PRIMO-CABG II: Pexelizumab for the Reduction of Infarction and Mortality in Coronary Artery Byp
PRIMO-CABG II: Pexelizumab for the Reduction of Infarction and Mortality in Coronary Artery Bypass Graft Surgery II
"The use of a specifically designed drug that can block the detrimental effects of complement activation seems logical. But..."
Presenter: Peter K. Smith, MD (Duke University Medical Center, Durham, North Carolina)
Complement activation via C3 and C5 plays an important role in inflammation, vasoconstriction, vascular leakage, leukocyte activation, cardiac damage, and apoptosis. The inhibition of complement activation can modulate inflammation and the resultant tissue damage. Pexelizumab is an anti-C5 antibody fragment that effectively blocks C5, thus blocking the formation of C5a and C5b-9 (membrane attack complex).
The first Pexelizumab for the Reduction of Infarction and Mortality in Coronary Artery Bypass Graft Surgery (PRIMO-CABG I) trial demonstrated that the use of pexelizumab yielded an 18% risk reduction in death or myocardial infarction (MI) (P = .07) compared with placebo when administered to patients undergoing CABG surgery. Subgroup analysis showed that patients with ≥ 2 risk factors derived the greatest benefit.
The PRIMO-CABG II trial was designed to assess the effectiveness of pexelizumab in patients with ≥ 2 risk factors undergoing on-pump CABG with or without valve replacement. Predefined risk factors included:
Composite of death and MI thru postoperative Day 30.
Secondary Endpoints
All-cause death through postoperative Day 90 and new or worsening HF through postoperative Day 30.
Results
A total of 4254 patients at 199 US sites and 50 sites in Europe were randomized to receive pexelizumab (2.0 mg/kg bolus plus infusion of 0.05 mg/kg per hour for 24 hours) or placebo (bolus plus infusion). Baseline characteristics are shown in the following table. Dr. Smith noted that most of the risk factors in PRIMO-CABG II are greater than those observed in general cardiac surgery practice.
Table 1. PRIMO-CABG II: Baseline Characteristics
CABG = coronary artery bypass graft; MI = myocardial infarction; S/P = status-post
Investigators reported no significant difference between the treatment and placebo groups with respect to the incidence of the combined endpoint of death or MI (15.2% vs 16.3%, respectively; P = .2) or with respect to any of the individual endpoints (Figure 1). However, there was a trend toward a mortality benefit in the pexelizumab group and was associated with a 17.4% risk reduction.
Subgroup analysis evaluating the effects of the prespecified risk factors on the primary endpoint failed to show a definite advantage for any of the subgroups. It should be noted, however, that all but 1 showed a nonsignificant trend toward a positive effect of the study drug. There was no difference in the rate of serious adverse events between the pexelizumab and placebo groups (31.2% vs 31.5%, respectively).
Figure 1. PRIMO-CABG II: primary endpoint.
Conclusions
The outcome of patients who undergo CABG surgery has significantly improved throughout the years, despite the fact that in the present day, more complex and sick patients are referred for this surgical procedure. The use of a specifically designed drug that can block the detrimental effects of complement activation seems logical. But, often in medicine, not everything that is logical and/or that has proved to have a beneficial effect in early clinical trials remains consistent when tested in a randomized, placebo-controlled study.
Nevertheless, as the authors stated, it seems that certain subsets of patients may derive some benefit from this treatment. Further exploration is needed in this field.
References
"The use of a specifically designed drug that can block the detrimental effects of complement activation seems logical. But..."
Presenter: Peter K. Smith, MD (Duke University Medical Center, Durham, North Carolina)
Complement activation via C3 and C5 plays an important role in inflammation, vasoconstriction, vascular leakage, leukocyte activation, cardiac damage, and apoptosis. The inhibition of complement activation can modulate inflammation and the resultant tissue damage. Pexelizumab is an anti-C5 antibody fragment that effectively blocks C5, thus blocking the formation of C5a and C5b-9 (membrane attack complex).
