Study design and setting
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. The hospital is located in Northwest Ethiopia, which is 750 km away from the capital, Addis Ababa. The hospital had a catchment population of 5 million people.
Study subjects and variables
Study subjects
Patients older than 18 years old, and were on warfarin with follow up at Cardiac and Hematology Clinic, University of Gondar hospital were considered as study population.
Patients older than 18 years old, who were on warfarin for at least 6 months, had at least six INR determinations with each consecutive INR determination ≤ 56 days apart were included in the study. Frequent records of INR at first month of drug initiation or during dose adjustments were excluded until stable INR values were obtained.
Study variables
Dependent variables: Proportion of time spent in the therapeutic INR range (TTR)
Independent variables: 1) Socio-demographic characteristics include age, gender, occupation, marital status, educational level, income level, residence and religion .2) Clinical characteristics include indication for warfarin, warfarin dosage, warfarin-plus drugs intake, adherence to warfarin, frequency of INR monitoring, co-existing comorbidities, nutritional status, alcohol intake and dietary habits.
Sample size and sampling procedure
The sample size was calculated using single population proportion formula with the assumption of 95% confidence 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 re-translated back to English with maintaining its consistency. Patients were interviewed to obtain socio-demographic data. Relevant medical history and laboratory parameters were obtained from patients’ records.
The proportion of INRs within the therapeutic range of 2.0-3.0 was calculated as number of INRs within the therapeutic range divided by the total number of INR measurements. TTR was calculated using Rosendaal’s method, which used linear interpolation to assign an INR value to each day between successive observed INR values. The individual TTR determined the proportion of time spent in the therapeutic range of 2.0-3.0 for each patient. Those individuals with TTR ≥65% were declared to achieve ‘optimal’ INR control.
Data analysis
Data were entered into EPI Info version 4.4.1 and transported to SPSS version 20 for analysis.
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 significant 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 confidentially. During the data collection process, those patients who were found to have atrial fibrillation and venous thromboembolism were taken care of as per the recommendations of AHA/ACC guideline and American Society of Hematology guideline respectively.
Definition of terms
TTR (proportion of time spent in the therapeutic range): The duration of time in which the patient’s international normalized range (INR) values were within a desired range (INR = 2.0–3.0).
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) findings.
Chronic liver disease: Distorted liver architecture and decreased hepatic function as a result of chronic inflammation leading to chronic hepatitis or hepatic cirrhosis. Diagnosis was settled by ultrasound-evidenced 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 filling 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 confirmed by radioimmunoassay (RIA) test revealing low serum TSH and/or raised free T3/T4.