What is the best DOAC for underweight individuals (i.e., 30 kg patients) for treatment of PE?

Comment by InpharmD Researcher

Given the paucity of clinical data evaluating the use of DOACs in underweight patients, a definitive conclusion on the preferred DOAC for the treatment of PE cannot be made. Identified studies tend to collectively analyze patients with extreme body weights, with underweight individuals only presenting a small proportion of the assessed population. Additionally, subgroup analyses based on various types of DOACs (primarily rivaroxaban and apixaban) or indications for anticoagulants are also limited. One meta-analysis reports rivaroxaban alone to be associated with a lower rate of VTE recurrence or stroke compared to underweight patients who received mixed DOACs (rivaroxaban, apixaban, dabigatran); whereas another retrospective study finds apixaban, but not rivaroxaban or dabigatran, has led to lower incidences of overall VTE and bleeding compared to warfarin. Dabigatran, in particular, has been demonstrated to cause drug-induced bleeding at low body mass indexes and thus may be avoided. Future studies exclusive to underweight individuals are required to elucidate the optimal use (e.g., standard vs reduced dose) of DOACs in this population.

Background

Dosing strategies of direct oral anticoagulants (DOACs) for patients with extreme body weights, including underweight patients, were discussed in a 2020 review published by the American Heart Association (AHA). Although previous large randomized trials of DOACS for venous thromboembolism (VTE) have not excluded patients based on weight, extreme-body-weight populations have been underrepresented, resulting in limited guidance for best practices in these patients. While limited data exist for patients with obesity, data for underweight patients remains scarce. For low-body-weight patients (<60 kg), renal function should be assessed due to the common overestimation of renal function in patients with lower muscle mass. Furthermore, patients with low body weight are most likely to be elderly, frail, or renally impaired, resulting in a predisposition to adverse outcomes. The dose of apixaban and edoxaban, for example, is recommended to be reduced for patients with weight <60 kg based on pharmacokinetic data finding increased systemic exposure in such patients. Similar dose reduction may be prudent with rivaroxaban due to increased systemic exposure exhibited in patients with loss of muscle mass, although no concrete data are available. Dabigatran has demonstrated drug-induced bleeding at low body mass indexes (BMI; <23.9 kg/m2) and is not considered to be an ideal choice in underweight patients. Patient ethnicity may also impact the efficacy and safety of DOACs, with one Korean study concluding that the use of DOACs (including regular doses of dabigatran, rivaroxaban, apixaban, and edoxaban) was safe and more effective compared to warfarin in patients with extremely low-body-weight (<50 kg). Ultimately, due to limited applicable data, the use of DOACs in underweight patients should be accompanied by monitoring for efficacy and safety. Although no methods are FDA-approved, monitoring parameters that may be considered include qualitative measures such as activated partial thromboplastin time (aPTT), thrombin time, and prothrombin time, quantitative measures, such as anti-factor Xa levels, plasma drug concentrations, dilute thrombin time, and ecarin thrombin time, and finally, general monitoring including signs and symptoms of bleeding, complete blood count, and a comprehensive metabolic panel to evaluate liver function, albumin, total bilirubin, and serum creatinine. [1]

A 2022 systematic review and meta-analysis evaluated the safety and efficacy of DOACs versus warfarin in patients who were treated for VTE and atrial fibrillation (AF) across different BMIs. The pooled analysis of data stemmed from observational cohorts (retrospective or prospective) as well as randomized controlled trials (RCTs), which included a total of 12 studies (N= 254,908). Overall, this meta-analysis did not reveal a significant difference in the recurrence of VTE or stroke between underweight and normal-weight patients who received DOAC therapy (p= 0.32; risk ratio [RR] 2.12, 95% confidence interval [CI] 0.48 to 9.30; I2= 85%). However, a subgroup comparative analysis of patients who received mixed DOACs (rivaroxaban, apixaban, dabigatran) therapy versus the patients who only received rivaroxaban demonstrated a significantly higher rate of VTE recurrence or stroke with the underweight patients who received mixed DOACS compared with rivaroxaban alone (p= 0.01; I2= 84.5%). Unfortunately, the data does not reflect any risk or benefit with a specific DOAC in underweight patients to conclude an optimal DOAC therapy for this specific population. [2]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the best DOAC for underweight individuals (ie 30 kg patient) for the treatment of PE?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

