Abstract
Background:
The effectiveness and safety of direct oral anticoagulants (DOAC) compared with warfarin remains uncertain in obese patients. We assessed the comparative effectiveness and safety of DOACs with warfarin for the treatment of VTE among obese patients.
Methods:
This multi-center retrospective cohort study included adults with a BMI ≥35 kg/m2 or weight ≥120 kg prescribed either DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) or warfarin for a VTE diagnosis. The primary outcome was the 12-month rate of recurrent VTE. The secondary outcome was the 12-month rate of major bleeding.
Results:
Among 5,626 patients, 67% were prescribed warfarin and 33% were prescribed a DOAC. The 12-month VTE recurrence rate was 3.6% (67/1823) for patients treated with DOAC compared with 3.8% (143/3664) for patients treated with warfarin [odds ratio for recurrent VTE on warfarin versus DOAC (OR) (95% CI) =1.06 (0.79, 1.44)]. The 12-month major bleeding rate was 0.5% (10/1868) for patients on DOAC versus 2.4% (89/3758) on warfarin [OR = 4.25 (2.19, 8.22)]. Similar proportions of recurrent VTE occurred across BMI thresholds on DOAC and warfarin: for BMI ≥35 kg/m2 (N=5412), 3.6% vs 3.8%, respectively [OR 1.08 (0.80, 1.46)]; for BMI ≥40 kg/m2 (N=2321), 4.4% vs 3.5%, respectively [OR 0.80 (0.51, 1.26)]; and for BMI ≥50 kg/m2 (N=560), 3.1% vs 3.7%, respectively [OR 1.18 (0.39, 3.56)].
Conclusion:
Similar proportions of recurrent VTE occurred in patients with obesity treated for VTE with DOACs and warfarin. DOACs were associated with lower major bleeding compared to warfarin in patients with obesity and VTE.
Keywords: venous thromboembolism, obesity, anticoagulants, factor Xa inhibitors, warfarin
Introduction
Four direct oral anticoagulants (DOACs) - apixaban, dabigatran, edoxaban, and rivaroxaban - are approved for the treatment and prevention of recurrent venous thromboembolism (VTE) and have become first-line treatment for most patients.[1, 2] While the labeling for the DOACs do not restrict use in patients at the extreme high-end of body weight, guidance in 2016 urged caution in this population due to lack of clinical data and pharmacokinetic/pharmacodynamics (PK/PD) studies that suggested body weight may alter drug exposure.[3] Since then, observational data, along with post-hoc analysis of randomized trials data, suggest safety and efficacy in patients with obesity.[4–19] Subsequently, in 2021, the International Society on Thrombosis and Haemostasis (ISTH) updated their guidance to suggest that apixaban and rivaroxaban are safe and effective to treat VTE in obese patients,[20] however, data remain limited. Therefore, our study objectives were to assess the effectiveness and safety of anticoagulation with DOACs compared to warfarin for the treatment of VTE in patients with obesity.
Methods
We conducted a multi-center retrospective cohort study at 4 tertiary academic healthcare settings (Massachusetts General Hospital, Medical College of Wisconsin, Northwestern Medicine, and Penn State College of Medicine). Adults with body mass index (BMI) ≥35 kg/m2 or weight ≥120 kg, prescribed either a DOAC (apixaban, dabigatran, edoxaban, and rivaroxaban) or warfarin for a diagnosis of VTE from 01/01/2013- 07/01/2018, and who had at least 12 months of follow-up in their respective healthcare systems were included. Patients were excluded if they had an alternative indication for anticoagulation or if they did not have 12 months of follow-up, unless date of death occurred prior to 12 months. Subjects were identified by query of electronic health records (EHR) for first occurrence of International Classification of Disease (ICD) 9 or 10 code for VTE (see Supplementary Index), with additional chart review of the EHR as necessary to ascertain data elements. Data collected from the EHR included demographics, race category (Asian, Black/African American, White, Other, Unknown), ethnic category (Non-Hispanic, Hispanic, Other/unknown), insurance category (self-pay, private, Medicaid/Medicare, unknown/other), VTE diagnosis, co-morbid conditions, anticoagulant prescriptions, concurrent medications, laboratory values, thrombotic and bleeding diagnoses, and date of death. Recurrent VTE was defined as VTE as primary encounter diagnosis in emergency department or inpatient setting within 12 months of index anticoagulation date.[16, 19] Major and clinically-relevant, non-major bleeding, as defined by ISTH criteria,[21, 22] were identified by ICD codes (see Supplementary Index). Those patients with body mass index (BMI) >100 kg/m2 were excluded as they were deemed biologically implausible. Subjects with missing data to calculate BMI were also excluded, and missing data for medications and outcomes were set to none.
