cancer vte in the era of doacs - care™ education...•asco guideline update •initial...
TRANSCRIPT
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!