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Does Obesity affect AntiCoagulation? Weighing in on DOACs for VTE treatment in obesity
Source: http://bizarro.com/201310/30/flathead-funnies/
Isaac J. Perales, Pharm.D. PGY-1 Pharmacy Resident University Health System
Division of Pharmacotherapy The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center The University of Texas Health San Antonio
October 18 and 27, 2017
Learning Objectives: 1. Review venous thromboembolism (VTE) treatment guidelines2. Discuss current guidance on anticoagulants in extremely obese/high body weight patients3. Evaluate primary literature for efficacy of DOACs in extremely obese/high body weight
patients
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Assessment Questions: 1. Direct oral anticoagulants (DOACs) are the first line treatment for provoked and unprovoked VTE?
a. True b. False
2. What is the International Society on Thrombosis and Haemostasis (ISTH) recommended weight and
BMI cutoff suggesting against the use of the DOACs? a. < 60 kg or < 18 kg/m2 b. > 100 kg or > 30 kg/m2 c. > 120 kg or > 40 kg/m2 d. > 150 kg or > 45 kg/m2
3. Which of the DOACs has a widely accepted “therapeutic” plasma concentration range for peak and
trough measurement? a. Dabigatran b. Rivaroxaban c. Apixaban d. Edoxaban e. None of the above
4. Which of the DOACs has a clinical trial evaluating venous thromboembolism (VTE) recurrence in
patients > 120 kg? a. Dabigatran b. Rivaroxaban c. Apixaban d. Edoxaban e. None of the above
***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com ***
Faculty (Speaker) Disclosure: Isaac J. Perales has indicated he has no relevant financial relationships to disclose relative to the content of his presentation
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Introduction & Background
I. Venous thromboembolism (VTE)1-3
a. Includes deep vein thrombosis (DVT) and pulmonary embolism (PE)
i. DVT is a blood clot that occurs in a deep vein, usually in the lower leg, thigh, or
pelvis
ii. PE occurs when a clot breaks free and enters the arteries of the lungs
b. Pathophysiology of venous thromboembolism starts with coagulation
i. Activated thrombin converts soluble plasma fibrinogen into insoluble fibrin or a
clot
II. Incidence of VTE3-8
a. Estimates in USA per year vary widely
i. First event
1. ~260,000 cases per year among Caucasian population
2. ~287,000 cases per year among African-American population
ii. ~548,000 hospitalizations per year
b. Overall VTE rate ranges from 104-183 cases per 100,000 person-years
i. ~900,000 cases per year
c. Risk factors Table 1. Risk Factors for VTE and Associated Risk Risk Factor Odds Ratio 95% CI
Major surgery 18.95 9.22-38.97
Active cancer 14.64 7.73-27.73
Neurologic disease with leg paresis 6.10 1.97-18.89
Hospitalization 5.07 3.12-8.23
Nursing home confinement 4.63 2.77-7.74
Trauma/fracture 4.56 2.46-8.46
Pregnancy/postpartum 4.24 1.30-13.84
Oral contraceptives 4.03 1.83-8.89
Non-contraceptive estrogen plus progestin 2.53 1.38-4.63
Estrogen alone 1.81 1.06-3.09
d. Hospitalization
i. Community rates of VTE 8 per 100,000
ii. Hospital rates of VTE 330 per 100,000
e. Male gender
i. Men: 130 per 100,000 patient-years
ii. Women: 110 per 100,000 patient-years
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f. Age
i. Incidence of DVT and/or PE increases drastically in older age among both men
and women
Figure 1. Relation of Age with VTE Incidence
g. Obesity
i. Meta-analysis evaluating five high-quality studies of obesity risk for VTE
1. Odds ratio of 1.84 (95% CI, 1.55-2.18; I2=69.2%; P=0.01) for increased
risk of VTE among obese patients
ii. Hypotheses for obesity-related hypercoagulable state
1. Increased abdominal fat may limit venous return persistent increased
intra-abdominal pressure and venous stasis in femoral veins
2. Inactivity and poor gait may contribute to venous stasis
3. Hyper-expression of tumor necrosis factor- (TNF-) and transforming
growth factor- (TGF-) chronic pro-inflammatory state impairs
endothelial function
4. Increased expression of clotting factors and impaired fibrinolysis
5. Visceral adipose tissue may overproduce leptin induce platelet
