Randomized trial comparing 600- with 300-mg loading dose of clopidogrel in patients with non–ST elevation acute coronary syndrome undergoing percutaneous coronary intervention: Results of the Platelet Responsiveness to Aspirin and Clopidogrel and Troponin Increment after Coronary intervention in Acute coronary Lesions (PRACTICAL) Trial
Article Outline
Background
There is uncertainty about the benefit of a higher loading dose (LD) of clopidogrel in patients with non–ST elevation acute coronary syndrome (NSTEACS) undergoing early percutaneous coronary intervention (PCI).
Methods
We compared the effects of a 600- versus a 300-mg LD of clopidogrel on inhibition of platelet aggregation, myonecrosis, and clinical outcomes in patients with NSTEACS undergoing an early invasive management strategy. Patients with NSTEACS (n = 256, mean age 63 years, 81.6% elevated troponin) without thienopyridine for at least 7 days were randomized to receive 600- or 300-mg LD of clopidogrel. Percutaneous coronary intervention was performed in 140 patients, with glycoprotein IIb/IIIa inhibitor use in 68.6%. Adenosine diphosphate (ADP)–induced platelet aggregation was measured by optical platelet aggregometry immediately before coronary angiography.
Results
Post-PCI myonecrosis was defined as a next-day troponin I greater than 5 times the upper limit of reference range and greater than baseline levels. Clopidogrel 600-mg LD compared with 300-mg LD was associated with significantly reduced ADP-induced platelet aggregation (49.7% vs 55.7% with ADP 20 μmol/L) but did not reduce post-PCI myonecrosis or adverse clinical outcomes to 6 months. There was no association between preprocedural platelet aggregation and outcome.
Conclusions
These data confirm a modest incremental antiplatelet effect of a 600-mg clopidogrel LD compared with 300-mg LD but provide no support for a clinical benefit in patients with NSTEACS managed with an early invasive strategy including a high rate (69%) of glycoprotein IIb/IIIa inhibitor use during PCI.
Despite the routine use of aggressive antiplatelet therapy with aspirin and clopidogrel and the addition of a glycoprotein IIb/IIIa (GPIIb-IIIa) inhibitor in selected high-risk patients, 0.5% to 2% of patients undergoing percutaneous coronary intervention (PCI) experience a major ischemic complication or death after the procedure and approximately one-third experience elevation or re-elevation of blood markers of cardiac myocyte necrosis.1, 2 Myocyte necrosis (myonecrosis) after PCI is associated with an increased risk of late ischemic events and death.1 Suboptimal platelet inhibition by clopidogrel may contribute to an increased risk of ischemic events after PCI.3, 4, 5
Inhibition of adenosine diphosphate (ADP)–induced platelet aggregation by clopidogrel is time and dose dependent.6, 7, 8 Many patients demonstrate incomplete inhibition of ADP-induced platelet aggregation within 24 hours of a 300-mg loading dose (LD) of clopidogrel.9 Small randomized trials in stable patients undergoing PCI have shown that a 600-mg compared with a 300-mg LD of clopidogrel achieves more rapid and complete inhibition of ADP-induced platelet aggregation,6, 7, 8 and might reduce the risk of ischemic complications.4, 10 It is unclear whether there is a clinical benefit of a higher LD of clopidogrel in patients with acute coronary syndrome undergoing PCI who are often treated with GPIIb-IIIa inhibitors.11
In a randomized controlled trial, we compared the effect of a 600- versus a 300-mg LD of clopidogrel on inhibition of platelet aggregation, myonecrosis, and clinical outcomes in patients with non–ST elevation acute coronary syndrome (NSTEACS) undergoing an early invasive management strategy. We also examined the association between preprocedure platelet aggregation and post-PCI myonecrosis and clinical outcomes.
Methods
The Platelet Responsiveness to Aspirin and Clopidogrel and Troponin Increment after Coronary intervention in Acute coronary Lesions (PRACTICAL) Trial involved 10 Australian hospitals. The trial was approved by the ethics committee of each participating hospital, and all patients provided written informed consent.
