Sudan Journal of Medical Sciences Volume 17, Issue no. 4, DOI 10.18502/sjms.v17i4.12548 Production and Hosting by Knowledge E Research Article Efficacy and Safety of Warfarin Therapy: Comparison Between Specialized INR Clinic and General Medical Clinic Osman Elsayed Osman1, Rabeea Ibrahim Haroun Ismail2, Rayan Khalid3, and Imad Fadl-Elmula4* 1Department of Medicine, Faculty of Medicine, Al Neelain University, Khartoum, Sudan 2Department of Cardiology, Ahmed Gasim Specialized Hospital, Khartoum, Sudan 3Department of Physiology, Assafa College, Khartoum, Sudan 4Department of Clinical Genetics, Assafa College, Khartoum, Sudan ORCID: Imad Fadl-Elmula: https://orcid.org/0000-0003-3191-9485 Abstract Background: Although warfarin is known as effective oral anticoagulant to prevent thromboembolic events, its’ narrow therapeutic index requires ambient and good follow-up to reduce its therapeutic complications. There is a continuous debate whether the best practice to accomplish this goal is in a specialized international normalized ratio clinic (INR-C) or in a general medical clinic (General-C). Few, if any, studies have been done in Sudan to compare the safety and efficacy of anticoagulant therapy in those clinics. Thus, the objective of this study was to compare the efficacy and safety of anticoagulant therapy in INR-C and in General-C. Methods: This is a prospective hospital-based study where 200 patients were divided into two groups (group A and B) of 100 patients. Group A were in the INR-C at Ahmed Gasim specialized hospital and group B in the General-Cat AL-Shaab teaching hospital. The study was conducted from September 2019 to April 2020. All patients were on warfarin treatment and regular follow-ups were conducted. Demographic and clinical data were collected and analyzed statistically using SPSS version 20. Ethical approval was obtained from the ethical committee of the Sudanese Medical Specialization Board (SMSB). Results: Of the 200 patients, 118/59% were females and 82/41% were males. Target international normalized ratio (INR) for group (A) was achieved in 56% of the patients in the first visit, increased to 63% in the second visit, and 75% in the third follow-up, compared with 24% of the patients from group (B) in the initial and second follow-up visit, to 43% in the third visit (P value=0.05). Knowledge about drug and food interaction of coagulation agents was higher (91%) among patients in group (A) compared with group (B) (56%). Drug interaction awareness was found in 89% of the patients in group (A) compared with only 40% in group (B) (P value=0.05). Major bleeding was reported in 2% and 14% of the patients of group (A) and (B) respectively, whereas minor bleeding was seen in 4% of group (A) and 11% of group (B). Conclusion: The study showed that INR-C is more efficient and safer for patients on regular warfarin therapy compared with the General-C. Keywords: specialized INR clinic, anticoagulant therapy, warfarin How to cite this article: Osman Elsayed Osman, Rabeea Ibrahim Haroun Ismail, Rayan Khalid, and Imad Fadl-Elmula* (2022) “Efficacy and Safety of Warfarin Therapy: Comparison Between Specialized INR Clinic and General Medical Clinic,” Sudan Journal of Medical Sciences, vol. 17, Issue no. 4, pages 476–484. DOI 10.18502/sjms.v17i4.12548 Page 476 Corresponding Author: Imad Fadl-Elmula; email: dean@assafa.edu.sd Received 6 June 2021 Accepted 7 February 2022 Published 31 December 2022 Production and Hosting by Knowledge E Osman Elsayed Osman et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Editor-in-Chief: Prof. Mohammad A. M. Ibnouf http://www.knowledgee.com http://crossmark.crossref.org/dialog/?doi=10.18502/sjms.v17i4.12548&domain=pdf&date_stamp=2022-12-12 https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Sudan Journal of Medical Sciences Osman Elsayed Osman et al 1. Introduction Warfarin is an oral anticoagulant frequently used to control and prevent thromboembolic disorders [1]. Due to the diverse genetic profile of humans, the anticoagulant effect of warfarin must be monitored based on the international normalized ratio (INR) to ensure an accurate and safe dose of warfarin that is within the therapeutic range for each patient [2]. For the purposes of follow-up of patients