1

VTE TREATMENT FOR CANCER PATIENTS: TO

DOAC OR NOT TO DOAC…THAT IS THE

QUESTIONCrystal Anyiam

PGY1 Pharmacy ResidentCentral Texas Veterans Healthcare System

October 25, 2019

Objec&ves

• Understand the pathophysiology of hypercoagulable risk in cancer

• Review guideline updates of DOAC use in cancer pa=ents

• Discuss currently recommended treatment op=ons for VTE

• Evaluate clinical data regarding apixaban use in cancer

• Develop recommenda=ons for poten=al place in therapy of apixaban

1

Disclosures

• No conflicts of interest to disclose

2

Definitions Slide

• DOAC- Direct Oral Anticoagulation• NCCN- National comprehensive Cancer

Network• ASCO- American Society of Clinical Oncology• LMWH- Low Molecular Weight Heparin• VTE- Venous thromboembolism• GIB- Gastrointestinal bleeding

3

Introduc)on

• It is known that patients with cancer have an increased risk of VTE• However, management of VTE is challenging,

because the risk of recurrent VTE and bleeding are both increased in this type of patient population• The reported risk of thrombotic events is 4 times as

high in patients with cancer and increases if the patient is receiving chemotherapy, compared with the general population

4

Pathophysiology of Hypercoagulable Risk in

Cancer

5

2

Etiology of VTE

6N Engl J Med. 2008 Mar 6;358(10):1037-52.

Pathophysiology of Hypercoagulable State in Cancer Patients

7

Tumor Cell

Procoagulant ac,vi,es

Superficial adhesion molecules

Proangiogenic factors

Inflammatory cytokines

N Engl J Med. 2008 Mar 6;358(10):1037-52.

Estimated Prevalence of VTE in Common Types of Cancer

8

Cancer Prevalence %All malignancies 10-15Pancreas 28Lung 27Stomach 13Colon 3Breast postmenopausal 3-8Breast premenopausal 1-2Prostate 2Unknown primary tumor 1

Neoplasia:2002 Nov; 4(6): 465–473.

Practice knowledge

According to the Virchow’s Triad diagram, hypercoagulable state is typically seen in which population?

A. Athletes

B. Cancer patients

C. Patients with heart valve disease

D. Patients with history of atrial fibrillation

9

Clinical Prac*ce Guideline Updates for VTE Treatment

in Cancer Pa*ents

10

2019 ASCO Guideline VTE Treatment

11

Initial anticoagulation • Low molecular weight heparin (LMWH) Unfractionated heparin (UFH)• Minimum 5 days with

edoxaban• Minimum 5 days or longer until

therapeutic with warfarin• Fondaparinux 5-10 days

• Minimum 5 days or longer until therapeutic with warfarin

• Rivaroxaban 21 days

Secondary prophylaxis to prevent recurrence for at least 6 months

• LMWH• Edoxaban or rivaroxaban• Warfarin

NS Key, et al Journal of Clinical Oncology

3

2019 NCCN Guideline VTE Treatment

Initial anticoagulation • Low molecular weight heparin (LMWH) Unfractionated heparin (UFH)• Minimum 5 days with

edoxaban• Minimum 5 days or longer until

therapeutic with warfarin• Fondaparinux 5-10 days

• Minimum 5 days or longer until therapeutic with warfarin

• Rivaroxaban 21 days

Secondary prophylaxis to prevent recurrence for at least 6 months

• LMWH• Edoxaban or rivaroxaban• Warfarin• Apixaban* • LMWH + Dabigatran*

12MB Streiff, et al: Natl Compr Canc Netw 2019;10.6004/nccn.2019.0092

Guideline recommended DOACs for VTE Treatment

in Cancer Patients

13

Hokusai VTE-Cancer Trial - Edoxaban

• To compare edoxaban with dalteparin for the treatment of patients with cancer associated VTE

Objective

• Randomized, open-label, noninferiority • Compared edoxaban (n=525) with LMWH

(n=525) in patients with active cancer who had acute symptomatic VTE for 6 months and followed for 12 months

