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 Table of Contents  
Year : 2022  |  Volume : 13  |  Issue : 4  |  Page : 291-295  

Evaluation of adverse drug reaction in patients warfarin therapy

1 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
2 Department of Biology Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
3 Department of Cardiovascular, Faculty of Medicine, Universitas Padjadjaran, Jatinangor, Indonesia
4 Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Indonesia

Date of Submission10-Jun-2022
Date of Decision09-Jul-2022
Date of Acceptance01-Aug-2022
Date of Web Publication10-Oct-2022

Correspondence Address:
Prot. apt. Taofik Rusdiana
Ph.D, Raya Bandung Sumedang Road Km. 21, Hegarmanah, West Java 45363 Bandung
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/japtr.japtr_439_22

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This research aimed to understand the adverse drug reaction (ADR) in heart disease outpatients who were administered warfarin at a hospital in Bandung city. The research was conducted using a cross-sectional design with an observational approach. Subsequently, data were collected from 74 patients who met the inclusion criteria. The causality assessment was made by the Naranjo Algorithm and the incidence of bleeding was classified based on the Bleedscore™. The result showed that the most common ADR were nausea, dizziness, stomach ache, ecchymosis, petechiae, bleeding in the mouth, melena, etc. Furthermore, the INR value was the most significant factor in the incidence of ADR. It was 6.445 using a value of P = 0.001 or a confidence interval of 95%. The most common side effect of warfarin in cardiac outpatients was superficial bleeding, followed by internal bleeding (melena). The INR value is the most significant factor in measuring the incidence of ADR.

Keywords: Adverse drug reaction, bleeding, international normalized ratio value, warfarin

How to cite this article:
Putriana NA, Rusdiana T, Rostinawati T, Akbar MR, Destiani DP. Evaluation of adverse drug reaction in patients warfarin therapy. J Adv Pharm Technol Res 2022;13:291-5

How to cite this URL:
Putriana NA, Rusdiana T, Rostinawati T, Akbar MR, Destiani DP. Evaluation of adverse drug reaction in patients warfarin therapy. J Adv Pharm Technol Res [serial online] 2022 [cited 2022 Nov 28];13:291-5. Available from: https://www.japtr.org/text.asp?2022/13/4/291/358216

  Introduction Top

Cardiovascular disease is one of the biggest causes of death in the world, killing about 17.9 million people in 2016, which accounted for 31% of all deaths worldwide.[1] Subsequently, the prevalence of heart disease in Indonesia and the province of West Java is 1.5% and 1.6%, respectively, as reported by the Basic Health Research (RISKESDAS), Ministry of Health in 2018.[2] Anticoagulants are a class of drugs used to inhibit the formation and functions of several blood clotting factors to treat cardiovascular diseases. Warfarin is an example of an anticoagulant that inhibits the formation of Vitamin K. Warfarin has a narrow therapeutic index indicated for the prevention and treatment of venous thromboembolism, thromboembolic complications with atrial fibrillation, and pulmonary embolism. The main problem with warfarin use is the high variation in response between individuals, which results in many cases of drug-related problems in the form of adverse drug reactions (ADRs).[3]

ADR have a clinical and economic impact, including a decrease in the quality of life. In various studies, it has been considered a major cause of morbidity and mortality.[4] Anticoagulant drugs like warfarin is a major cause of ADRs, accounting for 60% of those that require hospitalization and 70% of those that occur in hospitals.[5] The study conducted by Budnitz et al.[6] also showed that warfarin is the most commonly prescribed drug that causes ADR, leading to emergency department (ED) visits.[6] Consequently, it is the first-order drug with the most cases at ED visits in the US.[7]

Bleeding is a serious, life-threatening ADR from warfarin use and, patients can see its manifestation in the form of nosebleeds, bleeding in the gastrointestinal tract, melena, or bruises.[8] Bleeding due to warfarin correlates with international normalized ratio (INR) value. A previous study showed that 44% of patients who experienced bleeding had an INR value >3.0, whereas 48% of patients with a thromboembolic event had an INR value of <2.15.[9] In addition, risk factors for ADR, including warfarin-associated bleeding are advanced age, serious comorbidities such as cancer, chronic kidney disease, liver dysfunction, arterial hypertension, stroke, alcohol abuse, and concomitant use of antiplatelet or other drugs.[9]

Since there are no studies in Indonesia that examine the ADR of warfarin, an evaluation of such ADRs is carried out in heart disease patients at a hospital in Bandung city. This study aims to obtain information related to the incidence of ADRs while receiving warfarin therapy and also factors related to prevention and diagnosis of serious reactions so that necessary follow-up can be carried out, such as adjustments to drug use.

