Thromboembolism & cancer

Thromboembolism

& cancer

James H. Williams Jr., MD

UCIMC Hospitalist

Pulmonary Medicine

University of California, Irvine

JHW

Thromboembolism is

a normal physiologic response to injury

• Thrombosis

– controls hemorrhage

– provides scaffold for neutrophil influx

– walls off inflammatory sites

– promotes repair (cell growth & angiogenesis)

• Pulmonary embolism

– expedites return of flow in systemic veins

– usually well-tolerated via V/Q redistribution

• abundant, recruitable pulmonary vasculature

• hypoxic constriction diminishes V/Q mismatch

JHW

Excessive, pathophysiologic events

• Thrombosis

– large thrombi in large veins

• stasis -> promotes extension of clot -> edema, large emboli

• hypercoaguable states-> excessive, rapid clot extension ->

• extensive endothelial injury-> larger clot ->

– extensive thrombosis of small veins

• marked tissue edema, pain

• when results from cellulitis, limits antibiotic penetration?

• Embolism

– inadequate V/Q redistribution

• larger clot (usually legs, IVC, pelvis)

• inadequate pulmonary vascular-alveolar reserves

JHW

Thrombosis versus Fibrinolysis

©2008 UpToDate® • www.uptodate.com

Licensed to Univ Of California Irvine

(thrombin = II)

Tissue-vascular injury induces intravascular

thrombosis, with re-cannulization by fibrinolysis.

Circulating d-dimer reflects active clotting process.

JHW

Increased risk for DVT-PE

ACCP Guideines.

Chest 2012; 141 (2 Suppl); 199 S.

JHW

ACCP Guideines. Chest 2012; 141 (2 Suppl); 200 S.

Weigh risk of bleeding with

anticoagulation decision

JHW

4 clinical risk factors: score

-cancer 1

-paralysis, paresis, cast LE 1

-bedridden 3 days or major surgery in last 4 wks 1

-pervious DVT/PE 1

5 clinical signs:

-tender LE deep veins 1

-entire leg swollen 1

-calf 3 cm larger circumference (10 cm below tibial tuberosity) 1

-pitting edema in same leg 1

-collateral (non-varicose) superficial veins 1

Alternative diagnosis at least as likely -2

Wells DVT pre-test probability score NEJM 2003; 349:1227-1235

?

Original Wells score: > 3 high probability

1-2 moderate probability

0 low probability

Modified Wells score: >2 DVT likely

JHW

Risk factors: Points:

Clinic signs/syptoms cw DVT 3

Alternative Dx to PE less likely 3

HR >100 1.5

Immobile or surgery last 4 wks 1.5

PMH DVT or PE 1.5

Hemoptysis 1

Cancer 1

Clinical probability:

Low <2

Intermediate 2-6

High >6

Clinical predictors of PE

Fedullo & Tapson, NEJM 2003; 349:1247-56

From Wells, et al. Thromb Haemost 2000;83:416-20

(<10%)

(30%)

Modified Wells:

Low <4

High >4 (40-80%)

JHW

VTE with cancer

– Cancer promotes VTE formation

• increased incidence of new VTE

• increased risk recurrent VTE

• VKA warfarin titration more difficult

– Cancer associated incr risk hemorrhage

• vitamin K deficiency

• chemotherapy associated thrombocytopenia

• tumor-related hemorrhage

• VKA slow onset-offset interfere with procedures

– Consider more stable anticoagulants

• parenteral heparins (LMWH)

• NOAC’s (DOAC’s)

JHW

Therapeutic approach

DECISION TO TREAT DVT/PE

SHOULD BE INDIVIDUALIZED

weighing

RISK ANTICOAGULATION (hemorrhage) vs

BENEFIT (inhibition of clot extension, embolism)

JHW

Anticoagulant options

• Parenteral anticoagulants

– Unfractionated heparin (UFH) – IV relatively rapid onset-offset • IV weight based load & initial infusion, then modified by PTT

• SC weight based q8-12hr, +/- modified by PTT @ 6hrs

– Low molculular weight heparins (enoxaparin, dalteparin) • SC weight based bid or qd, +/- modified by LMWH level (anti-Xa effect)

