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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.