Novel Oral Anti-coagulants in Patients with Malignancy

Lori-Ann Linkins, MD, MSc(Clin Epi), FRCPC McMaster University, Hamilton, ON

Disclosures

• Speaker honorarium from Bayer (rivaroxaban; Xarelto) and Pfizer (dalteparin; Fragmin)

• Research funding from Bayer for a study evaluating rivaroxaban for treatment of HIT

Novel Oral Anticoagulants in Patients with Malignancy

• Dabigatran (Pradaxa)

• Rivaroxaban (Xarelto)

• Apixaban (Eliquis)

• Edoxaban (not yet available)

Terminology: NOAC = DOAC

Novel Oral Anticoagulants in Patients with Malignancy

• Dabigatran (Pradaxa), Rivaroxaban (Xarelto), Apixaban (Eliquis)

• Approved in Canada for: • thromboprophylaxis following THR and TKR

• prevention of stroke in patients with afib

• treatment of acute DVT/PE and prevention of recurrent DVT/PE

Efficacy of NOACs in Cancer Patient Subgroups

NOAC Comparator Number of NOAC Patients

Risk of Recurrent VTE (%)

NOAC Warfarin

Dabigatran Warfarin 173 5.8 7.4

Rivaroxaban

Enox/Warfarin 354 4.5 6.6

Apixaban Enox/Warfarin 81 3.7 6.4

Total 608

Schulman et al ,TH 2015; Prins et al, Lancet Hematol 2014; Agnelli et al, Eur Heart H, 2014

VTE, venous thromboembolism

Safety of NOACs in Cancer Patient Subgroups

NOAC Comparator Number of NOAC Patients

Risk of Major Bleed (%)

NOAC Warfarin

Dabigatran Warfarin 159 3.8 4.6

Rivaroxaban

Enox/Warfarin 353 2.3 5.0

Apixaban Enox/Warfarin 81 2.3 5.0

Total 593

Schulman et al ,TH 2015; Prins et al, Lancet Hematol 2014; Agnelli et al, Eur Heart H, 2014

Meta-Analysis of NOACs in Cancer: Recurrent VTE

Vedovati et al., Chest 2015;147;475-483.

Apixaban Rivaroxaban Edoxaban Dabigatran

OR 0.63; 95% CI, 0.37-1.10

Meta-Analysis of NOACs in Cancer: Bleeding

Apixaban Rivaroxaban Edoxaban Dabigatran

Vedovati et al., Chest 2015;147;475-483.

OR 0.77; 95% CI, 0.41-1.44

Novel Oral Anticoagulants in Patients with Malignancy

• NOACs appear to be at least as effective and safe as warfarin for treatment of VTE in patients with malignancy

• However...

Novel Oral Anticoagulants in Patients with Malignancy

• Only a small proportion of patients in the NOAC clinical trials had cancer (2-6%)

• Definitions of active cancer differed between studies; patients were highly selected

• Comparator was warfarin, not LMWH (standard of care)

Novel Oral Anticoagulants in Patients with Malignancy

• Dependent on GI absorption

• Anticoagulant levels are not easily monitored

• No specific antidotes to reverse anticoagulant effect in emergent settings

• Cost can be a factor

• May interact with antineoplastic agents

NOAC Drug Interactions

Source: adapted from: Short NJ, Connors JM. The Oncologist 2014; Lee AYY et al. Blood 2013.

CYP 3A4* P-gp†

Inducers (may reduce DOAC plasma levels)

• Chemotherapy: paclitaxel • Targeted therapies: vemurafenib • Hormonal therapies: enzalutamide • Immune modulators: dexamethasone,

prednisone

• Chemotherapy: vinblastine, doxorubicin • Immunomodulators: dexamethasone

Inhibitors (may increase DOAC plasma effect)

• Chemotherapies: Several anti-mitotic agents, etoposide, doxorubicin, idarubicin, cyclophosphamide, ifosphamide, lomustine

• Targeted therapies: imatinib, crizotinib and other tyrosine kinase inhibitors

• Hormonal therapies: tamoxifen, anastrozole, bicalutamide, abiraterone

• Immunomodulators: cyclosporine, sirolimus, temsirolimus & tacrolimus

• Supportive care: aprepitant, fosaprepitant, fentanyl, methadone, acetaminophen

• Targeted therapies: imatinib, nilotinib, lapatinib, sunitinib, crizotinib, vandetanib

• Hormonal therapies: tamoxifen, enzalutamide, abiraterone

• Immunomodulators: cyclosporine, temsirolimus, tacrolimus

Novel Oral Anticoagulants in Patients with Malignancy

• Consensus statement from Canadian experts:

“We do not recommend the use of the DOACs for acute treatment of cancer-associated thrombosis”

Carrier et al, Curr Oncology 2015

Novel Oral Anticoagulants in Patients with Malignancy

My approach:

• Consider NOAC if treated for at least one month with LMWH and no potential interactions

• Prefer to continue LMWH if still receiving chemo even if no documented interaction

• Take quality of life into account on case-by-case basis