Professor Anthony MaraveyasHull University Teaching Hospitals NHS Trust&Hull-York Medical School.

Cancer Associated Thrombosis: An Update

Disclosures

• Honoraria: Bristol-Myers Squibb (BMS), Bayer, Daiichi Sankyo• Advisory Boards: BMS, Bayer Leo • Speaker's Bureau: Bayer, Pfizer • Grant: BMS, Leo

The History of Cancer and Thrombosis

1. Trousseau A. Clin Med Hotel Dieu Paris 1865;3:654–712.2. Bouillaud JB & Bouillaud S. Arch Gen Med 1823;1:188–204;3. Billroth T. Lectures on surgical pathology and therapeutics: a

handbook for students and practitioners, 1878;2:1829–1894.

Close interrelation between cancer and thrombosis:‘two-way’ (clinical) association

• Thrombosis can occur as a complication of cancer1

• Thrombosis can be the first presenting sign of occult cancer2

• Presence of cancer cells in thrombotic material3

Virchow’s Triad in Cancer Associated Thrombosis

Virchow’s Triad in cancer2

HYPERCOAGULABILTY

Increased blood cell activation and aggregability, e.g., NETs ‘tumour educated’ platelets

Loss of haemostasis with increase in pro-coagulants, eg, increased fibrinogen, TF +MVs.

VASCULAR DAMAGE

Damaged or dysfunctional endothelium Loss of anticoagulant nature and

therefore acquisition of a procoagulantnature

Endothelial layer permeability / Angiogenesis

CIRCULATORY STASIS

Increased vascular compression/distortion Increased stasis due to immobility (being bed-bound, in

a wheelchair).

Adapted from Blann AD and Dunmore S Cardiology Research and Practice Volume 2011

Possible mechanisms in cancer patients

cfDNA, cell-free DNA; FXIIa, activated factor XII; NETs, neutrophil extracellular traps; P-sel, P-selectin; TF+ MVs, tissue factor-positive microvesicles; TF, tissue factor; vWF, von Willebrand factor. Adapted from Hisada Y et al. J Thromb Haemost 2015;13:1372–1382.

MonocytePlatelet EndotheliumcfDNA

vWF P-sel

TF+ MVs Neutrophil

ChemotherapyTumour

Venous thrombus

FXIIaNETs

TF NETs

VTE in Patients with Cancer – Cancer-Associated ThrombosisRisk factors:1

Patient-related Tumour-related Treatment-related Biomarkers

Prevalence and risk ratios: Approximately 20% of first venous thromboembolic

events occur in patients with active cancer2

VTE is a common cause of death in patients with cancer3–5

VTE recurrence rate is twice as high in patients with VTE and cancer compared with those with VTE and no cancer2,6,7

Common cancers contribute the greatest burden2

6

A

1. Ay C et al, Thromb Haemost 2017;117:219–230; 2. Cohen AT et al, Thromb Haemost 2017;117:57–65; 3. Horsted F et al, PLoS Med 2012;9:e1001275; 4. Khorana AA et al, J Thromb Haemost 2007;5:632–634; 5. Chew HK et al, Arch Intern Med 2006;166:458–464; 6. Sallah S et al, Thromb Haemost 2002;87:575–579; 7. Stein PD et al, Am J Med 2006;119:60–68

Incidence and Prevalence of VTE After Cancer Diagnosis

Incidence rate of first VTE Prevalence of first VTECommon cancer types (%) First VTE (N=6592)

Prostate (men) 17.5

Breast (women) 15.1

Lung 13.9

Colon 12.5

Haematological 10.1

Ovarian (women) 9.5

Bladder 4.8

Uterus (women) 4.2

Pancreas 3.9

Stomach 3.6

Brain 2.5

0 5 10 15

Bladder

Breast

Prostate

Haematological

Colon

Uterus

Lung

Stomach

Ovary

Brain

Pancreas

Incidence rate of first VTE per 100 patient-years

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

How does the patient present?

