Antithrombotic Choice During PCI Influences Outcomes in Poor Clopidogrel Responders

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In patients receiving percutaneous coronary intervention (PCI) for non-ST-segment elevation myocardial infarction (NSTEMI), the impact of clopidogrel resistance on clinical outcomes may be influenced by the choice of adjunctive antithrombotic therapy. According to a subanalysis of the ISAR-REACT-4 trial appearing online June 6, 2012, ahead of print in the Journal of the American College of Cardiology, high on-clopidogrel platelet reactivity is associated with poorer 30-day outcomes in patients on bivalirudin vs. the combination of abciximab plus unfractionated heparin.

The main findings of ISAR-REACT-4, published in the New England Journal of Medicine in November 2011, showed in 1,721 patients that bivalirudin matched abciximab plus unfractionated heparin for 30-day combined efficacy (death, recurrent MI, urgent TVR) and led to much less bleeding.

Dirk Sibbing, MD, and colleagues at Deutsches Herzzentrum (Munich, Germany), conducted the current subanalysis by looking at 564 patients (47.2%) who underwent platelet function testing during the course of ISAR-REACT-4. The remainder of the original cohort either enrolled prior to the availability of such tests or presented during off hours. Notably, the excluded population had lower ejection fraction and more frequent history of MI.

Fallout of Platelet Reactivity Varies

Within the platelet function substudy, baseline characteristics were similar between the 2 treatment arms. The 30-day combined efficacy endpoint was 9.6% overall and statistically equivalent for bivalirudin and abciximab plus heparin at 7.7% and 11.4%, respectively (P = 0.13). Moreover, a similar proportion of patients taking each regimen showed high platelet reactivity during PCI (37.6% with bivalirudin and 35.0% with abciximab/heparin; P = 0.53).

Yet the picture for 30-day outcomes with high on-clopidogrel reactivity differed substantially depending on whether the adjunctive antithrombotic regimen was bivalirudin or abciximab plus heparin. Abciximab patients had similar results irrespective of platelet reactivity; but among bivalirudin patients, high reactivity more than quadrupled the rate of the combined endpoint (table 1).

Table 1. Combined Efficacy Endpoint^a at 30 Days

^a Death, recurrent MI, TVR.

In the abciximab plus heparin group, none of the individual ischemic endpoints differed by platelet reactivity. In contrast, bivalirudin patients who had high reactivity saw increased rates of death/recurrent MI (21.1% vs. 5.0%; P < 0.001), any recurrent MI (20.2% vs. 4.4%; P < 0.001), and large MI (11.0% vs. 1.7%; P < 0.001) compared with those who did not.

Major TIMI bleeding occurred in only 5 patients taking abciximab (1.8%) and 1 taking bivalirudin (0.3%).

Abciximab Bridging the ‘Prothrombotic Milieu’

In an e-mail communication, Dr. Sibbing told TCTMD that the researchers were surprised by the “huge difference with regard to [high platelet reactivity] within the bivalirudin group while finding only a marginal impact” in the abciximab plus heparin group. “When looking at the Kaplan-Meier curves for both groups, one may think of a vulnerable phase for patients around the PCI procedure; a prothrombotic milieu,” he explained. “This can be bridged by abciximab but [high platelet reactivity] patients on bivalirudin do require higher levels of P2Y12 inhibition to achieve an optimal outcome.”

When weighing the results, Dr. Sibbing noted, it is important to remember that ISAR-REACT-4 as a whole “clearly” showed benefit from bivalirudin. “In addition, in our platelet substudy we saw the lowest event rate (5%) of all subgroups in non-[high platelet reactivity] patients that received bivalirudin. Thus, the drug is in no way harmful in NSTEMI patients but may require a closer monitoring of platelet function and P2Y12 inhibition,” he said.

Platelet testing might identify patients who would fare better on prasugrel and ticagrelor, Dr. Sibbing suggested. “The level of P2Y12 inhibition is of utmost importance, especially in NSTEMI patients,” he noted. “If this is true, it follows that monitoring platelet [function] should also play a major role in these patients. All available P2Y12 receptor blockers have their own advantages and disadvantages. There is not a single drug for everyone.

“I think the future lies in an individualized treatment approach that builds up on testing platelets,” he concluded, adding that such assessment should occur near the time of PCI.

A Few Caveats

But Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), seemed skeptical of the results in an e-mail communication with TCTMD. “There are numerous reasons as to why this study should be considered exploratory at best, and should not guide practice,” he stressed.

The 30-day ischemic event rates in ISAR-REACT-4 overall were “nearly identical” at 12.8% with abciximab and 13.4% with bivalirudin (P = 0.76), Dr. Stone pointed out. “Thus, to perform subset analysis from a negative trial looking for positive subsets is statistically inappropriate. And here we have a subset of a subgroup—very limited.”

“[E]ven more important, the subgroups analyzed are not representative,” given that their 30-day outcomes are much better than what was seen in the entire study, he added. “I am not sure where this bias came from but it raises major questions about the entire [subanalysis].  If you add up all the events in the 2 groups (pooled across HPR), the ischemic MACE rates are ~7.6% in the heparin + abciximab group and 11.4% in the bivalirudin group – hardly equivalent as in the original trial.”

The authors acknowledge that the platelet substudy cohort is much lower risk than the larger ISAR-REACT-4 population. Beyond this limitation, “it is crucial to note that present data are observational, stem from a post hoc analysis of a randomized trial, and must be considered as hypothesis generating,” Dr. Sibbing and colleagues advise, suggesting further research on newer antithrombotics and in stable CAD patients undergoing PCI.

Study Details

Platelet function was measured using the Multiplate analyzer (Verum Diagnostica, Munich, Germany), with adenosine diphosphate-induced platelet aggregation values of ≥ 468 units per minute indicating high reactivity. All patients had received clopidogrel (600-mg loading dose then 75 mg twice daily for remainder of hospitalization up to 3 days, followed by 75 mg daily for a recommended 12 months) and aspirin (500 mg loading dose then 100 mg twice daily).

 

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Source:
Sibbing D, Bernlochner I, Schulz S, et al. Prognostic value of a high on-clopidogrel treatment platelet reactivity in bivalirudin versus abciximab treated non-ST-segment elevation myocardial infarction patients: ISAR-REACT-4 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-4) platelet substudy. J Am Coll Cardiol. 2012;Epub ahead of print.

 

 

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