Abstract
Introduction: Oral anticoagulant is essential for the treatment and prevention of thromboembolism. Warfarin is an effective oral anticoagulant in prevention and treatment of thromboembolism. However, warfarin is frequently associated with adverse event (AE) requiring hospitalization. Method: We performed a retrospective cohort study of all patients admitted to a large tertiary public hospital for warfarin-related AEs. Patients were grouped based on bleeding severity and the direct medical cost was also calculated. Results: During the 4 years study period, a total of 224 patients were admitted for warfarin-related AEs. Mean age of patients admitted was 65.1 years (standard deviation [SD] = 11.5). More than half, 59.6%, of them were on warfarin for prevention of stroke in atrial fibrillation or atrial flutter. Major bleeding occurred among 50.9% of the patients with gastrointestinal bleed, 34 (29.8%), as the common site of bleed. Patients with major bleed had longer median hospital stay of 4 days (interquartile range [IQR] = 5) compared to 3 (IQR = 3) days in non-major bleed. There were 17 (14.9%) death among the major bleeders. Mean medical cost for managing warfarin-related AEs was USD 708.08. Conclusion: The admitted patients were equally distributed in terms of bleeding severity. Medical cost incurred for managing warfarin-related AEs increased with the severity of bleeding.
Keywords: cardiac agents, adverse events, anticoagulants, blood products
Introduction
Oral anticoagulant is essential for the treatment and prevention of thromboembolism. Oral anticoagulant is used to prevent thromboembolism in patients with prosthetic heart valves, treat deep vein thrombosis (DVT) and pulmonary embolism (PE). Warfarin sodium was approved for use in medicine in 1954 and has been the primary oral anticoagulant that was effective in preventing and treating thromboembolism. The main adverse event of warfarin is overwarfarinisation due to its narrow therapeutic index, multiple drug-drug interactions, drug-food interaction, and drug-disease interaction.
It was reported that 6.1% of newly diagnosed AF patients initiated on warfarin develops bleeding events within 30 days of warfarin initiation. 1 Asian patients on warfarin are at higher risk of major bleeding, especially intracranial bleed compared to non-Asians. 2 Besides the increased risk of bleeding, warfarin therapy also post difficulties in determining the ideal international normalized ratio (INR) target and maintaining INR within the target among Asians. 3 Warfarin contributed to 10.5% of all admissions for AEs among adults in 2 large general hospitals in England. AEs associated with warfarin were gastrointestinal (GI ) bleed, hematuria, and elevated INR. 4
To date, there are limited studies evaluating warfarin-related AEs and medical costs in Malaysia. This study aimed to determine the incidence of warfarin-related AEs leading to hospitalization and its cost implication among patients diagnosed with overwarfarinisation.
Methodology
This retrospective cohort study was conducted by reviewing medical records of patients in Hospital Raja Permaisuri Bainun, Ipoh, Malaysia. The study populations were adult patients (aged 18 years or more) with established warfarin therapy (eg, atrial fibrillation, deep vein thrombosis, pulmonary embolism, intracardiac thrombus, or heart valve replacement) hospitalized due to overwarfarinisation between 1st January 2016 and 31st December 2019. Overwarfarinisation was defined as per the ICD-10-CM Diagnosis Code T45.7X1. Hospital Raja Permaisuri Bainun is a tertiary public healthcare facility catering large number of patients on warfarin. Patients with insufficient or incomplete data in medical records were excluded.
The data obtained were demographic information, warfarin indication and admission data. Admission data included potential cause, bleeding severity and management of warfarin-related AEs. Charlson Comorbidity Index (CCI) 5 and modified Outpatient Bleeding Risk Index (mOBRI) 6 were calculated for this population. We used Lexicomp® Drug Interactions to identify possible drug-drug interactions between warfarin and drugs used by patients at the time of admission. Each patient had their severity of bleeding classified as either major or non-major bleeding. Major bleeding was defined as bleeding occurring in an anatomically critical site (eg, intracranial), associated with hemodynamic compromise, or associated with a drop of hemoglobin 2 g/dL or more (when baseline is known) or requiring 2 units or more of packed red blood cells (RBCs) transfusion. Non-major bleeding are bleeds not classified as major bleeding. 7 Data on management of warfarin-related AEs were length of hospital stay, laboratory and imaging diagnostics conducted and drugs prescribed.
