Introduction
============

Warfarin therapy is widely used for the prevention of thromboembolic events for a variety of medical conditions.  The dosing of warfarin is patient-specific.  Although there are several methods to initiate warfarin therapy, most clinicians elect to begin with empiric doses of 5 mg daily, and titrate as needed to achieve a therapeutic international normalized ratio (INR) ([@b9]; [@b4]; [@b1]).  Experience shows that within a cohort, patients may require as little as 0.5 mg up to as much as 20 mg or greater of warfarin daily to maintain a target INR.  This large variability in warfarin dose may be explained, to some extent, by concomitant medications, gender, nutritional status, liver disease, alcohol consumption, diarrhea, hyperthyroidism, fever, chronic heart failure (CHF), and more recently, ethnicity. 

For over a decade, evidence has indicated that elderly patients require smaller total weekly warfarin maintenance doses (TWD) compared with younger counterparts ([@b8]; [@b11]; [@b2]; [@b1]; [@b16]).  Several studies have also suggested that women require lower warfarin doses than do men ([@b2]).  More recently, evidence has shown that patients of African American descent require larger doses of warfarin to maintain therapeutic INRs ([@b3]; [@b2]; [@b5]; [@b14]).  However, little evidence is available concerning the impact of other factors, such as body mass index (BMI) and vitamin K intake. 

Objective
=========

The purpose of this investigation is to determine the influence of various patient-specific factors, use of concomitant medications, and weekly vitamin K intake on TWD in the population of patients at our internal medicine clinic.  Clearly defined effects of patient factors on warfarin dose may better facilitate achievement of therapeutic INRs following initiation of warfarin therapy. 

Methods
=======

This research was approved by the hospital's institutional review board through the exempt process, thus consent was not required for patients. 

Study location and population
-----------------------------

This study was conducted within a university-based internal medicine clinic.  All adult patients (18 to 100 years old) who were using warfarin therapy and were followed by clinical pharmacists for anticoagulation management and education were eligible.  Additionally, to further reduce confounders, only those patients with stable TWD for three consecutive months were included.  Patients who were deemed as noncompliant with warfarin therapy were excluded.  Noncompliance was defined, per patient report, as missing greater than one dose for two consecutive months, as documented in their electronic medical record (EMR).  Patients with target INR ranges of 2 to 3 or 2.5 to 3.5 were included, while patients with target INR ranges outside of these values were excluded. 

Data collection took place via retrospective chart review.  Information collected included age, gender, ethnicity, weight, height, vitamin K consumption, date of warfarin initiation, indication, target INR range (either 2.0 to 3.0 or 2.5 to 3.5) and TWD.  Body mass index (BMI) was calculated via weight and height.  Patients' weekly dietary vitamin K content was quantified just prior to their anticoagulation appointment using a 2-page survey.  The presence of various health conditions was also collected, such as heart failure and thyroid disorders.  Use of alcohol, tobacco, amiodarone, aspirin, a multivitamin, and cytochrome P450 (CYP) inducers were also identified.  Those medications identified as CYP inducers for the purpose of this study included the following: carbamazepine, phenobarbital, phenytoin, primidone, rifampin, ritonavir, and St. John's Wort. 

Statistical analysis
--------------------

Descriptive statistics were calculated for the entire sample and then separately for high and low warfarin dose patients, using a two sample t-test to detect statistically significant differences between the two groups.  High dose was considered to be greater than or equal to 50 mg of TWD, while low dose was considered as less than or equal to 25 mg.  We also examined individual Pearson correlation statistics for meaningful associations between each of the patient specific variables and TWD.  Finally, we analyzed an ordinary least squares regression of the combined factors in predicting warfarin dose. 

Results
=======

A total of 170 patients were provided pharmaceutical care for anticoagulation within the internal medicine clinic.  Due to warfarin noncompliance or unstable weekly warfarin dose, 36 patients were excluded.  An additional three patients were excluded for having target INR ranges other than 2.0--3.0 or 2.5--3.5.  A total of 131 patients were analyzed. 

