Canadian Society of Internal Medicine

Annual Meeting Quebec City, October 2012

The 2012 ACCP guideline

regarding the pregnant patient:

A case-based discussion

Dr. Michèle Mahone CHUM Montréal, Québec.

Canadian Society of Internal Medicine

Annual Meeting Quebec City, October 2012

M.Mahone October 17th 2012

The following presentation represents the views of the speaker

at the time of the presentation. This information is meant for

educational purposes, and should not replace other sources

of information or your medical judgment.

A selection of slides from this talk will be available

on the CSIM website in PDF format.

Canadian Society of Internal Medicine

Annual Meeting Quebec City, October 2012

The speaker has not received fees/honoraria.

Some of the drugs, devices, or treatment modalities mentioned

in this presentation are: aspirin

LMWH

Rivaroxaban

Dabigatran

Conflict Disclosures

Objectives

• After the conference, the participant will be able to:

– Follow an analysis and resolution of complex clinical cases on thrombophilia, antithrombotic and anticoagulation therapies in pregnant women by experts in the field.

– Review the new recommendations of the 2012 CHEST consensus. Recognize the inherent difficulties linked to a paucity of evidence-based medicine in the literature.

– Attend a discussion between various specialists who will attest to the diversity of practices in the field of obstetrical medicine.

Themes that will be discussed:

• New antithrombotic drugs in pregnancy

• Asymptomatic thrombophilia

• Secondary prophylaxis for obstetrical complications during pregnancy

METHODS

• Structured clinical questions

• Update of English literature search from January 2005 to January 2010.

• If a benefit is uncertain and a probability of important harm exists, they generally recommended against.

• Patient preference: Recommendations in this article, therefore, reflect our

belief that although average women considering antithrombotic therapy will also want to avoid medicalizing their pregnancy, they will put an extremely high value on avoiding fetal risk.

Case 1

• 32 year-old G1Po, 6 weeks pregnant

• Left deep vein thrombosis 4 weeks ago

• She was put on rivaroxaban

• What to do ?

• Risk for fetus and mother ?

• What does the ACCP 9th edition guideline say ?

Drug counseling

• What is the general risk of malformation? • The timing of the exposition and dosage • Other medications or drug usage • Comorbidities • Data on medication and pregnancy

– Do not use FDA classification – Pubmed search – Drugs in Pregnancy and Lactation. Briggs et al., 2008. – Motherisk (Toronto) www.motherisk.org – Centre IMAGE Hôpital St-Justine (Montreal)

Developmental progression and susceptibility to teratogens

New antithrombotic

• No human data available

• Animal data (rabbits and rats) – Increases miscarriage

– Low birth weight

– Increase in malformations

– Placental abnormalities

Boehringer Ingelheim . Summary of product characteristics: dabigatran etexilate. Date of text revision: March 2009

Bayer Schering Pharma AG . Summary of product characteristics: rivaroxaban. Date of text revision: May 2009

Rivaroxaban

• Anti-Xa inhibitor

• Half life of 5-9 hours

• Crosses placenta

• Found in breast milk

ACCP 9th Edition: Fetal complication of antithrombotic therapy during

pregnancy and breast-feeding

• 3.0.4. For pregnant women, we recommend avoiding the use of oral direct thrombin (e.g. dabigatran) and anti-Xa (e.g. rivaroxaban, apixaban) inhibitors (Grade 1C).

• 4.0.4. For breast-feeding women, we recommend alternative anticoagulants rather than oral direct thrombin (e.g. dabigatran) and factor Xa inhibitors (e.g. rivaroxaban, apixaban) (Grade 1C).

ACCP 9th Edition: Maternal and fetal complications of anticoagulant therapy

• 2.2.1. For pregnant patients, we recommend LMWH for the prevention and treatment of VTE, instead of UFH (Grade 1B).

