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Anticoagulation Management in Patients Receiving Warfarin at Private Cardiac Centers in Addis Ababa, Ethiopia

Authors Getachew R, Tadesse TA , Shashu BA, Degu A , Alemkere G

Received 11 November 2022

Accepted for publication 1 February 2023

Published 10 February 2023 Volume 2023:14 Pages 107—117

DOI https://doi.org/10.2147/JBM.S397189

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Martin H Bluth



Roza Getachew,1 Tamrat Assefa Tadesse,1 Bekele Alemayehu Shashu,2 Amsalu Degu,3 Getachew Alemkere1

1Department of Pharmacology and Clinical Pharmacy School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 2Department of Internal Medicine School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 3Department of Pharmaceutics and Pharmacy Practice, School of Pharmacy & Health Sciences, United States International University Africa, Nairobi, Kenya

Correspondence: Tamrat Assefa Tadesse, Email [email protected]

Introduction: Anticoagulants are the cornerstone therapy for thromboembolism prevention and treatment. Warfarin is the frequently prescribed drug and remains the oral anticoagulant of choice in low- and middle-income countries, including Ethiopia. It is a narrow therapeutic index drug that needs high-quality anticoagulation monitoring with frequent international normalization ratio (INR) testing.
Objective: The study aimed to assess anticoagulation management with warfarin among adult outpatients at two selected private cardiac centers in Addis Ababa, Ethiopia.
Methods: A hospital-based retrospective study design that enrolled 374 patients receiving warfarin was employed at two private cardiac centres in Addis Ababa, Ethiopia. The time in the therapeutic range (TTR) was calculated using the Rosendaal method. The data were analyzed using Statistical Package for Social Science version 25.
Results: The mean age of the patients was 57 years, and 218 (58.3%) participants were females. Out of 3384 INR tests, 1562 (46.5%) were within the therapeutic range and the mean percentage of TTR was 47.24%. Only 25.67% of the patients spent their TTR ≥ 65%. The present study revealed that dose adjustments were required 1764 times. In non-therapeutic INR values of 1764 that required warfarin dose adjustment, 59.7% of the doses were adjusted. About 262 (70.1%) of co-prescribed medications had interaction with warfarin. Sixty-four patients (17.11%) experienced bleeding events.
Conclusion: Anticoagulation management with warfarin was suboptimal in private cardiac Addis Ababa, Ethiopia, private cardiac centers. Warfarin adjustment practice for nontherapeutic INR values was not minimal, and many patients encountered bleeding during their course of therapy.

Keywords: warfarin, anticoagulation, time in the therapeutic range, international normalization ratio, Ethiopia

Introduction

The safety and efficacy of warfarin therapy depend on careful monitoring and maintenance of the international normalized ratio (INR) within an optimal therapeutic range.1 Its narrow therapeutic range, frequent drug, herbal, and food interactions, and the effect of comorbidities place patients at risk of bleeding and thromboembolic complications if the recommended anticoagulation target ranges are not achieved.2–7 Furthermore, factors related to drugs, patients, and healthcare will compromise the overall quality of anticoagulation management with warfarin therapy which is reflected by actual time spent within the therapeutic INR, ie, time in the therapeutic range (TTR).3,8–10 The TTR estimates the percentage of time a patient’s INR is within the desired treatment range or goal and is widely used as an indicator of anticoagulation control.11

A minimum TTR of 65% is required for warfarin therapy to be regarded as effective,12,13 and below this value, warfarin is unlikely to prevent thromboembolic disease effectively. In another way, the risk of both thromboembolism and bleeding has also been shown to depend on the percentage of INR in the therapeutic range.14 However, in the real world, maintaining adequate anticoagulation with warfarin has proved to be challenging due to the complexity of warfarin therapy. This was demonstrated by studies conducted globally with low TTR (<65%).1,11,15–23 The problem seems the worst in Africa, as the lowest TTRs were reported in different regions of the continent.7,20,24–27 Similarly, in Ethiopia, only four studies were conducted in government health facilities and reported lower TTRs in the range of 29–38%.28–31 Despite the wide availability of warfarin as an oral anticoagulant, information on its level of anticoagulation control is scarce in Ethiopia, especially in private settings. Therefore, this study aimed to determine the proportion of time spent in the therapeutic INR range and investigate dose adjustment practice in patients taking warfarin in selected private health facilities in Addis Ababa, Ethiopia.

