Evaluation of Anticoagulation Outcome among Patients Taking Warfarin: A Single-Center Experience, Northwest Ethiopia

Warfarin is a widely used oral anticoagulant in clinical practice. It is used to prevent arterial emboli in patients with atrial brillation, or prevent and treat venous thromboembolism. The ecacy and safety of warfarin depends on maintaining the INR within the therapeutic range. The proportion of time spent in the therapeutic INR range (TTR) is used to evaluate quality of anticoagulation control. optimal


Abstract Background
Warfarin is a widely used oral anticoagulant in clinical practice. It is used to prevent arterial emboli in patients with atrial brillation, or prevent and treat venous thromboembolism. The e cacy and safety of warfarin depends on maintaining the INR within the therapeutic range. The proportion of time spent in the therapeutic INR range (TTR) is used to evaluate quality of anticoagulation control.

Methods
A hospital-based cross sectional study was conducted between November 1, 2019 and October 31, 2020 at Cardiac and Hematology Clinic, University of Gondar hospital. A consecutive sampling method was used to recruit 338 study subjects. Proportion of time spent in the therapeutic range (TTR) was calculated using the Rosendaal's linear interpolation method. TTR ≥65% was described as 'optimal' International Normalized Ratio (INR) control. The Data were entered into EPI Info version 4.4.1 and transported to SPSS version 20 for analysis. Logistic regression analysis was used to identify associated factors with optimal anticoagulation outcome (TTR ≥65%). P-values <0.05 were used to declare signi cant association.

Result
A total of 338 study subjects were included in the study. The mean age of patients was 49 years. The majority of study participants attended formal education (79%) and were urban dwellers (57%). Atrial brillation was the commonest indication for warfarin therapy.  (5,7,11,13,14). Global studies documented that old age, obese individuals, dietary habits and other drugs intake, excessive alcohol consumption, renal or hepatic dysfunction were among the listed causes of poor INR control (TTR<65%) (8,9,11,13,(19)(20)(21)(22)(23)(24). The aim of the study is to determine the TTR and associated factors among patients taking warfarin in hospital setting, Northwest Ethiopia. Sample size and sampling procedure

Methods
The sample size was calculated using single population proportion formula with the assumption of 95% con dence level, 5% margin of error, and taking 30% for TTR in sub-Saharan African region. Consecutive sampling method was used to recruit 338 study subjects.

Data collection instrument and procedures
Data were collected through an investigator administered pre-designed questionnaire. The questionnaire was prepared in English and translated into local language (Amharic) for data collection, and then retranslated back to English with maintaining its consistency. Patients were interviewed to obtain sociodemographic data. Relevant medical history and laboratory parameters were obtained from patients' records. Patient characteristics were reported as counts (percentages) for categorical variables, and mean with standard deviation for continuous variables. Bi-variable and multi-variable logistic regression models were constructed to identify independently associated factors with optimal INR control (TTR ≥65%).
Those variables with a P-value < 0.25 in the bi-variate analysis were exported to multi-variate analysis to control the possible effect of confounders. Crude odds ratio (COR) and adjusted odds ratio (AOR) were reported. P-values < 0.05 were used to declare signi cant association.

Ethical considerations
The research protocol complied with Declaration of Helsinki and was approved by local ethics committee.
Study subjects were recruited only after informed written consent was obtained. All data obtained were treated con dentially. During the data collection process, those patients who were found to have atrial brillation and venous thromboembolism were taken care of as per the recommendations of AHA/ACC guideline and American Society of Hematology guideline respectively. Chronic kidney disease: Abnormalities of kidney structure or function present for more than 3 months, with implications for health. Diagnosis of chronic kidney disease was settled by clinical, biochemical (raised serum creatinine) and/or imaging (ultrasound-proven reduced kidney size) ndings.
Chronic liver disease: Distorted liver architecture and decreased hepatic function as a result of chronic in ammation leading to chronic hepatitis or hepatic cirrhosis. Diagnosis was settled by ultrasoundevidenced liver surface irregularity and/or elevated serum transaminase >3x upper limit of normal.
Heart failure: Clinical syndrome that results from any structural or functional impairment of ventricular lling or ejection of blood. The Framingham criteria were used to diagnose heart failure.
Hyperthyroidism: Clinical state that involves excess synthesis and secretion of thyroid hormones by the thyroid gland. Diagnosis of hyperthyroidism was made in the presence of suggestive clinical symptoms and signs including enlarged thyroid gland, and con rmed by radioimmunoassay (RIA) test revealing low serum TSH and/or raised free T3/T4.

Socio-demographic characteristics of study participants
A total of 338 patients taking warfarin, who had follow-up at Cardiac and Hematology Clinic, university of Gondar hospital were included in the study. The mean age of study subjects was 49 years. The majority of study participants were females (64%), married (73%) and urban dwellers (57%). Most respondents were Christian by religion (86%), and attended formal education (79%) ( Table-1).

Proportion of INRs and Time in Therapeutic Ranges
The mean proportion of INRs and TTR obtained from the study were shown in Figure-2  Factors associated with TTR <65% or ≥65% On bi-variable analysis, venous thromboembolism as indication for warfarin therapy was found to have signi cant association with TTR ≥65% (COR=0.135, 95% CI: 0.02-0.99, P-value=0.049), but not found to be signi cant on multivariable analysis. Multi-variable analysis didn't reveal signi cant association of socio-demographic characteristics including age, gender, educational level and monthly income with optimal INR control (TTR ≥65%). By the same token, clinical characteristics including dose of warfarin, warfarin adherence, frequency of INR determination, other concomitant drug intake, co-existing comorbidities, consumption of green leafy vegetables and alcohol intake didn't show signi cant association with optimal INR control (TTR≥65%) ( Table-3).
Limitation of the study Selection bias couldn't be avoided as consecutive sampling method was used to recruit study subjects.

Recommendation
The authors recommend large scale prospective study to determine risk factors for poor INR control (TTR<65%) in Ethiopia. Institution-based validated protocol might be required to overcome the poor TTR level. "Anticoagulation (INR) clinic' would be required to 'scale-up' INR control.