Should We RELOAD Patients on Long-term Clopidogrel?

Abstract & Commentary

By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco; Dr. Boyle reports no financial relationships relevant to this field of study.

Source: Collet JP, et al. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose: the Reload with Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term with Dual Antiplatelet Therapy (RELOAD) study. Circulation. 2008;118:1225-1233.

Platelet inhibition with clopidogrel has become an important weapon against recurrent coronary events in patients with coronary artery disease. However, recent evidence shows that patient response to clopidogrel is variable, with some patients having suboptimal inhibition of platelet aggregation. Because platelet function testing is not widely available to tailor individual therapy for each patient, research has focused on a one-dose-fits-all approach to loading and maintenance doses of clopidogrel. While this approach has led to substantial reductions in clinical event rates, some patients still present with recurrent events on clopidogrel; whether a repeat loading dose will improve the platelet reactivity in these patients has not been studied. Accordingly, Collet et al designed this study to address the question of whether reloading with clopidogrel will improve platelet aggregation parameters.

They enrolled 166 patients who were stable on clopidogrel therapy and were scheduled for coronary angiography for either stable angina or unstable angina. Patients had to be stable on clopidogrel for at least one week, but over 90% were on clopidogrel for at least one month. In an interesting trial design, platelet function testing was performed at baseline, and the patients were then assigned to receive a 300 mg, 600 mg, or 900 mg initial loading dose; platelet function testing was performed four hours later. The three groups then received an additional 600 mg, 300 mg or 0 mg loading dose, respectively, so that all patients received a total of 900 mg after four hours, and platelet function testing was repeated at 24 hours. All patients were on low-dose aspirin and clopidogrel 75 mg/day thereafter for the 30-day follow-up. Collet et al used several methods to assess platelet function at each time-point. They measured residual platelet aggregation (RPA) by light transmission aggregometry in response to ADP 20 micromol/L at baseline, four hours after the first loading dose and at 24 hours. From this data, they calculated the inhibition of RPA (IRPA) as a percentage change in RPA from baseline to 4 and 24 hours, to reflect the anti-platelet effect of the repeat loading doses of clopidogrel. The primary endpoint of the study was IRPA at four hours. As a comparison, the also used ADP doses of 5, 10, and 50 micromol/L. They also included suboptimal response to clopidogrel (defined as > 50% RPA at baseline and < 10% IRPA after loading dose) as a secondary endpoint. In addition, they also used the VerifyNow point-of-care P2Y12 assay to measure suboptimal inhibition (defined as < 15%) at baseline and after loading doses. Importantly, patients taking other anti-platelet medication, oral anticoagulants, or non-steroidal anti-inflammatory drugs were excluded from the study.

The baseline characteristics were not different between groups. Approximately half the patients in each group had stable angina and the other half had unstable angina. Approximately 50% in each group underwent percutaneous coronary intervention (PCI). The primary endpoint, IRPA at four hours, was significantly greater in the 900 mg loading group vs the 600 mg loading dose (64 ± 38% vs 40 ± 53%; p = 0.017) or the 300 mg loading dose (30 ± 57%; p = 0.0008). After 24 hours, when all three treatment strategies had received a total of 900 mg of clopidogrel, there was no difference in IRPA between groups. There was a strong correlation between the RPA measured by light transmission aggregometry and the P2Y12 reaction units measured by the VerifyNow point-of-care assay.

Suboptimal response to clopidogrel at baseline was seen in 15.3%, assessed by RPA in > 50% and in 11.1% assessed by P2Y12 assay. There was a poor concordance (Kappa statistic 0.2) between these two methods to identify poor responders. Measured by IRPA < 10%, fewer poor responders were found four hours after 900 mg loading dose, than with either the 600 mg or 300 mg loading doses (p = 0.004), but by 24 hours, when all groups had a total of 900 mg, there was no longer a difference between groups. As expected, there were no differences in bleeding between groups because they all eventually had the same total loading dose. Importantly, there were no TIMI major bleeds. TIMI minor bleeds were seen in 4, 3, and 3 patients in the 300 mg, 600 mg, and 900 mg initial loading dose groups, respectively. No strokes, one peri-procedural myocardial infarction (600 mg group), and two deaths (one aortic dissection — 300 mg group; one cancer-900 mg group) occurred during the 30-day follow-up. Collet et al conclude that the level of platelet inhibition can be improved in patients treated with a maintenance dose of 75 mg/day of clopidogrel undergoing PCI by using high reloading doses.

Commentary

Collet et al demonstrate a dose-dependent improvement in platelet inhibition four hours after a repeat loading dose in patients who are chronically on clopidogrel 75 mg/day. The highest dose of 900 mg in this study reduced the RPA, improved the percent IRPA, and reduced the number of poor responders to clopidogrel. The data presented here are consistent with recent reports in the literature that higher loading doses can reduce platelet aggregation and reduce clinical events. This study was not designed or powered to address hard clinical event end-points. However, it demonstrates that clopidogrel responsiveness can be modulated by higher doses. Previously, some had suggested that doses higher than 600 mg conferred no additional benefit on platelet reactivity. This study stands in direct contradiction to this theory. The initial 4-hour data after the first loading dose is strengthened by the 24-hour data that shows all group can improve their RPA with a total dose of 900 mg of clopidogrel.

The poor concordance between the P2Y12 assay and the light transmission aggregometry in identifying poor responders to clopidogrel is intriguing. Without demonstrating differences in clinical endpoints, it is not possible to say which is more accurate in identifying clopidogrel hyporesponsiveness, and this requires further study. The low rates of clinically significant bleeding are encouraging. These data support the use of high loading doses of 900 mg of clopidogrel in patients undergoing PCI regardless of the presence or absence of prior long-term therapy.