‘Unprovoked’ VTE • 4% end up having an underlying cancer diagnosis within 12 months of presentation

Hospital acquired • The most lethal

– Frailty– Coexisting complications– First and last port of call (advanced presentation with complications)– Procedures (surgery) – Immobility (Bone metastases-Brain metastases)– Bleeding risks (not allowing thromboprophylaxis)– Difficult to diagnose from what else is going on

Ambulant • Conventional presentation • Incidental

Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715

• Population-based case-control (MEGA) study

• N=3220 consecutive patients with 1st VTE vs. n=2131 control subjects

• CA patients = 7x OR for VTE vs. non-CA patients

Effect of Malignancy on Risk of Venous Thromboembolism (VTE)

0

10

20

30

40

50

Hem

atol

ogic

al

Lung

Gas

troi

ntes

tinal

Bre

ast

Dis

tant

met

asta

ses

0 to

3 m

onth

s

3 to

12

mon

ths

1 to

3 y

ears

5 to

10

year

s

> 15

yea

rs

Adj

uste

d od

ds ra

tio

Type of cancer Time since cancer diagnosis

2822.2 20.3

4.9

19.8

53.5

14.3

2.6 1.13.6

Dia

gnos

is

Star

t che

mo

+ in

patie

nt

Che

mo

Rel

apse

Met

asta

sis

Remission

Ris

k of

ven

ous

thro

mbo

embo

lism

Cancer journey

General population

Cancer patient

The Cancer Journey and VTE Risk

Figure adapted from .Lyman GH et al. Cancer 2011;117:1334–1349

LMWH Vs Warfarin

Treatment of Cancer Associated Thrombosis

Warfarin failure in Cancer Patients

20

0 1 2 3 4 5 6 7 8 9 10 11 12Time (months)

30

0

10

Cum

ulat

ive

prop

ortio

n re

curre

nt V

TE (%

)

Cancer

No cancer

20.7% vs 6.8%; HR 3.2 at 1 year

Warfarin to maintain INR 2–3

Major bleeding 12.4% vs 4.9%; HR 2.2

VTE and bleeding not predicted by INR

Number of

patients

Cancer 181 160 129 92 73 64

No cancer 661 631 602 161 120 115

Prandoni P, et al. Blood. 2002;100:3484-3488.

Amiodarone26%

Ciprofloxacin22%Cotrimoxazole

15%

Metronidazole8%

Fluconazole7%

Omeprazole5%

Cimetidine5%

NSAID‘s3%

Erythromycin3%

Carbamazepine3%

APAP3%

Frequency of Potentially Interacting Drugs

n=59

Capecitabine

Tamoxifen

Sorafenib

Sunitinib

Twilley C. H. 2002

5 to 7 days

Dalteparin 200 IU/kg OD

Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo

Control Group

Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo

Experimental Group

1 month 6 monthsLee AY, et al. N Engl J Med. 2003;349:146-153.

Cancer patients with acute DVT or PE (n=677)

CLOT Study: Reduction in Recurrent VTE

CLOT Study: Reduction in Recurrent VTE

Lee et.al. N Engl J Med, 2003;349:146

0

5

10

15

20

25

Days Post Randomization0 30 60 90 120 150 180 210

Prob

abilit

y of

Rec

urre

nt V

TE, % Risk reduction = 52%

p-value = 0.0017

Dalteparin

OAC

Recurrent VTE

Study RR (95% CI)*,1 RR (95% CI)*,1 ARR

CLOT2 0.51 (0.33–0.79) 7.8%

Hull3 0.44 (0.19–0.99) 9.0%

Deitcher4 0.66 (0.18–2.52) 3.4%

Romera5 0.26 (0.06–1.02) 15.7%

CATCH6 0.69 (0.45–1.07) 3.1%

Efficacy and Safety Profile of LMWH Versus VKAs in the Treatment of CAT

Recurrent VTE

LMWH is associated with a significant reduction in the risk of recurrent VTE without a significant increase in major bleeding events versus VKA

0.01 0.1 0.2 0.5 1 2 3

Favours LMWH Favours VKA

0.1 0.2 0.5 1 2 5 10 100

Favours LMWH Favours VKA

*Random effects model

1. Carrier M, Prandoni P, Expert Rev Hematol 2017;10:15–22; 2. Lee AYY et al, N Engl J Med 2003;349:146–153; 3. Hull RD et al, Am J Med 2006;119:1062–1072; 4. Deitcher SR et al, Clin Appl Thromb Hemost 2006;12:389–396; 5. Romera A et al, Eur J Vasc Endovasc Surg 2009;37:349–356; 6. Lee AYY et al, JAMA 2015;314:677–686