– Heparin pentamer fragment (fondaparinux) • SC loosely weight based (lower risk of HIT)

– Parenteral thrombin inhibitors (argatraban) • IV weight based

• Oral anticoagulants

– Oral thrombin inhibitors • indirect thrombin (etc) inhibitor via VKA (warfarin)

– bridge acutely with initial LMWH-UFH

• direct thrombin inhibitor (dabigatran)

– Oral Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban)

JHW

ANTICOAGULATION FOR

VTE WITH CANCER

JHW

ACCP guidelines methodology

– Graded on basis of strength of recommendation (1 or 2)

• Grade 1. Panel confident good (benefit) outweigh bad (risk/cost).

– GOOD = strong/clear therapeutic effect

– BAD = risk of harm, difficulty, cost

• Grade 2. Weak, less clear.

– Graded on strength of evidence (A, B, C).

• Grade A. Data strong -> multiple RTC’s support.

• Grade B. Data inconsistent &/or not as strong.

• Grace C. Data weak, often observational.

– EXAMPLE:

• Grade 1A is meant to be generally applied unless an exceptional case

• Grade 2C is only a suggestion that should be cautiously considered on

a case by case basis.

Chest 2008; 133 (6 Suppl): 113-122 & 123-131S

Chest 2012; 141 (2 Suppl): 53S -70S

Chest 2016; 149 (2): 315-52

JHW

ACCP Guidelines 2016 Cancer-related VTE

(Chest 2016; 149: 315-52)

JHW

LMWH vs warfarin for VTE with cancer

– RCCT – 338 in each arm (676 total)

• LMWH daltiparin x5-7d, then

– Bridged to warfarin

– continue daltiparin 200 IU/kg x1ml, then 150 IU/Kg after.

• daltiparin reduced by 2500 IU if plts 50-100K, and held if <50K.

– Cancer new/active dx within last 6 months

• excluded

– skin SCC, BCC,

– wt<40 Kg, ECOG 3-4

– thrombocytopenia <75 at recruitment

– recent hemorrhage (2 wks)

– Increased risk serious hemorrhage (active ulcer, neurosurgery)

NEJM 2003; 349:146-53

JHW

Continued LMWH more effective than warfarin with cancer

NEJM 2003; 349:146-53

Daltaparin 200 units/Kg once daily x 1 mo, then 150 units/kg for next 5 months, max 18,000

Thrombocytopenia: both held if <50K (LMWH until >100K), for 50-99K warfarin reduced to

INR 1.5-2, & LMWH reduce 5000 units if on decline rather than rise

Fewer recurrent VTE events with LMWH dalteparin

JHW

Continued LMWH more effective than

warfarin in cancer patients

NEJM 2003; 349:146-53

Fewer recurrent VTE events with LMWH dalteparin

JHW

Complications

• Major bleeding

– LMWH 19/338 (6%) VKA 12/335 (4%) (NS)

• Any bleeding

– LMWH 14%, VKA 19% (NS)

• Overall mortality not different

– LMWH 130 (39%), VKA 136 (41%) (NS)

NEJM 2003; 349:146-53

JHW

Enoxaparin vs warfarin for VTE with cancer

– RCCT – 101 pts divided into 3 grps

• LMWH enoxaparin bid x5d, then Rx 175 more days80

– enoxaparin 1 mg /Kg bid (n=31)

– enoxaparin 1.5 mg /Kg daily (n=36)

– warfarin INR 2-3 (n=34)

– Cancer new/active dx within last 6 months

• excluded

– skin ca (SCC, BCC), Wt>120 Kg, ECOG 3-4, CrCl<30,

– plts <50, hemorrhage last 2 wks, other risk (active ulcer, neurosurg)

– Endpoints

• Recurrent DVT/PE

• Bleeding

Clin Applied Thrombostasis_Hemostasis 2006; 12: 389-96

JHW

Enoxaparin vs warfarin for VTE with cancer Clin Applied Thrombostasis_Hemostasis 2006; 12: 389-96

Comparable recurrent VTE events

Numbers too small for statistical significance, but trend enoxaparin 1.0 mg bid safer than 1.5 daily

Numbers small, but efficacy for preventing recurrent VTE similar among all groups

JHW

Tinzaparin vs warfarin for VTE with cancer

– RCCT – international, 900 pts, 2 grps

• LMWH tinzaparin x5-10d, then warfarin v tinzaparin 6 months

– Tinzaparin 175 IU/Kg daily (n=449)

– warfarin INR 2-3 (n=451), INR checked at least q2wks

– Cancer new/active dx within last 6 months

• excluded

– Non-melanoma skin (SCC, BCC), CrCl<20

– Hx HIT, contraindication to anticoagulation,

– already on anticoag, life expectancy <6mo.