Our primary outcome was 12-month rate of recurrent VTE. Secondary outcomes included 12-month rate of major bleeding, clinically-relevant, non-major bleeding (CRNMB), and time to recurrent VTE.
Descriptive statistics were used to summarize participant characteristics. Univariate and multivariable logistic regression were used to assess if the anticoagulant (warfarin versus DOAC) was associated with the primary and secondary outcomes. Multivariable logistic regression models were adjusted for age at prescription, race, ethnicity, insurance category, and site. We assessed the primary outcome overall as well as stratified by BMI category (35-<40, 40-<45, 45-<50, ≥50 kg/m2), weight category (120-140 and ≥140 kg), and BMI threshold (BMI ≥35, ≥40, and ≥50 kg/m2). We calculated VTE recurrence rate by individual DOAC compared with warfarin. Using cause-specific Cox proportional hazards model, adjusted for the same variables as in the logistic regression analysis, we assessed time to recurrent VTE by medication group (warfarin versus DOAC), accounting for competing risk of death.
We performed a sensitivity analysis to account for inherent differences and potential biases between the two medication groups as this was a non-randomized study, utilizing inverse probability-of-treatment weighting (IPTW). Propensity-scores (predicted probability of initiating DOAC given baseline covariates) were calculated, and each patient was weighted by the inverse of the probability of their treatment option (weight = 1/propensity score) to balance patient characteristics between treatment groups [23] We computed propensity scores using demographic (age, insurance, race and ethnicity) and clinical factors (malignancy, antiphospholipid syndrome, BMI category, renal disease and liver disease). In order to avoid bias in estimates of treatment effect due to extreme weights, after generating propensity-scores, those patients with scores >0.9 or <0.1 were excluded.[24] Residual differences in baseline covariates between weighted DOACs and warfarin cohorts were assessed by calculating absolute standardized differences, with differences <0.1 considered well-balanced.
Results
Participant characteristics
5,626 patients met study criteria and were included in the analysis. Subjects were primarily female (57%), of White/Caucasian race (72%) and non-Hispanic ethnicity (93%), with a mean age of 58 years (standard deviation [SD] 15). Mean BMI was 41 kg/m2 (SD7), with highest BMI of 80 kg/m2, and mean weight was 118 kg, with highest weight of 270 kg. Warfarin was prescribed to 67% (3,758) of patients and a DOAC was prescribed to 33% (1,868), with rivaroxaban composing the majority of DOAC prescriptions (71.9%) (Table 1). Body weight was missing for 197 subjects. Twenty-eight subjects died within 12 months. From propensity score analysis, 264 had propensity weights >0.9 and <0.1.
