Efficacy and safety of different low-molecular-weight heparins in preventing thrombotic disease in patients with atrial fibrillation: a network meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

CHEN Linhua ,  ZHOU Lingyun , LI Dianke , WANG Jianglin , YIN Wenjun , LIU Kun , ZHOU Ge , FANG Weijin ,  ZUO Xiaocong

Department of Pharmacy, the Third Xiangya Hospital of Central South University, Changsha 410013, P.R.China;

Corresponding author：

ZHOU Lingyun, Email: yun19871001@163.com; ZUO Xiaocong, Email: zuoxc08@126.com

Keywords：

Atrial fibrillation; Thrombotic disease; Low molecular weight heparins; Network meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202104017

Video：

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Objective To systematically review the efficacy and safety of different low-molecular-weight heparins (LMWHs) for prevention of thromboembolic events in patients with atrial fibrillation (AF).Methods PubMed, The Cochrane Library, EMbase, CBM, CNKI, VIP and WanFang Data databases were electronically searched to collect randomized clinical trials (RCTs) on efficacy and safety of different low-molecular-weight heparins (LMWHs) in preventing thrombotic diseases in patients with atrial fibrillation from inception to March 2021. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies; then, meta-analysis was performed by using Stata 16.0 software.Results A total of 11 RCTs involving 7 400 patients who were treated with enoxaparin, dalteparin, or tinzaparin to prevent thromboembolic events were included. The results of network meta-analysis showed that: in patients with AF and perioperative AF patients, there were no statistical differences in the incidence of stroke, TIA, major bleeding, minor bleeding, and all-cause mortality caused by dalteparin, enoxaparin, and tinzaparin. Furthermore, the surface under the cumulative ranking area (SUCRA) showed that enoxaparin was superior for prevention of stroke and TIA than dalteparin and tinzaparin. As for major bleeding, minor bleeding, and all-cause death, dalteparin treatment was superior than enoxaparin.Conclusions Current evidence showed enoxaparin to be a viable option for high ischemic risk AF patients requiring LWMH treatment, while dalteparin to be a viable option for those with bleeding high risk. Due to limited quality and quantity of the included studies, more high-quality studies are required to verify the above conclusions.

Citation： CHEN Linhua, ZHOU Lingyun, LI Dianke, WANG Jianglin, YIN Wenjun, LIU Kun, ZHOU Ge, FANG Weijin, ZUO Xiaocong. Efficacy and safety of different low-molecular-weight heparins in preventing thrombotic disease in patients with atrial fibrillation: a network meta-analysis. Chinese Journal of Evidence-Based Medicine, 2021, 21(10): 1154-1161. doi: 10.7507/1672-2531.202104017 Copy

