IJCS | Volume 32, Nº2, March/April 2019

115 Colet et al. Adverse events in warfarin users Int J Cardiovasc Sci. 2019;32(2)110-117 Original Article Outside the hospital environment, particularly in non-specialized health settings, warfarin may be prescribedwithout a routine assessment of INR, potential interactions with foods and other drugs, and clinical outcomes. According to Holbrook et al., 27 INR should be monitored every 2-4 days after initiation of anticoagulant therapy until therapeutic range is achieved, and as INR stabilization is achieved, monitoring can be weekly. INR monitoring intervals may be gradually increased to every four weeks, as long as INR is within therapeutic range. A monitoring frequency of up to once every 12 weeks may be considered for patients with stable INR, whose treatment remained unchanged within at least three months before. Based on our results, few patients had INR values maintained within recommended range. The low intake of vitamin K in our study group rules out the possibility of interactions between warfarin and vitamin K-rich foods. Dietary sources of vitamin K, such as leafy vegetables (spinach, broccoli, lettuce), fish, cereals, grains, nuts and cashew apple, 28 are not part of the diet of low income population in Brazil. We did not find any Brazilian study assessing the consumption of vitamin K among patients taking warfarin. A study by Ferreira 11 conducted in Portugal, though, reported a moderate consumption of these foods by most of warfarin users. Cultural, dietary, and income factors may explain this difference. Chang et al., 28 support that a high or irregular consumption of vitamin K significantly contributes to INR variation. For Violi et al., 29 however, restriction of vitamin K intake does not seem to be an adequate strategy to improve anticoagulation quality withwarfarin. Rather, the authors recommend a balanced and stable dietary habit. 30 Figure 2 depicts the distribution of patients according to the risk of drug interactions, INR values within therapeutic range and clinical events. Of 66 patients at risk of interactions involving warfarin, only 14 patients had INR values within therapeutic ranges during most of the following-up period (51-100%). These patients reported 16 bleeding events and one episode of thrombosis. Bleeding and thrombosis events were more frequent in the other two groups of patients with a shorter TTR. Both patients not at risk of drug interactions involving warfarin had a TTR shorter than 50% and one of them reported bleeding. In addition, among patients at risk of bleeding, 25 (37.3%) 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. It is worth pointing out that the causes of adverse effects are multifactorial. In addition to the drug interactions discusses in the present study, other factors like low adherence to treatment, self-medication, lack of a continuing monitoring of therapy, 6 age older than 70 years, first month of anticoagulation therapy, uncontrolled hypertension, renal insufficiency, previous gastrointestinal bleeding, and alcohol abuse, 30 may have contributed to the occurrence of bleeding and venous thromboembolism reported by our patients. Conclusions Warfarin users in primary care were subjected to a mean of three moderate/severe drug interactions. Exposure to a variety of drugs probably contributed to high occurrence of bleeding. On the other hand, a low vitamin K intake was observed, indicating a low probability of an influence of diet on coagulation in response to warfarin. Therefore, there is an urgent need for effective interventions aimed at preventing drug interactions and promoting a safe use of warfarin among its users. For this purpose, it is recommended a higher integration between highly qualified health staff members. Besides, results of this study will serve as a basis for the next step of this investigation that will focus on pharmacotherapymonitoring of anticoagulated patients, aiming at minimizing adverse events from warfarin. Author contributions Conception and design of the research: Colet CF, Amador TA, Heineck I. Acquisition of data: Colet CF. Analysis and interpretation of the data: Colet CF, Amador TA, Heineck I. Statistical analysis: Colet CF, Amador TA, Heineck I. Obtaining financing: Colet CF, Amador TA, Heineck I. Writing of the manuscript: Colet CF, Amador TA, Heineck I. Critical revision of the manuscript for intellectual content: Colet CF, Amador TA, Heineck I. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding This study was funded by FAPERGS.