Exploring Side Effects of Warfarin in Outpatients at Tertiary Hospital in Indonesia
Background: Patients with atrial fibrillation, venous thromboembolism, valvular disease, cardioembolic stroke, and acute myocardial infarction are prescribed the oral anticoagulant warfarin to treat thrombi. To guarantee its efficacy and safety, anticoagulants must be closely monitored. Furthermore, warfarin has a narrow therapeutic index, which increases the risk of side effects, particularly in the early stages of treatment. Objective: This study aimed to analyze the incidence of warfarin side effects in outpatients at Dr. Soetomo General Hospital. Methods: A retrospective cross-sectional design was adopted for outpatients at the Cardiology Department of Dr. Soetomo General Hospital from March to May 2023. Data were collected on the incidence of side effects in outpatients who received warfarin for a minimum of one month through an interview process. Other data, including age, sex, duration of warfarin therapy, comorbidities, and INR at the last scan, were extracted from medical records. The Chi-Square test was used to examine the data. Results: The results showed that 88 patients (42.7%) had side effects of excessive bleeding (126 type, 57.3%). These included gum bleeding (22.3%), hematoma (20.4%), melena (7.7%), menometrorrhagia (2.4%), epistaxis (1.9%), hematuria (1.5%), hematemesis (1.0%), hemoptysis (1.0%), spontaneous venous bleeding (1.0%), hematochezia (0.5%), hemostasis during blood sampling ( 0.5%), tongue bleeding (0.5%), and subconjunctival bleeding (0.5%). Conclusion: The incidence of side effects during warfarin treatment was high, accounting for approximately 42.7% of cases. Furthermore, one patient experienced more than one side effect.
Ababneh M, Nasser SA, Rababa'h A, Ababneh F.(2021). Warfarin Adherence and Anticoagulation Control in Atrial Fibrillation Patients: A Systematic Review. European Review for Medical and Pharmacological Sciences. Eur Rev Med Pharmacol Sci; 25; 7926-7933. doi: 10.26355/eurrev_202112_27642
Abohelaika, Salah., Wynne, Hilary., Avery, Peter., Robinson, Brian., Kesteven, Patrick., Kamali, Farhad. (2016). Impact of Age on Long-Term Anticoagulation and How Gender and Monitoring Setting Affect it: Implications for Decision Making and Patient Management. British Journal of Clinical Pharmacology; 82; 1076–1083. doi: 10.1111/BCP.13046.
Ageno, W., Gallus, A. S., Wittkowsky, A., Crowther, M., Hylek, E. M., & Palareti, G. (2012). Oral Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombosis, American College Of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest; 141. e44S - e88S. doi: 10.1378/chest.11-2292.
Al-Momany., Nairooz, Makahleh, Zeid., Al-Omari, Nadia., Al-Sarayreh, Hana. (2019). Analysis of Factors That Interrupt with INR Control in the First Anticoagulation Clinic Monitoring Jordanian Patients. Clinical and Applied Thrombosis/Hemostasis; 25; 1-9. doi: 10.1177/1076029619870252.
Al-Saikhan, F. (2020). Warfarin Therapy Adherence and Health Related Quality of Life Among Patients Using Warfarin in Saudi Arabia. Nigerian Journal of Clinical Practice; 23; 398–407. doi: 10.4103/NJCP.NJCP_608_18.
Ardissino, Diego., Merlini, Piera. Angelica., Bauer, Kenneth. A., Galvani, Marcello., Ottani, Filippo., Franchi, Francha., Bertocchi, Federico., Rosenberg, Robert. D., Mannucci, Pier. Mannucio. (2003). Coagulation Activation and Long-Term Outcome in Acute Coronary Syndromes. Blood; 102; 2731–2735. doi: 10.1182/blood-2002-03-0954.
Barcellona, D., Schirru, P., Mameli, A., Cornacchini, S., Fenu, L., & Marongiu, F. (2022). Over-Anticoagulation by Vitamin K Antagonists and Gender Differences. International Journal of Cardiology; 362; 147–151. doi: 10.1016/j.ijcard.2022.05.003.
Battistella, Marisa., Mamdami, Muhammad., Juurlink, D.
N., Rabeneck, L., Laupacis, A. (2005). Risk of Upper Gastrointestinal Hemorrhage in Warfarin Users Treated with Nonselective NSAIDS or COX-2 Inhibitors. Arch Intern Med; 165. 189-192. doi: 10.1001/archinte.165.2.189.