Methodology

• Composite of recurrent venous thromboembolism or major bleeding during the 12 months aNer randomizaOon, tesOng the hypothesis that edoxaban would be noninferior to dalteparin for this measure

Primary outcome

14Raskob GE et al: N Engl J Med 2018;378:615–624

Hokusai VTE-Cancer Trial -Edoxaban

15

Inclusion criteria

• Non-basal or squamous-cell skin cancer either active within the prior 6 months or diagnosed within the prior 2 years

• Qualifying VTE• Intent to administer

LMWH for ≥6 months

Exclusion criteria

• Therapeutic anticoagulation for a non-VTE indication prior to randomization

• Active bleeding or contraindication to study drug

Raskob GE et al: N Engl J Med 2018;378:615–624

Hokusai VTE-Cancer Trial - Edoxaban

• Patient population• Age 64 years, 47% female• Weight: 79 kg• Active cancer: 98%• Metastatic disease: 52%• Recurrent cancer: 31%

Raskob GE et al: N Engl J Med 2018;378:615–624 16

Hokusai VTE-Cancer Trial – EdoxabanOutcomes

Secondary: Recurrent VTEEdoxaban (7.9%) VS Dalteparin (11.3%)

HR 0.71; 95% CI 0.48-1.06; P=0.09

Primary: Recurrent VTE or Major Bleeding

Edoxaban (12.8%) VS Dalteparin (13.5%)HR 0.97; P=0.006 for noninferiority

17Raskob GE et al: N Engl J Med 2018;378:615–624

4

Hokusai VTE-Cancer Trial – EdoxabanAdverse Events

18

Major or clinically relevant nonmajor bleedingEdoxaban (18.6%) VS Dalteparin (13.9%)

HR 1.40; 95% CI 1.03-1.89

Clinically relevant nonmajor bleedingEdoxaban (14.6%) VS Dalteparin (11.1%)

HR 1.38; 95% CI 0.98-1.94

Major bleedingEdoxaban (6.9%) VS Dalteparin (4.0%)

HR 1.77; 95% CI 1.03-3.04; P=0.04

Raskob GE et al: N Engl J Med 2018;378:615–624

SELECT-D Trial- Rivaroxaban

19

• To compare rivaroxaban with dalteparin for the treatment of patients with cancer associated VTE

Objective

• Prospective, randomized, open label, multicenter pilot

• Compared rivaroxaban (n=203) with LMWH (n=203) in patients with active cancer who had symptomatic or incidental VTE for 6 months

Methodology

• VTE recurrence at 6 monthsPrimary outcome

Young AM, et al J Clin Oncol 2018:36:2017–2023

SELECT-D Trial-Rivaroxaban

20

Inclusion criteria • Active solid tumor or

hematologic malignancy• Cancer defined as cancer

other than basal cell or non-squamous cell skin cancer

• Active defined as diagnosis or treatment within prior 6 months, recurrent/metastatic cancer, or cancer not in complete remission

Exclusion criteria • Current anticoagulation or

antiplatelet therapy• Active bleeding or a high risk

of bleeding, contraindicating anticoagulant treatment

Raskob GE et al: N Engl J Med 2018;378:615–624

SELECT-D Trial- RivaroxabanOutcomes

21

Secondary: Major Bleeding at 6 monthsRivaroxaban (6%) VS Dalteparin (4%)

HR 1.83; 95% CI 0.68-4.96

Primary: VTE recurrence at 6 monthsRivaroxaban (4%) VS Dalteparin (11%)

HR 0.43; 95% CI 0.19-0.99

Young AM, et al J Clin Oncol 2018:36:2017–2023

Considerations When Choosing a DOAC based on Guideline Recommendation

22

Dosing

Dietary consideration/ drug interactions

Cost

Reversal agent

Safety

22

Edoxaban vs Rivaroxaban

Edoxaban RivaroxabanDosing for treatment 60 mg once daily after at

least 5 days of an injectable

anticoagulant

or

30 mg once daily

15 mg BID for 21 days, then

20 mg once daily

Safety considerations Major bleeds in patients with

mucosal tumors or active

mucosal lesion

Major bleeds in patients with

GI and genitourinary

malignancies

Major bleeds in patients with

mucosal tumors or active

mucosal lesion

Dietary considerations None Must take with meal for

adequate absorption

Drug interactions P-gp substrate CYP3A4 & P-gp substrate

Anticoagulant Reversal No reversal agent Andexxa

Cost $$ $23

5

a) Plavixb) LMWH + Warfarinc) LMWH + Edoxaband) Alteplase

24

Patient Case 1

A 42 year old female patient with stage IV breast cancer develops a DVT, which of the following options is appropriate;

