Letters to the Editor
559
Intermediate doses of low-molecular-weight heparin for the long-term treatment of pregnancy thromboembolism. A systematic review Esteban Gándara1,2*; Marc Carrier1,2*; Marc A. Rodger1,2* 1Thrombosis
Program, Division of Hematology, Department of Medicine, University of Ottawa - The Ottawa Hospital, Ottawa, Ontario, Canada; 2Clinical Epidemiology Unit, Ottawa Health Research Institute, Ottawa, Ontario, Canada
Dear Sirs, After an initial phase of therapeutic anticoagulation ( 1,000 ml. They all occurred within the first 24 hours.
VTE and major bleeding were reported in one study. In patients treated for PAVTE, some experts (6) favour more aggressive treatment strategies for VTE (using full-dose LMWH, given twice a day and targeting anti-Xa levels) in order to overcome physiological changes associated with pregnancy (2, 3). Studies have suggested that only a small group of patients require changes in doses based on anti-Xa levels (20) and that the outcome of those treated with twice daily dosed is not better to that of those receiving once daily doses (21, 22). The last edition of the American College of Chest Physicians guidelines suggests the use of once daily full dose LWMH for long-term treatment without monitoring, but also and acknowledges the potential role of intermediate dose strategies for PAVTE (1). Furthermore, reducing the intensity of anticoagulation therapy following a course of full-dose anticoagulation appears to be associated with a reduction in bleeding risk (23), costs and patient discom-
fort (1). Our results suggests that the rate of recurrent VTE in patients with PAVTE (consisting mostly of patients with DVT) treated with an intermediate dose strategy is not different to the estimates produced by two systematic reviews including multiple anticoagulation strategies in patients with PAVTE (24, 25), but we could not identify any studies that compared intermediate to full-dose strategies. Our systematic review has important limitations. First, the inclusion of non-randomised studies could have led to an underestimation of the event rate. Second, characteristics of the groups could not be retrieved to allow any sensitivity analysis. Third we could not answer if intermediate doses can be given once daily and without anti-Xa monitoring. Fourth, only four patients with PE were included. Fifth, at least one of the studies included patients with distal DVT, which could lead to an overestimation of the positive effect. And finally, the quality of reporting was low.
In conclusion, the results suggest that the use of intermediate doses of LMWH for the long-term treatment of pregnancyassociated DVT could be an effective strategy following an initial course of full-dose anticoagulation, but confirmatory evidence is needed before its widespread adoption. Acknowledgements
The authors would like to thank Alexandra Davis for providing support in the design in the literature search and retrieval of articles. Dr. Marc Rodger is a Career Scientist of the Heart and Stroke Foundation of Ontario, a Faculty of Medicine and Department of Medicine Clinical Research Chair and was also supported by the Ministry of Research and Innovation’s Early Researcher Award. The Department of Medicine, OHRI and the University of Ottawa provided financial support for Dr. Gándara. This study was conducted as a part of the MSc. in Epidemiology Thesis of Dr. Gandara. The study was awarded the Peter
Thrombosis and Haemostasis 111.3/2014 Downloaded from www.thrombosis-online.com on 2014-12-22 | ID: 1000471717 | IP: 132.174.255.116 For personal or educational use only. No other uses without permission. All rights reserved.
© Schattauer 2014
Letters to the Editor
561
Garner prize as best oral presentation at the Annual Meeting from the North American Society of Obstetric Medicine. Quebec City, October 2012.
8.
Conflicts of interest
None declared.
9.
References
10.
1. Bates SM, Greer I, Middeldorp S, et al. VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; Suppl: e691S-e736S. 2. Abou-Nassar K, Kovacs MJ, Kahn SR, et al. The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia. A randomized trial. Thromb Haemost 2007; 98: 163-171. 3. Sephton V, Farquharson RG, Topping J, et al. A Longitudinal Study of Maternal Dose Response to Low Molecular Weight Heparin in Pregnancy. Obstet Gynecol 2003; 101: 1307-1311. 4. Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004; 191: 1024-1029. 5. Arya R. How I manage venous thromboembolism in pregnancy. Br J Haematol 2011; 153: 698-708. 6. Middeldorp S. How I treat pregnancy-related venous thromboembolism. Blood 2011; 118: 5394-5400. 7. Hull RD, Townshend G. Long-term treatment of deep-vein thrombosis with low-molecular-weight
© Schattauer 2014
11.
12.
13. 14.
15.
