Weighing the Options for Anticoagulation in ObesityCaitlin S. Brown, PharmD

Pharmacy Grand RoundsMay 24, 2016

Objectives• Review pharmacokinetic changes in obesity

• Discuss dosing and monitoring strategies when using low molecular weight heparin

• Outline evidence and recommendations for utilization of direct oral anticoagulants

Overweight Adults in the United States

69%

31%

BMI ≥ 25kg/m2 BMI < 25kg/m2

Ogden CL, et al. JAMA. 2014;311:806-814.Overweight & Obesity. CDC. http://www.cdc.gov/obesity/. BMI = Body mass index

Obese Adults in the United States

35%

65%

BMI ≥30kg/m2 BMI <30kg/m2

Ogden CL, et al. JAMA. 2014;311:806-814.

1 in 3 adults you take care of will be obese

Overweight & Obesity. CDC. http://www.cdc.gov/obesity/.

What Will Obesity in the U.S. Be In The Future?

32%37%

41%46%

51%

0%

10%

20%

30%

40%

50%

60%

2010 2015 2020 2025 2030

Obe

se In

divi

dual

s

Year

Finkelstein EA, et al. Am J Prev Med. 2012;42:563-570.

Pharmacokinetics in Obesity

Volume of Distribution

(Vd)

Elimination Half-Life

(T1/2)

Clearance(CL)

Drugs with High Vd

60kg patient

130kg patient

Intravascular Extravascular

Fat

Fat

Vd = Volume of distribution

Drugs with Low Vd

60kg patient

130kg patient

Intravascular Extravascular

Fat

Fat

Clearance• Defined as the volume of blood cleared of drug

in a given time

• In obese patients:• Altered hepatic blood flow• Higher absolute clearance

Hanley MJ, et al. Clin Pharmacokinet. 2010;49:71-87.

Elimination Half-Life• Defined as time it takes for concentration to fall

to half its original concentration

Hanley MJ, et al. Clin Pharmacokinet. 2010;49:71-87.

T½ = (ln 2 x Vd) / CL

CL = Clearance

Which of the following statements is true?A. Obese and non-obese patients have similar

PK profilesB. Vd is increased in obese patientsC. T1/2 is equivalent in obese and non-obese

patientsD. Compared to non-obese patients, obese

patients have equivalent CL

Venous Thromboembolism Prophylaxis

What Does the Package Insert Say?

Indication eCrCl ≥ 30mL/min eCrCl < 30mL/min

Prophylaxis of VTE 40mg daily 30mg daily

Treatment of VTE 1mg/kg Q12H 1mg/kg daily

Enoxaparin [package insert]. Sanofi-adventis. 2013.

“The safety and efficacy of prophylactic doses of Lovenox in obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for

dose adjustment”

VTE = Venous thromboembolism

VTE Prophylaxis in Obesity• Standard fixed prophylactic doses suboptimal

• Relationship between BMI and thrombosis

Garcia-Raso A, et al. Epidemiology reports. 2014: 1-8. Wolberg AS, et al. Anesth Analog. 2012;114:275-285.

Pringler U, et al. Crit Care Med. 2003;5:1405-1409.

Stasis of Blood Flow

HypercoagulabilityVessel Wall Injury

Virchow’s Triad

Samama MM, et al. Thromb Haemost. 1995;73:977-986.

Unfractionated Heparin and Low Molecular Weight Heparin for VTE Prophylaxis

Wang TF, et al. Thrombosis and Haemostasis. 2014;111:88-93.

Study Design Retrospective cohort study at 3 hospitals

Population Adult obese (> 100kg) inpatients (> 48 hours) who received thromboprophylaxis with UFH or enoxaparin

InterventionStandard - UFH 5,000 units BID/TID or enoxaparin 40mg daily vsHigh-dose - UFH 7,500 units TID or enoxaparin 40mg BID

PrimaryEndpoint Rates of VTE in the standard vs high-dose groups

SecondaryEndpoints

-VTE rates stratified by BMI-Hemorrhage

UFH = Unfractionated heparin

Did High-Dose Prophylaxis Reduce VTE?

1.5%

0.8%

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

1.6%

Standard High-dose

Rat

es o

f VTE

Dosing Regimen

p = 0.05

Wang TF, et al. Thrombosis and Haemostasis. 2014;111:88-93.