Direct medical cost was considered in the calculation of warfarin-related AEs management cost. The cost of admission was based on the Fees (Medical) (Cost of Services) Order 2014. The cost of blood and blood products (fresh frozen plasma [FFP], packed red blood cells [RBC], prothrombin complex concentrate [PCC] were ascertained through National Blood Center (Malaysia). The procurement cost of drugs were obtained from the hospital’s drug price catalogue for the year 2019. The cost of laboratory and diagnostic imaging were based on the Fees (Medical) (Amendment) Order 2017. The space and personnel involved in the management of over-warfarinisation was not solely dedicated to its cause. Thus, we assumed the daily in-patient treatment charges stated in Fees (Medical) (Cost of Services) Order 2014 (Third Schedule) was representative of the space and personnel cost.
All cost were adjusted for inflation using the 2019 Consumer Price Index (https://www.dosm.gov.my/cpi_calc/index.php) in Malaysian Ringgit (MYR). A conversion based on central parity rate in 2019 was applied to express the costs in US Dollars (USD).
Statistical Analysis
The sample size was not calculated. All eligible patients identified during the study period were included. All data were entered into Microsoft Excel® and analyzed using STATA (StataCorp, College Station, TX, USA). The normality of the data was assessed visually and determined by using the Sharpiro–Wilk test. Mean and standard deviation (SD) were used to describe normally distributed data, and if the data is non-normally distributed, median and inter-quartile range (IQR) were used. For normally distributed variable, Student’s t-test was applied to assess the difference between cohorts and Mann–Whitney U test was applied for non-normally distributed variables. For dichotomous variable, a Chi-squared test was used.
Ethical Consideration
The study was registered with National Medical Research Registry (NMRR-18-1538-42135) and ethical approval obtained from National Medical Research and Ethics Committee (MREC), Ministry of Health (MOH). Data that deemed identifiable to the patients were not collected in this study. The master list of study ID will be destroyed one month after the date of publication.
Results
The average patient-year that was treated with warfarin in this hospital was 833. A total of 248 admissions involving 224 patients for warfarin-related AEs were observed during the 4 years. Recurrent admissions for warfarin-related AEs were observed in 22 patients: 1 had a total of 3 admissions and another 21 had a total of 2 admissions during the study period. This translated to 7.4 admissions for warfarin-related AEs per 100 patient-year and 3.4 admissions for major bleeding per 100 patient-year.
Majority of the study population (n = 224) were male, 51.3% (115) and of Malay ethnicity, 44.2% (99). Mean age of the study population was 65.1 years (SD = 11.5). Out of 224 patients, 59.6% (133) of patients were on warfarin for stroke prevention with either underlying atrial fibrillation or atrial flutter. Other baseline characteristics of these patients presenting with non-major bleeding compared to major bleeding are presented in Table 1. Among the non-major bleeding admission, 82 (36.6%) patients had no symptoms of bleeding. Patients presented with major bleeding had more concurrent illness; with mean number of illness of 3.2 (SD = 1.3) versus 2.7 (SD = 1.4), in patient with non-major bleeding, P = .005. Both CCI and mORBI score were significantly higher among the major bleeders with mean score of 4.0 (SD = 1.9) and 1.4 (SD = 0.9), respectively. Concurrent antiplatelet use was observed in 59 patients: 42 on low dose acetylsalicylic acid, 6 on clopidogrel, and 11 on dual antiplatelet. The use of anti-platelet was higher among patients presented with major bleeding as opposed to group with non-major bleeding, History of admission for warfarin-related AEs, renal impairment and documented use of NSAID were not significantly different between both bleeding severity groups.
Table 1.
Characteristic of Patients Admitted for Warfarin-related Adverse Events.