aggregation and over-translation of plasminogen activator inhibitor-1
(PAI-1)
h. Ethnicity
i. VTE incidence may be higher in African-Americans and lower in Asians, Native-
Americans, and Hispanics
III. Recurrence of VTE4
a. ~30% of patients experience recurrence within 10 years
i. Risk is higher within the first 6-12 months immediately following VTE
1. Acute VTE treatment does not affect rate of recurrence after three-
month duration of therapy
b. Patients with recurrent event are more likely to have same type of VTE
c. Independent predictors of recurrence
i. Patient age
ii. Body Mass Index (BMI)
iii. Male sex
iv. Active cancer
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v. Neurologic disease with leg paresis
vi. Idiopathic VTE
vii. Hypercoagulable disorders
1. Lupus anticoagulant
2. Antiphospholipid antibody syndrome
3. Deficiency in antithrombin, protein C, or protein S
4. Hyperhomocysteinemia
IV. Predictors of mortality8-11
a. PE associated with 18-fold higher risk of early death compared to DVT
b. Risk factors for reduced survival
i. Increasing age
ii. Male sex
iii. Lower BMI
iv. Confinement to a
hospital/nursing home
v. Heart failure
vi. Chronic lung disease
vii. Active cancer
c. The “Obesity Paradox”
i. Multiple studies have found decreased mortality among obese patients
compared to non-obese patients with VTE
ii. Proposed mechanism Activity of the endocannabinoid system in obese
patients
1. Decrease in ventricular arrhythmias
2. Coronary vasodilation
3. Protection from ischemia effects
4. Inhibition of cardiac myocyte and fibroblast death
5. Anti-inflammatory effects
Obesity in the United States of America
I. More than one-third of U.S. adults are obese12
II. Prevalence of self-reported obesity in adults in 201613
Figure 2. Prevalence of Obesity in America Heat Map
Source: https://www.cdc.gov/obesity/data/prevalence-maps.html
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III. Prevalence of self-reported obesity of Hispanic adults from 2014-201613
Figure 3. Prevalence of Obesity among Hispanic-Americans Heat Map
Source: https://www.cdc.gov/obesity/data/prevalence-maps.html
Treatment of VTE
I. Clotting cascade14
Figure 4. Clotting Cascade with Drug Targets
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Surgery Trauma Estrogen Therapy
Pregnancy/post-partum
Immobilization Cancer Hypercoagulable
disorders
II. Anticoagulants for VTE Treatment15-17
Table 2. Anticoagulants for the Treatment of VTE Drug Mechanism of Action Dose
Heparin Potentiates anti-thrombin III and prevents fibrinogen to fibrin conversion
80 U/kg bolus (max 10,000 U), initial infusion rate 18 U/kg/hr (max 2,000 U/hr), titrate based on protocol to heparin anti-FXa assay 0.3 – 0.7 U/mL
Fondaparinux Factor Xa inhibitor 5-10 mg SC QD
Enoxaparin Increases antithrombin III-mediated inhibition of Factor Xa
1 mg/kg SC BID or 1.5 mg/kg SC QD
Warfarin Vitamin-K antagonist 2-10 mg PO QD initially, titrate to INR goal 2.0-3.0
Dabigatran Direct thrombin inhibitor 150 mg PO BID after 5-10 days of parenteral anticoagulation
Rivaroxaban Factor Xa inhibitor 15 mg PO BID for 21 days, then 20 mg QD
Apixaban Factor Xa inhibitor 10 mg PO BID for 7 days, then 5 mg BID
Edoxaban Factor Xa inhibitor 60 mg PO QD after 5-10 days of parenteral anticoagulation
U = units; kg = kilogram; hr = hour; FXa = factor Xa; SC = subcutaneously ; QD = daily; BID = twice a day; INR = International Normalized Ratio;
III. Guideline Recommendations15
a. Treatment of proximal DVT or PE with a direct oral anticoagulant (DOAC) over warfarin
i. Grade 2B evidence
ii. Not selected first line in previous CHEST guidelines due to lack of extensive
literature on the DOACs
1. Most recent guidelines state that several Phase III trials and meta-
analyses prompted the selection of the DOACs as 1st line
b. Alternatively, warfarin is preferred over low-molecular weight heparin (LMWH)
i. No injections
ii. Less expensive
iii. Similar efficacy in non-cancer patients
c. Duration of therapy is based on if VTE was provoked or unprovoked
i. Provoked and transient 3 months
ii. Unprovoked “Extended therapy”
1. Indefinite duration of treatment
2. Anticoagulation may be discontinued based on high bleeding risk (> 2
