Cancer VTE in the era of DOACs

Dr. Deepa SuryanarayanUniversity of Calgary

ØSpeakers bureau or advisory boards – Bayer, Leo-Pharma, BMS-Pfizer

Disclosures

Objectives

Overview of epidemiology and clinical burden of venous thromboembolism in cancer

1

Review published and upcoming evidence of DOACs in treatment of cancer associated thrombosis

2

Briefly discuss management of bleeding on DOACs in cancer VTE

3

Cancer VTE- Disease burden and clinical impact

Heit et al, Arch Intern Med 2000; Khorana AA et al, J Clin Oncol 2009; Horsted F PLoS Med. 2012

Cancer is a strong and independent significant risk factor for occurrence of venous thromboembolism.

Active cancer accounts for ~20% of overall incidence of VTERisk of VTE in cancer patients is increased 4-7 fold

CAT causes significant mortality and morbidity in cancer patients

2nd leading cause of deathRisk of VTE recurrence is high in cancer patientsSequelae of CAT is not limited to physical but can also confer significant psychological burden on patients.

Cancer course and VTE risk

7Lyman GH, Cancer 2010;7:1334–1349; Cohen AT et al, Thromb Haemost 2017;117:57-65

Hospitalisation : Biopsy, Surgery, CVC insertion

Metastases

Palliative care

Diagnosis

Chemotherapy

Remission

VTE risk in cancer patients

VTE risk in the general population

Time

Risk

(O

dd R

atio

)

• Incidence rate of a first venous thromboembolic event in patients with active cancer: 5.8 (95% CI 5.7–6.0) per 100 person-years

Control group

LMWH

Vitamin K antagonist (INR 2.0-3.0)

CANTHANOX1

N=146 Enoxaparin 1.5 mg/kg od

LITE2

N=200 Tinzaparin 175 U/kg od

Dalteparin 200 IU/kg od ~150 IU/kg odCLOT3

N=672

CATCH4

N=900 Tinzaparin 175 U/kg od

5-7 days 1 month 3 months 6 months

LMWHs Versus Vitamin K Antagonists in the Treatment of CAT

1. Meyer G, et al. Arch Intern Med. 2002 Aug 12-26; 162(15):1729-35; 2. Hull RD, et al. AM J Med. 2006;119:1062-72; 3. Lee et al. N Engl J Med 2003;349:146;4. Lee et al. JAMA 2015;314:67

Anticoagulant treatment of CAT- Meta-analysis of clinical trials comparing LMWH with VKA

Recurrent VTE Major Bleeding

Recurrent VTE:RR: 0.56

95% CI: 0.43-0.74

Major Bleeding:RR: 1.07

95% CI: 0.66-1.73 Carrier M et al. Thromb Res 2014;134:1214-9

Direct oral anticoagulants – A safe and reasonable alternative to LMWH?

Hokusai-VTE cancer and SELECT-D

Hokusai-VTE cancer(Edoxaban vs LMWH)

SELECT-D (Rivaroxaban vs LMWH)

Trial design PROBE Design, Phase IIIB Study(n=1046)

Prospective, openlabel,randomized, multicenter pilot trial(n=406)

Trial population Objectively confirmed acute VTE and cancer other than basal-cell/ squamous-cell skin cancer diagnosed within 2 yrs or deemed active

Cancer patients with VTE>18 years

Primary outcome Composite of the first recurrent VTE or major bleeding event

Recurrent VTE

Secondary outcome Recurrent VTE and major bleeding event (analyzed separately)and survival free of recurrent VTE or major bleeding

Major bleeds and clinically relevant non-major bleeds, acceptability, survival and health economics

Duration 6 months 6 months

Raskob GE, Hokusai VTE Cancer Investigators. N Engl J Med 2018; 378:615-624; Young Am et al (SELECT-D). J Clin Oncol. 2018;36(20):2017–2023

HOKUSAI-VTE RESULTSPrimary outcome

Raskob GE, et al. Hokusai VTE Cancer Investigators N Engl J Med. 2018;378(7):615.

12.8%

13.8%

HR with edoxaban, 0.97; 95% CI:0.70,1.36; P=.0056 for non-inferiority

Hokusai – Recurrent VTE

Raskob GE, Hokusai VTE Cancer Investigators. N Engl J Med 2018; 378:615-624.

