The management of venous thromboembolism inpatients with cancer

Rupert M. Bauersachs, MDDept. of Vascular Medicine, Klinikum DarmstadtCenter of Thrombosis and Hemostasis, University of MainzProfessorship for Vulnerable Individuals and Populations (VIP)

Speaker name:

Rupert M. Bauersachs, MDI have the following potential conflicts of interest to report:

Consulting: ASPEN, Bayer, BMS, Daiichi-Sankyo, LEO

Employment in industry

Stockholder of a healthcare company

Owner of a healthcare company

Research support: ASPEN, Bayer, BMS, Daiichi-Sankyo, LEO

I do not have any potential conflict of interest

Disclosure

Munich Vascular Conference (MAC) 2019 2

Management of VTE in patients with cancer

Munich Vascular Conference (MAC) 2019 3

• Challenges of Cancer-associated thrombosis (CAT)• Evidence for LMWH• Evidence for NOACs• Guidelines• Practical implications

In cancer:VTE => leading cause of death5

VTE => worsened prognosis 5

VTE => up to 20% of cancer patients2

VTE in 50% of cancer pts at autopsy3

CancerMalignancy and thrombosis:

a double-sided clinical relationshipVTE

VTE:First sign of cancer 5

20% have active cancer4

VTE - prevention & treatment less effective 5

Epidemiology, pathophysiology

1. Khorana AA, et al. J Thromb Haemost 2007;5:632-4. 2. Farge D, et al. Thromb Res 2010;125(Suppl 2):S108-16.3. Falanga A, Zacharski L. Ann Oncol 2005;16:696-701.4. Monreal M, et al. J Thromb Haemost 2006;4:1950-65. Luxembourg B, Bauersachs R: Malignancy and thrombosis: A double-sided

clinical relationship VASA 2005; 34:225–234.

Wun T, White RH. Cancer Invest 2009;27:63–74

0

2

4

6

8

10

12

14

16

VTE

rate

per

100

pat

ient

-yea

rsVTE Risk Associated with Specific Types of Cancer

0

50000

100000

150000

200000

250000

American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014

Frequencies of Various Types of Cancer

Estimated new cases (US: 2014)

VTE Epidemiology Group Study:Incidence of First VTE in Patients with Active Cancer

Patients with active cancer and a first VTE (N=6592). Active cancer was defined as a primary diagnosis of cancer (excluding non-melanoma skin cancer) as a hospital discharge diagnosis or treatment with radiation, chemotherapy or bone marrow transplantation during hospitalization*Patients allocated to different cancer types when ≥2 were recorded on the same day. For some, no cancer type was specified

Cohen AT et al, Thromb Haemost 2017;117:57–65

0

4

8

12

16

20

Prostate (m) Breast (f) Lung Colon Haematol. Ovarian (f) Bladder Uterus (f) Pancreas Stomach Brain

30

20

10

00 2 4 6 8 10 12

Cum

ulat

ive

prop

ortio

n of

re

curr

ent m

ajor

ble

edin

g, %

Time, m

CancerNo cancer

HR=2.2

12.4%

4.9%

The Challenge of CAT:Recurrences and Bleeding During Anticoagulation

*Defined as overt and associated with either a decrease in the haemoglobin level (at least 2.0 g/dl) or the need for transfusion (≥2 units of blood), if it was retroperitoneal or intracranial, or if the treatment had to be discontinued permanently.

Prandoni P, et al. Blood 2002;100:3484–3488.8

Major Bleeding*30

20

10

00 2 4 6 8 10 12

Cum

ulat

ive

prop

ortio

n of

re

curr

ent V

TE, %

Time, m

CancerNo cancer

HR=3.2

20.7%

6.8%

Recurrent VTE

The Challenge of CAT:Long-term LMWH vs VKA: CLOT Study

Lee AY et al. N Engl J Med 2003;349:146 VKA = vitamin K antagonist; VTE = venous thromboembolism

0

10

20

Dalteparin Dalteparin / VKA

Ble

edin

g (%

)

Major Minor

Dalteparin 200 IU/kg

Oral VKA Target INR 2.5

Dalteparin 200 IU/kg OD Dalteparin ~ 150 IU/kg OD

Oral VKA armN = 338

Dalteparin armN = 338

R

Days 0–5Month 1 Months 2–6

NOAC Phase III VTE TrialsInclusion of Patients with Cancer

Phase III NOAC trials including more than 30,000 patients

van der Hulle T, et al. J Thromb Haemost. 2014;12:1116–1120 Bauersachs RM. Thromb Res. 2015;134:Suppl 1:S16-22

10

0 10.000 20.000 30.000

Cancer

No cancer

1217 patients

2.01 (1.29,3.13)

1.68 (0.86,3.28)

% NOAC VKA

Recurrent- VTECancer 4.1 6.1 RR 0.66 (0.38,1.2)

No cancer 2.6 2.5 RR 0.98 (0.83,1.2)

Major bleeding or CRNMBCancer 15.0 16.0 RR 0.94 (0.70,1.3)

No cancer 7.4 9.1 RR 0.81 (0.64,1.02)

Study RR (95% CI) RR (95% CI)

EINSTEIN 0.63 (0.22,1.79)

Hokusai 1.51 (0.37,6.17)

RE-COVER 0.82 (0.28,2.38)

AMPLIFY 0.46 (0.09,2.44)

Combined* 0.78 (0.42,1.44)

Efficacy and Safety of NOACs vs VKA in the Treatment of CAT

*Random effects model Carrier M, et al. Thromb Res. 2014;134:1214–1219.

