Commentary

Clopidogrel Loading Dose Pre-PCI: How High?

Eugenia Nikolsky, MD, PhD and George Dangas, MD, PhD
Eugenia Nikolsky, MD, PhD and George Dangas, MD, PhD
Letter to the Editor In response to: Angiolillo, et al. Vol. 16, No. 6, Pages 325-329 Is a 300 mg Clopidogrel Loading Dose Sufficient to Inhibit Platelet Function Early After Coronary Stenting? A Platelet Function Profile Study The establishment of combination antiplatelet therapy with aspirin plus ticlopidine as the best medical regimen to prevent stent thrombosis has led to the widespread use of this combination in parallel with the extensive use of coronary stent implantation procedures.1 The widespread use of ticlopidine has allowed practitioners to realize several rare but potentially life-threatening side effects of this medication, particularly with prolonged therapy.2 The emergence of clopidogrel as another thienopyridine derivative with far fewer side effects than ticlopidine was therefore “naturally“ embraced by the cardiology community as a credible alternative to the risky ticlopidine,3 and enabled the demonstration of the incremental benefit of its combination with aspirin with prolonged use in high risk patients.4,5 However, the development of clopidogrel therapy has not been that simple. Concerns were originally raised regarding its efficacy against stent thrombosis when first administered the day of the stent procedure without a loading dose.6 This unfavorable “first impression” was attenuated by the demonstration of better results with a 150 mg loading dose and a 300 mg loading dose preprocedure.7 Both regimens were safe when patients had a stent procedure, but were considered a risk for bleeding if the patient ended up needing aortocoronary bypass surgery. Without complete resolution of this bleeding risk issue, even higher doses of clopidogrel have been utilized as an initial loading dose. Recently, a large study conducted in Germany8 showed that a loading dose of 600 mg of clopidogrel plus a 75 mg twice daily dosage throughout hospitalization (as opposed to the “classic” once-daily dosage) was as effective and in fact safer than intravenous infusion of abciximab in stable patients undergoing elective stent procedures. However, this study contained no comparison of the 300 mg loading dose versus 600 mg loading dose clopidogrel regimens. The article by Angiollilo, et al. provides mechanistic insight as to why a 300 mg loading dose of clopidogrel may not be adequate. The investigators compared the pharmacodynamic efficacy of a 300 mg loading dose with the pretreatment dosage of clopidogrel for 2 days prior to a coronary stent procedure; all patients were on aspirin therapy for at least 1 week preprocedure. Platelet studies were conducted preprocedure, then 4 hours and 24 hours postprocedure; both platelet aggregation in response to a thrombogenic stimulus (6 mmol of adenosine diphosphate [ADP]) as well as plasma markers of platelet reactivity were measured. The results indicated that platelet aggregation, glycoprotein IIb/IIIa activation, and P-selectin expression were low throughout the studied period in the pretreatment group. In contrast, these parameters were significantly higher preprocedure and at 4 hours postprocedure in the loading dose group. Therefore, the loading dose group appears to achieve comparable platelet inhibition to the pretreatment dosage only after 24 hours postprocedure. For clinical purposes, this probably signifies a rather delayed response that could potentially be improved by administration of an even higher loading dose (450 mg or 600 mg) and justifies adherence to a pretreatment protocol whenever possible. This has also been suggested by other pharmacodynamic studies.10 This study did not investigate whether the difference might be significant even at 24 hours if a more potent platelet stimulus was used, e.g., 20 mmol of ADP. This study also did not assess if a twice daily dosage of clopidogrel after the initial loading dose might bring this treatment arm closer to the pretreated patients. Interestingly, in a recent randomized clinical study,11 the efficacy of the 300 mg loading dose was questioned, as it seemed beneficial only when administered at least 6 hours preprocedure. Therefore, the pharmacodynamic findings of this study appear to corroborate (and tie together) clinical evidence from several studies as described above. Based on these findings, it appears likely that a 300 mg loading dose may be inadequate. Whether this is a uniform phenomenon or more applicable to certain types of patients has not yet been investigated. It also appears likely that a higher loading dose is preliminarily safe. However, this latter issue may not be fully verified until a large number of patients have been treated with such high doses both in coronary stent implantation and pre-aortocoronary bypass graft settings. It appears the dosage of clopidogrel pericoronary stent implantation has been an ever-changing target. Surveillance strategies could be very valuable in determining the relative efficacy and safety profile of these dosage regimens, as it is unlikely that pivotal trials can be adequately funded for specific product approval, due to the rarity of stent thrombosis and the anticipated marginal differences in bleeding complications between the various dosage regimens.
References
1. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995;91:1676–1688. 2. Bennett CL, Connors JM, Carwile JM, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Eng J Med 2000;342:1773–1777. 3. Bertrand ME, Rupprecht HJ, Urban P, et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102:624–629. 4. Yusuf S, Zhao F, Mehta SR, et al. for the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. 5. Mehta SR, Yusuf S, Peters RJ, et al. for the Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Lancet 2001;358:527–533. 6. Dangas G, Mehran R, Abizaid AS, et al. Combination therapy with aspirin plus clopidogrel versus aspirin plus ticlopidine for prevention of subacute thrombosis after successful native coronary stenting. Am J Cardiol 2001;87:470–472. 7. Moussa I, Oetgen M, Roubin G, et al. Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation. Circulation 1999;99:2364–2366. 8. Kastrati A, Mehilli J, Schuhlen H, et al. for the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232–238. 9. Angiollilo DJ, Fernandez-Ortiz A, Bernardo E, et al. Is a 300 mg clopidogrel loading dose sufficient to inhibit platelet function early after coronary stenting? A platelet function profile study. J Invas Cardiol 2004;16:325–329. 10. Moussa I, Sofer D, Chui M, et al. What is the appropriate loading dose of clopidogrel prior to stent implantation? Insights from a platelet inhibition study. Am J Cardiol 1999;84(suppl 6A). Abstract TCT–182. 11. Steinhubl SR, Berger PB, Mann JT III, et al. for the CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. J Am Med Assoc 2002;288:2411–2420.