7.9%

11.3%HR 0.71; 95% CI 0.48-1.06; P=0.09

Hokusai- Major Bleeding

Raskob GE, Hokusai VTE Cancer Investigators. N Engl J Med 2018; 378:615-624.

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

Edoxaban (n=522) Dalteparin (n=524)

Major bleeding, no. (%)

33 (6.3) 17 (3.2)

Fatal 0 2 (0.4)

Intracranial 2 (0.2) 4 (0.8)

GI 20 (3.8) 6 (1.1)

Upper 17 (3.3) 3 (0.6)

Lower 3 (0.6) 3 (0.6)

Urogenital 5 (1.0) 0

Other 6 (1.1) 7 (1.3)

Severity of major bleeding, n (%)

Edoxaban (n=33) Dalteparin (n=17)

1 0 0

2 21 (64) 5 (29)

3 12 (36) 11 (65)

4 0 1 (6)

6.9%

4.0%

HR: 1.77 (95% CI 1.03-3.04)p = 0.04

Select-d - Results

Young AM et al (SELECT-D). J Clin Oncol. 2018;36(20):2017–2023

Select-d- Results

Young AM et al (SELECT-D). J Clin Oncol. 2018;36(20):2017–2023

ADAM-VTE: Apixaban vs Dalteparin in active cancer associated thrombosis

• Patients with cancer associated VTE randomly assigned to received either apixaban 10 mg twice daily for 7 days followed by 5 mg BID for 6 months vs dalteparin

• Primary outcome was major bleeding. Secondary outcomes included VTE recurrence and a composite of major and CRNMB

• Out of 300 randomized 257 included in primary analysis• Results:

– Major bleeding occurred in 0% of 145 patients receiving apixaban vs 1.4% of 142 patients receiving dalteparin (p=0.138)

– Recurrent VTE in 0.7% of apixaban vs 6.3% of dalteparin patients (HR 0.099; 95% ci 0.013-0.780, P=0.0281)– Major bleeding or CRNMB were 6% in both arms.

Smaller numbers, low event rates and did not meet prespecified primary outcome. Await CARAVAGGIO!

McBane R et al. The ADAM VTE trial. J Thromb Haemost2019 Oct 20.

Cancer patients with symptomatic or

unsuspected proximal lower limb

DVT

Cancer patients with symptomatic or

unsuspected PE in a segmental or more

proximal artery

R

Apixaban

10 mg bidApixaban5 mg bid

<72 hours*Dalteparin 200 IU/kg Qd Dalteparin 150 IU/kg Qd

30 days observation

period

Day 1 Day 7 Day 30 6 months

Principle Investigator Giancarlo Agnelli

Countries Involved 11

Centres Involved ~140

Sample Size 1168 patients

Aim: To demonstrate the non inferiority of apixaban vs. dalteparin in the prevention of VTE recurrences in cancer patients with VTE

Caravaggio Study Design

What’s new in treatment of Cancer VTE?• NCCN guidelines version 2.2018

• LMWH as monotherapy preferred for first 6 months.• Alternatives include Rivaroxaban, apixaban,LMWH/VKA, LMWK/Edoxaban,

LMWH/Dabigatran• Indefinite duration recommended with active cancer or persistent risk factors for VTE

recurrence.• ASCO guideline update

• Initial anticoagulation can include LMWH,UFH,Fondaparinux and Rivaroxaban.• Long term anticoagulation can involve treatment with LMWH, edoxaban or rivaroxaban for

at least 6 months. VKA’s may be used if DOAC’s are not accessible.• DOACs cautioned with patients with GI malignancies.

NCCN Clinical Practice Guidelines in Oncology®. Version 2.2018

Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update [published online August 5, 2019]. J Clin Oncol.

DOACs for cancer VTE-

Guidance from ISTH

• Final treatment recommendation should be made after shared decision making with patients regarding a potential reduction in recurrence but higher bleeding rates with specific NOACs, incorporating patient preferences and values

Khorana AA, et al. J Thromb Haemost. 2018;16:1891-1894.