1.	López-López JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ, 2017, 359: j5058.
2.	黄从新, 张澍, 黄德嘉, 等. 心房颤动: 目前的认识和治疗的建议-2018. 中国心脏起搏与心电生理杂志, 2018, 32(4): 315-368.
3.	Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J, 2021, 42(5): 373-498.
4.	Chiang CE, Okumura K, Zhang S, et al. 2017 consensus of the Asia pacific heart rhythm society on stroke prevention in atrial fibrillation. J Arrhythm, 2017, 33(4): 345-367.
5.	Ceornodolea AD, Bal R, Severens JL. Epidemiology and management of atrial fibrillation and stroke: review of data from four European countries. Stroke Res Treat, 2017, 2017: 8593207.
6.	Guerrini M, Bisio A. Low-molecular-weight heparins: differential characterization/physical characterization. Handb Exp Pharmacol, 2012, (207): 127-157.
7.	Arepally GM. Heparin-induced thrombocytopenia. Blood, 2017, 129(21): 2864-2872.
8.	Onishi A, St Ange K, Dordick JS, et al. Heparin and anticoagulation. Front Biosci (Landmark Ed), 2016, 21: 1372-1392.
9.	Lu E, Shatzel JJ, Salati J, et al. The safety of low-molecular-weight heparin during and after pregnancy. Obstet Gynecol Surv, 2017, 72(12): 721-729.
10.	Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest, 2016, 149(2): 315-352.
11.	Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev, 2019, (10): ED000142.
12.	Feiz F, Sedghi R, Salehi A, et al. Study of the efficacy, safety and tolerability of low-molecular-weight heparin vs. unfractionated heparin as bridging therapy in patients with embolic stroke due to atrial fibrillation. J Vasc Interv Neurol, 2016, 9(1): 35-41.
13.	Goette A, Merino JL, Ezekowitz MD, et al. Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial. Lancet, 2016, 388(10055): 1995-2003.
14.	Zeuthen EL, Lassen JF, Husted SE. Haemostatic activity in patients with atrial fibrillation treated with low-molecular-weight heparin before and after electrical cardioversion. J Thromb Thrombolysis, 2004, 17(3): 185-189.
15.	Siu CW, Jim MH, Lau CP, et al. Low molecular weight heparin versus unfractionated heparin for thromboprophylaxis in patients with acute atrial fibrillation: a randomized control trial. Acute Card Care, 2011, 13(3): 196-198.
16.	Berge E, Abdelnoor M, Nakstad PH, et al. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST study group. Heparin in acute embolic stroke trial. Lancet, 2000, 355(9211): 1205-1210.
17.	Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med, 2015, 373(9): 823-833.
18.	Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the role of Coumadin in preventing thromboembolism in atrial fibrillation (AF) patients undergoing catheter ablation (COMPARE) randomized trial. Circulation, 2014, 129(25): 2638-2644.
19.	Stellbrink C, Nixdorff U, Hofmann T, et al. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the anticoagulation in cardioversion using enoxaparin (ACE) trial. Circulation, 2004, 109(8): 997-1003.
20.	Yigit Z, Küçükoglu MS, Okçün B, et al. The safety of low-molecular weight heparins for the prevention of thromboembolic events after cardioversion of atrial fibrillation. Jpn Heart J, 2003, 44(3): 369-377.
21.	Klein AL, Jasper SE, Katz WE, et al. The use of enoxaparin compared with unfractionated heparin for short-term antithrombotic therapy in atrial fibrillation patients undergoing transoesophageal echocardiography-guided cardioversion: assessment of cardioversion using transoesophageal echocardiography (ACUTE) Ⅱ randomized multicentre study. Eur Heart J, 2006, 27(23): 2858-2865.
22.	Yu HT, Shim J, Park J, et al. When is it appropriate to stop non-vitamin K antagonist oral anticoagulants before catheter ablation of atrial fibrillation? A multicentre prospective randomized study. Eur Heart J, 2019, 40(19): 1531-1537.
23.	Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest, 2001, 119(Suppl 1): 64S-94S.
24.	Nuotio I, Hartikainen JE, Grönberg T, et al. Time to cardioversion for acute atrial fibrillation and thromboembolic complications. JAMA, 2014, 312(6): 647-649.
25.	Ayoub K, Nairooz R, Almomani A, et al. Perioperative heparin bridging in atrial fibrillation patients requiring temporary interruption of anticoagulation: evidence from meta-analysis. J Stroke Cerebrovasc Dis, 2016, 25(9): 2215-2221.
26.	Cardoso R, Knijnik L, Bhonsale A, et al. An updated meta-analysis of novel oral anticoagulants versus vitamin K antagonists for uninterrupted anticoagulation in atrial fibrillation catheter ablation. Heart Rhythm, 2018, 15(1): 107-115.

