Safe and Effective Anticoagulation with Warfarin within One-year Time Period-Team Work of Healthcare Professionals

Background: At the study site, Quality team found many incident reports of bleeding due to increased INR in patients on Warfarin anticoagulation therapy. These patients were unaware about adverse effects of anticoagulation therapy and drug-drug/food-drug interactions. Hence to ensure safety in anticoagulation with Warfarin, team of a Pharmacologist, Clinical Pharmacist and Quality manager decided to conduct a clinical audit to improve high alert medication safety with warfarin. Materials and Methods: After obtaining Institutional Ethics committee approval, clinical audit proposal form was submitted to the Clinical Audit Committee. Clinical Pharmacists took their clinical rounds to identify patients on anticoagulation with warfarin, asked for their consent in local language, reviewed their case files for data and interviewed them. Action plan was made based on the observations in gap analysis conducted from April-May 2018. Interventions were planned to improvise these standards and analysis continued monthly. Bilingual warfarin education leaflets were given to all patients on warfarin therapy. Results: Improved awareness on drug-drug and food-drug interactions was observed among the patients from 61.50% to 92.30% in one year. Increase in adherence of INR checking from 76.9% to 100% patients. ADRs to warfarin were recognized and action was taken to treat them within 24 hr by the end of one year of the study. Conclusion: Marked improvement was observed in the patients’ awareness on drug-drug and food-drug interactions as well as INR monitoring, ADR reporting by clinicians and clinical interventions to prevent harm to the patient.


INTRODUCTION
Warfarin is used as an oral anticoagulant in conditions like deep vein thrombosis and pulmonary embolism and to prevent stroke in patients who have atrial fibrillation, valvular heart disease or artificial valves.It is a drug with narrow safety margin, its pharmacokinetics and pharmacodynamics is affected by genetic variables, associated with many known drug-drug and drug-food interactions and regular monitoring of International Normalized Ratio (INR) is needed to provide safe and effective care for patients on warfarin. ,In this University teaching hospital, Quality team found many incident reports of bleeding due to increased INR in patients on anti-coagulation therapy with Warfarin.After analysis it was found that most of these patients were unaware about side effects of anticoagulation therapy and drug-drug/food-drug interactions.This led to wrong dietary lifestyle culminating in complications like mild to severe bleeding episodes.
According to rational pharmacotherapy principles, rational indication for warfarin should be mentioned by clinicians in the case files and patients should check their INR at prescribed intervals as per the physician's advice.Patients should have knowledge about the anticipated adverse drug reactions and drug-drug and drug-food interactions of warfarin.Action should be taken within 24 hr of recognition of adverse drug reaction to warfarin regarding its treatment.Maintaining INR in patients on oral anticoagulation with warfarin within the therapeutic range is a challenge for the physician to achieve maximal therapeutic benefit without encountering adverse effects in these patients.
There was a challenging situation in these patients on anticoagulation therapy with warfarin to prevent bleeding episodes which are at times are life threatening adverse events.Hence to ensure safety in anticoagulation with Warfarin, the team of a Pharmacologist, Clinical Pharmacist along with Quality manager decided to conduct a clinical audit to improve high alert medication safety with warfarin.

MATERIALS AND METHODS
After obtaining Institutional Ethics committee and Clinical Audit Committee approval from the tertiary care teaching hospital, audit criteria and measurable standards were set as follows: • 100% Patients should have rational indication for Warfarin recorded.
• Have the adverse drug reactions or deranged INR of patients on warfarin recorded (Past/present/follow up).
• In 100% cases, action is taken within 24 hr after recognition of adverse drug reaction to warfarin.
• At least 90% patients check their INR at prescribed intervals by physician.
• At least 90% patients are educated regarding drug-drug and drug-food interactions of the medication.
To measure the standards, data collection checklist was formulated which included patient interview and consent form.Before implementation of this clinical audit, training of Clinical pharmacist was conducted on the audit process and medication related information like dose, indication, adverse drug reactions, drug-drug and food-drug interactions along with management of these aspects.It was decided that data will be collected on daily basis for in-patients and analysis to be done on monthly basis.All patients care areas were distributed amongst team of Clinical Pharmacists.Clinical pharmacists took their clinical rounds to identify in-patients on anticoagulation with warfarin and these patients were included in the clinical audit.Patient's consent was taken for the involvement in the study in local language and their case files were reviewed for rationality of indication for warfarin, correct dose, duration of therapy whether mentioned or

Statistical Analysis
Data was expressed as percentages and analysed using Epi Info software version 7.2.The audit criteria before and after intervention was compared by Chi square test and p value<0.05 was considered statistically significant.

