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Reload With Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term With Dual Antiplatelet Therapy - RELOAD
Description:
Current evidence seems to indicate that due to individual variability in response to clopidogrel, as many as 30% of patients on maintenance clopidogrel (75 mg/day) may show elevated platelet reactivity. Earlier studies also seem to indicate that reloading patients already on maintenance therapy with 600 mg of clopidogrel is associated with improved platelet inhibition. Accordingly, the RELOAD study sought to determine whether a dose-response relationship could be demonstrated across three loading dose (LD) regimens: 300 mg, 600 mg, and 900 mg in patients with stable or unstable angina, who were already on 75 mg daily of clopidogrel.
Hypothesis:
There will be a dose-response relationship across the three LDs of clopidogrel: 300 mg, 600 mg, and 900 mg, in patients who were already on 75 mg daily of clopidogrel.
Study Design
Study Design:
Patients Enrolled: 166
Mean Follow Up: 24 hours (platelet assay), 30 days (clinical)
Mean Patient Age: 63 years
Female: 21
Mean Ejection Fraction: 54.1%
Patient Populations:
- Age >18 years
- Maintenance dose of clopidogrel for at least >7 days
- Scheduled to undergo cardiac catheterization for unstable coronary disease or stable angina
Exclusions:
- Maintenance dose of 75 mg clopidogrel for ≤7 days
- Ongoing ST-elevation MI
- Patients in whom catheterization was performed before randomization or was scheduled to be performed <24 hours after randomization
- Contraindication to low molecular weight heparin, clopidogrel, or aspirin
- Patients with severe, uncontrolled hypertension
- Patients with low platelet count (<100,000/mm3)
- Increased risk of bleeding, including recent surgical intervention (<3 weeks)
- Patients with a history of severe systemic bleeding
- Recent or planned use of nonpermitted concomitant medications (any antiplatelet agent other than aspirin or clopidogrel, oral anticoagulants, direct thrombin inhibitors, or nonsteroidal anti-inflammatory drugs)
Primary Endpoints:
IRPA with 20 µmol/L ADP at 4 hours after LD1 between 600 mg and 900 mg of clopidogrel LD1
Secondary Endpoints:
- IRPA with 5, 10, and 50 µmol/L ADP at 4 hours after LD1
- Kinetic profile of clopidogrel-mediated IRPA across the three groups (change from baseline at 4 and 24 hours post-LD1)
- TIMI major and minor bleeding up to 30 days
- Cardiovascular death, MI, and stroke up to 30 days
Drug/Procedures Used:
Consecutive patients were serially allocated to clopidogrel 300 mg, 600 mg, and 900 mg. Four hours after the first LD, patients received a second LD, so that all patients received a total of 900 mg LD. Thus, those initially allocated to 300, 600, or 900 mg (LD1) were given 600, 300, or 0 mg (LD2) clopidogrel, respectively. Thereafter, all patients remained on 75 mg daily of clopidogrel, and ≤100 mg aspirin.
Concomitant Medications:
Statins (95.6%), angiotensin-converting enzyme inhibitors (77.5%), beta-blockers (88.2%)
Principal Findings:
A total of 166 consecutive patients were studied. Baseline characteristics were similar between the three groups. About 32% had evidence of diabetes, and 48.8% had prior myocardial infarction. About 48% were admitted with acute coronary syndrome, 43% with stable angina, and 9.2% for planned percutaneous coronary intervention (PCI). Coronary angiography was performed in 97% of the patients, and about 51% underwent PCI. The mean time interval between the first and second loading doses was about 268 minutes. More than 91% of the patients had been on clopidogrel 75 mg daily for more than 1 month.
The primary endpoint (Inhibition of Residual Platelet Aggregation [IRPA] with 20 µmol/L adenosine diphosphate [ADP] at 4 hours after LD1) was significantly greater after clopidogrel 900 mg compared with clopidogrel 600 mg (64.0% vs. 40.3; p = 0.017), and clopidogrel 300 mg (64.0% vs. 30.7%, p = 0.0008) (p for trend = 0.0024). The absolute change in IRPA with 20 µmol/L ADP from baseline to 4 hours after LD1 was also significantly better with 900 mg of clopidogrel compared with 600 mg and 300 mg, respectively (13.4% vs. 7.6% vs. 5.0%, p = 0.007). Patients loaded with 900 mg LD1 also had lower intersubject variability compared with 600 mg LD1 (0.13 vs. 0.29, p = 0.006). The absolute change in % inhibition using the VerifyNow P2Y12 assay was significantly better with clopidogrel 900 mg compared with 600 mg and 300 mg, respectively (22.4 vs. 21.6 vs. 11.4, p = 0.0051). The greater antiplatelet effect of the 900 mg LD regimen measured by IRPA with 20 µmol/L ADP was confirmed at 24 hours when all dosing strategies displayed the same antiplatelet effect.
The incidence of suboptimal response (IRPA <10%) was better with 900 mg compared with 600 mg and 300 mg clopidogrel, respectively (p = 0.0036). Maximal platelet aggregation (MPA) >50% was noted in 27.6% of all patients at baseline (who were on maintenance clopidogrel therapy), which decreased to 5% at 24 hours with 900 mg LD of clopidogrel.
No major Thrombolysis in Myocardial Infarction (TIMI) bleeding was noted during the study. Minor TIMI bleeding was <1% in all patients. Clinical events were infrequent, and similar between the three strategies.
Interpretation:
Although nonrandomized, the results of the RELOAD trial are interesting, and confirm earlier findings that nearly one-third to one-fourth of patients on long-term maintenance therapy with clopidogrel 75 mg daily have inadequate platelet inhibition. The results also indicate that a loading dose of 900 mg of clopidogrel is more efficacious than either 600 mg or 300 mg in inhibiting platelet activity within 4 hours, and that comparable platelet inhibition is obtained at 24 hours whether 900 mg is administered as a single dose, or as 2 doses of 300 mg and 600 mg. An LD of 900 mg of clopidogrel can decrease the number of poor responders to 5% at 24 hours. It is conceivable that doses higher than 900 mg may achieve even greater platelet inhibition.
Another finding of this study is that an LD of 600 mg of clopidogrel is not more efficacious than 300 mg. This study was not powered to study clinical endpoints, and further studies on this topic, with special emphasis on clinical outcomes including bleeding risk, are necessary.
The IRPA with 20 µmol/L ADP at 4 hours obtained with 900 mg LD of clopidogrel (64%) in this study is similar to that noted at 6 hours with prasugrel 60 mg LD in the PRINCIPLE-TIMI 44 trial (74.8%). Further studies evaluating the relative superiority of prasugrel over clopidogrel will need to factor in this dose-response relationship of clopidogrel as well.
References:
Collet JP, Silvain J, Landivier A, et al. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose: the Reload with Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term with Dual Antiplatelet Therapy (RELOAD) study. Circulation 2008;118:1225-33.
Keywords: Myocardial Infarction, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Angina, Stable, Cardiac Catheterization, Thiophenes, Ticlopidine, Piperazines, Purinergic P2Y Receptor Antagonists, Percutaneous Coronary Intervention, Coronary Angiography, Diabetes Mellitus
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