Assessing the Impact of Using Heparin and Bivalirudin on Clinical Outcome of Subjects Undergoing Percutaneous Coronary Intervention: A Meta-Analysis
Abstract
Background: Bivalirudin is increasingly used as an alternative to heparin in patients undergoing percutaneous coronary intervention (PCI) due to its potential for reducing adverse clinical outcomes. This meta-analysis aimed to compare the effectiveness and safety of bivalirudin versus heparin across various clinical outcomes.
Method: A total of 27 studies were included, comprising 63,624 patients: 30,492 received Bivalirudin, and 33,132 received Heparin. Key endpoints analyzed include net adverse clinical events (NACE), major adverse clinical events, major bleeding, mortality, stroke, and stent thrombosis. Data were pooled using a random-effects model, and heterogeneity was assessed using the I² statistic. Publication bias was evaluated using Begg’s and Egger’s tests.
Results: Bivalirudin significantly reduced the risk of major bleeding (MD=-0.4445, 95% CI [-0.6276, -0.2615], P<0.0001, I²=76.79%) compared to Heparin. However, no significant differences were found for major adverse clinical events (MD=-0.0993, P=0.3194) or mortality (MD=-0.1959, P=0.0893). There was moderate heterogeneity in most analyses, particularly for NACE (I²=68.24%) and stent thrombosis (I²=55.33%). No significant differences were observed for stroke prevention or stent thrombosis. Subgroup analyses demonstrated significant reductions in major bleeding with Bivalirudin, particularly in STEMI patients (log OR=-0.37, P<0.0001), though no differences in MACE or stent thrombosis were observed. High heterogeneity in NSTEMI populations (I²=81.4%) underscores the need for individualized therapy.
Conclusion: Although bivalirudin significantly lowers major bleeding compared with Heparin, it shows no clear advantage in mortality or other major clinical outcomes. Substantial heterogeneity across studies indicates variability in patient populations and procedural settings. Further research is needed to define its optimal role in specific PCI subgroups.
1. Stone GW, McLaurin BT, Cox DA, et al (2006). Bivalirudin for patients with acute coronary syndromes. N Engl J Med, 355(21):2203-16.
2. Kastrati A, Neumann F-J, Mehilli J, et al (2008). Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med, 359(7):688-96.
3. Steg PG, James S, Harrington RA, et al (2010). Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation, 122(21):2131-41.
4. Anantha-Narayanan M, Anugula D, Gujjula NR, et al (2018). Bivalirudin versus heparin in percutaneous coronary intervention—a systematic review and meta-analysis of randomized trials stratified by adjunctive glycoprotein IIb/IIIa strategy. J Thorac Dis, 10(6):3341- 3360.
5. Verdoia M, Schaffer A, Barbieri L, et al (2016). Bivalirudin versus unfractionated heparin in acute coronary syndromes: an updated meta-analysis of randomized trials. Rev Esp Cardiol (Engl Ed), 69(8):732-45.
6. Grajek S, Michalak M, Gwizdała A, et al (2018). Patients treated with bivalirudin are still at higher risk of stent thrombosis: a comprehensive meta-analysis of randomised clinical trials of bivalirudin and heparin for percutaneous coronary interventions. Kardiol Pol, 76(4):740-9.
7. Lincoff AM, Bittl JA, Harrington RA, et al (2003). Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA, 289(7):853-63.
8. Lincoff AM, Kleiman NS, Kereiakes DJ, et al (2004). Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA, 292(6):696-703.
9. Stone GW, White HD, Ohman EM, et al (2007). Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet, 369(9565):907-19.
10. White HD, Ohman EM, Lincoff AM, et al (2008). Safety and efficacy of bivalirudin with and without glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention 1-year results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol, 52(10):807-14.
11. Stone GW, Witzenbichler B, Guagliumi G, et al (2008). Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med, 358(21):2218-30.
12. Qaderdan K, Vos GA, McAndrew T, et al (2017). Outcomes in elderly and young patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with bivalirudin versus heparin: Pooled analysis from the EUROMAX and HORIZONS-AMI trials. Am Heart J, 194:73-82.
