Optimal Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention: New Insights From the ARMYDA-2 Study

Percutaneous coronary intervention (PCI) with stenting has been shown to enhance platelet aggregation.¹ Accordingly, optimization of antiplatelet therapy has a crucial role in patients undergoing percutaneous revascularization and even more “aggressive” antiplatelet therapies have been employed to prevent postprocedural thrombotic complications.^2,3 Dual oral antiplatelet pretreatment with aspirin plus ticlopidine has dramatically reduced the occurrence of subacute thrombosis and early adverse events after coronary stenting.⁴

Clopidogrel is an antiplatelet agent extensively used in clinical practice; it inhibits the adenosine diphosphate (ADP) receptor and affects intracellular signaling events that modulate the ADP-induced platelet activation. Administration of clopidogrel has been associated with better safety profile than ticlopidine, as well as at least similar clinical efficacy.^5,6 Moreover, in the Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) study⁷ on patients with acute coronary syndromes (ACS) enrolled in the randomized Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial and receiving PCI, pretreatment with 300-mg clopidogrel loading dose at a mean of 6 days before the procedure was associated, as compared with placebo, with a 30% relative risk reduction of death, myocardial infarction (MI) and repeat revascularization (p = 0.03). Moreover, the recent randomized Clopidogrel for the Reduction of Events (CREDO) trial8 on patients undergoing elective or urgent PCI has shown that pretreatment with a 300-mg loading dose of clopidogrel at least 6 hours before the procedure is associated with 38% relative risk reduction of death, MI and urgent target vessel revascularization (TVR) at 28 days versus assumption of clopidogrel, without loading dose, at the time of the procedure (p = 0.05). Accordingly, the 300-mg loading dose of clopidogrel, given at least 6 hours before the procedure plus aspirin, represents the conventional antiplatelet therapy in patients with ACS, as well as in those undergoing elective percutaneous intervention.^8,9 However, the rationale for using a 300-mg loading dose of clopidogrel derives from dose-finding data on healthy volunteers.¹⁰

Conversely, in patients with coronary artery disease (CAD), there is an enhanced platelet reactivity as compared with healthy individuals,¹¹ possibly requiring a more aggressive platelet inhibition. A higher loading dose with 600 mg of clopidogrel causes an earlier and stronger inhibition of ADP-induced platelet activation than a 300 mg dose. In particular, the higher regimen has been associated with about 30% of ADP-induced platelet aggregation rate at 6 hours and 25% at 24 hours, versus about 45% and 40% after conventional regimen.¹² Moreover, in the CREDO trial, a time-dependence in the clinical benefit of a 300-mg clopidogrel loading dose has been demonstrated, with at least 15 hours of pretreatment required to significantly decrease adverse events.¹³ Conversely, in vitro studies have shown that a 600-mg clopidogrel loading regimen is associated with maximal platelet inhibition 2 hours after drug administration.¹⁴ Data from ISAR-REACT trial on patients at low-to-intermediate risk undergoing PCI have confirmed that increasing the pretreatment interval beyond 2 to 3 hours with a 600-mg clopidogrel loading dose is not associated with significant clinical benefit.¹⁵ Thus, as long as a higher “antithrombotic status” remains the goal of drug therapy in the setting of PCI, a more rapid and intense suppression of platelet activation represents the rationale for pretreatment with a 600-mg loading regimen for reduction of early ischemic events. This is accomplished by decreasing procedural ischemia and distal embolization, protecting the microvascular bed and counterbalancing post procedural activation of coagulation.

