Assessment of Direct Oral Anticoagulants (DOACs) in Obese Patients at the Cheyenne VA Medical Center
Dylan Ren PharmD Candidate 2020
University of Wyoming, School of Pharmacy Faculty and Clinical Mentor:
Abstract
Purpose: As obesity rates continue to increase and the use of direct oral anticoagulants (DOACs) is becoming more common in the treatment of atrial fibrillation, venous
thromboembolism and prevention of venous thromboembolism, additional concerns with DOAC use in the obese population are arising. Due to limited studies and the data available in this patient population, there is uncertainty of the risks and benefits with the use of DOACs. The purpose of this medication utilization evaluation is to assess DOAC use in obese veterans at the Cheyenne VAMC and to determine the number of cardiovascular, thromboembolic and/or bleeding events in such a population.
Methods: An initial patient population was obtained by identifying those who had an active prescription for apixaban, dabigatran, rivaroxaban or edoxaban between the dates of 8/1/2014 to 8/1/2017 and a BMI of ≥35 kg/m2 or a weight ≥110kg. A chart review was performed to verify that the patient had actually filled the DOAC prescription and that the BMI was ≥35 kg/m2 or weight was ≥110kg at the time of DOAC use. Patients were then categorized into groups based upon their BMI or weight characteristics while on DOAC therapy. This included Group A: initial BMI ≥40 kg/m2 or weight ≥120kg, Group B: weight that progressed to a BMI ≥40 kg/m2 or weight ≥120kg, and Group C: initial BMI ≥35 kg/m2 but <40 kg/m2 or weight ≥110 kg but <120kg. This was followed by a chart search and review for the following key terms; VTE, DVT, TIA, CVA, stroke, embolism, thrombosis, and bleed to determine if a cardiovascular, thromboembolic, or bleeding event occurred while on DOAC therapy.
Results: A total of 93 individuals were included in the initial data collection and review. Of those, 21 were excluded for having a BMI <35 kg/m2 or weight <110 kg at the time of initial DOAC therapy or the DOAC was never taken by the patient. Of the eligible 72 patients included in the review, a total of 4 cardiovascular or thromboembolic events and 1 severe bleed occurred throughout all the groups. Events that occurred in patients with an initial BMI ≥40 kg/m2 or weight ≥120kg were as follows: 2 confirmed transient ischemic attacks (TIA) events on apixaban and rivaroxaban, one recurrent deep vein thrombosis (DVT) event, which was suspected to be due to noncompliance on dabigatran, and a severe bleed, a left-leg hematoma on rivaroxaban. There was 1 recurrent DVT suspected due to noncompliance that occurred in an individual with a BMI ≥35 kg/m2 or weight ≥110 kg on rivaroxaban therapy.
Conclusion: DOACs should be used with caution in obese patients and avoided if possible due to current limited evidence. Closer monitoring of weights and appropriateness of use should be considered in this specific patient population and adherence should be heavily emphasized. Although there is limited data, if a DOAC is being strongly considered in this population, emerging studies suggest the use of apixaban or rivaroxaban versus other DOACs. Although cardiovascular, thromboembolic, and/or bleeding events occurred within the obese veteran population at the Cheyenne VA, further studies are warranted before clear conclusions and recommendations may be drawn regarding DOAC use in obese patients.
Background:
Venous thromboembolism (VTE) is a disease in which the blood clots inappropriately, affecting approximately 300,000 to 600,000 individuals in the United States and leading to considerable morbidity and mortality1. The term VTE can be used to encompass either a deep vein thrombosis (DVT), a clot that occurs in the deep veins of the body, a pulmonary embolism (PE), which is a clot that occurs in the artery of the lungs due to a clot dislodging from another location, or both1. DVT’s are commonly characterized by pain, erythema, and warmth and occur much more frequent than PE’s with approximately two-third of patients presenting with one as compared to PE’s, however, it is possible for a patient to clinically present with both a DVT as well as a VTE1. In general, DVT’s are less severe than PE’s, which have an estimated mortality rate of 20 to 25% due to clots traveling from the lungs to the brain resulting in a stroke, however, clots in the deep veins also have potential to dislodge leading to the aforementioned events. As such, it is of up most priority to appropriately treat these disease states. In addition to their high morbidity and mortality, individuals are at an increased risk of other co-morbid conditions, such as pulmonary hypertension, chronic venous insufficiency, and other complications.