  Methods Top

Study design

This study used a cross-sectional approach, collecting observational data by searching primary data using the Naranjo Algorithm for ADR events, and assessing the causality based on probability scores. Bleeding events were classified based on the BleedScore™. Meanwhile, secondary data were obtained in the form of sociodemographic and clinical data from medical records consisting of gender, age, height, weight, indications, doses of warfarin given, duration of therapy, other diseases, other drugs being taken, and the patient's INR value.

Ethical approval

This research study was submitted for permission to The Health Research Ethics Committee, Faculty of Medicine, University of Padjadjaran. This permission has been approved by the Ethics Commission of Padjadjaran University, Bandung, Indonesia (No. 28/UN6. KEP/EC/2021).

Eligibility criteria

Inclusion criteria are all outpatients that treated with oral warfarin at the cardiac polyclinic who came for control in March 2021 at Hasan Sadikin Hospital, patients who had been on warfarin for at least 1 month, and patients with INR laboratory data were eligible for this study. However, the exclusion criteria included unwillingness to be the subject of research and incomplete or untraceable medical records.

Population and sample

The sample in this study was outpatient cardiac polyclinic according to the inclusion criteria. The total population of patients treated with warfarin during the data collection period was 90 patients. The minimum sample required is 73 samples (using the Slovin formula).

Statistical analysis

Univariate analysis was employed for descriptive analysis to determine the characteristics of each research variable, such as the number and percentage (n, %). Furthermore, bivariate analysis was also used with Chi-square to find variables that can be included in the multivariate model with P < 0.25. Finally, multivariate regression (logistics regression) was employed to see the factors related to the incidence of ADR as seen from the odds ratio (OR) with P < 0.05.

  Result and Discussion Top

Data collection

Data were collected from 74 patients who had met the inclusion criteria. The data obtained are primary in the form of direct interviews using the Naranjo algorithm of the ADR. Furthermore, each point in every question will be summed and matched with the Naranjo Algorithm Scale, a score of 0 which is Doubtful indicates that it is not a side effect; 1–4 implies it is Possible to be a side effect; 5–8 means it is Probably a side effect of the suspected drug; 9 is Definite implying that side effects are certain. In addition to primary data, secondary data obtained from medical records were also taken.

Characteristics of the participants

Sociodemographic and clinical characteristics of the participants and the results of the bivariate analysis (P value) using Chi-square can be seen in [Table 1]. It also shows the results of the multivariate analysis using logistic regression. The average of the respondents' age was 40–64 years and 62% of the patients were women. The most common indications for warfarin treatment are for patients with rheumatic heart disease. Furthermore, the sociodemographic and clinical characteristics of the patients considered as a factor affecting the incidence of ADR was tested using the statistical method of multivariate regression analysis or logistic regression to see the risk of the independent variables or predictors on the incidence of ADR as seen from the OR value. [Table 1] shows variables that passed the candidate test to include the multivariate model were drug interaction, comorbidities, INR values, and dose (P < 0.25).
Table 1: Sociodemographic and clinical characteristic

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Adverse drug reactions and causality Naranjo algorithm

[Table 2] shows the incidence of ADR from warfarin in cardiac outpatients at one of Bandung city hospitals. Of the 74 participants, 43 patients (58%) experienced ADR and 31 (42%) did not experience ADR. The most common ADR was superficial bleeding (63%) in the form of ecchymosis or purple/blue blackish bruising that generally appeared on the hands or feet, followed by bleeding when brushing teeth and petechiae or red spots.
Table 2: The incidence of adverse drug reactions Warfarin and causality of Naranjo