RESULTS
As safer and equi-effective options to warfarin are available, we did not get many case files for review, so total 13 case files were reviewed initially in April and May 2018 and we found 2 cases of bleeding as adverse reactions, 2 cases of increased INR and 4 cases of anticipated drug-drug interactions among these cases.Table 2 shows the recommendation plan prepared for executing the progress of the Warfarin clinical audit to achieve the set criteria.The plan involved team work by Pharmacologist, Clinical Pharmacists and Clinicians in the study set-up.
Figure 2 shows increase in recognition and management of ADRs to warfarin within 24 hr of reporting (p=0.05).Among the total 84 cases reviewed during the study period, only 4 incident reports of bleeding due to increased INR with Warfarin therapy were found.Adherence of INR checking in patients on Warfarin significantly increased from 53.8% to 100% patients (p<0.001).Patient's awareness about warfarin medication was significantly found to be increased from 61.5% to 100% (p<0.01)due to education on drug-drug and food-drug interactions through patient education leaflets.Even if the sample size (13 case files) was small for the initial review, warfarin being a high-risk medicine, needed to be prescribed rationally and the awareness as well as management of its adverse reactions to be streamlined for patient safety.Gap analysis (April-May 2018) during the study revealed that nearly 31% of the in-patients on Warfarin either had deranged INR or developed adverse effect of bleeding due to the drug which reduced to 4.7% within one-year period.Rational use of medicine not only includes prescribing it for right indication but also considers the follow up of laboratory parameters, informing patients about the frequency of monitoring, common adverse reactions, drug-drug and drug-food interactions and situations where patient needs to report back to the doctor for opinion.We a team of Pharmacologist, Clinical Pharmacist and Quality manager decided to include all these points for rational use of warfarin.Even if the Figure 2 shows that in gap analysis, 100% clinicians had prescribed warfarin for right indication, the case file review and patient interview revealed that doctors were not aware about the importance of INR monitoring and action to be taken in case of deranged aim of controlling adverse effects and also to promote a safe and effective anticoagulant therapy with warfarin.

CONCLUSION
At the study site, bilingual warfarin education leaflets are given to all patients on warfarin therapy by clinicians and patient counselling is done by clinical pharmacists during their clinical rounds.Marked improvement has been observed in the patients' awareness on drug-drug and food-drug interactions as well as INR monitoring; ADR reporting by clinicians and clinical intervention to prevent harm to the patient is also enhanced.

ACKNOWLEDGEMENT
Authors acknowledge the participants for their involvement in the study and the clinicians, nursing staff and dietician for providing counselling and educational leaflets about warfarin.

Figure 1 :
Figure 1: Fish bone diagram for Root Cause Analysis of Warfarin clinical audit gap analysis.

Figure 2 :
Figure 2: Comparative analysis of Warfarin clinical audit criteria before and after interventions.*p<0.05 after comparing values before and after intervention using Chi square test.
not, drug-drug and food-drug interactions if any, prescribed intervals for checking INR and adverse drug reactions if encountered.Then patients were interviewed for knowledge about the medication (warfarin), drug-drug and food-drug interactions, prescribed intervals for checking INR and adverse drug reactions with the drug.All this information was noted down in the data collection checklist form for individual patient.After initial data collection, a gap analysis was done in the month of April-May 2018 to know the baseline situation of the clinical audit standards.Based on these findings, interventions like establishment of separate Clinical Pharmacy and Pharmacovigilance department and preparation of patient education leaflets (local language), Nutritionist advice, proper counselling for Warfarin details (drug information, drug-drug interactions, warning signs for adverse effects, importance and frequency of INR monitoring), were planned to improvise these standards and analysis continued monthly.This data was clubbed together for further months and presented quarterly in Clinical audit committee meetings till April 2019.

Table 1
depicts the results of gap analysis performed for warfarin clinical audit where other than rational indication for prescribing warfarin, all other criteria were poorly met in patient care.Figure1explains the root cause analysis of the observations in gap analysis of the clinical audit considering man, method, material and miscellaneous factors responsible for the unmet criteria of Warfarin clinical audit.

Table 2 : Action plan prepared after gap analysis for Warfarin clinical audit at study site.
INR. Also, patients were not counselled satisfactorily about INR monitoring, signs of adverse drug reactions and drug interactions with warfarin.Education of patients on warfarin about importance of monitoring of INR significantly improved their adherence of INR checking from 53.8% to 100% patients (p<0.001)within one-year study period.Study by Omari et al. 4 also mentions the benefit of educational session and warfarin booklet given to patients that most of them reached their target INR within 8 weeks and did not need hospitalization or emergency visits during the study period of 9 months.Kagansky et al. also mentioned that better methods of oral anticoagulant therapy education may further reduce bleeding complications.
Kuruvilla et al. and Park et al.are also of the opinion that patient counselling for purpose and method of taking warfarin, its adverse effects and drug-drug and drug-food interactions is crucial but is not always optimized.Colet et al. conclude through their study that patients on warfarin therapy should be followed up properly and regularly for drug-drug interactions with the