| Patient characteristics | Non-major bleeding n = 110 | Major bleeding n = 114 | Total N = 224 | P-value |
|---|---|---|---|---|
| Age (in years), mean (SD) | 65.8 (12.1) | 66.5 (11.0) | 65.1 (11.5) | .663 |
| Gender, Male, n (%) | 59 (53.6) | 56 (49.1) | 115 (51.3) | .499 |
| Ethnicity, n (%) | ||||
| Malay | 45 (40.9) | 54 (47.4) | 99 (44.2) | .209 |
| Chinese | 47 (42.7) | 49 (43.0) | 96 (42.9) | |
| Indian | 18 (16.4) | 11 (9.6) | 29 (12.9) | |
| Indication for Warfarin, n (%) | ||||
| Atrial fibrillation and atrial flutter | 62 (56.9) | 71 (62.3) | 133 (59.6) | .254 |
| Valve replacement | 20 (18.3) | 15 (13.2) | 35 (15.7) | |
| Deep vein thrombosis | 7 (6.4) | 13 (11.4) | 20 (9.0) | |
| Pulmonary embolism | 5 (4.6) | 3 (2.6) | 8 (3.6) | |
| Combination | 11 (10.1) | 5 (4.4) | 16 (7.2) | |
| Others | 4 (3.7) | 7 (6.1) | 11 (4.9) | |
| Concurrent illness, mean (SD) | 2.7 (1.4) | 3.2 (1.3) | 3.2 (1.3) | .005 |
| Renal impairment, n (%) | 16 (14.5) | 22 (19.3) | 39 (17.4) | .448 |
| Hypertension, n (%) | 76 (69.1) | 86 (75.4) | 162 (72.3) | .288 |
| Cerebral vascular accident, n (%) | 11 (10.0) | 17 (14.9) | 28 (12.5) | .266 |
| Cancer, n (%) | 5 (4.5) | 3 (2.6) | 8 (3.6) | .493 |
| CCI, mean (SD) | 3.5 (1.7) | 4.0 (1.9) | 3.7 (1.8) | .046 |
| mORBI, mean (SD) | 1.2 (0.8) | 1.4 (0.9) | 1.3 (0.8) | .048 |
| History of over-warfarinisation, Yes, n (%) | 20 (18.9) | 31 (28.4) | 51 (23.7) | .068 |
| Use of antiplatelet, Yes, n (%) | 20 (18.2) | 39 (34.2) | 59 (26.3) | .006 |
| Use of NSAID, Yes n (%) | 12 (10.9) | 9 (7.9) | 21(9.4) | .439 |
Note. n = number; %, percentage; SD = standard deviation; CCI = Charlson Comorbidity Index; mOBRI = Modified Outpatient Bleeding Risk Index; NSAID = non-steroidal anti-inflammatory drug.
The primary site of bleeding among the patients presented with major bleeding was gastrointestinal bleed 29.8% (34), followed by hematuria 19.3% (22), and intracranial bleed 16.7% (19), as shown in Table 2. Out of 34 patients that presented with gastrointestinal bleed, 22 were diagnosed with upper gastrointestinal bleed and 12 patients were diagnosed with lower gastrointestinal bleeding.
Table 2.
Bleeding Site of Patients Admitted for Warfarin-related Adverse Events.
| Site of bleed | Number (%) |
|---|---|
| Gastrointestinal bleed | 34 (29.8) |
| Hematuria | 22 (19.3) |
| Intracranial bleed | 19 (16.7) |
| Subcutaneous hemorrhage | 9 (7.9) |
| Bruises | 8 (7.0) |
| Intramuscular bleed | 4 (3.5) |
| Hemoptysis | 4 (3.5) |
| Gum bleed | 3 (2.6) |
| Vaginal bleed | 3 (2.6) |
| Intraarticular bleed | 3 (2.6) |
| Subconjuctival hemorrhage | 3 (2.6) |
| Epitaxis | 2 (1.8) |
Documented possible reasons for warfarin-related AEs are presented in Table 3. The most common causes of warfarin-related AEs were the use of analgesia within 1 week (13), medication error (11), and use of traditional medication within 1 week (6). The majority of the medication error (7/11) cases were due to patients taking unintentional wrong doses. Other possible reasons documented were newly diagnosed illnesses such as cancers, thrombocytopenia, and uncontrolled hypertension. Three patients developed overwarfarinisation due to drug interaction where 1 had carbimazole withdrawn without warfarin dosage adjustment and another had ciprofloxacin prescribed for diabetic foot ulcer without frequent INR monitoring.
Table 3.