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INR values and comorbidities had a significance of <0.05 and were considered factors associated with the incidence of ADR. Furthermore, patients were categorized into two groups, comprising those with acceptable INR values between 2 and 3, and those with unacceptable INR values <2 and >3. Subsequently, about 28 patients had an INR within the target range, while 49 patients were not within the targetted INR range. The P value obtained is 0.001, where the INR value influences the incidence of ADR and was the most significant factor in the incidence of ADR on warfarin use. OR INR obtained from the analysis carried out is 6.4, where patients with an unacceptable INR value would experience an ADR 6 times higher than patients with an acceptable INR value. Subsequently, ADR associated with warfarin are directly related to the level of INR level INR. The study by Gulseth et al.[9] discovered that the ADR of warfarin with an INR range that did not reach the target (2 and >3) was as high as 44% of patients who experienced bleeding with an INR level >3. Meanwhile, 48% of patients who experienced thromboembolic events had an INR level <2.15.[9] In this study, 23 patients with INR values >3.0 experienced bleeding events seen from the classification of the Bleedscore™ Subsequently, as many as 14 patients experienced bleeding when INR values were below 3.0.

Comorbidities are found in patients in the form of hypertension, diabetes mellitus, hyperthyroidism and gout. Their presence in patients was found to be statistically significant to the incidence of ADR with a P = 0.037. This is supported by a retrospective cohort study by Zhang et al.[10] and a prospective cohort study by Bassi et al.,[11] which found that patients with comorbidities were at greater risk of developing ADR.[10],[11] The presence of multiple disease conditions simultaneously predisposes the patient to drug-disease interactions that can eventually lead to ADR. A total of 8 patients with hypertension experienced bleeding, and it was found that hypertension is one of the risk factors for ADR and warfarin-related bleeding.[11]

[Table 1] shows the P value from the bivariate analysis for the candidate test of the multivariate logistic regression analysis model is 0.935, which indicates that there is no relationship between age and the incidence of ADR. These results are consistent with previous research by Ozturk et al.,[12] which found no statistically significant difference between age and the incidence of bleeding due to warfarin-related ADR, as well as a previous study by Sari et al.,[13] which found no relationship between age and the incidence of ADR on antiretroviral drug treatment.[13] This is in contrast to the cohort study conducted by Fang et al.[14] which showed that elderly patients over 80 years of age had a greater risk of warfarin-related bleeding events[14] as well as the study conducted by Uygungül et al.[15] that age is related to the incidence of ADR related to warfarin bleeding, with the elderly being at a higher risk of bleeding events, but this is also in line with the INR value of patients who are unstable and do not reach the target range.[15] According to the literature, age has a significant effect on the development of ADR at extreme ages, particularly in geriatric patients with various disease conditions who are more vulnerable to ADR.[16] In addition, the limited number of elderly patients can also limit the statistical significance because some elderly patients receive treatment at the Geriatric Clinic.

The most widely used drug that poses warfarin-related interactions by increasing its effect is erythromycin, which is used by 46% of the population, while spironolactone, which is used by 8% [Table 3], reduces the effects of warfarin. Drug interactions that occur are not statistically significant to ADR with P = 0.615. However, according to the data, 31 out of 48 patients who had a drug interaction experienced an ADR, while 14 out of 26 patients who did not have a drug interaction did not have an ADR. This variable may not have reached statistical significance due to the small sample size.
Table 3: Drug interactions of Warfarin

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One of the main factors related to ADR is the dose administered, drug formulation, and pharmacokinetic or pharmacodynamic abnormalities.[17] Furthermore, drug doses were categorized based on the patient's average daily dose, at 3 mg or higher. The results showed no relationship between drug dose and the incidence of ADR (P > 0.05). Every drug is given according to the recommended dose by looking at various factors. The dose given between individuals is not the same, and the dose of warfarin is given by looking at the main factor, namely the INR value of patients who are monitored regularly.[18] Subsequently, another factor that may influence the risk of bleeding is genetic variants. Gene mutation in Vitamin K epoxide reductase complex 1 (VKORC1) and CYP2C9 gene mutations can lead to a higher risk of bleeding in patients taking warfarin.[19],[20] In addition to affecting the activity of warfarin, of course, this will have an impact on ADR in the form of bleeding where a study conducted by Reitsma et al.[21] showed that the genetic polymorphism of VKORC1 has a high risk of bleeding (OR = 1.7, 95% confidence interval: 1.1–2.5).[21]

  Conclusion Top

The most common side effect of warfarin in cardiac outpatients was superficial bleeding, followed by internal bleeding (melena). The INR value is the most significant factor in measuring the incidence of ADR.


The Authors Are Grateful To Adila Resca Harda and Nurses Team at Department of Cardiovascular Hasan Sadikin Hospital For Technical Support.