Did High-Dose Prophylaxis Increase Hemorrhage?

8.4%

7.2%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

9.0%

10.0%

Standard High-Dose

Rat

es o

f Hem

orrh

age

Dosing Regimen

Wang TF, et al. Thrombosis and Haemostasis. 2014;111:88-93.

p = 0.15

VTE Prophylaxis RecommendationsWeight ≥ 100kg

And/orBMI ≥ 40 kg/m2

eCrCl < 30mL/min eCrCl ≥ 30mL/min

Heparin 7,500 units TID

Enoxaparin 40mg BID

Heparin 7,500 units TID

Treatment Dosing of Low Molecular Weight Heparin

46F admitted with unilateral LLE swelling and redness, found to have a DVT on ultrasound. Initiated on enoxaparin for bridging to warfarin treatment.

LLE = Left lower extremity DVT = Deep vein thrombosiseCrCl = Estimated creatinine clearance

Hgb:11g/dLPlatelets: 368 x 109 LINR: 1.2 Wt: 200 kgBMI: 39.1 kg/m2

eCrCl = 96 mL/min

Which dosing strategy would you chose for this patient?

200kg, eCrCl=96mL/min

A. 150mg BIDB. 150mg BID and check anti-XaC. 200mg BIDD. 200mg BID and check anti-Xa

Anti-Xa Monitoring• Peak levels drawn 3 – 5 hours after steady

state

• LMWH therapeutic range• 0.5 – 1.00 IU/mL for BID dosing• 1.00 – 2.00 IU/mL for once daily dosing

• Low antithrombin III (AT III) levels can decrease the efficacy of heparins

Heparin Anti-Xa Assay. Mayo Medical Laboratories. Accessed May 18, 2016.Houbouyan L, et al. Clin Chem. 1996;42:1223-1230.

Pharmacokinetics of Enoxaparin

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

0 2 4 6 8 10 12 14 16 18 20 22 24

Ant

i-Xa

Act

ivity

(IU

/mL)

Time (hours)

Obese Non-Obese

Sanderink GJ, et al. Clinical Pharmacology & Therapeutics. 2002;72:308-317.

VTE Treatment Dosing with Enoxaparin

Deal EN, et al. J Thromb Thrombolysis. 2011;32:188-194.

Study Design Retrospective case series

Population

Received enoxaparin with a corresponding anti-Xa and BMI ≥40kg/m2

• 26 patients• Median weight 162kg (58% > 150kg)• 27% ICU patients

PrimaryEndpoint Achievement of goal anti-Xa level (0.5-1 IU/mL)

SecondaryEndpoints Bleeding events

Anti-Xa Levels

15%

46%

38%

0%5%

10%15%20%25%30%35%40%45%50%

Perc

enta

ge o

f Pat

ient

s

Anti-Xa Level

• No patient had subtherapeutic levels

• No thrombotic events occurred in the study

• 40% of patients with a supratherapeutic level had bleeding events

• Median starting dose was 0.8mg/kg

• Doses ranged from 80mg – 150mg BID

Deal EN, et al. J Thromb Thrombolysis. 2011;32:188-194.

Enoxaparin AlgorithmWeight ≥ 100kg

and/orBMI ≥ 40 kg/m2

eCrCl<30mL/min eCrCl>30mL/min

1mg/kg Q24HMax: 150mg

0.8mg/kg Q12HMax: 150mg

Check anti-Xa 3-5 hours after 4th dose

46F admitted with unilateral LLE swelling and redness, found to have a DVT on ultrasound. Initiated on enoxaparin for bridging to warfarin treatment.

Hgb:11g/dLPlatelets: 368 x 109 LINR: 1.2 Wt: 200 kgBMI: 39.1 kg/m2

eCrCl = 96 mL/min

Which dosing strategy would you chose for this patient?

200kg, eCrCl=96mL/min

A. 150mg BIDB. 150mg BID and check anti-XaC. 200mg BIDD. 200mg BID and check anti-Xa

Direct Oral Anticoagulants (DOACS)

Pharmacokinetics

Dabigatran Rivaroxaban ApixibanVolume of Distribution 60-70 L 50L 20-70L

Protein Binding 35% >90% 87%

Patel JP, et al. British Journal of Haematology. 2011;155:137-149.