Documented Possible Cause of Warfarin-related Adverse Events.
| Documented cause | Cases |
|---|---|
| Consumption of analgesia within 1 week | 13 |
| Medication error | 11 |
| Consumption of traditional medications within 1 week | 6 |
| Newly diagnosed Illness | 3 |
| Drug interaction | 3 |
| Uncontrolled hypertension | 2 |
INR and hemoglobin (Hb) at admission were significantly different between both groups. Mean INR and Hb among patients presented with major bleeding were 8.3 (SD = 4.9) and 10.2 (SD = 2.7), respectively. Patients with non-major bleeding had a lower mean INR of 6.9 (SD = 2.9) and higher Hb of 11.6 (SD = 2.2). This corresponded to significantly higher INR and FBC testing among patients with major bleeding than non-major bleeding as shown in Table 4. Percentage of patients who received vitamin K, FFP and RBC were also significantly higher among patients with major bleeding. A total of 17 patients received 3-factor PCC and the it’s use was not significantly different between both groups. The median length of stay in the hospital was higher among major bleeders; 4 days (IQR = 5) compared to non-major bleeders; 3 days (IQR = 3), (P = .002). There were 17 (14.9%) deaths among major bleeders compared to 4 (3.7%) deaths among non-major bleeders, P = .004. Intracranial bleed was the most common cause of death recorded among 47.6% of patients who succumbed to death.
Table 4.
Treatment and Outcome of Patients Admitted for Warfarin-related Adverse Events.
| Outcome variables | Non-major bleeding n = 110 | Major bleeding n = 114 | Total N = 224 | P-value |
|---|---|---|---|---|
| Laboratory testings | ||||
| INR at Admission, mean (SD) | 6.9 (2.9) | 8.3 (4.9) | 7.6 (4.1) | .016 |
| INR Test, median (IQR) | 3 (2) | 4 (4) | 4 (2) | .004 |
| Hb at Admission, mean (SD) | 11.6 (2.2) | 10.2 (2.7) | 10.9 (2.6) | <.001 |
| FBC Test, median (IQR) | 1 (1) | 4 (4) | 2 (3) | <.001 |
| Treatment received | ||||
| Vitamin K, n (%) | 45 (40.9) | 72 (63.2) | 117 (52.2) | <.001 |
| Fresh Frozen Plasma, n (%) | 16 (14.5) | 73 (64.0) | 89 (39.7) | <.001 |
| Red Blood Cell, n (%) | 7 (6.4) | 44 (38.6) | 51 (22.8) | <.001 |
| 3 Factor PCC, n (%) | 6 (5.5) | 11 (9.6) | 17 (7.6) | .236 |
| Clinical outcomes | ||||
| Length of Stay (days), median (IQR) | 3 (3) | 4 (5) | 3 (4) | .002 |
| Outcome, Death, n (%) | 4 (3.7) | 17 (14.9) | 21 (9.4) | .004 |
| Cause of Death | ||||
| Intracranial Bleed | — | 10 | 10 | |
| Acute coronary syndrome | 2 | 1 | 3 | |
| Upper gastrointestinal bleed | — | 2 | 2 | |
| Multiorgan bleed | — | 2 | 2 | |
| Prostate cancer | — | 1 | 1 | |
| Addison disease complicated with overwarfarinisation | — | 1 | 1 | |
| Cardiogenic shock | 1 | — | 1 | |
| Septic shock | 1 | — | 1 | |
Note. SD = standard deviation; IQR = interquartile range; INR = international normalized ratio; Hb = hemoglobin; PCC = prothrombin complex concentrate.
The mean cost of treatment for warfarin-related AEs in a Malaysian tertiary hospital was USD 708.08 (95% CI 615.10, 801.06). Mean cost for managing warfarin-related AEs admission with no bleeding bleeding was USD 292.41 (95% CI 252.18, 332.64), and minor bleeding was USD 467.21 (95% CI 228.78, 705.65. Mean cost of major bleeding was highest for intracranial bleeding USD 2, 348.26 (95% CI 2, 131.84, 2, 564.67) followed by gastrointestinal bleeding; USD 1, 283.74 (95% CI 1, 122.52, 1, 444.97). The mean cost of other major bleeding was USD 557.57 (95% CI 461.25, 653.91). Diagnostics cost are the cost drivers in the management of warfarin-related AEs, followed by the length of hospital stay. However treatment modalities were the cost drivers in major bleeding.
