Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance - ACCEL-RESISTANCE

Jun 05, 2009
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Trial Sponsor:
Grants from the Research Foundation of Gyeongsang National University Hospital and the Cardiovascular Research Foundation (Korea), and a grant from the Korean Ministry of Health & Welfare as part of the Korea Health 21 Research & Development Project
Date Published:
01/01/2009
Date Updated:
06/05/2009
Original Posted Date:
06/05/2009
References

Description:

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.

Hypothesis:

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.

Study Design

Study Design:

Patients Screened: 300
Patients Enrolled: 60
Mean Follow Up: 30 days
Mean Patient Age: 63 years
Female: 33
Mean Ejection Fraction: 59.5%

Patient Populations:

  • Age ≥18 years
  • Undergoing PCI
  • Identified as having HPPR

Exclusions:

  • 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

Primary Endpoints:

  • 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

Drug/Procedures Used:

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).

Concomitant Medications:

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%)

Principal Findings:

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.

Interpretation:

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.

References:

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


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