Cancer Associated Thrombosis · • metastatic disease •tumour type: pancreas, lung...

Cancer Associated ThrombosisReview and Update

Agnes Lee MD MSc FRCPCAgnes Lee, MD, MSc, FRCPCUniversity of British Columbia, Vancouver, BCOctober 2012

DisclosuresDisclosures• Bayer

• Boehringer Ingelheim

B i t l M S ibb• Bristol‐Myers Squibb

• Eisai

• Leo Pharma

Pfi er• Pfizer

• Sanofi‐Aventis

ObjectivesObjectives

To review evidence and updates in:To review evidence and updates in:

• Epidemiology and Pathophysiology

• Risk Assessment Models

• Role of Outpatient Primary Prophylaxis

• Treatment of VTE• Treatment of VTE

Cancer‐Associated Thrombosis

• ~20% of all VTE cases are associated with cancer

Cancer Associated Thrombosis

• higher mortality among patients with VTE than withoutwithout

• 2nd leading cause of death in cancer patients

• activation of coagulation is important for tumour progression and metastasis

• effective prophylaxis and treatment will reduce morbidity and may decrease overall mortality

Heit Arch Intern Med 2000. Heit Arch Intern Med 1999. Sorensen NEJM 2000. Pradoni N Engl J Med 1992. Sorensen N Engl J Med 1988. Chew Arch Intern Med 2006. Khorana J Thromb Haemost 2007.

Virchow's TriadVirchow s Triad

Venous stasisobesity

Vascular injurysurgery

Risk factors are cumulative

immobilitychronic heart disease

chemotherapytrauma

catheterizationcumulative

Hypercoagulabilitymalignancy

hereditary risk factors>40

Anderson & Spencer Circulation. 2003.

age >40

Risk Factors for VTE in CancerRisk Factors for VTE in Cancer• Risk varies from 1 – 30% depending on:

Patient‐related Cancer‐related Treatment‐related

• Older age• Race

P i VTE

• Primary site• Histology

St

• Surgery• Chemotherapy

H l th• Prior VTE• Platelet count• Obesity

• Stage• Grade • Time interval

• Hormonal therapy• Antiangiogenic

agents• Obesity• Comorbid

conditions

• Time interval since diagnosis

g• ESA• Hospitalization

Lyman J Clin Oncol 2007. Heit Arch Intern Med 2000. Blom JAMA 2005.

• Catheters

Who Are At Risk for CAT?Who Are At Risk for CAT?• Highest VTE risk in:

– Older patients

– Pancreatic, brain, upper GI, lung, ovarian, lymphoma, , , pp , g, , y p ,

– Metastatic disease

– First 3 months after cancer diagnosisFirst 3 months after cancer diagnosis

– First month after surgery

– During systemic chemotherapy (especially cisplatin– During systemic chemotherapy (especially cisplatin, anthracyclines, thal/lenalidomide, bevacizumab)

• Important to educate patients regarding signsImportant to educate patients regarding signs and symptoms of VTE



• Epidemiology and Pathophysiology




Risk StratificationRisk Stratification

RiskRisk of VTE

Patient‐related

9

Risk Factors

Khorana Model for Outpatients

P ti t Ch t i ti S

Khorana Model for Outpatients

Patient Characteristic Score

Site of Cancer

V hi h i k ( h ) 2Very high risk (stomach, pancreas)

High risk (lung, lymphoma, gynecologic, GU excluding prostate)

2

1

h h l l 3 0 000/ 3 1Pre‐chemotherapy platelet count > 350,000/mm3 1

Hb < 10g/dL or use of ESA 1

Prechemotherapy leukocyte count > 11,000/mm3 1

BMI > 35 kg/m2 1

Khorana et al. Blood 2008.

Khorana Model Validation• Prospective follow up of 819 patients• Median observation time/follow‐up: 656 days

Khorana Model Validation

Median observation time/follow up: 656 days

6 mo cumulative VTE ratesL k t t P 0 001) 6‐mo cumulative VTE rates:Patients Events

n %

S ≥3 93 17 7%

Log‐rank test P<0.001)

Score ≥3 93 17.7%

Score 2 221 9.6%

S 1 229 3 8%Score 1 229 3.8%

Score 0 276 1.5%

Ay et al Blood 2010.



