Introduction

Direct oral anticoagulants (DOACs) emerged in response to the search for an ideal anticoagulant, after warfarin had been the only available anticoagulant for a long time ^1,2. The DOACs like rivaroxaban, apixaban, dabigatran, edoxaban and betrixaban (the first three of these available on the Colombian market), are widely recommended for their proven efficacy and greater safety when compared in patients with nonvalvular atrial fibrillation (AF) ^3-6.

Warfarin is a medication directly related to hemorrhagic adverse events, with an estimated 3% frequency of major and fatal bleeding at three months ⁷, which could be higher in our setting due to lack of adherence to treatment, difficulties in patient education, irregular follow up and a low percentage of time in therapeutic range (TTR) ^2,8. In contrast, DOACs have proven to have advantages over warfarin, like rapid onset of action, a predictable effect, low interindividual vari ability, few drug interactions, improved adherence, decreased hospitalization costs, and no need for periodic monitoring and frequent dose adjustments, along with decreased major bleeding as a fundamental safety outcome ^9,10.

From a pharmacokinetics perspective, these medications are known to differ substantially in oral bioavailability, plasma protein binding and renal excretion ^11,12. The latter is higher for dabigatran (80%), while with edoxaban, rivaroxaban, apixaban and betrixaban, 50, 33, 27 and 11% of the dose is excreted unchanged, respectively ^3,13-15.

It is common to find patients with an indication for an ticoagulation in daily medical practice, mainly due to atrial fibrillation (AF), and many of these have chronic kidney dis ease (CKD) ^16,17. Thus, conventional treatment must be studied to see if it is equally valid for this specific population.

The large, randomized trials which have evaluated the effectiveness and safety of direct anticoagulants vs. warfarin have, in general, excluded patients with advanced CKD and on dialysis, and therefore their treatment is currently controversial ^18-21. So far, only observational studies with small sample sizes ^22-24 and pharmacologically based studies are available as the sole support for making complex medical de cisions, but we still do not know if they are the best decisions for the patients and the healthcare system. Thus, the objective of this paper is to describe the sociodemographic, clinical and laboratory characteristics of anticoagulated individuals with advanced CKD in stages 3, 4 and 5 at IPS Universitaria Universidad de Antioquia in the city of Medellín (Colombia), and to report the cases of minor, major and fatal hemorrhage which occurred.

Materials and methods

Results

A total of 7,267 care encounters were recorded in the anticoagulation clinic's database between January 2017 and December 2018. After removing duplicate records, 1,338 medical charts were reviewed to select those which met the inclusion criteria, for a total of 238 patients (Figure 1).

Figure 1 Flowchart showing the participant selection process. 

The main reason for anticoagulation was AF (81.9%), followed by venous thromboembolic disease both in lower limbs and the lungs (7.6%). The most frequent age group was 81-90 years (39.1%), the sex distribution was similar with 52.1% women and 47.9% men, and 65.5% had contributive and 34.5% had subsidized health insurance.

The most frequently used anticoagulant was warfarin (45%), followed by rivaroxaban (31.5%) and apixaban (14.3%). A total of 36 patients changed anticoagulant during follow up (Table 1).

Table 1 Description of the patients’ baseline characteristics. 

The average TTR in patients on warfarin was 48.8% and the median was 51% (0-100% for minimum and maximum values, respectively).

The majority of patients were in stage G3a (37.3%) and G3b (40.7%) CKD, and the greatest frequency of bleeding was in this stage. There were only 5.8% in G5 and, of these, 100% were on renal replacement therapy (Table 2).

Table 2 Stage of chronic kidney disease and bleeding occurrence. 

Out of all the patients studied, bleeding was seen in 20 (8.4%), and of these, 7 (35%) had major bleeding. Warfarin was the anticoagulant associated with 50% of these cases, followed by rivaroxaban (20%) and apixaban and dabigatran (15% each). The most frequent site of major bleeding was the digestive tract (five patients); there was only one case of fatal bleeding in a 95-year-old patient with stage 3b kidney disease who was receiving apixaban and had a seizure, mod erate head trauma and central nervous system (CNS) bleed ing. The remaining hemorrhages were minor (13 patients); 46.1% were due to warfarin and 15% to dabigatran. The most common site for these bleeds was soft tissues (30%).

