Clopidogrel for Percutaneous Coronary Revascularization: Title and subTitle BreakTime for More Pretreatment, Retreatment, or Both?

Antiplatelet agents—aspirin, thienopyridines, and glycoprotein IIb/IIIa (GpIIb/IIIa) inhibitors—have become cornerstones in the treatment of ischemic heart disease for patients with acute coronary syndrome (ACS) and for those undergoing percutaneous coronary intervention (PCI). Depending on the clinical scenario and the concomitant anticoagulants used, regimens combining 2 or more of these antiplatelet agents have resulted in fewer ischemic events and sometimes more bleeding events compared with aspirin alone. In patients with ST-segment elevation myocardial infarction (STEMI), aspirin has been shown to safely reduce mortality vs placebo,¹ and it therefore serves a foundational role in thrombolytic therapy regimens. The addition of the most potent platelet aggregation inhibitors, GpIIb/IIIa receptor antagonists, to thrombolytic therapy (aspirin, heparin, and a fibrinolytic agent) in STEMI patients has not resulted in lower mortality rates but has reduced reinfarction rates. A meta-analysis of randomized trials testing abciximab (a GpIIb/IIIa inhibitor) among 23 166 STEMI patients receiving thrombolytic therapy reported 30-day mortality rates of 5.8% for both the abciximab and control groups, whereas the respective rates of reinfarction were 2.3% and 3.6% (odds ratio [OR], 0.64; P<.001).² Offsetting this benefit, however, abciximab was associated with a higher rate of major bleeding complications (5.2% vs 3.1%; OR, 1.77; P<.001).

Recently, the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 investigators reported their findings from 3491 STEMI patients receiving thrombolytic therapy who were randomized to receive a 300-mg loading dose and then a 75-mg daily dose of clopidogrel (a thienopyridine) or placebo.³ The study was not specifically powered to assess clinical end points at 30 days, but cardiac mortality rates appeared similar between the clopidogrel and placebo groups (4.4% vs 4.5%), even though the rate of reinfarction was lower with clopidogrel (4.1% vs 5.9%; OR, 0.69; P = .02). The respective rates of major bleeding complications were similar between the 2 groups (1.9% vs 1.7%). Weighing the observations from the abciximab-STEMI meta-analysis and CLARITY-TIMI 28, it can be concluded that the addition of either abciximab or clopidogrel to the aspirin component of thrombolytic therapy reduces the 30-day occurrence of reinfarction by roughly one-third but does not affect mortality (although preliminary data from a mega trial [N=45 852] of clopidogrel vs placebo in STEMI show a 7% relative risk reduction in death when added to aspirin⁴ ). The addition of abciximab significantly increases major bleeding complications while the addition of clopidogrel does not.

Clopidogrel also has a well-established record of reducing ischemic events without increasing bleeding complications when used for PCI. Unlike intravenously administered GpIIb/IIIa inhibitors, which are effective in minutes, clopidogrel requires hours to days after oral administration to become effective, according to the initial dose. Several post-hoc analyses from large-scale PCI trials showed patients receiving clopidogrel hours to days before, rather than at the time of PCI, experienced substantially fewer periprocedural ischemic events.^{5 - 6} The first prospective study of clopidogrel pretreatment, Clopidogrel for Reduction of Events During Observation (CREDO),⁷ randomized 2116 patients to 300-mg pretreatment vs no pretreatment and observed that clopidogrel at this loading dose needed to be given at least 15 hours prior to PCI to be significantly effective and 24 hours preprocedure to be maximally effective.⁸ For patients scheduled in advance for cardiac catheterization and possible PCI, pretreatment with clopidogrel at least a day before the procedure became intuitive.

On the other hand, because the biological effect of clopidogrel lasts for days, many physicians have been reluctant to pretreat patients until coronary angiography has excluded their need for surgical revascularization. This concern was borne out in the Clopidogrel in Unstable Angina to prevent Recurrent Events (CURE) trial, in which patients with ACS randomized to receive clopidogrel and undergoing surgical revascularization within 5 days of receiving clopidogrel had a 53% increased risk for major bleeding compared with similar patients receiving placebo.⁹

In this issue of JAMA, Sabatine et al¹⁰ address several important issues regarding clopidogrel pretreatment before PCI among STEMI patients. As part of the CLARITY trial, 3275 patients underwent coronary angiography 2 to 8 days after receiving thrombolytic therapy along with clopidogrel or placebo. Of these patients, 57% underwent percutaneous coronary revascularization during the index hospitalization and form the basis for PCI-CLARITY. The decision to perform PCI was at the operator’s direction, although a similar number of patients pretreated with clopidogrel (n = 933) vs placebo (n = 930) underwent PCI, and these 2 groups were reasonably well matched regarding baseline characteristics. Sabatine et al observed a substantial reduction in the composite end point of cardiovascular death, reinfarction, or stroke from PCI to 30 days among those pretreated with clopidogrel (3.6% vs 6.2%; OR, 0.54 [95% confidence interval {CI}, 0.35-0.85]; P = .008). In addition, clopidogrel pretreatment was associated with a reduced odds of reinfarction or stroke prior to PCI (4.0% vs 6.2%; OR, 0.62 [95% CI, 0.40-0.95]; P = .03). Major bleeding events occurred at a similar frequency between the groups (0.5% vs 1.1%, respectively; P = .21).