Patients
Patients were eligible for inclusion if they presented with NSTEACS (ischemic symptoms lasting ≥10 minutes without persistent ST elevation on electrocardiograph [ECG]) and had at least one of the following high-risk features: ischemic ECG changes (≥2 leads demonstrating ST depression ≥0.5 mV, T-wave inversion ≥2 mV, or transient ST elevation ≥1 mm), elevated cardiac troponin, or history of coronary artery disease (previous myocardial infarction [MI], coronary revascularization, or positive stress test). To be eligible, patients also had to be scheduled for coronary angiography no sooner than 2 hours after the study drug administration, with a view to performing PCI (if indicated) no later than midnight of the following day.
Exclusion criteria included the following: treatment with abciximab, a thienopyridine, or dipyridamole within the previous 7 days; treatment with eptifibatide, tirofiban, or nonsteroidal antiinflammatory drug within the previous 48 hours; inability to take aspirin or clopidogrel; and high risk of bleeding.
Trial design and intervention
An open-label 300-mg LD of clopidogrel was given to all patients who had not already received a 300-mg LD as part of routine clinical practice in the previous 12 hours. Patients were randomized using sequentially numbered drug kits to receive the blinded study drug, consisting of either 300 mg of clopidogrel (“clopidogrel 600-mg group”) or matching placebo (“clopidogrel 300-mg group”). Investigators were encouraged to minimize the delay between administration of the initial open-label 300-mg LD of clopidogrel and administration of blinded study drug, and under no circumstances was the delay to exceed 12 hours. All other treatments were administered at the discretion of the treating physician. A GPIIb-IIIa inhibitor was not to be used before coronary angiography unless patients exhibited ongoing clinical instability.
After coronary angiography, subsequent management (PCI, medical management, or coronary artery bypass graft surgery [CABG]) and the use of GPIIb-IIIa inhibitor during PCI were left to the discretion of the treating physician.
Blood samples for platelet aggregation studies were collected via the arterial sheath immediately before angiography (preangiography sample). Additional blood samples were collected by venipuncture on the morning after the procedure from all patients who underwent PCI (morning-after sample). Citrate- and edetic acid-anticoagulated plasma samples, and serum samples were stored in aliquots at −80°C and later transported on dry ice to the central core laboratory where they were analyzed for markers of myonecrosis.
Platelet aggregation studies
Sites were selected on their capacity to perform platelet aggregometry using modern equipment and a standardized procedure. Adenosine diphosphate–induced platelet aggregation was performed by optical platelet aggregometry (8 sites—Chronolog instruments, Havertown, PA; 2 sites—Monitor IV Plus, Helena, Beaumont, TX) using platelet-rich plasma adjusted to a count of 250,000/mm3. Final agonist concentrations were ADP 4, 10, and 20 μmol/L. Results were reported as percent light transmission determined by the amplitude of the aggregation tracing. Samples were also assessed with the PFA-100 platelet function analyzer (Dade Berhing, Marburg, Germany). All platelet aggregation studies were completed within 4 hours of sample collection.
Cardiac myonecrosis marker analysis
Troponin I was measured using a 3-site sandwich immunoassay with chemiluminescence detection on a Bayer Advia Centaur analyzer (Bayer, Leverkusen, Germany) in the core laboratory at Royal Perth Hospital, Perth, Australia.
Outcomes
The primary outcome was post-PCI myonecrosis in patients who underwent PCI. Secondary clinical outcomes were death, MI, stroke, target vessel revascularization, and hospitalization for recurrent ischemia to 6 months. The main safety outcome was major bleeding. Outcomes were determined during hospitalization and by a telephone call at 1 and 6 months.
Outcome definitions
Post-PCI myonecrosis was defined as a postprocedure troponin I level above the preprocedure troponin I level and greater than 5 times the upper limit of the reference range (0.1 ng/mL).