risk factors)
iii. Provoking factors18
Figure 5. VTE Provoking Factors
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Use of Anticoagulants in Obesity I. Use of warfarin and enoxaparin in high body weight and obesity
Figure 6. Warfarin & Enoxaparin High Body Weight/ Obesity Considerations
II. Analysis of DOAC phase III sub-groups7,24
a. Two meta-analyses demonstrated no significant differences between obese/high body
weight patients versus normal body weight patients treated with a DOAC or warfarin
Table 3. Summary of Meta-analyses on Effects of Body Weight on VTE and Bleeding Study Di Minno MN, et al. 2015 Boonyawat K, et al. 2017
Study groups DOACs versus warfarin in high body weight patients with acute VTE
*High body weight defined by each randomized controlled trial (RCT)
High body weight (>100 kg) versus non-high body weight (60-100 kg) in patients on a DOAC
Thromboembolic events
6 RCTs 6 RCTs
DOAC group: 2.7% (75/2,732) High body weight group: 2.2% (105/4,858)
Warfarin group: 2.8% (76/2,714) Non-high body weight group: 2.7% (735/27,692)
RR, 0.98; 95% CI, 0.72-1.35; P = 0.92; I
2 = 0%
RR, 0.91; 95% CI, 0.57-1.47; P = 0.70; I
2 = 79%
Bleeding events 4 RCTs 5 RCTs
DOAC group: 6.7% (154/2,303) High body weight group: 6.5% (289/4,418)
Warfarin group: 7.1% (164/2,323) Non-high body weight group: 6.4% (1,638/25,683)
RR, 0.93; 95% CI, 0.65-1.32; P = 0.67; I
2 = 54%
RR, 1.03; 95% CI, 0.85-1.25; P = 0.78; I
2 = 51%
III. Guidance on use of DOACs in obese and high body weight patients15,25-29
Table 4. Guidance on DOACs in High Body Weight or Extremely Obese Prescribing Information
No dose adjustments recommended
CHEST Guidelines No mention of restrictions or dose adjustments
International Society on Thrombosis and Haemostasis (ISTH)
Suggest against DOAC use
Warfarin19-22
•Require larger weekly doses
•Longer time to therapeutic INR
•Potentially more bleeding
Enoxaparin23
•Dose based on actual body weight with no dose capping
•Twice daily dosing preferred
•Anti-factor Xa monitoring in patients >190 kg
•Peak level 4 hours post-dose
•1 mg/kg twice daily dosing: 0.6 – 1.0 IU/mL
•1.5 mg/kg daily dosing: 1.0 – 2.0 IU/mL
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a. ISTH suggest against use of the DOACs in patients > 120 kg or BMI > 40 kg/m2
i. Based on lack of clinical data in this patient population
ii. Phase III clinical trials had different weight or BMI cutoffs in sub-group analyses
iii. ISTH suggests checking drug-specific peak and trough levels of DOACs if initiated
in this patient population
iv. Graves et al. suggests the use of DOACs in this patient population if peak and
trough levels are within reported drug level ranges30
b. DOAC therapeutic drug monitoring (TDM)29,31
i. Routine monitoring is not required
ii. Lack of well-defined therapeutic ranges for DOAC drug levels
1. Drug levels display high variability depending on the dose, timing of lab
draw, and testing method
2. The most reliable method for quantifying DOAC drug levels is obtaining
drug concentrations by means of liquid chromatography tandem mass
spectrometry (LC-MS)
a. Complicated, expensive, and often unavailable
b. Accurate drug concentrations but may not reflect in vivo
anticoagulant activity
3. Studies evaluating DOAC plasma levels demonstrate significant overlap
among peak and trough levels
Figure 7. Reported Peak and Trough Plasma Concentrations
4. Reported drug levels in literature32-35
Table 5. Select Reported DOAC Plasma Concentrations Drug Patient Population Peak (ng/mL) Trough (ng/mL)
Dabigatran 150 mg BID
AF & VTE (n=35) 45 – 487 18 – 206
Rivaroxaban 20 mg QD
DVT (n=870) 189 – 419 6 – 87
Apixaban 5 mg BID
VTE (n=unknown) 59 – 302 22 – 177
Edoxaban 60 mg QD
AF (n=234) 120 – 150 10 – 40 BID=twice daily; AF=atrial fibrillation; VTE=venous thromboembolism; QD=daily; DVT=deep vein thrombosis
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iii. Additionally, there is no data or guidance on adjusting doses based on levels
iv. No published literature evaluating DOAC TDM impact on clinical outcomes
Clinical Question
Are DOACs an appropriate VTE treatment option in patients > 120 kg or BMI > 40 kg/m2?
