LMWH in Cancer and Pregnancy

Leslie Zypchen, MD, FRCPCDivision of HematologyVancouver General HospitalVancouver, BC

Faculty/Presenter Disclosure

• Faculty: Dr. Leslie Zypchen• Relationships with commercial interests:*

• Grants/Research Support: N/A • Speakers Bureau/Honoraria: Celgene, Janssen, Novartis, Roche,

Otsuka, Lundbeck, BMS and Genzyme• Advisory Boards: Celgene relapsed & refractory myeloma• Consulting Fees: N/A• Other: Participated in or have participate in a clinical trial within the past

two years with GSK, BI and Pfizer/BMS

Disclosure of Commercial Support• This program has received financial support from Alexion Canada, Leo

Pharma, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Covidien, Novartis, Octapharma, BMS/Pfizer Alliance, Pfizer Canada Injectables, Aspen Pharmacare and Sanofi in the form of an Unrestricted Educational Grant

• This program has not received in-kind support from any commercial organization

• Potential for conflict(s) of interest:• Dr. Leslie Zypchen has received payment from Novartis, Boehringer

Ingelheim, BMS/Pfizer Alliance• Leo Pharma, BMS/Pfizer Alliance, Pfizer, Aspen, Sanofi

developed/licenses/distributes/benefits from the sale of a product that will be discussed in this program: Tinzaparin/Innohep, Dabigatran/Pradaxa, Dalteparin/Fragmin, Nadroparin/Fraxiparine, Semuloparin

Mitigating Potential Bias

• Except in the circumstance of a particular LMWH being used in a study, the term “LMWH” is used rather than a particular agent

• When mentioning novel oral anticoagulants, various agents are chosen as examples

Program Objectives• To discuss the evidence and some practical issues

surrounding the use of LMWH for the treatment of cancer associated thrombosis and as primary thromboprophylaxisin cancer outpatients

• To briefly discuss the pharmacology of LMWH in pregnancy

• To highlight the available evidence, some controversies, and some practical issues surrounding the use of LMWH for the treatment and prophylaxis of VTE in pregnancy

Audience Poll: A 72 yr old M with colon cancer on chemotherapy presents with a DVT – What do you recommend?

A. LMWH with bridging to warfarinB. LMWHC. RivaroxabanD. IVC filter

A. B. C. D.

0% 0%0%0%

10

Audience Poll: A 33 yr old F presents with a proximal DVT in her 1st trimester of pregnancy - what do you recommend?

A. Unfractionated heparinB. LMWH with bridging to warfarinC. LMWHD. Dabigatran

A. B. C. D.

0% 0%0%0%

10

Is LMWH Still a Player?• Still a great anticoagulant

• High level of physician familiarity & comfort• Easy to manipulate dose• No drug or dietary interactions• No regular monitoring required• Partially reversible

• Still the best anticoagulant in CANCER and the only safe anticoagulant in PREGNANCY!

YES!!!

LMWH in Cancer Associated Thrombosis

• Treatment of CAT

• Primary prevention of CAT in cancer outpatients

LMWH is Standard of Care for CATRecurrent VTE in 676 pts with CAT randomized to 6 m dalteparin vs VKA

VKA

Dalteparin

17%

9%

HR 0.48, ~RRR 50%

200 U/kg X 1 m,150 U/kg X 5 m

Lee et al (“CLOT”), NEJM 2003.

LMWH is Standard of Care for CATVTE recurrence rates in Cochrane MA of trials of LMWH vs VKA

Favours LMWH Favours VKA

For CAT treatment, LMWH is more effective and convenient than a VKA and is endorsed by all major guidelines

HR 0.47 (0.32-0.71)

Akl et al, Cochrane Database Syst Rev 2011; NCCN 2011; ACCP 2012; ASCO 2013.

Practical Issues for CAT Treatment1. Should we dose reduce LMWH @ 4 wk?

• In CLOT trial: Dalteparin to 75% @ 4 wk

2. What should we do after 3-6 m of AC?• No evidence available beyond 6 m• Recent trial of LMWH vs warfarin halted

NO if worried about VTE, YES if worried about bleeding

Options: Same LMWH, reduce LMWH, switch to warfarin

NCT01164046, clinicaltrials.gov; Lee & Peterson, Blood 2013.

Practical Issues for CAT Treatment3. What should we do if pt “fails” LMWH?

• Small published experience and expert opinion

4. What should we do if renal impairment?• All LMWHs renally excreted (tinzaparin least so)• Based on pharmacology and expert opinion

Effective and safe to LMWH by 20-25%

Options: Tinzaparin, check anti-Xa levels, use warfarin

Carrier et al, J Thromb Haemost 2009; Lee & Peterson, Blood 2013.