Study RR (95% CI)*,1 RR (95% CI)*,1 ARI

CLOT2 1.57 (0.79–3.14) 2.0%

Hull3 1.00 (0.38–2.64) 2.1%

Deitcher4 3.04 (0.52–18.99) 6.1%

CATCH6 1.09 (0.51–2.32) 0.3%

Major bleeding events

CAT, cancer-associated thrombosis; CI, confidence interval; HR, hazard ratio; LMWH, low molecular weight heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism*Dalteparin versus VKA; in the VKA arm the estimated time in therapeutic range was 46% (30% below and 24% above); #tinzaparin versus warfarin; in the warfarin arm the time in therapeutic range was 47% (26% below and 27% above); ‡meta-analysis included four other small studies in addition to the CLOT study; §meta-analysis included three other small studies in addition to the CLOT study 1. Lee AYY et al, New Engl J Med 2003;349:146–153; 2. Lee AYY et al, JAMA 2015;314:677–686; 3. Akl EA et al, Cochrane Database Rev 2014;7:CD006650

LMWH: Effective and Safe – Residual Burden of Disease

LMWH monotherapy LMWH overlapping with VKA

HR (95% CI)

n/N (%) n/N (%)

Recurrent VTE

CLOT study*1 27/336 8.0 53/336 15.8

CATCH study#2 31/449 6.9 45/451 10.0

Meta-analysis‡3 42/591 7.1 82/571 14.4

Major bleeding

CLOT study*1 19/338 5.6 12/335 3.6

CATCH study#2 12/449 2.9 11/451 2.4

Meta-analysis§3 37/556 6.7 32/536 6.0

0.1 1 10Favours LMWH Favours VKA

Not reported

Multivariate predictors of VTE recurrence

Population-based cohort study performed using the Olmstead county database; 477 patients (1533 patient-years of follow-up) with cancer and VTE were identified

Chee CE et al, Blood 2014;123:3972‒3978

Risk of VTE Recurrence May Depend on Tumour Type, Stage of Disease and Co-morbidities

70

Cum

ulat

ive

inci

denc

e of

VTE

re

curr

ence

(%)

1009080

605040302010

00 1 2 3 4 5 6 7 8 9 10

Time after incident VTE (years)

Active cancer without predictors Active cancer with predictors Other secondary VTE

Characteristic HR 95% CI p-value

Stage IV pancreatic cancer 6.38 2.69–15.13 <0.0001

Brain cancer 4.57 2.07–10.09 0.0002

Myeloproliferative or myelodysplastic disorder 3.49 1.59–7.68 0.002

Ovarian cancer 3.22 1.57–6.59 0.001

Stage IV cancer (non-pancreas) 2.85 1.74–4.67 <0.0001

Lung cancer 2.73 1.63–4.55 0.0001

Neurological disease with leg paresis 2.38 1.14–4.97 0.02

Cancer stage progression 2.14 1.30–3.52 0.003

Warfarin therapy 0.43 0.28–0.66 <0.0001

Cumulative incidence of first VTE recurrence

CI, confidence interval; HR, hazard ratio; LMWH, low molecular weight heparin; VTE, venous thromboembolism

Duration of Anticoagulation After VTE in Real-World Clinical Practice: RIETE Registry (N=6944)

Fewer than 50% of patients with cancer are treated for >12 months

Ageno W et al, Thromb Res 2015;135:666–672

Cum

ulat

ive

inci

denc

e (%

)

Days

28%9%

Unprovoked

Persistence in patients with CAT(after excluding patients who died): only 43.2% at 1 year still receiving anticoagulant treatment

TransientCancer

Persistence with Index Therapy in Patients with Cancer Is Higher With Warfarin Than LMWH

*Discontinuation was defined as a gap of no more than 60 days between the end of the days of supply of a dispensing and the start date of the next dispensing of the index therapy, if any

Khorana AA et al, Res Pract Thromb Haemost 2017;1:14–22

Cohort Median treatment duration

Kaplan–Meier rates6 months 12 months

LMWH 3.3 37% 21%

Warfarin 7.9 61% 35%

Warfarin (n=1403)

LMWH (n=735)

100

75

50

25

0

Prop

ortio

n of

pat

ient

s st

ill o

n in

dex

ther

apy

(%)

0 2 4 6 8 10 12Time (months)

FOR REACTIVE USE ONLY.

