Table 1.
Summary of the study designs, patient characteristics, and outcomes.
|
Study Name
and Year |
Trial Design
Comparison Group and Inferiority or Superiority Margins |
Patient Characteristics | Procedure Type and Reason for PCI | Sample Size (n) | GPI Usage with Bivali and Heparin, Respectively | Dose of Bivali | Dose of Heparin | ACT Cut-off | Primary Outcome and Follow-up Duration | Results of Primary Outcome of Bivali as Compared to Heparin |
|---|---|---|---|---|---|---|---|---|---|---|
| VALIDATE-SWEDEHEART (2017) |
Multicenter, RCT Bivali vs heparin Superiority |
Age: 68 (Median) Gender: M (73.4%), F (26.6%) DM: 16.6% CKD: NA HTN: 51.7% HLP: 31.5 Previous Stroke: 4% Prior MI:16.2% Prior CABG: 4.9% |
PCI Reason for PCI: STEMI/NSTEMI |
6006 | Bailout GPI 2.4% and 2.8% | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 70-100U/kg | ≥250 secs | Composite of all-cause mortality, MI or major bleeding 180 days |
Non-inferior |
| MATRIX (2015) | Multicenter, RCT Bivali vs UFH Superiority |
Age: 65.4 ± 11.9 (Mean) Sex: M (76.2%), F (23.8%) DM: 22.2% CKD: 1.3% HTN: 62.2% HLP: 43.7 Prior Stroke: 5.0% Prior MI: 14.3% Prior CABG: 3.0% |
PCI Reason for PCI: STEMI/NSTEMI |
7213 | GPI (4.6%)* and (25.9%)# | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 70-100U/kg (without GPI) and 50-70U/kg (with GPI) | NA | MACE (composite of death, MI or stroke) and NACE (composite of major bleeding or MACE) 30 days |
Non-inferior |
| Naples III (2015) | Single center, RCT Bivali vs UFH Superiority |
Age: 78 ± 4 (Mean) Sex: M (52.5%), F (47.5%) DM: 44% CKD: 45.7% (<30 ml/min/1.73 m2 patients were not included) HTN: 83.5% HLP: 56.5 Prior Stroke: NA Prior MI: 40% Prior CABG: 13.4% |
Elective trans-femoral PCI in high bleeding risk patients Reason for PCI: Stable/unstable angina pectoris (with negative biomarkers) |
837 | Tirofiban# 0.5% and 1.3% | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 70U/kg | ≥250 secs | Major bleeding 30 days and 1 year |
Non-inferior |
| BRIGHT (2015) | Multicenter, RCT Bivali vs heparin alone vs heparin plus tirofiban Superiority |
Age: 57.8 ± 11.7 (Mean) Sex: M (82.1%), F (17.9%) DM: 21.2% CKD: 10.9% HTN: 42.1% HLP: 37.1 Prior Stroke: 8.1% Prior MI: 4.4% Prior CABG: NA |
Emergent PCI Reason for PCI: STEMI, NSTEMI |
2194 | Bivali- Tirofiban (4.4%)*, Heparin-Heparin alone (n=729) (5.6%)*, Heparin plus tirofiban (n=730) |
0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h, additional median 3-hour Post procedural dose infusion of bivali | 100U/kg (without tirofiban) and 60 U/kg (with tirofiban) | ≥225 secs | NACE (composite of all-cause death, reinfarction, TVR, or stroke) or bleeding 30 days and 1 year |
Superior in reducing NACE with post-PCI infusion in bivalirudin group |
| EUROMAX trial (2014) | RCT Bivali vs heparin plus routine GPI vs heparin plus bailout GPI Superiority |
Age: 61 (Median) Sex: M (76.7%), F (23.3%) DM: 14.2% CKD: 16.6% HTN: 45.1% HLP: 37.7% Prior Stroke: NA Prior MI: 9.2% Prior CABG: 2.4% |
Primary PCI Reason for PCI: STEMI |
2198 | Bivali- GPI 3.9% (protocol deviation) 7.9% (bailout), Heparin- Routine GPI (n=649) and bailout GPI (n=117) |
0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 100U/kg (without GPI) and 60 U/kg (with GPI) | NA | Composite of death or major bleeding 30 days |
Bivalirudin is superior in reducing major bleeding but increases stent thrombosis risk |
| HEAT- PPCI (2014) | Single center, RCT Bivali vs UFH Equivalent |