• Epidemiology




LMWH in Solid TumoursLMWH in Solid TumoursPROTECHT

N=1150SAVE‐ONCO

N=3212N 1150

5%

Placebo Semuloparin5%

Placebo Nadroparin

N 3212

4%P<0.0001

3.4%4%

P=0.02

3.9%

2%

3%

P=NS

1 2% 1 1% 1 2%2%

3%

P=NS2.0%

0%

1%

1.2% 1.1% 1.2%

0%

1%

0%

0.7%

0%VTE Major BleedVTE Major Bleed

Agnelli Lancet 2009. Agnelli N Engl J Med 2012.

LMWH in Pancreatic CancerLMWH in Pancreatic CancerPROSPECT‐CONKO 004 FRAGEM

10%

no treatment enoxaparin

N=312

25%

no treatment dalteparin N=123

8%

10%

P<0.01

9.9% 20%

P=0.002

23%

4%

6%P 0.01

P=0.610%

15%

P=NS

0%

2%

1.3%2.6%

3.8%

0%

5%3.4% 3.4% 3.2%

0%VTE bleeding

Riess presented at ASCO May 2009. Maraveyas Eur J Cancer 2011.

0%AVTE bleeding

Who Should Get Primary Prophylaxis?Who Should Get Primary Prophylaxis?

• Routine primary prophylaxis is not indicated inRoutine primary prophylaxis is not indicated in ambulatory patients

• Should be considered in patients with multipleShould be considered in patients with multiple risk factors:– Previous history of thrombosis

– Advanced pancreatic cancer on chemotherapy

– High Khorana Scoreg

• Prophylaxis with LMWH effective in reducing VTE

I t t t d t ti t di i d• Important to educate patient regarding signs and symptoms

Who Should Get Primary Prophylaxis?

• ACCP 2012 recommendation: Grade 2B

Who Should Get Primary Prophylaxis?

– In outpatients with solid tumours who have additional risk factors for VTE and who are at lowadditional risk factors for VTE and who are at low risk of bleeding, we suggest prophylactic‐dose LMWH or LDUH over no prophylaxis

– Additional risk factors: previous venous thrombosis, immobilization, hormonal therapy,thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide

Kahn et al. Chest 2012;141(2) Suppl:e195S‐e226S



• Epidemiology




Treatment of CATTreatment of CAT• All major consensus guidelines recommend j gmonotherapy with LMWH as the preferred treatment for CAT

• Recommendations are based on results of 3 open‐label, randomized controlled trialsp

– CATHANOX study: enoxaparin vs warfarin

– CLOT study: dalteparin vs warfarin or acenocoumarolCLOT study: dalteparin vs warfarin or acenocoumarol

– LITE study: tinzaparin vs warfarin

Kearon et al Chest ACCP 9th edition 2012. NCCN 2011. Lyman et al J Clin Oncol 2007. ESMO 2011.

Study DesignStudy Design

LMWH

Vitamin K antagonist (INR 2.0 to 3.0)Control Group

Tinzaparin 175 U/kg ODLITE

CATHANOX Enoxaparin 1.5 mg/kg OD

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

Tinzaparin 175 U/kg OD

CLOT

LITE

Dalteparin 200 IU/kg OD then 150 IU/kg OD

5 – 7 days 1 month 3 months 6 months

CLOT

Risk of Recurrent VTE with LMWHRisk of Recurrent VTE with LMWHCLOT Trial Cochrane Syst Review

20

25

TE, %

HR (95% CI)

Recurrent VTE0.47

log‐rank P = 0.002

5

10

15

Recurrent V

T

dalteparin, 9%

VKA, 17%Recurrent VTE

(0.32 – 0.71)

Major bleeding1.05

0

5

0 30 60 90 120 150 180 210

dalteparin, 9% j g(0.53 – 2.10)

Thrombocyto‐penia

1.02(0 60 – 1 74)

Days Post Randomization

risk reduction = 52%HR 0 48 (95% CI 0 30 0 77)

p (0.60 1.74)

Overall survival0.96

(0.81 – 1.14)

Lee et al New Engl J Med 2003. Akl et al Cochrane Database Syst Rev 2011.