13. Schulz S, Mehilli J, Ndrepepa G, et al (2010). Bivalirudin vs. unfractionated heparin during percutaneous coronary interventions in patients with stable and unstable angina pectoris: 1-year results of the ISAR-REACT 3 trial. Eur Heart J, 31(5):582-7.
14. Parodi G, Migliorini A, Valenti R, et al (2010). Comparison of bivalirudin and unfractionated heparin plus protamine in patients with coronary heart disease undergoing percutaneous coronary intervention (from the Antithrombotic Regimens aNd Outcome [ARNO] trial). Am J Cardiol, 105(8):1053-9.
15. Kastrati A, Neumann FJ, Schulz S, et al (2011). Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med, 365(21):1980-9.
16. Schulz S, Kastrati A, Ferenc M, et al (2013). One-year outcomes with abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary interventions in patients with non-ST-segment elevation myocardial infarction: updated results from the ISAR-REACT 4 trial. EuroIntervention, 9(4):430-6.
17. Steg PG, van 't Hof A, Hamm CW, et al (2013). Bivalirudin started during emergency transport for primary PCI. N Engl J Med, 369(23):2207-17.
18. Fabris E, Kilic S, Van't Hof AWJ, et al (2017). One-Year Mortality for Bivalirudin vs Heparins Plus Optional Glycoprotein IIb/IIIa Inhibitor Treatment Started in the Ambulance for ST-Segment Elevation Myocardial Infarction: A Secondary Analysis of the EUROMAX Randomized Clinical Trial. JAMA Cardiol, 2(7):791-6.
19. Feldman A, Suleiman K, Bushari L, et al (2014). Bivalirudin versus Unfractionated Heparin during Percutaneous Coronary Intervention in Patients at High Risk for Bleeding. Int J Angiol, 23(4):227-32.
20. Shahzad A, Kemp I, Mars C, et al (2014). Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet, 384(9957):1849-58.
21. Valgimigli M, Frigoli E, Leonardi S, et al (2015). Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. N Engl J Med, 373(11):997-1009.
22. Leonardi S, Frigoli E, Rothenbühler M, et al (2016). Bivalirudin or unfractionated heparin in patients with acute coronary syndromes managed invasively with and without ST elevation (MATRIX): randomised controlled trial. BMJ, 354:i4935.
23. Han Y, Guo J, Zheng Y, et al (2015). Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA, 313(13):1336-46.
24. Erlinge D, Omerovic E, Fröbert O, et al (2017). Bivalirudin versus Heparin Monotherapy in Myocardial Infarction. N Engl J Med, 377(12):1132-42.
25. Wester A, Attar R, Mohammad MA, et al (2020). Bivalirudin Versus Heparin Monotherapy in Elderly Patients with Myocardial Infarction: A Prespecified Subgroup Analysis of the Validate-Swedeheart Trial. Circ Cardiovasc Interv, 13(4):e008671.
26. James S, Koul S, Andersson J, et al (2021). Bivalirudin Versus Heparin Monotherapy in ST-Segment-Elevation Myocardial Infarction. Circ Cardiovasc Interv, 14(12):e008969.
27. Li J, Liu X, Ma S, et al (2022). Effectiveness and safety of bivalirudin in elderly patients with coronary artery disease undergoing percutaneous coronary intervention: A real-world study. Catheter Cardiovasc Interv, 99 Suppl 1:1448-55.
28. Li Y, Liang Z, Qin L, et al (2022). Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial. Lancet, 400(10366):1847-57.
29. Chai L, Liu J, Zhang Y, et al (2023). Comparison of net adverse clinical events between bivalirudin and heparin as anticoagulants for percutaneous coronary intervention in Chinese patients. Exp Ther Med, 26(5):530.
30. Collet JP, Thiele H, Barbato E, et al (2021). 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J, 42(14):1289-1367.
31. Bangalore S, Pencina MJ, Kleiman NS, et al (2014). Heparin monotherapy or bivalirudin during percutaneous coronary intervention in patients with non-ST-segment-elevation acute coronary syndromes or stable ischemic heart disease: results from the Evaluation of Drug-Eluting Stents and Ischemic Events registry. Circ Cardiovasc Interv, 7(3):365-73.