Financial support and sponsorship

The authors are grateful to the Rector of Universitas Padjadjaran for funding this study (RDDU grant 2022).

Conflicts of interest

There are no conflicts of interest.

  References Top

WHO. Cardiovascular Diseases (CVDs) Fact Sheet. Cardiovascular Diseases (CVDs); 2017. Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds). [Last accessed on 2021 Jun 17; last updated on 2017 May 23].  Back to cited text no. 1
Kementerian Kesehatan RI. Laporan Nasional Riskesdas 2018, pdf. Jakarta: Badan Penelitian dan Pengembangan Kesehatan; 2019. p. 1-674.  Back to cited text no. 2
Obayashi K, Nakamura K, Kawana J, Ogata H, Hanada K, Kurabayashi M, et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther 2006;80:169-78.  Back to cited text no. 3
Arulmani R, Rajendran SD, Suresh B. Adverse drug reaction monitoring in a secondary care hospital in South India. Br J Clin Pharmacol 2008;65:210-6.  Back to cited text no. 4
Routledge PA, O'Mahony MS, Woodhouse KW. Adverse drug reactions in elderly patients. Br J Clin Pharmacol 2004;57:121-6.  Back to cited text no. 5
Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med 2007;147:755-65.  Back to cited text no. 6
Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US Emergency Department visits for outpatient adverse drug events, 2013-2014. JAMA 2016;316:2115-25.  Back to cited text no. 7
Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug reactions as cause of admission to hospital: Prospective analysis of 18 820 patients. BMJ 2004;329:15-9.  Back to cited text no. 8
Gulseth MP, Grice GR, Dager WE. Pharmacogenomics of warfarin: Uncovering a piece of the warfarin mystery. Am J Health Syst Pharm 2009;66:123-33.  Back to cited text no. 9
Zhang M, Holman CD, Price SD, Sanfilippo FM, Preen DB, Bulsara MK. Comorbidity and repeat admission to hospital for adverse drug reactions in older adults: Retrospective cohort study. BMJ 2009;338:a2752.  Back to cited text no. 10
Bassi PU, Osakwe AI, Ogar CK, Elagbaje C, Nwankwo BB, Balogun ST, et al. Impact of comorbidity on adverse drug reaction profile in a cohort of patients treated with Artemisinin combination therapies for uncomplicated malaria in Nigeria. Pharmacol Res Perspect 2017;5:e00302.  Back to cited text no. 11
Ozturk M, Ipekci A, Kiyak SK, Akdeniz YS, Aydin Y, Ikizceli I, et al. Bleeding complications in warfarin-treated patients admitted to the emergency department. J Clin Med Res 2019;11:106-13.  Back to cited text no. 12
Sari SP, Isnaini SR, Puspitasari AW. Monitoring side effects of antiretroviral therapy in patients with human immunodeficiency virus/acquired immunodeficiency syndrome. Int J Appl Pharm 2018;10:321-4.  Back to cited text no. 13
Fang MC, Go AS, Hylek EM, Chang Y, Henault LE, Jensvold NG, et al. Age and the risk of warfarin-associated hemorrhage: The anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc 2006;54:1231-6.  Back to cited text no. 14
Uygungül E, Ayrik C, Narci H, Erdoğan S, Toker I, Demir F, et al. Determining risk factors of bleeding in patients on warfarin treatment. Adv Hematol 2014;2014:369084.  Back to cited text no. 15
Gurwitz JH, Field TS, Harrold LR, Rothschild J, Debellis K, Seger AC, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA 2003;289:1107-16.  Back to cited text no. 16
Masubuchi N, Makino C, Murayama N. Prediction of in vivo potential for metabolic activation of drugs into chemically reactive intermediate: Correlation of in vitro and in vivo generation of reactive intermediates and in vitro glutathione conjugate formation in rats and humans. Chem Res Toxicol 2007;20:455-64.  Back to cited text no. 17
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:160S-98S.  Back to cited text no. 18
Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005;5:262-70.  Back to cited text no. 19
Epstein RS, Moyer TP, Aubert RE, O Kane DJ, Xia F, Verbrugge RR, et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 2010;55:2804-12.  Back to cited text no. 20
Reitsma PH, van der Heijden JF, Groot AP, Rosendaal FR, Büller HR. A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med 2005;2:e312.  Back to cited text no. 21


  [Table 1], [Table 2], [Table 3]


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