Adjusted OR (95% CI)Pancreatic

Stomach

Ovarian

Brain

Lung

Age ≥80 vs 60–69 years

Radiation therapy vs chemotherapy

OR adjusted by age, gender, tumour type, cancer therapy, lifestyle factors and co-morbidities; prostate cancer was used as a reference group for calculating ORs by tumour location

Katholing A et al, ESMO 2016: Poster 1479P

FavoursVKA

Favours parenteral therapy

Database Analysis: Predictive Factors for Use of Parenteral Versus OACs for VTE Treatment in Patients with Active CancerMatched cohort retrospective database analysis (2008–2015)

—Retrospective analysis of data from general practices in England from patients with cancer and VTE• 1228 parenteral anticoagulant users

were matched to 1228 VKA users—Some tumour types were strongly

associated with preferential use of parenteral therapies

0.25 1 4 16

CI, confidence interval; LMWH, low molecular weight heparin; OAC, oral anticoagulant; OR, odds ratio; VKA, vitamin K antagonist; VTE, venous thromboembolism

Long Term Treatment of VTE in Cancer

ASCO: Extended anticoagulation with LMWH or VKA may be considered beyond 6/12 for patients with metastatic disease or patients who are receiving chemotherapy.• Length of secondary prophylaxis?

– LONGHEVA NCT01164046 (Netherlands) – Warfarin vs LMWH (+6 m)

– ALICAT ISRCTN37913976 (UK)- LMWH vs No anticoagulant (+6 m)– Funded by HTA NIHR

10%

4% 5% 4%

Month 1-12N=334

Month 1N=334

Month2-61N=302

Month 7-12N=192

Incidence of Major Bleeding Events

1.9% per month through the whole study (12 months)

• Incidence of new or recurrent VTE: 11.1% (1.4% per patient-month)

• 154 (46.1%) patients died, 115 during the study period (4/115 due to

VTE, 2/115 due to bleeding Adapted from Kakkar A, et al. J Thromb Haemost. 2013;11:AS12.3.

Cumulative Probability of Survival

Reason for Death Frequency

Underlying Cancer 105

VTE 4

Bleeding 2

Long-term Management of VTE in Cancer Patients: The DALTECAN Study

What Is Important for Patients?

1. No interference with cancer treatment 39%2. Efficacy/recurrent VTE 24%3. Major bleeding 19%4. Route of administration 13%

5. Monitoring 2%6. Minor bleeding 2%7. Frequencency of administration 1%

Noble S et al, Haematologica 2015;100:1486–1492

From LMWH to DOACS (Anti fXa inhibitors)

Treatment of Cancer Associated Thrombosis

*Rivaroxaban 15 mg BID for 21 days followed by 20 mg OD. For patients with CrCl 30–49 ml/min dosing recommendations as in rivaroxaban SmPC; #Dalteparin 200 IU/kg OD for the first 30 days followed by 150 IU/kg ODbid, twice daily; CrCl, creatinine clearance; DVT, deep vein thrombosis; od, once daily; PE, pulmonary embolism; VTE, venous thromboembolismThe second randomization phase for extended treatment of VTE from 6 to 12 months for patients with PE as an index event or patients with Residual DVT at 5 month assessment was closed due to low recruitment. Sample size reduced from 530 to 400 patients for main trial comparison (95% CI for VTE recurrence +/-4.5%)Young A et al, Thromb Res 2016;140:S172–S173; EudraCT number: 2012-005589-37; Bach M et al, Thromb Haemost 2016;116:S24–S32; Data on File

Study design: Prospective, randomized, open-label, multicentre pilot phase III study

select-d: Phase III Pilot Study Comparing Rivaroxaban versus Dalteparin for the Treatment of Cancer Associated Thrombosis

Stratification variables:• Stage of disease• Baseline platelet count • Type of VTE • Risk of clotting by tumor type

Study population: Cancer patients

with symptomatic DVT and/or PE RVT negative

before 6 months N~130 No treatment

Follo

w-u

p

R

6 months

Rivaroxaban

Placebo

R

12 months

PE index event or RVT positive

before 6 months N~300

N~530 Rivaroxaban*

Dalteparin#

DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism; Ci, Confidence interval Young A et al. J Clin Oncol 2018;doi:10.1200/JCO.2018.78.8034

select-d Primary Outcome: Lower Incidence of VTE Recurrence Events with Rivaroxaban Versus Dalteparin

DalteparinRivaroxaban

Number at riskDalteparin 203 171 139 115

Rivaroxaban 203 174 149 134

40

35

30

25

20

15

10

5

00 1 2 3 4 5 6

Time from trial entry (months)