Table 1:
Patient characteristics
| DOAC (N=1868) |
Warfarin (N=3758) |
Total (N=5626) |
|
|---|---|---|---|
|
| |||
| BMI kg/m2 | |||
|
| |||
| Mean (SD) | 40.0 (5.8) | 41.4 (7.2) | 41.0 (6.8) |
|
| |||
| BMI Category (kg/m2) | |||
|
| |||
| <35 | 45 (2.4%) | 90 (2.4%) | 135 (2.4%) |
|
| |||
| 35-<40 | 1138 (61.0%) | 2032 (54.1%) | 3170 (56.3%) |
|
| |||
| 40-<45 | 385 (20.6%) | 780 (20.8%) | 1165 (20.7%) |
|
| |||
| 45-<50 | 173 (9.3%) | 423 (11.3%) | 596 (10.6%) |
|
| |||
| ≥50 | 127 (6.8%) | 433 (11.5%) | 560 (10.0%) |
|
| |||
| Weight (kg)- mean (SD) * | 115.8 (21.7) | 119.0 (25.8) | 117.9 (24.5) |
|
| |||
| 120-140 kg | 720 (39.1%) | 1498 (41.8%) | 2218 (40.9%) |
|
| |||
| ≥ 140 kg | 230 (12.5%) | 586 (16.3%) | 816 (15.0%) |
|
| |||
| Age (years)- mean (SD) | 55.6 (15.0) | 58.4 (14.6) | 57.5 (14.8) |
|
| |||
| Sex- female | 1053 (56.4%) | 2172 (57.8%) | 3225 (57.3%) |
|
| |||
| Oral anticoagulant | |||
| Apixaban | 472 (25.3%) | ||
| Dabigatran | 52 (2.8%) | ||
| Edoxaban | 1 (0.1%) | ||
| Rivaroxaban | 1343 (71.9%) | ||
|
| |||
| Race Category | |||
|
| |||
| White | 1396 (74.7%) | 2674 (71.2%) | 4070 (72.3%) |
|
| |||
| Black | 342 (18.3%) | 817 (21.7%) | 1159 (20.6%) |
|
| |||
| Unknown/Other | 130 (7.0%) | 267 (7.1%) | 397 (7.1%) |
|
| |||
| Ethnic Category | |||
|
| |||
| Not Hispanic/Latin-X | 1719 (92.0%) | 3502 (93.2%) | 5221 (92.8%) |
|
| |||
| Hispanic/Latin-X | 104 (5.6%) | 181 (4.8%) | 285 (5.1%) |
|
| |||
| Other/Unknown | 45 (2.4%) | 75 (2.0%) | 120 (2.1%) |
|
| |||
| Insurance Category | |||
|
| |||
| Medicaid/Medicare | 880 (47.1%) | 2008 (53.4%) | 2888 (51.3%) |
|
| |||
| Private | 803 (43.0%) | 1108 (29.5%) | 1911 (34.0%) |
|
| |||
| Unknown/Other | 185 (9.9%) | 642 (17.1%) | 827 (14.7%) |
|
| |||
| Co-morbidities | |||
|
| |||
| CVD+ | 491 (26.3%) | 1386 (36.9%) | 1877 (33.4%) |
|
| |||
| Liver disease | 153 (8.2%) | 432 (11.5%) | 585 (10.4%) |
|
| |||
| Renal failure | 62 (3.3%) | 416 (11.1%) | 478 (8.5%) |
|
| |||
| Malignancy | 498 (26.7%) | 1010 (26.9%) | 1508 (26.8%) |
|
| |||
| Antiphospholipid syndrome | 56 (3.0%) | 163 (4.3%) | 219 (3.9%) |
missing N=197, 25 in DOAC and 172 in warfarin;
CVD= cardiovascular disease (coronary artery disease or peripheral vascular disease)
Primary Outcome
The overall VTE recurrence at 12 months was 3.6% in patients on DOAC compared with 3.8% in patients on warfarin (odds ratio (OR) for recurrent VTE on warfarin versus DOAC [95% Confidence Interval (CI)] = 1.06 [0.79, 1.44]; p=0.68). When adjusted for age at prescription, race, ethnicity, insurance category, and site, there was no difference between DOAC and warfarin in VTE recurrence at 12 months (OR 1.06 [95% CI 0.79, 1.45]; p=0.70) (Figure 1).
Figure 1:
Odds of recurrent VTE on warfarin versus DOAC by BMI, adjusted for age, race, ethnicity and insurance
VTE: venous thromboembolism; DOAC: direct oral anticoagulant; BMI: body mass index
When stratified by BMI category, there were no significant differences in VTE recurrence at 12 months between DOAC and warfarin groups (Table 2): for BMI 35 to <40 kg/m2, 3.2% versus 4.1%, respectively [OR 1.30 (95% CI 0.88, 1.96); p=0.19]; for BMI 40 to <45 kg/m2, 3.9% vs 3.5% , respectively [OR 0.88 (95% CI 0.47, 1.72); p=0.71]; for BMI 45 to <50 kg/m2, 6.4% vs 3.5%, respectively [OR 0.54 (95% CI 0.25, 1.23); p=0.13], and for BMI ≥50 kg/m2, 3.1% vs 3.7%, respectively [OR 1.18 (95% CI 0.42, 4.18); p=0.77].
