1. New Concepts in Cancer-Associated Thrombosis
What Do the Latest NOAC Data Suggest?
Moderator
NOAC = non-vitamin K antagonist oral anticoagulant
Lord Ajay K. Kakkar, MD, PhD, FRCS, FRCP
Professor of Surgery
University College London
London, United Kingdom

2. Panelists Gary H. Lyman, MD, MPH Alok A. Khorana, MD
Professor of Medicine
Fred Hutchinson Cancer Research Center
University of Washington
School of Medicine
Seattle, Washington
Alok A. Khorana, MD
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Case Western Reserve University
Sondra and Stephen Hardis Chair in Oncology Research
Vice Chair (Clinical Services)
Director, GI Malignancies Program
Taussig Cancer Institute
Cleveland Clinic
Cleveland, Ohio

3. Cancer-Associated Thrombosis (CAT) Prevalence and Burden
VTE is a major complication of cancer and a leading cause of death among cancer patients
Approximately 20% of all VTE cases occur in patients with cancer
VTE affects up to 20% of patients with cancer before death and has been reported in up to 50% of cancer patients at the time of postmortem examination
CAT has important clinical and economic consequences, including
Increased morbidity resulting from hospitalization and anticoagulation use
Bleeding complications
Increased risk of recurrent VTE
Cancer treatment delays
CAT = cancer-associated thrombosis
VTE = venous thromboembolism
Lyman GH. Cancer. 2011;117:

4. Risk Factors for VTE in Patients With Cancer
Age
Ethnicity
Comorbidities
Platelet counts
Leukocyte counts
Hemoglobin
Tissue factor
D-dimer
P-selectin
Thrombin generation potential
Surgery/ hospitalization
Chemotherapy
Antiangiogenics
CVC
ESA/transfusions
Primary site
Histology
Grade
Initial period after diagnosis
Cancer-related
Treatment-related
Patient-related
Biomarkers
CVC = central venous catheter
ESA = erythropoiesis-stimulating agent
Lyman GH. Cancer. 2011;117:

5. Khorana Risk Score Characteristic Score Site of Cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic, bladder, testicular) 2 1
Platelet Count
≥ 350,000/mm3
Hemoglobin Level
< 10g/dL or use of ESA
Leukocyte Count
> 11,000/mm3
Body Mass Index
≥ 35 kg/m2
Khorana AA, et al. Blood. 2008;111:

6. Biomarkers in Risk Assessment
Prespecified analysis of the CATCH trial
Patients in the highest quartile of TF at the time of initial VTE experienced the greatest VTE recurrence
In competing risk regression analysis of time to recurrent VTE, TF remained strongly associated with recurrent VTE
Results suggest that TF is a potential biomarker of recurrent VTE in patients with cancer receiving anticoagulation therapy
Tissue Factor[a]
Observational cohort study of patients with newly diagnosed cancer or progression of disease after remission
Incorporation of biomarkers into the Khorana risk score improved risk prediction
Patients at very high risk of VTE could be defined more precisely and the probability of VTE could be predicted more accurately
P-Selectin and D-Dimer[b]
TF = tissue factor
a. Khorana AA, et al. J Clin Oncol. 2017;35: b. Ay C, et al. Blood. 2010;116:

7. Guidelines Recommendation for Primary Thromboprophylaxis
Ambulatory Patients with Cancer
NCCN[a]
Suggests risks/benefits discussions regarding the option of thromboprophylaxis in individuals considered to be at high risk for VTE based on an assessment of VTE risk factors
ASCO®[b]
Routine thromboprophylaxis is not recommended for ambulatory patients with cancer; it may be considered for highly select high-risk patients
ASCO® = American Society of Clinical Oncology
NCCN = National Comprehensive Cancer Network
a. NCCN Clinical Practice Guidelines in Oncology®. Version b. Lyman GH, et al. J Clin Oncol. 2015;33:

8. Cochrane Review Efficacy/Safety of LMWH for VTE Prevention
Based on pooled estimates from 8 RCTs in ambulatory patients receiving chemotherapy
Risk of Symptomatic VTE
LMWH
Inactive Control
Pooled
Events
Total
Risk Ratio Random, 95% CI
Total (95% CI)
1829
1417
0.53 [0.38, 0.75]
Total events 50 82
Test for Overall effect: Z = 3.58 ( P = .0003)
0.01
0.1 10
100
Favors LMWH
Favors Control
Risk of Major Bleeding
LMWH
Inactive Control
Pooled
Events
Total
Risk Ratio Random, 95% CI
Total (95% CI)
2207
1811
1.30 [0.75, 2.23]
Total events 53 39
Test for Overall effect: Z = 0.94 ( P = .35)
CI = confidence interval
LMWH = low molecular weight heparin
RCT = randomized controlled trial
RR = risk ratio
0.01
0.1 10
100
Favors LMWH
Favors Control
Di Nisio M, et al. Cochrane Database Syst Rev. 2016;12:CD