16.
heparin: An update of the evidence. Thromb Haemost 2013; 110: 14-22. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic Therapy for VTE Disease Antithrombotic Therapy for VTE Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e419S-e494S. Rodger M. Evidence base for the management of venous thromboembolism in pregnancy. Hematology Am Soc Hematol Educ Program 2010; 173-180. Bauersachs RM. Treatment of venous thromboembolism during pregnancy. Thromb Res 2009; 123: S45-S50. Miller S, Lester F, Hensleigh P. CEU: Prevention and Treatment of Postpartum Hemorrhage: New Advances for Low-Resource Settings. J Midwifery Womens Health 2004; 49: 283-292. Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2009. Report. Available at http://www.ohri.ca/programs/ clinical_epidemiology/oxford.asp. Laird NM, Mosteller F. Some statistical methods for combining experimental results. Int J Technol Assess Health Care; 6: 5-30. Barillari G, Springolo F, Daminiato R, et al. Safety and efficacy of nadroparin for the management of venous thromboembolism or thrombophilia in pregnancy. J Thromb Haemost 2007; 5: Abstract P-S-623. Daskalakis G, Antsaklis A, Papageorgiou I, et al. Thrombosis prophylaxis after treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 1997; 74: 165-167. Lyall H, Myers B. Incidence and management of 82 cases of pregnancy-associated venous thromboembolism occurring at a single centre--com-
17. 18.
19.
20.
21.
22. 23.
24.
25.
parison with Voke et al. Br J Haematol 2008; 142: 309-311. Mitic G, Povazan L, Lucic AM. Treatment of pregnancy related venous thromboembolism. Med Pregl 2009; 62: 346-351. Smith MP, Norris LA, Steer PJ, et al. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 2004; 190: 495-501. Ulander VM, Stenqvist P, Kaaja R. Treatment of deep venous thrombosis with low-molecularweight heparin during pregnancy. Thrombosis Res 2002; 106: 13-17. Rodie VA, Thomson AJ, Stewart FM, et al. Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series. Br J Obstet Gynecol 2002; 109: 1020-1024. Voke J, Keidan J, Pavord S, et al. The management of antenatal venous thromboembolism in the UK and Ireland: a prospective multicentre observational survey. Br J Haematol 2007; 139: 545-558. Knight M, UKOSS. Antenatal pulmonary embolism: risk factors, management and outcomes. Br J Obstet Gynecol 2008; 115: 453-461. Iorio A, Guercini F, Pini M. Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants. J Thromb Haemost 2003; 1: 1906-1913. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106: 401-407. Romualdi E, Dentali F, Rancan E, et al. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J Thromb Haemost 2013; 11: 270-281.
Thrombosis and Haemostasis 111.3/2014 Downloaded from www.thrombosis-online.com on 2014-12-22 | ID: 1000471717 | IP: 132.174.255.116 For personal or educational use only. No other uses without permission. All rights reserved.
559
Intermediate doses of low-molecular-weight heparin for the long-term treatment of pregnancy thromboembolism. A systematic review Esteban Gándara1,2*; Marc Carrier1,2*; Marc A. Rodger1,2* 1Thrombosis
Program, Division of Hematology, Department of Medicine, University of Ottawa - The Ottawa Hospital, Ottawa, Ontario, Canada; 2Clinical Epidemiology Unit, Ottawa Health Research Institute, Ottawa, Ontario, Canada
Dear Sirs, After an initial phase of therapeutic anticoagulation ( 1,000 ml. They all occurred within the first 24 hours.
VTE and major bleeding were reported in one study. In patients treated for PAVTE, some experts (6) favour more aggressive treatment strategies for VTE (using full-dose LMWH, given twice a day and targeting anti-Xa levels) in order to overcome physiological changes associated with pregnancy (2, 3). Studies have suggested that only a small group of patients require changes in doses based on anti-Xa levels (20) and that the outcome of those treated with twice daily dosed is not better to that of those receiving once daily doses (21, 22). The last edition of the American College of Chest Physicians guidelines suggests the use of once daily full dose LWMH for long-term treatment without monitoring, but also and acknowledges the potential role of intermediate dose strategies for PAVTE (1). Furthermore, reducing the intensity of anticoagulation therapy following a course of full-dose anticoagulation appears to be associated with a reduction in bleeding risk (23), costs and patient discom-
fort (1). Our results suggests that the rate of recurrent VTE in patients with PAVTE (consisting mostly of patients with DVT) treated with an intermediate dose strategy is not different to the estimates produced by two systematic reviews including multiple anticoagulation strategies in patients with PAVTE (24, 25), but we could not identify any studies that compared intermediate to full-dose strategies. Our systematic review has important limitations. First, the inclusion of non-randomised studies could have led to an underestimation of the event rate. Second, characteristics of the groups could not be retrieved to allow any sensitivity analysis. Third we could not answer if intermediate doses can be given once daily and without anti-Xa monitoring. Fourth, only four patients with PE were included. Fifth, at least one of the studies included patients with distal DVT, which could lead to an overestimation of the positive effect. And finally, the quality of reporting was low.
