Evaluation of Patients Hospitalized Due to Bleeding Complications Associated with Warfarin Treatment

Öz

The most significant complication of warfarin therapy is bleeding. The disadvantages of warfarin include its narrow therapeutic range and drug-drug interactions. This study aimed to determine the severity of bleeding events associated with warfarin treatment, mortality, and factors that may influence these outcomes. A total of 119 patients hospitalized due to bleeding complications associated with warfarin use between January 2007 and December 2010 were included in the study. Demographic and clinical data—including age, gender, comorbidities, International Normalized Ratio (INR), and mortality—were analyzed. Bleeding severity was classified according to the Fihn criteria as minor bleeding and major bleeding (severe, life-threatening and fatal bleeding). Fifty-six patients (51.4%) were female,53 (48.6%) were male, and 53.2% of the patients were aged 65 years and older. Hypertension (50.5%) and diabetes mellitus (22.0%) were the most common comorbid conditions. The primary indications for warfarin use were atrial fibrillation (35.8%), followed by cardiovascular diseases (32.1%), history of stroke (26.6%), and prosthetic heart valve (22.0%). The most common presenting symptoms were ecchymosis and upper gastrointestinal bleeding. Major bleeding was significantly more common in males (p=0.046). Ninety-eight percent (n=107) of patients experiencing bleeding had supratherapeutic INR values. Mortality was significantly higher in patients aged 65 years and older (p=0.029). There was no significant difference between genders in terms of overall bleeding event frequency and mortality. In conclusion, advanced age and labile INR are significant factors in warfarin-related bleeding events. Mortality due to warfarin-related bleeding is significantly higher in older patients.

Anahtar Kelimeler

• oral anticoagulant therapy
• warfarin
• bleeding
• haemorrhage

Varfarin Tedavisine Bağlı Kanama Komplikasyonları Nedeniyle Hastaneye Yatırılan Hastaların Değerlendirilmesi

Öz

Varfarin tedavisinin en önemli komplikasyonu kanamadır. Varfarinin, terapötik aralığının dar olması ve ilaç-ilaç etkileşimleri dezavantajları arasında yer almaktadır. Çalışmada varfarin tedavisine bağlı kanama olaylarının şiddeti, mortalite ve etki edebilecek faktörlerin belirlenmesi amaçlandı. Ocak 2007-Aralık 2010 tarihleri arasında varfarin kullanımına bağlı kanama nedeniyle hastaneye yatırılan 109 hasta dahil edildi. Demografik ve klinik özellikler -yaş, cinsiyet, eşlik eden hastalıklar, INR düzeyi ve mortalite- analiz edildi. Kanama şiddeti Fihn kriterlerine göre minör kanama ve major kanama (ciddi, hayatı tehdit edici ve fatal kanama) olarak sınıflandırıldı. Hastaların; 56’sı kadın (%51,4), 53’ü (%48,6) erkek, %53,2’si 65 yaş ve üzerindeydi. Komorbid hastalıklar içinde birinci sıklıkta hipertansiyon (%50,5), ikinci sıklıkta diabetes mellitus (%22,0) saptandı. Varfarin kullanım endikasyonları arasında en sık atriyal fibrilasyon (%35,8), sonrasında kardiyovasküler hastalıklar (%32,1), geçirilmiş stroke (%26,6) ve prostetik kalp kapağı (%22,0) gelmekte idi. En sık geliş semptomu ekimoz ve üst gastrointestinal kanama idi. Majör kanama erkek cinsiyette anlamlı şekilde yüksekti (p=0,046). Kanama geçiren hastaların %98’i (n=107) supraterapötik INR değerine sahipti. Mortalite ileri yaş (≥65 yaş) hastalarda anlamlı şekilde yüksekti (p=0,029). Genel kanama olaylarının sıklığı ve mortalite açısından her iki cinsiyet arasında fark yoktu. Sonuç olarak ileri yaş ve labil INR varfarin ilişkili kanama olaylarında etkilidir. Varfarine bağlı kanama olaylarında mortalite ileri yaş hastalarda anlamlı şekilde daha yüksektir.

Anahtar Kelimeler

• oral antikoagülan tedavi
• warfarin
• kanama
• hemoraji

Kaynakça

1. 1. Lim GB. Milestone 2: Warfarin: from rat poison to clinical use. Nat Rev Cardiol. Published online December 14, 2017.
2. 2. Hylek EM. Vitamin K antagonists and time in the therapeutic range: implications, challenges, and strategies for improvement. J Thromb Thrombolysis. 2013;35(3):333-335.
3. 3. Wadsworth D, Sullivan E, Jacky T, et al. A review of indications and comorbidities in which warfarin may be the preferred oral anticoagulant. J Clin Pharm Ther. 2021;46(3):560-570.
4. 4. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694.
5. 5. Merli GJ, Tzanis G. Warfarin: what are the clinical implications of an out-of-range-therapeutic international normalized ratio? J Thromb Thrombolysis. 2009;27(3):293-299.
6. 6. Vitry AI, Roughead EE, Ramsay EN, et al. Major bleeding risk associated with warfarin and co-medications in the elderly population. Pharmacoepidemiol Drug Saf. 2011;20(10):1057-1063.
7. 7. Comoretto RI, Rea F, Lucenteforte E, et al. Bleeding events attributable to concurrent use of warfarin and other medications in high-risk elderly: meta-analysis and Italian population-based investigation. Eur J Clin Pharmacol. 2018;74(8):1061-1070.
8. 8. Halperin JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation. 2014;130(2):138-146.