Methods

Study Setting

The study was conducted at two private cardiac centers in Addis Ababa, Ethiopia, namely Gesund Cardiac and Medical Center (GCMC) and Addis Cardiac Hospital (ACH). GCMC is a 31-bed cardiac center; annually, it serves around 41,500 patients and about 2000 of them receive warfarin. ACH is Ethiopia’s first specialized cardiovascular hospital with advanced investigations and treatment modalities for cardiac diseases, including heart surgery, implantable devices, and percutaneous coronary intervention. The hospital has 43 beds and serves 51,700 patients annually. Among these, 1683 patients were receiving warfarin therapy during our study period.

Study Design and Period

A retrospective study was carried out at ACH and GCMC from 1 February to 30 April 2021 on patients receiving warfarin.

Source and Study Population

All adult patients receiving warfarin for 3 months and above for various indications at study centers were the source population. All eligible patients on warfarin who had follow-ups at ACH and GCMC from 1 January 2019 to 31 December 2020 (2 years) were considered as the study population.

Sample Size Determination and Sampling Techniques

The sample size was determined using the single population proportion formula,32 ie,

where n = minimum sample size, Z = standard normal distribution (Zα/2=1.96) with 95% confidence interval, d = absolute precision or tolerable margin of error (d) = 5% (0.05) and P = prevalence is essential proportion). From a recent previous study in Northern Ethiopia, a proportion of 0.3791, ie, a mean TTR of 37.91%33 was used. With a 10% contingency to cater to incomplete medical records, the final sample size was 398. Finally, we reviewed 374 patients’ charts (187 from each site) that fulfilled the inclusion criteria during the study period. A 2-year list of hospital identification numbers of warfarin-treated patients was generated from the health record. The actual sampling fraction (kth) was calculated by dividing the total number of the study population attending the hospital during the study period (3671) by the estimated sample size of the study. Thus, approximately every 9 patients’ chart was reviewed.

Eligibility Criteria

Adult patients (≥18 years) who had been on warfarin for ≥3 months with two or more INR values were included in the study. Nonetheless, medical records of patients with incomplete information about the INR values and other pertinent findings were excluded from the study.

Data Collection Instruments and Techniques

The data abstraction instrument was prepared by reviewing different literature. The data were collected by three pharmacists and one nurse after providing relevant training. Then, all the required pieces of information such as demographic characteristics, indications of anticoagulation, comorbidities, drugs prescribed with warfarin, and corresponding INR results were recorded by reviewing the medical records of the patients. The data abstraction tool had been pretested on 5% of the study participants before actual data collection. All relevant amendments were made after pretesting the data abstraction tool. Percentages of TTR were calculated using the Rosendaal method,34 and the mean frequency of INR values and percentage of warfarin dose adjusted were determined.

Data Analysis and Interpretation

Data were analyzed using Statistical Package for Social Science (SPSS) version 25.0 software. Socio-demographic and clinical characteristics were summarized by percentages and frequencies. Micromedex Healthcare Series [online database] Version 5.135 was used to analyze drug interactions with warfarin.

Ethical Considerations

Ethical clearance was obtained from the Ethics Review Committee of the School of Pharmacy, College of Health Sciences of Addis Ababa University (ERB/SOP/244/13/2021). This study complies with the guidelines of the Declaration of Helsinki. Confidentiality of the information was maintained by avoiding the use of individual identifiers like names and the patients’ hospital identification numbers.

Results

The mean age of the study participants was 57± 18 years, with an age range of 18–92 years. The majority of the study participants were female (218, 58.3%). Heart failure (36.89%) and hypertension (17.2%) were the most common comorbidities in patients receiving warfarin in this study. Polypharmacy was seen in 51.34% of the patients (Table 1).