– Child-bearing potential (women and men)

– Endpoints

• DVT-PE recurrence

• Hemorrhage (major= fatal, critical area (ICH), or 2 units blood)

JAMA 2015; 314: 677-86

JHW

Tinzaparin vs warfarin for VTE with cancer JAMA 2015; 314: 677-86

LMWH tended to have fewer overall DV-PE recurrences (p=0.07),

with mild trend toward lesser bleeding (but primarily clinically significant non-major)

JHW

Tinzaparin vs warfarin for VTE with cancer

JAMA 2015; 314: 677-86

*

* Required any medical or surgical intervention

JHW

Tinzaparin vs warfarin for VTE with cancer JAMA 2015; 314: 677-86

Overall mortality similar

JHW

Warfarin vs oral Xa inhibitors

for DVT-PE with cancer

JHW

Recent publication

Emerging role for DOACs ?

Time to change guidelines ?

JHW

Edoxaban vs dalteparin

Oral Xa-inhibitor vs SC LMWH for VTE with cancer

• RCCT n=1050 with DVT-PE and cancer • active cancer, Dx within last 2 yrs (not skin SCC, BCC)

• Rx LMWH x5d, then randomized for 6-12 mo • LMWH

– dalteparin 200 IU/Kg/d x1mo, then 150 IU/Kg/d, unless plts <100K,

then reduce dose by 2500 IU/d

• Oral Xa inhibitor

– Edoxaban 60 mg/d, or 30 mg/d if CrCl 30-50, wt<60Kg, on P-gP inh

• Endpoints • Composite recurrent DVT-PE or major bleeding

NEJM Dec 2017;

JHW

Edoxaban vs Dalteparin

Oral Xa-inhibitor vs SC LMWH for VTE with cancer

NEJM Dec 2017;

Composite difference NS

JHW

Edoxaban vs Dalteparin

Oral Xa-inhibitor vs SC LMWH for VTE with cancer

NEJM Dec 2017;

More recurrent DVT-PE with dalteparin (p=0.09)

JHW

Edoxaban vs Dalteparin

Oral Xa-inhibitor vs SC LMWH for VTE with cancer

NEJM Dec 2017;

More major bleeding with edoxaban (p= 0.04)

JHW

Comparing DOACs against warfarin

for VTE in unselected populations

JHW

Thrombosis Res 2014; 134: 774-82

DOACs at least effective as warfarin for DVT/PE (unselected populations)

Meta-analysis DOAC’s vs warfarin for DVT/PE

JHW

DOACs at least as safe as warfarin for DVT/PE (unselected populations)

Meta-analysis DOAC’s vs warfarin for DVT/PE

Thrombosis Res 2014; 134: 774-82

apixaban

safer?

JHW

Considering DOAC for VTE with cancer

– ACCP 2016 favored LMWH, if possible

• LMWH more effective than warfarin

• LMWH as safe as warfarin ?

• Fewer data comparing DOAC with cancer

• BUT, noted some not willing to inject LMWH long-term

– Recent study compared DOAC with LMWH

• Edoxaban vs Dalteparin

– Composite score (recurrence VTE + major bleeding) same.

– Edoxaban at least as effective (edoxaban trend more effective)

– Edoxaban had more major bleeding (p=0.04)

– Consider alternative DOAC ? – Apixaban tended to be as effective, and safer in non-cancer, unselected

(non-cancer) patients with extended therapy

JHW

ACCP Guidelines 2016 Cancer-related VTE

(Chest 2016; 149: 315-52)

JHW

I THINK YOUR GETTING IT!

JHW

Questions?