DOAC compared with warfarin for VTE in low weight patients: A retrospective cohort study conducted through the VENUS network
Design	Retrospective cohort study N= 726
Objective	To assess the effectiveness and safety of direct oral anticoagulants (DOACs) compared with warfarin for initial treatment of venous thromboembolism (VTE) in patients with body mass index (BMI) <18 kg/m² or weight <50 kg
Study Groups	Warfarin (n= 521) DOAC (n= 205)
Inclusion Criteria	Adults with BMI <18 kg/m² or weight <50 kg who were prescribed either a DOAC or warfarin for a diagnosis of VTE and who had at least 12 months of follow-up in their respective healthcare systems
Exclusion Criteria	Alternative indication for anticoagulation; weight >80 kg; did not have 12 months of follow-up unless the date of death occurred prior to 12 months
Methods	Data were obtained using a query of an electronic health record (EHR), with extra chart analysis of the EHR as needed to determine data items. Demographics, race, and ethnicity, insurance type, co-morbid conditions such as renal disease, anticoagulant prescriptions, concurrent medications, laboratory values, thrombotic and bleeding diagnoses, and date of death were all collected from the EHR. The presence of an International Classification of Disease (ICD) 9 or 10 code for VTE (in any position) was defined as a diagnosis of VTE for the inclusion criteria.
Duration	January 2013 to July 2018
Outcome Measures	Primary: 12-month cumulative incidence of recurrent VTE Secondary: Major bleeding at 12 months; other bleeding
Baseline Characteristics		Warfarin (n= 521)	DOAC (n= 205)
	Age, years	64.7 ± 20.7	64.2 ± 20.1
	Female	378 ± 72.6	163 ± 79.5
	White	336 ± 64.5	150 ± 73.2
	BMI, kg/m²	18.0 ± 2.1	18.5 ± 2.2
	Weight, kg	48.5 ± 5.8	49.0 ± 5.4
	BMI <18 kg/m²	356 (68.3%)	113 (55.1%)
	Weight <50 kg	389 (76.0%)	156 (76.1%)
	Oral anticoagulant Apixaban Dabigatran Edoxaban Rivaroxaban	--	66 (32.2%) 7 (3.4%) 0 (0) 132 (64.4%)
	Insurance category Private Medicaid./Medicare Unknown/other	93 (17.9%) 314 (60.3%) 114 (21.9%)	44 (21.5%) 132 (64.4%) 29 (14.1%)
	Co-morbidities CVD Liver disease Renal disease Malignancy	216 (41.5%) 45 (8.6%) 93 (17.9%) 184 (35.3%)	63 (30.7%) 12 (5.9%) 10 (4.9%) 86 (42.0%)
	CVD: Cardiovascular disease; BMI: Body mass index
Results	Endpoint*	Warfarin (n= 521)	DOAC (n= 205)	Hazard ratio (HR) warfarin vs DOAC	p-value
	Recurrent VTE at 12 months	28 (5.4%)	8 (3.9%)	1.39 (0.63 to 3.05)	--
	Major bleeding at 12 months	14 (2.7%)	2 (1.0%)	2.78 (0.63 to 12.22)	0.18
	Other bleeding	114 (22.0%)	40 (19.7%)	1.14 (0.80 to 1.64)	0.47
	*Primary and secondary outcomes for low-weight patients (BMI <18 kg/m² or weight <50 kg)
Adverse Events	Adverse Events: See results
Study Author Conclusions	In conclusion, in this large, VTE-specific cohort, we found no significant difference in the safety and effectiveness of DOAC versus warfarin for treatment of VTE in low weight patients.
InpharmD Researcher Critique	Owing to the limited number of outcome events, the study lacked the power to detect differences by individual DOACs, resulting in the grouping of DOACs into one category. The study couldn't determine the dosage of DOACs or the time in therapeutic range for warfarin, precluding conclusive statements about their impact on the results. Additionally, the study faces other limitations, including its retrospective nature, reliance on ICD coding, and inability to assess drug-drug interactions impacting adverse outcomes.

References:

Martin KA, Lancki N, Kreuziger LB, et al. DOAC compared with warfarin for VTE in low weight patients: A retrospective cohort study conducted through the VENUS network. Thromb Res. 2023;229:146-148. doi:10.1016/j.thromres.2023.07.004