Previous observational data¹⁶ have suggested a beneficial effect of a 600-mg clopidogrel loading dose in patients undergoing coronary stenting, with about a 45% risk reduction of adverse cardiac events at one month. A recent randomized trial¹⁷ has employed pretreatment with a 600-mg clopidogrel loading dose before PCI in patients with stable coronary artery disease. Data demonstrated that this regimen obviates the need for periprocedural glycoprotein IIb/IIIa infusion, with similar occurrence of the primary endpoint (death, MI, urgent TVR) at 30 days: 4% both in the placebo and abciximab group (p = 0.82). Moreover, recent data¹⁸ did not show a significant impact of abciximab on the risk of death and MI in diabetic patients undergoing elective percutaneous intervention after pre-treatment with a 600-mg loading dose of clopidogrel before the procedure. However, these two trials^17,18 were not focused on clinical evaluation of a high clopidogrel loading dose versus conventional regimen, and no previous randomized study has specifically evaluated whether the enhanced anti-aggegation due to the 600-mg dose also translates into an independent clinical benefit. Thus, the Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty (ARMYDA-2) trial¹⁹ was the first randomized study of head-to-head comparison between pretreatment with a 600-mg versus 300-mg loading dose of clopidogrel before coronary intervention. In particular, this study has evaluated the safety of this higher regimen given 6 hours before the procedure and its effects on release of markers of cardiac injury (creatine kinase-MB, troponin-I and myoglobin) and 30-day outcome after percutaneous revascularization. ARMYDA-2 was a multi-center, randomized, prospective clinical trial. Patients with a) stable angina, positive stress test and indication to coronary angiography or b) non ST-segment elevation ACS undergoing coronary angiography, were included. A total of 255 patients with significant CAD (reduction 20 and prevent the decreasing of platelet inhibition by concomitant use of statins metabolized by cytochrome P450.^21,22 Moreover, clopidogrel may attenuate inflammatory mechanisms23 and influence linking mechanisms between thrombosis and inflammation by reducing platelet-leucocyte and platelet-endothelial interactions.²⁴ These effects might contribute to reduce myocardial necrosis due to microembolization during PCI. The ARMYDA-2 trial confirmed results of the first Atorvastatin for Reduction of Myocardial Damage during Angioplasty (ARMYDA) study,²⁵ in which pretreatment with atorvastatin 40 mg/day for 7 days significantly reduced procedural myocardial injury in patients undergoing elective PCI. In fact, pretreatment with statins was associated with about 70% risk reduction of MI (odds ratio 0.28, 0.10–0.84; p = 0.020). An additive benefit was demonstrated in patients randomized to 600-mg dose who were taking statins before intervention (0.20, 0.10–0.74; p = 0.017). Finally, safety endpoints were similar in the two randomization arms of the ARMYDA-2 trial. Postprocedural elevation of creatine kinase-MB is relatively frequent after PCI, occurring in up to 40% of cases.^26–28 A significant correlation between the degree of creatine kinase-MB or troponin elevation and adverse events has been demonstrated.29,30 Minor elevations of markers of myocardial damage may occur after uncomplicated procedures and excellent final angiographic results.³¹ However, even minor creatine kinase-MB raises are related to small but definite myocardial necrosis³² and influence prognosis. In the ARMYDA-2 trial, postprocedural elevation (secondary study endpoint) of all markers of myocardial damage (creatine kinase-MB, troponin-I and myoglobin) was significantly lower in patients treated with high loading dose of clopidogel compared to those receiving the conventional dose. The ARMYDA-2 study did include patients with stable angina or ST-segment elevation ACS and normal baseline creatine kinase-MB levels. Thus, these results cannot be directly extrapolated to higher-risk populations requiring emergency procedures, but it is likely that higher-risk patients (with ST-segment elevation MI or non ST-segment elevation ACS and elevated baseline creatine kinase-MB levels) may have a stronger clinical benefit from a 600-mg clopidogrel loading regimen. Moreover, ARMYDA-2 was not designed to compare a high loading dose of clopidogrel versus glycoprotein IIb/IIIa inhibitors in patients undergoing PCI. Accordingly, this study cannot directly support the hypothesis that high-dose clopidogrel can be used as a substitute for IIb/IIIa inhibitors at this time, but supports the use of a 600-mg loading dose of clopidogrel in addition to the conventional drug therapy in the setting of PCI (including IIb/IIIa inhibitors when needed).

Results of the ARMYDA-2 trial cannot definitely clarify whether clinical benefit of pretreatment with a high clopidogrel loading regimen before percutaneous revascularization is due to a higher effectiveness in platelet inhibition or acting more rapidly in achieving maximal inhibition of platelet aggregation at the time of the procedure. However, the results of the ARMYDA-2 trial may influence practice patterns concerning antiplatelet therapy in the setting of PCI, suggesting that pretreatment with a 600-mg loading dose of clopidogrel given 6 hours before the procedure plus aspirin is safe and effective, and may represent the treatment of choice.

Correspondence: g.disciascio@unicampus.it