Marc A Rodger1, William M Hague2, John Kingdom3, Susan R Kahn4, Alan Karovitch5, Mathew Sermer3, Anne Marie Clement6, Suzette Coat7, Wee Shian Chan8, Joanne Said9, Evelyne Rey10, Sue Robinson11, Rshmi Khurana12, Christine Demers13, Michael J Kovacs14, Susan Solymoss15, Kim Hinshaw16, James Dwyer17, Graeme Smith18, Sarah McDonald19, Jill Newstead-Angel20, Anne McLeod21, Meena Khandelwal22, Robert M Silver23, Gregoire Le Gal24, Ian A Greer25, Erin Keely24, Karen Rosene-Montella26, Mark Walker6, Philip S Wells24. 1. Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada; Ottawa Hospital Research Institute, Ottawa, ON, Canada. Electronic address: mrodger@ohri.ca. 2. Obstetric Medicine, Robinson Institute, University of Adelaide, Women's and Children's Hospital, Adelaide, South Australia, Australia. 3. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada. 4. Centre for Clinical Epidemiology, Jewish General Hospital, Montreal, QC, Canada. 5. Department of Medicine, University of Ottawa/Ottawa Hospital, Ottawa, ON, Canada. 6. Ottawa Hospital Research Institute, Ottawa, ON, Canada. 7. Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia. 8. Department of Medicine, University of British Columbia, Vancouver, BC, Canada. 9. Maternal Fetal Medicine, NorthWest Academic Center, University of Melbourne, Melbourne, Australia. 10. Departments of Medicine and Obstetrics and Gynecology, University of Montreal, and CHU Sainte-Justine Research Center, Montreal, QC, Canada. 11. Department of Medicine, Dalhousie University, Halifax, NS, Canada. 12. Departments of Medicine and Obstetrics and Gynecology, University of Alberta, Royal Alexandra Hospital, Edmonton, AB, Canada. 13. Department of Medicine, Université de Laval, Quebec, QC, Canada. 14. Department of Medicine, London Health Sciences Centre, University of Western Ontario, London, ON, Canada. 15. Department of Medicine, McGill University, St Mary's Hospital Center, Montreal, QC, Canada. 16. Department of Obstetrics, Sunderland Royal Hospital, Sunderland, Tyne and Wear, UK. 17. Department of Obstetrics and Gynaecology, York Hospital, York, UK. 18. Department of Obstetrics and Gynecology, Queen's University, Kingston, ON, Canada. 19. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Department of Radiology, and Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada. 20. Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada. 21. Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. 22. Department of Obstetrics and Gynecology, Cooper Medical School of Rowan University/Cooper Hospital, Camden, NJ, USA. 23. Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, UT, USA. 24. Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa/Ottawa Hospital, Ottawa, ON, Canada. 25. Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK. 26. Department of Medicine, The Warren Alpert Medical School of Brown University, Women's Medicine Collaborative, Providence, RI, USA.
Abstract
BACKGROUND: Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. METHODS: In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov, number NCT00967382, and with Current Controlled Trials, number ISRCTN87441504. FINDINGS:Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned toantepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 [17·1%; 95% CI 11·4-24·2%] vs no dalteparin 27/143 [18·9%; 95% CI 12·8-26·3%]; risk difference -1·8% [95% CI -10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 [19·6%] vs no dalteparin 24/141 [17·0%]; risk difference +2·6% [95% CI -6·4 to 11·6%]). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19·6%]) than in the no dalteparin group (13/141 [9·2%]; risk difference 10·4%, 95% CI 2·3-18·4; p=0·01). INTERPRETATION:Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.
RCT Entities:
BACKGROUND:Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. METHODS: In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov, number NCT00967382, and with Current Controlled Trials, number ISRCTN87441504. FINDINGS: Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 [17·1%; 95% CI 11·4-24·2%] vs no dalteparin 27/143 [18·9%; 95% CI 12·8-26·3%]; risk difference -1·8% [95% CI -10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 [19·6%] vs no dalteparin 24/141 [17·0%]; risk difference +2·6% [95% CI -6·4 to 11·6%]). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19·6%]) than in the no dalteparin group (13/141 [9·2%]; risk difference 10·4%, 95% CI 2·3-18·4; p=0·01). INTERPRETATION: Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.
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