Bertomeu, González., V, Anguita. M., Moreno. Arribas, J., Cequier, Á., Muñiz, J., Castillo, J., Sanchis, J., Roldán, I., Marin, F., Bertomeu-Martínez, V. (2015). Quality of Anticoagulation with Vitamin K Antagonists. Clinical Cardiology; 38; 357–364. doi: 10.1002/clc.22397.
Chan, Pak. Hei., Hai, Jo. Jo., Chan, Esther. W., Li, Wen. Hua., Tse, Hung. Fat., Wong, Ian. C. K., Lip, Gregory. Y.H., Siu, Chung. Wah. (2016). Use of The Same-TT2R2 Score to Predict Good Anticoagulation Control with Warfarin in Chinese Patients with Atrial Fibrillation: Relationship to Ischemic Stroke Incidence. PLOS ONE; 11; 1-9. doi: 10.1371/journal.pone.0150674.
Ciurus, T., Cichocka, Radwan, A., Lelonek, M. (2015). Factors Affecting The Quality of Anticoagulation With Warfarin: Experience of One Cardiac Centre. Kardiochirurgia i Torakochirurgia Polska; 12; 334–340. doi: 10.5114/kitp.2015.56784.
Costa, Viana, C. da, Silva, Praxedes, M. Freitas, Nunes, de Sousa. (2021). Sex Influence on The Time in Therapeutic Range (TTR) During Oral Anticoagulation with Coumarin Derivatives: Systematic Review and Meta-Analysis. British Journal of Clinical Pharmacology; 87; 4488-4503. doi: 10.1111/bcp.14892.
Gieling, Emilie. M., Van, den, Ham. Hendrika. A., Van, Onzenoort. Hein., Bos, Jacqueline., Kramers, Cornelis., de Boer, Antonius., de Vries, Frank., Burden, Andrea. M. (2017). Risk of Major Bleeding And Stroke Associated With The Use of Vitamin K Antagonists, Nonvitamin K Antagonist Oral Anticoagulants and Aspirin in Patients with Atrial Fibrillation: A Cohort Study. British Journal of Clinical Pharmacology; 83; 1-7. doi: 10.1111/bcp.13265.
Gross, Peter. L., Chan, Noel. C. (2021). Thromboembolism in Older Adults. In Frontiers in Medicine; 7; 1-9. doi: 10.3389/fmed.2020.470016.
Hanigan, Sarah., Kong, Xiaxowen. Haymart, Brian., Kline, Rogers. Eva., Kaatz, Scott., Krol, Gregory., Shah, Vinay., A, Ali. Mona., Almany, Steve., Kozlowski, Jay., Froehlich, James., Geofreey, Barnes. (2021). Standard Versus Higher Intensity Anticoagulation for Patients with Mechanical Aortic Valve Replacement and Additional Risk Factors for Thromboembolism. The American Journal of Cardiology; 159; 100–106. doi: 10.1016/j.amjcard.2021.08.023.
Hauta-Aho, Milka., Tirkkonen, Tuire., Vahlberg, Tero., Laine, Kari. (2009). The Effect of Drug Interactions on Bleeding Risk Associated with Warfarin Therapy in Hospitalized Patients. Annals of Medicine; 41; 619–628. doi: 10.1080/07853890903186168.
Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL. (2020). ESC Guidelines for The Diagnosis and Management of Atrial Fibrillation Developed in Collaboration with The European Association. Eur Heart J; 42; 373-498. doi: 10.1161/CIRCULATIONAHA.111.032433.
Health, Q. (2024). Guideline for Warfarin Management in The Community Guideline for Warfarin. https://www.health.qld.gov.au/. Accessed: 10 August 2024.
Hicks, Karen. A., Stockbridge, Norman. L., Targum, Shari. L., Temple, Robert. J. (2011). Bleeding Academic Research Consortium Consensus Report: The Food and Drug Administration Perspective. Circulation; 123 ; 2664–2665. doi: 10.1161/CIRCULATIONAHA.111.032433.
How, Choon. How. (2015). Novel Oral Anticoagulants for Atrial Fibrillation. Singapore Medical Journal; 56(12); 657–659. doi: 10.11622/smedj.2015184.
Ikeda, Takanori., Yasaka, Masahiro., Kida, Makoto., Imura, Miki. (2018). A Survey Of Reasons for Continuing Warfarin Therapy in The Era of Direct Oral Anticoagulants in Japanese Patients With Atrial Fibrillation: The SELECT Study. Patient Preference and Adherence; 12; 135–143. doi: 10.2147/PPA.S152584.
