TIPPS

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Rodger MA, et al. "Antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia". Lancet. 2014. 384(9955):1673-1683.
PubMedFull text

Clinical Question

Among pregnant women with thrombophilia, does antepartum prophylactic deltaparin reduce the risk of pregnancy complications including venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications?

Bottom Line

Antepartum prophylactic dalteparin in pregnant women with thrombophilia does not decrease the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications. Deltaparin has a greater risk of minor bleeding.

Major Points

Guidelines

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=284
    • Antepartum dalteparin (n=143)
    • Standard (n=141)
  • Setting: 36 centers in 5 countries
  • Enrollment: Feb 2000 to September 2012
  • Mean follow-up:
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

One or more of the following:

  • Previous preeclampsia
  • Previous unexplained intra-uterine growth restriction
  • Previous recurrent miscarriage:
    • Three (3) or more unexplained miscarriage at less than 10 weeks gestation;
    • Two (2) or more unexplained fetal loss between 10 and 16 weeks gestation;
    • One (1) or more unexplained fetal loss at or greater than 16 weeks gestation
  • Previous abruptio placenta
  • Previous personal history of VTE:
    • Previous documented secondary proximal VTE,
    • Previous documented calf-vein thrombosis (idiopathic or secondary),
    • Previous superficial phlebitis
  • First degree relative with symptomatic thrombophilia
  • Pregnancy: between 4 and 20 weeks of gestation
  • Thrombophilia
  • Two abnormal tests, and no normal tests:
    • Protein S
    • Protein C
    • Antithrombin
  • Two positive tests:
    • Anticardiolipin immunoglobulin M (IgM) (>30 U/ml)
    • Anticardiolipin immunoglobulin G (IgG) (>30 U/ml)
    • Anti-b2 glycoprotein IgG (>20 U/ml)
    • Anti-b2 glycoprotein IgM (>20 U/ml)
    • Lupus anticoagulant
  • One positive test:
    • Factor V Leiden (heterozygous or homozygous)
    • Prothrombin gene defect (heterozygous or homozygous)

Exclusion Criteria

  • Less than 4 weeks gestation or greater than 20 weeks gestation
  • No confirmed thrombophilia
  • Contraindication to heparin therapy including:
    • History of heparin induced thrombocytopenia
    • Platelet count less than 100,000 109/L
    • History of osteoporosis or steroid use
    • Actively bleeding
    • Documented peptic ulcer within 6 weeks
    • Heparin, bisulfite or fish allergy
    • Severe hypertension (Systolic Blood Pressure >200mmhg and/or Diastolic Blood Pressure >120mmHg)
    • Serum creatinine greater than 80 umol/L (1.3mg/dl) and an abnormal 24 hour urine creatine clearance (<30ml/min)
    • Severe hepatic failure (INR >1.8)
  • Geographic inaccessibility
  • Need for anticoagulants, discretion of the investigator such as but not limited to:
    • Recurrent fetal loss and phospholipid antibody syndrome
    • Prior idiopathic proximal VTE:
    • History of idiopathic deep venous thrombosis (DVT) or pulmonary embolism (PE) treated with anticoagulants (> 1 month of heparin or warfarin) or inferior vena cava (IVC) interruption
    • Idiopathic is a VTE occurring outside all of the following periods: antepartum, postpartum, oral contraceptive use, surgery, immobilization, cast, and malignancy
    • Mechanical heart valve
  • Legal lower age limitations (country specific)
  • Prior participation in TIPPS
  • Unable/unwilling to provide informed consent

Baseline Characteristics

  • Mean age: 72 years
  • Mean BMI: 28
  • Mean HbA1c: 8.8%
  • Units of insulin: 14 units/day

Interventions

  • Randomized to intensive (targeting HbA1c <6%) or standard (HbA1c 7-7.9%) glycemic therapy

    • Then 46% were randomized to intensive (SBP <120) vs. standard (SBP <140) blood pressure therapy
    • Remaining 54% randomized to fenofibrate vs. placebo; all received statin
  • Intensive glycemic control group attended monthly visits for 4 months, then every 2 months, with additional visits and telephone calls as needed
  • Standard therapy group had glycemic control visits every 4 months

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Composite of VTE, pre-eclampsia, IUGR, and fetal loss
2.11% vs. 2.29% (HR 0.90; 95% CI 0.78-1.04; P=0.16)

Secondary Outcomes

Composite of rates of pregnancy induced hypertension, preterm labor and abruptio placenta
1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04)
Safety including rates of bleeding, thrombocytopenia, and fractures
0.79% vs. 0.56% (HR 1.35; 95% CI 1.04-1.76; P=0.02)
Bone mineral density

Subgroup Analysis

Adverse Events

Criticisms

Funding

The trial was funded by Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.

Further Reading