Literature Review
I. Edoxaban36
a. Only data available for use in obesity is in a sub-group analysis of the Hokusai VTE trial
i. No significant differences in patients > 100 kg comparing edoxaban to warfarin
for VTE recurrence
1. Edoxaban: 3.6% (22/611)
2. Warfarin: 3.5% (23/654)
II. Dabigatran37,38
a. Breuer L, et al. N Engl J Med. 2013
Table 6. Dabigatran Case Report #1 Patient Demographics Treatment Regimen Outcomes
48-year-old male, 153 kg BMI: 44.7 kg/m
2
CrCl: 163 mL/min PMH: HTN, CHF, AF
Dabigatran 150 mg BID for 4 weeks with reported adherence
Presents with ischemic stroke Dabigatran plasma concentrations showed poor PK parameters.
Cmax: 50 ng/mL
Cmin: 0 ng/mL
b. Rafferty JA, et al. Ann Pharmacother. 2013
Table 7. Dabigatran Case Report #2 Patient Demographics Treatment Regimen Outcomes
69-year-old female, 135 kg BMI: 48.3 kg/m
2
CrCl: 125 mL/min PMH: HTN, CAD, AF, T2DM, hypothyroidism, GERD, HLD, COPD, OSA
Dabigatran 150 mg BID for 6 years with adherence confirmed by outpatient pharmacy
Presents with bilateral PE Patient switched to warfarin with enoxaparin bridge
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III. Apixaban39
a. Upreti VV, et al. Br J Clin Pharmacol. 2013
Table 8. Apixaban PK/PD Study
Purpose Assess effects of extremes of body weight on the pharmacokinetics of apixaban
Assess effect of apixaban on anti-factor Xa activity and evaluate safety and tolerability
Design Open label, single dose, parallel group pharmacokinetic/pharmacodynamic study
Patient Population
Inclusion criteria
Healthy subjects
18-45 years of age
Exclusion criteria
Patients with BMI < 30 kg/m2 in the
high body
weight group (> 120 kg)
Patients with BMI > 30 kg/m2 in the low or normal
body weight group (< 50 kg and 65 – 85 kg, respectively)
Pregnant
Illness/injury associated with increased bleeding risk
GI disease or surgery that could alter absorption
Acid reducing agents within 4 weeks of dose
Groups 1. < 50 kg (low body weight) 2. 65 – 85 kg (reference body weight) 3. > 120 kg (high body weight)
Outcomes Primary outcomes Pharmacokinetic parameters:
Maximum plasma concentration (Cmax)
Area under curve (AUC)
Time to maximum plasma concentration (tmax)
Terminal half-life
Apparent volume of distribution (Vd)
Apparent total body clearance
Renal clearance
Secondary outcomes Pharmacodynamic parameters:
Anti-factor Xa activity at 3 hours and 12 hours
Subject-reported or observed adverse events
Methods Single dose of apixaban 10 mg
Plasma concentrations measured at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours post-dose
Anti-factor Xa activity was measured prior to dosing and at 3, 12, and 24 hours post-dose
Anti-factor Xa assay results reported as activity units of low molecular weight heparin
Plasma samples quantitatively assessed with mass spectrometry
Assessed subject-reported or directly observed adverse events and vital signs or laboratory assessments for safety and tolerability
Statistics Geometric means and coefficients of variation (CV) were reported for Cmax, AUC, Vd, total body clearance, and renal clearance
Calculated 18 patients per group to provide 90% confidence that estimated geometric means ratios would be within 19% of true value for Cmax and within 18% of true value for AUC
Point estimates and 90% confidence intervals were calculated to compare Cmax and AUC
Log-linear regression analysis conducted for Cmax and AUC by body weight and BMI
Scatter plot of anti-factor Xa activity versus apixaban concentration constructed across weight groups
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Results
Baseline characteristics
Patients were in mid to late 20s, white, and majority male in high body weight group
High body weight group o Mean body weight (range): 137 kg (120-175 kg) o Mean BMI (range): 42.6 kg/m