Safety and efficacy of oral anticoagulants in extreme weights
Design	Retrospective review N= 492
Objective	To evaluate the safety and efficacy of direct oral anticoagulants (DOACs) in underweight and obese patients compared to warfarin
Study Groups	Body mass index (BMI) < 18.5 kg/m² (n= 80) BMI >30 kg/m2 (n= 412) DOACs (n= 244) Apixaban (n= 101) Dabigatran (n= 43) Rivaroxaban (n= 100) Warfarin (n= 248)
Inclusion Criteria	Inpatient hospital admission, patients receiving at least 90 days of apixaban, rivaroxaban, dabigatran, or warfarin as a home medication, BMI <18.5 kg/m² or BMI >30 kg/m², and history of either venous thromboembolism (VTE) or atrial fibrillation (AF)
Exclusion Criteria	DOAC or warfarin indication for hip or knee arthroplasty, anticoagulation therapy duration <90 days, a change in DOAC within 90 days from evaluation, and DOAC or warfarin initiation during the admission
Methods	Patients' charts were retrospectively reviewed to identify eligible patients and collect clinical data of interest at a University hospital in New York. Criteria used to define a VTE, stroke, and bleed were extrapolated from Phase 3 trials used for DOACs, such as EINSTEIN, ARISTOTLE, and AMPLIFY trials.
Duration	Between October 2016 and September 2020
Outcome Measures	Primary efficacy: occurrence of thrombosis or cerebral vascular accident Primary safety: rates of bleeding Secondary: rates of VTE and rates of ischemic stroke; rates of bleeding events; evaluation in each BMI category among each DOAC compared to warfarin and between a combined DOAC group compared to warfarin
Baseline Characteristics		Warfarin (n= 248)	Apixaban (n= 101)	Rivaroxaban (n= 100)	Dabigatran (n= 43)	Overall DOAC (n= 244)
	Age, years	72	70	70	75	71
	Female	47.18%	51.49%	48%	55.81%	50.82%
	Weight, kg	94	95	97	95	95.8
	BMI <18.5 kg/m²	47 (18.95%)	10 (9.9 %)	13 (13 %)	10 (23.26 %)	33 (13.52 %)
	History of Cancer^§ AF^ VTE^* CKD/AKI^*	7.66% 73.39 % 25.4 % 45.56 %	19.8% 75.25% 31.68% 50.5%	26% 56% 43% 24%	13.95% 90.7% 25.58% 44.19%	21.31% 70.08% 35.25% 38.52%
	Indication for anticoagulation - VTE^*	65 (26.21%)	33 (32.67%)	42 (42%)	5 (11.63%)	80 (32.79%)
	AKI: acute kidney injury; CKD: chronic kidney disease ^*4-Group comparison p-value< 0.05 ^§2-Group warfarin vs. DOAC p-value< 0.05
Results	Endpoint (BMI <18.5 kg/m²)	Warfarin (n= 248)	Apixaban (n= 101)	Rivaroxaban (n= 100)	Dabigatran (n= 43)	Overall DOAC (n= 244)
	Bleeding confirmation^*	7 (14.89%)	1 (10%)	5 (38.46%)	5 (50%)	11 (33.33%)
	Bleeding types No bleed^* Hematoma Hematuria Melena/GI bleed^§ Positive stool guaiac/FOBT^ Hemoptysis/epistaxis	40 (85.11 %) 3 (6.38 %) 2 (4.26%) 0 1 (2.13%) 1 (2.13%)	9 (90%) 0 0 1 (10%) 0 0	8 (61.54%) 1 (7.69%) 0 3 (23.08%) 1 (7.69%) 0	5 (50%) 1 (10%) 0 1 (10%) 3 (30%) 0	22 (66.67%) 2 (6.06%) 0 5 (15.15%) 4 (12.12%) 0
	Clot	1 (2.13%)	0	0	2 (20%)	2 (6.06%)
	When each DOAC was compared to warfarin in rates of VTE, apixaban showed a statistically significant lower rate of VTE (p= 0.0149). However, no statistical significance was identified in the rate of VTE between DOACs combined vs. warfarin (p= 0.1529). When each DOAC was compared to warfarin, apixaban showed the lowest rate of overall bleeding (p= 0.0194). However, no statistical difference in the rate of bleeding was observed between DOACs combined vs. warfarin (p= 0.3284). It’s important to mention that the significant p-values linked to apixaban were only found in the abstract, and no further discussion was provided within the main study or the supplementary data.
	^*4-Group comparison p-value< 0.05 ^§2-Group warfarin vs. DOAC p-value< 0.05
Adverse Events	See results
Study Author Conclusions	In summary, the current evaluation confirms the findings of prior studies in that DOAC use in obese patients has not led to adverse outcomes. What is novel about this study is that the same observation holds true in underweight patients. Our analysis identifies the use of apixaban demonstrating a statistically significant benefit over other DOACs in lower risk of bleeding in underweight patients with BMI <18.5 and in rates of VTEs in obese patients with BMI >40, which may give confidence to the clinician to use DOACs, particularly apixaban, in underweight and obese patients.
InpharmD Researcher Critique	As with other clinical studies, underweight patients (BMI <18.5 kg/m²) only represent a small portion of the overall patient population to draw definitive conclusions on the preferred DOAC in this population. Additionally, only ~30% of patients received DOACs for treatment of VTE, without a specified subpopulation with pulmonary embolism.