9. PROTECHT and SAVE-ONCO Efficacy of LMWH in VTE Prevention
Patients With VTE Events , %
2.0
3.9
P = .02
n = 1608
n = 1604
Patients With VTE Events, %
1.2
3.4
P < .001
SAVE-ONCO[b]
Incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer receiving chemotherapy can be reduced with LMWH thromoboprophylaxis
a. Agnelli G, et al. Lancet Oncol. 2009;10: ; b. Agnelli G, et al. N Engl J Med. 2012;366:

10. CASSINI Study Design R End of study
Rivaroxaban 10 mg daily
Placebo
Patients with various cancer types initiating systemic chemotherapy‡ at high risk for VTE* N = 1080†
30-day follow-up
End of study
CUS
Assessed the efficacy and safety of rivaroxaban vs placebo for VTE prophylaxis in ambulatory patients with cancer initiating systemic cancer therapy and at high risk for VTE
Short design: Multinational, multicenter, randomized, double-blind, placebo-controlled phase 3b superiority study
180±3 days treatment period with follow-up visits every 8 weeks (±7 days) R
CUS = compression ultrasound
*As indicated by a Khorana risk score ≥ 2; †Patients were stratified at randomization by tumor type (pancreatic or other; up to ~25% of the patients randomly assigned were expected to have advanced pancreatic cancer); ‡Systemic cancer therapy was initiated within 72 hours of the first dose of study drug when at all possible, or within ±1 week of receiving the first dose of study drug with the intention of continuing systemic cancer therapy during the double-blind treatment period. CUS at screening and follow-up visits.
Khorana AA, et al. Thromb Haemost. 2017;117: Khorana AA, et al. N Engl J Med. 2019; 380:

11. AVERT Study Design Apixaban 2.5 mg twice daily R Placebo
End of study period: 7 months R
Newly diagnosed cancer site or progression after complete or partial remission
Initiating new course of chemotherapy for a minimum of 3 months
VTE risk stratification score of ≥ 2
N = 574
Estimated 1:1
Apixaban 2.5 mg twice daily
Placebo
Treatment period of 6 months
Assessed the efficacy and safety of apixaban vs placebo for VTE prophylaxis in ambulatory patients with cancer receiving chemotherapy and at high risk for VTE
Primary outcome: first episode of objectively documented, symptomatic or asymptomatic VTE
Kimpton M, et al. Thromb Res. 2018;164:S124-S129; Carrier M, et al. N Engl J Med. 2019;380:

12. CASSINI vs AVERT Similarities/Differences in Study Design
CASSINI[a]
AVERT[b]
Patient population
Ambulatory patients with solid tumors at high risk of VTE (Khorana score of ≥ 2)
Entry criterion
Thrombosis free by CUS
CUS not performed
Treatment duration
180 days
Primary efficacy
Time to first occurrence of objectively confirmed VTE*
ITT = intent to treat
mITT = modified intent to treat
Primary analysis
ITT
mITT
Supportive analysis
On-treatment period
*Includes symptomatic or asymptomatic VTE and VTE-related death.
a. Khorana AA, et al. Thromb Haemost. 2017;117: b. Kimpton M, et al. Thromb Res. 2018;164:S124-S129.

13. CASSINI Efficacy/Safety Outcome
 Cumulative Incidence
Rivaroxaban
Placebo
HR (95% CI)
P Value
VTE, n, % (ITT)
25/420, 6.0
37/421, 8.8
0.66 (0.40, 1.09)
.10
VTE, n, % (during treatment)
11/420, 2.6
27/421, 6.4
0.40 (0.20, 0.80) -
Major bleeding (ITT), n, %
8/405, 2.0
4/404, 1.0
1.96 (0.59, 6.49)
.26
From N Engl J Med, Khorana AA, et al., Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer, 380, , Copyright © Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

14. AVERT Efficacy/Safety Outcome
During the treatment period, major bleeding occurred in 6 of 288 patients (2.1%) in the apixaban group and in 3 of 275 patients (1.1%) in the placebo
group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24).
NS = nonsignificant
Cumulative Incidence
Apixaban
Placebo
HR (95% CI)
P Value
NNT/NNH
VTE (mITT), %
4.2
10.2
0.41 (0.26, 0.65)
< .001
NNT =17
Major bleeding (mITT), %
3.5
1.8
2.00 (1.01, 3.95)
.046
NNH = 59
Major bleeding (on treatment), %
2.1
1.1
1.89 (0.39, 9.24) NS
NNH = 100
Carrier M, et al. N Engl J Med. 2019;380:

15. Guidelines Recommendation for Treatment of CAT
NCCN[a]
LMWH as monotherapy preferred for first 6 months
Alternatives include rivaroxaban, apixaban, LMWH/warfarin, LMWH/edoxaban, LMWH/dabigatran
Minimum duration of 3 months is recommended
Indefinite duration recommended with active cancer or persistent risk factors for VTE recurrence
ASCO®[b]
LMWH as monotherapy for 6 months
Warfarin is a suggested alternative
NOACs not recommended
Indefinite duration should be considered with active cancer or persistent risk factors for VTE recurrence
a. NCCN Clinical Practice Guidelines in Oncology®. Version b. Lyman GH, et al. J Clin Oncol. 2015;33:

16. Efficacy/Safety of LMWH vs VKA in CAT Treatment
Risk of Recurrent VTE in 6 Months
Risk of Major Bleeding in 6 Months
M-H = Mantel-Haenszel
VKA = vitamin K antagonist
Wang TF, et al. Res Pract Thromb Haemost. 2018;2:

17. NOACs for Treatment of CAT Guidance From ISTH
Anticoagulant Therapy
Suggest Use of
Specific 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
GI = gastrointestinal
GU = genitourinary
ISTH = International Society on Thrombosis and Haemostasis
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:

18. Hokusai VTE Cancer Study Design
Patients with cancer and VTE (n = 1046)
LMWH
Dalteparin 200 IU/kg
R 1:1
Edoxaban 60 mg*
Dalteparin 150 IU/kg
Day 0
Day 5
Day 30
Month 12
CrCl = creatinine clearance
Primary outcome: Composite of recurrent VTE or major bleeding
van Es N, et al. Thromb Haemost. 2015;114:
*30 mg in patients with CrCl mL/m or weight <60 kg

19. Hokusai VTE Cancer Primary Outcome Components
Edoxaban vs dalteparin
HR (95% CI) = 0.71 (0.48, 1.06) P = .09
HR (95% CI) = 1.77 (1.03, 3.04) P = .04
-3.4%
2.9%
Raskob GE, et al. N Engl J Med. 2018;378:

20. Hokusai VTE Cancer Primary Outcome
Composite of first recurrent VTE or major bleeding event
HR with edoxaban = 0.97
(95% CI: 0.70, 1.36)
P = .006 for noninferiority
Raskob GE, et al. N Engl J Med. 2018;378:

21. SELECT-D Study Design Primary outcome: recurrent VTE
Patients with cancer and VTE recurrence (n = 406)
Rivaroxaban 15 mg twice/day for 3 wk then 20 mg/day
Dalteparin 200 IU/kg/day for 1 mo then 150 IU/kg/day
R 1:1
Rivaroxaban 20 mg/day
Placebo
6 mo
PE index event or
RVT positive
6 mo vs 12 mo of treatment
CRNM = clinically relevant nonmajor
PE = pulmonary embolism
RVT = residual vein thrombosis
Primary outcome: recurrent VTE
Safety outcome: major bleeding and CRNM bleeding
Young A, et al. Thromb Res. 2016;140:S172-S173.

22. SELECT-D Primary Endpoint -- Recurrent VTE at 6 Months
Rivaroxaban vs dalteparin
HR (95% CI) = 0.43 (0.19, 0.99)
(n = 203) (n = 203)
Young AM, et al. J Clin Oncol. 2018;36:

23. SELECT-D Major and CRNM Bleeding at 6 Months
Rivaroxaban vs dalteparin
HR (95% CI) = 1.83 (0.68, 4.96)
HR (95% CI) = 3.76 (1.63, 8.69)
(n = 203)
Patients with esophageal or GI cancer tended to experience more major bleeds with rivaroxaban than with dalteparin
Young AM, et al. J Clin Oncol. 2018;36:

24. Pathogenesis of NOAC-Related GI Bleeding
Mucosa
GI tract
Topical effect on the mucosa
NOAC
Topical effect
Systemic anticoagulant effect from NOAC
Incomplete absorption
(topical anticoagulant effect)
Direct caustic effect
(eg, tartaric acid in dabigatran)
Inhibition of mucosal healing
© Medscape, LLC
Cheung KS, et al. World J Gastroenterol. 2017;23:

25. Diminishing Recurrent VTE Rates in Cancer Patients With Anticoagulant Therapy
Warfarin[a]
10% to 16%
LMWH[a]
6% to 9%
NOACs[b,c]
4% to 8%
a. Wang TF, et al. Res Pract Thromb Haemost. 2018;2: ; b. Raskob GE, et al. N Engl J Med. 2018;378: ;
c. Young AM, et al. J Clin Oncol. 2018;36:

26. Persistence With Anticoagulation for CAT
Khorana AA, et al. Res Pract Thromb Haemost. 2017;1:14-22.

27. Applicability of New Data to Routine Clinical Practice
CAT Treatment
NOACs provide an oral option to LMWH
CAT Prevention
NOACs are a potential option but patient selection is critical
VTE
Bleeding
Risk Assessment

28. Summary
CAT is a major concern as it leads to hospitalization, delays in cancer treatment, and mortality
Validated risk tools allow an understanding of the risk of CAT
CASSINI and AVERT suggest that in high-risk patients rivaroxaban and apixaban are effective and safe in preventing CAT
Hokusai VTE Cancer and SELECT-D suggest that NOACs may provide a convenient way to prevent CAT recurrences
In the prevention and treatment trials, NOACs were associated with a higher risk of major bleeding, especially GI bleeds
Before making anticoagulant therapy recommendations, options must be thoughtfully discussed with every patient

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