Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance - ACCEL-RESISTANCE
Recent studies have demonstrated a high post-treatment platelet activity (HPPR) with clopidogrel as predictive of adverse outcomes after percutaneous coronary intervention (PCI), including stent thrombosis. HPPR can partially be overcome with a higher loading (LD) or maintenance dose (MD) of clopidogrel. The ACCEL-RESISTANCE trial sought to investigate whether triple antiplatelet therapy, with the addition of cilostazol, would be associated with greater platelet inhibition in patients with HPPR, compared with a higher MD of clopidogrel.
Triple antiplatelet therapy, with aspirin, clopidogrel, and cilostazol, would be associated with a greater inhibition of platelet aggregation (IPA) compared with a higher MD of clopidogrel in patients with HPPR.
Patients Screened: 300
Patients Enrolled: 60
Mean Follow Up: 30 days
Mean Patient Age: 63 years
Mean Ejection Fraction: 59.5%
- Age ≥18 years
- Undergoing PCI
- Identified as having HPPR
- Acute myocardial infarction
- Hemodynamic instability
- Active bleeding and bleeding diatheses
- Oral anticoagulation therapy with warfarin
- Use of periprocedural glycoprotein IIb/IIIa inhibitors
- Contraindication to antiplatelet therapy
- Left ventricular ejection fraction <30%
- Leukocyte count <3000/mm3
- Platelet count <100,000/mm3
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ≥3 times upper limit of normal
- Serum creatinine level ≥2.5 mg/dl
- Stroke within 3 months
- Noncardiac disease with a life expectancy <1 year
- Rate of HPPR
- IPAs of maximal platelet aggregation with 5 and 20 µmol/L ADP
- IPAs of late platelet aggregation with 5 and 20 µmol/L ADP
- Percentages of platelet disaggregation
- Percentage change in P2Y12 reaction units
Patients with HPPR noted at least 12 hours after receiving 300 mg LD of clopidogrel and aspirin were randomized to receive adjunctive cilostazol (200 mg LD within 6 hours, followed by 100 mg twice daily for 30 days), in addition to clopidogrel 75 mg daily, or a higher MD of clopidogrel (150 mg daily for 30 days).
All patients received a 300 mg LD of clopidogrel, and aspirin at least 12 hours prior to PCI, followed by 200 mg/day of aspirin throughout the study period. Other medications: statins (91%), beta-blockers (75%), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (88%)
Of 300 patients undergoing PCI, a total of 60 patients had high HPPR, and were randomized as 30 patients in each arm. Baseline characteristics were fairly similar between the two arms. About 12% of the patients had undergone prior PCI, and none had undergone prior coronary artery bypass grafting. The left anterior descending artery was the target vessel in about 50% of the patients, and the majority of lesions were classified as American Heart Association/American College of Cardiology class B2/C.
Baseline IPA, as measured by maximal platelet aggregation with 5 and 20 µmol/L of adenosine diphosphate (ADP), was similar between the high-MD and cilostazol arms (61.1% vs. 61.3%, p = 0.94, and 72.3% vs. 70.3%, p = 0.22, respectively). Both groups had a roughly 11.8% platelet inhibition (using the VerifyNow P2Y12 assay).
Although both groups achieved significantly better results at 30 days, cilostazol was associated with a significant reduction in maximal platelet aggregation, as measured with 5 and 20 µmol/L of ADP compared with high-MD clopidogrel (43.9% vs. 29.5%, p < 0.001, and 57.2% vs. 42.1%, p < 0.001). Similarly, the cilostazol arm had a significantly higher % platelet inhibition (48.4% vs. 35.7%, p = 0.015). Clinical events were not measured.
The results of the ACCEL-RESISTANCE trial indicate that cilostazol may be more effective than high-dose clopidogrel in inhibiting platelet activity in patients with HPPR post-PCI. Clinical endpoints were not directly studied, however. Thus, it is unknown if this difference translates into a reduction in stent thrombosis. Similarly, it is unknown if this strategy is associated with a higher risk of bleeding.
Further investigations into such a triple antiplatelet strategy, with an emphasis on clinical endpoints, as well as a comparison with prasugrel, are warranted.
Jeong YH, Lee SW, Choi BR, et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J Am Coll Cardiol 2009;53:1101-9.
Keywords: Platelet Aggregation Inhibitors, Thiophenes, Coronary Disease, Ticlopidine, Piperazines, Tetrazoles, Percutaneous Coronary Intervention, Stents, Thrombosis, Platelet Aggregation, Coronary Artery Bypass
< Back to Listings