Myocardial infarction was defined as new ischemic symptoms or ECG demonstrating new pathologic Q waves in ≥2 contiguous leads or new left bundle branch block in the presence of creatine kinase–MB (CK-MB) >2× upper limit of reference range. For patients within 24 hours of PCI, MI was defined as CK-MB >3× upper limit of reference range and >50% of prior baseline where baseline CK-MB was elevated. Myocardial infarction occurring within 24 hours of CABG surgery required an elevation of CK-MB >5× upper limit of reference range. Myocardial infarction was adjudicated by a clinical events adjudication committee blinded to treatment allocation.
Stroke was defined as loss of neurologic function caused by an ischemic or hemorrhagic event and lasting at least 24 hours or leading to death.
Target vessel revascularization was defined as repeat intervention (PCI or CABG) on the target vessel subsequent to the index PCI. Hospitalization for recurrent ischemia was defined as any readmission to hospital with the principle discharge diagnosis being related to myocardial ischemia (eg, MI, unstable angina).
Major bleeding was defined according to thrombolysis in MI (TIMI) criteria12 as intracranial bleed or clinically overt bleeding associated with a fall in hemoglobin ≥50 g/L. Minor bleeding was defined as clinically overt bleeding associated with a fall in hemoglobin of 30 to 50 g/L.
Sample size and statistical analyses
Approximately 40% of patients with NSTEACS undergoing early PCI develop post-PCI myonecrosis.1 We hypothesized that a 600-mg LD of clopidogrel would reduce the incidence of post-PCI myonecrosis by 35% compared with a 300-mg LD. We estimated that a sample size of 350 patients with non-ST segment elevation myocardial infarction treated with PCI would provide an 80% power to detect a 35% reduction in post-PCI myonecrosis with a 600-mg compared with a 300-mg LD of clopidogrel (2-sided P = .05).
After 22 months of recruitment, 256 patients had been enrolled and 140 treated with PCI. In the face of slow recruitment and in view of the commencement of a large multicenter randomized controlled trial comparing 300- and 600-mg LD of clopidogrel in NSTEACS (Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNts-Organization to Assess Strategies in Acute Ischemic Syndromes-7 [CURRENT-OASIS-7], ClinicalTrial.gov Identifier NCT00335452), the trial was stopped. The achieved sample size was sufficient to provide an 80% power to detect a 53% reduction in the primary outcome assuming a control event rate of 40%. This risk reduction approximates the treatment effect observed in the Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-2 (ARMYDA-2) study.10
All analyses were by intention-to-treat. Statistical analyses were performed using SAS version 9.1 (SAS, Cary, NC). Continuous variables were described as means and standard deviations (SDs) and compared between treatment arms by t tests. Discrete variables were described as frequencies and proportion and compared between treatment arms using χ2 or Fisher exact tests. Statistical significance was considered as a 2 P < .05. A linear regression model was used to identify baseline characteristics (independent variables) that independently affect preprocedural platelet aggregation (dependent variable). Based on the univariate analysis, those variables with a P < .15 were selected to construct a multivariate model.
Results
Patients
There were 256 patients recruited between January 2004 and November 2005, of whom 124 patients were randomized to receive clopidogrel 300 mg and 132 received clopidogrel 600 mg. There were 140 (54.7%) patients treated with PCI, 34 (13.3%) patients who underwent CABG, and 82 (32.0%) patients treated with medical management.
Baseline characteristics
Baseline characteristics are summarized in Table I.