HR 0.48 (95% CI 0.30, 0.77)

Comparison of LMWHsComparison of LMWHsEnoxaparin Dalteparin Tinzaparin

Molecular weight (d) 4500 5600 6500

Anti‐Xa:Anti‐IIa ratio 4:1 2.5:1 1.9:1

R l lRenal clearance +++ ++ +

CAT indication No Yes No

30 mg

Prefilled Syringe sizes

30 mg40 mg60 mg80 mg

5000 U7500 U10,000 U12 500 U

2,500 U3,500 U4,500 U10 000 Uy g g

100 mg120 mg150 mg

12,500 U 15,000 U18,000 U

10,000 U14,000 U18,000 U

MDV Concentration 100 mg/mL 25,000 U/mL 20,000 U/mL

Recurrent VTE and Bleeding on

30 30

VKA%

Hazard ratio 3.2

Cancer 21%

%

Hazard ratio 2.2

20

rren

t VTE, % 20

r Bleed

ing, %

Cancer 12%

10Recur

No Cancer 7% 10Major

No Cancer 5%

0 1 2 3 4 5 6 7 8 9 1011120

0 1 2 3 4 5 6 7 8 9 10 11 120

Time (months)

Prandoni et al. Blood 2002.

Time (months)

Unanswered QuestionsUnanswered Questions

• Duration of treatment?• Duration of treatment?

• Treatment of recurrent thrombosis?

• Treatment in patients with high risk of bleeding?

• Role of novel anticoagulants?• Role of novel anticoagulants?

Duration of AnticoagulationDuration of Anticoagulation• No clinical trial evidence on optimal durationp• Decision depends on risk of recurrence versus risk of bleeding– incidence of these events not well documented– case fatality may differ from non‐cancer patients

• Other important considerations:– quality of life– life expectancy – drug cost – tolerability and patient preference

Recurrence and Bleeding• Risk factors for recurrent VTE

Recurrence and Bleeding

• younger age (less than 65 y)• metastatic disease• tumour type: pancreas, lung (adenocarcinoma), adenocarcinoma of unknown primary

• Risk factors for major bleeding• recent major bleeding

i di• metastatic disease• creatinine clearance < 30 ml/min

N d bi k i di i bl di• No data on biomarkers in predicting recurrence or bleeding

Lee et al Proc ASCO 2009. Trujilli‐Santos et al Thromb Haemost 2008. Louzada et al Blood Coagul Fibrinolysis 2011.

Duration of AnticoagulationDuration of Anticoagulation• General expert/guidelines consensus:

– minimum of 3 – 6 months

– continue as long as cancer is active or chemotherapy iscontinue as long as cancer is active or chemotherapy is ongoing

– discontinue if risk of serious bleeding is high or patient g g ppreference

• Consider risk factors for recurrence and bleedingg

• Frequently evaluate patients and tailor therapy according to risk benefits preferenceaccording to risk, benefits, preference

Lyman et al J Clin Oncol 2007. Kearon et al Chest ACCP 9th Edition. NCCN 2011 guidelines.

Treatment of Recurrent VTETreatment of Recurrent VTE• Experienced‐based recommendations:p

– switch to LMWH for “warfarin failures”

LMWH dose escalation for “LMWH failures”– LMWH dose escalation for LMWH failures

• Possible mechanisms for LMWH failure:

– Accelerated clearance or increased nonspecific binding

– Massive thrombin generation

– Acquire AT deficiency

– NoncomplianceNoncompliance

Luk et al Am J Med 2001. Carrier et al J Thromb Haemost 2009.

Approach to Recurrent VTESymptomatic recurrent VTE

Failure on Warfarin Failure on LMWH

Switch to full dose LMWH* Increase LMWH by ~25% or back up to full dose*

Reassess in 5-7 days†

No improvement Symptomatic improvemento p o e e t Sy pto at c p o e e t

Check peak anti-Xa level Continue same dose

Increase LMWH dose accordingly to aim for:1.6 – 2.0 U/mL for once daily dosing or

0.8 – 1.0 U/ml for twice daily dosing

Resume usual follow-up

*full dose refers to the recommended weight-adjusted dose of LMWH for the initial therapy of VTE.†Reassessment should consist of clinical evaluation of symptoms. Radiological imaging is not required except when deterioration is noted and further extension or new thrombosis is suspected.

Lee. Hematology 2010 ASH Education Book.

Once vs Twice Daily Injections• Patients with acute DVT/PE (15% had cancer)

Once vs Twice Daily Injections

• Randomized to UFH, enoxaparin 1.5 mg/kg OD, or enoxaparin 1.0 mg/kg bid

All Pts, N

Recurrent VTE

Cancer Pts, n

Recurrent VTE,

UFH IV 290 12 (4.1%) 45 3 ( 6.7%)

enoxaparin OD 298 13 (4.4%) 49 6 (12.2%)

enoxaparin bid 312 9 (2.9%) 47 3 ( 6.4%)

Merli et al Ann Intern Med 2001.