Kementerian Kesehatan RI. (2018). Laporan Riskesdas 2018 Nasional. https://www.badankebijakan.kemkes.go.id/laporan-hasil-survei/. Accessed: 11 August 2024.
Kimmel, S. E., Christie, J., Kealey, C., Chen, Z., Price, M., Thorn, C. F., Brensinger, C. M., Newcomb, C. W., & Whitehead, A. S. (2008). Apolipoprotein E Genotype and Warfarin Dosing Among Caucasians and African Americans. Pharmacogenomics Journal; 8; 53–60. doi: 10.1038/sj.tpj.6500445.
Lackland, Daniel. T. (2014). Racial Differences in Hypertension: Implications for High Blood Pressure Management. The American Journal of the Medical Sciences; 348; 135–138. doi: 10.1097/MAJ.0000000000000308.
Lee, Kuan. Ken., Doudesis, Dimitrios., Bing, Rong., Astengo, Federica., Perez, Jesus, R. Perez., Anand, Atul., McIntyre, Shauna., Bloor, Nicholas., Sandler, Belinda, B., Lister, Steven., Pollock, Kevin. G., Qureshi, A. C., McAllister, David., Shah, Anoop. S. V., Mills, Nicholas. L. (2023). Sex Differences in Oral Anticoagulation Therapy in Patients Hospitalized with Atrial Fibrillation: A Nationwide Cohort Study. Journal of the American Heart Association; 12; 1-22. doi: 10.1161/JAHA.122.027211.
Mascolo, Annamaria., Ruggiero, Rosanna., Sessa, Maurizio., Scavone, Cristina., Sportiello, L., Rafaniello, Concetta., Rossi, Francesco., & Capuano, Analisa. (2019). Preventable Cases of Oral Anticoagulant Induced Bleeding: Data From The Spontaneous Reporting System. Frontiers In Pharmacology; 10; 1-12. doi: 10.3389/fphar.2019.00425.
Morgan, Crisopher. L., McEwan. Phil., Tukiendorf. Andrzej. , Robinson. Paul. Andreas, Clemens. Andreas., Plumb, Jonathan. M. (2009). Warfarin Treatment in Patients with Atrial Fibrillation: Observing Outcomes Associated with Varying Levels Of INR Control. Thrombosis Research; 124; 37–41. doi: 10.1016/j.thromres.2008.09.2016.
Ningrum, V. DA., Dyah Widyastuti, I., Sufriyanto Yusuf, Bacrie., & Dullah, Wahyudin. (2020). Bleeding Incidence in Patients Administered with Warfarin At Secondary Hospitals in Yogyakarta Province. Indonesian Journal of Pharmacy Indonesian J Pharm; 31; 217–228. doi: 10.22146/ijp.814.
Ozturk, Mustafa., Ipekci, Afsin., Kiyak, Sevil. Kusku., Akdeniz, Yonca. Sinem., Aydin, Yavuz., Ikizceli, Ibrahim., Sogut, Ozgur. (2019). Bleeding Complications in Warfarin Treated Patients Admitted to the Emergency Department. Journal of Clinical Medicine Research; 11; 106. doi: 10.14740/jocmr3669.
Penttilä, Tero., Lehto, Mika., Niiranen, Jussi., Mehtälä, Juha., Khanfir, Houssem., Lassila, Riitta., Raatikainen, Pekka. (2019). Differences In The Risk of Stroke, Bleeding Events, and Mortality Between Female and Male Patients with Atrial Fibrillation During Warfarin Therapy. European Heart Journal Cardiovascular Pharmacotherapy; 5; 29–36. doi: 10.1093/ehjcvp/pvy026.
Putriana, Norisca. Aliza., Rusdiana, Taofik., Rostinawati, Tina., Akbar, Mohammad. Rizki., Destiani, Dika. Pramita. (2022). Evaluation of Adverse Drug Reaction in Patients Warfarin Therapy. Journal of Advanced Pharmaceutical Technology & Research; 13(4); 291. doi: 10.4103/japtr.japtr_439_22.
Ranieri, M. (2015). Casebook in Clinical Pharmacokinetics and Drug Dosing. American Journal of Health System Pharmacy; 72; 1238–1240.
Rydberg, Diana. M., Linder, Marie., Malmström, Rickard. E., & Andersen, Morten. (2020). Risk Factors for Severe Bleeding Events During Warfarin Treatment: The Influence of Sex, Age, Comorbidity and Co-Medication. European Journal of Clinical Pharmacology; 76; 867–876. doi: 10.1007/s00228-020-02856-6.