Anticoagulant Therapy Suggest Use ofSpecific NOACs(edoxaban or rivaroxaban)

In patients with low risk of bleeding and no drug-drug interactions with current systemic therapy

LMWH

In patients with high risk of bleeding, including• Patients with luminal GI cancers with an intact primary• Patients with cancers at risk of bleeding from the GU

tract, bladder, or nephrostomy tubes• Patients with active GI mucosal abnormalities such as

duodenal ulcers, gastritis, esophagitis, or colitis

Cancer-associated thrombosis without contraindication to anticoagulation(both incidental and symptomatic; lower limb DVT and PE)

Treatment Algorithm in Cancer associated thrombosis

Carrier M et al. Curr Oncol 2018;25:329-37. 21

Reassess on a regular basis (at least every 3 months or if there are changes in management or patient condition)

Cancer status: still active?

Non-high risk

High risk

Other types, non-active GI/urethelial tumours

Active GI or urothelial tumours

No

Yes

Yes

No

Consider stopping

Risk of bleeding?(Consider well-documented risk factors for bleeding including GI toxicity [that is, GI comorbidity, previous GI bleed, treatment

associated with GI toxicity], thrombocytopenia [<50,000 platelets/mL], renal impairment [GFR per the Cockcroft-Gault formula of 30-50 mL/min], recent and/or life-threatening bleeding, intracranial lesion, and use of antiplatelet agents)

Type of cancer?

Drug-drug interactions with DOACs based on pharmacist-led pharmacokinetic review?

DOAC*LMWH

The high stakes balancing act of anticoagulation

¡ Efficacy and safety are equally important

¡ Imbalance in either one of them can result in substantial harm

All anticoagulants

cause bleeding!

Address Modifiable Bleeding Risk Factors

1. Olesen et al. Thromb Haemost 2011;106:739–49.

Co-prescribe PPI (if recent/recurrent GI

bleeding)

Measure and monitor renal

function Ensure blood pressure controlled to target

Limit alcohol(encourage abstinence)

Correct anemia and determine cause

Provide mobility aids Discontinue ASA and NSAIDs if possible

Practical considerations DOAC reversal• When was the last dose taken?• Indication for reversal and it’s

urgency• What was the indication for

anticoagulation?• What’s the renal function?• Estimate half life based on renal

clearance

Dabi Riva Apix Edox

Drug target

Thrombin

Factor Xa

Factor Xa

Factor Xa

Half life 12-17 hr

5-9 h 8-15 h 8-10 h

Renal 80% 33% 25% 35-39%

Plasma protein binding

35% 92-95% 87% 40-59%

Half life DOACs and

renal function

Renal function

Dabigatran Rivaroxaban Apixaban Edoxaban

CrCl>80 14-17 h 5-9h 8-15h 10-14h

CrCl 50-79 16.6h 8.7h 14.6h ~8.6h

CrCl 30-49 18.7h 9h 17.6h ~9.4h

CrCl <30 27.5h 9.5h 17.3h ~16.9h

Dialyzable Yes No Yes No

Prior to rushing for an antidote-Institute general measures

• Factors to take into consideration– Hemodynamic stability of the patient, any clear source of bleeding?– DOAC: Type of DOAC, dosage and time of last ingestion– Evaluate the renal function– Coagulation assessment

• Dabigatran: aPTT, TT, dTT, ECT• Factor Xa inhibitors: Anti-factor Xa assays (ideally calibrated for each

agent)

Heidbuchel H, et al. Europace.2015;17:1467-1507.

Therapeutic measures in case of minor or severe bleeding in patients on DOAC therapy.

Hein Heidbuchel et al. Europace 2015;17:1467-1507

The quest for the antidote!

DOAC Reversal Agents

31LMWH: low molecular weight heparin; UFH: unfractionated heparin. 1. Praxbind (idarucizumab) Product Monograph. Boehringer Ingelheim Canada Ltd.; 2. Macle et al. CJC. 2016;32:1170-85; 3. Connolly et al. N Engl J Med. 2016;375:1131-41.