IVC FiltersIVC Filters• Efficacy and safety remain ill‐defined after 40 years of usage

• Accepted indication:– acute VTE with contraindication to anticoagulation

• Controversial indications:– failure of anticoagulation– free‐floating or iliocaval thrombosis– primary prophylaxis in trauma or surgical patients

• Long‐term data from single RCT showed no reduction in total VTE or mortality

Streiff Blood 2000. Decousus et al N Engl J Med 1998. PREPIC investigators Circulation 2005.

IVC Filters ComplicationsIVC Filters Complications• Insertion complications occur in 4 – 11%

• Long‐term complications are not infrequent– thrombosis (6 – 36%)

– filter tilt, fracture, migration or embolization (3 – 69%)

– IVC perforation (3 – 86%)

– post‐thrombotic syndrome (5 – 70%)

• Retrievable filters may reduce long‐term complications but– mixed results regarding long‐term safety

– often become permanent as retrieval rates are low (18 – 60%)

– PE still happens (2 – 6%)!

Streiff Blood 2000. Durack et al Cardiovasc Intervent Radiol 2012. Hammond et al Clin Radiol 2009. Imberti et al J Thromb Thrombolysis 2012.

Filters: FDA Safety AlertFilters: FDA Safety Alert• Between 2005 and 2010, 921 adverse event reports on

filters were received by FDA– 36% involved device migration

– 16% involved embolizations

– 8% involved perforation of the IVC

• May be related to retrievable filters remaining in situ for long periods

d i fil i• Recommendation to remove filter as soon as protection from PE is no longer neededAVOID THE FILTER LIKE THE PLAGUE

FDA Safety Alert Bulletin Aug 2010 http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm221707.htm

Bleeding or ThrombocytopeniaBleeding or Thrombocytopenia

• Multiple reasons for bleeding in cancer patients• Multiple reasons for bleeding in cancer patients

• In patients with bleeding who also require i l i d idanticoagulation, need to consider:

– severity and source of bleed (e.g. epistaxis vs ICH)

– whether source can be treated or eliminated

– how long is the bleeding event likely to last

– likelihood of recurrence of bleeding event

• No evidence based guidance on management• No evidence‐based guidance on management

Bleeding or Thrombocytopenia• Treat bleeding source whenever possible

Bleeding or Thrombocytopenia

• If active, serious bleeding:– hospitalize and withhold anticoagulationhospitalize and withhold anticoagulation

– insert retrievable filter only if risk of recurrent VTE is very high (within 1 – 4 weeks of diagnosis)

– start anticoagulation and remove filter when bleeding stops

• If platelet count less than 50x109/L:– transfuse platelets if VTE recent (< 30 days)

– reduce dose of LMWH if VTE established (> 30days)

XIIAnticoagulant Sites of Action

XII

XI Direct Factor Xa Inhibitors

fondaparinux

VIIVIIIIX

Unfractionated H i

InhibitorsRivaroxaban ApixabanEdoxaban

V

XHeparin

WarfarinLow

Molecular

BetrixabanDarexaban

II

V WarfarinMolecular Weight Heparin

Direct Thrombin ( )

I

(IIa) InhibitorsBivalirudinLepirudinArgatroban

Fibrin Clot

ArgatrobanDabigatran

Courtesy of Dr. J Ansell.

Comparative PharmacologyComparative Pharmacology

Characteristic Dabigatran Rivaroxaban ApixabanCharacteristic Dabigatran Rivaroxaban Apixaban

Target Thrombin Factor Xa Factor Xa

Action onset 1 – 2 h 2 – 4 h 1 – 3 h

Half life 12‐17 h 5‐13 h 12‐15 h

Renal clearance 80% 33% (66%) 25%

Dosing BID (OD) OD (BID) BID

Drug interactions P‐gp P‐gp/CYP3A4 P‐gp/CYP3A4

Lab monitoring No No No

Antidote No No No

Drug InteractionsDrug Interactions• inhibitors and inducers of P‐glycoprotein +/‐ CYP3A4:

antifungalsritonavir rifampicin

Inducers

amiodaroneverapamil

clarithromycin

rifampicinphenytoin

carbamazepineh b bitclarithromycin

quinidinetamoxifen

phenobarbitonedexamethasonedoxorubicin

TKIscyclosporintacrolimus

vinblastineSt. John’s wort

Inhibitors

Dabigatran in DVT/PE Treatment

INR in range 60%• 2539 patients with DVT/PE

RECOVER I

above range 19%below range 21%

p /

• All received LMWH x 10 days

• Dabi 150 mg bid vs warfarin• Dabi 150 mg bid vs warfarin

• P<0.001 for non‐inferiority in efficacy (2.4% vs 2.1%)efficacy (2.4% vs 2.1%)

