Although the efficacy and safety of clopidogrel in patients with end-stage renal disease remains unclear, it is used in almost 10% of hemodialysis (HD) patients for various indications. These include the prevention of cardiovascular disease, stroke, and arteriovenous fistula failure. It is interesting to note that most of the randomized controlled trials that showed efficacy of clopidogrel in the prevention of these conditions excluded patients with end-stage renal disease. Moreover, studies have shown that the use of clopidogrel in HD patients is associated with adverse outcomes related to high risk for bleeding and thrombosis. Aspirin and clopidogrel resistance are new “concepts” that illustrate the variability among patients in the measured response to this therapy. Currently, there are several laboratory methods that measure specific platelet inhibition after specific antiplatelet therapies; these measurement tools could potentially be used to tailor antiplatelet therapy according to the results of these tests. Clopidogrel resistance is defined as incomplete blockade of the platelet membrane P2Y12 receptor and is assessed by various laboratory tests in a patient compliant with clopidogrel therapy. When assessment of platelet aggregation was performed, the variability in no response was such that 4% to 30% of patients treated with clopidogrel do not have an adequate inhibition of the platelet activity.

The association of clopidogrel resistance and chronic kidney disease was studied by Park et al, who reported that the inhibition of platelet activity by clopidogrel is related to creatinine levels and that the efficacy of clopidogrel is lower in patients with chronic kidney disease than in those with normal kidney function.

The study included 36 patients with chronic kidney disease (17 patients on HD), mostly men (n = 34), and was conducted in Korea, limiting the ethnic diversity and the possibility to generalize these results. In addition, the definition of clopidogrel resistance was based on a single measurement of P2Y12 reaction units (PRUs). To objectively assess platelet reactivity to clopidogrel, a VerifyNow P2Y12 analyzer (Ultegra Rapid Platelet-Function Assay; Accumetrics, San Diego, California) was used, which shows the direct effects of drugs on the P2Y12 receptors. This analyzer expresses the objective values of platelet aggregation by analyzing the degree of light penetration. It compensates for the disadvantages of the gold standard, conventional light transmission aggregometry, in terms of prolonged time required for analysis, necessity of trained examiners, and need for a large number of blood samples and repeated tests.

Additionally, the VerifyNow P2Y12 analyzer gives measurements that are consistent with those obtained by conventional aggregometry. The data are expressed as PRUs, baseline PRUs, and percentage of inhibition. Because the first report suggesting the existence of clopidogrel resistance involved patients with a relatively common ethnicity, our original objective was to evaluate not only the prevalence of clopidogrel resistance in HD patients but also to evaluate how demographic variables affect clopidogrel resistance in these patients. However, because platelet function is affected by HD, we started with a pilot study to assess the variability of the VerifyNow P2Y12 analyzer before and after HD.

We studied platelet responsiveness after therapy with clopidogrel in 21 HD patients. We excluded patients with previous treatment with glycoprotein IIb/IIIa inhibitors within 10 days of testing; diagnosis of acute myocardial syndrome, acute coronary syndromes, or hemodynamic instability within 3 weeks of testing; active malignancy; acute hemorrhagic disease; liver disease (with abnormal hepatic function test results, such as elevated bilirubin or international normalized ratio); and platelet counts <100,000/ml. A blood sample was collected from each patient before starting and at the end of the HD session using the dialysis access in a 3.8% sodium citrate tube. To measure clopidogrel resistance, we used a point-of-care analyzer, the VerifyNow P2Y12.

We found a difference in PRUs before and after HD (299.71 ± 48.4 vs 274.09 ± 60, p = 0.029).

End-stage renal disease leads to significant hemostatic changes, with increases in hemorrhagic and thrombotic complications. The exposure to dialysis circuit can lead to changes in platelet reactivity. These changes are complex, with biphasic effects: an initial increase in platelet reactivity on the initiation of the HD session and decreased reactivity by the end of the HD session. The changes in platelet aggregation observed during HD are partially mediated through alteration of the adenosine diphosphate–mediated activation of platelets. In this pilot study, we found that defining platelet reactivity in HD patients using the VerifyNow P2Y12 has serious pitfalls in terms of the difference in the values of pre- and post-HD blood samples. This pilot study included patients with different ethnicities who were using clopidogrel for long durations (most of the patients had been taking clopidogrel for >1 year); the most common indication for clopidogrel use was cardiac stenting, and most of our patients had diabetes. Our study sheds light on the limitations of using these new platelet function tests to assess platelet reactivity in HD patients and on the increase in the complexity of defining clopidogrel resistance in HD patients.