol. 4, 559-565 (1977) O'Malley, K., Stevenson, I.H., Ward, C.A., Wood, A.J.J., Crooks, J.: Determinants of anticoagulant control in patients receivingwarfarin. Br. J. Clin. Pharmacol. 4, 309-314 (1977) Peyman, M. A.: The significanceof haemorrhage during the treatment of patients with the coumarin anticoagulants. Acta Med. Scand. (Suppl.) 339, 1-62 (1958) Shepherd, A. M. M., Hewick, D. S., Moreland, T. A., Stevenson, I. H.: Age as a determinant of sensitivityto warfarin. Brit. J. Clin. Pharmacol. 4, 315-320 (1977) Toohey, M.: Clinical trial of phenylindanedione as an anticoagulant. Brit. IVied.J. 21, 650-652 (1953) Received: June 8, 1978 in revised form: December 4, 1978 accepted: December 20, 1978 Prof. Dr. M. D. Rawlins Wolfson Unit of Clinical Pharmacology Claremont Place Newcastle upon Tyne/England