Salem, Deeb. N., Stein, Paul. D., Al-Ahmad, A., Henry, Bussey. I., Horstkotte, D., Miller, Nancy., Pauker, Stephen. G. (2004). Antithrombotic Therapy in Valvular Heart Disease-Native and Prosthetic The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest Journal; 126; 457S-482S. doi: 10.1378/chest.126.3_suppl.457S.
Shendre, A., Parmar, G. M., Dillon, C., Beasley, T. M., & Limdi, N. A. (2018). Influence of Age on Warfarin Dose, Anticoagulation Control and Risk of Hemorrhage. Pharmacotherapy; 38; 588–596. Accessed: 11 August 2024. doi: 10.1002/phar.2089.
Shikdar, Sufana.,Vashisht, Rishik., Zubari, Muhammad., T, Bhattacharya. Priyanka. (2023). International Normalized Ratio (INR). StatPearls Publishing. https://www.ncbi.nlm.nih.gov/. Accessed: 11 August 2024.
Shurin, Susan. B., Nabel, Elizabeth. G. (2008). Pharmacogenomics-Ready for Prime Time? The New England Journal of Medicine;. https://www.nejm.org/doi/abs/10.1056/NEJMe0800801. Accessed: 11 August 2024.
Snipelisky, David., Kusumoto. (2013). Current Strategies to Minimize The Bleeding Risk of Warfarin. Journal of Blood Medicine; 89; 1-11. doi: 10.2147/jbm.s41404.
So, Charlotte. H., Eckman, Mark. H. (2017). Combined Aspirin and Anticoagulant Therapy in Patients with Atrial Fibrillation. Journal of Thrombosis and Thrombolysis; 43; 7–17. doi: 10.1007/s11239-016-1425-5.
Takahashi, H., Wilkinson, G. R., Nutescu, E. A., Morita, T., Ritchie, M. D., Scordo, M. G., Pengo, V., Barban, M., Padrini, R., Ieiri, I., Otsubo, K., Kashima, T., Kimura, S., Kijima, S., & Echizen, H. (2006). Different Contributions Of Polymorphisms In VKORC1 and CYP2C9 to Intra and Inter-Population Differences in Maintenance Dose of Warfarin in Japanese, Caucasians and African-Americans. Pharmacogenetics and Genomics; 16; 101–110.
doi: 10.1097/01.fpc.0000184955.08453.a8.
Tapaskar, Natalie., Ham, Sandra. A., Micic, Dejan., Sengupta, Neil. (2022). Restarting Warfarin vs Direct Oral Anticoagulants after Major Gastrointestinal Bleeding and Associated Outcomes in Atrial Fibrillation: A Cohort Study. Clinical Gastroenterology and Hepatology; 20; 381-389. 10.1016/j.cgh.2020.11.029.
Toth, Peter. P. (2016). Considerations for Long-Term Anticoagulant Therapy in Patients with Venous Thromboembolism in the Novel Oral Anticoagulant Era. Vascular Health and Risk Management; 12; 23–34. doi: 10.2147/VHRM.S88088.
Touchette, Daniel, R. E, Margaret. Mcguinness. Stoner, Steve. Shute, David. Jennifer M. Edwards. Kathy. (2007). Improving Outpatient Warfarin Use for Hospitalized Patients with Atrial Fibrillation. Pharmacy practice; 6; 43-50. doi: 10.4321/s1886-36552008000100007.
Vyas, Vrinda., Sankari, Abdulghani., Goyal, Amandeep. (2022). Acute Pulmonary Embolism. https://www.ncbi.nlm.nih.gov/books/NBK560551/. Accessed: 4 October 2024.
Waheed, Sheikh. M., Kudaravalli, Pujitha., Hotwagner. David. T. (2021). Deep Vein Thrombosis. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK507708/. StatPearls. Accessed: 12 November 2024.
World Health Organisation. (2019). Cardiovascular Diseases (CVDs). https://www.who.int/health-topics/cardiovascular-diseases/. Accessed: 12 November 2024.
Yabeyu, Abdella. Birhan., Adugna, Ayanaw. Meaza., Taye, Haile. Kaleab., Demelash, Kifle. Zemen. (2022). Evaluation of Patients Knowledge of Warfarin at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. Metabolism Open; 13; 2589–9368. doi: 10.1016/j.metop.2021.1001555.
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