• 3.0.1. For women receiving anticoagulation for the treatment of VTE who become pregnant, we recommend LMWH over vitamin K antagonists during the first trimester (Grade 1A), in the second and third trimesters (Grade 1B), and during late pregnancy when delivery is imminent (Grade 1A).

Case 1

• Discuss the risk: probably low given the timing and dosage

• Stop Rivaroxaban immediately and switch to LMWH at therapeutic dosage

• Remainder of pregnancy

– Induction at 38 weeks

– Switch to UFH at 36 weeks

PANEL

ACCP 9th Edition: Treatment of proven acute VTE during pregnancy

• 7.1.1. For pregnant women with acute VTE, we recommend therapy with adjusted-dose subcutaneous LMWH over adjusted-dose UFH (Grade 1B).

• 7.1.2. For pregnant women with acute VTE, we recommend LMWH over vitamin K antagonist treatment antenatally (Grade 1A).

• 7.1.3. For pregnant women with acute VTE, we suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a minimum total duration of therapy of 3 months) in comparison with shorter durations of treatment (Grade 2C).

• 7.1.4. For pregnant women receiving adjusted- dose LMWH therapy and where delivery is planned, we recommend discontinuation of LMWH at least 24 h prior to induction of labor or cesarean section (or expected time of neuraxial anesthesia) rather than continuing LMWH up until the time of delivery (Grade 1B).

Treatment of proven acute VTE during pregnancy

• Weight adjusted of LMWH

• Routine anti-Xa level difficult to justify

• Bid or daily regimen

• Anticoagulation throughout the pregnancy

• Decrease the dose to 75% if – high risk of bleeding

– Risk of osteoporosis

• Delivery plan

Summary:

• Better the devil you know than the devil you don’t

• New oral direct thrombin and anti-Xa inhibitors are probably not safe in pregnancy and breastfeeding.

• Minimum duration of treatment is 3 months

PANEL

Case 2

• 28 year-old G1P0, 6 weeks

• Family history of thromboembolic disease

• Antithrombin deficiency, type 1

• No personal history of thrombosis

• What is her risk of thrombosis ?

• Prophylaxis or not ?

• What does the ACCP 9th guideline tell us ?

What is the risk of thromboembolic disease in asymptomatic thrombophilia ?

Thrombophilia Estimated absolute risk in antepartum and postpartum (95%CI) WITH FAMILY HISTORY

Deficit in antithrombin 3.0 (0.08-15.8)

Deficit in protein C 1.7 (0.4-8.9)

Deficit en protein S 6.6 (2.2-14.70)

Factor V Leiden heterozygote 3.1 (2.1-4.6)

Prothrombin heterozygote 2.6 (0.9-5.6)

Leiden homozygote 14.0 (6.3-25.8)

Adapted from Bates et al, ACCP9th 2012

Antithrombin deficiency

Rhéaume et al., 2012. Systematic review.

Overall (I-squared = 0.0%, p = 0.755)

Study

Van Boven 1999

Folkeringa 2007

Friederich 1996

16.25 (2.93, 90.00)

RR (95% CI)

16.07 (0.90, 287.70)

23.28 (1.38, 393.24)

6.03 (0.39, 94.07)

100.00

Weight, %

33.69

39.61

26.70

1 .00254 1 393

Risk Ratio for Thrombosis in Retrospective Cohorts Studies

of Antithrombin Deficiency

Estimated absolute risk 1.6 % (0.29-9)

Antithrombin deficiency

Rhéaume et al., 2012. Systematic review.

Overall (I-squared = 0.0%, p = 0.630)

Martinelli 2002

Meglic 2003

Mitic 2009

Study

6.66 (1.59, 27.95)

1.96 (0.12, 31.58)

OR (95% CI)

8.46 (0.90, 79.51)

11.55 (0.61, 218.16)

100.00

39.51

Weight, %

35.53

24.96

1 .00458 1 218

Odds ratio for thrombosis in case-control studies of Antithrombin deficiency

Estimated absolute risk 0.67 % (0.16-2.80)

ACCP 9th: Prevention of VTE in pregnant women with thrombophilia and no prior VTE

THROMBOPROPHYLAXIS

NO < 1% POSTPARTUM 4% ANTEPARTUM + POSTPARTUM >10%

All thrombophilia Except Leiden Homo or

Protrombin Homo

NO FAMILY HX

Leiden Homo or Protrombin

Homo NO FAMILY HX

Leiden Homo or Protrombin Homo

FAMILY HX

All others thrombophilia

WITH FAMILY HX

WHAT DO I DO ?

