Comparing Efficacy and Safety of DOACs used for Prevention

Comparing Efficacy and Safety of DOACs used for Prevention of VTE or Stroke in Patients with Morbid Obesity versus Patients within Studied Weight Limits: a single-center, retrospective cohort study

Nguyet Nguyen, Pharm.D., PGY-1 Pharmacy ResidentKansas City VA Medical Center

JUNE 2020

VETERANS HEALTH ADMINISTRATION

Disclosure

The speaker has no actual or potential conflicts of interests in relation to this presentation

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Abbreviations

• ACC: American College of Cardiology• A. Fib: atrial fibrillation• AHA: American Heart Association• CDC: Centers for Disease Control and

Prevention• CHEST: American College of Chest

Physicians• CPRS (Computerized Patient Record

System)• CVDs: cardiovascular diseases• DOAC: direct oral anticoagulants• DVT: deep vein thrombosis• HRS: Heart Rhythm Society

• ISTH: International Society on Thrombosis and Haemostasis

• PE: pulmonary embolism• PK: pharmacokinetics• PD: pharmacodynamics• VTE: venous thromboembolism

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Objective

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• Discuss the efficacy and safety of direct oral anticoagulants (DOACs) use in morbidly obese patients


Background

• Cardiovascular diseases are the leading cause of death worldwide1

– Includes DVT, PE and arrhythmias

• In the United States, approximately 795,000 people will experience a stroke and ~140,000 people will die from a stroke per year3

– Atrial fibrillation, most common type of arrythmia, can lead to stroke

• CDC estimates that ~900,000 people in the United States will experience a DVT or PE per year and 10-30% of those patients will die within 1 month of diagnosis2

• Obesity affects over 90 million people in the United States and is associated with a higher risk of developing atrial fibrillation, stroke, and VTE4

41. Cardiovascular disease. www.who.int. Accessed Sept.15,2019.2. Venous thromboembolism. CDC. Published June 2015.3. Stroke. CDC. Published Jan 2019.4. Lau, DH., et al. Circulation.2017;136(6):583-596.

http://www.who.int/


Background: DOACs

55. Eliquis (apixaban). Revised August 2014.6. Pradaxa (dabigatran). Revised April 2014.7. Savaysa (edoxaban). Revised September 2015.8. Xarelto (rivaroxaban). Revised November 2012.

• Four direct-acting oral anticoagulants have been approved by the United States FDA since 2010

– Apixaban5 (2012, 2014)– Dabigatran6 (2010, 2014)– Edoxaban7 (2015)– Rivaroxaban8 (2011)

• Approved indications include:– Treatment of VTE– Prevention of recurrent VTE– Prevention of ischemic stroke in patients with non-valvular A. Fib

• Compared to warfarin, these drugs offer more convenient dosing, fewer drug and food interactions, and less monitoring requirements


Background: Guidelines

• ACC/AHA/HRS 2019 Focus update of the 2014 Atrial Fibrillation guidelines recommend the use of DOACs over the use of warfarin (except with moderate-to-severe mitral stenosis or a mechanical heart valve)9

• CHEST 2016 update for Antithrombotic Therapy for VTE Disease guidelines recommends use of DOACs over warfarin in patients with DVT of the leg or PE and no cancer10

• ISTH 2016 guidance suggests not using DOACs in patients with BMI > 40 kg/m3 or weight of > 120 kg11

69. January, CT., et.al. J Am Coll Cardio. 2019;74(1):104-132.10. Kearon, C., et.al. CHEST. 2012;141(2):e410S-e496s.11. Martin, K., et.al. J Thromb Haemost. 2016;14(6):1308-1313.


Background: Clinical Trials

• Weights used for sub-group analysis varied from trial to trial– Some trials did not complete sub-group analysis on weight

• Results of the sub-group analyses showed that DOACs were either equivalent or non-inferior to warfarin in prevention of VTE or stroke (except risk for VTE was higher with dabigatran in VTE)

– Results had wide confidence intervals and were not found to statistically significant

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11. Martin, K., et.al. J Thromb Haemost. 2016;14(6):1308-1313.

Major Phase III DOAC trials provided insufficient data for use in obese patients


Background: PK/PD Studies

811. Martin, K., et.al. J Thromb Haemost. 2016;14(6):1308-1313.12. Upreti, V., et.al. Br J Clin Pharmacol. 2013;76(6):908-916.