9. 9. Ghate SR, Biskupiak J, Ye X, Kwong WJ, Brixner DI. All-cause and bleeding-related health care costs in warfarin-treated patients with atrial fibrillation. J Manag Care Pharm. 2011;17(9):672-684.
10. 10. Fihn SD, McDonell M, Martin D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med. 1993;118(7):511-520.
11. 11. Raj G, Kumar R, McKinney WP. Long-term oral anticoagulant therapy: update on indications, therapeutic ranges, and monitoring. Am J Med Sci. 1994;307(2):128-132.
12. 12. Backus B, Beyer-Westendorf J, Body R, et al. Management of major bleeding for anticoagulated patients in the Emergency Department: a European experts consensus statement. Eur J Emerg Med. 2023;30(5):315-323.
13. 13. Rydberg DM, Linder M, Malmström RE, Andersen M. Risk factors for severe bleeding events during warfarin treatment: the influence of sex, age, comorbidity and co-medication. Eur J Clin Pharmacol. 2020;76(6):867-876.
14. 14. Raza S, Pinkerton P, Hirsh J, Callum J, Selby R. The historical origins of modern international normalized ratio targets. J Thromb Haemost. 2024;22(8):2184-2194.
15. 15. Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):287S-310S.
16. 16. Labaf A, Själander A, Stagmo M, Svensson PJ. INR variability and outcomes in patients with mechanical heart valve prosthesis. Thromb Res. 2015;136(6):1211-1215.
17. 17. Bartholomew RR, Noble BN, Stanislaw JJ, et al. Frequency and clinical outcomes of pharmacist-driven switching from warfarin to direct oral anticoagulants in an underserved patient population: A retrospective cohort study. Am J Health Syst Pharm. 2023;80(Suppl 3):S103-S110.
18. 18. Wiedermann CJ, Stockner I. Warfarin-induced bleeding complications - clinical presentation and therapeutic options. Thromb Res. 2008;122 Suppl 2:S13-8.
19. 19. Vitry AI, Roughead EE, Ramsay EN, et al. Major bleeding risk associated with warfarin and co-medications in the elderly population. Pharmacoepidemiol Drug Saf. 2011;20(10):1057-1063.
20. 20. Labaf A, Grzymala-Lubanski B, Stagmo M, et al. Thromboembolism, major bleeding and mortality in patients with mechanical heart valves- a population-based cohort study. Thromb Res. 2014;134(2):354-359.
21. 21. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093-1100.
22. 22. Villa Zapata L, Hansten PD, Panic J, et al. Risk of Bleeding with Exposure to Warfarin and Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review and Meta-Analysis. Thromb Haemost. 2020;120(7):1066-1074.
23. 23. Malhi H, Atac B, Daly AK, Gupta S. Warfarin and celecoxib interaction in the setting of cytochrome P450 (CYP2C9) polymorphism with bleeding complication. Postgrad Med J. 2004;80(940):107-109.
24. 24. Zhou L, Ding Y, Gao Y, et al. Genetic influence on bleeding and over-anticoagulation risk in patients undergoing warfarin treatment after heart valve replacements. Expert Opin Drug Metab Toxicol. 2020;16(1):1-9.
25. 25. Wang M, Zeraatkar D, Obeda M, et al. Drug-drug interactions with warfarin: A systematic review and meta-analysis. Br J Clin Pharmacol. 2021;87(11):4051-4100.
26. 26. Barcellona D, Schirru P, Mameli A, et al. Over-anticoagulation by vitamin K antagonists and gender differences. Int J Cardiol. 2022;362:147-151.
27. 27. Simon TA, Pan X, Kawabata H, Huang HY, Azoulay L. The Association Between Bleeding and the Incidence of Warfarin Discontinuation in Patients with Atrial Fibrillation. Cardiovasc Ther. 2016;34(2):94-99.
28. 28. Nekkanti H, Mateti UV, Vilakkathala R, et al. Predictors of warfarin-induced bleeding in a South Indian cardiology unit. Perspect Clin Res. 2012;3(1):22-25.
29. 29. Penttilä T, Lehto M, Niiranen J, et al. Differences in the risk of stroke, bleeding events, and mortality between female and male patients with atrial fibrillation during warfarin therapy. Eur Heart J Cardiovasc Pharmacother. 2019;5(1):29-36.
30. 30. Pancholy SB, Sharma PS, Pancholy DS, et al. Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants. Am J Cardiol. 2014;113(3):485-490.
31. 31. Ballestri S, Romagnoli E, Arioli D, et al. Risk and Management of Bleeding Complications with Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Venous Thromboembolism: a Narrative Review. Adv Ther. 2023;40(1):41-66.
32. 32. Gómez-Outes A, Alcubilla P, et al. Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants. J Am Coll Cardiol. 2021;77(24):2987-3001.
33. 33. Gomes T, Mamdani MM, Holbrook AM, et al. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013;185(2):E121-E127.