The first Pexelizumab for the Reduction of Infarction and Mortality in Coronary Artery Bypass Graft Surgery (PRIMO-CABG I) trial demonstrated that the use of pexelizumab yielded an 18% risk reduction in death or myocardial infarction (MI) (P = .07) compared with placebo when administered to patients undergoing CABG surgery. Subgroup analysis showed that patients with ≥ 2 risk factors derived the greatest benefit.
The PRIMO-CABG II trial was designed to assess the effectiveness of pexelizumab in patients with ≥ 2 risk factors undergoing on-pump CABG with or without valve replacement. Predefined risk factors included:
Diabetes mellitus
Prior CABG
Urgent intervention
Female gender
History of neurologic event
History of congestive heart failure
≥ 2 previous MIs
Composite of death and MI thru postoperative Day 30.
Secondary Endpoints
All-cause death through postoperative Day 90 and new or worsening HF through postoperative Day 30.
Results
A total of 4254 patients at 199 US sites and 50 sites in Europe were randomized to receive pexelizumab (2.0 mg/kg bolus plus infusion of 0.05 mg/kg per hour for 24 hours) or placebo (bolus plus infusion). Baseline characteristics are shown in the following table. Dr. Smith noted that most of the risk factors in PRIMO-CABG II are greater than those observed in general cardiac surgery practice.
Table 1. PRIMO-CABG II: Baseline Characteristics
| Pexelizumab (n = 2142) |
Placebo (n = 2112) |
|
|---|---|---|
| Age (yrs) | 66 | 66 |
| Male gender (%) | 60 | 61 |
| Diabetes (%) | 61 | 59 |
| Urgent intervention (%) | 71 | 73 |
| S/P heart failure (%) | 39 | 40 |
| S/P CABG (%) | 10.6 | 9.4 |
| S/P MI (≥ 2) (%) | 31 | 33 |
| Combined CABG/valve (%) | 17 | 16 |
Investigators reported no significant difference between the treatment and placebo groups with respect to the incidence of the combined endpoint of death or MI (15.2% vs 16.3%, respectively; P = .2) or with respect to any of the individual endpoints (Figure 1). However, there was a trend toward a mortality benefit in the pexelizumab group and was associated with a 17.4% risk reduction.
Subgroup analysis evaluating the effects of the prespecified risk factors on the primary endpoint failed to show a definite advantage for any of the subgroups. It should be noted, however, that all but 1 showed a nonsignificant trend toward a positive effect of the study drug. There was no difference in the rate of serious adverse events between the pexelizumab and placebo groups (31.2% vs 31.5%, respectively).
The PRIMO-CABG II study did not meet its primary endpoint of a reduction in mortality or perioperative MI rates.
The treatment effect on MI prevention was less marked than that seen in the PRIMO-CABG I study.
However, the nonsignificant mortality reduction of 17.4% was consistent with the PRIMO-CABG I results.
When combining the results of the pexelizumab surgical randomized trials, the reduction in mortality was 21% and did reach statistical significance (P = .043).
This is the first systemic drug ever to show a mortality benefit for cardiac surgery patients.
The outcome of patients who undergo CABG surgery has significantly improved throughout the years, despite the fact that in the present day, more complex and sick patients are referred for this surgical procedure. The use of a specifically designed drug that can block the detrimental effects of complement activation seems logical. But, often in medicine, not everything that is logical and/or that has proved to have a beneficial effect in early clinical trials remains consistent when tested in a randomized, placebo-controlled study.
Nevertheless, as the authors stated, it seems that certain subsets of patients may derive some benefit from this treatment. Further exploration is needed in this field.
References
Verrier ED, Shernan SK, Taylor KM, et al; PRIMO-CABG Investigators. Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial. JAMA. 2004;291:2319-2327.
Smith PK, Levy JH, Shernan SK. Pexelizumab, a terminal complement inhibitor in coronary artery bypass graft surgery: results from the Pexelizumab for the Reduction of Infarction and Mortality in CABG II trial. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session; March 11-14, 2006; Atlanta, Georgia. Abstract 411-12.