Baseline demographics showed those analyzed for the study to range in age from 23 to 98 years (mean age 67 years).  The majority was Caucasian (71%), followed by African American (29%), with more females (55%) than males.  Descriptive statistics for the sample are summarized in [Tables 1](#tbl1){ref-type="table"} and [2](#tbl2){ref-type="table"}, including indications for warfarin therapy and weekly vitamin K intake for 77 patients. 

###### 

Descriptive statistics for the sample of 131 patients

  Continuous variables                                                    Mean value       Standard deviation
  ----------------------------------------------------------------------- ---------------- --------------------
  TWD (mg/week)                                                           36.61            16.03
  Age (years)                                                             66.91            13.06
  Weight (kg)                                                             83.91            20.91
  Height (cm)                                                             172              10.3
  BMI (kg/m^2^)                                                           28.39            6.34
  Vitamin K consumption (mcg/week)[\*\*\*](#tf1-3){ref-type="table-fn"}   1764.93          1745.91
  **Ethnicity**                                                           **Percentage**   
  Caucasian                                                               71.0%            
  African American                                                        29%              
  **Dichotomous variables**                                               **Percentage**   
  Female                                                                  55.0%            
  Amiodarone use                                                          12.1%            
  Aspirin use                                                             36.6%            
  Tobacco use                                                             9.9%             
  Alcohol use                                                             22.1%            
  CYP inducer                                                             7.7%             
  Multivitamin use[\*\*](#tf1-2){ref-type="table-fn"}                     21.5%            
  History of CHF                                                          16.8%            
  History of Hypothyroidism                                               14.6%            
  LFT 3× ULN[\*](#tf1-1){ref-type="table-fn"}                             1.6%             
  Target INR 2.5--3.5                                                     12.9%            

**Notes:** Data only available for 129 patients

Data only available for 130 patients

Data only available for 77 patients

###### 

Descriptive statistics -- Indications for warfarin therapy (n = 131)

  Indications                             Mean value
  --------------------------------------- ------------
  History of atrial fibrillation          49.6%
  History of deep vein thrombosis         24.5%
  History of pulmonary embolism           12.2%
  Prosthetic valve                        10.8%
  Other indication for warfarin therapy   21.6%

The mean weight, height, and BMI were 83.9 kg, 172 cm, and 28.4 kg/m^2^, respectively.  The most common indications for warfarin use were atrial fibrillation (n = 69, 50%), deep vein thrombosis (DVT) (n = 32, 23%), pulmonary embolism (PE) (n = 16, 21%), cerebral vascular accident (CVA) or transient ischemic attack (TIA) (n = 20, 15%), and valve replacement (n = 13, 9%).  The majority of patients had INR target ranges of 2.0 to 3.0 (n = 115 out of 131, or 87.8%).  Concomitant medication use and presence of CHF and thyroid disorders are also presented in [Table 1](#tbl1){ref-type="table"}. 

Simple pairwise correlation statistics between each of the variables and TWD are presented in [Table 3](#tbl3){ref-type="table"}.  The concomitant use of CYP-inducing medications resulted in the largest correlation coefficient (r = 0.30).  The difference in mean TWD between patient groups who did and did not use CYP inducers was found to be statistically significant using a paired t-test (p \< 0.001). 

###### 

Pearson correlation coefficients between TWD and patient specific variables

  Variable                        Correlation coefficient
  ------------------------------- -------------------------------------------
  Demographics                    
  Age                             −0.241[\*\*](#tf3-1){ref-type="table-fn"}
  BMI                             0.076
  Caucasian                       −0.109
  Female                          −0.050
  Medication use                  
  Amiodarone                      −0.066
  Aspirin                         −0.019
  CYP inducer                     0.300[\*\*](#tf3-1){ref-type="table-fn"}
  Multivitamin                    −0.084
  LFT 3× ULN                      0.042
  Comorbidities                   
  CHF                             −0.095
  Hypothyroidism                  −0.112
  Prior embolism                  0.108
  Other patient characteristics   
  Target INR 2.5--3.5             0.068
  Vitamin K consumption           0.026
  Tobacco use                     −0.004
  Alcohol use                     0.108

**Notes:** Statistically significant at the 1% level. 

When the low (≤25 mg TWD, n = 24) versus high (≥50 mg TWD, n = 105) TWD patient groups were analyzed to discern areas where the two populations differed, age and CYP were the only statistically significant differences.  Those patients within the high dose group tended to be younger and to use CYP-inducing medications (see [Table 4](#tbl4){ref-type="table"}). 