on warfarin therapy, some authors favor specialized international normalized ratio clinics (INR-C) whereas others argue in favor of general medical clinics (General-C) that may very well achieve similar therapeutic outcomes [3,4]. The anticoagulant thrombosis center has high clinical and laboratory expertise which provides diagnosis, treatment, and follow-up of patients with thromboembolic events [5]. To achieve these goals, such clinics must provide patients with individualized anticoagulation education, management, and close follow- up to ensure that their INR values remain within the therapeutic goals by maintaining a therapeutic range (TTR) at or above 70% that is associated with clinical benefit in terms of efficacy and safety [6]. 2. Material and Methods This study is a cross-sectional prospective hospital-based study that includes 200 patients, all on warfarin therapy. Of those, 100 patients were recruited from the INR-C at Ahmed Gasim specialized hospital (group A), and the remaining 100 patients were from General-C at AL-Shaab teaching hospital (group B), from September 2019 to April 2020. The demographic and clinical data including INR was collected using a predesigned questionnaire. The ethical approval was obtained from the ethical committee of the Sudanese Medical Specialization Board (SMSB). The data were analyzed using SPSS program version 20 and the results were expressed as mean +/- the standard deviation. Frequency count was done on the data and the result was reported as a percentage. The results were considered statistically significant if the P value< 0.05. 3. Results The results of both groups revealed that 118 (59%) of the patients were females and 82 (41%) were males of which 32% were >60 years of age, 23% were between 50–60 years, 18.5% were between 40–49 years, and 26.5% were aged less than 40 years. DOI 10.18502/sjms.v17i4.12548 Page 477 Sudan Journal of Medical Sciences Osman Elsayed Osman et al The results also showed that 119 (59.5%) patients were the inhabitants of Khartoum State, 40 (20%) patients were from central states, 24 (12%) patients were from western states, 13 (6.5%) patients from eastern states, and only 4 (2%) patients were from Western states. Of the 200 patients included in the study, 144/72% were unemployed, 28/14% worked in manual labor, 14/7% were governmental employees, and 14/7% were from the private sector. The indications for warfarin therapy of the patients of group (A) were mechanical heart valve replacement in 47%, atrial fibrillation in 28%, rheumatic heart disease in 13%, cardiomyopathy in 8%, pulmonary embolism in 3%, and deep vein thromboembolism in 1%. These indications were assigned for 17%, 29%, 31%, 17%, 3%, 4%, and 0% of the patients in group (B) respectively (P value=0.05: statistically significant difference). Almost all patients (98%) from Ahmed Gasim specialized hospital were lifelong users of warfarin compared with (85%) of the patients at AL-Shaab teaching hospital. The frequency of follow-up was monthly for 89% of the patients, weekly for 9%, and yearly for 2% of the patients in group (A) compared to 86%, 14%, and 0% of the patients in group (B) respectively (P value < 0.05: statistically significant difference). Patient’s knowledge about warfarin/food and warfarin/other medications interaction was reported by 91% and 89% of the patients in group (A) compared to 65% and 40% of the patients in group (B) respectively (P value < 0.05: statistically significant difference) (Table 1). Table 1: The level of knowledge in INR-C (group A) and General-C (group B). Group A B Knowledge about drug diet interaction Yes 91 65 No 9 35 Knowledge about medications that should not be used Yes 89 40 No 11 60 P value = 0.014 < 0.05 significant Major bleeding was reported in 2% of the patients attending the INR-C (group A), whereas 4% experienced minor bleeding. For those attending General-C (group B) 14% reported major bleeding and 11% experienced minor bleeding (Table 2). First, second, and third INR targets were reached in 56%, 63%, and 75% of the patients attending INR-C (group A), compared with 24%, 24%, and 43% of patients attending DOI 10.18502/sjms.v17i4.12548 Page 478 Sudan Journal of Medical Sciences Osman Elsayed Osman et al Table 2: The complications and management percent of warfarin therapy in patients on regular follow up in INR-C (group A) and General-C (group B). Complications during treatment Group A B No complication seen 94 75 Major bleeding (hospital attendance) 2 14 Minor bleeding (no attendance) 4 11 Measures required for patients No measures needed 0 14 Managed at outpatient 2 6 Admitted to hospital 4 5 Management of complications Observation 4 16 Vitamin K 2 5 Fresh frozen plasma 0 2 Blood transfusion 0 2 Possible risk factors for complications Full compliance this is not a risk factor 94 75 No compliance 6 10 Stopped medications 0 15 P value = 0.012 < 0.05 significant General-C (group B) respectively (P value < 0.05: statistically significant difference) (Table 3). Table 3: Time in therapeutic range (TTR) measurements in INR-C (group A) and General-C (group B). TTR measurements Group A B First visit Below target 38 59 Within target range 56 24 Above target 6 17 Second visit Below target 30 56 Within target range 63 24 Above target 7 20 Third visit Below target 21 45 Within target range 75 43 Above target 4 12 P value = 0.025 > 0.05 significant DOI 10.18502/sjms.v17i4.12548 Page 479 Sudan Journal of Medical Sciences Osman Elsayed Osman et al 4. Discussion Although new-generation oral anticoagulants are increasingly being introduced, war- farin remains the best choice for patients with mechanical prosthetic valves and valvular AF, especially in developing countries in which the incidence of rheumatic heart disease remains high; thus, valvular AF (atrial fibrillation) is a serious health problem in many developing countries including Sudan [7]. The present study showed, as have many other studies, the crucial role of INR-C not only in the control of TTR but also in reducing the incidence of major and minor bleeding, increasing drug interaction knowledge among patients, and finally, better patients compliance among those attending INR-C (group A) [8]. INR monitoring can be performed in hospitals, general outpatient clinics, and spe- cialized INR outpatient clinics. In addition to that it can be self-monitored in selective cases [9]. Several studies revealed that a vast majority of thromboembolic and bleeding events happened once the INR is outside the therapeutic range that is, higher INR increases the risk of bleeding, whereas lower INR increases the risk of thromboembolism [10]. Our results showed lower mean TTR in patients with major events (bleeding and ischemic events) compared with those with no major events. Moreover, we have shown that the type of follow-up clinic is an independent predictor of major events. According to our knowledge, this is the first ever study in Sudan that compared the warfarin patient’s follow-up in INR-C and General-C. The results suggested that patients attending INR-C had higher TTR levels and decreased bleeding and ischemia events rates. Thus, by increasing the number of INR-C in Sudan, we can ensure a good quality of warfarin follow-up and reduced morbidity. It was very important to assess and compare the level of the drug interaction knowl- edge provided by the two clinics (INR-C and the General-C clinic), especially in devel- oping countries where most of the patients are semiliterate. For such patients, one may expect low compliance to warfarin that may lead to significant complications [11,12]. The results of the present study showed clearly that patients attending INR-C were more knowledgeable about coagulation drugs interaction with food and with other medications compared with patients attending General-C (P value<0.05: statistically significant difference). Moreover, patients’ good compliance that is, attending follow- ups was seen in the INR-C in contrast to poor compliance in the General-C [13]. DOI 10.18502/sjms.v17i4.12548 Page 480 Sudan Journal of Medical Sciences Osman Elsayed Osman et al Although major and minor bleeding were reported in both clinics, yet they were far less in patients attending the INR-C. Similar to previous studies, it was shown that the only common side effect of warfarin is bleeding [14,15]. In this study, the measures done for patients with complications in group (A) were admission to the hospital 4(66.6%) and management as outpatients 2(33.4%), while