Stable CAD

The beneficial effects of clopidogrel have been extensively demonstrated in patients with stable CAD, and several investigations have been performed to explore different loading doses before stenting in order to minimize thrombotic risk. The Clopidogrel for the Reduction of Events During Observation (CREDO) trial [15] showed a 38% relative risk reduction of death, myocardial infarction (MI), and urgent target vessel revascularization (TVR) at 28 days in patients undergoing elective or urgent PCI and pretreated with 300 mg loading dose of clopidogrel before the procedure versus the assumption of clopidogrel, without loading dose, at the time of intervention (p = 0.05). Accordingly, a 300 mg clopidogrel loading dose has represented the conventional therapy for P2Y12 inhibition in patients undergoing elective PCI for several years. Following pharmacodynamic studies demonstrating greater platelet inhibition with higher (600 mg) clopidogrel loading dose, the Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty (ARMYDA)-2 study [16] assessed in a randomized head-to-head comparison a 600 mg and a 300 mg loading dose of clopidogrel in low- to moderate-risk patients undergoing PCI. The primary end point (30-day occurrence of death, MI, TVR) occurred in 4% of patients in the high versus 12% of patients in the conventional loading dose group (p = 0.041), with 600 mg clopidogrel load associated with a 52% risk reduction of periprocedural MI at multivariate analysis (OR, 0.48; 95% CI, 0.15–0.97; p = 0.044). Interestingly, no higher inhibition of platelet aggregation or clinical benefit was observed with increasing the loading dose (900 mg) compared with 600 mg in the Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis (ALBION) [17] and the Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect (ISAR-CHOICE) [18] studies. On the basis of these findings, the latest updates of both ACCF/AHA/SCAI [14] and ESC/EACTS [19] guidelines for myocardial revascularization recommend that a 600 mg loading dose of clopidogrel be administered at least 2 h before elective PCI. However, according to the ESC/EACTS guidelines [19], a 300 mg loading dose, ideally administered the day before the planned procedure or at least 6 h before, may also be considered as an appropriate antiplatelet strategy.

Other crucial issues regarding clopidogrel loading in patients with stable CAD have been further investigated. The potential benefit of a drug reload in patients already on chronic clopidogrel treatment was tested in the ARMYDA-4 study [20], where a further 600 mg loading dose in patients on chronic therapy with 75 mg/day clopidogrel did not translate into significant clinical benefit in patients with stable CAD undergoing coronary stenting. Furthermore, whether in-laboratory clopidogrel loading (i.e., after coronary angiogram and immediately before PCI) provides similar protection from periprocedural ischemic complications compared with pretreatment several hours before the procedure was investigated in the ARMYDA-5 [21] and PRAGUE-8 [22] trials. The results from both these randomized trials showed no significant difference in 30-day major adverse cardiovascular event (MACE) incidence in “preloaded” patients compared with those receiving a 600 mg clopidogrel load immediately before PCI, suggesting that a selective antiplatelet strategy for patients with previously unknown coronary anatomy is safe and may prevent the potential bleeding risk associated with DAPT when coronary bypass surgery is required instead of percutaneous revascularization.

Of note, both ACCF/AHA/SCAI [14] and ESC/EACTS [19] guidelines do not recommend the use of newer P2Y12 inhibitors (i.e., prasugrel and ticagrelor) as antiplatelet agents for patients with stable CAD, given the absence of specific clinical studies investigating this issue. Nevertheless, given their greater platelet inhibition, emerging evidence suggests a potential role of newer P2Y12 inhibitors especially in high-risk patients with persistent high platelet reactivity despite clopidogrel [23, 24]. However, despite these positive results from pharmacodynamic studies, the net clinical benefit (possible reduction of ischemic events without significant increase in bleeding) of these new antiplatelet drugs in patients with stable CAD is yet to be demonstrated.

Non-ST-segment-elevation acute coronary syndrome (NSTEACS)

Non-ST-segment-elevation acute coronary syndrome (NSTEACS) includes a large range of clinical settings and patient characteristics. DAPT is universally accepted as the optimal treatment to reduce thrombotic risk in NSTEACS patients undergoing PCI. The effects of clopidogrel in addition to aspirin have been well established in patients with NSTEACS. In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial [25], clopidogrel (300 mg loading dose and then 75 mg/day) was shown to reduce the relative risk of the composite end point of cardiovascular death, nonfatal MI, and stroke by 20% versus aspirin alone in patients with NSTEACS. In the subgroup of patients receiving PCI [26], the benefit of clopidogrel was even higher, with 30% relative risk reduction of death, MI, and repeat revascularization. A higher dose of clopidogrel (600 mg) has been tested in the setting of ACS in the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events – Seventh Organization to Assess Strategies in Ischemic Symptoms (CURRENT-OASIS 7) trial [27]. In this study, no significant difference was observed between a 600 mg and a 300 mg dose of clopidogrel in reducing the primary outcome of death, MI, or stroke at 30 days. However, a higher dose of clopidogrel showed a significant benefit in the subgroup of patients undergoing PCI, especially in reducing the rates of stent thrombosis [28].

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