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Study RR (95% CI) RR (95% CI)

EINSTEIN 0.64 (0.23,1.81)

Hokusai 0.52 (0.16,1.72)

RE-COVER 0.78 (0.35,1.76)

AMPLIFY 0.58 (0.14,2.34)

Combined* 0.66 (0.39,1.11)

Major Bleeding Events

0.1 1 100.1 1 10Lower risk with NOAC Higher risk with NOAC

Lower risk with NOAC Higher risk with NOAC

Recurrent VTE

Hokusai-VTE-Cancer: Study Design

Study population: Patients with cancer*

and acute symptomatic or incidental VTE#

Short design: Multinational, prospective, randomized, open-label, blinded endpoint (PROBE), non-inferiority trial

N=10503

12 months

Edoxaban60 mg od‡

Dalteparin150 IU/kg

*Cancer must be other than basal-cell or squamous cell carcinoma of the skin, be active or diagnosed within 2 years prior to randomization and objectively confirmed. Active cancer was defined as any of the following: diagnosis of cancer within the past 6 months; recurrent, regionally advanced or metastatic disease; currently receiving treatment or having received any treatment for cancer during the 6 months prior to randomization; or a haematological malignancy not in complete remission; #symptomatic or incidental VTE;‡dose adjustment to 30 mg od in patients with a body weight ≤60 kg or CrCl 30–50ml/min, or concomitant use of P-glycoprotein inhibitorsRaskob GE et al. N Engl J Med 2017; doi: 10.1056/NEJMoa1711948

R

1 monthDay 0

Day ≥5

LMWH

Dalteparin200 IU/kg

1:1

Primary EP Combination:

• Recurrent VTE plus• Major Bleeding

• Treatment ≥ 6 and ≤ 12 months• Patient characteristics (Edoxaban vs LMWH) comparable• Thrombocytopenia 50.-100.000/µl: 5,3 %• Metastases: 53,0 %; ECOG ≥3: 22% • active anti-cancer treatment: 72,3 %

12,8

7,96,9

13,5

11,3

4

0

5

10

15

20

25

Composite of first recurrent VTE ormajor bleeding

Recurrent VTE Major Bleeding

Patie

nts

(%)

LMWH/edoxabanDalteparin

Hokusai-VTE-Cancer: Primary and Secondary Outcomes

Modified Intention-to-treat population for 12 months (N=1046).

Raskob GE et al. N Engl J Med 2017; doi: 10.1056/NEJMoa1711948

HR (95% CI)

0.97 (0.70–1.36)

p=0.006

HR (95% CI)

0.71 (0.48–1.06)

p=0.09

HR (95% CI)

1.77 (1.03–3.04)

p=0.04

CAT, cancer-associated thrombosis; GI, gastrointestinal Kraaijpoel N et al, Thromb Haemost 2018;118:1439–1449

10

15

20

Maj

or b

leed

ing

even

t (%

)

Number of on-treatment days

0 30 60 90 120 150 180 210 240 270 300 330 360

Edoxaban

Dalteparin

5

0

Patients with GI cancer Patients with non-GI cancer

150120

10

15

20

Maj

or b

leed

ing

even

t (%

)

Number of on-treatment days0 30 60 90 180 210 240 270 300 330 360

EdoxabanDalteparin

5

0

Hokusai-VTE-Cancer: GI-bleeding and cancer type

15

CAT, cancer-associated thrombosis; GI, gastrointestinal Kraaijpoel N et al, Thromb Haemost 2018;118:1439–1449

0% 20% 40% 60% 80% 100%

Esophageal

Stomach

Colorectal

Hepatobilary

Pancreatic

Achs

entit

elMajor GI-Bleeding

Upper Lower None

All were not resected

Hokusai-VTE-Cancer: GI-bleeding and cancer type

Favours NOAC Favours LMWH

StudyNOAC LMWH Risk ratio

Events Patients Events Patients Weight M-H, Random (95% CI)Hokusai-VTE-Cancer 29 522 17 524 73.5% 1.71 (0.95, 3.08)

select-d 11 203 6 203 26.5% 1.83 (0.69, 4.86)

Total 725 727 100.0% 1.74 (1.05, 2.88)Total eventsHeterogeneity: Tau2=0.00; Chi2=0.01, df=1 (p=0.91), I2=0%Test for overall effect: Z=2.17 (p=0.03)

10.01 0.1 10 100

Cancer-Associated Thrombosis: LMWHs Versus NOACs*Recurrent VTE

Major bleedingFavours NOAC Favours LMWH

StudyNOAC LMWH Risk ratio

Events Patients Events Patients Weight M-H, Random (95% CI)Hokusai-VTE-Cancer 34 522 46 524 73.4% 0.74 (0.48, 1.14)

select-d 8 203 18 203 26.6% 0.44 (0.20, 1.00)

