Table 1.
Major clinical studies investigating an anti-inflammatory therapeutic strategy to protect the myocardium against acute ischemia/reperfusion injury.
| Target | Clinical study | Patient population | Treatment | Outcome | Mechanism |
|---|---|---|---|---|---|
| Neutrophils | Baran et al. (2001) LIMIT AMI | 394 STEMI thrombolysed <12 h | IV rhuMAb CD18 0.5 mg/kg or 2.0 mg/kg prior to thrombolysis | No effects on coronary blood flow, MI size (SPECT), or ST-segment resolution | rhuMAb CD18 is a monoclonal antibody to the CD18 subunit of the β2 integrin adhesion receptors to prevent neutrophil adhesion |
| Neutrophils | Faxon, Gibbons, Chronos, Gurbel, and Sheehan (2002) HALT MI | 420 STEMI PPCI <6 h Per-PPCI TIMI ≤1 | IV Hu23F2G 0.3 mg/kg or 1.0 mg/kg prior to PPCI | No effects on MI size (SPECT), corrected TIMI frame count or clinical events at 30 days | Hu23F2G (LeukArrest), a humanized MAb to the neutrophils integrin receptor CD11/CD18 |
| Complement cascade C1 | de Zwaan et al. (2002) | 22 STEMI thrombolysed <12 h | IV C1-inhibitor 48 h infusion initiated 6 h after reperfusion | Reduction in MI size (CK-MB or Trop T) but small study | Cetor is a monoclonal antibody to human C1-inhibitor which inhibits activation of the complement cascade. |
| Complement cascade C1 | Thielmann et al. (2006) | 57 STEMI emergency CAG <12 h | IV C1-inhibitor 6 h infusion initiated 10 min prior to reperfusion (unclamping of aorta) | Reduction in peri-operative myocardial injury size (Trop I) | Berinert is a monoclonal antibody to human C1-inhibitor which inhibits activation of the complement cascade. |
| Complement cascade C1 | Fattouch et al. (2007) | 80 STEMI emergency CAG <12 h | IV C1-inhibitor 3 h infusion initiated 10 min prior to reperfusion (unclamping of aorta) | Reduction in peri-operative myocardial injury size (Trop I) | A monoclonal antibody to human C1-inhibitor which inhibits activation of the complement cascade. |
| Complement cascade C5 | Mahaffey et al. (2003) COMPLY | 943 STEMI thrombolysed <6 h | IV Pexelizumab 2.0-mg/kg bolus, or 2.0-mg/kg bolus plus 0.05 mg/kg/h for 20 h prior to or soon after start of thrombolysis | No effects on MI size (CK-MB or Trop I) or clinical events | Pexelizumab, is an Anti-C5 Complement Antibody which inhibits activation of the complement cascade. |
| Complement cascade C5 | Granger et al. (2003) COMMA | 960 STEMI PPCI <6 h | IV Pexelizumab 2.0-mg/kg bolus plus 0.05 mg/kg/h for 20 h prior to PPCI | No effects on MI size (CK-MB). However, reduction in mortality at 90 days. | Pexelizumab, is an Anti-C5 Complement Antibody which inhibits activation of the complement cascade. |
| Complement cascade C5 | Verrier et al. (2004) PRIMO-CABG | 3099 CABG ±valve | IV Pexelizumab 2.0-mg/kg bolus plus 0.05 mg/kg/h for 20 h prior to or soon after start of thrombolysis | No effects on peri-operative MI size (CK-MB or Trop I) or clinical events | Pexelizumab, is an Anti-C5 Complement Antibody which inhibits activation of the complement cascade. |
| Complement cascade C5 | Armstrong et al. (2007) APEX MI | 5745 STEMI PPCI Ant/Inferolat <6 h | IV Pexelizumab 2.0-mg/kg bolus plus 0.05 mg/kg/h for 24 h prior to PPCI | No effects on mortality at 30 days. | Pexelizumab, is an Anti-C5 Complement Antibody which inhibits activation of the complement cascade. |
| Fibrin | Atar et al. (2009) FIRE | 234 STEMI PPCI | IV FX-06400 mg in 2 divided doses at time of PPCI | 49% reduction in 7 day AUC hsCRP non-significant 21% (P = .21) reduction in MI size (LGE MRI on day 5). No difference in 48 h troponin. | FX06 is a naturally occurring peptide fragment of fibrin which prevents binding to an endothelial specific molecule, VE-cadherin, thereby reducing plasma leakage into tissues and acting as an anti-inflammatory agent. |
| IL-1 | Abbate et al. (2010) VCU-ART | 10 STEMI PPCI | Subcutaneous IL-1receptor antagonist (IL-1ra, 100 mg) or placebo daily for 14 days. | Smaller increase in index LVESV at 10–14 weeks assessed by MRI. | Anakinra (Kineret™ from Amgen) is a humanized anti-IL-1R antibody. |
| IL-1 | Abbate et al. (2013) VCU-ART2 | 25 STEMI PPCI pooled analysis | Subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. | Failed to show a statistically significant effect on indexed LVESV, LVEDV or LVEF. | Anakinra (Kineret™ from Amgen) is a humanized anti-IL-1R antibody. |
| IL-1 | Morton et al. (2015) MRC-ILA Heart Study | 182 NSTEMI undergoing PCI | Subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. | 49% reduction in 7 day AUC hsCRP. However, there was an increase in MACE (death, stroke, and new MI). | Anakinra (Kineret™ from Amgen) is a humanized anti-IL-1R antibody. |
| P-selectin | Tardif et al. (2013) SELECT-ACS | 322 NSTEMI undergoing PCI | IV Inclacumab (20 mg/kg) initiated prior to angiography for 1 h | 24% and 34% reduction in peak Trop I at 16 and 24 h post-PCI (borderline significant) | Inclacumab is a humanized antibody that inhibits P-selectin, an adhesion molecule involved in interactions between endothelial cells, platelets, and leukocytes. |
| IL-6 | Kleveland et al. (2016) | 117 NSTEMI undergoing PCI | IV Tocilizumab (20 mg/ml) initiated prior to angiography for 1 h | 52% reduction in median AUC hsCRP and 22% reduction in median AUC hsTropT | Tocilizumab is a humanized anti-IL-6R antibody that binds to both membrane-bound and soluble (s) IL-6R |