Platelet Reactivity Linked With Ischemic Stroke Risk Post-DES Implantation: ADAPT-DES Substudy

High platelet reactivity in patients taking clopidogrel who have already had a successful coronary DES implantation is associated with a greater risk of ischemic stroke, according to post hoc analysis of the ADAPT-DES study. However, experts are warning against the temptation to use more potent P2Y12 inhibition in the hopes of preventing noncoronary events.

The literature regarding the ability of antiplatelet agents to prevent stroke is mixed, yet many cardiologists have been holding out hope that they could essentially prevent multiple adverse events with the right prescription.

“I believe that this is something that clinicians should have in the back of their minds in the sense that you are not only preventing events within the stent. You are probably having benefits also outside the stent, outside the coronary vasculature in terms of prevention of spontaneous MI, probably prevention of cerebrovascular events, and possibly you have to consider peripheral artery events,” lead study author Gennaro Giustino, MD (Icahn School of Medicine at Mount Sinai, New York, NY), told TCTMD. “It sometimes gets forgotten, but it is something that is important to discuss with our patients when we are making decisions about antiplatelet therapy.”

For the study, published this week in JACC: Cardiovascular Interventions, Giustino and colleagues looked at the original cohort of 8,528 patients from ADAPT-DES who successfully underwent PCI with DES and were prescribed aspirin for at least 2 years and clopidogrel for at least 1 year. Platelet reactivity unit (PRU) levels were screened at baseline with the VerifyNow assay (Accumetrics), and the median follow-up time was about 2 years.

Stroke occurred in 1.0% of patients—0.8% ischemic and 0.2% hemorrhagic—a rate that was comparable to the overall definite or probable stent thrombosis rate at 2 years (1.1%). Patients who were in the highest quintile of P2Y12 inhibition at baseline were less likely to have an ischemic stroke throughout the study than those who were in the lowest quintile (0.51% vs 1.34%; adjusted P = 0.04). Additionally, PRU > 208, which was the cutoff level in the original ADAPT-DES study for predicting stent thrombosis, was independently associated with an increased risk for ischemic stroke (adjusted HR 1.81; 95% CI 1.08-3.04).

Results were maintained in analyses of patients regardless of their CHA2DS2-VASc score (P = 0.30 for interaction) and oral anticoagulation status at discharge (P = 0.99 for interaction).

Lastly, and unexpectedly, the occurrence of ischemic stroke was linked with higher cardiovascular mortality (adjusted HR 4.57; 95% CI 1.86-11.24) and all-cause mortality (adjusted HR 4.16; 95% CI 1.95-8.87) at 2 years.

Problems with PRUs

In an editorial accompanying the study, Neal Kleiman, MD (Houston Methodist DeBakey Heart and Vascular Center, TX), writes that “these results might be regarded as reassuring. The risk of hemorrhagic stroke over 2 years of treatment with aspirin and clopidogrel was quite low; PRU measurement offered some measure of ability to predict ischemic strokes and suggested strategies to prevent them.

“However, it would be a mistake to be too sanguine about these findings,” he states. “Acting upon these observations in the stent world has produced paradoxical results and the body of literature is internally inconsistent. Nonselectively substituting more potent P2Y12 antagonists (prasugrel and ticagrelor) for clopidogrel in two large trials of patients with ACS lowered the rates of myocardial infarction and stent thrombosis. However, tailored strategies directed at patients with evidence of increased on-treatment platelet reactivity, that is, those who would seem most likely to benefit have not been successful.”

Speaking with TCTMD, Sorin Brener, MD (NewYork-Presbyterian Brooklyn Methodist Hospital), who was not involved with the study, agreed with Kleiman. “It’s very difficult to evaluate an endpoint which is quite rare and for which the study is not geared toward,” he said. “The most important thing to take away is that it’s much more important what the baseline characteristics are than what the PRUs are.”

This is particularly the case, Brener explained, because PRU levels were only measured at discharge in ADAPT-DES and these levels inevitably change over time with clopidogrel treatment. Additionally, the study does not adjust for time on clopidogrel, he said, “so all the strokes that occur between 1 and 2 years, we don't know if they occurred on clopidogrel—which would imply maybe that the PRU values are the same as they were at the beginning when the patient was enrolled in the study—or they were off it—in which case it’s totally irrelevant.”

‘Much to Be Learned’

Both the CHANCE trial and a subanalysis of SOCRATES have sought to discover if the more potent P2Y12 inhibitors prasugrel (Effient; Eli Lilly) and ticagrelor (Brilinta; AstraZeneca) could do a better job than aspirin with or without clopidogrel in preventing ischemic strokes. Yet both came back negative, with the exception of ticagrelor proving superior to aspirin in patients with ipsilateral carotid artery stenoses in the latter trial.

The totality of evidence, Kleiman suggests, is that “in patients who present with coronary artery disease, uniform substitution of more powerful antiplatelet drugs (at least within the P2Y12 antagonist class) provides superior protection against coronary ischemic events, but probably not stroke. Therapy tailored to platelet aggregation measurements probably adds little.”

This is likely because “stroke is a much more heterogeneous disease than acute myocardial infarction,” Brener said. “Not all strokes are the same [so] to give blanket powerful platelet inhibition in the hope of preventing all ischemic strokes, I don't think that's a reasonable approach. . . . We have a hammer and everything looks like a nail, but not everything is related to thrombosis and giving antithrombotic agents will not help for people that do not have a thrombotic disease.”

We have a hammer and everything looks like a nail, but not everything is related to thrombosis and giving antithrombotic agents will not help for people that do not have a thrombotic disease.    Sorin Brener

Still, Giustino said that while he agrees “the evidence for antiplatelet therapy in preventing events outside the coronary arteries is maybe not as strong as within the coronaries, . . . the evidence is coming up and this is an area that I believe needs more investigation.” He emphasized, however, that this nonrandomized subanalysis can only be “hypothesis-generating” and cannot prove causation.

“The problem here is that with more potent platelet inhibition, there is also a price to pay, which is increased risk for bleeding. This is something that needs to be obviously always considered. My personal preference is first do not harm, so if there is even a minimal concern that a patient is at high risk for bleeding, . . . I will like to avoid that risk,” Giustino observed. However, if “the safety profile of the therapy in general is beneficial,” he said he would be more apt to give a more potent P2Y12 inhibitor despite the lack of any positive randomized trial data in this regard.

Brener disagreed with this strategy, saying that platelet function testing is likely not “as important as we think for stroke prevention, either primary or secondary.” Some have been using PRU levels “to connect something we can measure to many things we cannot measure, in order to feel, so to speak, empowered that we know what is going on,” he said. “The reason there are associations is because it's a marker, so people who have high PRUs are also the people who have probably more vascular inflammation and they have more events, that's true, but it’s not because of the PRU.”

Ultimately, “there is thus a long way to go in this field,” Kleiman writes. The evidence so far “leaves much to be learned about the role of platelet activity in ischemic stroke.”

Note: Several study co-authors are faculty members of the Cardiovascular Research Foundation, the publisher of TCTMD.