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While high on-treatment platelet reactivity following drug-eluting stent (DES) implantation does not improve prediction of long-term adverse events, an elevated level of C-reactive protein (CRP) does add incremental prognostic value, according to a retrospective study published in the December 13, 2011, issue of the Journal of the American College of Cardiology. Moreover, the authors state, the combination of the 2 markers provides the strongest predictive power.

Investigators led by Seung-Jung Park, MD, of Asan Medical Center (Seoul, South Korea), analyzed 2,849 patients with stable angina or ischemia or non-ST-elevation acute coronary syndromes who received DES at their institution between March 2006 and December 2009. Soon after PCI (24-48 hours), all patients were tested with the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). In addition, baseline CRP values were measured in 2,546 patients using a latex-enhanced high-sensitivity CRP immunoassay (Cobas Integra, Roche Diagnostics, Mannheim, Germany).

High on-treatment platelet reactivity, defined as a P2Y12 reaction unit (PRU) value greater than 235 and/or platelet inhibition less than 15%, was found in 58.3% of patients. Elevated CRP, defined as 3 mg/L or more, was observed in 24.7% of patients.

CRP Bests Platelet Reactivity as Prognostic Marker

At a median follow-up of 2.2 years, event rates for the primary endpoint (first occurrence of the composite of death, nonfatal MI, stent thrombosis, or stroke) were similar regardless of whether patients’ PRU was above or below the high reactivity threshold. Likewise, no difference was observed for the individual endpoints of death, MI, stroke, definite or probable stent thrombosis, or for TIMI major bleeding (table 1). 

Table 1. Two-Year Outcomes by PRU Cutpoint

 
By contrast, an elevated CRP level was associated with increased rates of the primary endpoint as well as death and stroke. Though rates of MI, stroke, and definite or probable stent thrombosis were 2 to 3 times greater with elevated CRP, the differences did not reach statistical significance, and there was no link between CRP level and TIMI major bleeding (table 2).

Table 2. Two-Year Outcomes by CRP Level

 
These results were consistent across a range of clinical presentations (HR 3.08; 95% CI 1.73-5.47; P < 0.01 for stable angina and HR 2.88; 95% CI 1.50-5.55; P = 0.002 for ACS; P for interaction = 0.64), and remained significant after adjustment for multiple confounders.

When incorporated into a model based on conventional clinical and procedural risk factors, CRP improved risk prediction (P = 0.03), while high on-treatment platelet reactivity did not (P = 0.54).

Importantly, however, patients with both high on-treatment platelet reactivity and elevated CRP were found to be at the highest risk for future thrombotic events, and the two factors combined were the most predictive of the primary endpoint (C-statistic 0.762; P = 0.03).

The Innovation Is Combination

In a telephone interview with TCTMD, Stephen G. Ellis, MD, of the Cleveland Clinic (Cleveland, OH), called the 2 main findings “unsurprising.”

“What is new is the suggestion that maybe high CRP has a role [as a filter for] measurement of platelet reactivity in patients on dual antiplatelet therapy,” Dr. Ellis said. “We’ve demonstrated that measuring platelet reactivity in everybody isn’t useful. So now we have to identify groups that are at high risk, and CRP may well be one of those ways of identifying those patients.”

In fact, in an accompanying editorial, Grant W. Reed, MD, and Christopher P. Cannon, MD, both of Brigham and Women’s Hospital (Boston, MA), say the current data “raise the question of whether patients with high CRP would benefit the most from platelet function testing and tailored antiplatelet therapy. As CRP is a marker of inflammation, it is plausible that patients with elevated CRP would have higher platelet reactivity at baseline, be more likely to exhibit [high on-treatment platelet reactivity] and benefit from more potent antiplatelet agents.”

However, Dr. Ellis recommended caution since the finding of a prognostic interaction between CRP and platelet function was post hoc and therefore hypothesis generating and in need of prospective validation.

Not a Clean Blow Against Platelet Testing

On the other hand, Paul A. Gurbel, MD, of the Sinai Hospital of Baltimore (Baltimore, MD), offered several reasons not to give too much weight to the negative findings regarding the usefulness of platelet function testing. Foremost is that the study was underpowered, he told TCTMD in a telephone interview.

Dr. Gurbel noted that the event rates are exceptionally low—lower even than those reported for the latest-generation stents. Furthermore, more than half of the study population had stable angina, and GRAVITAS has shown that low-risk patients such as these diminish the predictive capacity of platelet reactivity, he said. In the study setting, Dr. Gurbel observed, “it would be hard to find any marker that would be highly predictive of outcomes.”

Dr. Gurbel also pointed to some potential confounders, including the failure to report use of the antiplatelet agent cilostazol, which is commonly prescribed in Korea, or compliance with dual antiplatelet therapy. In addition, there is some evidence to suggest that, compared with Caucasians, Korean patients tolerate high platelet reactivity without increased thrombotic risk, suggesting that the optimal predictive PRU cutpoint should be higher in that subgroup.

Dr. Gurbel acknowledged that combining CRP and platelet reactivity to enhance risk stratification may be a good strategy, but it needs further validation.

Meanwhile, he said he will continue to use platelet reactivity, where appropriate, as the primary measure of thrombotic risk. After all, he noted, if a patient has severe enough CAD to need PCI, “I don’t care what their CRP is, I want to be sure in the setting of complex stenting or ACS that their platelet function is at an acceptable level before I send them home.”

Study Details

All patients were prescribed a 200-mg loading dose of aspirin and 75 mg of clopidogrel daily for more than 5 days or a 300-mg or 600-mg loading dose of clopidogrel at least 12 hours before PCI. After the procedure, patients were prescribed 100 mg to 200 mg of aspirin per day indefinitely and 75 mg of clopidogrel daily for at least 12 months.

The types of DES used (41.5% SES, 12.5% PES, 19.9% ZES, 15.5% EES, 8.0% ZES, and 2.5% other types) did not differ between patients with or without high on-treatment platelet reactivity.

2. Reed GW, Cannon CP. Personalized therapy following drug-eluting stenting using platelet function testing and C-reactive protein. J Am Coll Cardiol. 2011;58:2640-2641.

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