• A study completed by Upreti, et.al. compared apixaban use in extremes of weight (≤ 50 kg and ≥ 120 kg) and found that high body weight had ~31% lower Cmax and ~23% lower AUC compared to the reference body weight (65-85 kg)12

• Studies of patients taking rivaroxaban showed similar peak plasma concentrations and was not significantly affected by body weight


Purpose

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• Determine if DOACs can be used safely in obese patients

• Determine if DOACs provide same therapeutic benefits in prevention and treatment of VTE in obese patients

• Determine if DOACs provide same therapeutic benefits in prevention of stroke in obese patients with non-valvular atrial fibrillation


Design

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• Single-center, retrospective cohort study

• IRB approved

• Study period: June 2014 to June 2019

• Population: Veterans at the Kansas City VA Medical Center

• Data: Obtained through VISN 15 Central Data Warehouse• ICD-10 event codes for VTE, stroke, and bleed events• Retrospective chart review in CPRS


Criteria

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INCLUSION EXCLUSION

Age ≥ 18 years Cancer

Initiated on DOAC (June 2014 to June 2019)

Non-adherence (overdue for refill > 4 weeks)

Diagnosis of A. Fib/Flutter or VTE(ICD-10 codes)

No follow up within 6 months of DOAC initiation

Dual-antiplatelet therapy


Primary Outcomes

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Efficacy• To compare the rate of recurrent VTE (DVT/PE) in patients on DOAC therapy who

weigh > 120 kg compared to patients who weigh ≤ 120 kg

• To compare the rate of stroke in patients with non-valvular A. Fib on DOAC therapy who weigh > 120 kg compared to patients who weigh ≤ 120 kg

• Sub-group analysis: Patients who weigh ≥ 150 kg compared to patients who weigh ≤ 120 kg


Primary Outcomes

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Safety• To compare the rate of major bleeding events in patients on DOAC therapy who

weigh > 120 kg compared to patients who weigh ≤ 120 kg• Sub-group analysis: Patients who weigh ≥ 150 kg compared to patients who weigh

≤ 120 kg

– Major bleeding in Non-surgical Patients (as defined by ISTH)11:

• Fatal bleeding and/or• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular,

retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome and/or

• Bleeding causing a fall in hemoglobin level of 2g/dL (1.24 mmol/L) or more, leading to transfusion of two or more units of whole blood clots or red cells



Secondary Outcomes

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Safety• To compare the rate of minor bleeding events in patients on DOAC therapy who

weigh > 120 kg compared to patients who weigh ≤ 120 kg• Sub-group analysis: Patients who weigh ≥ 150 kg compared to patients who weigh

≤ 120 kg

– Clinically relevant minor bleed (as defined by ISTH)11:

• A clinically relevant minor bleed is an acute or subacute clinically overt bleed that does not meet criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following:

• Hospital admission for bleeding, or • Physician guided medical or surgical treatment for bleeding, or• Change in antithrombotic therapy (including interruption or discontinuation of the study drug)



Results: Patient Population

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Study cohort: > 120 kg :197 KCVA Veterans identified that were initiated on DOAC for VTE or atrial fibrillation

with weight > 120 kg

162 patients met criteria

35 patients met exclusion criteria per chart review:

Cancer: 25DAPT: 12

Comparator cohort: ≤ 120 kg 162 randomized Veterans meeting the same criteria

with weight ≤ 120 kg


Results: Patient Demographics

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Baseline Patient Characteristics Study Arm: number of patients > 120 kg (n = 162)

Comparator Arm: number of patents ≤ 120 kg (n = 162)

DOAC indication: VTE, n 30(18.5%)

34(21.0%)

DOAC indication: Atrial Fibrillation, n 125(77.2%)

121(74.7%)

DOAC indication: Both, n 7(4.3%)

7(4.3%)

Age, mean years 69 76

VTE indication (n =37, 41), mean years 66 70

Atrial fibrillation (n =132, 128), mean years 70 78

Age ≥ 75 years, n 36 (22.2%) 84 (51.9%)



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Male, gender, n 157 (94.6%) 159 (95.8%)

VTE indication (n = 37, 41), n 33 39

Atrial fibrillation (n =132, 128), n 127 125

Renal Function, mean CrCl ml/min 96 64

Weight, mean kg 140 90

VTE indication (n = 37, 41), mean kg 136 91

Atrial fibrillation (n = 132, 128), mean kg 141 87

Weight ≥ 150 kg, n 40

CHA2DS2- VASC Score, mean 3.3 3.5


• Column text


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Apixaban, n 78(48.1%)

102(63.0%)