2 (32-54 kg/m
2)
n = 53
PK/PD Parameter Reference body weight (65-85 kg)
(n=16)
High body weight (> 120 kg)
(n=19)
Geometric mean ratio; 90% CI
Cmax (CV) 207 ng/mL (24) 144 ng/mL (28) 0.692; 0.586 – 0.818
AUC (CV) 2024 ng/mL*h (24) 1561 ng/mL*h (31) 0.771; 0.652 – 0.912
Median tmax (range) 3.03 hrs (2.0-6.0) 3.98 hrs (1.0-6.0) N/A
Mean half-life (SD) 12 hrs (5.35) 8.8 hrs (3.15) N/A
Apparent Vd (CV) 61 L (22) 75.6 L (28) N/A
Renal clearance (CV) 12.6 mL/min (45) 17.8 mL/min (42) N/A
Apparent total body clearance (CV)
82.3 mL/min (19) 106.8 mL/min (35) N/A
Mean anti-factor Xa activity 3 hrs post-
dose (SD)
2.79 IU/mL (0.85) 1.85 IU/mL (0.74) N/A
Mean anti-factor Xa activity 12 hrs post-
dose (SD)
0.77 IU/mL (0.17) 0.70 IU/mL (0.29) N/A
Anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentrations o Regardless of body weight
14 reported adverse events o Most common were headache and nausea o One episode of epistaxis reported on day 2 from a patient in the middle body weight group
Author’s Conclusions
Effects of extremes of body weight on apixaban exposure are considered modest and unlikely to be clinically meaningful
Reviewer’s Critique
Strengths Measured PD parameters
Correlated anti-factor Xa activity to plasma concentration
High body weight group defined as > 120 kg with a BMI > 30 kg/m2
Limitations Small, healthy population
Single dose of apixaban
Did not analyze many of the PK/PD parameters
Did not assess clinical outcomes
Study sponsored by Bristol-Myers Squibb and Pfizer
Take Home Points
Apixaban exposure was significantly decreased among high body weight patients
Clinical implications of this cannot be evaluated without clinical outcomes data
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IV. Rivaroxaban40-42
a. Safouris A, et al. J Neurol Sci. 2014
Table 9. Rivaroxaban Case Report Patient Demographics Treatment Regimen Outcomes
67-year-old male, 124 kg BMI: 39.6 kg/m
2
CrCl: 132 mL/min PMH: Non-valvular AF Presents with ischemic stroke
Started on dabigatran 150 mg BID Switched to rivaroxaban 20 mg daily
Dabigatran plasma concentrations lower than previously reported
Cmax: 70 ng/mL
Cmin: 30 ng/mL
Rivaroxaban plasma concentrations within previously reported range
Cmax: 200 ng/mL
Cmin: 30 ng/mL
*No information given on patient’s clinical outcome
b. Kubitza D, et al. J Clin Pharmacol. 2007
Table 10. Rivaroxaban PK/PD Study
Purpose Investigate influence of extremely low and high body weight on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rivaroxaban in healthy patients
Design Single-center, randomized, single-blind, placebo-controlled, parallel group PK/PD study
Patient Population
Inclusion criteria
Healthy subjects
18-55 years of age
Exclusion criteria
Any known coagulation disorders
Any known conditions increasing bleeding risk
Groups 1. Low body weight: < 50 kg 2. Middle body weight: 70 to 80 kg 3. High body weight: > 120 kg
Outcomes Primary outcomes
AUC
Cmax
Secondary outcomes
AUC normalized to dose and body weight
Cmax normalized to dose and body weight
Tmax, half-life, Vd
PK parameters: anti-factor Xa activity (anti-FXa), prothrombin time (PT), activated partial thromboplastin time (aPTT)
Area under the effect-time curve from first to last reading (AUC0-tn)
Maximum PD effect of dose (Emax)
Safety and tolerability
Methods Single dose of rivaroxaban 10 mg administered with standardized breakfast
Subjective tolerability adverse events (AEs) questioning and subject-reported events
Objective tolerability investigator assessment of vital signs and labs
Blood samples drawn at 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 24, and 48 hours post-dose
Urine samples drawn at 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose
Rivaroxaban plasma concentrations determined by mass spectrometry