###### 

Comparison of high and low warfarin dose patient populations

  Variable                        Low (≤25mg) warfarin dose (n = 35)   High (≥50mg) warfarin dose (n = 26)   P-value from a two sample t-test or chi-squared test
  ------------------------------- ------------------------------------ ------------------------------------- ------------------------------------------------------
  Demographics                                                                                               
  Average TWD                     19.4 mg                              60.7 mg                               \<0.0001[\*\*](#tf4-2){ref-type="table-fn"}
  Age                             72.3                                 61.6                                  0.001[\*\*](#tf4-2){ref-type="table-fn"}
  BMI                             27.1                                 29.3                                  \>0.10
  Caucasian (%)                   0.77                                 0.62                                  \>0.10
  Female (%)                      0.63                                 0.50                                  \>0.10
  Medication use                                                                                             
  Amiodarone (%)                  0.08                                 0.09                                  \>0.10
  Aspirin (%)                     0.37                                 0.35                                  \>0.10
  CYP Inducers (%)                0.0                                  0.15                                  0.016[\*](#tf4-1){ref-type="table-fn"}
  Multivitamin (%)                0.26                                 0.23                                  \>0.10
  LFT 3× ULN (%)                  0.03                                 0.04                                  \>0.10
  Comorbidities                                                                                              
  CHF (%)                         0.20                                 0.17                                  \>0.10
  Hypothyroidism (%)              0.23                                 0.12                                  \>0.10
  Prior Embolism (%)              0.43                                 0.50                                  \>0.10
  Other patient characteristics                                                                              
  Target INR 2.5--3.5 (%)         0.11                                 0.19                                  \>0.10
  Vitamin K consumption           1881.5                               2040.4                                \>0.10
  Tobacco use (%)                 0.11                                 0.04                                  \>0.10
  Alcohol use (%)                 0.17                                 0.27                                  \>0.10

**Notes:** Statistically significant at the 5% level

Statistically significant at the 1% level. 

We compared those patients consuming \>3000 mcg of vitamin K per week with those consuming \< 250 mcg of vitamin K per week and found no difference in the TWD.  The mean TWD for the lower consumption was 35.8 mg (n = 17), the mean for the higher consumption was 37.3 mg (n = 14), and a two sample t-test with equal variances concluded no difference (p = 0.83). 

Finally, we analyzed an ordinary least squares regression of the combined factors in predicting warfarin dose (see [Table 5](#tbl5){ref-type="table"}).  Because the regression is restricted to patients with no missing data, the resulting sample size was 130.  Variables with many missing observations, such as vitamin K consumption, were excluded from this stage of the analysis to preserve sample size and increase the chances of obtaining statistically significant results. 

###### 

Ordinary least squares regression of weekly warfarin dose explained by patient specific variables (n = 130)

  Variable                        Coefficient   Standard error
  ------------------------------- ------------- -----------------------------------------
  Demographics                                  
  Age                             −0.24         0.12[\*](#tf5-1){ref-type="table-fn"}
  BMI                             0.026         0.233
  Caucasian                       −2.75         3.42
  Female                          −2.55         3.08
  Medication use                                
  Amiodarone                      −3.35         6.60
  Aspirin                         −1.62         2.86
  CYP inducer                     17.19         5.41[\*\*](#tf5-2){ref-type="table-fn"}
  Comorbidities                                 
  CHF                             −2.66         3.78
  Hypothyroidism                  −1.99         4.22
  Prior embolism                  −0.36         3.01
  Other patient characteristics                 
  Tobacco use                     −5.17         4.74
  Alcohol use                     3.32          3.46

**Notes:** R-squared = 0.1676.  Adjusted R-squared = 0.0822

Statistically significant at the 5% level

Statistically significant at the 1% level. 