Several points from CLARITY and PCI-CLARITY are worth highlighting. To begin, few patients presenting with STEMI undergo a coronary artery bypass graft (CABG) during the index hospitalization, so little concern should be given regarding early clopidogrel administration and the subsequent need for urgent surgery. Only 6% of patients in CLARITY underwent CABG surgery, and a similar percentage with a declining trend over time has also been noted in the National Registry of Myocardial Infarctions database.¹¹ Second, patients who undergo PCI in the setting of an ACS (non-STEMI and STEMI) are at particularly high risk for periprocedural myocardial infarction. As such, it is not surprising that the relative risk reduction in ischemic events provided by clopidogrel was twice as high among CLARITY patients who underwent PCI than those who did not. Specifically, patients receiving clopidogrel pretreatment before angiography and who were treated medically or underwent CABG surgery had approximately a 17% risk reduction for reinfarction at 30 days (2.0% vs 2.4%) compared with a 35% reduction among similarly treated patients who underwent PCI (5.9% vs 8.9%). In PCI-CLARITY, roughly two thirds of the reinfarctions occurred in the 3.1 days (median) before PCI, with the remainder occurring during or soon after revascularization. Importantly, clopidogrel treatment provided a consistent level of protection against reinfarction during both of these intervals (OR, 0.60). A similar bimodal occurrence of events and protection has been observed among non-STEMI ACS patients treated before and during PCI with GpIIb/IIIa inhibitors.¹²

A third important point concerns the remaining uncertainty about the optimal dose and timing of clopidogrel administration. The 300-mg loading dose used in CLARITY is established to be effective,^{7 ,13} yet other studies suggest the 300-mg loading dose is incompletely effective or requires a longer minimum interval for peak effect than noted in PCI-CLARITY.^{8 ,14 - 15} Patti et al¹⁵ reported in the Antiplatelet Therapy for Reduction of Myocardial Damage during Angioplasty (ARMYDA-2) study that a 600-mg loading dose of clopidogrel 4 to 8 hours before PCI safely and more effectively reduced the occurrence of periprocedural infarctions than a 300-mg loading dose. Yet, even the 600-mg dose may not be optimal, as suggested by data from the recently presented Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation, and Ongoing Necrosis (ALBION)¹⁶ trial, in which a 900-mg loading dose provided an even greater and more rapid antiplatelet effect than 600 mg as determined by several ex vivo measures of platelet function. Patients receiving long-term clopidogrel therapy may also benefit from an additional loading dose. Kastrati et al¹⁷ demonstrated that a 600-mg loading dose of clopidogrel given to patients already receiving long-term (>1 month) clopidogrel therapy was able to achieve additional aggregation inhibition beyond that provided by the daily dose. The PCI-CLARITY study provided an opportunity to assess some of these concepts clinically since it was recommended that all patients undergoing coronary stent placement receive an open-label 300-mg loading dose of clopidogrel after the initial angiogram. Patients who were randomized to receive a 300-mg loading dose and then a 75-mg daily dose of clopidogrel at enrollment (pretreatment) and who subsequently received an additional 300-mg dose at the time of PCI (retreatment) had the lowest rate of death, reinfarction, and stroke following PCI to 30-day follow-up compared with those who received a clopidogrel loading dose only at enrollment, only during PCI, or at neither time (Figure).

Finally, like any study, PCI-CLARITY has limitations, particularly since PCI was not randomized. The trial excluded many patient groups known to be at particularly high risk for death, reinfarction, or major bleeding events such as patients older than 75 years, those with prior CABG surgery, prior intracranial hemorrhage or nonhemorrhagic stroke, or with a creatinine level higher than 2.5 mg/dL (221 μmol/L). While the investigators carefully performed propensity analysis to correct for selection bias for undergoing PCI, it is possible that residual confounding factors were present. For example, undiscerned factors may exist that explain why patients receiving a GpIIb/IIIa inhibitor had event rates higher than patients not receiving GpIIb/IIIa inhibitors or why one fourth of patients did not receive open-label clopidogrel loading at the time of PCI.

Despite these limitations, PCI-CLARITY provides important data, and application of the study findings seems straightforward—patients receiving thrombolytic therapy for STEMI should also receive a 300-mg loading dose of clopidogrel followed by 75 mg daily. Additionally, clinicians should consider giving 600 mg of clopidogrel as a loading dose, even though this approach has not been formally tested with thrombolytic therapy. So far, no major safety concerns have emerged with 600- or 900-mg loading doses. Finally, all patients not receiving a loading dose within several days of angiography should be considered for clopidogrel retreatment (ie, repeat loading dose) at the time of PCI.