Table I. Baseline and angiographic characteristics
| Whole population (n = 256) | Patients undergoing PCI (n = 140) | |||
|---|---|---|---|---|
| Clopidogrel 300 mg (n = 124) | Clopidogrel 600 mg (n = 132) | Clopidogrel 300 mg (n = 71) | Clopidogrel 600 mg (n = 69) | |
| Age ± SD (y) | 64.2 ± 12.5 | 61.2 ± 11.9 | 63.4 ± 12.4 | 61.9 ± 11.6 |
| Male gender, n (%) | 80 (65.0%) | 100 (76.3%) | 50 (70.4%) | 60 (86.96%) |
| Weight, mean ± SD (kg) | 80.0 ± 14.7 | 84.4 ± 16.6 | 79.9 ± 12.91 | 85.1 ± 16.74 |
| CV risk factor | ||||
 Hypertension, n (%) | 67 (54.5%) | 66 (50.4%) | 35 (49.3%) | 29 (42.0%) |
| Hypercholesterolemia, n (%) | 61 (49.6%) | 68 (51.9%) | 38 (53.5%) | 37 (53.6%) |
| Diabetes mellitus, n (%) | 23 (18.7%) | 32 (24.4%) | 11 (15.5%) | 19 (28.5%) |
| Current smoker, n (%) | 36 (29.27) | 33 (25.19) | 22 (30.99) | 20 (28.99) |
| Past vascular disease | ||||
| Previous MI, n (%) | 22 (17.9%) | 25 (19.1%) | 10 (14.1%) | 12 (17.4%) |
| Previous PCI, n (%) | 14 (11.4%) | 15 (11.5%) | 10 (14.1%) | 10 (14.5%) |
| Previous CABG, n (%) | 7 (5.69%) | 12 (9.16%) | 3 (4.23%) | 10 (14.5%) |
| Previous stroke/transient ischemic attack, n (%) | 4 (3.25%) | 3 (2.29%) | 3 (4.23%) | 0 (0%) |
| Baseline medications | ||||
| Aspirin, n (%) | 47 (38.5%) | 55 (42.0%) | 26 (36.6%) | 28 (40.6%) |
| Angiotensin-converting enzyme inhibitors, n (%) | 32 (26.2%) | 34 (26.0%) | 19 (26.8%) | 20 (29.0%) |
| β-Blockers, n (%) | 27 (22.1%) | 30 (22.9%) | 13 (18.3%) | 16 (23.2%) |
| Statins, n (%) | 40 (32.3%) | 41 (31.3%) | 25 (35.2%) | 22 (31.9%) |
| On presentation | ||||
| Elevated troponin, n (%) | 101 (82.1%) | 107 (81.1%) | 59 (83.1%) | 63 (91.3%) |
| Ischemic ECG changes, n (%) | 54 (43.9%) | 54 (40.9%) | 28 (39.4%) | 24 (34.8%) |
| Angiographic | ||||
| Left main disease, n (%) | 7 (5.74%) | 13 (9.85%) | 2 (2.82%) | 3 (4.35%) |
| Multivessel disease, n (%) | 69 (55.6%) | 69 (52.3%) | 44 (62.0%) | 43 (63.3%) |
| Timings (h) | ||||
| Chest pain to open-label clopidogrel LD, median (interquartile range) | 11.5 (5.8-21.0) | 13.5 (7.0-25.8) | 11.9 (5.9-20.9) | 12.6 (7.0-23.5) |
| Open-label clopidogrel LD to study drug | 6.1 ± 7.1 | 4.5 ± 4.9 | 6.1 ± 8.3 | 4.8 ± 5.5 |
| Study drug to preangiogram blood | 14.6 ± 10.4 | 13.0 ± 10.2 | 15.7 ± 10.4 | 14.4 ± 9.4 |
| Preangiogram bloods to morning after bloods | – | – | 20.7 ± 2.7 | 19.1 ± 15.7 |
| Management | ||||
| PCI, n (%) | 71 (57.3%) | 69 (52.3%) | – | – |
| Medical, n (%) | 40 (32.3%) | 42 (31.8%) | – | – |
| CABG, n (%) | 13 (10.4%) | 21 (15.9%) | – | – |
Most of the patients (81.6%) had an elevated troponin at presentation. Almost 40% were on aspirin before presentation, and all patients were treated with aspirin after admission. GPIIb-IIIa inhibitors were used in 100 patients (39.1%), and in 3 patients, the GPIIb-IIIa inhibitor was commenced before coronary angiography.