Age and CYP-inducing medications were again found to be the only statistically significant predictors (at the 5% and 1% levels of significance, respectively) of TWD.  The regression coefficient on age quantifies the inverse association with dose requirements, while controlling for all other variables included in the regression.  It indicates that the TWD is 2.4 mg less for each additional decade of patient age.  The coefficient on CYP inducers indicates that the concomitant use of a CYP inducer is associated with an additional 17.2 mg of warfarin a week, while controlling for patient demographics (age, BMI, race, gender), medications (amiodarone and aspirin), comorbidities (CHF, hypothyroidism, and a history of prior thromboembolic event), and tobacco or alcohol use. 

Discussion
==========

Our analysis included patients with target INRs of 2--3 and 2.5--3.5.  The correlation coefficient of 0.07 indicated that target INR had a relatively low influence on TWD in our sample.  It was therefore decided to include both target populations in an effort to increase power.  To check for potential bias resulting from this decision, we reran each of the analyses on the larger subgroup with INR targets of 2--3 and found that statistical significance and directions of correlations were unchanged. 

As expected, this investigation suggests that one of the strongest and statistically significant patient-specific factors that affect TWD is the concomitant use of CYP-inducing medications.  The predominately active warfarin isomer (S) is metabolized through CYP450 2C9, while the less active isomer (R) is a substrate of the 1A2, 2C19, and 3A4 isoenzymes.  Addition of medications that induce the metabolism of these enzymes would thus increase plasma warfarin concentrations, and thus decrease the TWD need.  The concomitant use of CYP inducers resulted in the largest correlation coefficient (r = 0.30).  The difference in mean TWD between patient groups that did and did not use CYP-inducing medications were found to be statistically significant using a t-test (p \< 0.001).  Because a simple correlation is not adjusted for other patient-specific characteristics, the relationship may be confounded.  To address this issue, we conducted a regression analysis which indicates that the concomitant use of a CYP inducer is associated with 17.2 additional milligrams of warfarin per week, adjusting for all other variables in the model.  In this investigation, the most commonly used CYP-inducing medications were phenytoin, phenobarbital, and primidone; therefore, when initiating warfarin therapy in a patient who currently uses one of these inducers, the clinician should consider empirically initiating therapy at a higher dose. 

Age was also a statistically significant predictor of TWD, with a regression correlation coefficient of −0.24.  This inverse association indicates that a TWD of 2.4 fewer milligrams are prescribed for each additional decade of patient age, adjusting for all other variables in the regression analysis.  Similar data have been published by [@b7] who found that as patients age the TWD declined by 0.4 mg per year of life.  Age was also found to be significantly different between the high and low warfarin dose groups, with high dose patients tending to be younger (see [Table 4](#tbl4){ref-type="table"}).  Patients in the low and high categories of warfarin use averaged 72 and 62 years of age, respectively.  These findings confirm previously published literature; warfarin dose for maintenance therapy is inversely proportional to age ([@b8]; [@b11]; [@b2]; [@b16]; [@b7]; [@b12]). 

A very weak correlation existed between gender and TWD.  Although not statistically significant, the regression analysis quantified this difference with female patients requiring a 2.55 mg lower TWD when compared with males.  This finding is similar compared with previous studies which showed that women require an average of 4.5 mg less of warfarin per week ([@b1]; [@b7]).  Conversely, several published articles cite gender to be an important factor in predicting warfarin dose ([@b13]; [@b2]).  Regardless of the effect gender plays in warfarin dosing, studies are consistent in reporting lower doses required for women compared with men. 