Apixaban 2.5 mg twice daily, n 5 15

Apixaban 5 mg twice daily, n 73 87

Dabigatran, n 13(8.1%)

7(4.3%)

Rivaroxaban, n 71(43.8%)

53(32.7%)

Rivaroxaban 15mg daily, n 12 14

Rivaroxaban 20 mg daily, n 59 39

VETERANS HEALTH ADMINISTRATION 19

Results: Primary Outcome

6.06%

7.81%

# O

F EV

ENTS

STROKE EVENTS

> 120 kg ≤ 120 kg

n = 128

n = 132

p-value = 0.2890


Results: Primary Outcome

10.81%

9.76%

Axis

Titl

e

Axis Title

VTE EVENTS

> 120 kg ≤ 120 kg

n = 37

n = 41

p-value = 0.4391


Results: Safety Outcomes – Bleed Events

MAJOR BLEEDS (PRIMARY) MINOR BLEEDS (SECONDARY)

6.17%

3.09%

7.41%8.02%

# O

F EV

ENTS

n = 162 per cohort

> 120 kg ≤ 120 kg

p-value = 0.3294 p-value = 0.2617


Results: Subgroup Analysis

STROKE EVENTS VTE EVENTS

6.25%

12.50%

7.81%

9.76%

INCI

DEN

CE, %

EFFICACY> 150 kg ≤ 120 kg

n = 32n = 128

n = 8

n = 41

p-value = 0.3820p-value = 0.4073


Results: Subgroup Analysis

MAJOR BLEED EVENTS (PRIMARY) MINOR BLEED EVENTS (SECONDARY)

7.50%

5.00%

7.41%8.02%

INCI

DEN

CE, %

SAFETY> 150 kg ≤ 120 kg

n = 40 n = 162

n = 40

n = 162

p-value = 0.2568p-value = 0.4920


Limitations

• Use of ICD-10 codes to identify indications and events• Single-site review• Randomized comparator arm vs. entire population

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Conclusions

• The results of this retrospective study provides further evidence of similar efficacy and safety outcomes of DOAC use between different weight groups

• Additional studies are needed to confirm these findings and if confirmed, this will allow for a more convenient option, in terms of dosing, monitoring, and drug interactions, for anticoagulation therapy in morbidly obese patients

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Acknowledgements

Amy Sipe, B.S Pharm, VISN 15 Academic Detailing - Clinical Pharmacist Specialist Kansas City VA Medical Center

Michael Brown, PharmD Candidate 2021, VALOR StudentKansas City VA Medical Center

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INSERT REFERENCE


References

1. Cardiovascular diseases (CVDs). https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds). Accessed September 15, 2019.

2. CDC. Data and statistics on venous thromboembolism | CDC. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/dvt/data.html. Published June 22, 2015. Accessed September 15, 2019.

3. Stroke fact sheet|Data & Statistics|DHDSP|CDC. https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_stroke.htm. Published January 9, 2019. Accessed September 15, 2019.

4. Lau DH, Nattel S, Kalman JM, Sanders P. Modifiable risk factors and atrial fibrillation. Circulation. 2017;136(6):583-596. doi:10.1161/CIRCULATIONAHA.116.023163

5. Eliquis (apixaban). Princeton, NJ and New York, NY; Bristrol-Meyers Squibb and Pfizer Drugs; Revised August 2014. 6. Pradaxa (dabigatran). Ridgefield, CT; Boehringer Ingelheim Pharmaceuticals, Inc.; Revised April 2014.7. Savaysa (edoxaban). Parsippany, NJ; Daiichi Sankyo Co., LTD.; Revised Sept. 2015.8. Xarelto (rivaroxaban). Titusville, NJ; Janssen Pharmaceuticals; Revised Nov. 2012. 9. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused update of the 2014 AHA/ACC/HRS guideline for

the management of patients with atrial fibrillation. J Am Coll Cardiol. 2019;74(1):104-132. doi:10.1016/j.jacc.2019.01.011

10. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease. Chest. 2012;141(2):e419S-e496S. doi:10.1378/chest.11-2301

11. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-1313. doi:10.1111/jth.13323

12. 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: Effect of extremes of body weight on the PK/PD of apixaban. Br J Clin Pharmacol. 2013;76(6):908-916. doi:10.1111/bcp.12114

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Questions?

Nguyet Nguyen, Pharm.D.PGY-1 Pharmacy Practice Resident

Kansas City VA Medical [email protected]

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Comparing Efficacy and Safety of DOACs used for Prevention