All patients initially received a 300-mg LD of open-label clopidogrel. The mean delay between open-label clopidogrel and study drug administration was 5.25 hours (SD = 6.10 hours). The mean time between study drug administration and angiography was 13.2 hours (SD = 14.4 hours) and between study drug administration and PCI was 16.1 hours (SD = 10.9 hours).
Procedure details
Table II provides the details of PCI. Glycoprotein IIb/IIIa inhibitors were used during the procedure in 96 patients (68.6%).
Table II. Procedural details for PCI cohort (n = 140)
| Clopidogrel 300 mg (n = 71) | Clopidogrel 600 mg (n = 69) | |
|---|---|---|
| PCI vessels attempted | ||
| Left main, n (%) | 1 (1.41%) | 1 (1.45%) |
| Left anterior descending, n (%) | 38 (53.5%) | 34 (49.3%) |
| Circumflex, n (%) | 27 (38.0%) | 19 (27.5%) |
| Right coronary artery, n (%) | 24 (33.8%) | 19 (27.5%) |
| Vein graft, n (%) | 1 (1.41%) | 7 (10.14%) |
| Multivessel PCI, n (%) | 16 (22.5%) | 11 (15.9%) |
| PCI details | ||
| Number of lesions, n ± SD | 1.46 ± 0.67 | 1.38 ± 0.67 |
| Number of stents, n ± SD | 1.69 ± 0.99 | 1.48 ± 0.80 |
| GPIIb-IIIa Inhibitor use, n (%) | 49 (69.01%) | 47 (68.12%) |
| Adjunctive device | ||
| Atherectomy, n (%) | 0 (0%) | 1 (1.45%) |
| Thrombectomy, n (%) | 0 (0%) | 1 (1.45%) |
| Distal protection device, n (%) | 1 (1.41%) | 2 (2.90%) |
| High-risk features | ||
| Visible thrombus, n (%) | 20 (28.17%) | 23 (33.33%) |
| Side branch occlusion, n (%) | 1 (1.41%) | 2 (2.90%) |
| Distal embolization, n (%) | 2 (2.82%) | 1 (1.45%) |
| Culprit pre-PCI TIMI flow 0/1, n (%) | 17 (23.9%) | 20 (29.0%) |
| PCI success, n (%) | 70 (98.6%) | 67 (97.1%) |
Platelet aggregation
Preangiography ADP-induced optical platelet aggregometry was performed a mean of 13.7 (SD = 10.3) hours after study drug administration in 198 patients. Clopidogrel 600-mg compared with 300-mg LD significantly reduced ADP-induced platelet aggregation with ADP 10 μmol/L: absolute difference 7.8% (relative reduction 13.5%), 95% CI 2.72% to 12.89%; with ADP 20 μmol/L: absolute difference 5.7% (relative reduction 10.5%), 95% CI 1.02% to 10.45% (Figure 1, A). Similar results were obtained in patients undergoing PCI (Figure 1, B).
Figure 1.
(A) ADP-induced platelet aggregation by randomization for the entire cohort. (B) ADP-induced platelet aggregation by randomization in patients treated with PCI. CV, Coefficient of variation.
Independent predictors of ADP 20 μmol/L–induced platelet aggregation are presented in Table III. The time between administration of open-label clopidogrel and the study medication was not an independent factor affecting platelet aggregation.