• No difference in major bleeding (1.6% vs 1.9%)g ( )

Dabigatran is non‐inferior to warfarin for prevention ofrecurrent or fatal VTE with comparable major bleeding risk

Schulman et al. New Engl J Med 2009. Buller et al. New Engl J Med 2010.

recurrent or fatal VTE with comparable major bleeding risk

Rivaroxaban in DVT TreatmentEINSTEIN DVT

• 3449 patients with DVTINR in range 58%b 16%• 3449 patients with DVT

• Enox/warfarin vs Riva 15mg BID x 3 weeks then 20 mg OD e

(%) 3.0

Enox/VKA (3.0%; 51/1,718)4.0 above range 16%

below range 24%

g

• No LMWH in rivaroxaban arm

• P<0.001 for non‐inferiority in umulative even

t rate

2.0

Rivaroxaban (2.1%; 36/1,731)

P<0.001 for non inferiority in efficacy (2.1% vs 3.0%)

• No difference in major bl d ( )

Cu0 30 60 90 120 150 180 210 240 270 300 330 360

0

1.0

bleeding (0.8% vs 1.2%) 0 30 60 90 120 150 180 210 240 270 300 330 360

Time to event (days)

Rivaroxaban is non inferior to enox/warfarin for prevention of

Buller et al. New Engl J Med 2010.

Rivaroxaban is non‐inferior to enox/warfarin for prevention ofrecurrent or fatal VTE with comparable major bleeding risk

Rivaroxaban in PE TreatmentEINSTEIN PE• 4832 patients with PE

Recurrent VTE

p

• Enox/warfarin vs Riva 15mg x 3 weeks then 20 mg OD

• No LMWH in rivaroxaban arm

• P<0.001 for non‐inferiority in ff ( )

Major Bleeding

efficacy (2.1% vs 1.8%)

• fewer major bleeding with rivaroxaban (1 1% vs 2 2%;rivaroxaban (1.1% vs 2.2%; p=0.003)

Rivaroxaban is non inferior to enox/warfarin for prevention of

Buller et al. New Engl J Med 2012.

Rivaroxaban is non‐inferior to enox/warfarin for prevention ofrecurrent or fatal VTE with lower risk of major bleeding

Limitations in Cancer PatientsLimitations in Cancer Patients• Paucity of clinical trial data

• No comparison against long‐term LMWH

• Unreliable administration and absorption in patients withUnreliable administration and absorption in patients with N+V+D and mucosal erosion

• Liver and renal dysfunction is common in cancery

• Lack of experience on management for procedures and thrombocytopenia

• Drug interactions may be clinically important

• Lack of measurement (therapeutic range) and antidoteLack of measurement (therapeutic range) and antidote

How Should You Treat CAT?How Should You Treat CAT?• Get over YOUR fear/reluctance of injectionsGet over YOUR fear/reluctance of injections

• Have patient do his/her first injection in clinic

• Allow alcohol to dry before injection• Allow alcohol to dry before injection

• Firm pressure for 2 min after injection to reduce bruising, hematoma and pain – DO NOT RUBhematoma and pain DO NOT RUB

• Rotate sites and use “love handles”

I li i ff t f t th fill d i• Insulin syringe offers greater comfort than prefilled syringes

• Round UP on dose to nearest prefilled syringe

• Dose based on body weight without capping


• CAT is a common costly and potentially fatal


• CAT is a common, costly and potentially fatal complication

P i hi h i k h i h d d• Patients at highest risk are those with advanced disease receiving systemic chemotherapy and other additional risk factorsadditional risk factors

• Primary prophylaxis is not routinely indicated but h ld b di d ith ti t t hi h i kshould be discussed with patients at high risk

• LMWH is still the treatment of choice but we need to encourage research using new oral anticoagulants

Cancer Associated Thrombosis · • metastatic disease •tumour type: pancreas, lung...

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