32. Liu XQ, Luo XD, Wu YQ. (2020). Efficacy and safety of bivalirudin vs heparin in patients with coronary heart disease undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials. Medicine (Baltimore), 99(6):e19064.
33. Anantha-Narayanan M, Anugula D, Gujjula NR, et al (2018). Bivalirudin versus heparin in percutaneous coronary intervention-a systematic review and meta-analysis of randomized trials stratified by adjunctive glycoprotein IIb/IIIa strategy. J Thorac Dis, 10(6):3341-60.
34. Kheiri B, Rao SV, Osman M, et al (2020). Meta-analysis of bivalirudin versus heparin in transradial coronary interventions. Catheter Cardiovasc Interv, 96(6):1240-8.
2. Kastrati A, Neumann F-J, Mehilli J, et al (2008). Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med, 359(7):688-96.
3. Steg PG, James S, Harrington RA, et al (2010). Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation, 122(21):2131-41.
4. Anantha-Narayanan M, Anugula D, Gujjula NR, et al (2018). Bivalirudin versus heparin in percutaneous coronary intervention—a systematic review and meta-analysis of randomized trials stratified by adjunctive glycoprotein IIb/IIIa strategy. J Thorac Dis, 10(6):3341- 3360.
5. Verdoia M, Schaffer A, Barbieri L, et al (2016). Bivalirudin versus unfractionated heparin in acute coronary syndromes: an updated meta-analysis of randomized trials. Rev Esp Cardiol (Engl Ed), 69(8):732-45.
6. Grajek S, Michalak M, Gwizdała A, et al (2018). Patients treated with bivalirudin are still at higher risk of stent thrombosis: a comprehensive meta-analysis of randomised clinical trials of bivalirudin and heparin for percutaneous coronary interventions. Kardiol Pol, 76(4):740-9.
7. Lincoff AM, Bittl JA, Harrington RA, et al (2003). Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA, 289(7):853-63.
8. Lincoff AM, Kleiman NS, Kereiakes DJ, et al (2004). Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA, 292(6):696-703.
9. Stone GW, White HD, Ohman EM, et al (2007). Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet, 369(9565):907-19.
10. White HD, Ohman EM, Lincoff AM, et al (2008). Safety and efficacy of bivalirudin with and without glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention 1-year results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol, 52(10):807-14.
11. Stone GW, Witzenbichler B, Guagliumi G, et al (2008). Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med, 358(21):2218-30.
12. Qaderdan K, Vos GA, McAndrew T, et al (2017). Outcomes in elderly and young patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with bivalirudin versus heparin: Pooled analysis from the EUROMAX and HORIZONS-AMI trials. Am Heart J, 194:73-82.
13. Schulz S, Mehilli J, Ndrepepa G, et al (2010). Bivalirudin vs. unfractionated heparin during percutaneous coronary interventions in patients with stable and unstable angina pectoris: 1-year results of the ISAR-REACT 3 trial. Eur Heart J, 31(5):582-7.
14. Parodi G, Migliorini A, Valenti R, et al (2010). Comparison of bivalirudin and unfractionated heparin plus protamine in patients with coronary heart disease undergoing percutaneous coronary intervention (from the Antithrombotic Regimens aNd Outcome [ARNO] trial). Am J Cardiol, 105(8):1053-9.
15. Kastrati A, Neumann FJ, Schulz S, et al (2011). Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med, 365(21):1980-9.
16. Schulz S, Kastrati A, Ferenc M, et al (2013). One-year outcomes with abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary interventions in patients with non-ST-segment elevation myocardial infarction: updated results from the ISAR-REACT 4 trial. EuroIntervention, 9(4):430-6.
17. Steg PG, van 't Hof A, Hamm CW, et al (2013). Bivalirudin started during emergency transport for primary PCI. N Engl J Med, 369(23):2207-17.