Discussion
Incidence of major bleeding among patients in our hospital was estimated as 3.4 per 100 patient-years. Similarly, a tertiary care hospital in Thailand 8 and a Swedish academic center reported a major bleeding rate of 3.1 and 3.7 per 100 patient-years, respectively. 9 However, varying incidence of major bleeding was noted in a tertiary care academic center in Minneapolis (5.2 per 100 patient-years) 10 and in a large Tasmania referral hospital (2.4 per 100 patient-years). 11
Patients admitted for warfarin-related AEs in our study were mostly elderly with a mean age of 66.1 years (95% confidence interval of 64.6 - 67.7). However, increasing age did not correlate with the severity of bleeding or death, as also stipulated by Ozturk et al. 12 Patients admitted for warfarin-related AEs were reported as elderly in few studies with median age of population studied ranged from 61 to 65 years.13,14 Priksi et al. reported that patients aged 65 years or more were associated with major bleeding, and mean age of population studied was 60 years. 8
In our study, patients with more concurrent illness were associated with major bleeding. The presence of hypertension, cerebrovascular disease, and cancer was reported as predictors of severe bleeding8,9 In our study, none of above the illness were associated with major bleeding. Limdi et al. reported that patients with severe renal impairment had higher incidences of major bleeding than mild or moderate renal impairment. 15 In this study, patients with renal impairment was not staged based on severity. In future, staging renal impairment would better reflect the effect on bleeding outcome. Patients with renal impairment contributed to 17% of patients in this study.
The use of antiplatelet was associated to patients admitted for major bleeding. Patients on warfarin need their antiplatelet reviewed from time to time to minimize the risk of bleeding. It has been reported in a large cohort study that 37.5% of patients on warfarin are on concurrent acetylsalicylic acid without indication. 16 In this cohort, patients with concurrent warfarin and acetylsalicylic acid therapy had an increased risk of bleeding compared to single warfarin therapy, with similiar rate of thrombosis events. 16
The most common bleeding site was the gastrointestinal, urinary, and intracranial. These were the common sites of bleeding reported by various studies as well.8,13,17 The leading cause of death in our setting was intracranial bleed and gastrointestinal bleed. As presented by various studies, mortality risk are high among patients admitted with warfarin-related intracranial and gastrointestinal bleeding.8,13,18 It has been reported that patients on warfarin are associated with higher incidences of fatal bleeding compared to direct oral anticoagulants (DOACs). 19 In a middle-income country such as Malaysia, when the cost restricts the use of DOACs, it is vital to monitor patients on warfarin for preventable bleeding admissions. Medication error was documented as one of the contributing factor to warfarin-related AEs requiring admission in this setting. More than half of the identified cause for warfarin-related AEs was dosing error in a hospital in Cape Town. 14 Besides this preventable cause, potential drug interaction with warfarin should be reviewed for patients on warfarin. Dose adjustment of warfarin upon initiation or cessation of drugs with potential interaction with warfarin is essential.
The mean cost of managing patients presenting with warfarin-related AEs regardless of bleeding severity is high. Management of intracranial bleed incurred highest hospitalization cost compared to other bleeding events in this study. It was also reported that mean healthcare cost (including hospitalization, outpatient care, private doctor care, and prescribed medication cost) was highest for intracranial bleeding followed by gastrointestinal bleeding among atrial fibrillation patients either on warfarin or dabigatran. 20 One year after intracranial and any other major bleeding events, average cost for social care increased higher than healthcare cost. 20 In a retrospective cohort of atrial fibrillation patients on either warfarin or DOACs, direct hospital cost was not significantly different. 21 Therefore, identifying bleeding risk and preventing major bleeding, events are important to prevent burden to healthcare. This study maybe subjected to confounding risks, due to its retrospective nature and the data collection method which used information from the medical records.
Conclusion
Patients on warfarin may experience warfarin-related AEs resulting in either major bleeding or non-major bleeding that may require hospital admission. Admissions due to warfarin-related AEs incur healthcare cost which increases with severity of bleeding.
