Download this article's Factoid in PDF (& PPT for Gold Subscribers)

Even relatively mild anemia predicts high residual platelet reactivity following percutaneous coronary intervention (PCI) in patients pre-treated with clopidogrel, according to data published online January 27, 2012, in the American Journal of Cardiology.

For the prospective, single-center study, investigators led by Catalin Toma, MD, of the University of Pittsburgh Medical Center (Pittsburgh, PA), assessed platelet reactivity in 255 consecutive patients on clopidogrel at least 12 hours after PCI using both light transmission aggregometry (LTA) in response to 5 µmol/L ADP (PAP4, Bio/DATA Corp, Horsham, PA) and the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA).

In addition, a subgroup of 50 clopidogrel-naïve patients was tested before and after PCI. In total, 30.6% of patients were already on long-term clopidogrel therapy at presentation, and 70.5% of those received an additional loading dose (median 300 mg). All clopidogrel-naïve patients, meanwhile, received a clopidogrel loading dose (median 600 mg).

The 2 methods of assessing platelet aggregation showed relatively good correlation. Overall, the proportions of patients with high residual platelet reactivity were 23.4% by LTA and 40.4% by VerifyNow.

A Strong Predictor of High Reactivity

In multivariate analysis, gender, anemia, and clopidogrel loading at the time of PCI emerged as independent predictors of platelet reactivity on LTA, while anemia and diabetes were independent predictors on VerifyNow—leaving anemia as the only common predictor.

Regardless of the assay used, more anemic than nonanemic patients exhibited high levels of residual platelet reactivity (table 1).

Table 1. Prevalence of High Residual Platelet Reactivity by Anemia Status

Among clopidogrel-naïve patients, no difference in percent aggregation was seen between the anemic group (n = 14) and the nonanemic group (n = 36) at baseline. However, after clopidogrel loading and PCI, the absolute decrease in platelet aggregation was greater in nonanemic patients than in anemic patients. The same pattern was seen for percent platelet inhibition assessed by VerifyNow (table 2).

Table 2. Change in Platelet Reactivity in Clopidogrel-Naïve Patients After Clopidogrel Loading

^a P2Y12 reaction units

In line with these results, before clopidogrel loading there was a weak association between preprocedural hemoglobin levels and percent maximum aggregation by LTA or VerifyNow, whereas after drug loading a correlation of platelet aggregation response to ADP relative to hemoglobin levels was present on both assays (P = 0.006 for LTA, P = 0.0007 for VerifyNow). The same robust correlation was seen between hemoglobin levels and both LTA and VerifyNow results after PCI for the entire study cohort (P < 0.0001 for both assays).

The authors observe that even though the anemia seen in the study was mild (median hemoglobin 11.3 g/dL), anemic patients were nonetheless about twice as likely to have high residual platelet reactivity as nonanemic patients.

Multiple Possible Mechanisms

Dr. Toma and colleagues acknowledge that the study does not address mechanisms to explain the association between anemia and platelet reactivity. They do, however, offer some intriguing possibilities:

• Increased platelet production and turnover in anemia, together with the relatively short half-life of the active metabolite of clopidogrel,  may mean that younger platelets escape inhibition
• Erythropoietin, produced in response to chronic anemia, may activate platelets

Another hypothesis, Dr. Toma told TCTMD in an email communication, centers on the role of nitric oxide (NO). Red blood cells are an important source of NO, which inhibits platelet activity, but they are diminished in anemia.

Anemia might help explain a phenomenon seen in recent studies, the investigators say. Up to half of patients with initial high residual platelet reactivity show improvement in their response to clopidogrel within 30 days of PCI despite no change in therapy. The improvement may be due to resolution of mild anemia, they suggest.

But the main clinical contribution of the study is its exploration of the well-established connection between anemia and increased risk of recurrent ischemic events and cardiac death, Dr. Toma said.

Anemia Just a Marker of Inflammation?

But in a telephone interview with TCTMD, Mauro Moscucci, MD, of the University of Miami Miller School of Medicine (Miami, FL), said a key issue—not addressed in the study—is whether anemia is present at baseline or develops after intervention. The latter may be due to acute blood loss or hemodilution from administration of fluids after PCI, he indicated. The former, however, is more likely to be a type called anemia of chronic disease, which has been linked to adverse outcomes. “But that risk is not due to anemia per se—the anemia is just a marker of disease severity and activation of inflammatory pathways,” he explained.

As for any clinical implications, Dr. Moscucci said that for now he does not change his approach if he finds that a patient scheduled for PCI is anemic. Even though anemia predicts increased ischemic risk, “there are no data whatsoever that correction of anemia can modify adverse outcomes,” he said.

In terms of antiplatelet therapy, Dr. Moscucci said that if a causal connection between anemia and adverse events is confirmed, an interesting question will be whether the chronic inflammation or other abnormalities associated with anemia impair activation of the prodrug clopidogrel, reducing the availability of its active metabolite and thus its effectiveness. In that situation, it might be appropriate to use a direct-acting agent like prasugrel, he said.

But Drs. Moscucci and Toma both cautioned against changing practice based on the current data. In his e-mail, Dr. Toma said he would “first try to understand the mechanism of the anemia, whether this is a temporary or correctable issue. We clearly need to better understand the physiological link between anemia and platelet function before making clinical recommendations.”

Dr. Moscucci said that despite its lack of statistical power and other limitations, the study was interesting and hypothesis-generating. Dr. Toma reported that he hopes to confirm the findings using different platelet function tests and then explore the mechanistic connection between anemia and platelet function.

Dr. Moscucci concluded that it will be important to stratify patients according to quartiles of hemoglobin level and use standard definitions of anemia in future studies.

Study Details

High residual platelet reactivity was defined as greater than 46% for LTA and greater than 235 PRU for VerifyNow. 

Related Stories:

• Anemia Worsens Prognosis After Primary PCI—Especially for Men
• Thrombocytopenia in PCI Patients Signals Higher Complication Risk