In conclusion, the results suggest that the use of intermediate doses of LMWH for the long-term treatment of pregnancyassociated DVT could be an effective strategy following an initial course of full-dose anticoagulation, but confirmatory evidence is needed before its widespread adoption. Acknowledgements
The authors would like to thank Alexandra Davis for providing support in the design in the literature search and retrieval of articles. Dr. Marc Rodger is a Career Scientist of the Heart and Stroke Foundation of Ontario, a Faculty of Medicine and Department of Medicine Clinical Research Chair and was also supported by the Ministry of Research and Innovation’s Early Researcher Award. The Department of Medicine, OHRI and the University of Ottawa provided financial support for Dr. Gándara. This study was conducted as a part of the MSc. in Epidemiology Thesis of Dr. Gandara. The study was awarded the Peter
Thrombosis and Haemostasis 111.3/2014 Downloaded from www.thrombosis-online.com on 2014-12-22 | ID: 1000471717 | IP: 132.174.255.116 For personal or educational use only. No other uses without permission. All rights reserved.
© Schattauer 2014
Letters to the Editor
561
Garner prize as best oral presentation at the Annual Meeting from the North American Society of Obstetric Medicine. Quebec City, October 2012.
8.
Conflicts of interest
None declared.
9.
References
10.
1. Bates SM, Greer I, Middeldorp S, et al. VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; Suppl: e691S-e736S. 2. Abou-Nassar K, Kovacs MJ, Kahn SR, et al. The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia. A randomized trial. Thromb Haemost 2007; 98: 163-171. 3. Sephton V, Farquharson RG, Topping J, et al. A Longitudinal Study of Maternal Dose Response to Low Molecular Weight Heparin in Pregnancy. Obstet Gynecol 2003; 101: 1307-1311. 4. Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004; 191: 1024-1029. 5. Arya R. How I manage venous thromboembolism in pregnancy. Br J Haematol 2011; 153: 698-708. 6. Middeldorp S. How I treat pregnancy-related venous thromboembolism. Blood 2011; 118: 5394-5400. 7. Hull RD, Townshend G. Long-term treatment of deep-vein thrombosis with low-molecular-weight
© Schattauer 2014
11.
12.
13. 14.
15.
16.
heparin: An update of the evidence. Thromb Haemost 2013; 110: 14-22. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic Therapy for VTE Disease Antithrombotic Therapy for VTE Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e419S-e494S. Rodger M. Evidence base for the management of venous thromboembolism in pregnancy. Hematology Am Soc Hematol Educ Program 2010; 173-180. Bauersachs RM. Treatment of venous thromboembolism during pregnancy. Thromb Res 2009; 123: S45-S50. Miller S, Lester F, Hensleigh P. CEU: Prevention and Treatment of Postpartum Hemorrhage: New Advances for Low-Resource Settings. J Midwifery Womens Health 2004; 49: 283-292. Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2009. Report. Available at http://www.ohri.ca/programs/ clinical_epidemiology/oxford.asp. Laird NM, Mosteller F. Some statistical methods for combining experimental results. Int J Technol Assess Health Care; 6: 5-30. Barillari G, Springolo F, Daminiato R, et al. Safety and efficacy of nadroparin for the management of venous thromboembolism or thrombophilia in pregnancy. J Thromb Haemost 2007; 5: Abstract P-S-623. Daskalakis G, Antsaklis A, Papageorgiou I, et al. Thrombosis prophylaxis after treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 1997; 74: 165-167. Lyall H, Myers B. Incidence and management of 82 cases of pregnancy-associated venous thromboembolism occurring at a single centre--com-
17. 18.
19.
20.
21.
22. 23.
24.
25.
parison with Voke et al. Br J Haematol 2008; 142: 309-311. Mitic G, Povazan L, Lucic AM. Treatment of pregnancy related venous thromboembolism. Med Pregl 2009; 62: 346-351. Smith MP, Norris LA, Steer PJ, et al. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 2004; 190: 495-501. Ulander VM, Stenqvist P, Kaaja R. Treatment of deep venous thrombosis with low-molecularweight heparin during pregnancy. Thrombosis Res 2002; 106: 13-17. Rodie VA, Thomson AJ, Stewart FM, et al. Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series. Br J Obstet Gynecol 2002; 109: 1020-1024. Voke J, Keidan J, Pavord S, et al. The management of antenatal venous thromboembolism in the UK and Ireland: a prospective multicentre observational survey. Br J Haematol 2007; 139: 545-558. Knight M, UKOSS. Antenatal pulmonary embolism: risk factors, management and outcomes. Br J Obstet Gynecol 2008; 115: 453-461. Iorio A, Guercini F, Pini M. Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants. J Thromb Haemost 2003; 1: 1906-1913. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106: 401-407. Romualdi E, Dentali F, Rancan E, et al. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J Thromb Haemost 2013; 11: 270-281.
Thrombosis and Haemostasis 111.3/2014 Downloaded from www.thrombosis-online.com on 2014-12-22 | ID: 1000471717 | IP: 132.174.255.116 For personal or educational use only. No other uses without permission. All rights reserved.
