Warfarin is one of the most used oral anticoagulants. According to the Food and Drug Administration, it is among the top ten drugs in terms of the risk of severe side effects.1 Warfarin is characterized by a narrow therapeutic window, high interaction with other drugs and frequent bleeding.2

The effect of warfarin may be either increased or decreased when combined with some drugs or foods. These interactions can be potentially harmful to patients and caused increased health-related costs,3 which justifies the need to identify potential interactions involving warfarin that may lead to adverse effects.

The risk for adverse events caused by drug interactions with warfarin increases with the number of drugs administered concomitantly,4 whereas vitamin K-rich diets may decrease warfarin therapeutic effect.5 The occurrence of adverse events may be prevented by monitoring of the therapy by health providers involved in its prescription, delivery and follow-up of anticoagulated patients.6

The high frequency of interactions of warfarin with other drugs has been described in studies with hospitalized patients.7^,8 Nevertheless, studies evaluating drug-drug interactions in primary health care are less common. If, on the one hand, these patients generally use less medication than hospitalized patients due to their less severe conditions, monitoring of diet and medication use is less frequent. The aim of this study was to evaluate the occurrence of adverse effects related to drug-drug interactions in warfarin users in the primary health care.

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.

Figure 1

ASA: acetylsalicylic acid

In an 18-month follow-up of 68 patients using warfarin, 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 with warfarin 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 they were neither followed in an anticoagulation outpatient clinic nor followed for pharmacotherapy, and hence were more vulnerable to drug interactions.

The most cited drugs and drug classes that have the potential to interact with warfarin are antibiotics,18^,19 anticoagulants (heparin and enoxaparin),7^,17 diuretics (spironolactone),17 betablockers,17^,20 proton-pump inhibitors,7^,18^,21 nonsteroidal inflammatory drugs,8^,17^,18^,22 serotonin selective reuptake inhibitors,19 amiodarone,22 paracetamol,8^,14^,19 simvastatin,7 tramadol,7 levothyroxine.21 All these drugs were prescribed and taken by our study group.

Many patients who reported bleeding and thromboembolism episodes were exposed to omeprazole, simvastatin and paracetamol. These drugs interact with warfarin by means of competition for the cytochrome P450 metabolism. Nearly 30% of our patients had CYP2C9 polymorphism (data not shown), which would increase the risk for drug interactions. A careful evaluation of risks and benefits would be useful in prescribing simvastatin to anticoagulated patients, due to high severity of the interaction of this drug with warfarin and questionable benefit for patients with low cardiovascular risk.23 Three patients with low cardiovascular risk were taking simvastatin, who may benefit from simvastatin deprescribing. Deprescribing is the process of discontinuing drugs when existing or potential harms outweigh the benefits, considering patient’s need of treatment, level of functioning, life expectancy, values, and preferences. Deprescribing should be a patient-centered intervention; it is not free of uncertainties, and requires shared decision making, informed patient consent, and close monitoring of effects.24 With respect to omeprazole, it would be prudent to advise patients about safe limits of its use, since important increases in INR may occur during one to two weeks of initiation of moderate/high doses (2-4 g/day) of omeprazole.10 For omeprazole users, INR monitoring should be performed, with necessary changes in the dosage, or even discontinuation of treatment, aiming to maintain INR at desirable levels.10 Similar to simvastatin, the use of both omeprazole25 and paracetamol26 have been pointed out as excessive and irrational, emphasizing the need to evaluate the real need for its use.

Outside the hospital environment, particularly in non-specialized health settings, warfarin may be prescribed without 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 Ferreira11 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 with warfarin. 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.

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 pharmacotherapy monitoring of anticoagulated patients, aiming at minimizing adverse events from warfarin.