1. López-López JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ, 2017, 359: j5058.
2. 黄从新, 张澍, 黄德嘉, 等. 心房颤动: 目前的认识和治疗的建议-2018. 中国心脏起搏与心电生理杂志, 2018, 32(4): 315-368.
3. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J, 2021, 42(5): 373-498.
4. Chiang CE, Okumura K, Zhang S, et al. 2017 consensus of the Asia pacific heart rhythm society on stroke prevention in atrial fibrillation. J Arrhythm, 2017, 33(4): 345-367.
5. Ceornodolea AD, Bal R, Severens JL. Epidemiology and management of atrial fibrillation and stroke: review of data from four European countries. Stroke Res Treat, 2017, 2017: 8593207.
6. Guerrini M, Bisio A. Low-molecular-weight heparins: differential characterization/physical characterization. Handb Exp Pharmacol, 2012, (207): 127-157.
7. Arepally GM. Heparin-induced thrombocytopenia. Blood, 2017, 129(21): 2864-2872.
8. Onishi A, St Ange K, Dordick JS, et al. Heparin and anticoagulation. Front Biosci (Landmark Ed), 2016, 21: 1372-1392.
9. Lu E, Shatzel JJ, Salati J, et al. The safety of low-molecular-weight heparin during and after pregnancy. Obstet Gynecol Surv, 2017, 72(12): 721-729.
10. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest, 2016, 149(2): 315-352.
11. Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev, 2019, (10): ED000142.
12. Feiz F, Sedghi R, Salehi A, et al. Study of the efficacy, safety and tolerability of low-molecular-weight heparin vs. unfractionated heparin as bridging therapy in patients with embolic stroke due to atrial fibrillation. J Vasc Interv Neurol, 2016, 9(1): 35-41.
13. Goette A, Merino JL, Ezekowitz MD, et al. Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial. Lancet, 2016, 388(10055): 1995-2003.
14. Zeuthen EL, Lassen JF, Husted SE. Haemostatic activity in patients with atrial fibrillation treated with low-molecular-weight heparin before and after electrical cardioversion. J Thromb Thrombolysis, 2004, 17(3): 185-189.
15. Siu CW, Jim MH, Lau CP, et al. Low molecular weight heparin versus unfractionated heparin for thromboprophylaxis in patients with acute atrial fibrillation: a randomized control trial. Acute Card Care, 2011, 13(3): 196-198.
16. Berge E, Abdelnoor M, Nakstad PH, et al. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST study group. Heparin in acute embolic stroke trial. Lancet, 2000, 355(9211): 1205-1210.
17. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med, 2015, 373(9): 823-833.
18. Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the role of Coumadin in preventing thromboembolism in atrial fibrillation (AF) patients undergoing catheter ablation (COMPARE) randomized trial. Circulation, 2014, 129(25): 2638-2644.
19. Stellbrink C, Nixdorff U, Hofmann T, et al. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the anticoagulation in cardioversion using enoxaparin (ACE) trial. Circulation, 2004, 109(8): 997-1003.
20. Yigit Z, Küçükoglu MS, Okçün B, et al. The safety of low-molecular weight heparins for the prevention of thromboembolic events after cardioversion of atrial fibrillation. Jpn Heart J, 2003, 44(3): 369-377.
21. Klein AL, Jasper SE, Katz WE, et al. The use of enoxaparin compared with unfractionated heparin for short-term antithrombotic therapy in atrial fibrillation patients undergoing transoesophageal echocardiography-guided cardioversion: assessment of cardioversion using transoesophageal echocardiography (ACUTE) Ⅱ randomized multicentre study. Eur Heart J, 2006, 27(23): 2858-2865.
22. Yu HT, Shim J, Park J, et al. When is it appropriate to stop non-vitamin K antagonist oral anticoagulants before catheter ablation of atrial fibrillation? A multicentre prospective randomized study. Eur Heart J, 2019, 40(19): 1531-1537.
23. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest, 2001, 119(Suppl 1): 64S-94S.
24. Nuotio I, Hartikainen JE, Grönberg T, et al. Time to cardioversion for acute atrial fibrillation and thromboembolic complications. JAMA, 2014, 312(6): 647-649.
25. Ayoub K, Nairooz R, Almomani A, et al. Perioperative heparin bridging in atrial fibrillation patients requiring temporary interruption of anticoagulation: evidence from meta-analysis. J Stroke Cerebrovasc Dis, 2016, 25(9): 2215-2221.
26. Cardoso R, Knijnik L, Bhonsale A, et al. An updated meta-analysis of novel oral anticoagulants versus vitamin K antagonists for uninterrupted anticoagulation in atrial fibrillation catheter ablation. Heart Rhythm, 2018, 15(1): 107-115.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of different low-molecular-weight heparins in preventing thrombotic disease in patients with atrial fibrillation: a network meta-analysis

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