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.
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Clinical Question

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

Bottom Line

Among pregnant women with a thrombophilia, antepartum dalteparin prophylaxis increased the risk of minor bleeding without decreasing the risk of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications.

Major Points

Pregnancy is a hypercoagulable state associated with venous thromboembolism. Moreover, microvascular thrombosis has long been considered a driver of pregnancy-related complications including pregnancy loss, placental insufficiency, intrauterine growth restriction, and preeclampsia. Early anecdotes and smaller studies suggested a potential benefit to antepartum anticoagulation in reducing rates of thrombosis, pregnancy loss, and other pregnancy-related complications, but a randomized trial was needed.

The Thrombophilia in Pregnancy Prophylaxis Study (TIPPS) screened overall over 3,000 women at high risk of VTE or pregnancy-related complications and ultimately randomized 292 to antepartum anticoagulation with prophylactic-dose dalteparin, or to no dalteparin. The enrollment criteria were somewhat complex and varied, and required a history of confirmed thrombophilia and high risk of VTE or pregnancy-associated complications (eg, prior preeclampsia or major placental abruption). Over half of patients met the thrombophilia criterion due to factor V Leiden heterozygosity, and over half met the high-risk inclusion criterion with a prior pregnancy complication, and about a third had a first-degree relative with VTE. In the dalteparin arm, patients received 5,000 units daily until week 20, followed by 5,000 units twice daily until at least week 37. All patients received postpartum prophylaxis for 6 weeks beginning 6-28 h after delivery. The primary endpoint was a composite of VTE, severe or early preeclampsia, birth of a small-for-gestational-age infant, or pregnancy loss. The primary analysis demonstrated no difference in the rate of the primary outcome (17.1% in the dalteparin arm compared to 18.9% in the control; P=0.70). Minor bleeding was more common in the dalteparin arm (19.6% vs. 9.2%; P=0.01).

Overall, the authors conclude that antepartum prophylaxis should not be routinely administered for purposes of reducing VTE risk or pregnancy-related complications in pregnant woman at high risk of these complications. Additionally, some interesting observations were made in subgroup analyses. For example, all patients in the dalteparin arm who developed VTE had a history of calf-vein thrombosis, suggesting that patients with a history of even a distal leg thrombosis may need higher-dose anticoagulation. Similarly, among patients in the control arm who did not have a personal history of VTE, none developed a VTE, supporting guidelines that recommend against antepartum prophylaxis.

Guidelines

Guidelines are conflicting as to how to reduce the risk of VTE and other associated complications of pregnancy. Importantly, As of June 2019 many guideline statements have not yet been updated with the results of the TIPPS trial. The reader is directed to Bates SM, et al.[1] for a summary of available guidance on the prevention of VTE in pregnancy.

Design

  • Multicenter, open-label, randomized controlled trial
  • N=284 pregnant women with thrombophilia at high risk of VTE or pregnancy-associated complications
    • Antepartum and postpartum dalteparin (n=143)
    • Postpartum dalteparin only (n=141)
  • Setting: 36 centers in 5 countries
  • Enrollment: 2000-2012
  • Primary outcome: composite of VTE, severe/early-onset preeclampsia, SGA infant birth, or pregnancy loss
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

All 4 of the following must be met:

  1. Thrombophilia
    • Factor V Leiden homozygosity or heterozygosity
    • Prothrombin gene mutation
    • Protein C/S or AT deficiency
    • Antiphospholipid antibody positive
  2. High-risk for VTE or pregnancy-associated complications
    • Prior pre-eclampsia
    • Prior unexplained birth of small-for-gestational-age infant
    • Prior major placental abruption
    • Pregnancy loss (≥3 at <10 weeks gestation, ≥2 between 10-16 weeks gestation, or ≥1 at ≥16 weeks)
    • Prior thrombosis including PE, DVT, calf vein thrombus, superficial phlebitis
    • First-degree relative with VTE
  3. Confirmed pregnancy
  4. Signed informed consent

Exclusion Criteria

  • 21 weeks or more gestational age
  • Contraindication to heparin therapy
  • Geographic inaccessibility
  • Need for anticoagulation
  • Prior participation in TIPPS trial
  • Below legal age to provide informed consent

Baseline Characteristics

From the dalteparin arm unless otherwise specified.

  • Age: 31.9 years (mean)
  • Gestational age at randomization: 12 weeks
  • Ethnic origin: 9% non-white
  • Smoking status: 38% ever smoker
  • BMI: 26.3 (mean)
  • Obstetric history: G3P1 (mean)
  • Outcomes of prior livebirths: neonatal death 9%, infant death 3%
  • Thrombophilia inclusion criteria
    • Factor V Leiden: 64% (of these 96% were heterozygous)
    • PT gene mutation 21%
    • Protein S deficiency 8%
    • Protein C deficiency 4%
    • AT deficiency 1%
    • Antiphospholipid antibody 8%
  • High-risk inclusion criteria
    • Prior pregnancy complications 63% (14% preeclampsia, 18% SGA infant, 43% pregnancy loss)
    • VTE risk factors 46% (31% first-degree relative with VTE, prior provoked VTE / calf vein thrombus / superficial phlebitis 20%)

Interventions

  • Randomization to either:
    • Dalteparin 5,000 units SC daily until 20 weeks, then 5,000 units SC BID
    • No dalteparin
      Initially received a matching placebo, but due to poor enrollment the protocol was amended after 2 years to be open-label dalteparin versus no dalteparin.
  • Randomization was stratified by country and gestational age at randomization
  • All patients received dalteparin 5,000 units SC daily for 6 weeks post-partum beginning 6-28 hours after delivery.
  • No comment was made in the manuscript regarding anti-Xa adjustment, so it is presumed this was not allowed.
  • Patients were followed per standard obstetrical guidelines.
  • Outcomes were centrally adjudicated by investigators blinded to treatment assignment.

Outcomes

Outcomes are dalteparin versus control.

Primary Outcomes

Composite of VTE, severe/early preeclampsia, small-for-gestational-age infant, or pregnancy loss
17.1% vs. 18.9% (P=0.70)

Secondary Outcomes

Symptomatic VTE
0.7% vs. 1.4% (P=0.62)
Preeclampsia
5.5% vs. 3.5% (P=0.42)
Severe/early preeclampsia
4.8% vs. 2.8% (P=0.38)
Small-for-gestational-age infant
6.2% vs. 8.4% (P=0.47)
Pregnancy loss
8.2% vs. 7.0% (P=0.69)
Major bleeding
2.1% vs. 1.4% (P=1.0)
Minor bleeding
19.6% vs. 9.2% (P=0.01)
Bone mineral density
2.16 vs. 2.23 (P=0.21)

Subgroup Analysis

Prespecified subgroup analysis showed no differences between groups.

Adverse Events

Major bleeding
2.1% vs. 1.4% (P=1.0)
Minor bleeding
19.6% vs. 9.2% (P=0.01)
Bone mineral density
2.16 vs. 2.23 (P=0.21)

Criticisms

  • Noncompliance with treatment may have reduced effect sizes.
  • Slow enrollment (>12 years) increases the risk that effects may have been altered by time trends or other effects.
  • Most patients were enrolled with lower risk thrombophilias (most commonly fVL heterozygosity) and thus results may not be generalizable to higher risk populations.

Funding

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

Further Reading

  1. Bates SM et al. Guidance for the treatment and prevention of obstetric-associated venous thromboembolism. J. Thromb. Thrombolysis 2016. 41:92-128.