Table 1 Socio-Demographic and Clinical Characteristics of Patients

Indication of Warfarin

The most common indication of warfarin was for atrial fibrillation patients, followed by chronic rheumatic valvular heart disease (Figure 1).

Figure 1 Indication of warfarin therapy.

INR Distribution

During 2-year follow-up period, of 374 patients, 88.51% and 11.49% had target INR ranges of 2–3 and 2.5–3.5 with 1477 and 85 INR values within respective target ranges, respectively. The average number of INR tests per patient was 4. The detailed INR distribution is shown in Figure 2.

Figure 2 INR values distributions within different intervals among patients taking warfarin for achieving target ranges (A :2.0−3.0, B: 2.5−3.5).

Time in the Therapeutic Range

According to the Rosendaal method, the mean percentages of TTR were 47.24% (Figure 3), and only 25.67% of the patients spent their time above TTR of 65%.

Figure 3 Time spent in different INR ranges in patients taking warfarin.

Warfarin Dose Adjustment

This study revealed that dose adjustments were required 1764 times for nontherapeutic INR values. However, it was only adjusted 1053 times (873 for sub-therapeutic and 180 times for the supratherapeutic range). The details for warfarin dose adjustment for non-therapeutic INR values are given in Table 2.

Table 2 Warfarin Dose Adjustment Practice for Non-Therapeutic INRs in Patients Receiving Warfarin

Drug–Drug Interactions Among Patients Taking Warfarin

About 262 (70.0%) patients were prescribed medications with the potential of interacting with warfarin. Furosemide (89.84%), spironolactone (72.9%) and metoprolol succinate (63.63%) were the most repeatedly observed drugs that interact with warfarin in the present study. Only major and moderate interactions were reported based on the Micromedex interaction checker (Table 3).

Table 3 Warfarin Drug Interactions Among Patients Taking Warfarin

Bleeding Events

In this study, 64 (17.11%) patients encountered minor and major bleeding events. Of these, 42 patients experienced minor bleeding events (nasal and vaginal bleeding) with therapeutic INR value. Seven patients had INR values of 3.1–4.99, while 11 patients had INR values greater than 5, and 4 patients experienced intracranial hemorrhages with an INR value of >5.

Discussion

This study aimed to assess anticoagulation management with warfarin at private health facilities in Addis Ababa, Ethiopia. The majority of the study participants (58.3%) were females, and the mean age was 57 years. This female predominance was comparable to the study done in Kenya,36 and Ethiopia.29,37,38 In contrast, other studies conducted in Poland39 and Canada16 reported male predominance. Atrial fibrillation (43.85%) was the commonest indication for warfarin therapy in the current study.

The duration of time a patient is on oral anticoagulant influences the stability of INR. Moreover, dietary habits and the presence of drug interaction may alter INR levels associated with warfarin treatment.40 This study revealed that the mean frequency of INR monitoring per patient was every 47.85 days. The frequency of INR monitoring obtained in this study (every 47.85 days) was more infrequent when compared with the study done in western Ethiopia, where most patients (84%) had INR determined every month.37 In addition, a study from Kenya showed that the median frequency of INR monitoring was 18.5 days.36 Another study in Ethiopia reported the interval between two INR tests was 35 days.41 Comparatively, there was more frequent monitoring of INR in the study settings as compared to reports from a tertiary care teaching hospital in Ethiopia (64 days per patient).38 These disparities could probably be linked to the difference in the patient size population and specific trends in the management of patients receiving warfarin therapy in the study settings, which can affect their capacity to monitor INR frequently. Furthermore, it is also noticed that warfarin monitoring is patient-tailored. However, current guidelines suggest that at least a 4-week monitoring is essential. This time should be reduced to a few days on several occasions including in the case of frequent non-therapeutic INRs and the occurrence of bleeding and thrombotic events.