Table 2:
VTE recurrence rate at 12 months by anticoagulant and BMI/weight
| DOAC | Warfarin | OR | |
|---|---|---|---|
| BMI category (kg/m2) | |||
| Overall | 67/1823 (3.6%) | 143/3668 (3.8%) | 1.06 (0.79, 1.44) |
| ≥35 | 66/1823 (3.6%) | 141/3668 (3.8%) | 1.06 (0.79, 1.44) |
| ≥40 | 30/685 (4.4%) | 58/1636 (3.5%) | 0.80 (0.52, 1.27) |
| ≥50 | 4/127 (3.1%) | 16/433 (3.7%) | 1.18 (0.42, 4.18) |
| 35-<40 | 36/1138 (3.2%) | 83/2032 (4.1%) | 1.30 (0.88, 1.96) |
| 40-<45 | 15/385 (3.9%) | 27/780 (3.5%) | 0.88 (0.47, 1.72) |
| 45-50 | 11/173 (6.4%) | 15/423 (3.5%) | 0.54 (0.25, 1.23) |
| Weight (kg) | |||
| 120-140 | 16/490 (3.3%) | 32/912 (3.5%) | 1.08 (0.59, 2.03) |
| ≥140 | 9/230 (3.9%) | 18/586 (3.1%) | 0.78 (0.35, 1.84) |
When stratified by BMI threshold, recurrent VTE rates remained similar for patients treated with DOAC compared with warfarin: for BMI ≥35 kg/m2 (N=5491), 3.6% vs 3.8%, respectively [OR 1.06 (0.79, 1.44); p=0.68]; for BMI ≥40 kg/m2 (N=2321), 4.4% vs 3.5%, respectively [OR 0.80 (0.52, 1.27); p=0.34]; and for BMI ≥50 kg/m2 (N=560), OR 1.18 [(0.42, 4.18); p=0.77] as above. VTE recurrence rates were also similar across individual medications: 2.3% with apixaban and 4.1% with rivaroxaban, compared with 3.8% with warfarin (p=0.30). Our study was not powered to compare individual DOACs.
Secondary outcomes:
Of all subjects, 99/5626 (1.8%) had a major bleeding event at 12 months, including 0.5% in patients on DOAC compared with 2.4% in patients on warfarin [OR 4.15 (2.46, 9.27); p<0.001]. In those with BMI 35 to <40 kg/m2, DOACs were associated with significantly less bleeding than warfarin [0.4% vs 2.8%; OR 4.96 (2.63, 10.60); p<0.001], while similar rates of major bleeding occurred between the two groups in other BMI categories (Figure 2, Supplemental Table 1). CRNMB rates were also similar between DOAC and warfarin (16.1% vs 17.4%, respectively; OR 1.09 [0.94, 1.27]; p=0.25).
Figure 2:
Odds of major bleeding on warfarin versus DOAC by BMI
VTE: venous thromboembolism; DOAC: direct oral anticoagulant; BMI: body mass index
Time to recurrent VTE, with death as a competing risk, was similar in warfarin and DOAC groups [Hazards ratio 1.07 [0.79, 1.44]; p=0.67] (Figure 3), when adjusted for age, race and ethnicity categories, insurance category, and site.
Figure 3:
Time to recurrent VTE by medication group, with death as competing risk
DOAC= direct oral anticoagulant; rvte= recurrent venous thromboembolism
In the sensitivity analysis using IPTW, similar treatment effect of warfarin versus DOAC occurred for 12-month rate of recurrent VTE [OR 1.08 (0.89, 1.32); p=0.44], whereas warfarin had higher OR for 12-month rate of major bleeding [OR 3.76 (2.51, 5.64); p<0.001].