References:

Chin-Hon J, Davenport L, Huang J, Akerman M, Hindenburg A. Safety and efficacy of oral anticoagulants in extreme weights [published online ahead of print, 2023 Sep 12]. Thromb Res. 2023;231:1-6. doi:10.1016/j.thromres.2023.09.001

Safety and efficacy of direct oral anticoagulants across body mass index groups in patients with venous thromboembolism: a retrospective cohort design
Design	Multi-site, retrospective review N= 1,059
Objective	To describe the safety and efficacy of direct oral anticoagulant (DOAC) therapy in patients of extreme weights for the treatment of venous thromboembolism (VTE) using body mass index (BMI) groups
Study Groups	Underweight (n= 17) Normal weight and overweight (n= 517) Obese (n= 383) Extremely obese (n= 142)
Inclusion Criteria	Aged ≥18 years, prescribed apixaban, rivaroxaban, dabigatran, or edoxaban for an initial VTE event, including either pulmonary embolism (PE) or deep-vein-thrombosis (DVT), in the retrospective period
Exclusion Criteria	Use of long-term anticoagulation prior to the index VTE event
Methods	Data were compiled via retrospective chart review of medical records. Patients were identified using ICD-9 and ICD-10 codes for PE or DVT. After the index event, patients were followed for 12 months and categorized into BMI categories: extremely obese (BMI ≥40 kg/m²), obese (BMI 30-39.9 kg/m²), normal weight/overweight (BMI 18.5-29.9 kg/m²), or underweight (BMI <18.5 kg/m²).
Duration	Patients experienced initial VTE between November 2012 and August 2017 Follow-up: 12 months from index date
Outcome Measures	Primary: recurrent VTE (including DVT or PE) Safety: incidence of major bleed within 12 months of index date
Baseline Characteristics		Underweight (n= 17)	Normal/overweight (n= 517)	Obese (n= 383)	Extremely obese (n= 142)
	Age ≥65 years	94%	91%	89%	89%
	Female	65%	46%	45%	59%
	White	76%	89%	90%	87%
	Discharge DOAC Rivaroxaban Apixaban Dabigatran	70% 24% 6%	75% 24% 1%	77% 21% 2%	75% 24% 1%
	Comorbidities Atrial fibrillation Diabetes Stroke/transient ischemic attack Provoked VTE Past major bleed	6% 18% 6% 6% 18%	12% 16% 10% 15% 10%	12% 25% 9% 20% 7%	8% 36% 5% 21% 11%
	Fall	41%	13%	8%	9%
	Patients in the underweight group were more likely to be female and have a fall within 12 months from the index event. Patients who were in the extremely obese group were more likely to have diabetes and less likely to have any history of cancer compared to other groups.
Results	Endpoint	Underweight (n= 17)	Normal/overweight (n= 517)	Obese (n= 383)	Extremely obese (n= 142)
	Recurrent VTE Rate Odds ratio (95% confidence interval) p-value	0.059 1.13 (0.14 to 8.87) 0.90	0.052 Reference Reference	0.047 0.89 (0.49 to 1.65) 0.72	0.078 1.52 (0.74 to 3.15) 0.26
	Major bleed Rate Odds ratio (95% confidence interval) p-value	0.294 3.73 (1.26 to 11.0) 0.02	0.101 Reference Reference	0.104 1.04 (0.67 to 1.61) 0.85	0.063 0.61 (0.29 to 1.26) 0.18
	Prescribed dabigatran, but not rivaroxaban or apixaban, has been identified as a risk factor for major bleeding after adjusting for BMI (odds ratio 5.80; 95% confidence interval 1.66 to 15.6; rivaroxaban as reference).
Adverse Events	See above.
Study Author Conclusions	Recurrence of VTE was not shown to have an association with BMI. However, the proportions of major bleeding were statistically different among the weight categories, specifically underweight patients having a higher proportion of bleeding compared to normal/overweight patients. This data supports that DOACs can be considered a reasonable treatment for VTE in extremely obese patients. DOAC use for VTE treatment in underweight patients should be used cautiously and with close monitoring until larger studies show their safety.
InpharmD Researcher Critique	While preferred DOAC and associated outcomes for each agent for underweight patients were not investigated within the study, the majority of underweight patients (70%) were treated with rivaroxaban. Information regarding dosing regimens and potential dose adjustments was not described. A limited sample size of underweight patients was included.

References:

Cardinal RM, D'Amico F, D'Addezio A, Dakers K, Castelli G. Safety and efficacy of direct oral anticoagulants across body mass index groups in patients with venous thromboembolism: a retrospective cohort design. J Thromb Thrombolysis. 2021;52(2):567-576. doi:10.1007/s11239-020-02361-8