IJCS | Volume 32, Nº2, March/April 2019

112 Colet et al. Adverse events in warfarin users Int J Cardiovasc Sci. 2019;32(2)110-117 Original Article Results Sixty-eight patients were followed for 18 months. Sixty-three (92.6%) completed the follow-up and 5 (7.3%) died during the study period. Of the 68 patients, 55.1%were female, with mean age of 64 ± 14 years. Most patients (63.2%) had some elementary school and 51.5% had an income of one minimum age. Mean number of medications taken by patients was 10 ± 4, and all patients were taking at least one medication in addition to warfarin. In descending order, the most frequent medications were drugs acting on the cardiovascular system (49.2%), blood and hematopoietic organs (16.0%), nervous system (14.8%) and alimentary tract and metabolism (13.5%). Analysis of drug-drug interactions showed that 66 (97.1%) of patients were subjected to interactions involving warfarin, and 51 (73.9%) and 65 (94.2%) patients were at risk of experiencing one or more severe and moderate interaction, respectively. The mean of potential interactions involving warfarin was 3 ± 1.5 per patient (Figure 1). All interactions identified can affect the effect of warfarin. In 177 patients, this effect would be increased, thereby increasing the risk of bleeding. In 23 patients, the effect of warfarin would be decreased, increasing the risk of thromboembolic events. Among the interactions that would increase the effect of warfarin, 61 patients had severe and 116 moderate interactions. Simvastatin and amiodarone can cause severe interactions with warfarin, and were found in 47.5% and 14.8% of patients, respectively. The most frequent drugs with potential moderate interactions with warfarin were omeprazole (33.1% of patients) and paracetamol (18.6%). All interactions that would reduce the effect of warfarinwere classified as moderate, and the most common drug was spironolactone (60.9%). A total of 87 bleeding episodes were detected in 37 patients, and 4 venous thromboembolism events were detected in 4 patients; 56.5% of these patients used omeprazole), 35.9% simvastatin and 25.0% paracetamol. Figure 2 depicts the distribution of patients by risk (present or not) of drug interactions, TTR and frequency of bleeding and venous thromboembolism events. Among the 66 patients at risk of drug interactions involving warfarin, in only 14 patients the INR was maintained within the recommended therapeutic range during most of the follow-up period (51-100%), with 16 bleeding events and one venous thromboembolism event reported. Bleeding and thromboembolism events were more frequently reported by patients whose INR values were maintained within therapeutic range for a shorter time. Patients without potential drug interactions involving warfarin (n = 2), showed a TTR lower than 50%, with bleeding reported by one of them. In addition, 25 (37.3%) of patients at risk of drug interactions did not show any INR value within therapeutic range during follow-up. Considering INR values outside the therapeutic range, 70% of them were below and 30% above recommended range. With respect to cardiovascular risk, 8 (11.6%) patients had a low risk, 10 (14.5%) a moderate risk and 51 (73.9%) a high risk. Among those with low cardiovascular risk, 3 were taking simvastatin. Potential interactions between warfarin and foods (particularly vitamin K- rich foods) were assessed by food records of the patients, and a low vitamin K intake was detected in most patients (Table 1). Discussion In an 18-month follow-up of 68 patients usingwarfarin, we found that almost all of them (97.1%) were at risk of drug interactions (± 3 interactions per patient). These interactions were either severe (61) or moderate (116), and probably contributed to the occurrence of adverse events (84 bleeding and 4 thrombosis events). Dietary assessment revealed a low vitamin K intake, excluding the possibility of interactions between warfarin and foods. Nevertheless, many drugs could be implicated in the development of adverse events, mainly simvastatin, omeprazole and paracetamol. Mean number of drugs was 9.6 ± 4.5 per day, higher than that reported in studies on the use of warfarin among patients in outpatient treatment (4.2 - 4.8 drugs/ day. 13-15 The number of medications taken by a patient is considered an exposure factor to drug interactions. Cruciol-Souza et al., 16 reported that the use of 7 or more medications significantly increased the risk of patients to drug interactions. The percentage of estimated interactions withwarfarin was comparable to that reported in other studies (81-100%). 2,7,8,17,18 Mean number of drug interactions involving warfarin (2.91 ± 1.52 per patient) was similar to that found by Teklay et al., 17 despite to different methods, setting and time of follow-up between the studies. One peculiarity of our study cohort was the fact that theywere