Platelet Reactivity Affects Outcome With Bivalirudin in NSTEMI Patients

June 06, 2012

June 6, 2012 (Munich, Germany) — A new substudy of the ISAR-REACT-4 trial has found that those patients with high on-clopidogrel-treatment platelet reactivity (HPR) randomized to bivalirudin (Angiomax, the Medicines Company) fared significantly worse in terms of the primary efficacy end point than those with low platelet reactivity [1]. The same was not true for those who were randomized to abciximab (ReoPro, Eli Lilly) plus unfractionated heparin (UFH); in this group, platelet reactivity did not seem to affect outcome, note Dr Dirk Sibbing (German Heart Center, Munich) and colleagues in their paper published online June 6, 2012 in the Journal of the American College of Cardiology.

This is the first study to explore the prognostic value of platelet-function testing in this setting, and "the main result was a differential impact of high on-clopidogrel-treatment platelet reactivity," Sibbing told heartwire , noting that the platelet test was performed just prior to the PCI procedure in ISAR-REACT-4, a time point he believes is "best suited to clinical practice."

The main results of ISAR-REACT-4, which were reported at the AHA meeting last year, confirmed that bivalirudin is preferable to abciximab plus heparin as adjunctive antithrombotic treatment in NSTEMI patients undergoing PCI; although the primary outcome was similar between the two groups, there was a markedly reduced risk of major bleeding with bivalirudin.

The new findings suggest that platelet-function testing seems to be important in these NSTEMI patients, says Sibbing, who adds that his institution now performs such tests routinely. In those identified as having HPR, an antiplatelet agent other than clopidogrel, such as the newer agents ticagrelor (Brilinta, AstraZeneca) or prasugrel (Effient, Lilly), should be used where possible, he says.

And he stresses that the new substudy findings "do not argue against the routine use of bivalirudin [as an antithrombotic] in NSTEMI patients." The results also suggest there may be a particularly "vulnerable phase" of a few days starting just before and continuing after a PCI procedure, wherein platelet inhibition is "very important," he adds.

Fivefold difference in events relating to platelet reactivity in bivalirudin patients

Sibbing explains the new analysis was performed in a total of 564 patients (274 in the abciximab/UFH group and 290 in the bivalirudin group) out of the original 1721 participating in ISAR-REACT-4, because platelet-function testing was not common at the start of the study but had become fairly routine in some of the institutions by the end.

Platelet reactivity was assessed using the Multiplate analyzer (Verum Diagnostica, Munich, Germany) in all cases, so as to obtain a "clear definition" of platelet response, he noted, and this was done in the cath lab directly before PCI after all patients had been preloaded with 600 mg of clopidogrel but prior to administration of bivalirudin or abciximab plus UFH.

For those who received abciximab plus UFH, the incidence of the primary efficacy end point (death, MI, target vessel revascularization) was similar in HPR patients vs no-HPR patients (9.4% vs 6.7%; odds ratio 1.4; p=0.43).

But for those taking bivalirudin, 22% of patients with HPR experienced the primary end point vs just 5% of those with no HPR (OR 5.4; p < 0.0001).

"There was a huge difference between the high- and low-platelet-reactivity patients [on bivalirudin]," with the former suffering from significantly more events, Sibbing observed. In those taking bivalirudin who had low platelet reactivity, the 5% event rate "was the lowest for all groups investigated" in ISAR-REACT-4, he noted.

The findings provide evidence for monitoring these patients with a platelet function test now that we have alternative, more intensified antiplatelet agents that can be used.

"The findings provide evidence for monitoring these patients with a platelet-function test now that we have alternative, more intensified antiplatelet agents that can be used," he reiterated.

However, he and his colleagues caution that the data are observational and stem from a post hoc analysis of a randomized trial and therefore, to some extent, must be considered "hypothesis generating."

Asked whether he thought those NSTEMI patients undergoing PCI who had HPR but perhaps could not take the newer antiplatelet agents--either because of cost or contraindications--would be better off with abciximab plus UFH than bivalirudin as an antithrombotic, Sibbing said this "would have to be tested in a separate trial."

Sibbing and colleagues report that this work was supported in part by Nycomed Pharma (former distributor of bivalirudin in Europe). Material for platelet-function testing was in part provided free of charge from Verum Diagnostica. Sibbing reports receiving fees for advisory-board activities from Verum Diagnostica and Eli Lilly and speaker fees from AstraZeneca. Disclosures for the coauthors are listed in the paper.