Practical Issues for CAT Treatment5. What should we do if thrombocytopenia?

• Based on expert opinion

Plts >50 considered safe for full dose AC

For acute VTE, attempt to transfuse for plts >50 oruse temporary IVC filter

For non acute VTE:• Plts 20-50: ½ dose LMWH• Plts <20: Hold LMWH, consider prophylactic LMWH

Lee & Peterson, Blood 2013.

LMWH for Primary CAT ProphylaxisSymptomatic VTE in Cochrane MA of trials of LMWH vs inactive control

Favours LMWH Favours control

RR 0.53 (0.38-0.75)

Dalteparin

Certoparin

Nadroparin

Enoxaparin

With no stat sig increase in major

bleeding

Cochrane Database of Systematic Reviews, 2014.

LMWH for Primary CAT Prophylaxis

POPn AGENT SYMPTOMATIC TE MAJOR BLEEDING

PROTECHT, 2009

n=1150 Nadroparin3800 U OD

LMWH BETTER

• 2% nadroparin

• 3.9% placebo

NO DIFF

•0.7% nadroparin

•0% placebo

SAVE-ONCO, 2012

n=3212 Semuloparin20 mg OD

uLMWH BETTER

• 1.2% semuloparin

• 3.4% placebo

NO DIFF

•2.8% semuloparin

•2% placebo

2 recent large RCTs compared prophylactic LMWH vs placebo in pts with locally advanced or metastatic solid tumours

NNT = 53

NNT = 45

Agenelli et al, Lancet 2009; Agnelli et al, NEJM 2012.

How to Pick the Right Patient?

1. Cancer site

2. Risk assessment tool

3. Biomarkers

Khorana et al, J Thromb Haemost 2014.

High Risk Cancer Site

POPn AGENT VTE* MAJOR BLEEDING

CONKO-004, 2010

n=312 Enoxaparin 1 mg/kg OD X 3 m, then 40 mg OD

LMWH BETTER

• 1.2% enoxaparin

• 9.9% no LMWH

NO DIFF

FRAGEM, 2012

n=123 Dalteparin200 U/kg OD X 1 m, then 150 U/kg OD

LMWH BETTER*

• 3.4% dalteparin

• 23% no LMWH

NO DIFF

•3.4% dalteparin

•3.2% no LMWH

2 recent RCTs compared LMWH vs. no LMWH in pts with advanced pancreatic cancer

Intermediate to treatment doses

NNT = 11

NNT = 5

Pelzer et al, 2010 ASCO abstract; Maraveyas et al, E J Cancer 2012.

Risk Assessment Tool“KHORANA SCORE” – a well validated and easy risk assessment tool

VTE rates, med 2.5 m:• Low risk (0) = 0.3%• Int risk (1-2) = 2%• High risk (>=3) = 7.1%Khorana et al, Blood 2008.

So…who should get primary prophylaxis?

• All patients should be educated about VTE, but not all should get LWMH prophylaxis

• Consider on a case by case basis:• Advanced pancreatic cancer• High risk Khorana score• Myeloma on combination IMID therapy

Khorana et al, J Thromb Haemost 2014.

Practical Issues for CAT Prophylaxis1. What agent should we use?

2. What dose should we use?

3. What duration should we use?

Any LMWH (semuloparin not an option)

Prophylactic for most cancers

Intermediate to therapeutic for pancreatic cancer

With initiation of chemotherapy, continue ~ 3 m

Khorana et al, J Thromb Haemost 2014.

LMWH in Pregnancy

• Pharmacology of LMWH in pregnancy

• Treatment of VTE in pregnancy

• Prevention of VTE in pregnancy

LMWH Pharmacokinetics in Pregnancy• Changes in pregnancy which may affect LMWH

• Increased GFR• Increased plasma volume• Weight gain• Binding to placental proteins

• Parameters known to increase in pregnancy• Clearance• Volume of distribution

Lebaudy, Clin Pharm Therapeutics 2008; Patel et al, Circ 2013.

LMWH Pharmacokinetics in PregnancyPharmacokinetic model of anti-Xa activity with enoxaparin 40 mg OD

4 hrs 24 hrs

Anti-Xa activity

Non pregnant

3rd trimester

Peak levels lower

Trough levels start to rise

Lebaudy, Clin Pharm Therapeutics 2008.

