|dc.description.abstract||Introduction: Warfarin has been an anticoagulant for prophylaxis and treatment of venous thrombosis and thromboembolism in patients with atrial fibrillation for more than five decades. Due to its narrow therapeutic index, warfarin management is considerably challenging. A small change in plasma concentration can cause adverse effects which are sometimes life threatening. Thus, it is essential to monitor it closely by measuring International Normalised Ratio (INR) and Time in Therapeutic Range (TTR). Many factors such as age, weight, BMI, gender, smoking status, comorbidity, genetic factors and drug interaction can affect warfarin treatment. Additionally, warfarin users frequently have hypertension which leads to co-administration with a cardiovascular medicine, including antiarrhythmic medicine, that may interact with warfarin. Hence, this study aims to determine the effect of these medications on warfarin control in the clinical setting during long-term therapy.
Method: A retrospective data analysis was conducted for patients receiving warfarin therapy for AF and DVT at a private pathology practice in Queensland from November 2007 to October 2014. Data included age, gender, current medications, comorbidities, INR test dates and results, reported bleeding and stroke events. The primary outcome was TTR and the secondary outcome was the number of adverse events, namely major bleeding, minor bleeding and stroke. The analysis consisted of three steps. The first step analysed all patients, while the second step analysed patients after excluding drug interaction with warfarin. Both the first and second steps were analysed regarding the use of medicine grouping within each drug classification, namely digoxin, Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II receptor blockers (ARBs), Beta-blockers (BBs) and Calcium channel blockers (CCBs). The third step was to analyse patients after excluding drug interaction with warfarin with regard to the use of particular drugs within each drug classification.
Results: From a total of 4,494 patients, 52.2% of patients were on BBs while one-fourth of patients were on ARBs (27.2%) and CCBs (25.3%). Around one-third of patients received ACEIs (32.8%) and digoxin (30.0%). In all patients, the users of drug classifications namely ACEIs, ARBs, BBs and CCBs had a higher median TTR as opposed to non-users. After excluding drug interaction patients, there were no significant differences between users and non-users of each drug classification in median TTR. In the third step analysis, users of felodipine had a higher median TTR as opposed to non-users of CCBs (90.40, 84.30-96.38 vs 83.71, 76.62-89.58, p=0.008). In addition, the use of enalapril and telmisartan saw an increase in numbers of minor bleeding (enalapril: 3 (42.9%) vs 64 (11.9%), p=0.0132 and telmisartan: 11 (21.6%) vs 73 (11.8%), p=0.0424). Users of amlodipine, atenolol, lercanidipine, and telmisartan had a higher risk of bleeding (amlodipine: 2.00, 1.00-2.00, p=0.008; atenolol: 2.00, 1.00-2.00 vs 1.00, 1.00-2.00, p<0.001; lercanidipine: 2.00, 1.00-2.00 vs 1.00, 1.00-2.00, p=0.013 and telmisartan: 2.00, 1.00-2.00 vs 1.00, 1.00-2.00, p<0.001). Furthermore, the risk of stroke was higher among users of amlodipine, atenolol, felodipine, lercanidipine and metoprolol (amlodipine: 4.00, 3.00-5.00 vs 3.00, 2.00-4.00, p<0.001; atenolol 4.00, 3.00-5.00 vs 3.00, 3.00-4.00, p<0.001; felodipine 4.50, 4.00-5.00 vs 3.00, 2.00-4.00, p<0.001; lercanidipine: and metoprolol: 4.00, 4.00-5.00 vs 3.00, 3.00-4.00, p<0.001).
Conclusion: The use cardiovascular drugs in our study did not negatively impact either warfarin control or event numbers. Additionally, the users and non-users in all drugs in our study had a high level of TTR (more than 80%). Thus, these drugs are safe to administer together with warfarin in a long-term therapy under close monitoring by a physician or warfarin care program. However, the effects of enalapril and telmisartan on minor bleeding are still unknown and our finding still needs further analysis to confirm these results.||