Review of Direct XA Inhibitors

25

✔

✔

25

Does Apixaban have a Place in Therapy for the

Treatment of VTE in Cancer Patients?

26

AMPLIFY Trial –Apixaban

27

• To perform a subgroup analysis to compare the efficacy and safety of apixaban and enoxaparin followed by warfarin for the treatment of VTE in patients with cancer enrolled in AMPLIFY

ObjecEve

• Randomized, double-blind study compared apixaban (n=88) with enoxaparin + warfarin (n=81) in paEents with acute symptomaEc VTE for 6 months

Methodology

• Recurrent VTE • VTE-related death and major bleedingPrimary Outcome

Agnelli G et al. 2015 Intern Soci on Thromb and Haemost 369:799–808

AMPLIFY Trial –Apixaban

Inclusion Criteria• Symptoma3c VTE,• Pa3ents with ac3ve cancer and history of cancer

Exclusion Criteria• Active bleeding or a high risk of bleeding• Long-term LMWH treatment deemed to be

necessary by the investigator

28Agnelli G et al. 2015 Intern Soci on Thromb and Haemost 369:799–808

AMPLIFY Trial – ApixabanResults

29*This subgroup is based on the patients who have active cancer and/or cancer history (without active cancer)

Agnelli G et al. 2015 Intern Soci on Thromb and Haemost 369:799–808

6

AMPLIFY Trial – ApixabanResults

30Agnelli G et al. 2015 Intern Soci on Thromb and Haemost 369:799–808

AMPLIFY Trial –ApixabanStrength

• Well designed randomized, double blind multicenter trial

• Results of this subgroup analysis are consistent with the previous studies

31

AMPLIFY Trial –ApixabanLimita5ons

• Trial excluded pa-ents treated with LMWH only

• Pa-ents enrolled were healthier healthier compared to the other previous

• Only a small number of pa-ents with cancer

32

AMPLIFY Trial –Apixaban

33

Overall, AMPLIFY demonstrated that apixaban was non-inferior to comparative therapy for the primary efficacy outcome of recurrent symptomatic VTE or VTE related death

In patients with active cancer, the overall mortality rates at 3 months were similar in patients in the apixaban group and in the enoxaparin/warfarin group

The results of this subgroup analysis suggest that apixaban is a convenient option for cancer patients with VTE

AddiGonal studies are needed to compare apixaban with low molecular weight heparin in cancer paGents

ADAM VTE Trial -Apixaban vs Dalteparin

34

• To investigate the safety of apixaban compared to dalteparin in patients with active cancerObjective

• A Phase III, Randomized, Open Label Study compared apixaban (n=145) with Dalteparin (n=142) in patients with acute symptomatic VTE for 6 months

• Participants also completed monthly questionnaires to measure satisfaction with the anticoagulation regimen

Methodology

• Major bleeding• VTE recurrence

Primary and Secondary Outcome

McBane et al; Blood 2018 132:421

ADAM VTE Trial -Apixaban vs Dalteparin

35

Inclusion criteria • Confirmed acute DVT, PE• Active cancer defined as

metastatic disease and/or any evidence of cancer• Life expectancy >= 60 days• Ability to complete

questionnaire(s) by themselves or with assistance• Ability to provide informed

written consent• Willing to return to enrolling

institution for follow-up

Exclusion criteria • Treatment with an anticoagulant

for more than 7 days for the current blood clot, prior to randomization• Active bleeding• Treatment of a thromboembolic

event =< 6 months prior to randomization

Raskob GE et al: N Engl J Med 2018;378:615–624

7

ADAM VTE Trial- Apixaban vs DalteparinBaseline characteristics

36

In the cohort, 65.5% of patients presented with metastatic disease at baseline, and 74 % of patients were receiving concurrent systemic cancer therapy