Total 725 727 100.0% 0.65 (0.42, 1.01)Total events 42 64Heterogeneity: Tau2=0.02; Chi2=1.21, df=1 (p=0.27), I2=17%Test for overall effect: Z=1.92 (p=0.06)

10.01 0.1 10 100

* Li A et al, Thromb Res 2019;173:158–163

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CARAVAGGIO: Study Design Prospective, randomized, open-label, multicentre study

Agnelli G et al, Thromb Haemost 2018;118:1668–1678

Apixaban

10 mg bid for 1 week, followed by 5 mg bid for 6 months

Dalteparin

200 IU/kg daily for 1 month, followed by 150 IU/kg for 5 months

Treatment period 6 months

— Patients with symptomatic or unsuspected proximal DVT or PE and cancer

N=~1170

R

Primary outcome: objectively confirmed recurrent VTE occurring during the study period, defined as the composite of proximal DVT of the lower limbs (symptomatic or unsuspected),

DVT of the upper limb (symptomatic) and PE (symptomatic or unsuspected)

bid, twice daily; DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism

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Management of VTE in patients with cancer

• Challenges of Cancer-associated thrombosis (CAT)• Evidence for LMWH• Evidence for NOACs• Guidelines• Practical implications

ESC Guideline

LMWH should be considered for the first 6 months over VKAs IIa A

Edoxaban considered as an alternative to LMWH in patients without GI cancer IIa B

Rivaroxaban considered as an alternative to LMWH in patients without GI cancer IIa C

Extended AC (> 6 mts) considered for indefinite period (or until cancer is cured) IIa B

Consider to manage incidental PE in the same manner as symptomatic PE (segmental or multiple subsegmental) IIa B

Task Force M, Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jimenez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Ainle FN, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL, Document Reviewers: Nazzareno Galie JSRGVAWASAAGAFAEBJBABFBJC, Document R. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019 Aug 31.2019/09/02.

ISTH, International Society of Thrombosis and Haemostasis; LMWH, low molecular weight heparin; NOAC, non-vitamin K antagonist oral anticoagulant; VTE, venous thromboembolism

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

ISTH Guidance for Treatment of Cancer-Associated VTE— NOACs suggested for patients with CAT and low risk of bleeding and no

DDI with current systemic therapy— Edoxaban and rivaroxaban are the only NOACs with RCT evidence

compared with LMWH in CAT— LMWH remains acceptable alternative

— LMWH suggested for patients with CAT and high risk of bleeding, including:• luminal GI cancers with intact primary, or with active GI mucosal

abnormalities (duodenal ulcers, gastritis, esophagitis, or colitis…)— NOACs may be acceptable alternative if no DDI with current systemic Tx

Summary

Patients with active cancer have a high risk of VTE recurrence1

• Prevalence and incidence of CAT vary by cancer type2,3

Randomized clinical trials suggest that NOACs are as effective as LMWH for the treatment of CAT to prevent VTE recurrence4,5

Current clinical guidance/guidelines recommended the use of NOACs and LMWH for treatment of patients with CAT, based on the individual clinical profile and patient preferences6

In patients with high risk of bleeding LMWH are preferred over NOACs. NOACS are contraindicated in case of malignant neoplasms at high risk of bleeding.

1. Cohen AT et al, Thromb Haemost 2017;117:57–65; 2. Cohen AT, et al. Thromb Haemost 2017;117:57-65; 3. Horsted F et al, PLoS Med 2012;9:e1001275; 4. Young A et al. J Clin Oncol 2018;36:2017–2023; 5. Raskob GE et al. N Engl J Med 2017;378:615–624; 6. Khorana AA et al, J Thromb Haemost 2018;16:1891–1894

LMWH

Unstable;high

bleeding risk

• E.g. acute leukaemia, active GI/UG lesion, oesophagus/stomach, not resected

• CrCl <30 ml/min; LFT >3x ULN• Antiplatelet agent• CNS neoplasm: primary/metastatic

• ECOG 4, poor prognosis• Acute chemotherapy; sepsis;

vomiting; mucositis; platelets <50,000 per μl

• Post-surgery <2 weeks• DDI

• Pancreatic cancer• Hepatic/renal cancer• Prostate cancer• Thyroid cancer• Lung/ovarian cancer• Chronic leukaemia• Uterine/breast cancer• Melanoma

NOAC

Stable;low

bleeding risk

• Preventive radiotherapy• Chronic chemotherapy• No active anticancer treatment; stable

disease

NOACs in Treatment of CAT: Treatment matrix

LMWH vs NOAC: no permanent decision! Adjustment to type/phase of malignancy and treatment, patient situation: Unstable, chemotherapy, vomiting, thrombocytopenia: NOAC LMWH Stable, low risk for complications and high QoL: LMWH NOAC

Bauersachs R. Akuttherapie und Prolongierte Sekundärprävention Venöser Thromboembolien. In: Lindhoff-Last E, Debus ES, KellersmannR, Tepe G, editors. med publico GmbH; 2019. p. 1-44.

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