Table III. Independent variables affecting ADP 20 μmol/L–induced platelet aggregation
| Variable (units) | Coefficient (SE)⁎ | P |
|---|---|---|
| Univariate analysis | ||
| Clopidogrel dose (0 = 300 mg, 1 = 600 mg) | −5.74 (2.39) | .017 |
| Time from study drug to blood sampling (h) | −0.42 (0.12) | .0004 |
| Baseline simvastatin (0 = no, 1 = yes) | 5.41 (3.30) | .10 |
| Statin use at time of platelet aggregation sampling (0 = no, 1 = yes) | −8.09 (2.52) | .002 |
| Atorvastatin at time of platelet aggregation sampling (0 = no, 1 = yes) | −6.36 (2.43) | .010 |
| Diabetes mellitus (0 = no, 1 = yes) | 6.18 (2.93) | .036 |
| Creatinine (μmol/L) | −0.10 (0.05) | .03 |
| Multivariate analysis | ||
| Clopidogrel dose (0 = 300 mg, 1 = 600 mg) | −5.05 (2.30) | |
| Time from study drug to blood sampling (hours) | −0.36 (0.12) | .0032 |
| Statin use at time of platelet aggregation sampling (0 = no, 1 = yes) | −5.57 (2.54) | .03 |
| Diabetes mellitus (0 = no, 1 = yes) | 8.45 (2.84) | .0033 |
⁎Coefficient indicates increment in percent platelet aggregation with ADP 20 μmol/L per unit change in predictor variable. For discrete variable, discrete units used are indicated in parentheses. For example, ADP 20 μmol/L–induced platelet aggregation is 5.57% lower in patients on statin at time of testing compared with patients not on statin. |
Outcomes
Primary outcomeSeven of the 140 patients who underwent PCI did not have blood collected and stored for core laboratory analysis of cardiac troponin I and could not be included in the primary outcome analysis. Post-PCI myonecrosis occurred in 27 patients (39.1%) in the clopidogrel 300-mg group and 25 patients (39.1%) in the clopidogrel 600-mg group, P = 1.0. Three patients in the clopidogrel 300-mg group and 6 patients in the clopidogrel 600-mg group experienced an elevation in CK-MB to at least 3 times the upper limit of normal (P = .31).
Clinical eventsOutcomes at discharge were available on all patients, and 6 month follow-up was successfully completed in 249 patients (97.2%). There were no significant differences in clinical outcomes between the 2 randomized treatment groups at discharge, 1 month or 6 months (Table IV).
Table IV. Clinical events
| Clopidogrel 300 mg (n = 124) | Clopidogrel 600 mg (n = 132) | Relative risk⁎ (95% CI) | P | |
|---|---|---|---|---|
| Clinical ischemic events at 6 m | ||||
| Death | 2 (1.65%) | 1 (0.78%) | 2.13 (0.20-23.19) | .51 |
| MI | 6 (4.96%) | 11 (8.59%) | 0.58 (0.22-1.52) | .26 |
| Stroke | 0 | 1(0.78%) | 0.35 (0.01-8.63) | .33 |
| Target vessel revascularization | 4 (3.31%) | 3 (2.34%) | 1.42 (0.32-6.21) | .64 |
| Hospitalizations for recurrent ischemia | 12 (9.91%) | 11 (8.59%) | 1.16 (0.53-2.53) | .72 |
| Death/nonfatal MI/nonfatal stroke/hospitalizations for recurrent ischemia | 16 (13.2%) | 17 (13.3%) | 1.00 (0.53-1.89) | .99 |
| Hemorrhage at 1 m | ||||
| TIMI major | 3 (2.42%) | 2 (1.52%) | 1.60 (0.27-9.40) | .60 |
| CABG related | 1 (0.81%) | 1 (0.76%) | 1.06 (0.07-16.34) | .96 |
| Non-CABG related | 2 (1.61%) | 1 (0.76%) | 2.12 (0.20-23.19) | .53 |
| TIMI minor | 3 (2.42%) | 3 (2.27%) | 1.06 (0.22-5.18) | .94 |
| Transfusion | 5 (4.03%) | 8 (6.06%) | 0.67 (0.22-1.98) | .46 |
| Other adverse effects at 1 m | ||||
| Rash, n (%) | 4 (3.39%) | 7 (5.43%) | 0.62 (0.19-2.08) | .44 |
| Thrombocytopenia (at discharge), n (%) | 1 (0.81%) | 1 (0.76%) | 1.06 (0.07-16.83) | .74 |
⁎Relative risk = risk in clopidogrel 300-mg group/risk in clopidogrel 600-mg group. |
TIMI major bleeding was seen in 5 patients at 1 month (1.95%), with no difference between treatment arms.