Age: 63.2 (Mean) Sex: M (72%), F (28%) DM:14% CKD: NA HTN: 41.5% HLP: 37.5 Prior Stroke: NA Prior MI:12% Prior CABG: 2% |
Primary PCI Reason for PCI: STEMI |
1812 | Bailout abciximab 13% and 15% | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 70U/kg | ≥200 secs for heparin and ≥225 secs for bivali | MACE (composite of all-cause mortality, CVA, reinfarction, TVR) and major bleeding 28 days |
Bivalirudin is inferior in reducing risk of MACE and stent thrombosis events |
| ARMYDA-7 BIVALVE (2012) | Multicenter, RCT Bivali vs UFH Superiority |
Age: 70.2 ± 9 (Mean) Sex: M (71.5%), F (28.5%) DM: 63% CKD: 21% HTN: 90.5% HLP: NA Prior Stroke: NA Prior MI: 35.5% Prior CABG: NA |
High risk PCI Reason for PCI: NSTEMI/UA/Stable angina pectoris |
401 | GPI#* 12% and 14% | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 75U/kg | NA | MACE (cardiac death, MI, stent thrombosis, TVR) or any bleeding event 30 days |
Superior in reducing bleeding events |
| ISAR-REACT 4 (2011) | Multicenter, RCT Bivali vs UFH plus Abciximab Superiority |
Age: 67.5 ± 11 (Mean) Sex: M (76.9%), F (23.1%) DM: 29% CKD: NA HTN: 85.5% HLP: 68.5 Prior Stroke: NA Prior MI: 20.4% Prior CABG: 10.5% |
PCI Reason for PCI: UA/NSTEMI |
1721 | None and Abciximab | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 70U/kg | NA | Composite of death, large recurrent MI, urgent TVR, or major bleeding 30 days |
Bivalirudin is superior in reducing bleeding events |
| NAPLES (2009) | RCT Bivali vs UFH plus Tirofiban |
Age: 65.3 ± 9 (Mean) Sex: M (65.1%), F (34.9%) DM: 100% CKD: 37.7% HTN: 76.4% HLP: 63.9 Prior Stroke: NA Prior MI: 44.7% Prior CABG: 8.0% |
Elective PCI in diabetic patients Reason for PCI: UA/Stable angina pectoris/asymptomatic |
335 | None and Tirofiban | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 70U/kg | ≥250 secs | Composite of death, MI, urgent TVR, or in hospital bleeding 30 days |
Bivalirudin is superior in reducing composite of death, MI, urgent TVR and in hospital minor bleeding |
| HORIZONS-AMI (2009) | Multicenter, RCT Bivali vs Heparin plus GPI Non-inferiority and superiority |
Age: 60.2 (Mean) Sex: M (76.5%), F (23.5%) DM: 16.5% CKD: 16.5% HTN: 53.5% HLP: 43% Prior Stroke: NA Prior MI: 10.5% Prior CABG: 3.0% |
PCI Reason for PCI: STEMI |
3602 | Abciximab, Eptifibatide (7.5%)* and Abciximab, Eptifibatide | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 60U/kg | ≥200-250 secs | NACE (MACE or major bleeding); MACE (composite of death, MI, TVR or stroke) 30 days,1 year and 3 year |
Bivalirudin is superior in reducing all-cause mortality, re-infarction and major bleeding |
| ISAR- REACT 3 (2008) | RCT Superiority Bivali vs UFH |
Age: 66.9 ± 10 (Mean) Sex: M (76.5%), F (23.5%) DM: 27.4% CKD: NA HTN: 89.2% HLP: 79.7 Prior Stroke: NA Prior MI: 31.1% Prior CABG: 11.7% |
PCI Reason for PCI: Stable/Unstable angina |
4570 | None | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 140U/kg bolus infusion followed by placebo infusion; except at one center 100U/kg | ≥250 secs only at one center |
NACE (composite of death, large recurrent MI, urgent TVR, or major bleeding) 30 days |
Bivalirudin is non-inferior in reducing NACE but did decrease incidence of major bleeding |
| POTECT-TIMI-30 (2006) | RCT Bivali vs UFH plus eptifibatide vs enoxaparin plus eptifibatide Superiority |
Age: 59.8 ± 10.4 (Mean) Sex: M (67.1%), F (32.9%) DM: 40.4% CKD: NA HTN: 65.6% HLP: 55.3 Prior Stroke: NA Prior MI: 21.3% Prior CABG: 7% |
PCI Reason for PCI: NSTEMI |
857 | None and Eptifibatide | 0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 50 U/kg bolus (UFH) 0.5 mg/kg IV enoxaparin |