VTE

recu

rren

ce (%

)Outcome at 6 months Rivaroxaban

(n=203)Dalteparin

(n=203)VTE recurrence, % (95% CI) 4 (2–9) 11 (7–16)

Lower limb DVT/PE recurrence,% (95% CI) 3 (1-7) 9 (6-15)

Type of PE, NoSymptomaticIncidentalFatal PE

211

261

select-d Secondary Outcome: Incidence of Major, Fatal and Clinically Relevant Non-Major Bleedings

2.90.5

3.45.4

0.5

12.3

0

5

10

15

20

Major bleeding Fatal Bleeding CRNMB

Patie

nts

(%)

Dalteparin Rivaroxaban

• All bleedings events were adjudicated .Overall survival at 6 months was 75%(63-76%) in the rivaroxaban group and 70%(69-81%) in the dalteparin group.

• CRNMB, clinically relevant non-major bleeding

Young A et al. J Clin Oncol 2018;doi:10.1200/JCO.2018.78.8034

Most Major Bleedings events were Gastrointestinal Bleedings*. Most CRNMB were GI or urologicNo Central Nervous System Bleeding was observed in rivaroxaban and dalteparin groups.

Treatment for up to 12 months (at least 6 months) Efficacy and safety data collected during the entire 12 month study period Independent blind adjudication of all suspected outcomes Severity of major bleeding at presentation also adjudicated

Hokusai VTE – Cancer Study Design

Raskob GE et al, N Engl J Med 2018;378:615–624

Primary Outcome: Time to First Occurrence of Recurrent VTE or Major Bleeding

13.5%

12.8%

HR=0.97 (0.7–1.36)

p=0.006

Raskob GE et al, N Engl J Med 2018;378:615–624

Time to Recurrent VTE, Major Bleeding and Survival

Recurrent VTE Major Bleeding Event-free Survival

HR=0.71 (0.48–1.06) HR=1.77 (1.03–3.04) HR=0.93 (0.77–1.11)

p=0.09 p=0.04 p=NS

E 7.9% vs D 11.3%

E 6.9% vs D 4.0%

E 55.0% vs D 56.5%

Raskob GE et al, N Engl J Med 2018;378:615–624

11

446

0

5

10

15

20

25

Recurrent VTE Major bleeding

Cum

ulat

ive

rate

at

6 m

onth

s (%

)

Dalteparin (n=203) Rivaroxaban (n=203)

11.3

4.0

7.9 6.9

0

5

10

15

20

25

Recurrent VTE Major bleeding

Inci

denc

e at

12

mon

ths

(%)

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

NOACs for the Treatment of CAT

select-d1*

No cross-comparison intended

*select-d: multicentre (UK), prospective, randomized, open-label, pilot trial (N=406). Cumulative rate of CRNM bleeding at 6 months: 4% (dalteparin) versus 13% (rivaroxaban; HR=3.76; 95% CI 1.63–8.69); #Hokusai-VTE-Cancer: multinational, prospective, randomized, open-label, blinded endpoint, non-inferiority trial (N=1050).2,3 Primary outcome (mITT): composite of recurrent VTE or major bleeding during the 12 month study period (HR=0.97; 95% CI 0.70–1.36). Incidence of CRNM bleeding at 12 months: 11.1% (dalteparin) versus 14.6% (edoxaban; HR=1.38; 95% CI 0.98–1.94)2

1. Young A et al, J Clin Oncol 2018;36:2017–2023; 2. Raskob GE et al, N Engl J Med 2018;378:615–624; 3. Van Es N et al, Thromb Haemost 2015;114:1268–1276

Hokusai-VTE-Cancer2,#

HR=0.43 (95% CI 0.19–0.99)

HR=1.83 (95% CI 0.68–4.96)

HR=0.71(95% CI 0.48–1.06);

p=0.09 HR=1.77(95% CI 1.03–3.04);

p=0.04

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

Hokusai-VTE: Bleeding GI Versus Non-GI Cancers

10

15

20

Maj

or b

leed

ing

even

t (%

)

Number of on-treatment days0 30 60 90 120 150 180 210 240 270 300 330 360

EdoxabanDalteparin

5

0

Patients with GI cancer Patients with non-GI cancer

Number at risk

Edoxaban 357 315 284 271 255 234 220 190 179 171 144 123 88Dalteparin 384 347 305 278 254 236 216 151 138 131 108 95 63

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

Number at risk

Edoxaban 165 134 121 108 97 89 79 70 64 59 48 38 28Dalteparin 140 123 116 108 94 89 79 67 60 54 48 40 25

High risk

Active GI or urothelial tumours

Canadian Expert Consensus GuidelineCAT without contraindication to anticoagulation

(both incidental and symptomatic; lower-limb DVT and PE)

Risk of bleeding?(Consider well-documented risk factors for bleeding including GI toxicity

[i.e. GI co-morbidity, previous GI bleed, treatment-associated with GI toxicity], thrombocytopenia [<50,000 platelets/ml/min], 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?