Association between preprocedural platelet aggregation and outcomesAmong the 133 patients who underwent early PCI and contributed to analysis of the primary outcome of post-PCI myonecrosis, 111 had preprocedural optical platelet aggregometry performed and 98 patients had preprocedural assessment with Platelet Function Analyzer-100. We found no correlation between preprocedural platelet aggregation and post-PCI myonecrosis (Figure 2, A) and no correlation between preprocedural platelet aggregation and clinical outcomes at 6 months among all randomized patients (Figure 2, B).
Figure 2.
(A) Incidence of post-PCI myonecrosis by quartile of platelet aggregation (n = 140). (B) Incidence of 6-month major adverse cardiac events (composite of death, nonfatal MI, nonfatal stroke, hospitalization for recurrent ischemia) by quartile of platelet aggregation (n = 256). Plt Agg, Optical platelet aggregometry.
Discussion
In this study, a 600-mg LD of clopidogrel produced significantly greater inhibition of ADP-induced platelet aggregation than a 300-mg LD but did not prevent post-PCI myonecrosis or clinical ischemic outcomes in patients with NSTEACS undergoing an early invasive management strategy. There was no association between preprocedural platelet aggregation and post-PCI myonecrosis among PCI-treated patients, more than two thirds of whom received a GPIIb-IIIa inhibitor during the procedure. A 600-mg LD of clopidogrel was not associated with increased risk of bleeding compared with 300-mg LD.
The lack of a relationship between clopidogrel LDs and post-PCI myonecrosis in our study contrasts with 2 previously reported studies comparing 300- and 600-mg LD of clopidogrel. The ARMYDA-2 study demonstrated a significant reduction in incidence of post-PCI myonecrosis from 44% to 26% in stable patients with the higher LD,10 and both ARMYDA-2 and Cuisset et al13 reported that a 600-mg LD of clopidogrel significantly reduced the incidence of 30-day major adverse cardiac events by about two thirds (from 12% to 4%-5%).10
Among the patients randomized in our study, 81.6% had an elevated troponin at the time of randomization, which contrasts with 9.5% and 23.5% troponin positivity in the study by ARMYDA-2 and Cuisset et al,13 respectively.10 A correspondingly higher proportion (69%) of patients in our study were treated with a GPIIb-IIIa inhibitor compared with 13% and 34% in ARMYDA-210 and Cuisset et al,13 respectively. The decision on the use of GPIIb-IIIa inhibitors during PCI in our study was at the discretion of treating physicians and is supported by current guidelines.14 The Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) study demonstrated a benefit of GPIIb-IIIa inhibitors in troponin-positive patients undergoing PCI even after a 600-mg clopidogrel LD.11 We believe the high rate of GPIIb-IIIa inhibitor use may have masked the potential incremental benefit of the 600-mg clopidogrel LD. This conclusion is supported by data from the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR-PLATELETS) study, which found no significant benefit of 600-mg compared with 300-mg clopidogrel LD in reducing post-PCI myonecrosis or MI when eptifibatide was used in stable patients undergoing PCI.4
The high rate of GPIIb-IIIa inhibitor use in our study may also have masked a relationship between preprocedural platelet aggregation (assayed on samples taken before PCI ± GPIIb-IIIa inhibition) and post-PCI myonecrosis. Studies that have demonstrated a relationship between platelet aggregation and post-PCI outcomes have either a low rate of GPIIb-IIIa inhibitor use3 or have tested platelet aggregation after administration of GPIIb-IIIa inhibitor.4, 5
We found substantial interindividual variability in ADP-induced platelet aggregation among patients receiving clopidogrel 300-mg LD, which was not reduced with a 600-mg LD. This is consistent with previous studies in patients with stable coronary artery disease.9, 15 Angiolillo et al15 reported that interindividual variability in ADP-induced platelet aggregation was not attenuated by a 600-mg compared with 300-mg LD of clopidogrel in stable patients undergoing elective PCI. The coefficient of variation for ADP-induced platelet aggregation at 24 hours was 0.44 in the 600-mg LD group and 0.38 in the 300-mg LD group, which is similar to that seen in our study (Figure 1, A).