≥200-250 secs | Coronary flow reserve and major bleeding 24-48h |
Bivalirudin is superior in reducing minor bleeding, transfusion events and has greater coronary flow reserve |
| ACUITY (2006) | Multicenter, RCT Bivali alone vs bivali plus GPI vs UFH plus GPI Superiority |
Age: 63 (Mean) Sex: M (69.9%), F (30.1%) DM: 28.0% CKD: 19.1% HTN: 67.0% HLP: 57.2% Prior Stroke: NA Prior MI: 31.3% Prior CABG:17.9% |
PCI Reason for PCI: UA, NSTEMI |
13819 | Bivali-with GPI (4604), Without GPI (4612) Heparin- With GPI (4603) GPI used: (Abciximab, Eptifibatide) |
0.1mg/kg bolus followed by an infusion of 0.25mg/kg/h, increased to 1.75mg/kg/h during PCI | 60U/kg bolus with infusion of 12U/kg/h Enoxaparin: 1 mg/kg twice daily subcutaneously before angiography, with an additional 0.3-0.75mg/kg IV bolus before PCI |
≥200-250 secs | Composite of death, MI or repeat revascularization or major bleeding 30 days |
Bivalirudin is superior in reducing major bleeding events with similar rates of ischemia |
| REPLACE-1 (2004) | Multicenter, RCT Bivali plus GPI vs Heparin plus GPI |
Age: 64.3 ± 11.3 (Mean) Sex: M (69.9%), F (30.1%) DM: 30.1% HTN: 73.3% HLP: NA Prior Stroke: NA Prior MI: 41.5% Prior CABG: 23.3% |
Elective or urgent PCI | 1056 | GPI 71.1% and 72.5% GPI used: (Abciximab, Eptifibatide, Tirofiban) |
0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 60-70 U/kg bolus | ≥200-300 secs | Composite of death, MI or repeat revascularization or major bleeding 48h |
Non-inferior |
| REPLACE-2 (2003) | Multicenter, RCT Bivali plus bailout GPI vs Heparin plus planned GPI Non-inferiority |
Age: 62.6 (Mean) Sex: M (74.4%), F (25.6%) DM: 27.1% HTN: 67% HLP: NA Prior Stroke: NA Prior MI: 37.0% Prior CABG: 18.4% |
Elective or urgent PCI | 6010 | Bivali- GPI 7.2% bailout use* GPI (all cases) plus 5.2% bailout* GPI used: (Abciximab, Eptifibatide) |
0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h | 65U/kg bolus (with GPI) |
≥225 secs | Composite of death, MI or repeat revascularization or major bleeding 30 days |
Non-inferior in regards to prevent acute ischemic events and superior in preventing bleeding events. |
| CACHET (2002) | RCT Bivali with or without abciximab vs Heparin plus abciximab |
Age: 62.5± 11.3 (Mean) Sex: M (77.2%), F (22.8%) DM: NA HTN: NA HLP: NA Prior Stroke: NA Prior MI: NA Prior CABG: NA |
PCI | 268 | Abciximab (76% planned and 24% bailout) and Abciximab | Phase A: 1 mg/kg bolus followed by an infusion of 2.5mg/kg/h Phase B: 0.5mg/kg bolus followed by an infusion of 1.75mg/kg/h Phase C:0.75mg/kg bolus followed by an infusion of 1.75mg/kg/h |
70 U/kg bolus | ≥200 secs | Composite of death, myocardial infarction or repeat revascularization or major bleeding 7 days |
Non-inferior in reducing ischemic events |
#Operator’s discretion. *In cases of no reflow or thrombotic complications. Bivali: Bivalirudin; GPI: Glycoprotein IIb/IIIa inhibitors; RCT: Randomized controlled trials; ACS: Acute coronary syndrome; STEMI: ST elevation myocardial infarction; NSTEMI: Non-ST elevation myocardial infarction; UA: Unstable angina; PCI: Percutaneous coronary intervention; MI: Myocardial Infarction; UFH: Unfractionated heparin; CKD: Chronic kidney disease; HTN: Hypertension; DM: Diabetes mellitus; M: Male; F: Female; HLP: Hyperlipidemia; CABG: Coronary artery bypass graft; TVR: Target vessel revascularization; NACE: Net adverse cardiac events; MACE: Major adverse cardiac events; NA: Not applicable; CVA: Cardiovascular accident.