Of the 10 patients who bled on warfarin, six had subthera peutic INRs, three had an INR in the 2-3 range and one had an INR less than 2.0 (Table 3).

Table 3 Analysis of hemorrhagic events according to type of bleeding: major or minor 

The description of each of the subjects who bled is shown in Table 4.

Table 4 Description of patients who had bleeding. 

Discussion

This study described stage 3, 4 and 5 CKD patients who were seen at the anticoagulation clinic at IPS Universitaria Universidad de Antioquia in Medellín, Colombia over a period of two years.

It is common to find patients with an indication for antico agulation in daily clinical practice, due to the high prevalence of AF which increases with age, being approximately 2.3% at age 40, and greater than 6% in those over 65 ²⁷. Fur thermore, CKD, with a prevalence of approximately 12% in the general population (2 per 100 population in Colombia) in 2014 ²⁸, has been defined as an independent cardiovascular risk factor as it has been pathophysiologically related to both thrombotic and hemorrhagic events ^29,30.

Approximately one out of every five patients with CKD has AF, which is 2-3 times more than in the population without CKD ³¹. For those on peritoneal dialysis, the prevalence is up to 7%, and for hemodialysis, it is 13%. The percentage of patients with AF and CKD also increases with age ³². Our study showed that 51.7% of the patients were over the age of 70.

According to the literature, AF is the most common rea son for anticoagulation in patients with CKD. In our study it accounted for 81.5% of the patients, similar to the findings of international reports ^33,34.

With regard to the safety of anticoagulants, a study per formed in Canada with 1,626 patients on hemodialysis who took warfarin yielded an adjusted HR for bleeding of 1.44 (95%CI: 1.13-1.85), and the authors suggest that the risk-benefit profile does not support the routine use of warfarin to reduce cerebrovascular accidents in patients on hemodialysis ³⁵. A meta-analysis in 2007 found that those with terminal CKD who were treated with warfarin had a 10 times greater risk of major bleeding than the general population and that these events occurred even when the INR was between 1.5 - 2.0 ³⁶. In our study, out of 107 patients on warfarin, 10 bled (9.34%); of these, only two were using ASA and not all were over anticoagulated at the time of bleeding. There was a 5.6% rate of minor bleeding and 3.7% rate of major bleeding, which is lower than that of Kooiman et al.'s (2014) study which reported 15.6% for the latter type of bleeding, keeping in mind that the sample in this study was larger (n=724) ³⁷. This study also reported bleeding in patients with INRs within the therapeutic range, which was found in our study (two patients with major bleeding and one with minor bleeding).

Despite the greater proven safety of DOACs, in our study we found that warfarin was the most commonly used medication (45.0%), even though 65.5% of the patients had contributive health insurance. This could lead us to question the reason for choosing warfarin over the rest of the antico agulants and to consider whether the weight of evidence in the Colombian population is sufficient for choosing the type of anticoagulant, or if social, economic and cultural factors have a greater weight when prescribing them.

An important outcome for patients on warfarin is TTR, which estimates the percentage of time during which the INR is within the desired treatment range, and is widely used as an indicator of anticoagulation monitoring ³⁸. This study found a TTR of 48.8%, which means that for more than half the time, the patients were outside the target. This target failure is well described in the literature, such as by Chaaban et al. (2015) who presented data on the use of warfarin in patients on hemodialysis (HD) versus those with normal kidney function and found that not only did HD patients have more hemorrhages, but the INR was only within the therapeutic range 25% of the time in this group ³⁹. Yang et al. (2017) recently published their study in which they found that only 21% of patients on dialysis had a TTR greater than 60%; in addition, they found that for 30% of the time, the INR was notably outside the range (INR less than 1.5 or greater than 3.5) ⁴⁰. All of this makes antico agulation with warfarin entirely unpredictable and creates the possibility of carrying out more studies on this topic, given that the population is different, possibly older, with serious associated illnesses and difficulties in accessing the healthcare system and adhering to treatment.