We found a weak correlation between ethnicity and TWD (r = −0.11), with African American patients requiring greater TWD than Caucasian patients.  Overall African Americans required approximately 2.75 mg more per week to maintain a therapeutic INR than did Caucasians, controlling for all other variables in the regression.  Although not statistically significant, this finding agrees with previous study results ([@b3]; [@b2]; [@b5]). 

Similarly, we found only a weak correlation between BMI and TWD (r = 0.08).  Adjusting for all other variables in the regression, we found that the small positive association remained, though it was not statistically significant.  Several other studies found no relationship between BMI or body weight and warfarin dose ([@b8]; [@b13]; [@b3]).  Sconce and colleagues, however, found that height has greater predictive value of warfarin dose than does body weight or BMI ([@b15]), while Singla and colleagues found that BMI influences TWD equally to gender (r^2^ = 5.3, p = 0.001) ([@b16]).  It is currently not clear how much of an effect, if any, BMI plays upon TWD. 

Although there have been various case reports of the affect of tobacco ([@b6]), alcohol ([@b10]), and aspirin use ([@b17]) on warfarin metabolism and INR, this study did not show a profound effect of these products on TWD. 

Unfortunately, alcohol use was not stratified into frequency, volume, or type consumed.  Patients were simply asked if they used alcohol.  Alcohol use has opposing effects on warfarin metabolism depending on whether it is consumed on a chronic, binge, or occasional basis ([@b1]).  Individuals who chronically ingest alcohol experience increased warfarin clearance through induction of CYP450 isoenzymes, which results in larger TWD requirements.  Conversely, binge drinking inhibits the hepatic metabolism of warfarin, thus smaller amount TWD are needed.  Likewise, tobacco use was not clearly established.  Again, patients were simply asked if they used tobacco; the study was not designed to assess amount, frequency, or tobacco products used.  Better assessment of these variables of alcohol and tobacco consumed may have produced a more predictive value on TWD. 

Of the 77 patients who completed the vitamin K survey, the average weekly intake did not prove to have a profound influence on TWD.  As patients assessed their average weekly vitamin K intake just prior to their anticoagulation appointment, rather than concurrently, the retrospective completion of surveys could be subject to recall bias. 

Interestingly, the adjusted R-squared value was also low, even for cross-sectional data.  It indicates that the regression model as a whole only explains 8% of the variation in TWD.  Both the low adjusted R-squared and the small number of statistically significant variables may be attributed to the relatively small sample size.  Other recent literature have suggested similar findings ([@b16]).  This may indicate that other variables, not analyzed in this study, may provide greater contributions to the determination of TWD. [ @b15] suggest that genetics, specifically CYP 2C9 and VKORC1 genetic polymorphisms, may contribute up to 55% of TWD variations. 

Limitations
===========

There are limitations inherent in this study.  All information collected was via retrospective chart review.  Furthermore, alcohol and tobacco use were not quantified at each visit.  Because height was not documented on every patient, BMI was unable to be calculated for each subject.  Lastly, the relatively small sample size means that this study may not have been adequately powered to detect a statistically significant difference between patient-specific factors, if a true difference did exist. 

Conclusion
==========

In summary, from a retrospective chart review of 131 patients with therapeutic INRs, we found factors having the greatest influence on TWD to include the concomitant use of CYP-inducing medications and age.  Positive relationships between TWD and the following factors exist: use of CYP450 inducer, younger age, taller height, and African American ethnicity.  Although it did appear that women required a smaller TWD than did men, we found that gender contributed only mildly.  Further studies with a greater samples size in this area may more precisely predict the effect of patient-specific factors on the TWD.  This information may help decrease consequences of supratherapetuic INRs while facilitating the achievement of therapeutic levels.  In turn, this may result in decreased time of concomitant injectable anticoagulant use and/or hospitalizations which could ultimately decrease heathcare costs. 

Disclosure
==========

This information was presented in part at the University Health System Consortium on December 3, 2005 in Las Vegas, NA.  Whitley HP, Brzezinski W, Fermo JD.  Effect of patient-specific factors on weekly warfarin dose.  Proceedings from the University Health System Consortium.  2005; December: 107.  The authors have no financial information to disclose.