Obese Patients in Dabigatran StudiesStudy Intervention Weight

(kg) BMI* Number (%)≥100kg

RE-LYAtrial Fibrillation

Dabigatran110mg BID

Dabigatran150mg BID

Warfarin

82.0±19.9*

82.5±19.4*

82.7±19.7*

N/A 3,099 patients(17%)

RE-COVERVTE

Heparin/ dabigatran150mg BID

Heparin/warfarin

84 (38-175)**

82 (39-161)**

28.9±5.7

28.4±5.5

438 patients (17.1%)

394 patients(15.4%)

RE-COVER IIVTE

Heparin/ dabigatran150mg BID

Heparin/warfarin

80 (36-184)**

81 (35-210)**

28.4±5.8

28.4±5.8

Guler E, et al. Anatol J Cardiol. 2015;15:1020-1029.Connolly SJ et al. NEJM. 2009;361:1139-1151Schulman S et al. NEJM. 2009;361:2342-2352.*mean±standard deviation

**median (range)

Di Minno MND et al. Ann Med. 2015;47:61-68.

Dabigatran• RE-LY subgroup analysis

• Case reports of stroke in obese patients • 153kg (BMI 44.7kg/m2) peak level was less

than the 25th percentile of therapeutic trough

Guler E, et al. Anatol J Cardiol. 2015;15:1020-1029.Bruer L, et al. NEJM. 2013;25:2440-2442.

Connolly SJ et al. NEJM. 2009;361:1139-1151.

Dabigatran Pharmacokinetics in Obesity

020406080

100120140160180200220240260280

8 a.m. 10 a.m. Noon 2 p.m. 4 p.m. 6 p.m. 8 p.m.

Plas

ma

Leve

l of D

abig

atra

n (n

g/m

L)

Daytime Hours

Obese Patients in Rivaroxaban Studies

Study Intervention BMI* Number (%) >90kg

ROCKET-AFAtrial Fibrillation

Rivaroxaban 20mg daily

Warfarin

28.3 (25-32)

28.1 (25-32)N/A

EINSTEIN-DVT

Rivaroxaban 15mg BID 20mg daily

Enoxaparin 1.0mg/kg warfarin

N/A

491 patients(28.4%)

486 patients(28.3%)

EINSTEIN-PE

Rivaroxaban 15mg BID 20mg daily

Enoxaparin 1.0mg/kg warfarin

N/A

683 patients(28.2%)

672 patients(27.8%)

Guler E, et al. Anatol J Cardiol. 2015;15:1020-1029.Patel MR, et al. NEJM. 2011;365:883-891.

Buller HR, et al. NEJM. 2011;366:1287-1297.Bauersachs R, et al. NEJM. 2010;363:2499-2510.

Di Minno MND et al. Ann Med. 2015;47:61-68.

*median (interquartile range)

Rivaroxaban• Post-hoc analysis comparing stroke outcomes

in normal weight, overweight, and obese patients with AF

• 5,206 patients in the obese group

AF = Atrial fibrillationCI = Confidence interval Balla, SR, et al. Arrhythmias and Clinical EP. Poster Presentation Number: 1180-92.

Hazard Ratio 95% CI p value

Overweight 0.77 0.62-0.95 0.013

Obese 0.62 0.50-0.78 <0.001

Obese Patients in Apixaban Trials

Guler E, et al. Anatol J Cardiol. 2015;15:1020-1029.

Study Intervention Weight(kg)* BMI*

Number (%) of ObesePatients

ARISTOLEAtrial

Fibrillation

Apixaban5mg BID

Warfarin

N/A

28±5

28±5

BMI ≥30kg/m2

7,159 patients(40%)

AMPLIFYVTE

Apixaban 10mg BID 5mg BID

Enoxaparin warfarin

84.6±19.8

84.6±19.8

N/A

≥100kg522 patients

(19.4%)

≥100kg518 patients

(19.2%)

Agnelli G, et al. NEJM. 2013;369:799-808.Granger CB, et al. NEJM. 2011;365:981-992.

*Mean±standard deviation Sadhu RK, et al. European Heart Journal. 2016; 1-10.

