A Comparative Study on the effect of Warfarin v/s Acenocoumarol in patients with Atrial fibrillation


Shilpa Mary Alias1, Vishnu S Nair1, Parvathy Byju1, Dr. Praveen G Pai2, Remya Reghu1

1Department of Pharmacy Practice, Amrita School of Pharmacy, Kochi – 682041,

Amrita Vishwa Vidyapeetham, Kerala.

2Department of Cardiology, Amrita Institute of Medical Sciences and Research Centre,

Amrita Vishwa Vidyapeetham, Kerala.

*Corresponding Author E-mail: remyareghu@aims.amrita.edu



Aim: To compare and evaluate the effectiveness of warfarin and acenocoumarol in atrial fibrillation patients. Methods: It was a prospective observational study for a period of 1 year. The effectiveness was determined by comparing individual mean Time in therapeutic range (TTR) calculated using “Fraction of INR in range” method as well as by evaluating stroke risk using CHA2DS2VASc scores. The safety of the drug therapy was assessed from the ADR occurred after the drug administration. The data was analyzed using statistical software (version 20). Result: A total of 218 patients were selected for the study. The mean age of patients treated with acenocoumarol was 57.01±13.07 years and that of patients treated with warfarin was 67.18±12.24 years respectively. Mean TTR was found to be 56.54% ± 19.67 vs 50.69% ± 23.57 for acenocoumarol and warfarin respectively (p value <0.05). After the drug initiation, 12 patients experienced stroke episodes in acenocoumarol group while 24 patients experienced stroke in warfarin treated group (p value <0.05). A total of 463 ADRs were observed during the study period, of which 174 belong to acenocoumarol treated patients and 289 to warfarin group. Among these, bleeding (127 patients) was the main ADR (55 vs 72) with p value of 0.001.

Conclusion: This study concluded that acenocoumarol is a better oral anticoagulant compared to warfarin while considering various factors like mean TTRs, ADRs observed, stroke incidence and QOL of patients.


KEYWORDS: Acenocoumarol, Warfarin, TTR, Atrial fibrillation, OAC.




Atrial Fibrillation is the most prevalent type of sustaining dysrhythmia that has evidently affected more than 33.5 million people around the world. Atrial fibrillation is the evident predecessor of stroke and thromboembolism that have substantial morbidity and mortality.1 The prevalence rate of atrial fibrillation has remarkably increased over the previous years.2 Patients with atrial fibrillation are at risk of developing stroke and antithrombotic prophylaxis is essential in patients with atrial fibrillation at risk of developing stroke.3,4  


Coumadin derivatives are the anticoagulant agents preferred for this purpose which include mainly warfarin and acenocoumarol. Warfarin is an anticoagulant medication that is used to slow down the blood clotting process, whereas Acenocoumarol is a blood thinner, used to treat thrombotic disorders that obstruct the normal blood flow in blood vessel.


Theoretically warfarin is a drug with long half-life as compared to acenocoumarol, so it is expected to provide more stability in anticoagulation but there exists conflicts between published literatures regarding the effectiveness of the two. It was found that in majority of these published literatures the sample size was small and the study duration was short5. So the study results cannot be considered as a generalized one. Hence, by rectifying these drawbacks we had conducted this study for a comparatively longer duration on a larger sample size. Our study results have the potential to alter the general prescribing patterns of both the drugs providing increased treatment goal achievement chances.


A drug providing greater stability of anticoagulation is safer and ensures reduced requirement for repeated checking of INR values, hence leading to the betterment of quality of life of the patients.


The alternate anticoagulant therapies, that may be suggested to substitute the coumadin derivatives is not economically feasible by all the patients hence there is a need to ascertain the best anticoagulant among the relatively accessible warfarin and acenocoumarol.



Study Design:

A Prospective Observational study conducted in a multi-speciality tertiary care teaching hospital for a period of 1 year.


Inclusion criteria:

·       All adult patients with age ≥18 years with confirmed diagnosis of atrial fibrillation.

·       Patients who were on warfarin and acenocoumarol as anticoagulant therapy.

·       Patient who were willing to provide information through phone.


Exclusion criteria:

·       Patients undergoing any other anticoagulant therapy.

·       Pediatric patients.

·       Patients unwilling to give consent form.


Method of data collection:

The study protocol was approved by the Institutional Ethics Committee before the enrolment of patients (IEC-AIMS-2017-PHARM-371). The effectiveness of the anticoagulation therapy was evaluated by assessing parameters like time in therapeutic range (TTR) and occurrence of stroke. TTR was calculated using “Fraction of INRs in range” method. All the patients were assessed for the risk for stroke using CHA2DS2VASc score and the occurrence of stroke in both the groups were observed. Both these parameters were assessed for each drug and compared. The safety of the drug therapy was evaluated from the ADR occurred after drug intake and causality was assessed by using Naranjo’s Causality Assessment Scale. Severity of observed ADR was assessed with Hartwig’s severity scale. Compliance to anticoagulation therapy was measured using MMAS-4 during the study period. Quality of Life of patients was assessed individually by using SF-12 quality of life questionnaire for both the drugs and compared.