Statistics Weight and gender differences of AUC, Cmax, AUC0-tn, Emax, and PT prolongation assessed using ANOVA
Point estimates by least squares-means ratios (LS-MR) and 90% confidence intervals (CI) were calculated by retransformation of logarithmic data
Geometric means were reported with percentage coefficient of variation (%CV) for AUC, Cmax, half-life, Vd, Emax, and AUC0-tn
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Results Baseline characteristics
Subjects were in mid 30s with gender balanced middle body weight and high body weight groups
High body weight group o Mean weight: 132 kg o Mean BMI: 43.5 kg/m
2
n = 48
PK/PD Parameter Middle body weight (70-80 kg)
(n=12)
High body weight (> 120 kg)
(n=12)
LS-MR; 90% CI
AUC (%CV) 1029 mcg*h/L (20.1) 1155 mcg*h/L (15.6) NS
Cmax (%CV) 143.4 mcg/L (26.5) 149.0 mcg/L (20.4) NS
Median tmax (range) 3.5 hrs (1.0-4.0) 4.0 hrs (2.0-4.0) N/A
Half-life (%CV) 7.2 hrs (42.1) 7.3 hrs (25.4) N/A
Apparent Vd (CV) 1.36 L/kg (37.4) 0.69 L/kg (35.8) N/A
Emax of anti-FXa (CV) 45.8% (14.0) 41.7% (11.6) 0.91; 0.84 – 0.99
AUC0-tn of anti-FXa (CV)
484.4%*h (35.4) 548.0%*h (35.3) NS
Emax of PT prolongation (CV)
56.5% (22.4) 46.6% (18.7) 0.82; 0.72 – 0.94
AUC0-tn of PT prolongation (CV)
460.0%*h (29.7) 420.5%*h (24.5) NS
21 AE reported by 12 subjects o Fatigue, headache, nausea, and dizziness o Mild or moderate in intensity o No AEs related to bleeding were observed
Author’s Conclusions
Rivaroxaban PK/PD not influenced by body weight to an extent considered likely to be clinically relevant
Reviewer’s Critique
Strengths High body weight population defined as > 120 kg with a mean BMI of ~44 kg/m2
Analyzed anti-factor Xa activity
Limitations Small, healthy population
10 mg dose not target daily dose for venous thromboembolism treatment
Did not correlate anti-factor Xa activity to plasma concentrations
Did not assess clinical outcomes
All authors were employees of Bayer
Take Home Points
Body weight had no significant effects on pharmacokinetics but has slight effects on some pharmacodynamics parameters which are unlikely to be clinically relevant
c. Arachchillage D, et al. Thromb Res. 2016
Table 11. Rivaroxaban Clinical Trial
Purpose To assess the effect of extreme body weight (EBW) on rivaroxaban levels and clinical outcomes with standard dose of rivaroxaban in the treatment of venous thromboembolism (VTE).
Design Non-randomized, single-center, observational cohort study
Patient Population
Inclusion criteria
Diagnosed with DVT or PE
Taking rivaroxaban
Exclusion criteria
Weight missing in medical record
Rivaroxaban levels not taken within 2-4 hours after the last dose
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Intervention Rivaroxaban 15 mg twice daily for three weeks followed by 20 mg once daily
Groups 1. Low body weight: < 50 kg 2. Reference body weight: 50 – 120 kg 3. High body weight: > 120 kg
Outcomes Primary outcomes
Rivaroxaban drug levels (taken 2-4 hrs post-dose)
Secondary outcomes
Recurrent VTE
Bleeding episodes
Prothrombin ratio (PTR)
Activated partial thromboplastin time (aPTT) ratio
Methods N = 219 patients with VTE
Rivaroxaban concentrations were measured 2-4 hours post-dose over a 15 month period
Bleeding episodes and recurrent VTE rates collected from VTE database, case notes, and electronic records during 12-18-month follow-up period
Patients had received rivaroxaban 20 mg daily for > 1 week before blood samples taken
Major bleeding events defined per ISTH criteria
Statistics Results reported as median or mean based on distribution with 95% confidence intervals
Multiple group comparisons performed using Kruskal-Wallis ANOVA and paired comparisons using Mann-Whitney U test after adjusting p-values by Bonferroni correction.
