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Even in the contemporary era of elective percutaneous coronary intervention (PCI) performed with stents and upfront thienopyridines, glycoprotein IIb/IIIa inhibitors (GPIs) may still provide incremental benefit by reducing the risk of periprocedural myocardial infarction (MI) without increasing major bleeding, according to a meta-analysis published in the March 8, 2011, issue of the Journal of the American College of Cardiology.

Investigators led by Anthony A. Bavry, MD, MPH, of the University of Florida, Gainesville (Gainesville, FL), searched multiple medical databases from their inception through February 2010 for clinical trials randomizing elective PCI patients to a GPI or a control treatment (placebo or usual care without a GPI). To focus on the current PCI era, they included only trials that featured routine use of stenting and thienopyridines, resulting in 22 studies involving 10,123 patients.

At 30 days the incidence of MI was reduced about 30% in patients who received GPIs compared with those who did not, while the rates of minor bleeding and thrombocytopenia were increased. There were no differences in all-cause mortality or major bleeding (table 1).

Table 1. Thirty-Day Outcomes

^a Based on 8 trials.

In addition, in the 10 trials in which TVR was reported, the incidence of this endpoint was similar regardless of GPI use (P = 0.13).

According to the investigators, the magnitude of the effect of GPI use on MI rates was similar for abciximab and small-molecule GPIs, while the risk of thrombocytopenia was increased with abciximab.

In addition, meta-regression analysis showed that the relative risk of periprocedural MI did not depend on:

• Thienopyridines being given before or after PCI (P = 0.99)
• The trial population including a high percentage of diabetics (P = 0.61)
• A higher dose of heparin being used in the control arm (P = 0.78)

Recent Studies Show Similar Benefit

The authors also observe that although significant advances occurred in PCI technology that improved the safety of the procedure over the time period covered by the meta-analysis, the more recent studies showed the same benefit from GPIs as earlier studies.

“We believe our analysis supports and potentially expands the use of GPIs in appropriate clinical situations,” they write.

In an accompanying editorial, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), notes that mortality rates in elective PCI are relatively low and thus “[p]otentially, longer follow-up would be necessary to see if the reductions in periprocedural MI translated into an impact on left ventricular function or on mortality.”

Weighing Fewer MIs Against ‘Minor’ Bleeding

On the other hand, increases in so-called minor bleeding “may have offset to an extent the benefits expected from the decreases in MI,” he suggests, adding that “uncertainty remains over the exact threshold at which a periprocedural MI ‘counts.’”

One challenge to routine use of GPIs comes from data regarding administration of bivalirudin with bailout use of GPIs, Dr. Bhatt observes. Bivalirudin reduces bleeding complications compared with GPIs while providing slightly less MI protection, he notes, adding that “the impact of significant bleeding at least equals and may surpass that of small periprocedural MIs.”

Nonetheless, older drugs should not be discarded simply because they are older, Dr. Bhatt comments. “This data set further validates the concept that additional platelet inhibition is warranted beyond that provided by aspirin and standard-dose thienopyridines,” he writes. “Whether this in fact will be GPIs or one of the novel antiplatelet regimens remains to be seen.”

In a telephone interview with TCTMD, Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), congratulated the authors for examining GPIs in the context of contemporary PCI adjunctive treatment, but he was skeptical of the study’s conclusions.

Meta-analysis May Exaggerate Questionable Results

A major problem with meta-analyses is that they tend to magnify the weaknesses of the individual trials included, Dr. Rao observed. “Here, for example, the conclusion that GPIs don’t increase major bleeding runs completely counter to those of large individual studies,” he said. “In fact, most people [accept] that IIb/IIIa inhibitors are associated with major bleeding.”

Furthermore, not only were the bleeding definitions inconsistent across the studies, but 7 studies did not even report major bleeding, Dr. Rao pointed out. “A IIb/IIIa inhibitor trial that does not report bleeding makes no sense to me and should be thrown out,” he commented.

“I’m not sure this meta-analysis provides any new direction with respect to the debate about the [relative impact] of cardiac marker elevations and bleeding,” he said. “And given the inherent limitations of the studies included, it’s hard to say that this is going to guide clinical practice.”

Will New GPI Regimens, Radial PCI Make a Difference?

Echoing the study authors, Dr. Rao pointed to investigations of innovative GPI strategies, such as giving such agents by bolus only or in an abbreviated infusion. “The idea is that if you change the way you give the drug, you maximize the benefit and minimize the bleeding risk,” he explained. “The problem is that those studies haven’t been large enough to be decisive, and unfortunately the [drug makers] haven’t been interested in updating their regimens to keep up with other developments in antithrombotic therapy.”

The growing popularity of radial PCI with its reduction in access-site bleeding is another factor that might give a boost to renewed GPI use, the editorial notes. Dr. Rao, a radial enthusiast, agreed that “some data suggest you may be able to be a little more aggressive with respect to anticoagulation if you use a radial approach.” On the other hand, “there are studies that counter that,” he noted, citing a recent article [Verheugt FWA, et al. J Am Coll Cardiol Intv. 2011;Epub ahead of print] which suggests that non-access site bleeding drives mortality risk.

“In the current era of the availability of other antithrombin agents, I see the role of IIb/IIIa inhibitors as being a bailout strategy,” Dr. Rao said. “You would use them for ischemic bailout, for example, in a patient who has an acute coronary syndrome on the way to the cath lab, or for someone who’s having procedural complications. But I don’t think [GPIs’] role is routine use, particularly in an elective PCI population.”

2. Bhatt DL. Glycoprotein IIb/IIIa inhibitors: Do they still have a role? J Am Coll Cardiol. 2011;57:1200-1201.

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