IIb/IIIa Inhibition for PCI of Bypass Grafts

Abstract & Commentary

Synopsis: GP IIb-IIIa inhibitors do not improve outcomes in bypass graft intervention as performed in trials.

Source: Roffi M, et al. Circulation. 2002;106: 3063-3067.

The long-term success of revascularization by coronary artery bypass graft (CABG) surgery is not infrequently limited by degeneration, and ultimately failure, of venous conduits. As the population of patients with vein grafts older than 10 or even 20 years old continues to grow, so does the frequency of their referral for repeat revascularization and particularly percutaneous revascularization. While, for the referring physician and patient, the concept of simply "popping a stent" into a diseased vein graft has considerable appeal, the interventionalist is keenly aware that these cases, even in the best of hands, carry with them considerable risk of adverse events, most notably periprocedural MI. Glycoprotein (GP) IIb-IIIa inhibitors have been shown to be highly effective in preventing adverse ischemic events and even death in many patients undergoing percutaneous coronary intervention (PCI), particularly among high-risk subgroups. Therefore, many interventionalists would not choose to perform vein graft PCI without the GP IIb-IIIa inhibitor "safety net."

But paradoxically, even though they are high risk, bypass graft interventions are one subgroup that, despite initially promising data for distal embolization, has never been shown to derive clinical benefit from GP IIb-IIIa inhibition. Unfortunately, until now, data concerning outcomes with GP IIb-IIIa inhibition in bypass graft PCI have been limited to reports of relatively small groups of patients from single centers, from subgroup analyses of individual studies, or from pooled data from early clinical trials. To better address this issue, Roffi and colleagues conducted a meta-analysis of data from 13,785 patients who underwent PCI in 5 previously published GP IIb-IIIa receptor inhibitor trials: EPIC, EPILOG, EPISTENT, IMPACT II, and PURSUIT. The first 3 of these trials evaluated abciximab and the latter 2 evaluated eptifibatide. Baseline characteristics were summarized and 30-day outcomes were subjected to logistic regression analysis. Six-month and 1-year outcomes were evaluated using Cox proportional hazard models.

Of the patients included in this analysis, 13,158 underwent PCI of a native coronary artery and 627 underwent PCI of a bypass graft. With respect to baseline characteristics, the patients undergoing bypass graft PCI represented a higher-risk population. They were older, had significantly higher prevalence of all cardiovascular risk factors, including diabetes, and had significantly higher rates of history of cardiovascular disease including heart failure, prior MI, stroke, and unstable angina. As expected, patients undergoing bypass graft PCI had significantly worse outcomes at 30 days and 6 months with respect to MI, urgent revascularization, death, and the composite end point. Most notable was a doubling of mortality at 30 days (2.1% vs 1.0%, P = 0.006) and at 6 months (4.7% vs 2.0%, P < 0.001) for patients undergoing bypass graft intervention when compared with patients undergoing native coronary intervention. In addition, PCI of a bypass graft was found to be an independent and highly significant predictor of death, MI, or urgent revascularization at 6 months (OR 1.40; 95% CI 1.11-1.79; P = 0.006).

Roffi et al then evaluated outcomes for 605 patients who underwent bypass graft intervention for whom complete follow-up data were available, comparing the 389 who were randomized to receive GP IIb-IIIa inhibitors (abciximab in 51%, eptifibatide in 49%) with 216 who received placebo. These groups were well matched with respect to baseline clinical characteristics except that patients receiving GP IIb-IIIa inhibitors were more likely to have a history of heart failure (15% vs 6%, P = 0.002) and somewhat less likely to have a history of unstable angina (70% vs 78%, P = 0.048). Among patients undergoing bypass graft PCI, there were no significant differences between the groups receiving GP IIb-IIIa inhibitors or placebo with respect to death, MI, urgent revascularization, or any combined end point. At 6 months, there was no difference in the composite of death, MI, or revascularization, with a trend toward more adverse events in patients receiving GP IIb-IIIa inhibition (39.4% vs 32.7%, P = 0.07). This lack of benefit for GP IIb-IIIa inhibition was consistent across all 5 trials included in this analysis. In addition, from a safety perspective, rates of major bleeding (6.8% vs 1.4%, P = 0.004) and minor bleeding (14.9% vs 8.1%, P = 0.016) were higher in the graft PCI patients receiving GP IIb-IIIa inhibitors.

Roffi et al conclude that GP IIb-IIIa inhibitors do not improve outcomes in bypass graft intervention as performed in the trials included in their analysis. They postulate that in graft PCI, the amount or composition of plaque embolization may render the GP IIb-IIIa inhibitors ineffective. Importantly, Roffi et al point out that, in this analysis, more than half of the ischemic events in patients undergoing graft PCI occurred late—not in the immediate periprocedural period, but beyond 30 days of follow-up. Therefore, they suggest it is likely that additional preventive strategies will be necessary if we are to improve long-term clinical outcomes in these patients.

They acknowledge the limitations inherent in pooled data analysis due to differences in inclusion criteria, drugs, and dosages used, and differences in end points collected in the group of trials included. They state that the vast majority of PCIs included in this analysis were performed on vein grafts, but that graft type was not specified in all of the trials. The strength of this method is that it allowed Roffi et al to evaluate a large randomized patient population and conclude that GP IIb-IIIa inhibition does not confer benefit in the setting of bypass graft PCI.

This report from Roffi et al further delineates the magnitude of increased risk associated with bypass graft intervention in a large group of patients suggested in previous observations and further clarifies the lack of benefit of GP IIb-IIIa inhibitors when given in conjunction with conventional bypass graft PCI. We have known for some time that bypass graft atherosclerosis is a different "animal," and, as such, behaves much differently than disease encountered when instrumenting native coronary arteries. As Kereiakas outlines in his accompanying editorial,1 graft atherosclerosis is bulky, friable, and prone to distal embolization of both large and small particulate matter, which contributes to mechanical obstruction as well as distal microvascular spasm and thrombosis, all of which contribute to the angiographic phenomenon of "no-reflow" and to clinically apparent ischemic complications. As Roffi et al point out, given the complexity of the pathobiology, it is likely that alternative mechanical strategies to prevent distal embolization, or perhaps a combination of mechanical and pharmacologic strategies, will be necessary to prevent the cascade of adverse events that result in ischemic complications. There is promise in this arena in the form of the recently published SAFER trial,2 which demonstrated a significant 42% relative risk reduction in 1-month major adverse complications when the GuardWire distal protection device was used in vein graft PCI. While the GuardWire is the only FDA-approved distal protection device currently available for clinical use, there are others in the pipeline, some of which are in clinical trials, which use alternative strategies to capture or even prevent distal embolization of debris. It is unclear whether adjunctive GP IIb-IIIa inhibitor administration might ultimately prove to confer benefit when used in combination with a mechanical distal protection device.

References

1. Kereiakes DJ. Circulation. 2002;106:2994-2996.

2. Baim DS, et al. Circulation. 2002;105:1285-1290.