Consensus Paper Details Link Between Platelet Reactivity and Ischemia, Bleeding

Although the strategy of personalizing antiplatelet therapy based on platelet function testing has yet to be proven beneficial in large-scale trials, a working group has published a review of current data that it says provides support for the idea of a link between platelet reactivity and both thrombotic and bleeding events. The updated consensus statement, published online October 9, 2013, ahead of print in the Journal of the American College of Cardiology, suggests that there may be a more far-reaching impact of platelet function testing on outcomes than previously thought.

The writing group, led by Paul A. Gurbel, MD, of the Sinai Center for Thrombosis Research (Baltimore, MD), reviewed the available evidence addressing the relationship of platelet reactivity—both high and low—to ischemic and bleeding events.

In a telephone interview with TCTMD, Dr. Gurbel said the new paper updates an earlier consensus document from the same writing group on the definition of high on-treatment platelet reactivity. While the link between high platelet reactivity and ischemic events is well established, Dr. Gurbel noted, the association between on-treatment platelet reactivity and bleeding events has been less clear. Large-scale platelet function studies such as POPULAR, GRAVITAS, and ARCTIC, for example, have been largely negative, providing no meaningful evidence of such a relationship. This may be due to the studies being underpowered, enrolling low-risk populations, and using only double-dose clopidogrel to overcome high platelet reactivity, he observed.

Evidence Is Out There

But the writing group outlines what it says is evidence for a strong independent relationship between platelet inhibition assessed by VASP-PRI and bleeding in ACS patients treated with prasugrel after successful PCI. Recognition of this relationship is critically important, Dr. Gurbel and colleagues say, since at least 2 recent studies (Mehran R, et al. Circulation. 2011;123:2736-2747, and Ndrepepa G, et al. J Am Coll Cardiol. 2008;51:690-697) suggest that a survival benefit might be attributable to reduction in bleeding alone.

Support for this theory also was seen in the large all-comers ADAPT-DES trial, in which patients underwent successful and uncomplicated PCI with a DES. A PRU greater than 208 was inversely related to TIMI major bleeding (adjusted HR 0.73; 95% CI 0.61-0.89; P = 0.002). This observation, the writing group adds, is consistent with a post-hoc analysis from GRAVITAS showing that the achievement of a PRU less than 208 was associated with significantly improved clinical outcomes.

“Thus, evidence for a therapeutic window of optimal on-treatment [platelet reactivity] to prevent both bleeding and ischemic events is emerging,” Dr. Gurbel and colleagues write. “This window would therefore inform future studies designed to optimally avoid thrombotic and bleeding events during P2Y12 inhibitor therapy.”

Dr. Gurbel said high platelet reactivity “may be the most potent risk factor for ischemic event occurrence in the stented patient, more powerful than any demographic variable.”

Platelet Function Testing Story Incomplete

“Something like this paper has been needed for some time,” commented Somjot S. Brar, MD, MPH, of Kaiser Permanente (Los Angeles, CA), in a telephone interview with TCTMD. “There have been important limitations in the clinical trials having to do with trial design and the populations selected and probably the endpoints as well. The story on platelet function testing really has not been completely told yet . . . and what the writing team has done here provides a platform for where we need to go.”

Dr. Brar said the relationship between platelet reactivity and bleeding risk cannot be overemphasized, nor can the importance of ongoing research into the therapeutic window.

“The current practice of a one-size-fits-all strategy [for antiplatelet therapy] doesn’t allow us to identify patients who are at higher risk of bleeding because they are too sensitive, or those at the other end of the extreme who are too resistant,” he said. “We have the tools to move away from this strategy into a more personalized approach, and we have the ability to mitigate risk, which is something we must incorporate into the design of future clinical trials. For some patients bleeding is as bad as having an MI, if not worse. Future endpoints need to be different from what we have seen in the past, and this paper helps us understand that a trial that focuses on ischemic events and bleeding is very important from everyone’s perspective.”

Dr. Brar added that another benefit of platelet function testing is that it can be used in patients on antiplatelet therapy who require surgery. “It decreases health care costs and length of stay and mitigates the risk of bleeding complications in these patients,” he said. “It’s a benefit to the interventionalist because we worry about what to do when we preload someone with clopidogrel and then they need CABG. This tool allows us to have confidence that you are going to be able to get that person through major surgery without excess bleeding complications.”

Note: Coauthors Ajay J. Kirtane, MD, SM, and Gregg W. Stone, MD, both of Columbia University Medical Center (New York, NY), are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

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Sources:
1. Tantry US, Bonello L, Aradi D, et al. Consensus and update on the definition of on-treatment platelet reactivity to ADP associated with ischemia and bleeding. J Am Coll Cardiol. 2013;Epub ahead of print.

2. Bonello L, Tantry US, Marcucci R, et al. Working Group on High On Treatment Platelet Reactivity. Consensus and future directions on the definition of high on treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010; 56:919-933.

 

 

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