Statistical analysis and interpretation:

Statistical analysis was performed using IBM SPSS version 20.0 software. Descriptive statistical methods were used to calculate the mean and range. Pearson Chi-square test and paired t test were employed for the calculation of p-values and a value <0.05 was taken as significant.



Demographic characteristics:

A total of 218 patients who satisfied the inclusion and exclusion criteria were selected as study sample with 109 patients in each group. In this study it was found out that males (53.25% vs 61.5%) were predominant than females (46.8% vs 38.5%) in both groups and most of the patients were in the age range of 71-80 years (36.7%). The mean age of patients treated with acenocoumarol was 57.01±13.07 years and that of patients treated with warfarin was 67.18±12.24 years respectively. In both the groups (acenocoumarol vs warfarin) hypertension (67.9% vs 61.5%) was the predominant comorbidity, followed by dyslipidemia (33% vs 48.6%), diabetes (33% vs 47.7%), stroke (11% vs 22%), COPD (14.7% vs 12.8%) hypothyroidism (17.4% vs 11%) and BPH (7.3% vs 7.3%).


INR categorization of sample population:

The total number of INRs in acenocoumarol group was found to be 922. Out of these, 263 were in sub therapeutic range, 149 in supra therapeutic and 510 were found to be in range. Total number of INRs in warfarin group was 992. Among these, 324 were sub therapeutic, 198 supra therapeutic and 470 were in range.



Time in therapeutic range (TTR) of sample population:

The mean TTR for acenocoumarol group was found to be 56.54% ± 19.67 and 50.69% ± 23.57 for warfarin group. The mentioned values were found to be statistically significant with a p value of 0.048.


Table 1. Comparison of mean time in therapeutic range of warfarin and acenocoumarol


Target INR

Mean TTR (%)


p value












Stroke risk assessment using CHA2DS2VASc score:

In acenocoumarol group most of the patients (83.4%) were found to be in high risk category and only 18 patients (16.5%) come under the intermediate risk. None of the patients came to low risk category. While in the warfarin treated group the distribution is as follows, high risk (90.8%), intermediate risk (3.6%) and low risk (5.5%).


Occurrence of stroke in sample population:

The occurrence of stroke in patients were assessed after initiation of anticoagulation therapy followed by atrial fibrillation detection in the study subjects.

Table 2. Comparison of stroke occurrence in each group


No. of patients with stroke occurrence (n)


No. of patients without stroke occurrence (n)


p value















Only 12 (11.01%) patients encountered a stroke episode in acenocoumarol treated group and 24 (22.01%) patients in warfarin treated group. This data was proven to be statistically significant with a p value of less than 0.05.



Out of 218 study patients, 463 adverse events were observed, in which 174 belong to acenocoumarol treated patients and the rest of 289 ADRs belong to the warfarin treated patients. Among them bleeding (58.25%) was the most prominent ADR in both the groups with 55(50.4%) patients in acenocoumarol group and 72(66.05%) in warfarin group. Other ADRs observed are depicted in figure 1. As per the Naranjo causality assessment scale, 211 ADRs were under definite category. Hartwig’s severity assessment revealed that in acenocoumarol group 190 (65.06%) ADRs belong to mild category, 73 (25%) belong to moderate category and 29 (9.9%) in high severity category while in warfarin taking study subjects 107 (62.57%) ADRs belong to mild, 26 (15.2%) belong to moderate category and 38 (22.22%) ADRs belong to high severity category.



Fig1. Adverse drug reactions observed in sample population.


Fig 2. Medication adherence by MMAS-8 scoring.



Medication adherence of sample population:

In acenocoumarol group 65 patients (59.63%) were in high adherence category, 38 patients (34.86%) in moderate and 6 patients (5.5%) in low adherence. In warfarin treated group 70 patients (64.22%) were in high adherence category, 33 patients (30.27%) in moderate and 6 patients (5.5%) in low adherence category.


Quality of life assessment:

Statistically significant betterment of QOL was seen in patients with use of acenocoumarol compared to warfarin over a number of domains which are physical functioning (acenocoumarol: 52.98±26.07; warfarin 40.60±30.76, p value 0.002), general health (acenocoumarol 74.31±20.25; warfarin 62.84±31.29, p value 0.002) and mental health (acenocoumarol 79.35±14.16, warfarin 73.67±13.36, p value 0.003).


Fig 3. Comparison of quality of life of patients on use of acenocoumarol and warfarin.


Warfarin group showed statistically significant association between medication adherence and TTR as well as medication adherence and quality of life domains like, physical functioning (40.60%), role physical (13.79%), general health (62.84%) and vitality (67.77%). Also, there was a positive correlation between age and the stroke occurrence risk of patients with atrial fibrillation.