DDIs with NOACs based on pharmacist-led PK review?

LMWH NOAC*

Other factors to consider:– Patient preference, after informing patient of

risks and benefits– Drug coverage– Body weight (consider LWMH in patients with

BMI >40 kg/m2 or weight >120 kg)– Burden of cancer (e.g. recurrence or

progression) and burden of VTE (consider LMWH for patients with severe symptoms, e.g. iliofemoral DVT, extensive PE, submassive PE, any thrombolysed patient)

– Renal impairment (consider LMWH for patients with GFR per the Cockcroft–Gault formula of 30–50 ml/min)

– Significant GI surgery or absorption disorders (consider LMWH for patients with impaired GI absorption)

– Pre-existing conditions and co-medication (e.g., ASA, other antiplatelet medications)

Non-high risk

Other types, non-active GI/urothelial tumours

No

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

Cancer status: still active? Consider stopping

Yes

Yes No

*Currently, edoxaban and rivaroxaban are the only NOACs with RCT evidence in CAT, with the evidence base stronger for edoxabanBMI, body mass index; CAT, cancer-associated thrombosis; DDI, drug-drug interaction; DVT, deep veinthrombosis; GFR, glomerular filtration Rate; GI, gastrointestinal, LMWH, low molecular weight heparin; PE, pulmonary embolism; UFH, unfractionated heparin

Adapted from Carrier M et al, Curr Oncol 2018;25:329–337

2019 ASCO Guidelines for the Treatment of CAT

Initial anticoagulation (5–10 days)

Long-term anticoagulation (<6 months)

Extended anticoagulation (≥6 months)

LMWH, edoxaban or rivaroxaban for at least 6 months is preferred because of their improved efficacy over VKAs

VKAs are an acceptable alternative for long-term therapy if LMWH or DOACs are not available

LMWH, DOACs or VKAs for extended anticoagulation beyond 6 months may be considered for selected patients* with active cancer

Initial anticoagulation may involve LMWH, UFH, fondaparinux or rivaroxaban

LMWH is preferred over UFH for the initial 5–10 days of anticoagulation for the patient with cancer with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance <30 ml/min)

*Such as those with metastatic disease or receiving chemotherapy

Key NS et al, J Clin Oncol 2019; doi: 10.1200/JCO.19.01461

Summary of Recent Guidelines/Guidance for the Treatment of CAT

ISTH SSC 20181 NCCN 20192 ASCO 20193

Anticoagulant choice NOACs (edoxaban and rivaroxaban) and LMWH are the preferred agents

Choice dependent on the risk of bleeding (LMWH preferred in patients with a high risk of bleeding) and potential for DDIs

Lists appropriate monotherapy/combined therapy options, including edoxaban, rivaroxaban and apixaban

Initial anticoagulation (first 5–10 days): LMWH or rivaroxaban preferred

Long-term (<6 months): LMWH, edoxaban or rivaroxaban (VKAs are acceptable alternatives for long-term therapy if LMWH/DOACs aren’t available)

Extended therapy (≥6 months): LMWH, edoxaban or rivaroxaban or VKAs

Duration of therapy No recommendations provided

No recommendations provided

Extended therapy beyond 6 months can be considered for select patients with active cancer

1. Khorana AA et al, J Thromb Haemost 2018;16:1891–1894; 2. NCCN guidelines v. 1.2019 (accessed 18 Apr 2019); 3. Key NS et al, J Clin Oncol 2019; doi: 10.1200/JCO.19.01461

What Are the Implications of These New Guidelines?

NOACs are now clearly an option for the treatment of cancer-associated VTE ‘One size fits all’ approach (e.g., LMWH for everyone) is no longer appropriate Patient selection is key, incorporating bleeding risk/renal function/

drug–drug interactions CAT treatment is not any more a ‘baseline assessment’ exercise Patient preferences should be considered

Thank You