Footnotes
Author’s Note: Subramaniam Thanimalai is now affiliated to Hospital Seberang Jaya, Pulau Pinang, Ministry of Health, Malaysia.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Doris George 
https://orcid.org/0000-0001-8476-999X
Hoo Seng Tan
https://orcid.org/0000-0001-5905-858X
References
- 1. 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. doi: 10.18553/jmcp.2011.17.9.672 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Shen AYJ, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/Ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol. 2007;50(4):309-315. doi: 10.1016/j.jacc.2007.01.098 [DOI] [PubMed] [Google Scholar]
- 3. Wang KL, Chiang CE. Optimal international normalized ratio for atrial fibrillation in Asians and Japanese: do we really know?. Circ J. 2013;77(9):2242-2243. doi: 10.1253/circj.CJ-13-0885 [DOI] [PubMed] [Google Scholar]
- 4. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329(7456):15-19. doi: 10.1136/bmj.329.7456.15 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. [DOI] [PubMed] [Google Scholar]
- 6. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105:91-99. [DOI] [PubMed] [Google Scholar]
- 7. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694. doi: 10.1111/j.1538-7836.2005.01204.x [DOI] [PubMed] [Google Scholar]
- 8. Priksri W, Rattanavipanon W, Saejear W, et al. Incidence, risk factors, and outcomes of warfarin-associated major bleeding in Thai population. Pharmacoepidemiol Drug Saf. 2019;28(7):942-950. doi: 10.1002/pds.4781 [DOI] [PubMed] [Google Scholar]
- 9. 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. doi: 10.1007/s00228-020-02856-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Khan F, Datta YH. ‘Risk of bleeding during long-term anticoagulation with warfarin: a tertiary care center experience’. Blood Coagul Fibrinolysis. 2015;26(1):110-112. doi: 10.1097/MBC.0000000000000186.Risk [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Admassie E, Chalmers L, Bereznicki LR. Bleeding-related admissions in patients with atrial fibrillation receiving antithrombotic therapy: results from the Tasmanian Atrial Fibrillation (TAF) study. Eur J Clin Pharmacol. 2017;73(12):1681-1689. doi: 10.1007/s00228-017-2337-9 [DOI] [PubMed] [Google Scholar]
- 12. Ozturk M, Ipekci A, Kiyak SK, et al. Bleeding complications in warfarin-treated patients admitted to the emergency department. J Clin Med Res. 2019;11(2):106-113. doi: 10.14740/jocmr3669 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Koçak S, Ertekin B, Erdemir Öztürk E, Dündar ZD, Acar T, Girişgin AS. Bleeding due to warfarin treatment: Five Years of experience. Turk Klin Cardiovasc Sci. 2019;31(3):125-134. doi: 10.5336/cardiosci.2019-65895 [DOI] [Google Scholar]
- 14. Jacobs A, Bassa F, Decloedt EH. A preliminary review of warfarin toxicity in a tertiary hospital in Cape Town, South Africa. Cardiovasc J Afr. 2017;28(6):346-349. doi: 10.5830/CVJA-2017-029 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol. 2009;20(4):912-921. doi: 10.1681/ASN.2008070802 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Schaefer JK, Li Y, Gu X, et al. Association of adding aspirin to warfarin therapy without an apparent indication with bleeding and other adverse events. JAMA Intern Med. 2019;179(4):533-541. doi: 10.1001/jamainternmed.2018.7816 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Hollowell J. The incidence of bleeding complications associated with warfarin treatment in general practice in the United Kingdom. Br J Gen Pract. 2003;53(489):312-314. [PMC free article] [PubMed] [Google Scholar]
- 18. Navarro JL, Cesar JM, Fernández MA, Fontcuberta J, Reverter JC, Gol-Freixa J. [Morbidity and mortality in patients treated with oral anticoagulants]. Rev Esp Cardiol. 2007;60(12):1226-1232. doi: 10.1157/13113927 [DOI] [PubMed] [Google Scholar]
- 19. Gómez-Outes A, Lagunar-Ruíz J, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2016;68(23):2508-2521. doi: 10.1016/j.jacc.2016.09.944 [DOI] [PubMed] [Google Scholar]
- 20. Jakobsen M, Kolodziejczyk C, Klausen Fredslund E, Poulsen PB, Dybro L, Paaske Johnsen S. Costs of major intracranial, gastrointestinal and other bleeding events in patients with atrial fibrillation – a nationwide cohort study. BMC Health Serv Res. 2017;17(1):1-11. doi: 10.1186/s12913-017-2331-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Xu Y, Schulman S, Dowlatshahi D, et al. Healthcare resource utilization and costs among patients with direct oral anticoagulant or warfarin-related major bleeding. Thromb Res. 2019;182(May):12-19. doi: 10.1016/j.thromres.2019.07.026 [DOI] [PubMed] [Google Scholar]