The TTR (47.24%) obtained in this study was higher than reports from Lithuania (40%),42 Uganda (41%),43 Spain (25.9%),44 Ethiopia (29%),38 Pakistan (34.9%),45 Botswana (30.8%)46 and Northern Ethiopia (33%).37 However, far away from recommended optimal TTR (≥70%), optimal anticoagulation in patients receiving warfarin47 and also low as compared to previous studies in New Zealand (63%)48 and Brazil (56.6%).49 This difference could probably be the higher level of health care in developing countries that had better anticoagulation monitoring services. In addition, this poor TTR in the study setting may be due to infrequent INR monitoring and a lack of separate anticoagulation clinics. The present study showed that 1764 INR tests were deemed to have warfarin dose adjustment. Nonetheless, doses were adjusted in only 1053 (59.69%) values. This can probably be linked to physicians’ adherence problems, lack of functional dose adjustment algorithm, warfarin drug–drug interaction, and drug–food interactions that affect warfarin serum levels. However, in the study settings, the management of nontherapeutic (sub-therapeutic) INR was better than in previous studies conducted in government hospitals in Ethiopia,29,38 although the management of nontherapeutic INR value was not satisfactory.

The most commonly prescribed warfarin-interacting drugs were furosemide, followed by spironolactone and metoprolol succinate in the study settings. The prevalence of drug–drug interactions with warfarin was found to be 70%. This result was comparable with a study conducted in Thailand that identified 71% warfarin drug interaction,1 but it is better than that of Ayder Referral Hospital, Ethiopia (99.2%).50 Other studies at Tertiary Care Hospitals in Ethiopia identified a lower percentage of warfarin drug interaction.41,51 This high percentage of drug–drug interaction with warfarin may be justified by the high prevalence of co-prescribed interacting medications.

The most common complication of warfarin therapy was bleeding. This study reveals 64 (17.11%) minor and major (intracranial hemorrhage) bleeding events, which were lower in incidence as compared with studies from Ethiopia (25%) and Thailand (32.56%).52,53 However, a retrospective study in Brazil reported comparable bleeding events (4.2% major and 10.3% minor bleeding episodes) with the present study.49

Limitations of the Study

Due to the retrospective nature of the study, the data will be affected by the completeness and accuracy of the information in the study settings. Therefore, it is difficult to clarify some problems in definite detail, such as the cause of non-adherence or the type of herbs that interact with warfarin, factors that may affect anticoagulation like adherence, diet, physical activity, and genetic variability. There was a risk of information bias as this retrospective study relied on information from patient files. It is also prone to missing patient information if they had sought other health facilities that were not documented.

Conclusion

Anticoagulation management with warfarin was suboptimal in the study settings, which can significantly affect the desired treatment outcomes of the patients. In addition, most of the co-prescribed medications had undesired drug–drug interactions with warfarin and need attention. Therefore, optimal interventional strategies are required to improve the treatment outcomes of patients receiving warfarin therapy.

Abbreviations

ACH, Addis Cardiac Hospital; AF, atrial fibrillation; DVT, deep vein thrombosis; INR, GCMC, Gesund Cardiac and Medical Center; INR, international normalization ratio; SPSS, Statistical Package for Social Science; TTR, time in therapeutic range; VTE, venous thromboembolism.

Data Sharing Statement

The datasets used in this study are available from the corresponding author upon request.

Declarations Ethics Approval and Consent to Participate

This study was approved by the Ethical Review committee of the School of Pharmacy, College of Health Sciences Addis Ababa University, Addis Ababa, Ethiopia (ERB/SOP/244/13/2021). Then, a support letter was written by the Department of Pharmacology and Clinical Pharmacy, School of Pharmacy to GCMC and ACH, and permission was obtained from the study settings to conduct the study. Information obtained from data collected during the study was only handled by the research team. Personal identifiers were not used, and data were analyzed in aggregate. The Ethics Committee waived the need for informed consent since this was an observational study using existing data.

Acknowledgments

The authors would like to acknowledge the staff members of ACH and GCMC healthcare facilities for their unreserved support during the entire data collection process for this project.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.

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