The four most prevalent types of cancer were breast, colorectal, lung, and pancreatic

Only four percent of participants had an upper gastrointestinal malignancy

McBane et al; Blood 2018 132:421

ADAM VTE Trial- Apixaban vs DalteparinOutcomes

37

Secondary: Recurrent VTEApixaban (3.4%) VS Dalteparin (14.1%)

HR 0.26, 95% CI, 0.09 - 0.80, p = 0.0182

Primary: Major bleeding Apixaban (0%) VS Dalteparin (2.1%)

p=0.9956

McBane et al; Blood 2018 132:421

ADAM VTE Trial-

Apixaban vs

Dalteparin

38

Strength• Study was specific to cancer• The use of questionnaires to

measure quality of life between apixaban and dalteparin

Limitation• Small number of enrolled

patients• Open-label design• Reliance on self-reported

questionnaire data to evaluate secondary outcomes

ADAM VTE Trial-Apixaban vs Dalteparin

39

Oral apixaban therapy was associated with very low

rates of bleeding and significantly lower VTE

recurrence

Quality of life outcome measures showed that

pa?ents markedly preferred oral apixaban over injectable dalteparin in the treatment

of cancer associated VTE

CARAVAGGIO Study-Coming soon

40

Enrollment is expected to finish at the end of May 2019, and follow-up of the last patient enrolled around late November

2019

Started enrollment in April 2017, with a target enrollment number of 1,168 patients

The aim of the Caravaggio study is to assess whether oral apixaban is non-inferior to

subcutaneous dalteparin for the treatment of VTE in patients with cancer

Agnelli et al 2018 Georg Thieme Verlag KG 10.1055/s-0038-1668523

CARAVAGGIO Study- Coming soon

41

An inves*gator-ini*ated, mul*-na*onal, prospec*ve, randomized, open-label with blind end-point evalua*on (PROBE), noninferiority clinical trial

The primary outcome of the study: recurrent VTE and major bleeding

Agnelli et al 2018 Georg Thieme Verlag KG 10.1055/s-0038-1668523

8

Recommendations for Potential Place in Therapy

of Apixaban

42

Advantages of Apixaban

• Apixaban vs Rivaroxaban • No dietary considera4ons• Dosing• Renal func4on• Reduced GIB

• Apixaban vs Edoxaban• Reduced GIB• Renal func4on• Ini4al an4coagula4on • Reversal agent

43

My Recommendation for DOAC Use

44

Is patient at increased risk

of bleeding

No

Rivaroxaban Edoxaban

Yes

Apixaban??

a) Edoxabanb) Rivaroxabanc) Apixaband) LMWH

45

Patient Case 2

A 64 year old male with GI cancer develops a PE, patient has difficulty injecting himself, which of the following options is most appropriate per guideline recommendation;

Take Home Points

46

Rivaroxaban and edoxabanare now recommended

options for VTE treatment from both cancer

guidelines

Apixaban may be considered as an op?on based on ongoing trials

Due to the increased risk for major bleeding events with DOACs compared

with LMWH when trea?ng VTE, LMWHs are s*ll preferred in seJngs

with an increased risk for bleeding

Based on data from this presentation when would YOU use apixaban in clinical practice

A. First-lineB. Second-lineC. Last lineD. Never

47

9

Acknowledgements

• Evaluator: Chelsey Roscoe, PharmD - PGY2 Ambulatory Care Pharmacy Resident - CommUnityCare

• Preceptors: Sarah Rustenhaven, PharmD – Clinical Pharmacy Specialist –Internal Medicine, CTVHCS; Sarah Fry, PharmD –Clinical Pharmacy Specialist - Anticoagulation Clinic, CTVHCS

• Mentor: Jennifer Jiang , PharmD – Clinical Pharmacy Specialist –Internal Medicine, CTVHCS

48

Ques%ons?

49