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Aspirin-specific high platelet reactivity measured immediately before percutaneous coronary intervention (PCI) portends a higher risk of ischemic events over 1 year, according to data from a large registry published in the September 2, 2014, issue of the Journal of the American College of Cardiology.

But according to an accompanying editorial, the study is shadowed by not only methodological problems but also the larger question of whether such pharmacodynamic information can be translated into a therapeutic strategy that improves outcomes. 

Rates of death or definite/probable stent thrombosis (primary endpoint) and other ischemic outcomes at both 30 days and 1 year were higher in patients with vs without high residual reactivity (table 1). 

Table 1. Outcomes Stratified by Residual Platelet Reactivity Threshold of 203 AU/min

At 30 days, there was no difference between the groups for the endpoint of in-hospital TIMI major or minor bleeding. Surprisingly, after propensity score matching the high-reactivity group showed increased bleeding compared with patients without elevated reactivity (6.7% vs 4.7%; P = .023), although they remained at a disadvantage in terms of death or definite/probable stent thrombosis (6.2% vs 4.5%; P = .027).

Aspirin Response Adds Predictive Power Beyond CV Risk Factors 

On multivariable analysis, high on-aspirin platelet reactivity was an independent predictor of the primary endpoint at 1 year (adjusted HR 1.46; 95% CI 1.12-1.89). Moreover, addition of high on-aspirin reactivity increased the discriminatory power of a predictive model based on standard cardiovascular risk factors, with a significant improvement in net reclassification (P < .001).

These data “provide evidence for a possible role of [high on-aspirin platelet reactivity] as a clinically useful biomarker that could be added to the well-established biomarkers in CAD patients,” the authors say.

While the current analysis is in line with results from previous small studies and a meta-analysis, it is discordant with the large ADAPT-DES trial, they acknowledge, offering possible explanations for the discrepant findings:

• Blood was sampled at different times points
• Different testing devices and reactivity thresholds were used, potentially affecting the size and composition of the groups at increased risk 

Moreover, Dr. Mayer and colleagues point out, the most common reason for high on-aspirin reactivity in other studies was thought to be patient noncompliance, but that issue was eliminated in this registry because measurements were taken shortly after monitored IV aspirin administration. 

Testing Method, Aggregation Cutpoint Questioned

In their editorial, Dominick J. Angiolillo, MD, PhD, and Jung Rae Cho, MD, both of the University of Florida College of Medicine-Jacksonville (Jacksonville, FL), observe that platelet reactivity was tested by only 1 assay and at a single time point in the study.

Moreover,the Multiplate analyzer does not measure platelet aggregation directly and its results do not reflect response to the aspirin-specific pathway, Udaya S. Tantry, PhD, of Sinai Hospital of Baltimore (Baltimore, MD), told TCTMD in an email, adding that “there is no consensus regarding the threshold for aspirin-specific high residual platelet aggregation.”

Underlining Multiplate’s lack of aspirin specificity, Dr. Tantry said, is the fact that ADP-induced platelet aggregation is also elevated in patients with high aspirin-specific platelet reactivity, raising the possibility that impaired clopidogrel metabolism might also be at play. Moreover, he noted, clinical factors usually associated with ‘aspirin resistance’ such as diabetes and smoking were not tied to high on-aspirin platelet reactivity in this study. 

Dr. Tantry also pointed out that “since aspirin and ADP blockers act in a synergistic way, significant differences in the administration of the latter agents may have played a role” in the current results.

He also advised caution in interpreting the apparent adverse clinical impact of high on-aspirin platelet reactivity, noting that all-cause death, though a major contributor to the composite primary endpoint, “is not a platelet-specific phenomenon.” Meanwhile, stent thrombosis is “only marginally significantly higher in patients with aspirin-specific high platelet aggregation,” he said, and the results may have been different—and closer to those of ADAPT-DES—had the patients been stratified according to the reactivity cutoff suggested by the authors’ ROC analysis.

The Main Challenge: What to Do With Test Results

“The role of [high on-aspirin platelet reactivity] testing for guidance of treatment remains unclear and cannot be answered by our data,” the authors admit, adding that “[r]ecent attempts to assess the impact of an intensified aspirin treatment on clinical outcome provide divergent results.” 

But the main challenge, Drs. Angiolillo and Cho say, lies in knowing what to do with pharmacodynamic test results.

Adding a glycoprotein inhibitor to IV aspirin during the acute post-PCI phase of high platelet reactivity has not provided benefit, they note, and the safety and efficacy of increasing the initial aspirin dosage or changing the maintenance regimen to twice-daily remain untested. In addition, although it has been suggested that prasugrel or ticagrelor might reduce thromboxane generation and thus potentially enhance aspirin’s effectiveness, that approach remains speculative.

“[D]efining the treatment strategies tailored to these high-risk patients that can improve outcomes … remains the ultimate objective that would enable this biomarker to be incorporated into routine clinical practice,” the editorial concludes.

Sources:
1. Mayer K, Bernlochner I, Braun S, et al. Aspirin treatment and outcomes after percutaneous coronary intervention: results of the ISAR-ASPI registry. J Am Coll Cardiol. 2014;64:863-871.

2. Angiolillo DJ, Cho JR. Aspirin treatment and outcomes in patients undergoing percutaneous coronary intervention: is there a role for pharmacodynamic testing [editorial]? J Am Coll Cardiol. 2014;64:872-874.

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