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Does Obesity affect AntiCoagulation? Weighing in on DOACs for VTE treatment in obesity

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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

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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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References:

1. Freedman JE, Loscalzo J. Arterial and Venous Thrombosis. In: Kasper D, Fauci A, Hauser S, Longo D,

Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill;

2014. http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu. Accessed September 13, 2017.

2. Centers for Disease Control and Prevention. Venous Thromboembolism in Adult Hospitalizations—United

States, 2007–2009. MMWR. 2012;61(22):401-422.

3. Centers for Disease Control and Prevention. Venous thromboembolism (blood clots). Web page.

https://www.cdc.gov/ncbddd/dvt/facts.html. Accessed October 7, 2017.

4. Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis.

2016;41:3-14.

5. Barsoum MK, Heit JA, Ashrani AA. Is progestin an independent risk factor for incident venous

thromboembolism? A population-based case-control study. Thromb Res. 2010;126:373-8.

6. Ageno W, Becattini C, Brighton T, et al. Cardiovascular risk factors and venous thromboembolism: a meta-

analysis. Circulation. 2008;117(1):93-102.

7. Di Minno MN, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral

anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of

randomized controlled trials. Ann Med. 2015;47(1):61-8.

8. Yang G, De Staercke C, Hooper WC. The effects of obesity on venous thromboembolism: a review. Open J

Prev Med. 2012;2(4):499-509.

9. El-Menyar A, Asim M, Al-Thani H. Obesity Paradox in Patients With Deep Venous Thrombosis. Clin Appl

Thromb Hemost. 2017; doi: 10.1177/1076029617727858. [Epub ahead of print]

10. Stein PD, Matta F, Goldman J. Obesity and pulmonary embolism: the mounting evidence of risk and the

mortality paradox. Thromb Res. 2011;128(6):518-23.

11. Barba R, Zapatero A, Losa JE, et al. Body mass index and mortality in patients with acute venous

thromboembolism: findings from the RIETE registry. J Thromb Haemost. 2008;6(4):595-600.

12. Centers for Disease Control and Prevention. Overweight & Obesity: Adult Obesity Facts. Web page.

https://www.cdc.gov/obesity/data/adult.html. Accessed September 4, 2017.

13. Centers for Disease Control and Prevention. Overweight & Obesity: Adult Obesity Prevalence Maps. Web

page. https://www.cdc.gov/obesity/data/prevalence-maps.html. Accessed September 4, 2017.

14. Melnikova I. The anticoagulants market. Nat Rev Drug Discov. 2009;8(5):353-4.

15. Kearon C, Akl EA, Ornelas J, et al. Anthithrombotic therapy for VTE disease: CHEST guideline and expert

panel report. CHEST. 2016;149(2):315-352.

16. Facts & Comparisons® [database online]. Hudson, OH: Lexi-Comp, Inc.; 2016. Available at: https://fco-

factsandcomparisons-com.ezproxy.lib.utexas.edu. Accessed October 7, 2017.

17. DRUGDEX® System [database online]. Greenwood Village, CO: Truven Health Analytics LLC; 2017.

Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed October 7, 2017.

18. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous

thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med.

2010;170(19):1710-6.

19. Mueller JA, Patel T, Halawa A, et al. Warfarin dosing and body mass index. Ann Pharmacother.

2014;48(5):584-8.

20. Wallace JL, Reaves AB, Tolley EA, et al. Comparison of initial warfarin response in obese patients versus

non-obese patients. J Thromb Thrombolysis. 2013;36(1):96-101.

21. Ogunsua AA, Touray S, Lui JK, et al. Body mass index predicts major bleeding risks in patients on warfarin.

J Thromb Thrombolysis. 2015;40(4):494-8.

Perales Page | 18

22. Hart R, Veenstra DL, Boudreau DM, et al. Impact of Body Mass Index and Genetics on Warfarin Major

Bleeding Outcomes in a Community Setting. Am J Med. 2017;130(2):222-228.

23. Nutescu EA, Spinler SA, Wittkowsky A, et al. Low-molecular-weight heparins in renal impairment and

obesity: available evidence and clinical practice recommendations across medical and surgical settings.

Ann Pharmacother. 2009;43(6):1064-83.

24. Boonyawat K, Caron F, Li A, et al. Association of body weight with efficacy and safety outcomes in phase III

randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis. J

Thromb Haemost. 2017;15:1322-33.

25. Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2015.

26. Xarelto® [package insert]. Leverkusen, Germany: Bayer Pharma AG; 2011.

27. Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2012.

28. Savaysa®[package insert]. Tokyo, Japan: Daiichi Sankyo Co; 2015.

29. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients:

guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14:1308-13.

30. Graves KK, Edholm K, Johnson SA. Use of oral anticoagulants in obese patients. JSM Atheroscler.

2017;2(4):e1035.

31. Favaloro EJ, Pasalic L, Curnow J, et al. Laboratory monitoring or measurement of direct oral anticoagulants

(DOACs): advantages, limitations and future challenges. Curr Drug Metab. 2017;18(7):598-608.

32. Hawes EM, Deal AM, Funk-Adcock D, et al. Performance of coagulation tests in patients on therapeutic

doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J

Thromb Haemost. 2013;11(8):1493-502.

33. Mueck W, Stampfuss J, Kubitza D, et al. Clinical pharmacokinetic and pharmacodynamic profile of

rivaroxaban. Clin Pharmacokinet. 2014;53(1):1-16.

34. ELIQUIS® [product monograph]. Montreal, Canada: Bristol-Myers Squibb Canada; 2016.

35. Weitz JI, Connolly SJ, Patel I, et al. Randomised, parallel-group, multicentre, multinational phase 2 study

comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial

fibrillation. Thromb Haemost. 2010;104(3):633-41.

36. Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous

thromboembolism. N Engl J Med. 2013;369(15):1406-15.

37. Breuer L, Ringwald J, Schwab S, et al. Ischemic stroke in an obese patient receiving dabigatran. N Engl J

Med. 2013;368(25):2440-2.

38. Rafferty JA, Prom R, Kujawski SZ. Acute pulmonary emboli in a patient on long-term dabigatran therapy.

Ann Pharmacother. 2013;47(4):e20.

39. Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics,

pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol.

2013;76(6):908-16.

40. Safouris A, Demulder A, Triantafyllou N, et al. Rivaroxaban presents a better pharmacokinetic profile than

dabigatran in an obese non-diabetic stroke patient. J Neurol Sci. 2014;346(1-2):366-7.

41. Kubitza D, Becka M, Zuehlsdorf M, et al. Body weight has limited influence on the safety, tolerability,

pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin

Pharmacol. 2007;47(2):218-26.

42. Arachchillage D, Reynolds R, Devey T, et al. Effect of extremes of body weight on drug level in patient

treated with standard dose of rivaroxaban for venous thromboembolism; real life experience. Thromb

Res. 2016;147:32-35.

43. Hillis C, Crowther MA. Acute phase treatment of VTE: Anticoagulation, including non-vitamin K antagonist

oral anticoagulants. Thromb Haemost. 2015;113(6):1193-202

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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