Discussion
In this large study of more than 5,500 patients with obesity treated for VTE, there was no significant difference in the rate of recurrent VTE at 12 months among patients treated with DOAC versus warfarin. DOAC use was associated with a lower rate of major bleeding compared with warfarin. We found similar safety and effectiveness across BMI and weight categories for DOAC compared with warfarin for the treatment of VTE. Notably, our study included a large number of patients at extremes of obesity, with more than 2,300 patients with BMI >40 kg/m2, and more than 500 patients with BMI > 50 kg/m2, categories of patients for whom data are extremely limited.
Our data are consistent with the growing body of evidence that demonstrates the safety and effectiveness of DOACs in patients with obesity that have been published in the five years since the initial ISTH guidance document.[4, 6–19] For example, one meta-analysis that examined “high weight” (>90-100 kg) subjects from the phase III randomized controlled trials of DOACs vs warfarin for VTE treatment found similar rates of VTE, VTE related death and bleeding in both groups.[6] Another meta-analysis of five observational studies, the majority of data (88%) for which resulted from one study consisting of administrative claims using ICD coding for obesity, found similar rates of efficacy and a non-significant trend toward reduced risk of major bleeding with DOAC (rivaroxaban, apixaban, and dabigatran) compared with warfarin for patients with BMI ≥40 kg/m2 or weight >120 kg being treated for VTE.[9] Several other investigations showed similar effectiveness when pooled DOACs were compared to warfarin in patients with BMI ≥30 kg/m2 or weight >120 kg.[5, 17, 18] Our study furthers knowledge in that it uses primary patient data restricted to class 2 obesity (BMI ≥35 kg/m2) or weight > 120 kg and above, and includes, to our knowledge, the largest population of patients with outcomes for VTE stratified by BMI. Importantly, our large real-world study applies specifically to the VTE population, of which there are fewer data compared to those for atrial fibrillation, due to its higher prevalence than VTE. Our data showing effectiveness and improved safety in VTE patients with obesity should help clinicians feel confident in prescribing apixaban and rivaroxaban in this population.
There are several strengths to our study. We used patient data from multiple sites in different geographical regions, which improves its generalizability. In addition, we included a large range of obese BMIs and weight categories. Limitations of our study include its retrospective nature with reliance on ICD coding to identify patients as well as to determine outcomes. However, we included only recurrent VTE diagnosed in Emergency Department or inpatient setting in an attempt to exclude carry-over VTE diagnosis codes. Furthermore, we required a 12-month follow-up to capture occurrence of primary and secondary outcomes more accurately. The sample size is small as BMI categories increase, limiting conclusions in these categories, though few previously published data for these extreme weights are available. Very few patients in our study were prescribed dabigatran and edoxaban, limiting conclusions specific to those medications. We were unable to ascertain the dose of DOACs nor time in therapeutic range on warfarin and therefore cannot conclude whether these affected our results.
In conclusion, our real-world study of a large population of patients with obesity treated for VTE demonstrates similar effectiveness and improved safety with DOACs as compared to warfarin.
Supplementary Material
Key Points:
Limited data exist for use of DOACs for treatment of VTE in patients with obesity
DOACs were as effective as warfarin at preventing recurrent VTE in obese patients
DOACs were associated with less major bleeding than warfarin in obese patients
Future studies should seek to confirm these findings in extreme obesity
Funding
This study was funded by Janssen Scientific Affairs. Janssen reviewed the study protocol and manuscript but was not involved in the data analysis or manuscript writing.
KM is supported by K23HL157758
Research reported in this publication was supported, in part, by the National Institutes of Health’s National Center for Advancing Translational Sciences, Grant Number UL1TR001422. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Competing Interests:
The following authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: CL, MEE, KS, SW, IW, LBK
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
RPR received research grants to her institution from BMS and Janssen and is a consultant to BMS and Janssen.
KAM received a research grant to her institution from Janssen Scientific Affairs.
Footnotes
Disclosures
The data were presented at the Thrombosis and Hemostasis Summit of North America in August 2022.
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