Atrial fibrillation (a. fib), similar to VTE, is a major public health burden that is increasing with our aging population. It is the most common type of arrhythmia that can cause rapid and irregular beating of the heart, specifically in the atrial chambers 2. This can lead to the sensation of rapid beating, chest pains, and palpitations in affected individuals. In the United States, approximately 2.2 million individuals are affected with a. fib, and it is the leading cause and diagnosis for individuals requiring hospitalization due to an arrhythmia3. Similar to VTE,
mortality, such as heart attack, stroke, VTE, and numerous other cardiovascular diseases4.
Adequate treatment of a. fib is essential for improved patient outcomes.
Therapy with anticoagulant agents, or “blood thinners” such as warfarin, the direct oral anticoagulants (DOACs), heparin, or enoxaparin are the recommended treatment options for both VTE as well as a. fib according to the American College of Cardiology (ACC) and the American College of Chest Physicians (CHEST)5,6. In VTE, blood clots are formed by the body through
the coagulation cascade, a biological pathway consisting of various co-factors that ultimately lead to the formation of fibrin, an insoluble protein. The anticoagulant agents inhibit the coagulation cascade at various points in the pathway as shown in figure 1, to prevent the formation of the fibrin clot or break down existing clots7. Through this, the use of these agents are able to both treat patients with an active clot, as well as serve as prophylaxis therapy in patients who are at high risk of recurrent clotting. In patients who present with a. fib, anticoagulation is warranted based on their risk for stroke, which is determined by the
CHADS2VASc score, a method that is commonly used in clinical practice8. Individuals with a
score ≥2 are appropriate candidates for anticoagulation according to the European Society of Cardiology9. Although these agents are effective for the treatment of VTE and a. fib, their blood
thinning properties increase the risk of bleeding and leads to numerous safety concerns, which may limit their use in high risk individuals or lead to potential serious adverse events.
Pharmacological options and modalities have been proven to be efficacious in the treatment of these disease states through clinical trials and studies. However, reduction of risk factors for these disease states and other manageable life-style changes remains just as important to improve patient outcomes. Obesity is one of the major risk factor for both of these disease states and has high prevalence10. According to the CDC, over 40% of adults in the United States
in 2017 to 2018, and the prevalence of obesity continues to increase at alarming rates11. As such,
it is important to emphasize and recognize the importance and high correlation between obesity and the prevalence of VTE and a. fib.
Figure 1: The Coagulation Cascade
Figure 17: The above diagram depicts the mechanism of action of various anticoagulant agents on the coagulation cascade.
Purpose:
The DOACs are a class of medications are indicated for VTE and a. fib that include four agents; apixaban, rivaroxaban, edoxaban, and dabigatran and are recommended by CHEST and the ACC over the other agents when used in the aforementioned disease states5,6. They offer various benefits over the other agent that make them simple to use, and very convenient for
patients. As compared to heparin and enoxaparin which are IV and injectable routes of
administration respectively, the DOACs are taken by mouth, which makes them ideal for treating individuals in the outpatient setting and more compliant. In addition, when compared to the warfarin, they are more accessible and generally preferred by patients due to the lack of
monitoring requirements associated with warfarin therapy through the international normalized ratio (INR)13. In addition, warfarin has numerous factors that may influence INR values, such as
numerous interactions with both food and medications, which may make it difficult for patients to obtain a therapeutic INR level14.
Although the DOACs offer numerous benefits, their safety in the obese population is largely unknown due to the population from the landmark trials that led to their approval containing a very small number and percentage of obese individuals15. In addition, the
International Society of Thrombosis and Hemostasis (ISTH) do not recommend their use in the obese population. Due to limited studies and the data available in this patient population, there is uncertainty of the risks and benefits with the use of DOACs. The purpose of this medication utilization evaluation is to assess DOAC use in obese veterans at the Cheyenne VAMC and to determine the number of cardiovascular, thromboembolic and/or bleeding events in such a population.
Methodology:
This MUE was a retrospective analysis that assessed the use of the DOACs in the obese population over a 3 year period at the Cheyenne VAMC. The inclusion criteria was as follows; individuals who had an active prescription for apixaban, dabigatran, rivaroxaban or edoxaban between the dates of 8/1/2014 to 8/1/2017 and a BMI of ≥35 kg/m2 or a weight ≥110kg. The
exclusion criteria was as follows; individuals who had a DOAC prescription, but had never taken the drug or those with a BMI <35 kg/m2 or weight <110kg. Baseline characteristics, such as age, renal function, comorbid conditions, or other factors were not taken into consideration or
documented for the purposes of this review and analysis. Patients who fell under the
aforementioned criteria during this time frame was then had their data pulled and loaded into an excel sheet for review and verification.