18. Fabris E, Kilic S, Van't Hof AWJ, et al (2017). One-Year Mortality for Bivalirudin vs Heparins Plus Optional Glycoprotein IIb/IIIa Inhibitor Treatment Started in the Ambulance for ST-Segment Elevation Myocardial Infarction: A Secondary Analysis of the EUROMAX Randomized Clinical Trial. JAMA Cardiol, 2(7):791-6.
19. Feldman A, Suleiman K, Bushari L, et al (2014). Bivalirudin versus Unfractionated Heparin during Percutaneous Coronary Intervention in Patients at High Risk for Bleeding. Int J Angiol, 23(4):227-32.
20. Shahzad A, Kemp I, Mars C, et al (2014). Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet, 384(9957):1849-58.
21. Valgimigli M, Frigoli E, Leonardi S, et al (2015). Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. N Engl J Med, 373(11):997-1009.
22. Leonardi S, Frigoli E, Rothenbühler M, et al (2016). Bivalirudin or unfractionated heparin in patients with acute coronary syndromes managed invasively with and without ST elevation (MATRIX): randomised controlled trial. BMJ, 354:i4935.
23. Han Y, Guo J, Zheng Y, et al (2015). Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA, 313(13):1336-46.
24. Erlinge D, Omerovic E, Fröbert O, et al (2017). Bivalirudin versus Heparin Monotherapy in Myocardial Infarction. N Engl J Med, 377(12):1132-42.
25. Wester A, Attar R, Mohammad MA, et al (2020). Bivalirudin Versus Heparin Monotherapy in Elderly Patients with Myocardial Infarction: A Prespecified Subgroup Analysis of the Validate-Swedeheart Trial. Circ Cardiovasc Interv, 13(4):e008671.
26. James S, Koul S, Andersson J, et al (2021). Bivalirudin Versus Heparin Monotherapy in ST-Segment-Elevation Myocardial Infarction. Circ Cardiovasc Interv, 14(12):e008969.
27. Li J, Liu X, Ma S, et al (2022). Effectiveness and safety of bivalirudin in elderly patients with coronary artery disease undergoing percutaneous coronary intervention: A real-world study. Catheter Cardiovasc Interv, 99 Suppl 1:1448-55.
28. Li Y, Liang Z, Qin L, et al (2022). Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial. Lancet, 400(10366):1847-57.
29. Chai L, Liu J, Zhang Y, et al (2023). Comparison of net adverse clinical events between bivalirudin and heparin as anticoagulants for percutaneous coronary intervention in Chinese patients. Exp Ther Med, 26(5):530.
30. Collet JP, Thiele H, Barbato E, et al (2021). 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J, 42(14):1289-1367.
31. Bangalore S, Pencina MJ, Kleiman NS, et al (2014). Heparin monotherapy or bivalirudin during percutaneous coronary intervention in patients with non-ST-segment-elevation acute coronary syndromes or stable ischemic heart disease: results from the Evaluation of Drug-Eluting Stents and Ischemic Events registry. Circ Cardiovasc Interv, 7(3):365-73.
32. Liu XQ, Luo XD, Wu YQ. (2020). Efficacy and safety of bivalirudin vs heparin in patients with coronary heart disease undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials. Medicine (Baltimore), 99(6):e19064.
33. Anantha-Narayanan M, Anugula D, Gujjula NR, et al (2018). Bivalirudin versus heparin in percutaneous coronary intervention-a systematic review and meta-analysis of randomized trials stratified by adjunctive glycoprotein IIb/IIIa strategy. J Thorac Dis, 10(6):3341-60.
34. Kheiri B, Rao SV, Osman M, et al (2020). Meta-analysis of bivalirudin versus heparin in transradial coronary interventions. Catheter Cardiovasc Interv, 96(6):1240-8.
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| Issue | Vol 54 No 12 (2025) | |
| Section | Review Article(s) | |
| Keywords | ||
| Heparin Bivalirudin Percutaneous coronary intervention | ||
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How to Cite
1.
Yu Y, Sun X, Su M. Assessing the Impact of Using Heparin and Bivalirudin on Clinical Outcome of Subjects Undergoing Percutaneous Coronary Intervention: A Meta-Analysis. Iran J Public Health. 2025;54(12):2579-2594.