With regard to the DOACs, apixaban is approved at a dose of 5 mg twice a day, which needs to be adjusted to 2.5 mg every 12 hours for patients who meet two of the following criteria: creatinine greater than 1.5 mg/dL, over the age of 80, or weight under 60 kg, according to the ARISTOTLE study ⁴¹. This study excluded patients with a GFR less than 25 mL/min, and thus the population with stage 4 and 5 CKD is not well represented. In spite of this, the updated 2019 AHA guidelines for AF and the FDA recommend using apixaban for patients with advanced CKD, including those on hemo-dialysis ⁴². This continues to be controversial because the recommendation is based on a pharmacodynamics study with 16 patients and a US Medicare register, and therefore the quality of the scientific evidence is not the best ^43,44. In 2019, preliminary results of the RENAL-AF study were presented, comparing apixaban vs. warfarin on dialysis. The study was not conclusive, as it did not achieve the expected enrollment and thus was stopped before the stipulated time. In addition, the TTR for patients on warfarin was 44%, with a large proportion of patients in the subtherapeutic range ⁴⁵. Our study showed that out of 34 patients on apixaban, three had bleeding (a rate of 8.8%). One of these was the only case of fatal bleeding; however, it was associated with head trauma which was the cause of death, this patient was elderly, and he had a GFR of 28 mL/min and therefore had an adjusted medication dose.

Likewise, rivaroxaban, in its main study (ROCKET-FA), excluded GFR < 30 mL/min ⁴⁶. There are observational and pharmacological studies which demonstrate the safety of rivaroxaban in stage G4 CKD, and therefore it is approved in the United States for this indication, while other countries like Canada only use its traditional recommendation ^47,48. In our study, 4 out of 75 subjects on rivaroxaban had bleeding (a 5.3% rate of bleeding) and all of these were in stage 3 CKD, except for one who required temporary renal replacement therapy.

Dabigatran is contraindicated for patients with GFR < 15 mL/min, according to international guidelines, but are there are no studies with large numbers of patients even for stage 4 CKD. Our study shows that this medication had the highest rate of bleeding (37.5%). Therefore, taking into ac count its high rate of renal excretion, we consider that it is not the drug of choice in patients with CKD ⁴⁹. Even so, it is approved by the FDA for an adjusted dose of 75 mg every 12 hours based on a pharmacological prediction model ⁵⁰.

The efficacy of oral anticoagulants has been very well established in controlled studies and more information is needed on their safety in different populations. This study described the clinical profiles and hemorrhagic events of anticoagulated individuals during follow up by IPS Uni versitaria Universidad de Antioquia from January 2017 to December 2018. This study represents the largest cohort published to date of patients with chronic kidney disease and the use of anticoagulants (both warfarin and DOACs) in Colombia and Latin America.

The limitations of the current study are related to its ret rospective nature, data collection and the absence of some data. Calculating the glomerular filtration rate using the CKD-EPI equation has some limitations given that race was not recorded for the vast majority of patients. The popula tion in stage G5 CKD was scant. Neither CHADs2Vasc nor HAS-BLED were considered for interpreting the results for patients with AF.

Conclusion

The most common reason for anticoagulation was AF and the most frequent kidney disease stage was G3. Over all, there was a low rate of major bleeding, which could be related to close follow up at an anticoagulation clinic. This type of bleeding was more frequent in patients on warfarin, which was associated with a low TTR (48.8%). The safest medications were apixaban and rivaroxaban with adjusted doses.

The number of patients in stage G5 CKD was very low, and therefore conclusions cannot be drawn regarding this particular group.

Randomized clinical trials are needed to determine the safest anticoagulation strategy in this population.