Therapeutic Anticoagulation Prevalence among Patients of a Cardiology Clinic receiving Warfarin and Association with Overweight

The outcome of warfarin therapy varies among individuals due to factors such as genetics, age, ethnicity, diet and weight which have been shown to have varying impact on therapeutic anticoagulation [3-10]. Although many studies have reported benefits of the use of these parameters to determine warfarin doses, clinically guided management still relies heavily on monitoring International Normalized Ratio (INR).


Introduction
Warfarin is an anticoagulant used extensively in the prevention of thromboembolic events for a variety of conditions relating to the cardiovascular system [1].It inhibits the enzyme using the Roche Diagnostic CoaguChek XS Plus system.The CoaguChek XS Plus system is a point-of-care system that consists of a CoaguChek XS Plus monitor and CoaguChek XS Plus PT test strips and produces results within seconds.The test strip consist of lyophilized reagents, thromboplastin and a peptide substrate [11,12] and has an INR measuring range from 0.8 to 8.0 with 97% accuracy when compared to lab results [13].
Subjects were classified as having therapeutic INR when INR was in the range of 2.0 to 3.0, except in the case of high risk mechanical prosthetic valves and systemic recurrent emboli, where the range is 2.0 to 3.5.These ranges are based on recommendation by the American Heart Association for antithrombotic therapy [14].
Descriptive statistic of mean ± standard deviation (SD) and median and Interquartile range (IQR) values for continuous data and proportions for counts was used for demographics.Continuous data was assessed for normal distribution.Chisquare (χ2) goodness of fit with degrees of freedom (df) was used to analyse significant differences between proportions.Subjects were divided dichotomously into obtaining therapeutic INR (2.0-3.0 and 2.0-3.5) and INR out of range and comparison between groups made using Mann-Whitney for continuous data and Fisher's exact test for nominal data.Spearman's rho was used to evaluate correlations.Statistical significance was accepted when p< 0.05.

Results
In total, 68 subjects consented to participate in the study; however, 65 were included in the data analysis, as data was missing for 3 subjects.Afro-Caribbean ethnicity (n=60); was significantly more represented and 5 were of Indian ethnicity (χ2=46.5;df =1; p<0.001).Females were significantly more represented than males (44 females; χ2= 8.1, df =1 p=0.004).The age of the subjects ranged between 26 years and 91 years; mean age of the group was 58.3 ± 15.5 years and the median age was 59.0(24) years; age was found to be normally distributed.BMI was only calculated for 61 of the subjects, as 4 subjects were wheelchair bound (no weight measured) giving a mean of 27.7 ± 6.1kg/m 2 and median of 26.7 (7.8) kg/m 2 ; BMI was not normally distributed.Of the subjects with BMI calculated, 25 were of normal weight, while 17 subjects were overweight and 19 were obese, however there was no significant difference in proportions across body weight (χ2=1.7;df= 2; p=0.426).
Period on warfarin therapy for subjects extended beyond a year for most subjects (n=42).Table 1 lists the indication for warfarin therapy; most of the subjects were being managed for atrial fibrillation.The warfarin dose ranged from 2.5 mg to 10 mg with the median dose being 6.1 (2.0) mg.There was no correlation between warfarin dose and age, gender or BMI.Three subjects were taking warfarin only; concomitant drugs included diuretics (59), inhibitors of the renin angiotensin system (36), beta blockers (29), digoxin (29), statins (22), calcium channel blockers (9), anti-platelets (11) and anti-diabetic (13).Subjects fully compliant with warfarin therapy were significantly more represented, as 50, reported not missing any dose of warfarin (χ2 =56.7; df=2; p<0.001), while 11 subjects indicated missing 1 to 3 doses per month and 4 missing more than 3 doses per month.
Significantly more of the subjects in this study, 48(73.8%),presented with non-therapeutic INR values and 17 (26.2%)subjects were identified to have INR in therapeutic range (χ2=14.8;df = 1, p<0.001) with 25 below INR target and 23 having INR above target.Analysis between these groups with age, gender warfarin dose and BMI, showed only BMI to have a small positive correlation with subjects achieving therapeutic INR range (Spearman's rho= 0.28; n=61; p=0.027).On further assessment for difference between the groups, subjects within the therapeutic INR range had significantly higher median BMI, 30.2 (11.8 kg/m 2) , than subjects with non-therapeutic INR, 26.0 (7.4 kg/m 2 ) (Mann-Whitney test, p=0.028).There was no difference in age, gender or the warfarin dose between subjects achieving therapeutic INR range and those with non-therapeutic INR Table 2.

Discussion
This study examined the prevalence of therapeutic anticoagulation among patients treated at a cardiology clinic where warfarin remains the most common anticoagulant prescribed.Given the major complications that can occur with non-therapeutic anticoagulation [15,16], it is of concern that 73.8% of the subjects in this study presented with nontherapeutic anticoagulation, all of whom have been on warfarin therapy for more than one month and most for more than one year.
Therapeutic anticoagulation correlated with increasing BMI and assessment of differences between subjects showed that subjects with therapeutic anticoagulation were overweight or obese.Furthermore, although previous studies suggest that larger doses of warfarin are required with increasing body

Therapeutic Anticoagulation Prevalence among Patients of a Cardiology Clinic receiving Warfarin and Association with Overweight
Copyright: © 2016 Gossell-Williams et al. weight [17,18,19], there is no evidence from this study to suggest such an association.
Limited reports examining the association of therapeutic coagulation with BMI exist; therefore the finding in this study requires further exploration.Similar findings were reported from a subset of patients for the AMADEUS trial; for 814 aging patients (≥ 75years old) on warfarin therapy, therapeutic anticoagulation (measured as percentage time in therapeutic INR) was reported to be more likely in obese patients [20].However, whether overweight improve warfarin efficacy requires more exploration into dietary factors, specifically, vitamin K status.
While the liver is a storage site for vitamin K, sequestration in adipose tissue has also been identified as significant to vitamin K regulation [21,22].Shea, et al. examined vitamin K status among 142 aging men and women.After controlling for dietary vitamin K intake, the study showed that there is poorer plasma vitamin K status and less availability of hepatic vitamin K with increasing adipose tissue [22].Shea et al. further suggested that adipose storage has a functional role in regulating plasma and hepatic vitamin K status; however this functional role is yet to be fully elucidated.We hypothesize that adipose tissue acts a reservoir to regulate plasma and hepatic vitamin K homeostasis, thus facilitating improved therapeutic anti-coagulation with warfarin.This is the first report to assess warfarin efficacy in Jamaican patients; however, the small sample size and reliance of patient recall of compliance are factors of this study that limit the findings related to age, gender and warfarin doses.A longitudinal study design to facilitate calculation of time spent in therapeutic anticoagulation may have provided a more robust measure of therapeutic anticoagulation than a single time point reading.
The study findings are also limited by the non-assessment of co-morbidities.Additionally, co-administered drug information collected was inadequate to facilitate assessment of the impact on warfarin therapy.
In conclusion, non-therapeutic anticoagulation was the more likely presentation among the subjects of this study; given the complication of poor anticoagulation, more research in this patient group is required and should include exploring factors contributing to finding of therapeutic anticoagulation among overweight subjects.

Table 1 :
List of the indications for warfarin for subjects (n=65) recruited in the study.
among Patients of a Cardiology Clinic receiving Warfarin and Association with Overweight.Int J Pharmacovigil 1(1): 4.

Table 2 :
Comparison of parameter between subjects with therapeutic anticoagulation (Therapeutic INR) and non-therapeutic anticoagulation (non-Therapeutic INR).