Our results are consistent with the conclusion that clopidogrel has limitations as an antiplatelet drug for patients with NSTEACS undergoing PCI, as has been previously reported.6, 9, 16 Clopidogrel has a slow onset of action, and there is substantial interindividual variability in ADP-induced platelet aggregation postclopidogrel, which is not improved with a higher LD. Reducing interindividual variability in the rate of onset and degree of inhibition may be essential to improve the efficacy of antiplatelet therapy. This concept is supported by recent studies of another P2Y12 inhibitor, prasugrel, which produced more rapid and complete inhibition of ADP-induced platelet aggregation with substantially less interindividual variability than clopidogrel and demonstrated greater efficacy in reducing ischemic event.16, 17 Definitive evidence concerning the benefits of a 600-mg LD of clopidogrel awaits the results of the 19,000-patient CURRENT-OASIS-7 trial currently underway examining the efficacy of a 600-mg LD and 150 mg/d maintenance dose of clopidogrel compared with 300-mg LD and 75 mg/d maintenance dose on 30-day outcomes in patients with NSTEACS.
Our study has several limitations. First, because of early termination, the planned sample size was not achieved, and so, it is possible that a clinically worthwhile treatment effect of the 600-mg LD may have gone undetected. Second, the study design allowed a delay between the 300-mg open-label clopidogrel dose and the blinded study drug. This design was used to facilitate patient recruitment at institutions where a 300-mg LD of clopidogrel is routinely administered to patients with NSTEACS on presentation. Although it is possible that this interval (mean 5.25 hours) contributed to the relatively modest incremental antiplatelet effect achieved, we believe it was not a significant factor because we found no evidence of an independent association between this interval and ADP-induced platelet aggregation on multivariate analysis. Third, we did not measure platelet aggregation before clopidogrel loading. Such baseline data would have been useful to further assess the possible relationship between higher levels of baseline troponin and baseline platelet reactivity. In addition, we are unable to comment on the degree of inhibition of platelet aggregation achieved compared with baseline in the 2 treatment arms. However, posttreatment aggregometry results are arguably the most clinically relevant and have been correlated with risk of adverse clinical outcomes after PCI in previous studies.3, 5, 13 Fourth, although we tried to standardize assessment of platelet aggregation, platelet aggregometry was performed in multiple sites and using different instruments. It was not possible for a central analysis of platelet aggregation because of geographic separation of sites and the need to complete platelet aggregometry immediately after sample collection. However, randomization should remove the effect this potential bias on the difference in platelet aggregation between treatment groups. Lastly, our primary end point of post-PCI myonecrosis was based on troponin increment, which has been shown to be associated with increased risk of late ischemic events, but may not differentiate postprocedural myonecrosis from myocyte necrosis resulting from the presenting NSTEACS because of the long half life. However, we also assessed postprocedural MI using definitions based on CK-MB (which has a shorter half-life) according to current guidelines12 that yielded similar results.
Conclusion
In conclusion, our study data confirm a modest incremental antiplatelet effect of a 600-mg clopidogrel LD compared with 300-mg LD but provide no support for a clinical benefit in patients with NSTEACS managed with an early invasive strategy including a high rate (69%) of GPIIb-IIIa inhibitor use during PCI.
References
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Clinical Trial Registration Information: Australian Clinical Trials Registry (http://www.actr.org.au/) number ACTRN012605000581662.
This study was supported by an unrestricted educational grant from Sanofi-Aventis, Sydney, Australia.
PII: S0002-8703(08)00831-4
doi:10.1016/j.ahj.2008.09.024
Crown Copyright © 2009. Published by Elsevier Inc. All rights reserved.