• Risk of bleeding is low

• Should cost be taken into the decision?

• Risk factors other than family history

• I worry about the large CI and the limited study data

• I give antepartum prophylaxis to AT women

– Prophylaxis versus intermediate dose

PANEL

Case 3

• 29 years-old G2P1, 6 weeks pregnant

• G1 severe preeclampsia at 30 weeks

– IUGR

• Thrombophilia screening ?

• Secondary prophylaxis ?

Association of thrombophilia and obstetrical complications

Thrombophilia Recurrent loss T1

Late loss Preeclampsia Abruptio IUGR

FVL heteroz. + ? - - - -

Prothrombin - - - - -

AT deficiency NA - - - NA

Protein C NA - - - NA

Protein S NA ? - - NA

APLA + + ? + +? +?

Adapted from: Rodger MA. Thromb Hemost; 2011. Do Prado et al., Obstect Gynecol; 2010 Bates et al 2012.

ACCP 9th Edition: Thrombophilia and pregnancy complications

• 10.2.1. For women with recurrent early pregnancy loss (three or more miscarriages before 10 weeks of gestation), we recommend screening for APLAs (Grade 1B).

• 10.2.2. For women with a history of pregnancy complications, we suggest not screening for inherited thrombophilia (Grade 2C).

ACCP 9th Edition: Thrombophilia and pregnancy complications

• No recommendation for or against screening for APLA if:

– Late pregnancy loss

– Preeclampsia

– IUGR

Prevention of recurrent preeclampsia in women without thrombophilia

• 11.1.1. For women considered at risk for pre-eclampsia, we recommend low-dose aspirin throughout pregnancy, starting from the second trimester, over no treatment (Grade 1B) .

Bates et al ACCP9th 2012

Prevention of recurrent preeclampsia in women without thrombophilia

• No recommendation on LMWH

• Awaits more data

Studies # Thrombophilia Interventions Outcomes

NNT

Mello et al. 2005

80 NO Dalteparin 5000 mg VS NO

Preeclamspia 7.3 vs. 28.2 %

5

Rey el al. 2009 116 NO Dalteparin 5000 mg VS NO

Severe PE, IUGR, abruptio, fetal death

5.5 vs. 23.6

5

NOH-PE 2011 224 NO Enoxaparin 40 mg vs NO

PE,Abruptio, IUGR, fetal death 8.9 vs. 25 %

7

FRUIT-RCT 2012

139 YES Dalteparin 5000 mg + ASA 80mg VS ASA

80mg

PE < 34 weeks 0% vs. 8.7%

PE 18.6 vs. 21.7% NS

12

32

Martelli et al. 2012

128 YES (70 VS 72%)

Nadroparin 3800 IU VS medical surveillance

PE, eclampsia, HELLP,IUGR, abruptio

21% vs. 18% NS

Secondary prophylaxis of obstetrical complications

Case 3

• Screening for antiphospholid syndrome

• ASA 81 mg HS

• Prophylactic dose of LMWH

– Dalteparin 5000 mg

– Enoxaparin 40 mg

– Tinzaparin 75 U/kg

PANEL

CONCLUSION

• Anticoagulation with women in childbearing age should be associated with adequate contraception.

• Prevention of VTE in asymptomatic women with thrombophilia is still controversial.

• There is no indication for screening for thrombophilia for obstetrical complication.

• ASA is the only recommended therapy for secondary prevention of obstetrical complication; the jury is still out for the role of LMWH.