Meta-analysis: Selective Use of Small-Molecule GPIs Best in NSTE ACS Patients

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Among patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), upstream use of small-molecule glycoprotein IIb/IIIa inhibitors (GPIs) decreases myocardial infarction (MI) risk but also increases major bleeding, with no apparent effect on mortality. The findings, from a meta-analysis published online June 28, 2011, ahead of print in Circulation: Cardiovascular Quality and Outcomes, suggest that selected periprocedural use in high-risk patients undergoing percutaneous coronary intervention (PCI) may be the best strategy, the authors say.

Pierluigi Tricoci, MD, PhD, MHS, of the Duke Clinical Research Institute (Durham, NC), and colleagues conducted a systematic review of 12 randomized clinical trials from the medical literature that documented 30-day outcomes for upstream small-molecule GPIs including tirofiban, eptifibatide, and lamifiban between 1996 and 2009. Among the trials, 7 compared GPIs vs. placebo (n = 24,031) and 5 looked at GPIs vs. upstream placebo and later provisional GPI use at the time of PCI (n = 19,643).

Overall, upstream GPI use significantly reduced death/MI and MI risk but not death alone. The same patterns were observed regardless of whether trials compared GPI with placebo or delayed provisional use, although the associations did not reach significance in the latter subgroup. There was no heterogeneity across trials for any of the outcomes considered (table 1).

Table 1. GPI Efficacy Outcomes

However, the “modest” benefit seen with upstream GPI use was counterbalanced by heightened risks of major and non-major bleeding as well as need for transfusion (table 2).

Table 2. GPI Bleeding Outcomes

Although treatment of NSTE ACS rapidly evolved over the decade-long period—with more routine use of early coronary angiography, clopidogrel pretreatment, and dual antiplatelet therapy as well as changing stent designs—the lack of heterogeneity among trials for ischemic outcomes indicates that results remained consistent, the paper notes.

In a telephone interview with TCTMD, study coauthor Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), said that the investigators’ main goals were to tease out differences between the trials that tested early GPI use vs. placebo and those that evaluated it in comparison with delayed, provisional use and to see how results might have changed over time.

In an e-mail communication with TCTMD, Tracy Y. Wang, MD, MHS, MSc, also of the Duke Clinical Research Institute but not affiliated with the study, agreed that “summaries of GPI [use are] important given newer agents and debates regarding their risk/benefit ratios compared with the traditional heparin and GPI combo.”

Searching for Equipoise

The paper elaborates on the difficulty of incorporating such decisions into clinical practice. “The relative value of preventing an ischemic event versus causing a bleeding event with the use of antithrombotic drugs is still debated, and an accepted formula to trade off efficacy versus bleeding (ie, how many bleeding events equal 1 MI) has yet to be establish,” the investigators say, adding that while bleeding’s negative effects are well known, the US Food and Drug Administration has stated that “nonfatal MI represents ‘irreversible tissue damage;’ therefore, the ‘benefit of preventing such events is generally worth the risk of bleeding events that have no irreversible consequences.’”

Considering both this tradeoff and the available evidence, routine upstream GPI use in NSTE ACS patients probably will be “limited to patients likely to undergo PCI and who are at high risk of ischemic complications and low risk of bleeding, although identification of these individuals warrants further study moving toward the development of stratified medicine,” Dr. Tricoci and colleagues conclude.

Dr. Stone advised that in NSTE ACS patients with a background of unfractionated heparin, GPIs should “be used in a selective approach in the cath lab, not started upfront in most patients but withheld for patients in whom the anatomy shows you’ll be doing PCI, in which case they would be given right before [the procedure].

“The alternative would be to use bivalirudin which, as shown in the ACUITY trial, would not require the routine cath-lab use of a GPI but would require the occasional bailout or provisional use of a GPI for refractory thrombotic or ischemic complications, which has averaged about 7% of PCI procedures,” he continued, noting that the strategy would decrease bleeding and lower the costs associated with GPI use. “That’s a valid approach but probably works best in patients that have been preloaded with a thienopyridine, which is the modern day approach for most patients with NSTE ACS.”

Dr. Wang, who agreed with the authors’ recommendations regarding upstream use of GPIs, suggested saving bivalirudin for lower-risk patients, “although with novel antiplatelet agents coming on board that have faster onset and greater potency, there will likely [be] continued shifts,” she concluded.

Note: Dr. Stone is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

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Source:
Tricoci P, Newby LK, Hasselblad V, et al. Upstream use of small-molecule glycoprotein IIb/IIIa inhibitors in patients with non-ST-segment elevation acute coronary syndromes: A systematic overview of randomized clinical trials. Circ Cardiovasc Qual Outcomes. 2011;Epub ahead of print.

 

 

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