A chart review was then performed to verify that the patient had actually filled the DOAC prescription and that the BMI was ≥35 kg/m2 or weight was ≥110kg at the time of DOAC use and that they had no reason for exclusion from the review. These individuals were then categorized and split into three differing groups based upon their BMI or weight
characteristics while on DOAC therapy. These groups consisted of the following; Group A: initial BMI ≥40 kg/m2 or weight ≥120kg, Group B: weight that progressed to a BMI ≥40 kg/m2 or weight ≥120kg, and Group C: initial BMI ≥35 kg/m2 but <40 kg/m2 or weight ≥110 kg but <120kg.
Once patients were assigned to their respective groups, a chart search and review for the following key terms; VTE, DVT, TIA, CVA, stroke, embolism, thrombosis, and bleed was performed to determine if any cardiovascular, thromboembolic, or bleeding event occurred while on DOAC therapy. Minors bleeds were not included and severe bleeds were determined based on documentation and assessment drawn from the provider clinical visits notes. This data was then compiled for review.
Figure 2: Methodology
Figure 2: The above figure depicts the methodology on how patients were selected, excluded, and divided into their respective groups. Chart review was performed to verify inclusion and group selection, as well as determination if a thrombotic, cardiovascular, or bleeding event occurred.
Results:
A total of 93 individuals were included in the initial data collection and review after the data was pulled based on our initial parameters and time-frame. Of those, 21 were excluded for having a BMI <35 kg/m2 or weight <110 kg at the time of initial DOAC therapy or the DOAC was never taken by the patient. Of the eligible 72 patients included in the review, 37 individuals were on therapy with apixaban, 36 on rivaroxaban, and 22 on dabigatran. There were no
individuals on therapy with edoxaban. For the number of endpoints, a total of 4 cardiovascular or thromboembolic events and 1 severe bleed occurred throughout all the groups. Events that
occurred in patients with an initial BMI ≥40 kg/m2 or weight ≥120kg were as follows: 2 confirmed transient ischemic attacks (TIA) events on apixaban and rivaroxaban, one recurrent deep vein thrombosis (DVT) event, which was suspected to be due to noncompliance per chart documentation by the provider on dabigatran occured, and a severe bleed, a left-leg hematoma on rivaroxaban. There was 1 recurrent DVT suspected due to noncompliance that occurred in an individual with a BMI ≥35 kg/m2 or weight ≥110 kg on rivaroxaban therapy as well based on the notes from the provider during the chart review.
Figure 4: Number of Events on DOAC Therapy
Figure 4: The above chart depicts the number of individuals included in each group, the DOACs taken by the patient, and the outcome of cardiovascular, thrombotic, or bleeding events.
Discussion and Conclusion:
This medication utilization evaluation was designed and aimed to evaluate the event rate of thrombotic and cardiovascular (which may be indicative of treatment failure) of DOACs therapy in obese individuals as well as severe bleeding to determine the use of DOACs from a safety standpoint in a single, medical center. The results from this study are difficult to interpret due to lack of comparison to another group, such as a placebo or anticoagulant agent. In addition, it is difficult to accurately compare it to literature reports due to vastly differing populations and study design although our event rate was higher than reported literature17. However, there are several important differences and limitations to this study. We did not document or factor in other risk factors for VTE or a. fib, such as age, kidney function, and comorbidities. In addition, our sample size is very small and limited to a single center with no comparison group. As such, the results of this study are difficult to apply, although they may be used to help initiate further studies of DOACs in obese patients at a later date.
Ultimately, DOACs should be used with caution in obese patients and avoided if possible due to current limited evidence. Closer monitoring of weights and appropriateness of use should be considered in this specific patient population and adherence should be heavily emphasized. Although there is limited data, if a DOAC is being strongly considered in this population, emerging studies suggest the use of apixaban or rivaroxaban versus other DOACs17. Although cardiovascular, thromboembolic, and/or bleeding events occurred within the obese veteran population at the Cheyenne VA, further studies are warranted before clear conclusions and recommendations may be drawn regarding DOAC use in obese patients.
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