Fisher’s exact test used to study associations
Results Baseline characteristics
Patients were >50 years old, mostly male, with predominance of deep vein thrombosis
150/167 patients received rivaroxaban during entire follow-up period
Overall 39/167 (23.4%) of patients had BMI > 40 kg/m2 and 44/167 (26.4%) were >120 kg
n = 167
Outcomes Reference Body Weight
(50-120 kg) (n = 105)
High Body Weight (>120 kg) (n = 44)
p-value
Rivaroxaban plasma concentrations, median (95% CI)
308 ng/mL (308-381)
281 ng/mL (242-327)
p = 0.21
Recurrent VTE, n/N (%) 4/105 (3.8%) 1/44 (2.3%) Not sufficiently powered
Major bleeding events, n/N (%) 2/105 (1.9%) 0/44 (0%) Not sufficiently powered
PTR, mean (95% CI) 1.20 (1.15-1.24) 1.19 (1.15-1.23) p = 0.82
aPTT ratio, mean (95% CI) 1.35 (1.31-1.51) 1.29 (1.23-1.48) p = 0.45
Author’s Conclusion
Study is encouraging for the use of standard rivaroxaban in patients > 120 kg or BMI > 40 kg/m2
Reviewer’s Critique Strengths Analyzed rivaroxaban, PTR, and aPTT to evaluate PK/PD parameters
High rate of patient adherence throughout entire follow-up period
Allowed at least 1 week on 20 mg daily dose before analysis in order to ensure achieved steady-state
Limitations Small cohort sizes
Not sufficiently powered to analyze VTE recurrence or major bleeding events
No clinical description or assessment of VTE recurrence
Reviewer’s Conclusions
Promising for use of rivaroxaban in high body weight or extremely obese patients
Small cohort size limits the confidence in safety and efficacy of rivaroxaban in these patients
Further larger scale studies are required before recommending in this patient population
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Summary & Recommendations
I. DOACs should not be used in patients > 120 kg or BMI > 40 kg/m2
II. If a DOAC must be used
a. Choose rivaroxaban only for provoked treatment duration (i.e. 3 months)
III. If available, conduct therapeutic drug monitoring
a. Utilize mass spectrometry to obtain peak concentration 2-4 hours post-dose
i. Verify if within reported plasma concentration ranges
b. If mass spectrometry unavailable, utilize anti-FXa assay calibrated to rivaroxaban
i. Correlate to plasma concentrations
ii. Verify if within reported plasma concentration ranges
Edoxaban
•Insufficient data in patient population in question
Dabigatran
•1 case report with poor plasma concentration
•1 case report with clinical failure
•1 case report with poor plasma concentration + clinical failure
Apixaban
•1 PK/PD study showing diminished AUC and Cmax
Rivaroxaban
•1 case report showing favorable plasma concentrations
•1 PK/PD study showing no significant differences
•1 observational study showing one recurrent VTE, but not sufficiently powered
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Appendix A: Nomenclature31
DOACs = Direct oral anticoagulants
NOACs = New/novel oral anticoagulants OR Non-vitamin K antagonist oral anticoagulants
TSOACs = Target specific oral anticoagulants
DSOACs = Direct specific oral anticoagulants
Appendix B. Risk factors for bleeding with anticoagulant therapy15
Risk factors
Age > 65 years
Age > 75 years
Previous bleeding
Cancer
Renal failure
Liver failure
Thrombocytopenia
Previous stroke
Diabetes
Anemia
Antiplatelet therapy
Poor anticoagulant control
Comorbidity and reduced functional capacity
Recent surgery
Frequent falls
Alcohol abuse
Nonsteroidal anti-inflammatory drugs
Appendix C: Summary of DOAC Phase III VTE trials43
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Appendix D: Weight and BMI cutoffs in Phase III sub-groups analyses29
Appendix E. Common coagulation tests for DOACs31
PT = Prothrombin time; APTT = activated partial thromboplastin assay; TT = thrombin time; dRVVT = dilue Russell viper venom time; dTT = dilute thrombin time;
DTI = direct thrombin inhibitor; ECT = ecarin clotting time; ECA = ecarin chromogenic assay; PICT = prothrombinase-induced clotting time
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