Evaluation of Warfarin Use in Cardiac Clinic Outpatients

The use of warfarin was monitored using the International Normalized Ratio (INR) value. This study aims to determine the relationship between the patient’s demographic variables and INR, as well as the therapy result and differences in their INR value. A cross-sectional study was used with retrospective observational data collected by tracing secondary information of medical records from outpatients with heart disease on warfarin therapy at Dr. Hasan Sadikin hospital Bandung between 2016 to 2020. Subsequently, the difference in patients’ INR value was analyzed with the Mann-Whitney test based on dosage. At the same time, the relationship between demographic variables and INR was examined using the Chi-square test and Spearman correlation. The INR examination results in 192 subjects showed 124 patients (64.6%) reached the target with an average value of 2.37 ± 0.21 and a warfarin dose of 19.31 ± 6.25 mg weekly, while 68 (35.4%) had an average of 1.82 ± 0.73 and a dose of 20.24 ± 6.24 mg weekly. Subsequently, the difference test with Mann Whitney (p = 0.004) showed a variation in the INR value based on the warfarin dose. The Spearman correlation analysis results indicated a relationship between BMI (p = 0.009), daily (0.010), and weekly dose (0.008) on the INR value with the correlation coefficient of 0.188; 0.186; and 0.192; indicating a negative association with very weak correlation strength. This study showed that a majority of patients reached the INR value of 2-3, and the demographic variables associated with this ratio were BMI and warfarin dose. The decision to increase and decrease the warfarin dose is determined by INR value and BMI.


Introduction
World Health Organization (WHO) stated that about 17.9 million deaths occurred globally due to heart disease in 2016. This condition occurs due to impaired function and blood vessels and consists of coronary and rheumatic heart disorder, cerebrovascular disease, and other conditions. 1 According to Riskesdas data, the 2018 prevalence of heart disease in Indonesia was 1.5%. 2 Consequently, anticoagulants are drugs that prevent the blood clotting process by inhibiting fibrin formation. One of the most common anticoagulants is warfarin, which is widely used to treat or prevent thromboembolismrelated diseases, including stroke, heart attack, embolism, atrial fibrillation, and deep vein thrombosis. This drug is still widely used even after six decades. 3,4 Warfarin has a narrow therapeutic index, which indicates that a slight dose difference causes a significant alteration in response. Therefore, administration of a large dose increases the bleeding risk, while a small quantity will cause failure in the treatment or prevention of thromboembolism. Since drug doses vary widely between patients and must be individualized, dosage adjustment is necessary and would lead to variations in its use. This variability is due to age, gender, ethnicity, anticoagulant indication, vitamin intake, body weight, albumin levels, and drugs consumed. 3 Anticoagulant status during warfarin use was monitored with INR, where the most common target value was between 2 to 3. Also, patient INR values are examined every 4 to 6 weeks for dose adjustment until it is stabilized. 5,6 In Lithuania, a study on warfarin showed the INR value for patients with atrial fibrillation was out of the target range by more than half (57.3%), where approximately 40% of cases occur because the subjects do not evaluate and adjust the dose. 7 Patient knowledge of warfarin therapy is still low, although the level of adherence is high. 8 Our study showed, most warfarin therapy has not reached the therapeutic INR range of 2 to 3. 9 Also, a study by Megawati et al., 2019 evaluating this drug use showed that only 27% of patients achieved the target range. 10 Consequently, INR monitoring can improve its stability within the therapeutic range and prevent serious complications. 11 Based on the background described above, an evaluation of warfarin use in heart disease patients at Dr. Hasan Sadikin Hospital was conducted to determine the drug use profile, effectiveness, and if the administered therapy dose has reached the target therapeutic INR value of 2 to 3. Dispensation of safe and effective warfarin doses improves the therapy's success and patient's life quality and avoids side effects of bleeding.

Study Design
This is a cross-sectional study with retrospective observational data collected by searching secondary information in medical records from outpatients with heart disease at Dr. Hasan Sadikin Hospital between January 2016 and December 2020. The obtained data included gender, age, height, weight, disease diagnosis, warfarin dose, duration of warfarin use, comorbidities, other drugs used concurrently, and INR values. Subsequently, the information was processed and analyzed statistically. This study has been approved by the Ethics Commission of Universitas Padjadjaran, Bandung, Indonesia (No. 28/ UN6. KEP/EC/2021).

Study Subject
The study subjects included all medical records from heart disease outpatients who used oral warfarin anticoagulants in Dr. Hasan Sadikin Hospital between January 2016 to December 2020. Also, patients were required to have used this drug for a minimum of one month and have measured the INR value at least once. The exclusion criteria were incomplete and untraceable medical record data.

Statistical Analysis
Descriptive analyses were used to represent subjects' demographic data, including gender, age, Body Mass Index (BMI), warfarin indication, and amount of it. The Mann-Whitney test was used to compare differences in INR values based on daily warfarin doses. Meanwhile, Chi-Square and Spearman methods were used to determine the relationship between the parameters. The analysis was performed using SPSS software with a p-value <0.05 for significant results.   13 Therefore, dose adjustments with good enough patient adherence to warfarin consumption were conducted based on the INR value for those who reached the target.
The success of warfarin therapy can also be achieved with the role of pharmacists. Our previous study showed that counseling from the professionals significantly influences the patient's knowledge and perception of the treatment. 14 Furthermore, education and comprehensive counseling on this therapy, including risks, benefits, and drug and food interactions, are considered essential components to achieving warfarin therapy success.
Low patient knowledge about warfarin and medical personnel education is why some individuals did not reach the INR target, 15 where limited knowledge of the drug's indications is associated with non-adherence to the therapy. 16  Warfarin dose-response is influenced by age, BMI, nutritional status, comorbid disease, drug interactions, pharmacogenetics, and ethnicity. 20 Therefore, monitoring the drug with INR is an essential factor affecting warfarin therapy's suitability. 21 The factors associated with INR values in this study included BMI (p = 0.009), daily (p = 0.010), and a weekly dose of warfarin (0.008). However, other respondent characteristics, such as gender, Also, genetic polymorphism is a factor that influences warfarin therapy, where the genes that affect the response to this treatment, including CYP2C9 and VKORC1. CYP2C9 plays a role in the drug's metabolism, which is associated with slower warfarin metabolism and a longer time to reach a stable INR value. At the same time, VKORC1 is the site gene for encoding VKORs related to the drug's sensitivity. 20,26 However, the analysis of the relationship between genetic polymorphisms and INR was not performed in this study because there was no genetic data in the patient's medical record, although genetics is a factor that affects the determination of the warfarin dose and patient's INR value.
This study's limitations include the location, which was restricted. Hence further investigations are expected to add this factor to obtain a larger patient number. In addition, only medical record data was used without considering other factors that influence the response to warfarin therapy, such as food interactions, genetic polymorphisms, and smoking habits.

Conclusion
Most patients have reached the target INR value of 2 to 3, and factors that affect the INR value are BMI and warfarin dose.