Demographic characteristics:

In our study, male patients (53.2% and 61.5%) were more predominant than female patients. Most of the patients were in the age group of 71-80 years. From our study atrial fibrillation were mostly seen in elderly patients. Similarly another study by Go AS et al6 and J. Heeringa et al7 showed that elderly people have increased chances for developing atrial fibrillation. This is because ageing is associated with stiffening of the arteries, that result in high blood pressure and increased workload of the heart. Over time this increased workload may lead to ventricular hypertrophy, thus making the heart more irritable, resulting in extra beats that can become risk factors for atrial fibrillation.

Co-morbidities observed:

Hypertension (67.9% and 61.5%) was the predominant co-morbid condition among both the groups, which may be due to its high prevalence in the population. Long-standing hypertension, especially if sub-optimally controlled, leads to LVH, structural changes and enlargement of the left atrium, heterogeneity of atrial conduction and fibrosis, all of which may contribute to the development of AF. A study conducted by Hasan Kaya et al8 also depicts hypertension as the most common co-morbidity among AF patients.


Medication adherence of sample population:

Majority of patients were in the high medication adherence category (59.63% and 64.22%) which could be explained by patient’s perception of the importance of anticoagulants over other medication. In a study conducted by Patel et al9 also, majority of patients reported medium or high adherence to oral anticoagulation. We also found that the acenocoumarol group showed no significant association between medication adherence and TTR while warfarin group showed a statistically significant association (p value < 0.05). The rate of adherence may differ by many factors, including types of population, study design, method of measurement, to quote a few16.


INR categorization of sample population:

Majority of patients were in the therapeutic INR range (55.3% and 47.4%) that may be because of the high medication adherence shown by the study groups.


Time in therapeutic Range (TTR) of sample population:

Mean TTR was found to be high in patients receiving acenocoumarol (56.54% ± 19.67) as compared to warfarin (50.69% ± 23.57) when calculated using fraction of INRs in range method. Mean TTR was found to be high among both the groups because majority of INRs were found to be in the therapeutic range. There is a statistically significant difference in mean TTR among patients prescribed with acenocoumarol versus warfarin (p value <0.05). Similarly Kulo et al10 performed a study in which acenocoumarol has shown significantly better anticoagulation stability with therapeutic INR values covering significantly longer time of treatment.


Assessment of risk for stroke using CHA2DS2VASc Score:

Stroke risk for atrial fibrillation patients was assessed using CHA2DS2VASc score and found that majority of patients were at high risk for stroke (83.4% and 90.8%) in both groups. For AF patients, risk for stroke increases because the rapid heartbeat allows blood to pool in the heart, which can cause clots to form and travel to the brain, resulting in stroke11. We also found statistically significant association between age and stroke risk which was similar to a study performed by Flegel KM, Hanley J et al,12 that suggested increasing age (>75 years) as one of the major risk factor for stroke development in AF patients.


Occurrence of stroke in sample population:

In this study both groups encountered stroke episodes (11.01% and 22.01%) which was one of the major complications associated with under dosing of vitamin K antagonists.


Adverse drug reactions observed in sample population:

Safety of the drugs were assessed by observing the occurrence of ADRs. In our study bleeding was the most prominent ADR seen in both the groups. Vazquez Fernando J et al13 and Ambrosi P et al14 stated in their meta-analysis that bleeding rates were much higher with the use of vitamin K antagonists. Majority of the ADRs were found to be in definite (64.2%) category as per Naranjo assessment and were severe (51.37% and 49.54 %) as per Hartwig’s severity assessment.


Quality of life of sample population:

One of our objectives was to evaluate the quality of life of patients on anticoagulation therapy using SF-12 quality of life questionnaire. Statistically significant difference in improvement of QOL was shown by patients taking acenocoumarol when compared to warfarin over various domains. This may be due to the increased number of elderly patients presented within warfarin group. Older patients are more likely to have low medication adherence which in turn results reduction in QOL. A study conducted by Reynolds, Matthew R et al,15 mentioned that elderly patients present worse QOL, especially in the relation to their physical activity.



The study mainly focussed on comparing the safety and effectiveness of warfarin and acenocoumarol in AF patients. From our study, the mean TTR was found to be high among acenocoumarol treated group rather than warfarin group. Risk for stroke as well as its occurrence was found to be high in case of warfarin group.


Major ADR occurred was bleeding among both the groups and it was also high among warfarin treated group. Significant difference in improvement of QOL was observed with acenocoumarol treated group compared to warfarin, whereas medication adherence was found to be higher among warfarin treated group.


Overall, from our study we conclude that acenocoumarol is a better OAC as compared to warfarin in terms of safety and effectiveness.



The authors are thankful to all the doctors and staffs of Cardiology department in the study centre for the successful completion of the study.



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Received on 03.05.2019           Modified on 29.12.2019

Accepted on 06.05.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(1):1-5.

DOI: 10.5958/0974-360X.2021.00001.9