LMWH is Safe For the Fetus

• Does not cross the placenta

• No risk of fetal teratogenicity

• No risk of fetal anticoagulation

Evidence for LMWH for VTE Treatment

Incidence

VTE recurrence* 1.97%

All antepartum bleeding* 3.28%

Major antepartum bleeding 1.41%

Major postpartum bleeding 1.9%

Meta-analysis of 18 studies, 981 F treated with a heparin for VTE in pregnancy

• Nice summary of studies looking at LMWH treatment of VTE in pregnancy

822 LMWH

• Observational studies only• Most studies low quality• Outcome definitions and f/u

non uniform• Various LMWH doses

(~therapeutic)• VTE and bleeding seemed

higher with UFH

*Most bad outcomes occurred during 1st week

Romualdi et al, J Thromb Haemost 2012.

Practical Issues for VTE Treatment1. Should we use OD or BID dosing of LMWH?

• No known increase in VTE recurrence with OD • In PK models, levels stay “therapeutic” with OD • Surveys show that OD is used frequently• ACCP suggests OD is fine

Use OD dosing unless very worried, if so use initial BID dose

Lebaudy et al, Clin Pharm Therapeutics 2008; Patel et al, Circ 2013; Bates et al, ACCP 2012.

Practical Issues for VTE Treatment2. Should we adjust dose with weight gain?

• In other higher risk groups, doses are reduced after initial treatment period

• This implies that it is fine to let the dose drift down with weight gain

• ACCP provides no guidance but does discuss potential dose reduction

Do not increase dose with weight gain unless very worried

Bates et al, ACCP 2012.

Practical Issues for VTE Treatment3. Should we adjust dose based on anti-Xa

levels?• In PK models, levels stay “therapeutic” with no dose

adjustment• No known correlation btw anti-Xa levels and clinical

outcomes• ACCP strongly discourages anti-Xa monitoring

Do not check anti-Xa levels or adjust dose unless very worried

Patel et al, Circ 2013; Bates et al, ACCP 2012.

Practical Issues for VTE Treatment

4. What should we do for labour and delivery?• Plan must be individualized

• Spontaneous labour

• Induced vaginal delivery

• Planned C-section

• Reduce to prophylactic

• Last BID dose AM prior to induction

• Halt and admit for IV UFH

• Halt and insert IVC filter

MODE OF DELIVERY LMWH MANAGEMENT

Timing of VTE?

Neuraxial anesthesia?

Comfort of rest of team?

Patient preference?

Bates et al, ACCP 2012.

Evidence for LMWH for VTE Prophylaxis• Similar to VTE treatment, data is from

observational studies

• But…different because no accepted standard of who needs prophylaxis or what dose of LMWH

• Studies involve various types of pts, used various regimens & doses of LMWH

VTE recurrence risk 0-15% (most 1-2%)

Bates et al, ACCP 2012.

Roeters Van Lennep et al, J Thromb Haemost 2011.

Evidence for LMWH for VTE Prophylaxis

• Retrospective cohort study of 91 F with 126 pregnancies @ risk for VTE

• Intermediate risk – Nadroparin 2850 U postpartum

• High risk – Nadroparin 2850 U ante & postpartum

E.g. single provoked VTE (inc. estrogen)

E.g. no prior VTE but high risk thrombophilia

Pregnancy related VTE 5.5%, post partum hemorrhage 22%

Who Needs VTE Prophylaxis?

CIRCUMSTANCES OF PRIOR VTE ANTEPARTUM POSTPARTUM

Single non estrogen provoked NO YES

All other circumstances!* YES YES

Pregnant F with prior VTE (2C)

*more aggressive dosing for higher risk patients

Bates et al, ACCP 2012.

VTE Prophylaxis – Who Needs It?

THROMBOPHILIA FAMILY HX ANTEPARTUM POSTPARTUM

Homo FVL or PTGMPos YES YES

Neg NO YES

All othersPos NO YES

Neg NO NO

Pregnant F with asymptomatic thrombophilia (2B,2C)

Bates et al, ACCP 2012.

Practical Issues for VTE Prophylaxis1. Who should we prophylax?

2. What dose of LMWH should we use?

3. When to start antepartum?• Risk equal across trimesters

Must individualize decision, consider ACCP guidelines

Depends on perceived risk: Prophylactic therapeutic

Early first trimester

Take home messages1. LMWH is standard of care for treatment of

cancer associated thrombosis, its’ use for primary prophylaxis is an evolving field

2. Although the evidence supporting the use of LMWH for treatment & prophylaxis of VTE in pregnancy is poor, it seems effective & safe and is standard of care

Thank you!