ARISTOTLESubgroup Analysis Based on BMI

2%

5.5%

3.4%

1.4%

3.4%

2.4%

1.5%

2.9%

2.3%

0%

1%

2%

3%

4%

5%

6%

Stroke/SE Death Major Bleeding

Even

ts p

er y

ear

18.5-25 kg/m2 25-30 kg/m2 ≥30 kg/m2

p < 0.0001

SE = Systemic embolism Sadhu RK, et al. European Heart Journal. 2016; 1-10.

How Does Apixaban Compare to Warfarin in Obese Patients with Atrial Fibrillation?

0.5 1 2 3

OutcomeBMI ≥30kg/m2

Hazard Ratio(95% CI)

Stroke/SE 0.76 (0.55-1.05)

Death 0.81 (0.67-0.99)

Major Bleeding 0.84 (0.67-1.07)

Favors Apixaban Favors WarfarinSadhu RK, et al. European Heart Journal. 2016; 1-10.

DOACS for VTE

DOAC vs Warfarin for VTE

0.2 0.5 1 52

Favors DOACs WarfarinDi Minno MND et al. Ann Med. 2015;47:61-68.

Study Risk Ratio (95% CI)

RE-COVER I&II 1.16 (0.58, 2.29)

EINSTEIN-DVT 0.99 (0.43, 2.26)

EINSTEIN-PE 1.28 (0.56, 2.90)

AMPLIFY 0.61 (0.29, 1.28)

Total 0.98 (0.72, 1.35)

DOACs Recommendations in Obesity• Avoid dabigatran in obese patients

• Rivaroxaban may be considered in obese patients

• Apixaban has the best evidence for utilization of DOACs in obese patients

In a post-hoc analysis comparing apixaban vs warfarin in obese patients (BMI≥30kg/m2) with atrial fibrillation warfarin prevented more strokes and systemic embolism?A. TrueB. False

Summary• Evaluate pharmacokinetics when dosing medications in

obese patients

• For VTE prophylaxis “high-dose” heparin or LMWH is recommended for patients ≥100kg and BMI ≥40kg/m2

• For VTE treatment dose adjustments are warranted and anti-Xa levels should be monitored

• Apixiban may be considered for anticoagulation in obese patients

Questions & Discussion

Dose Capping with Unfractionated Heparin• NSTEMI

• Obese patients took longer to reach goal aPTT

• No dose cap • Higher doses achieves therapeutic

anticoagulation more rapidly

• VTE• Weight-based nomograms with no cap• Studies have shown relationship between

patients’ weight and heparin requirement

Joncas, SX, et al. Obesity Journal. 2013;21:1753-1758.Patel JP, et al. BJH. 2011;155:137-149.

Fondaparinux• Vd = 8.2L

• Largely resides in the intravascular space• >94% protein bound

• Treatment of VTE based on the MATISSE trials• 10mg if >100kg

Patel JP, et al. British Journal of Haematology. 2011;155:137-149.Fondaparinux [package insert]. GlaxoSmithKline. 2001.

Anti-Xa Monitoring Cost• Mayo Clinic Hospital – Rochester

• $207.50

• Vancomycin trough level cost $150.00

Anti-Xa Dose AdjustmentsAnti-Xa Level

(U/mL) Hold Next Dose Dosage Change Next Anti-Xa Level

<0.35 No Increase by 25% 4 hour after next dose

0.35-0.49 No Increase by 10% 4 hour after next dose

0.5-1.0 No NoNext day, then weekly, then

monthly

1.1-1.5 No Decrease by 20% Before next dose

1.6-2.0 3 hours Decrease by 30%Before next dose and 4 hour after

next dose

>2.0 Until anti-Xa <0.5 Decrease by 40%Before next dose and 4h after next

dose

Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

ARISTOTLESubgroup Analysis Based on BMI

2%

5.1%

2.2%

1.4%

3.4%

2%

1%

2.6%2.1%

1.3%

3.2%

2.5%

0%

1%

2%

3%

4%

5%

6%

Stroke/SE Death Major Bleeding

Even

ts p

er y

ear

18.5-25 kg/m2 25-30 kg/m2 ≥30 kg/m2 WarfarinSE = Systemic embolism Sadhu RK, et al. European Heart Journal. 2016; 1-10.