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Cilostazol or Double-dose Clopidogrel in "Clopidogrel Resistance"?
Abstract & Commentary
By Michael H. Crawford, MD
Source: Jeong YH, 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: 1101-1109.
Dual anti-platelet therapy with aspirin and clopidogrel reduces cardiac events in patients who have acute coronary syndromes (ACS) and in patients who have percutaneous coronary intervention (PCI). Recently, the phenomenon of "clopidogrel resistance" has received much attention because of the clinical problems of stent thrombosis and recurrent ACS. However, a precise definition of this clinical entity is lacking. There are numerous platelet function tests available, yet all have limitations. Emerging data now suggest that platelet function testing may predict patients at higher risk for recurrent coronary events. At present, identifying patients at higher risk may be possible, but we have no clinical studies to guide us in managing this increased risk. Accordingly, Jeong et al compared the effect of increased maintenance dose of clopidogrel vs. addition of cilostazol on platelet function.
Three hundred patients undergoing elective PCI were screened. All received a loading dose of 300 mg of clopidogrel at least 12 hours before the procedure, ongoing clopidogrel 75 mg daily, and aspirin 200 mg daily for the duration of the study. During the PCI procedure, blood was drawn for platelet function testing by two complementary methods: light transmission aggregometry (LTA) and the P2Y12 VerifyNow assay. Patients with high post-treatment platelet reactivity (HPPR) were then randomized to receive either increased maintenance dose of clopidogrel (150 mg daily, n = 30) or addition of cilostazol 10 mg twice daily in addition to standard anti-platelet therapy (n = 30). Platelet function testing was repeated at 30 days. The baseline characteristics were well matched between groups, with average age being 63 years, 67% were male, 12% had chronic kidney disease, ejection fraction was approximately 60%, and 25% had diabetes. The lesion and procedural characteristics were also similar between the treatment groups.
There were no bleeding events and the drugs were not discontinued in any patient. After 30 days, both treatment groups had reduced rates of HPPR compared to baseline, but the group receiving adjunctive cilostazol had reduced HPPR compared to the high-dose clopidogrel group. At baseline, the maximal platelet aggregation measured by LTA in response to 5 micromol of ADP was no different between the groups (61.1 ± 7.8 vs. 61.3 ± 7.4 in high-dose clopidogrel and cilostazol groups, respectively; p = 0.943). After 30 days, however, the maximal aggregation was lower in both groups compared to baseline, but also lower in the cilostazol group compared to the high-dose group (43.9 ± 11.9 vs. 29.5 ± 12.7; p < 0.001). Similar reductions were seen in late aggregation, as well as in both maximal and late aggregation in response to 20 micromol ADP. Jeong et al confirmed these results using a different method, the VerifyNow P2Y12 assay. The percent platelet inhibition assessed by this method was also no different between the groups at baseline (11.8 ± 12.4% vs. 11.7 ± 19.2%, p = 0.979). After 30 days, the percent platelet inhibition had improved in both groups, but had improved more in the cilostazol group (35.7 ± 20.3 vs. 48.4 ± 19.2; p = 0.015 between groups). The percentage of platelet disaggregation in response to ADP also did not differ at baseline. This percentage increased in both groups, but to a greater degree in the cilostazol group. Jeong et al concluded that among patients with HPPR undergoing coronary stenting, adjunctive cilostazol reduces the rate of HPPR and achieves intensified platelet inhibition as compared with high maintenance dose clopidogrel of 150 mg/day.
Differing response to anti-platelet therapy between patients is an increasingly recognized risk factor for recurrent coronary events. Unfortunately, there is no clinical trial evidence to guide us on how to manage patients who do not achieve maximal platelet inhibition. The present study by Jeong et al gives us two alternatives to further improve the platelet inhibition in patients who show HPPR. It remains unknown whether this will translate into a reduction in clinical events, and prospective, randomized clinical trials are necessary to assess this. Although all platelet function tests have limitations, Jeong et al conducted a rigorous study using differing concentrations of ADP, examining both maximal and late aggregation, and using the P2Y12 point of care assay as well. The congruent results across all these endpoints using different methodologies increase the strength of the conclusions drawn.
Cilostazol is an interesting agent, possessing both anti-platelet and anti-restenosis properties, and is widely used in Asia. In the United States, it is FDA-approved only for symptomatic peripheral arterial disease. The present study is appealing because cilostazol may represent a new weapon in the fight against both restenosis and stent thrombosis in patients with coronary stents. Although not approved for this indication, Jeong et al show that it has additional anti-platelet effects in patients who have HPPR after clopidogrel loading. It bears mentioning that cilostazol can precipitate heart failure exacerbations and is contraindicated in patients with congestive heart failure. Therefore, these results are not necessarily applicable to all coronary artery disease patients. Despite the small size of this study and the lack of clinical endpoints, this provides clinicians with an alternative (off-label) option for patients who do not achieve maximal platelet inhibition with standard dual anti-platelet therapy. It needs to be evaluated whether reduction of HPPR with triple anti-platelet therapy could be translated into improved clinical outcomes.