in group (B) no measure was taken in 14 cases (56%), management at outpatient clinic 6 (24%), and admission in the hospital 5(20%). Management of complications were observation for 4 (66.7%) and vitamin K for 2(33.4%) in group (A) patients. For group (B) no management was done for 14 (56%), vitamin K for 5 (20%), fresh frozen plasma for 2 (7%), observation 2(8%), and blood transfusion 2 (8%) (P value < 0.05: significant difference). The risk factors of complications were noncompliance in 6(6%) of the patients in group (A), while in group (B) the risk for complications were stopping of medications 15(15%) and no compliance 10(10%) (P value < 0.05: statistically significant difference) [16]. In this study, the INR target value was reported in (75) in group (A) compared to (43) in group (B), P value < 0.05: significant difference. These results were similar to those of Li et al. in China who assessed the knowledge level regarding warfarin therapy among its users and identified the factors that significantly influence anticoagulation control [17]. Alghadeeer et al. investigated the differences in anticoagulation control of warfarin using TTR between pharmacists and other health-care providers. They enrolled 62 patients, of them 33 were in a pharmacist-led clinic and 29 in a physician-led clinic. TTR levels showed significant increase among patients in the pharmacist-led clinic (82%) compared to the physician-led clinic (24%) (p<0.001). In 27 patients followed by physicians and prospectively by clinical pharmacists, TTR increased during clinical pharmacists’ care (91.70%±2.93%) versus (61.39%±5.11%,) during physician care; p<0.001) [11]. The results of the present study showed that the TTR levels of the patients followed in INR-C were significantly higher than in patients who attended General-C. Moreover, it also showed lower rates of combined minor and major bleeding and ischemic events in INR-C compared with those attending the General-C. These results showed the benefits and importance of the INR-C for patients on warfarin therapy. The only negative argument may be the high cost of INR-C services, especially in countries with low-health resources such as Sudan. On the other hand, the high standard of service provided by the INR-C argues in its favor since it reduces morbidity and mortality. DOI 10.18502/sjms.v17i4.12548 Page 481 Sudan Journal of Medical Sciences Osman Elsayed Osman et al 5. Conclusion Based on the study results, one may conclude that the INR-C is more efficient and safer for follow-up of patients on warfarin therapy compared to General-C. In spite of the high cost of running INR-C in countries with low-health resources, the overall health outcome is beyond comparison with the General-C considering the expected complications and the high-concomitant cost. Acknowledgements None. Ethical Considerations The ethical approval was obtained from the ethical committee of the Sudanese Medical Specialization Board (SMSB). Competing Interests Authors declare no conflict of interest. Availability of Data and Material Data is available with corresponding author upon request. Funding None. References [1] Robinson, A. A., Trankle, C. R., Eubanks, G., Schumann, C., Thompson, P., Wallace, R. L., Gottiparthi, S., Ruth, B., Kramer, C. M., Salerno, M., Bilchick, K. C., Deen, C., Kontos, M. C., & Dent, J. (2020). Off-label use of direct oral anticoagulants compared with warfarin for left ventricular thrombi. 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A., & Momani, R. O. (2019). Analysis of factors that interrupt with INR control in the first anticoagulation clinic monitoring Jordanian patients. Clinical and Applied Thrombosis/Hemostasis, 25, 1076029619870252. https://doi.org/10.1177/1076029619870252 [17] Li, X., Sun, S., Wang, Q., Chen, B., Zhao, Z., & Xu, X. (2018). Assessment of patients’ warfarin knowledge and anticoagulation control at a joint physician- and pharmacist-managed clinic in China. Patient Preference and Adherence, 12, 783– 791. https://doi.org/10.2147/PPA.S156734 DOI 10.18502/sjms.v17i4.12548 Page 484 Introduction Material and Methods Results Discussion Conclusion Acknowledgements Ethical Considerations Competing Interests Availability of Data and Material Funding References