Reversal Agent Status

Idarucizumab(Praxbind)

• Reversal agent for dabigatran• Fully humanized monoclonal antibody fragment binds free and

protein-bound dabigatran with high affinity• Available in Canada as of May 2016

Andexanet-α

• Reversal agent for factor Xa inhibitors• Recombinant, modified human factor Xa decoy protein that

binds factor Xa inhibitors without intrinsic catalytic activity• Administered as an IV bolus (15-30 min) followed by a

2-hour infusion• Phase III development

Aripazine

• Universal reversal agent• Synthetic small molecule that binds to UFH, LMWH,

fondaparinux, dabigatran and factor Xa inhibitors• Phase I and II development

DOAC reversal agentsAgent Target Mechanism of action Administration and onset

of actionStatus of investigation

Idarucizumab Dabigatran Humanized FabSpecifically binds to dabigatran (affinity >350 x higher than binding of dabi to thrombin.

2 x 2.5 mg/50 mL IV bolus, may repeat dose

Onset<5 min

Approved for bleeding patients and emergency surgical patientsHealth Canada – March 2016

Andexanet alfa(PRT064445)

Fxainhibitors

Recombinant human Fxa variant: competitive affinity for direct Fxainhibitors

400 mg IV bolus plus 2 hour infusion – Apixaban800 mg IV bolus+infusion -Rivaroxaban

Onset<2 min

Licensed in United States, Phase 3 ongoing

Aripazine (PER977) Universal Synthetic small molecule: charge-charge interactions; hydrogen bonds

Single 100-300 mg IV dose (under investigation)

Onset 5-10 min

Phase 2

Lauw M, et al.Can J Cardiol.2014;30:381-384

REVERSE-AD: Trial Design, Laboratory Monitoring

• Circulation. 2015;132:2412-2422.

REVERSE-AD final cohort

Pollack et al. N Engl J Med.2017;377:431 -441

¡ Median time to hemostasis after antidote was 2.5 hrs¡ Time to cessation of bleeding in 98 patients with ICH could not be assessed.¡ 5% in each group had a thrombotic event at 30 days

ANNEXA-4 – Andexanet Alfa for bleeding associated with Factor Xa inhibitors• Adult patients with acute major bleeding

within 18 hrs of receiving : apixaban, rivaroxaban or edoxaban at any dose or enoxaparin.

• Study population (n=352)• Efficacy population (n=254)

• 82% of the cohort were adjudicated to have good or excellent hemostasis at 12 hours. 10% had a thrombotic event in 30 day follow up.

• Hemostatic efficacy was not related to the degree of reduction in anti-factor Xaactivity

Connolly SJ, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019

PCC concentrates

for major bleeding on

Fxa Inhibitors

• A systematic review evaluated safety and efficacy of 4 factor PCC for direct Fxa inhibitor related major bleeding.

• 10 case series with 340 patients were included• Pooled proportion of patients with effective

management of major bleeding was 0.69 (95% CI, 0.61-0.76) in 2 studies using ISTH criteria and 0.77 (95% CI, 0.07-0.26) in 8 studies not using ISTH criteria.

• VTE rate was 0.04 (95% CI, 0.01-0.08)• All cause mortality was 0.16 (95% CI, 0.07-0.26)• Based on the low quality of evidence and lack of

comparator group it is difficult to draw conclusions on efficacy of 4 factor PCC vs supportive care alone but may be still a reasonable option in the light of lack of availability of antidote or high cost.

Practical considerations

for antidotes for DOAC

reversal

• Rapid availability in health care centers and departments

• Ease of administration• Storage and administration: Andexanet alfa

vials should be refrigerated and reconstituted drug is stable for 8 hours at room temperature. Idarucizumab must be refrigerated between 2-8 degree Celsius. If exposed to light may be kept only for 6 hours.

• Institutional protocols need to be in place• Cost– Idaricuzumab costs $3500 for 5 g dose,

Andexanet (200g ) costs $3300 USD per 100 mg vial in comparison to PCC $2000-3000.

Take home points on management of bleeding on DOACs

• Always address modifiable risk factors• Institute timely supportive measures and hemostatic therapies • Reversal agents for DOAC should be considered as an “add on” to more

important supportive measures in the event of acute bleeding• Have institutional protocols in place • Always reassess regarding indication and re-initiation of anticoagulation

Thank you

Enjoy CHC WEST!